352§
Pierpaolo Di Micco, Alessandro Perrell, Giuseppe Camporese 3

Editorial Comment on the Special Issue Discussing COVID-19 and Thrombosis, Second Edition
Viruses. 2023 Sep 14;15(9):1922.

Abstract
The recent SARS-CoV-2 pandemic is ending after over three years, and the efforts of physicians in the daily clinical management of infection in inpatients and outpatients and vaccination campaigns allowed to medical experts to understand all possible scientific aspects of COVID-19 [...].

PMID: 37766328
DOI: 10.3390/v15091922


351§
Giuseppe Camporese, Pierpaolo Di Micco, Marcello Di Nisio, Walter Ageno, Romeo Costanzo Martini, Paolo Prandoni; SIAPAV Members

Common Practice in the Treatment of Superficial Vein Thrombosis Involving the Sapheno-Femoral Junction: Results from a National Survey of the Italian Society of Angiology and Vascular Medicine (SIAPAV)
Medicina (Kaunas) 2023 Jun 1;59(6):1068.

Abstract
Background and Objectives: Prophylactic doses of low-molecular-weight heparins or fondaparinux showed their efficacy and safety for treatment of all superficial vein thrombosis (SVT) of the lower limbs, yet not for those extended to the last 3 cm of the great saphenous vein, close to the sapheno-femoral junction, or considered as a deep-vein thrombosis. Some experts suggest that these patients should be managed with full anticoagulant doses but evidence to support this recommendation is lacking, suggesting the need for a properly designed trial. Materials and Methods: Before starting a new trial, the Italian Society of Angiology and Vascular Medicine (SIAPAV) decided to verify the common therapeutic approaches for patients with an SVT in Italian vascular centers based on a hypothetical significant variation in each daily clinical practice. A standardized questionnaire of 10 questions was administered to all SIAPAV affiliates by means of the official Society website. Results: From 1 December 2022 to 20 January 2023 a total of 191 members (31.8%) answered the questionnaire, showing a detailed and a substantial heterogeneity in the therapeutic approach to SVT patients among experienced vascular physicians and angiologists. Detailed results are reported in the relative section. Conclusions: The therapeutic approach of SVT extended to the iuxta-femoral segment of the great saphenous vein is still a matter of debate, and data to support therapeutic strategies are lacking. The wide heterogeneity in the management of SVT patients, including those with more extended thrombosis, confirmed that a randomized controlled clinical trial investigating the efficacy and the safety of a tailored therapeutic regimen in this particular subgroup of patients is strongly warranted.

PMID: 37374272
DOI: 10.3390/medicina59061068


350§
Gianni Pastore, Matteo Bertini, Carlo Bonanno, Giovanni Coluccia, Gabriele Dell'Era, Luca De Mattia, Domenico Grieco, Grigorius Katsouras, Massimiliano Maines, Lina Marcantoni, Leonardo Marinaccio, Gabriele Paglino, Pietro Palmisano, Matteo Ziacchi, Franco Zoppo, Franco Noventa

The PhysioVP-AF study, a randomized controlled trial to assess the clinical benefit of physiological ventricular pacing vs. managed ventricular pacing for persistent atrial fibrillation prevention in patients with prolonged atrioventricular conduction: design and rationale.
Europace. 2023 May 19;25(5):euad082.

Abstract
Aims: In patients with prolonged atrioventricular (AV) conduction and pacemaker (PM) indication due to sinus node disease (SND) or intermittent AV-block who do not need continuous ventricular pacing (VP), it may be difficult to determine which strategy to adopt. Currently, the standard of care is to minimize unnecessary VP by specific VP avoidance (VPA) algorithms. The superiority of this strategy over standard DDD or DDD rate-responsive (DDD/DDDR) in improving clinical outcomes is controversial, probably owing to the prolongation of the atrialventricular conduction (PR interval) caused by the algorithms. Conduction system pacing (CSP) may offer the most physiological-VP approach, providing appropriate AV conduction and preventing pacing-induced dyssynchrony.
Methods and results: PhysioVP-AF is a prospective, controlled, randomized, single-blind trial designed to determine whether atrial-synchronized conduction system pacing (DDD-CSP) is superior to standard DDD-VPA pacing in terms of 3-year reduction of persistent-AF occurrence. Cardiovascular hospitalization, quality-of-life, and safety will be evaluated. Patients with indication for permanent DDD pacing for SND or intermittent AV-block and prolonged AV conduction (PR interval > 180 ms) will be randomized (1:1 ratio) to DDD-VPA (VPA-algorithms ON, septal/apex position) or to DDD-CSP (His bundle or left bundle branch area pacing, AV-delay setting to control PR interval, VPA-algorithms OFF). Approximately 400 patients will be randomized in 24 months in 13 Italian centres.
Conclusion: The PhysioVP-AF study will provide an essential contribution to patient management with prolonged AV conduction and PM indication for sinus nodal disease or paroxysmal 2nd-degree AV-block by determining whether CSP combined with a controlled PR interval is superior to standard management that minimizes unnecessary VP in terms of reducing clinical outcomes.

PMID: 36974970
DOI: 10.1093/europace/euad082


349§
Ana Rodríguez-Cobo, Carmen Fernández-Capitán, Yale Tung-Chen, Giorgina Salgueiro-Origlia, Aitor Ballaz, Cristiano Bortoluzzi, Gabrielle Sarlon-Bartoli, Maria Lourdes Pesce, Dally Najib, Manuel Monreal, The Riete Investigators

Clinical Significance and Outcome in Patients with Asymptomatic Versus Symptomatic Subsegmental Pulmonary Embolism.
J Clin Med. 2023 Feb 18;12(4):1640.

Abstract
The clinical significance and optimal therapy of patients with subsegmental pulmonary embolism (SSPE) remain controversial. We used the data in the RIETE Registry to compare the baseline characteristics, treatment, and outcomes during anticoagulation and after its discontinuation in patients with asymptomatic vs. symptomatic SSPE. From January 2009 to September 2022, there were 2135 patients with a first episode of SSPE, of whom 160 (7.5%) were asymptomatic. Most patients in both subgroups received anticoagulant therapy (97% vs. 99.4%, respectively). During anticoagulation, 14 patients developed symptomatic pulmonary embolism (PE) recurrences, 28 lower-limb deep vein thrombosis (DVT), 54 bled, and 242 died. The patients with asymptomatic SSPE had similar rates of symptomatic PE recurrences (hazard ratio (HR): 2.46; 95% CI: 0.37-9.74), DVT (HR: 0.53; 95% CI: 0.03-2.80), or major bleeding (HR: 0.85; 95% CI: 0.21-2.42) to those with symptomatic SSPE, but had a higher mortality rate (HR: 1.59; 95% CI: 1.25-2.94). The rate of major bleeding outweighed the rate of PE recurrences (54 major bleeds vs. 14 PE recurrences), and the rate of fatal bleeds outweighed the rate of fatal PE recurrences (12 vs. 6 deaths). After discontinuing anticoagulation, the patients with asymptomatic SSPE had a similar rate of PE recurrences (HR: 1.27; 95% CI: 0.20-4.55) and a non-significantly higher mortality rate (HR: 2.06; 95% CI: 0.92-4.10). The patients with asymptomatic SSPE had similar rates of PE recurrences to those with symptomatic SSPE, during and after discontinuing anticoagulation. The unexpectedly higher rate of major bleeding than recurrences highlights the need for randomized trials to find the best management.

PMID: 36836176
DOI: 10.3390/jcm12041640


348§
Walter Ageno, Lorenza Bertù, Eugenio Bucherini, Giuseppe Camporese, Francesco Dentali, Matteo Iotti, Gianfranco Lessiani, Roberto Parisi, Paolo Prandoni, Michelangelo Sartori, Adriana Visonà, Elisabetta Bigagli, Gualtiero Palareti; RIDTS study group

Rivaroxaban treatment for six weeks versus three months in patients with symptomatic isolated distal deep vein thrombosis: randomised controlled trial.
BMJ. 2022 Nov 23;379:e072623.

Abstract
Objective: To compare two different treatment durations of rivaroxaban in patients with symptomatic isolated distal deep vein thrombosis (DVT).
Design: Randomised, double blind, placebo controlled clinical trial.
Setting: 28 outpatient clinics specialising in venous thromboembolism.
Participants: 402 adults (≥18 years) with symptomatic isolated distal DVT.
Interventions: After receiving standard dose rivaroxaban for six weeks, participants were randomly assigned to receive rivaroxaban 20 mg or placebo once daily for an additional six weeks. Follow-up was for 24 months from study inclusion.
Main outcomes measures: The primary efficacy outcome was recurrent venous thromboembolism during follow-up after randomisation, defined as the composite of progression of isolated distal DVT, recurrent isolated distal DVT, proximal DVT, symptomatic pulmonary embolism, or fatal pulmonary embolism. The primary safety outcome was major bleeding after randomisation until two days from the last dose of rivaroxaban or placebo. An independent committee adjudicated the outcomes.
Results: 200 adults were randomised to receive additional rivaroxaban treatment and 202 to receive placebo. Isolated distal DVT was unprovoked in 81 (40%) and 86 (43%) patients, respectively. The primary efficacy outcome occurred in 23 (11%) patients in the rivaroxaban arm and 39 (19%) in the placebo arm (relative risk 0.59, 95% confidence interval 0.36 to 0.95; P=0.03, number needed to treat 13, 95% confidence interval 7 to 126). Recurrent isolated distal DVT occurred in 16 (8%) patients in the rivaroxaban arm and 31 (15%) in the placebo arm (P=0.02). Proximal DVT or pulmonary embolism occurred in seven (3%) patients in the rivaroxaban arm and eight (4%) in the placebo arm (P=0.80). No major bleeding events occurred.
Conclusions: Rivaroxaban administered for six additional weeks in patients with isolated distal DVT who had an uneventful six week treatment course reduces the risk of recurrent venous thromboembolism, mainly recurrent isolated distal DVT, over a two year follow-up without increasing the risk of haemorrhage.

PMID: 36520715
DOI: 10.1136/bmj-2022-072623


347§
Alicia Lorenzo, Patricia Beroiz, Salvador Ortiz, Jorge Del Toro, Lucia Mazzolai, Alessandra Bura-Riviere, Adriana Visonà, Peter Verhamme, Pierpaolo Di Micco, Giuseppe Camporese, Teresa Sancho Bueso, Manuel Monreal; RIETE Investigators

Predictors of use of direct oral anticoagulants in patients with venous thromboembolism: Findings from the Registro Informatizado Enfermedad Tromboembólica registry.
Front Med (Lausanne). 2022 Nov 25;9:991376.

Abstract
Background: Current guidelines recommend the use of direct oral anticoagulants (DOACs) for patients with venous thromboembolism (VTE). However little is known about the use of DOACs in daily practice.
Methods: We used the RIETE registry to identify predictors of use of DOACs for initial and/or long-term therapy of VTE based on patient-related factors, institution-related factors or over time.
Results: Among 41,678 patients from March 2013 to September 2021, 12,286 (29%) used DOACs: for initial therapy 6,456; for long-term therapy 12,046. On multivariable analysis, independent predictors were: age < 65 years (odds ratio [OR]: 1.30; 95% CI: 1.23-1.38), body weight <50 kg (OR: 0.54; 95% CI: 0.45-0.65) or >120 kg (OR: 0.64; 95% CI: 0.53-0.77), initial VTE presentation as pulmonary embolism (OR: 1.18; 95% CI: 1.13-1.25), recent bleeding (OR: 0.53; 95% CI: 0.45-0.63), renal insufficiency (OR: 0.44; 95% CI: 0.38-0.51), liver cirrhosis (OR: 0.32; 95% CI: 0.20-0.52), thrombocytopenia (OR: 0.40; 95% CI: 0.34-0.49), atrial fibrillation (OR: 1.58; 95% CI: 1.42-1.75) and prior VTE (OR: 1.14; 95% CI: 1.06-1.22). The DOACs were more likely used in other European countries (OR: 8.97; 95% CI: 8.49-9.49), America (OR: 6.35; 95% CI: 5.67-7.11) or in other countries of the world (OR: 2.99; 95% CI: 2.70-3.31) than in Spain, and progressively increased from 2013-2015 to 2016-2018 (OR: 2.78; 95% CI: 2.62-2.95) and 2019-2021 (OR: 6.36; 95% CI: 5.95-6.80).
Conclusion: In this large multinational VTE registry, variations were observed in the use of DOACs according to patient or country factors, and over time. The safety, costs, and influence of the DOACs on VTE-related outcomes in daily practice warrant further investigation.

PMID: 36507510
DOI: 10.3389/fmed.2022.991376


346§
Ciro di Gennaro, Mariano Galdiero, Giovanna Scherillo, Stefano Parlamento, Maria Rita Poggiano, Claudia Arturo, Antonio Vasta, Beniamino Giordano, Viviana Pisano, Antonio Lobasso, Giuseppe Camporese, Pierpaolo Di Micco 1

Editorial COVID-19 and Thrombosis 2023: New Waves of SARS-CoV-2 Infection, Triage Organization in Emergency Department and the Association of VOCs/VOI with Pulmonary Embolism.
Viruses. 2022 Nov 5;14(11):2453.

PMID: 36366551
DOI: 10.3390/v14112453


345§
Enrico Bernardi, Giuseppe Camporese, Cristiano Bortoluzzi, Franco Noventa, Davide Ceccato, Chiara Tonello, Stefania Vohong, Elena Campello, Chiara Simion, Egidio Imbalzano, Pierpaolo Di Micco, Elena Callegari, Paolo Simioni

Safety and Efficacy of Rivaroxaban as Extended-Phase Anticoagulation in Patients with Cancer and Venous Thromboembolism: A Preliminary Data Analysis from the Mac Project.
Life (Basel). 2022 Oct 28;12(11):1725.

Abstract
Extended-phase anticoagulation with direct oral Xa inhibitors (OAXI) is suggested in patients with cancer-associated venous thromboembolism (CAT). We report on patients enrolled in the MAC (Monitoring AntiCoagulants) Project, given rivaroxaban as extended-phase anticoagulation after CAT. The primary efficacy outcome was the incidence of symptomatic recurrent VTE; the primary safety outcomes were incidence of major and non-major clinically relevant bleeding, adverse events, and all-cause mortality. The mean patients' follow-up was 19 months (SD 16); 64/604 (11%) had CAT. Recurrent VTE occurred in 9.3% and in 8.1% of patients with and without CAT (OR 1.2, 95% CI 0.5 to 2.9; p = 0.6). Major bleeding occurred in 4.7% and in 2.6%, respectively (OR = 1.8, 95% CI 0.5 to 6.6, p = 0.4), and non-major clinically-relevant bleeding in 4.7% and in 4.1% (OR = 1.2, 95% CI 0.3 to 3.9, p = 0.7). The relative figures for fatal haemorrhage and all-cause death were 1.6% versus 0%, and 1.6% versus 0.4%. Rivaroxaban appears to be effective and safe as extended-phase anticoagulation in patients with CAT. The mean treatment period was 3-times the standard 6-month course.

PMID: 36362880
DOI: 10.3390/life12111725


344§
Cristiano Bortoluzzi 1 , Enrico Bernardi, Giuseppe Camporese, Franco Noventa, Davide Ceccato, Chiara Tonello, Ngoc Vo Hong, Elena Campello, Chiara Simion, Egidio Imbalzano, Pierpaolo Di Micco, Elena Callegari, Paolo Simioni 6

Safety and Efficacy of Rivaroxaban for Extended-Phase Anticoagulation of Patients with Unprovoked or Recurrent Venous Thromboembolism: Real-Life Data from the MAC Project.
Life (Basel). 2022 Oct 20;12(10):1657.

Abstract
Venous thromboembolism (VTE) is a major cause of death in the world. After the acute-phase treatment, the optimal duration of anticoagulation is still debatable. The latest guidelines suggest maintaining long-term anticoagulation in patients with cancer-associated thrombosis (CAT) or with unprovoked VTE and a low bleeding risk. Methods: The MAC Project is an ongoing prospective-cohort, multi-center, observational study in Italy. The project aims to collect real-life clinical information in unselected patients given oral anticoagulants for VTE over a 5-year follow-up period. There were no exclusion criteria, except for life expectancy <6 months and refusal to sign the informed consent form or to attend the planned follow-up visit. All patients were followed-up prospectively with clinical controls scheduled at 3, 6, and 12 months after the index event, and then annually for up to 5 years. The primary efficacy and safety outcomes were symptomatic recurrent VTE and major bleeding. Results: We analyzed 450 consecutive patients treated with rivaroxaban and referred them to the MAC Project database for unprovoked or recurrent VTE. Of these, 267 (55%) were unprovoked VTE, and 377 (87%) were symptomatic. We followed up with the patients for a mean of 22 months (Q1 10.7; Q3 37.4 months). Recurrent VTE occurred in 12 patients on rivaroxaban treatment (IR 1.7 per 100 person-years). Males had more recurrence than women. During the follow-up period, we recorded 13 (2.9%) major bleeding, 12 (2.7%) clinically relevant non-major bleeding, 8 minor bleeding, and no fatal bleeding events. Overall, bleeding events occurred in 33 (7.3%) patients, most occurring within the first 2 years of treatment. In addition, we observed a statistically significant higher incidence of bleeding in patients with a baseline HAS-BLED score of 3 to 4 compared with those with a score of 0 to 2, with most events occurring during the first 3 months of treatment (RR 5.9). Discussion: Rivaroxaban appears to be safe and effective for the long-term treatment of patients with recurrent or unprovoked VTE. Our results match previously published data, and we are confident that the continuation of the follow-up for up to 5 years will confirm these outcomes.

DOI: 10.3390/life12101657
PMID: 36295091


343§
Camporese G, Aloi TL, Santoliquido A.

Delphi case: Sharing of clinical experiences for improvement in the treatment of chronic venous disease.
(2022) Front Cardiovasc Med. Jul 18;9:921235

Abstract
Chronic venous disease (CVD) is a common condition with major health consequences that is associated with poor long-term prognosis, significant socioeconomic impact, disabling symptoms, and reduced quality of life. To provide a novel evidence-based approach in the management of CVD, a consensus process ("Delphi Case") following a first Delphi Consensus was conceived. With a real-life fashion analysis, a steering committee formed by 3 expert leaders on chronic venous disease drove a panel of 77 expert Italian angiologists/vascular surgeons along a collegial discussion, integrating data coming from the guidelines recommendations of different Vascular Scientific Societies with the consensus agreement statements gathered from the first Delphi Consensus, and with data coming from the discussion of few statements in which there was disagreement. From July 15 to October 16, 2020, demographic, anamnestic, objective, and therapeutic data coming from a total of 2,275 patients were collected by the experts panel using a predefined case report form. The results of this second consensus provided a real-life picture of CVD management in the Italian population and clearly showed that a tailored therapeutic approach together with an appropriate lifestyle (e.g., diet, physical activity, weight loss) must be considered as the milestones for the CVD-related signs and symptoms clinical improvement in daily clinical practice. An evaluation of the adherence and of the efficacy of the prescribed pharmacological and compressive treatment in a medium-long term follow-up of the study population has been planned as the last step of this course and will be object of a future final publication.

DOI: 10.3389/fcvm.2022.921235
PMID: 35924214


342§
Di Micco P, Imbalzano E, Camporese G.

Special Issue "COVID-19 and Thrombosis".
(2022) Viruses. Jun 29;14(7):1425.

Abstract
Since the pandemic began, an association among COVID-19 and venous thromboembolism has been reported, in particular for inpatients [...].

DOI: 10.3390/v14071425
PMID: 35891405


341§
Poletto F, Spiezia L, Simion C, Campello E, Dalla Valle F, Tormene D, Camporese G, Simioni P.

Risk Factors of Venous Thromboembolism in Noncritically Ill Patients Hospitalized for Acute COVID-19 Pneumonia Receiving Prophylactic-Dose Anticoagulation.
(2022) Viruses. 2022 Mar 31;14(4):737

Abstract
Background: Therapeutic/intermediate-dose heparin reduces the risk of thromboembolic events but increases the risk of major bleeding in patients hospitalized for acute COVID-19 pneumonia. Objectives: To prospectively assess the incidence of objectively proven venous thromboembolism (VTE) and identify predisposing risk factors in a cohort of hospitalized patients with acute COVID-19 pneumonia undergoing prophylactic-dose heparin. Patients and methods: All consecutive patients admitted for acute COVID-19 pneumonia to the General Internal Medicine Unit of Padova University Hospital, Italy between November 2020 and April 2021, and undergoing prophylactic-dose heparin, were enrolled. Demographic and clinical characteristics and laboratory and radiological findings were recorded on admission. Cases were patients who developed VTE during their hospital stay. Univariable and multivariable logistic regression analyses were used to ascertain the risk factors associated with developing in-hospital VTE. Results: 208 patients (median age: 77 years; M/F 98/110) were included; 37 (18%) developed in-hospital VTE during a median follow-up of 10 days (IQR, 4-18). VTE patients were significantly younger (p = 0.004), more obese (p = 0.002), and had a lower Padua prediction score (p < 0.03) and reduced PaO2/FIO2 ratio (p < 0.03) vs. controls. Radiological findings of bilateral pulmonary infiltrates were significantly more frequent in VTE patients than controls (p = 0.003). Multivariable regression showed that obesity (1.75, 95% CI 1.02-3.36; p = 0.04) and bilateral pulmonary infiltrates on X-rays (2.39, 95% CI 1.22-5.69; p = 0.04) were correlated with increased risk of in-hospital VTE. Conclusions: Obesity and bilateral pulmonary infiltrates on imaging may help clinicians to identify patients admitted to medical wards for acute COVID-19 pneumonia at risk of developing VTE despite prophylactic-dose heparin. Further studies are needed to evaluate whether the administration of therapeutic/intermediate-dose heparin may help prevent VTE episodes without further increasing the bleeding risk.

DOI: 10.3390/v14040737
PMID: 35458467

340§
Camporese G, Bernardi E, Venturin A, Pellizzaro A, Schiavon A, Caneva F, Strullato A, Toninato D, Forcato B, Zuin A, Squizzato F, Piazza M, Stramare R, Tonello C, Di Micco P, Masiero S, Rea F, Grego F, Simioni P.

Diagnostic and Therapeutic Management of the Thoracic Outlet Syndrome. Review of the Literature and Report of an Italian Experience.
(2022) Front Cardiovasc Med. Mar 22;9:802183.

Abstract
The Thoracic Outlet Syndrome is a clinical potentially disabling condition characterized by a group of upper extremity signs and symptoms due to the compression of the neurovascular bundle passing through the thoracic outlet region. Because of the non-specific nature of signs and symptoms, to the lack of a consensus for the objective diagnosis, and to the wide range of etiologies, the actual figure is still a matter of debate among experts. We aimed to summarize the current evidence about the pathophysiology, the diagnosis and the treatment of the thoracic outlet syndrome, and to report a retrospective analysis on 324 patients followed for 5 years at the Padua University Hospital and at the Naples Fatebenefratelli Hospital in Italy, to verify the effectiveness of a specific rehabilitation program for the syndrome and to evaluate if physical therapy could relieve symptoms in these patients.

DOI: 10.3389/fcvm.2022.802183
PMID: 35391849

339§
Prandoni P, Lensing WA, Prins MH, Villalta S, Pesavento R, Tormene D, Noventa F, Palareti G

Elastic compression stockings for prevention of the post-thrombotic syndrome in patients with and without residual vein thrombosis and/or popliteal valve reflux
(2022) Haematologica Jan Vol 107, 1.

DOI: 10.3324/haematol.2021.279680
PMID: 34498448


338§
Imbalzano E, Orlando L, Sciacqua A, Nato G, Dentali F, Nassisi V, Russo V, Camporese G, Bagnato G, Cicero AFG, Dattilo G, Vatrano M, Versace AG, Squadrito G, Di Micco P.

Machine Learning to Calculate Heparin Dose in COVID-19 Patients with Active Cancer.
(2021) J Clin Med. Dec 31;11(1):219.

Abstract
To realize a machine learning (ML) model to estimate the dose of low molecular weight heparin to be administered, preventing thromboembolism events in COVID-19 patients with active cancer. Methods: We used a dataset comprising 131 patients with active cancer and COVID-19. We considered five ML models: logistic regression, decision tree, random forest, support vector machine and Gaussian naive Bayes. We decided to implement the logistic regression model for our study. A model with 19 variables was analyzed. Data were randomly split into training (70%) and testing (30%) sets. Model performance was assessed by confusion matrix metrics on the testing data for each model as positive predictive value, sensitivity and F1-score. Results: We showed that the five selected models outperformed classical statistical methods of predictive validity and logistic regression was the most effective, being able to classify with an accuracy of 81%. The most relevant result was finding a patient-proof where python function was able to obtain the exact dose of low weight molecular heparin to be administered and thereby to prevent the occurrence of VTE. Conclusions: The world of machine learning and artificial intelligence is constantly developing. The identification of a specific LMWH dose for preventing VTE in very high-risk populations, such as the COVID-19 and active cancer population, might improve with the use of new training ML-based algorithms. Larger studies are needed to confirm our exploratory results.

DOI: 10.3390/jcm11010219.
PMID: 35011959


337§
Camporese G, Bernardi E, Bortoluzzi C, Noventa F, Hong NV, Callegari E, Villalta S, Tonello C, Nardin M, Campello E, Spiezia L, Simioni P.

MAC Project-Monitoring Anticoagulant Therapy Observational Study: Rationale and Protocol.
(2021) Front Med (Lausanne). Jan 28;7:584459

DOI: 10.3389/fmed.2020.584459
PMID: 33585500

Abstract
Real-life studies complement data from registrative trials. Because of the delayed registration of direct oral anticoagulants in Italy, scarce real-life data on such treatments is available for the Italian population. The aim of the MAC project is to collect real-life clinical information in unselected patients given oral anticoagulants for venous thromboembolism, during a 5-year follow-up period. This is a prospective-cohort, multi-center, observational study performed in four Italian centers. The estimated samples size is 4,000 patients. The efficacy outcomes are: incidence of symptomatic recurrent venous thromboembolism and of post-thrombotic syndrome. The safety outcomes are: incidence of major bleeding, clinically relevant non-major bleeding, minor bleeding, serious adverse events, and mortality. The MAC project has the potential to improve our understanding of the epidemiology and of the therapeutic strategies adopted in Italian patients with venous thromboembolism. Clinical Trial Registration: WWW.ClinicalTrials.Gov, identifier: NCT0432939.


336§
Di Micco P, Imbalzano E, Russo V, Attena E, Mandaliti V, Orlando L, Lombardi M, Di Micco G, Camporese G, Annunziata S, Piccinocchi G, Pacelli W, Del Guercio M.

Heparin and SARS-CoV-2: Multiple Pathophysiological Links
(2021) Viruses. Dec 11;13:2486.

DOI: 10.3390/v13122486.
PMID: 34960754
Abstract
Low molecular weight heparin, enoxaparin, has been one of most used drugs to fight the SARS-CoV-2 pandemic. Pharmacological properties of heparin recognize its specific ability, as with other oligosaccharides and glycosaminoglycan, to bind several types of viruses during their pass through the extracellular matrix of the respiratory tract, as well as its anticoagulant activity to prevent venous thromboembolism. Antithrombotic actions of enoxaparin have been testified both for inpatients with COVID-19 in regular ward and for inpatients in Intensive Care Units (ICUs). Prophylactic doses seem to be able to prevent venous thromboembolism (VTE) in inpatients in the regular ward, while intermediate or therapeutic doses have been frequently adopted for inpatients with COVID-19 in ICU. On the other hand, although we reported several useful actions of heparin for inpatients with COVID-19, an increased rate of bleeding has been recorded, and it may be related to several conditions such as underlying diseases with increased risks of bleeding, increased doses or prolonged administration of heparin, personal trend to bleed, and so on.

335§
Di Micco P, Camporese G, Cardillo G, Lodigiani C, Carannante N, Annunziata A, Fiorentino G, Russo V, Imbalzano E.
Pathophysiology of Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) and Vaccine-Induced Thrombocytopenic Thrombosis (VITT) and Their Diagnostic Approach in Emergency.
(2021) Medicina (Kaunas). Sep 22;57:997. doi: 10.3390/
DOI: 10.3390/medicina57100997
PMID: 34684034
Abstract
SARS-CoV-2 induced a pandemic that is reported to have started in Asia and was then extended to other countries in the world. Main clinical aspects of this viral infection have been lung injuries with severe pneumonia requiring prolonged hospitalization and associated morbidities such as venous thromboembolism and/or superinfection by bacteria, fungus or other pests. Immediately there was a need to develop a sustainable therapeutic strategy, such as vaccination. Vaccines against Covid-19, in fact, exert a protective action for common people and reduce viral diffusion. Yet, vaccination of a large number of people raises the question of a well-known complication of several types of vaccines; this complication is immune thrombocytopenia, which is sometimes associated with thrombosis as well. In this short review, we summarized mechanisms involved in the pathogenesis of vaccine-induced prothrombotic immune thrombocytopenia and vaccine-induced thrombocytopenic thrombosis

334§
Di Micco P, Tufano A, Cardillo G, Imbalzano E, Amitrano M, Lodigiani C, Bellizzi A, Camporese G, Cavalli A, De Stefano C, Russo V, Voza A, Perrella A, Prandoni P.
The Impact of Risk-Adjusted Heparin Regimens on the Outcome of Patients with COVID-19 Infection. A Prospective Cohort Study
(2021) Viruses. Aug 30;13:1720.
DOI: 10.3390/v13091720
PMID: 34578301
Abstract
BACKGROUND: According to recent guidelines, all hospitalized patients with COVID-19 should receive pharmacological prophylaxis for venous thromboembolism (VTE), unless there are specific contraindications. However, the optimal preventive strategy in terms of intensity of anticoagulation for these patients is not well established. OBJECTIVES: To investigate the impact of individualized regimens of enoxaparin on the development of VTE and on the risk of major bleeding complications during hospitalization in patients with COVID-19 infection. METHODS: All consecutive patients admitted to the medical wards of six Italian hospitals between 15 September and 15 October 2020 with COVID-19 infection of moderate severity were administered enoxaparin in subcutaneous daily doses adjusted to the Padua Prediction Score stratification model: No heparin in patients scoring less than 4, 4000 IU daily in those scoring 4, 6000 IU in those scoring 5, and 8000 in those scoring six or more. Objective tests were performed in patients developing clinical symptoms of deep vein thrombosis and/or pulmonary embolism. Bleeding complications were defined according to the ISTH classification. RESULTS: From the 154 eligible patients, enoxaparin was administered in all: 4000 IU in 73 patients, 6000 IU in 53, and 8000 IU in the remaining 28. During the course of hospitalization, 27 patients (17.5%) died. VTE developed in 14 of the 154 patients (9.1%; 95% CI, 4.6% to 13.6%), and was fatal in 1. Major bleeding complications developed in 35 patients (22.7%; 95% CI, 16.1% to 29.3%), and were fatal in 8. CONCLUSIONS: Despite the use of risk-adjusted doses of enoxaparin, the rate of VTE events was consistent with that reported in contemporary studies where fixed-dose low-molecular-weight heparin was used. The unexpectedly high risk of bleeding complications should induce caution in administering enoxaparin in doses higher than the conventional low ones.

333§
Riva M, Berno T, Cipriani A, Altinier S, Fedrigo M, Noventa F, Adami F.
Dealing With High-Risk AL Amyloidosis Patients: A Single Hematologic Center Experience.
(2021) Clin Lymphoma Myeloma Leuk. Dec;21:e970-e974
DOI: 10.1016/j.clml.2021.07.015
PMID: 34489209

Abstract
PURPOSE: To assess the feasibility and the results of Bortezomib-based treatment of "high-risk" AL-amyloidosis patients in a hematology ward. METHODS: We report on 52 high-risk amyloidosis patients treated with first-line bortezomib-based chemotherapy. RESULTS: At day 30 from the beginning of the therapy, 23 patients (44%) achieved a hematological response (complete response plus very good partial response); 14 patients (27%) achieved a partial response; 15 patients (29%) were non-responders. After a median follow-up of 28.5 months, the survival rates were 18/23 (78%) for responders; 9/14 (64%) for partial responders and 3/15 (20%) for nonresponders with a median overall survival of 43, 24 and 11 months, respectively (log-rank test: P < .001). NHYA class I-II, NTproBNP < 6500 ng/L, the hematologic response, and the partial hematological response at day 30 independently predicted the survival. There has been no significant difference (P = .173) in survival between revised Mayo stage III and IV patients although there was a trend toward a better prognosis for Mayo stage III. A suboptimal hematological response at day 30 allowed a later organ response in 12/14 patients (85%) even without therapy change and no modification of the hematological status. CONCLUSIONS: These results show that high-risk AL-amyloidosis patients can be managed safely and effectively in a hematology ward. A partial hematologic response may herald a later better response, organ response, and can allow a subsequent second-line therapy and a good survival

332§
Di Micco P, Camporese G, Russo V, Cardillo G, Imbalzano E, Tufano A, Bernardi E, Fontanella A.
Clinical Differences between COVID-19 and a COVID-Like Syndrome
(2021) J Clin Med. Jun 7;10:2519
DOI: 10.3390/jcm10112519
PMID: 34200168
Abstract
COVID-19 is an infection due to SARS-CoV-2; this virus has been identified as the cause of the present pandemic. Several typical characteristics are present in this infection, in particular pneumonia with possible lung failure, but atypical clinical presentations are being described daily by physicians around the world. Ground-glass opacities with pneumonia are the most common and dangerous presentations of the COVID-19 disease, and they are usually associated with positive nasopharyngeal swab (NPS) tests with detectable SARS-CoV-2 viral RNA. Compared to the general population, hospital workers have been at a greater risk of infection ever since the first patients were hospitalized. However, hospital workers have also been reported as having COVID-like symptoms despite repeated negative swab tests but having tested positive for SARS-CoV-2 antibodies with serological tests. We can postulate that a COVID-like syndrome is possible, in particular in hospital workers, that is characterized by symptoms similar to those of COVID-19, but with repeated negative nasopharyngeal swabs. These repeated negative NSPs make the difference in daily clinical management with people that experienced a single false negative nasopharyngeal swab; furthermore, a clear clinical differentiation of these situations is still lacking in the literature. For this reason, here, we report our main findings from a cohort of patients with a COVID-like syndrome compared to a similar group affected by typical COVID-19.

331§
Botto G, Ameri P, Cappellari M, Dentali F, Ferri N, Parrini I, Porto I, Squizzato A, Camporese G.
Unmet Clinical Needs in Elderly Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Non-valvular Atrial Fibrillation.
(2021) Adv Ther. Jun;38:2891-2907.
DOI: 10.1007/s12325-021-01769-9
PMID: 34019247
Abstract
Vitamin K antagonists have been used for many years as the treatment of choice for long-term oral anticoagulation in patients with non-valvular atrial fibrillation. Unfortunately, the use of those drugs in the real-world setting, particularly among elderly patients, is suboptimal because of their limitations in management. Therefore, many patients were not adequately anticoagulated. Direct oral anticoagulants have been demonstrated to overcome almost all the limitations derived from the use of vitamin K antagonists. Direct oral anticoagulants are at least as effective as vitamin K antagonists in preventing thromboembolic events in patients with non-valvular atrial fibrillation and safer in reducing the risk of intracranial haemorrhage and all-cause mortality. However, as a result of the strict inclusion and exclusion criteria applied to patients, data coming from randomized controlled trials might not apply to the general population. Furthermore, elderly patients were scarcely represented in randomized controlled trials with direct oral anticoagulants. Therefore, in elderly patients with non-valvular atrial fibrillation, unmet clinical needs still exist. This review article highlights some of them and provides potential answers based on the results coming from randomized clinical trials, real-world data, and the authors' clinical experience.

330§
Galanaud JP, Trujillo-Santos J, Bikdeli B, Di Micco P, Bortoluzzi C, Bertoletti L, Pedrajas JM, Ballaz A, Alfonso J, Monreal M; RIETE Investigators.
Management of isolated distal deep-vein thrombosis with direct oral anticoagulants in the RIETE registry.
(2021) J Thromb Thrombolysis. Aug;52(2):532-541

DOI: 10.1007/s11239-020-02347-6
PMID: 33247808
Abstract
Isolated distal deep-vein thrombosis (DVT, infra-popliteal DVT without pulmonary embolism) is a common presentation of venous thromboembolism (VTE), but was an exclusion criterion from the pivotal trials that validated the use of direct oral anticoagulants (DOACs) for VTE management. Using data from the international RIETE registry, we analyzed and compared trends in DOACs prescription between January 2011 and June 2019 in patients with distal vs. proximal DVT. We also assessed DOACs' prescriptions and compared the outcomes (VTE recurrence, bleeding and death) of distal DVT patients treated with DOACs vs. those on vitamin K antagonists (VKAs). 2308 patients with distal DVT and 11,364 patients with proximal DVT were included in the current analysis. DOACs were more frequently prescribed in patients with distal than proximal DVT (25% vs. 16%, p < 0.001). DOACs use increased sharply during the observation period (P < 0.001 for trend). In 2018, 56% of patients with distal DVT received DOACs. Distal DVT patients treated with rivaroxaban or edoxaban received the dose recommended for VTE management in most (> 85%) cases. Patients treated with apixaban were older, more likely to have underlying conditions than patients treated with rivaroxaban and, in most cases (> 75%), did not receive the recommended 1-week loading dose for acute VTE management. Outcomes between distal DVT patients treated with VKAs or DOACs appeared to be similar. In patients with distal DVT, DOACs have become the most common anticoagulant regimen. Specific trials are needed to determine the optimal DOACs dose regimen for treatment of distal DVT.

329§
Pastore G, Marcantoni L, Lanza D, Maines M, Noventa F, Corbucci G, Rigatelli G, Baracca E, Roncon L, Zanon F.
Occurrence of persistent atrial fibrillation during pacing for sinus node disease: The influence of His bundle pacing versus managed ventricular pacing.
(2021) J Cardiovasc Electrophysiol. Jan;32:110-116.

DOI: 10.1111/jce.14810
PMID: 33179400
Abstract
INTRODUCTION: In patients with sinus node disease (SND), the dual-chamber pacemaker (PM) is programmed in DDDR mode with an algorithm to avoid unnecessary right ventricular (RV) pacing. This pacing mode may prolong PR interval with consequently atrioventricular (AV) asynchrony which is associated with a higher risk of atrial fibrillation (AF). We evaluate whether preserving AV synchrony by setting a fixed AV delay during physiological RV pacing, that is, His bundle pacing (HBP), could reduce the risk of AF occurrence in comparison with a standard pacing mode with an algorithm to avoid unnecessary RV pacing (DDD-VPA). METHODS AND RESULTS: We collected retrospective data from 313 consecutive patients who had undergone PM for SND. The first occurrence of persistent AF (>7 consecutive days) as a function of the pacing mode was evaluated. HBP and DDD-VPA were implemented in 82 and 231 patients, respectively. Persistent AF occurred in 128 (40.9%) patients over a median follow-up of 70 months (67-105). The DDD-VPA pacing mode was significantly correlated with the occurrence of persistent AF only when the basal PR was long (>180 ms). The risk of persistent AF was significantly lower in patients on HBP than in those on DDD-VPA, adjusted HR = .57 (95% CI, .36- .89, p=.014). Other independent predictors of persistent AF occurrence were: A history of AF (HR = 3.91; 95% CI, 2.48-6.19, p = .001), age, and long PR interval (HR = 2.98; 95% CI, 2.00-4.43, p=.001). CONCLUSION: In SND patients and long basal PR interval, the HBP may reduce the risk of persistent AF in comparison with the DDD-VPA

328§
Camporese G, Simioni P, Di Micco P, Fernández-Capitán C, Rivas A, Font C, Sahuquillo JC, Villares P, Prandoni P, Monreal M; RIETE Investigators.
Edoxaban for the Long-Term Therapy of Venous Thromboembolism: Should the Criteria for Dose Reduction be Revised?
(2021) Clin Transl Sci. Jan;14:335-342.
DOI: 10.1111/cts.12876
PMID: 33038286
Abstract
Edoxaban is used for venous thromboembolism (VTE) treatment. Real-life data are lacking about its use in long-term therapy. We aimed to assess the efficacy and the safety of edoxaban for long-term VTE treatment in a real-life setting. Patients with VTE included in the Registro Informatizado Enfermedad TromboEmbólica (RIETE) registry, receiving edoxaban 60 or 30 mg daily were prospectively followed up to validate the benefit of using different dosages. The main outcome was the composite of VTE recurrences or major bleeding in patients with or without criteria for dose reduction. Multivariable analysis to identify predictors for the composite outcome was performed. From October 2015 to November 2019, 562 patients received edoxaban for long-term therapy. Most (94%) of the 416 patients not meeting criteria for dose reduction received 60 mg daily, and 92 patients meeting criteria (63%) received 30 mg daily. During treatment, two patients developed recurrent VTE, six had major bleeding and nine died (2 from fatal bleeding). Among patients not meeting criteria for dose reduction, those receiving 30 mg daily had a higher rate of the composite event (hazard ratio (HR) 8.37; 95% confidence interval (CI) 1.12-42.4) and a significant higher mortality rate (HR 31.1; 95% CI 4.63-262) than those receiving 60 mg. Among patients meeting criteria for dose reduction, those receiving 60 mg daily had no events, and a nonsignificantly higher mortality rate (HR 5.04; 95% CI 0.54-133) than those receiving 30 mg daily. In conclusion, edoxaban seems to be effective and safe for long-term VTE treatment in real life. Criteria for dose reduction should be reformulated.

327§
Barco S, Schmidtmann I, Ageno W, Anušić T, Bauersachs RM, Becattini C, Bernardi E, Beyer-Westendorf J, Bonacchini L, Brachmann J, Christ M, Czihal M, Duerschmied D, Empen K, Espinola-Klein C, Ficker JH, Fonseca C, Genth-Zotz S, Jiménez D, Harjola VP, Held M, Iogna Prat L, Lange TJ, Lankeit M, Manolis A, Meyer A, Münzel T, Mustonen P, Rauch-Kroehnert U, Ruiz-Artacho P, Schellong S, Schwaiblmair M, Stahrenberg R, Valerio L, Westerweel PE, Wild PS, Konstantinides SV; HoT-PE Investigators; HoT-PE Trial Investigators.
Survival and quality of life after early discharge in low-risk pulmonary embolism.
(2021) Eur Respir J. Feb 4;57(2):2002368
DOI: 10.1183/13993003.02368-2020
PMID: 32859673
Abstract
INTRODUCTION: Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes. METHODS: The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism. RESULTS: The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of -9.1% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001). CONCLUSIONS: Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.

326§
Pavei P, Spreafico G, Bernardi E, Giraldi E, Ferrini M.
Favorable long-term results of endovenous laser ablation of great and small saphenous vein incompetence with a 1470-nm laser and radial fiber.
(2021) J Vasc Surg Venous Lymphat Disord. Mar;9(2):352-360.
DOI: 10.1016/j.jvsv.2020.06.015
PMID: 32599308
Abstract
OBJECTIVE: Scarce information is available on the long-term results of endovenous laser ablation (EVLA) for great saphenous vein (GSV) or small saphenous vein (SSV) insufficiency. We sought to provide data on the status of patients at least 9 years after EVLA. METHODS: In 2018, we undertook a cross-sectional survey of ambulatory patients who had undergone EVLA in our tertiary care center in 2008-2009. Of 240 eligible patients, 5 died of causes not related to EVLA, 20 refused to participate, and 12 were lost to follow-up. Thus, 203 patients were re-evaluated; of them, 161 (79%) had GSV insufficiency and 42 (21%) had SSV insufficiency. The mean follow-up was 114 months (standard deviation, 11 months). All included patients underwent an echocardiography-color Doppler (ECD) evaluation, a clinical visit, and a standardized medical history. We assessed the competence of the junction and of the treated and untreated saphenous trunk and the presence of recurrent varicose veins. The trunk was considered ablated if it was nonvisible on B-mode or, when visible, if it was noncompressible or without flow or reflux on color flow Doppler analysis. Any recurrent varicose vein with the leakage point located in the treated saphenous vein was considered a failure. We asked patients about the effect of EVLA on their preoperative complaints and about any new or recurrent symptoms. We also recorded any complication or additional subsequent treatment and all data necessary to calculate the clinical class (C of the Clinical, Etiology, Anatomy, and Pathophysiology [CEAP] classification) and the Venous Clinical Severity Score (VCSS). Finally, we investigated potential associations between the study outcomes and variables by multiple logistic regression techniques. RESULTS: Some 10 years after EVLA, we performed a single clinical and ECD evaluation in 203 patients. Only one recanalization (0.5%; 95% confidence interval, 0.0-2.7) of the treated GSV trunk was observed in an otherwise asymptomatic patient. Up to 98% of patients were asymptomatic or significantly improved after EVLA. Additional subsequent treatments occurred in 21% of patients with GSV insufficiency and 5% of patients with SSV insufficiency. Three complications were observed, two in the GSV group (varicophlebitis, saphenous nerve damage) and one (varicophlebitis) in the SSV group. The mean C class of CEAP and the mean VCSS were significantly lower at the end of follow-up, both in patients with GSV insufficiency (C class, 3.2 vs 1.5 [P = .00001]; VCSS, 6.3 vs 1.6 [P = .001]) and in patients with SSV insufficiency (C class, 2.9 vs 1.1 [P = .00001]; VCSS, 5.4 vs 0.7 [P = .001]). Only the maximum diameter of the GSV at the junction independently correlated with ECD-confirmed reflux in the treated saphenous trunk or in the anterior accessory saphenous vein (odds ratio, 1.10; 95% confidence interval, 1.01-1.21). CONCLUSIONS: EVLA using a 1470-nm diode laser with radial fibers provides stable and valuable long-term results in patients with either GSV or SSV insufficiency.


325§
Tormene D, Noventa F, Campello E, Gavasso S, Marobin M, Turatti G, Prandoni P, Simioni P.

The risk of arterial thrombosis in carriers of natural coagulation inhibitors: a prospective family cohort study.
(2021) Intern Emerg Med. Feb 22.
DOI: 10.1007/s11739-021-02656-5
PMID: 33619677

Abstract
BACKGROUND: Whether the carriership of inherited antithrombin (AT), protein C (PC), and protein S (PS) deficiency increases the risk of arterial thromboembolic events (ATE) is controversial. This information has the potential to inform the management of family members of probands with inherited deficiency of natural anticoagulants. PATIENTS/METHODS: We conducted a large prospective family cohort study in 640 subjects (of whom 341 carriers and 299 non-carriers) belonging to 86 families with inherited deficiency of AT, PC, or PS. RESULTS: A total of 4240 and 3810 patient-years were available for carriers and non-carriers, respectively. Risk factors for atherosclerosis were similarly distributed in the two groups. Of the 26 ATE that were recorded, 19 occurred in carriers (5.6%), as compared to 7 in non-carriers (2.3%) [p = 0.07]. After adjusting for confounders, the hazard ratio (HR) for ATE was 4.9 (95% CI 1.5-16.3) in carriers as compared to non-carriers. CONCLUSIONS: Among family members of probands with an inherited deficiency of natural anticoagulants, carriers exhibit a risk of ATE that is almost five times higher than in non-carriers.

324§
Camporese G, Bernardi E, Bortoluzzi C, Noventa F, Hong NV, Callegari E, Villalta S, Tonello C, Nardin M, Campello E, Spiezia L, Simioni P.

MAC Project-Monitoring Anticoagulant Therapy Observational Study: Rationale and Protocol.
(2021) Front Med (Lausanne). Jan 28;7:584459
DOI: 10.3389/fmed.2020.584459
PMID: 33585500
Abstract
Real-life studies complement data from registrative trials. Because of the delayed registration of direct oral anticoagulants in Italy, scarce real-life data on such treatments is available for the Italian population. The aim of the MAC project is to collect real-life clinical information in unselected patients given oral anticoagulants for venous thromboembolism, during a 5-year follow-up period. This is a prospective-cohort, multi-center, observational study performed in four Italian centers. The estimated samples size is 4,000 patients. The efficacy outcomes are: incidence of symptomatic recurrent venous thromboembolism and of post-thrombotic syndrome. The safety outcomes are: incidence of major bleeding, clinically relevant non-major bleeding, minor bleeding, serious adverse events, and mortality. The MAC project has the potential to improve our understanding of the epidemiology and of the therapeutic strategies adopted in Italian patients with venous thromboembolism.

323§
Campello E, Spiezia L, Simion C, Tormene D, Camporese G, Dalla Valle F, Poretto A, Bulato C, Gavasso S, Radu CM, Simioni P.

Direct Oral Anticoagulants in Patients With Inherited Thrombophilia and Venous Thromboembolism: A Prospective Cohort Study.
(2020) J Am Heart Assoc. Dec;9(23):e018917
DOI: 10.1161/JAHA.120.018917
PMID: 33222589

Abstract
Background In this prospective cohort study, we aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) versus heparin/vitamin K antagonists for the treatment of venous thromboembolism (VTE) in patients with inherited thrombophilia. Methods and Results We enrolled consecutive patients with acute VTE and inherited thrombophilia treated with DOACs (cases) or heparin/vitamin K antagonists (controls), matched for age, sex, ethnicity, and thrombophilia type. End points were VTE recurrence and bleeding complications; residual vein thrombosis and post-thrombotic syndrome; VTE recurrence after anticoagulant discontinuation. Two hundred fifty-five cases (age 52.4±17.3 years, Female 44.3%, severe thrombophilia 33.1%) and 322 controls (age 49.7±18.1 years, Female 50.3%, severe thrombophilia 35.1%) were included. The cumulative incidence of VTE recurrence during anticoagulation was 1.09% in cases versus 1.83%, adjusted hazard ratio (HR) 0.67 (95% CI, 0.16-2.77). The cumulative incidence of bleeding was 10.2% in cases versus 4.97%, HR 2.24 (95% CI 1.10-4.58). No major bleedings occurred in cases (versus 3 in controls). No significant differences regarding residual vein thrombosis and post-thrombotic syndrome. After anticoagulant discontinuation, DOACs yielded a significantly lower 2-year VTE recurrence risk versus traditional anticoagulants (HR, 0.61 [95% CI, 0.47-0.82]). Conclusions DOACs and heparin/vitamin K antagonists showed a similar efficacy in treating VTE in patients with thrombophilia. Although major bleeding episodes were recorded solely with heparin/vitamin K antagonists, we noted an overall increased bleeding rate with DOACs. The use of DOACs was associated with a lower 2-year risk of VTE recurrence after anticoagulant discontinuation.

322§
Avruscio G, Camporese G, Campello E, Bernardi E, Persona P, Passarella C, Noventa F, Cola M, Navalesi P, Cattelan A, Tiberio I, Boscolo A, Spiezia L, Simioni P;
COVID-VTE Study Group.

COVID-19 and Venous Thromboembolism in Intensive Care or Medical Ward.
(2020) Clin Transl Sci. Nov;13:1108-1114.

DOI: 10.1111/cts.12907
PMID: 32989908

Abstract
Despite thromboprophylaxis, patients with coronavirus disease 2019 (COVID-19) exhibit hypercoagulability and higher venous thromboembolic risk, although its real incidence is still unknown. The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with COVID-19 admitted to both intensive care units (ICUs) and medical wards (MWs). Consecutive patients admitted for COVID-19 to the MW and the ICU at Padua University Hospital, all receiving thromboprophylaxis, underwent systematic ultrasonography of the internal jugular, and the upper and lower limbs veins every 7 days (± 1 day) after the admission; and, if negative, once-weekly until discharge or death. In case of suspected pulmonary embolism, a multidetector computed tomographic angiography was performed. The primary outcome was the proportion of any deep-vein thrombosis (DVT) and symptomatic pulmonary embolism in both groups. An extended blood coagulative test was performed as well. From March 4 to April 30, 2020, a total of 85 patients were investigated, 44 (52%) in MWs and 41 (48%) in the ICU. Despite thromboprophylaxis, VTE occurred in 12 patients in the MWs (27.3%) and 31 patients in the ICU (75.6%) with an odds ratio of 9.3 (95% confidence interval (CI) 3.5-24.5; P < 0.001). Multiple-site DVT occurred in 55.6% of patients (95% CI 39.6-70.5). Increased D-dimer levels significantly correlated with VTE (P = 0.001) and death (P = 0.015). Summarizing, patients with COVID-19 admitted to the MW or ICU showed a high frequency of venous thromboembolism, despite standard-dose or high-dose thromboprophylaxis. Whether thrombosis, particularly asymptomatic events, may play a role in the morbidity and mortality of patients with COVID-19 remain to be clarified.

321§
Felice C, Nardin C, Di Tanna GL, Grossi U, Bernardi E, Scaldaferri L, Romagnoli M, Tonon L, Cavasin P, Novello S, Scarpa R, Farnia A, De Menis E, Rigoli R, Cinetto F, Pauletto P, Agostini C, Rattazzi M.

Use of RAAS Inhibitors and Risk of Clinical Deterioration in COVID-19: Results From an Italian Cohort of 133 Hypertensives.
(2020) Am J Hypertens. Oct 21;33(10):944-948.

DOI: 10.1093/ajh/hpaa096
PMID: 32511678

Abstract
BACKGROUND: The effect of chronic use of renin-angiotensin-aldosterone system (RAAS) inhibitors on the severity of COVID-19 infection is still unclear in patients with hypertension. We aimed to investigate the association between chronic use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and COVID-19-related outcomes in hypertensive patients. METHODS: A single-center study was conducted on 133 consecutive hypertensive subjects presenting to the emergency department with acute respiratory symptoms and/or fever who were diagnosed with COVID-19 infection between 9 and 31 March 2020. RESULTS: All patients were grouped according to their chronic antihypertensive medications (ACEIs, N = 40; ARBs, N = 42; not on RAAS inhibitors, N = 51). There was no statistical difference between ACEIs and ARBs groups in terms of hospital admission rate, oxygen therapy, and need for noninvasive ventilation. Patients chronically treated with RAAS inhibitors showed a significantly lower rate of admission to semi-intensive/intensive care units, when compared with the non-RAAS population (odds ratio (OR) 0.25, confidence interval (CI) 95% 0.09-0.66, P = 0.006). Similarly, the risk of mortality was lower in the former group, although not reaching statistical significance (OR 0.56, CI 95% 0.17-1.83, P = 0.341). CONCLUSIONS: Our data suggest that chronic use of RAAS inhibitors does not negatively affect clinical course of COVID-19 in hypertensive patients. Further studies are needed to confirm this finding and determine whether RAAS inhibitors may have a protective effect on COVID-19-related morbidity and mortality.


320§
Jara-Palomares L(1), Alfonso M(2), Maestre A(3), Jimenez D(4), Garcia-Bragado F(5), Font C(6), Reyes RL(7), Blasco LH(8), Vidal G(9), Otero R(10), Monreal M(11); RIETE investigators.

Comparison of seven prognostic tools to identify low-risk pulmonary embolism in patients aged <50 years.
(2019) Sci Rep. Dec 27;9(1):20064.

DOI: 10.1038/s41598-019-55213-8
PMID: 31882805

Abstract
In young patients with acute pulmonary embolism (PE), the predictive value of currently available prognostic tools has not been evaluated. Our objective was to compare prognostic value of 7 available tools (GPS, PESI, sPESI, Prognostic Algorithm, PREP, shock index and RIETE) in patients aged <50 years. We used the RIETE database, including PE patients from 2001 to 2017. The major outcome was 30-day all-cause mortality. Of 34,651 patients with acute PE, 5,822 (17%) were aged <50 years. Of these, 83 (1.4%) died during the first 30 days. Number of patients deemed low risk with tools was: PREP (95.9%), GPS (89.6%), PESI (87.2%), Shock index (70.9%), sPESI (59.4%), Prognostic algorithm (58%) and RIETE score (48.6%). The tools with a highest sensitivity were: Prognostic Algorithm (91.6%; 95% CI: 85.6-97.5), RIETE score (90.4%; 95%CI: 84.0-96.7) and sPESI (88%; 95% CI: 81-95). The RIETE, Prognostic Algorithm and sPESI scores obtained the highest overall sensitivity estimates for also predicting 7- and 90-day all-cause mortality, 30-day PE-related mortality, 30-day major bleeding and 30-day VTE recurrences. The proportion of low-risk patients who died within the first 30 days was lowest using the Prognostic Algorithm (0.2%), RIETE (0.3%) or sPESI (0.3%) scores. In PE patients less 50 years, 30-day mortality was low. Although sPESI, RIETE and Prognostic Algorithm scores were the most sensitive tools to identify patients at low risk to die, other tools should be evaluated in this population to obtain more efficient results.

319§
G. Camporese, D. Bernardi, E. Bernardi, G.P. Avruscio, F. Marchini, L. Bonfante, L. Furian, F. Neri, S. Villalta, F. Fabris, P. Simioni, M.T. Sartori

Absence of interaction between rivaroxaban, tacrolimus and everolimus in renal transplant recipients with deep vein thrombosis or atrial fibrillation
(2020) Vascular Pharmacology, Jul;130:106682
DOI: 10.1016/j.vph.2020.106682
PMID: 32438078
Abstract
No data are available on rivaroxaban use in renal transplant recipients and on its surmised interaction with immunosuppressants. The aim was to investigate potential interactions between rivaroxaban and im- munosuppressants in this setting. Renal transplant recipients with a stable renal function treated with rivar- oxaban and tacrolimus with or without everolimus were investigated. All drugs and creatinine concentrations were determined daily for 2 weeks after the start of anticoagulation. Blood samples were drawn at 8.00 am and 3–4 h later for trough and peak concentrations, respectively. Bleeding and thrombotic events were recorded during a minimum follow-up of 6 months. In 8 renal transplant patients, rivaroxaban levels showed a predictable pharmacokinetic trend, both at Ctrough (30–61 μg/L) and at Cpeak (143–449 μg/L), with limited variability in the 25th–75th percentile range. Tacrolimus (Ctrough 3–13 μg/L; Cpeak 3–16 μg/L), everolimus (Ctrough 3–11 μg/L; Cpeak 5–17 μg/L) and creatinine concentrations were stable as well. Immunosuppressors variability before and after rivaroxaban were 30% and 30% for tacrolimus, 27% and 29% for everolimus, respectively, as well as 14% and 3% for creatinine. For rivaroxaban monitoring, the reference change value better performed in identifying significant variations of its concentration. No patient had bleeding or thrombotic events, worsening of renal graft function, and signs of immunosuppressants toxicity during a mean follow-up of 23 (9–28) months. In conclusion, rivaroxaban does not seem to interact with tacrolimus and everolimus in renal transplant recipients. Both an- ticoagulant and immunosuppressive effects seem warranted, without major bleeding complications and effect on the graft function.


318§
Prandoni, P., Ageno, W., Ciammaichella, M., Mumoli, N., Zanatta, N., Imberti, D., Visonà, A., Bucherini, E., Di Nisio, M., Noventa, F., Maida, R., Mazzi, V., Del Ghianda, S., Rotiroti, G., Benedetti, R., Zalunardo, B., Pires, J.M., For the DOAC-PTS Investigators

The risk of post-thrombotic syndrome in patients with proximal deep vein thrombosis treated with the direct oral anticoagulants
(2020) Internal and Emergency Medicine, 15 (3), pp. 447-452.

PubMed ID: 31667697
DOI: 10.1007/s11739-019-02215-z

Abstract
The novel direct oral anticoagulants (DOAC) have been shown to be at least as effective as and safer than conventional anticoagulants for the initial and long-term treatment of venous thromboembolic disorders. However, the rate of post-thrombotic syndrome (PTS) in patients with deep-vein thrombosis (DVT) treated with the DOACs is unknown. With the adoption of the Villalta scale, we assessed the rate of PTS at the end of the follow-up period in a consecutive series of 309 outpatients with acute proximal DVT who had received at least 3 months of treatment with a DOAC and had been followed-up for up to 3 years. The rate of PTS development was compared with that recorded in a historical cohort of 1036 consecutive patients who had been treated with vitamin K antagonists (VKA) and had received a similar follow-up examination. Logistic regression analysis, including propensity scoring to adjust for differing probabilities of undergoing VKA/DOAC, was used to identify predictors of PTS. PTS developed in 87 patients (28.2%) treated with the DOACs (severe in 12), and in 443 patients (42.8%) treated with VKAs (severe in 61). After adjusting for estimated propensity score, age, gender, concomitant symptoms of pulmonary embolism, duration of anticoagulation and development of residual vein thrombosis, the risk of PTS in the DOAC-treated patients was reduced by 54% in comparison to patients treated with conventional anticoagulation (odds ratio 0.46; 95% CI 0.33 to 0.63). We conclude that in comparison to VKAs, the use of the direct oral anticoagulants has the potential to offer a more favorable prognosis in terms of PTS development.


317§
Soria, A., Fava, M., Bernasconi, D.P., Lapadula, G., Colella, E., Valsecchi, M.G., Migliorino, G.M., D'Ambrosio, R., Landonio, S., Schiavini, M., Spinetti, A., Carriero, C., Degasperi, E., Cologni, G., Gatti, F., Viganò, P., Hasson, H., Uberti-Foppa, C., Pasulo, L., Baiguera, C., Rossotti, R., Vinci, M., Puoti, M., Giorgini, A., Menzaghi, B., Lombardi, A., Pan, A., Aghemo, A., Grossi, P.A., Boldizzoni, R., Colombo, S., Viganò, M., Rumi, M.G., Del Poggio, P., Valenti, L., Giglio, O., De Bona, A., d'Arminio Monforte, A., Colombo, A., Spinelli, O., Pigozzi, M.G., Molteni, C., Bonfanti, P., Terreni, N., Perini, P., Capretti, A., Bella, D., Liani, C., Polo, S., Aimo, G., Pagnucco, L., Bhoori, S., Centenaro, R., Graffeo, M., Ciaccio, A., Dionigi, E., Lazzaroni, S., Carderi, I., Di Marco, M., Rizzardini, G., Noventa, F., Lampertico, P., Fagiuoli, S.

Comparison of three therapeutic regimens for genotype-3 hepatitis C virus infection in a large real-life multicentre cohort
(2020) Liver International, 40 (4), pp. 769-777.

PubMed ID: 31970845
DOI: 10.1111/liv.14386

Abstract
Background & Aims: In the direct-acting antiviral era, treatment of genotype-3 HCV (HCV-GT3) is still challenging. Real-life comparisons between recommended regimens, sofosbuvir (SOF)+daclatasvir (DAC), SOF/velpatasvir (VEL), glecaprevir/pibrentasvir (GLE/PIB), are scarce. We aimed at filling this data gap. Methods: Sustained virological response 12 weeks after treatment completion (SVR12) was assessed for all HCV-GT3 patients consecutively treated within the Lombardia web-based Navigatore HCV-Network; differences in SVR12 across regimens were evaluated by logistic regression. Results: Of the 2082 subjects with HCV-GT3, 1544 were evaluable for comparisons between regimens: SOF + DAC (1023, 66.2%), SOF/VEL (369, 23.9%), GLE/PIB (152, 9.8%). Patients treated with former regimens were more frequently male, cirrhotic, HIV-positive, pretreated, used ribavirin in their regimen, and had lower baseline HCV-RNA. SVR12 was similar across groups: 94.8% in SOF + DAC, 97.6% in SOF/VEL, 96.7% in GLE/PIB (P =.065). At univariate analysis, SVR12 was associated with female gender (97.9% vs 94.8%, P =.007) and lower median pretreatment Log10HCV-RNA (5.87 vs 6.20, P =.001). At multivariate logistic regression analysis, treatment with SOF/VEL was associated with a higher likelihood of SVR12 than SOF + DAC, but only in the absence of ribavirin (98% vs 90.3%). Female gender and lower pretreatment HCV-RNA were independently associated with SVR12. Conclusions: In a large real-life setting of HCV-GT3-infected patients with a high proportion of cirrhosis, the success rate was remarkable. The slight advantage of SOF/VEL on SOF + DAC was significant only without ribavirin. The current prescription shift towards novel regimens (ie SOF/VEL and GLE/PIB) in easier-to-treat patients allows ribavirin-free and shorter schedules without mining SVR12 in this difficult-to-treat genotype.


316§
D'Ambrosio, R., Pasulo, L., Giorgini, A., Spinetti, A., Messina, E., Fanetti, I., Puoti, M., Aghemo, A., Viganò, P., Vinci, M., Menzaghi, B., Lombardi, A., Pan, A., Pigozzi, M.G., Grossi, P., Lazzaroni, S., Spinelli, O., Invernizzi, P., Maggiolo, F., Terreni, N., Monforte, A.D., Poggio, P.D., Taddei, M.T., Colombo, S., Pozzoni, P., Molteni, C., Brocchieri, A., Bhoori, S., Buscarini, E., Centenaro, R., Mendeni, M., Colombo, A.E., Di Marco, M., Dionigi, E., Bella, D., Borghi, M., Zuin, M., Zaltron, S., Noventa, F., Annalisa, D.S., Lampertico, P., Fagiuoli, S.

Renal safety in 3264 HCV patients treated with DAA-based regimens: Results from a large Italian real-life study
(2020) Digestive and Liver Disease, 52 (2), pp. 190-198.

PubMed ID: 31813755
DOI: 10.1016/j.dld.2019.11.006

Abstract
Background: Sofosbuvir (SOF)-based regimens have been associated with renal function worsening in HCV patients with estimated glomerular filtration rate (eGFR) ≤ 45 ml/min, but further investigations are lacking. Aim: To assess renal safety in a large cohort of DAA-treated HCV patients with any chronic kidney disease (CKD). Methods: All HCV patients treated with DAA in Lombardy (December 2014–November 2017) with available kidney function tests during and off-treatment were included. Results: Among 3264 patients [65% males, 67% cirrhotic, eGFR 88 (9–264) ml/min], CKD stage was 3 in 9.5% and 4/5 in 0.7%. 79% and 73% patients received SOF and RBV, respectively. During DAA, eGFR declined in CKD-1 (p < 0.0001) and CKD-2 (p = 0.0002) patients, with corresponding rates of CKD stage reduction of 25% and 8%. Conversely, eGFR improved in lower CKD stages (p < 0.0001 in CKD-3a, p = 0.0007 in CKD-3b, p = 0.024 in CKD-4/5), with 33–45% rates of CKD improvement. Changes in eGFR and CKD distribution persisted at SVR. Baseline independent predictors of CKD worsening at EOT and SVR were age (p < 0.0001), higher baseline CKD stages (p < 0.0001) and AH (p = 0.010 and p < 0.0001, respectively). Conclusions: During DAA, eGFR significantly declined in patients with preserved renal function and improved in those with lower CKD stages, without reverting upon drug discontinuation.


315§
Becattini, C., Pace, U., Rondelli, F., Delrio, P., Ceccarelli, G., Boncompagni, M., Graziosi, L., Visonà, A., Chiari, D., Avruscio, G., Frasson, S., Gussoni, G., Biancafarina, A., Camporese, G., Donini, A., Bucci, A.F., Agnelli, G.

Rivaroxaban for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer. Design of the PRO-LAPS II STUDY
(2020) European Journal of Internal Medicine, 72, pp. 53-59.

PubMed ID: 31818628
DOI: 10.1016/j.ejim.2019.11.015

Abstract
Background: The clinical benefit of extending prophylaxis for venous thromboembolism (VTE) beyond hospital discharge after laparoscopic surgery for cancer is undefined. Extended prophylaxis with rivaroxaban is effective in reducing post-operative VTE after major orthopedic surgery without safety concern. Methods: PROLAPS II is an investigator-initiated, randomized, double-blind study aimed at assessing the efficacy and safety of extended antithrombotic prophylaxis with rivaroxaban compared with placebo after laparoscopic surgery for colorectal cancer in patients who had received antithrombotic prophylaxis with low molecular-weight heparin for 7 ± 2 days (NCT03055026). Patients are randomized to receive rivaroxaban (10 mg once daily) or placebo for 3 weeks (up to day 28 ± 2 from surgery). The primary study outcome is a composite of symptomatic objectively confirmed VTE, asymptomatic ultrasonography-detected DVT or VTE-related death at 28 ± 2 days from laparoscopic surgery. The primary safety outcome is major bleeding defined according to the International Society of Thrombosis and Haemostasis. Symptomatic objectively confirmed VTE, asymptomatic ultrasonography-detected DVT, major bleeding or death by day 28 ± 2 and by day 90 from surgery are secondary outcomes. Assuming an 8% event rate with placebo and 60% reduction in the primary study outcome with rivaroxaban, 323 patients per group are necessary to show a statistically significant difference between the study groups. Discussion: The PROLAPS II is the first study with an oral anti-Xa agent in cancer surgery. The study has the potential to improve clinical practice by answering the question on the clinical benefit of extending prophylaxis after laparoscopic surgery for colorectal cancer.


314§
Barco, S., Schmidtmann, I., Ageno, W., Bauersachs, R.M., Becattini, C., Bernardi, E., Beyer-Westendorf, J., Bonacchini, L., Brachmann, J., Christ, M., Czihal, M., Duerschmied, D., Empen, K., Espinola-Klein, C., Ficker, J.H., Fonseca, C., Genth-Zotz, S., Jiménez, D., Harjola, V.-P., Held, M., Prat, L.I., Lange, T.J., Manolis, A., Meyer, A., Mustonen, P., Rauch-Kroehnert, U., Ruiz-Artacho, P., Schellong, S., Schwaiblmair, M., Stahrenberg, R., Westerweel, P.E., Wild, P.S., Konstantinides, S.V., Lankeit, M., behalf of the HoT-PE Investigators

Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: An international multicentre single-arm clinical trial
(2020) European Heart Journal, 41 (4), pp. 509-518.

PubMed ID: 31120118
DOI: 10.1093/eurheartj/ehz367

Abstract
Aims: To investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban. Methods and results: We conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for >_3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of a = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%). Conclusion: Early discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE.


313§
Golemi, I., Cote, L., Iftikhar, O., Brenner, B., Tafur, A., Bikdeli, B., Fernández-Capitán, C., Pedrajas, J.M., Otero, R., Quintavalla, R., Monreal, M., Prandoni, P., Farge-Bancel, D., Barba, R., Di Micco, P., Bertoletti, L., Tzoran, I., Reis, A., Bounameaux, H., Malý, R., Verhamme, P., Bosevski, M., Caprini, J.A., Bui, H.M., Adarraga, M.D., Aibar, M.A., Aibar, J., Amado, C., Arcelus, J.I., Azcarate, P.M., Ballaz, A., Barba, R., Barrón, M., Barrón-Andrés, B., Bascuñana, J., Blanco-Molina, A., Camon, A.M., Carrasco, C., Castro, J., de Ancos, C., del Toro, J., Demelo, P., Díaz-Pedroche, M.C., Díaz-Peromingo, J.A., Díaz-Simón, R., Encabo, M., Falgá, C., Farfán, A.I., Fernández-Capitán, C., Fernández-Criado, M.C., Fidalgo, M.A., Font, C., Font, L., García, M.A., García-Bragado, F., García-Morillo, M., García-Raso, A., Gavín, O., Gaya, I., Gayol, M.C., Gil-Díaz, A., Guirado, L., Gómez, V., González-Martínez, J., Grau, E., Gutiérrez, J., Hernández Blasco, L.M., Iglesias, M., Jara-Palomares, L., Jaras, M.J., Jiménez, D., Jou, I., Joya, M.D., Lalueza, A., Lima, J., Llamas, P., Lobo, J.L., López-Jiménez, L., López-Miguel, P., López-Nuñez, J.J., López-Reyes, R., López-Sáez, J.B., Lorente, M.A., Lorenzo, A., Loring, M., Lumbierres, M., Madridano, O., Maestre, A., Marchena, P.J., Martín-Guerra, J.M., Martín Fernández, M., Mellado, M., Monreal, M., Morales, M.V., Nieto, J.A., Núñez, M.J., Olivares, M.C., Otalora, S., Otero, R., Pedrajas, J.M., Pellejero, G., Pérez-Pinar, M., Pérez-Rus, G., Peris, M.L., Pesce, M.L., Porras, J.A., Rivas, A., Rodríguez-Dávila, M.A., Rodríguez-Fernández, L., Rodríguez-Hernández, A., Rodríguez-Martín, C., Rubio, C.M., Ruiz-Alcaraz, S., Ruiz-Artacho, P., Ruiz-Ruiz, J., Ruiz-Sada, P., Sahuquillo, J.C., Salazar, V., Sampériz, A., Sánchez-Muñoz-Torrero, J.F., Sancho, T., Sanoja, I., Soler, S., Soto, M.J., Suriñach, J.M., Tolosa, C., Torres, M.I., Trujillo-Santos, J., Uresandi, F., Usandizaga, E., Valle, R., Vidal, G., Gutiérrez, P., Vázquez, F.J., Vilaseca, A., Vanassche, T., Vandenbriele, C., Verhamme, P., Hirmerova, J., Malý, R., Salgado, E., Benzidia, I., Bertoletti, L., Bura-Riviere, A., Debourdeau, P., Falvo, N., Farge-Bancel, D., Hij, A., Mahé, I., Moustafa, F., Braester, A., Brenner, B., Ellis, M., Tzoran, I., Barillari, G., Bilora, F., Bortoluzzi, C., Brandolin, B., Bucherini, E., Ciammaichella, M., Dentali, F., Di Micco, P., Grandone, E., Imbalzano, E., Lessiani, G., Maida, R., Mastroiacovo, D., Mumoli, N., Vo Hong, N., Pace, F., Parisi, R., Pesavento, R., Pinelli, M., Prandoni, P., Quintavalla, R., Rocci, A., Siniscalchi, C., Tufano, A., Visonà, A., Skride, A., Sablinskis, K., Sablinskis, M., Bosevski, M., Zdraveska, M., Bounameaux, H., Fresa, M., Ney, B., Mazzolai, L., Caprini, J., Tafur, A., Bui, H.M., Registro Informatizado de Enfermedad Tromboembolica Investigators

Incidence of major adverse cardiovascular events among patients with provoked and unprovoked venous thromboembolism: Findings from the Registro Informatizado de Enfermedad Tromboembólica Registry
(2020) Journal of Vascular Surgery: Venous and Lymphatic Disorders, 8 (3), pp. 353-359.e1.

PubMed ID: 31784355
DOI: 10.1016/j.jvsv.2019.03.011

Abstract
Objective: Overlap exists between the risk factors for coronary artery disease and venous thromboembolism (VTE). However, a paucity of data is available on the incidence of major acute cardiovascular events (MACE) and major adverse limb events (MALE) among patients presenting with VTE. Moreover, it is unknown whether the rate of cardiovascular outcomes differs among patients with unprovoked vs provoked VTE. Methods: We analyzed the data from 2009 to 2017 in the Registro Informatizado de Enfermedad Tromboembólica registry, an ongoing, multicenter, international registry of consecutive patients with a diagnosis of objectively confirmed VTE. The query was restricted it to patients with data entry for the arterial outcomes. The baseline prevalence of coronary artery disease risk factors was compared between patients with provoked (ie, immobility, cancer, surgery, travel >6 hours, hormonal causes) and unprovoked VTE. After the initial VTE event, we followed up patients for the composite primary outcome of incident MACE (ie, stroke, myocardial infarction, unstable angina) and/or MALE (ie, major limb events). We used the χ2 test for baseline associations and a Cox proportional hazard for multivariate analysis. We used IBM SPSS, version 24 (IBM Corp, Armonk, NY) for statistical analysis. A P value of <.05 was considered statistically significant. Results: We analyzed the data from 41,259 patients with VTE, of whom 22,633 (55.6%) had experienced a provoked VTE. During follow-up, the patients with provoked VTE were more likely to develop MACE or MALE than were patients with unprovoked VTE (hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.1-1.5). The association of arterial events with recent immobility (HR, 1.4; 95% CI, 1.5-12.1) and cancer (HR, 1.7; 95% CI, 1.4-1.9) was strong. After adjusting for multiple conventional cardiovascular risk factors, provoked VTE, compared with unprovoked VTE, was significantly associated with an increased hazard for MACE (HR, 1.4; 95% CI, 1.1-1.7). Cancer remained a significant adjusted predictor for both MACE (HR, 1.7; 95% CI, 1.4-2.1) and MALE (HR, 2.1; 95% CI 1.01-4.6) in those with provoked VTE. Conclusions: Among patients with VTE, provoked cases, specifically those with cancer-associated VTE, have an increased risk of major arterial events.


312§
Barillari, G., Bortoluzzi, C., Giorgi, M., Orabona, R., Pacetti, E., Sciatti, E., Zaffaroni, M., Dentali, F.

Management of antithrombotic therapy in gray areas of venous thromboembolism: a Delphi consensus panel
Intern Emerg Med. 2020 Oct;15(7):1255-1264.
DOI: 10.1007/s11739-020-02300-8
PMID: 32232785

Abstract
For some years now, direct-acting oral anticoagulants (DOACs) have entered the clinical practice for stroke prevention in non-valvular atrial fibrillation (NVAF) or for prevention and treatment of venous thromboembolism (VTE). However, there is uncertainty on DOACs’ use in some clinical scenarios that are not fully explored by clinical trials, but commonly encountered in the real world. We report a Delphi Consensus on DOAC use in VTE patients. The consensus dealt with seven main topics: (1) clinical superiority of DOACs compared to VKAs; (2) therapeutic options for patients with intermediate risk PE; (3) therapeutic management of patients with deep vein thrombosis (DVT); (4) DOACs’ role in oncological patients with VTE; (5) role of the reversal agent; (6) safety of low doses of DOACs in VTE patients; (7) DOACs long-term therapy (more than 12 months) in VTE patients; Forty-six physicians (cardiologists, internists, angiologists, oncologists, hematologists, and geriatricians) from Italy expressed their level of agreement on each statement by using a five-point Likert scale (1: strongly disagree, 2: disagree, 3: somewhat agree, 4: agree, 5: strongly agree). Votes 1–2 were considered as disagreement, while votes 3–5 as agreement. For each statement an agreement of ≥ 66% among the respondents was considered consensus. A brief discussion about the results for each topic is also reported.


311§
Avnery, O., Martin, M., Bura-Riviere, A., Barillari, G., Mazzolai, L., Mahé, I., Marchena, P.J., Verhamme, P., Monreal, M., Ellis, M.H., Adarraga, M.D., Aibar, M.A., Aibar, J., Amado, C., Arcelus, J.I., Ballaz, A., Barba, R., Barrón, M., Barrón-Andrés, B., Bascuñana, J., ina, A., Camon, A.M., Cañas, I., Carrasco, C., Castro, J., de Ancos, C., del Toro, J., Demelo, P., Díaz-Peromingo, J.A., Falgá, C., Farfán, A.I., Fernández-Capitán, C., Fernández-Criado, M.C., Fernández-Núñez, S., Fidalgo, M.A., Font, C., Font, L., Freire, M., Gallego, M., García, M.A., García-Bragado, F., García-Morillo, M., García-Raso, A., Gavín, O., Gayol, M.C., Gil-Díaz, A., Gómez, V., Gómez-Cuervo, C., González-Martínez, J., Grau, E., Gutiérrez, J., Hernández-Blasco, L.M., Iglesias, M., Jara-Palomares, L., Jaras, M.J., Jiménez, R., Jiménez-Castro, D., Jiménez-López, J., Joya, M.D., Lima, J., Llamas, P., Lobo, J.L., López-Jiménez, L., López-Miguel, P., López-Núñez, J.J., López-Reyes, R., López-Sáez, J.B., Lorente, M.A., Lorenzo, A., Loring, M., Madridano, O., Maestre, A., Martín del Pozo, M., Martín-Guerra, J.M., Martín-Romero, M., Mellado, M., Morales, M.V., Muñoz, N., Nieto-Cabrera, M.A., Nieto-Rodríguez, J.A., Núñez-Ares, A., Núñez, M.J., Olivares, M.C., Otalora, S., Otero, R., Pedrajas, J.M., Pellejero, G., Pérez-Rus, G., Peris, M.L., Porras, J.A., Rivas, A., Rodríguez-Dávila, M.A., Rodríguez-Hernández, A., Rubio, C.M., Ruiz-Artacho, P., Ruiz-Ruiz, J., Ruiz-Torregrosa, P., Ruiz-Sada, P., Sahuquillo, J.C., Salazar, V., Sampériz, A., Sánchez-Muñoz-Torrero, J.F., Sancho, T., Soler, S., Sopeña, B., Suriñach, J.M., Tolosa, C., Torres, M.I., Trujillo-Santos, J., Uresandi, F., Valle, R., Vidal, G., Villares, P., Gutiérrez, P., Vázquez, F.J., Vilaseca, A., Vanassche, T., Vandenbriele, C., Hirmerova, J., Malý, R., Salgado, E., Benzidia, I., Bertoletti, L., Debourdeau, P., Farge-Bancel, D., Hij, A., Moustafa, F., Schellong, S., Braester, A., Brenner, B., Tzoran, I., Sharif-Kashani, B., Bilora, F., Bortoluzzi, C., Bucherini, E., Ciammaichella, M., Dentali, F., Di Micco, P., Di Pangrazio, M., Maida, R., Mastroiacovo, D., Pace, F., Pallotti, G., Parisi, R., Pesavento, R., Prandoni, P., Quintavalla, R., Rocci, A., Siniscalchi, C., Tufano, A., Visonà, A., Vo Hong, N., Gibietis, V., Skride, A., Strautmane, S., Bosevski, M., Zdraveska, M., Bounameaux, H., Fresa, M., Ney, B., Caprini, J., Bui, H.M., Pham, K.Q., the RIETE Investigators

D-dimer levels and risk of recurrence following provoked venous thromboembolism: findings from the RIETE registry
(2020) Journal of Internal Medicine, 287 (1), pp. 32-41.

PubMed ID: 31394000
DOI: 10.1111/joim.12969

Abstract
Background: Patients with venous thromboembolism (VTE) secondary to transient risk factors may develop VTE recurrences after discontinuing anticoagulation. Identifying at-risk patients could help to guide the duration of therapy. Methods: We used the RIETE database to assess the prognostic value of d-dimer testing after discontinuing anticoagulation to identify patients at increased risk for recurrences. Transient risk factors were classified as major (postoperative) or minor (pregnancy, oestrogen use, immobilization or recent travel). Results: In December 2018, 1655 VTE patients with transient risk factors (major 460, minor 1195) underwent d-dimer measurements after discontinuing anticoagulation. Amongst patients with major risk factors, the recurrence rate was 5.74 (95% CI: 3.19–9.57) events per 100 patient-years in those with raised d-dimer levels and 2.68 (95% CI: 1.45–4.56) in those with normal levels. Amongst patients with minor risk factors, the rates were 7.79 (95% CI: 5.71–10.4) and 3.34 (95% CI: 2.39–4.53), respectively. Patients with major risk factors and raised d-dimer levels (n = 171) had a nonsignificantly higher rate of recurrences (hazard ratio [HR]: 2.14; 95% CI: 0.96–4.79) than those with normal levels. Patients with minor risk factors and raised d-dimer levels (n = 382) had a higher rate of recurrences (HR: 2.34; 95% CI: 1.51–3.63) than those with normal levels. On multivariate analysis, raised d-dimers (HR: 1.74; 95% CI: 1.09–2.77) were associated with an increased risk for recurrences in patients with minor risk factors, not in those with major risk factors. Conclusions: Patients with raised d-dimer levels after discontinuing anticoagulant therapy for VTE provoked by a minor transient risk factor were at an increased risk for recurrences


310§
Fuentes HE(1), Tafur AJ(2)(3), Caprini JA(3)(4), Alatri A(5), Trujillo-Santos J(6), Farge-Bancel D(7), Rosa V(8), Font L(9), Vilaseca A(10), Monreal M(11); RIETE Investigators.

Prediction of early mortality in patients with cancer-associated thrombosis in the RIETE Database.
Int Angiol. 2019 Jun;38(3):173-184.

DOI: 10.23736/S0392-9590.19.04110-5
PMID: 31112023

Abstract
BACKGROUND: Proper risk stratification of patients for early mortality after cancer-associated thrombosis may lead to personalized anticoagulation protocols. Therefore, we aimed to derive and validate a scoring system to predict early mortality in this population. To this end, we selected patients with active cancer and thrombosis from the Computerized Registry of Patients with Venous Thromboembolism database. METHODS: The main outcome was all cause mortality within the month following a thrombotic event. We used a simple random selection to split are data in a derivation and a validation cohort. In the derivation cohort, we used recursive partitioning and binary logistic regression to identify groups at risk and to determine the likelihood of the primary outcome. The risk score was developed based on odds ratios from the final multivariate model, and then tested in the validation cohort. RESULTS: In 10,025 eligible patients, we identified 6 predictors of 30-day mortality: leukocytosis ≥11.5x109/L; platelet count ≤160x109/L, metastasis, recent immobility, initial presentation as pulmonary embolism and Body Mass Index <18.5. The model divided the population into 3 risk categories: low (score 0-3), moderate (score 4-6), and high (score ≥7). The AUC for the overall score was 0.74, and using a cutoff ≥7 points, the model had a negative predictive value of 94.4%, a positive predictive value of 23.1%, a sensitivity of 73.3%, and a specificity of 64.6% in the validation cohort. CONCLUSIONS: Our validated risk model may assist physicians in the selection of patients for outpatient management, and perhaps anticoagulant, considering expanding anticoagulation options.


309§
Degasperi, E., Spinetti, A., Lombardi, A., Landonio, S., Rossi, M.C., Pasulo, L., Pozzoni, P., Giorgini, A., Fabris, P., Romano, A., Lomonaco, L., Puoti, M., Vinci, M., Gatti, F., Carolo, G., Zoncada, A., Bonfanti, P., Russo, F.P., Aghemo, A., Soria, A., Centenaro, R., Maggiolo, F., Rovere, P., Pasin, F., Paon, V., Faggiano, G., Vario, A., Grossi, G., Soffredini, R., Carriero, C., Paolucci, S., Noventa, F., Alberti, A., Lampertico, P., Fagiuoli, S.

Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure
(2019) Journal of Hepatology, 71 (6), pp. 1106-1115.

PubMed ID: 31433303
DOI: 10.1016/j.jhep.2019.07.020

Abstract
Background & Aims: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. Methods: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. Results: A total of 179 patients were included: median age 57 (18–88) years, 74% males, median HCV-RNA 1,081,817 (482–25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). Conclusions: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. Lay summary: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.


308§
Prandoni, P., Lensing, A.W.A., Prins, M.H., Villalta, S., Noventa, F.

Determinants of severe post-thrombotic syndrome: The role of thrombus location
(2019) Thrombosis Research, 178, pp. 171-172.

PubMed ID: 31035098
DOI: 10.1016/j.thromres.2019.04.001


307§
D'Ambrosio, R., Pasulo, L., Puoti, M., Vinci, M., Schiavini, M., Lazzaroni, S., Soria, A., Gatti, F., Menzaghi, B., Aghemo, A., Capelli, F., Rumi, M.G., Morini, L., Giorgini, A., Pigozzi, M.G., Rossini, A., Maggiolo, F., Pan, A., Memoli, M., Spinelli, O., Del Poggio, P., Saladino, V., Spinetti, A., De Bona, A., Capretti, A., Uberti-Foppa, C., Bonfanti, P., Terreni, N., Menozzi, F., Colombo, A.E., Giglio, O., Centenaro, R., Borghi, M., Baiguera, C., Picciotto, V., Landonio, S., Gori, A., Magnani, C., Noventa, F., Paolucci, S., Lampertico, P., Fagiuoli, S.

Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C
(2019) Journal of Hepatology, 70 (3), pp. 379-387.

PubMed ID: 30472321
DOI: 10.1016/j.jhep.2018.11.011

Abstract
Background and Aims: The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting. Methods: All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment. Results: A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m 2 , and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x10 3 /mm 3 and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes. Conclusions: In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks. Lay summary: A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles.


306§
Pastore, G., Maines, M., Marcantoni, L., Lanza, D., Zanon, F., Noventa, F., Corbucci, G., Rigatelli, G., Baracca, E., Zuin, M., Picariello, C., Carraro, M., Conte, L., Roncon, L., Barold, S.S.

The QR-max index, a novel electrocardiographic index for the determination of left ventricular conduction delay and selection of cardiac resynchronization in patients with non-left bundle branch block
(2019) Journal of Interventional Cardiac Electrophysiology.

PubMed ID: 31807986
DOI: 10.1007/s10840-019-00671-3

Abstract
Non-left bundle branch block (non-LBBB) remains an uncertain indication for cardiac resynchronization therapy (CRT). Non-LBBB includes right bundle branch block (RBBB) and non-specific LV conduction delay (NSCD), two different electrocardiogram (ECG) patterns which are not generally considered to be associated with LV conduction delay as judged by the invasive assessment of the Q-LV interval. We evaluated whether a novel ECG interval (QR-max index) correlated with the degree of LV conduction delay regardless of the type of non-LBBB ECG pattern, and could, therefore, predict CRT response. In 173 non-LBBB patients on CRT (92 NSCD, 81 RBBB), the QR-max index was measured as the maximum interval from QRS onset to R-wave offset in the limb leads. The correlation between QR-max index and Q-LV interval and the impact of the QR-max index on time to first heart failure hospitalization during 3-year follow-up were assessed. Q-LV correlated better with the QR-max index than with QRSd, particularly in the RBBB group (r = 0.91; p < 0.001 vs. r = 0.19; p < 0.089), while the correlations were r = 0.79 (p < 0.01) and r = 0.68 (p < 0.01), respectively, in the NSCD group. In both groups, the QR-max index was significantly more able than QRSd to identify CRT responders (AUC 0.825 vs. 0.576; p = 0.0008 in RBBB; AUC 0.738 vs. 0.701; p = 0.459 in NSCD). A QR-max index exceeding a cutoff value of 120 ms was associated with CRT response, with predictive values of 86.8 and 81.4% in RBBB and NSCD, respectively. The QR-max index reflects the degree of LV electrical delay regardless of QRS duration in RBBB and NSCD patients and is a useful indicator of suitability for CRT in non-LBBB patients.


305§
Aloi, T.L., Camporese, G., Izzo, M., Kontothanassis, D., Santoliquido, A.

Refining diagnosis and management of chronic venous disease: Outcomes of a modified Delphi consensus process
(2019) European Journal of Internal Medicine, 65, pp. 78-85.

PubMed ID: 30898385
DOI: 10.1016/j.ejim.2019.03.005

Abstract
Chronic venous disease (CVD) is a common condition with major health consequences that is associated with poor long-term prognosis, significant socioeconomic impact, disabling symptoms and reduced quality of life. To provide practical guidance for diagnosis and management of CVD, a Delphi panel of 5 experts in steering committee and 28 angiologists/vascular surgeons met with the major aim of providing a supplement for established national and international guidelines. A total of 24 statements were voted upon in two rounds, of which consensus was reached on 22 statements, indicating a high level of overall agreement. Consensus was reached on 7 of 8 statements relative to diagnosis (CEAP classification, diagnostic tools, QoL assessment, diagnostic imaging) and on 15 of 16 statements on management (conservative treatments, compressive therapy, pharmacological therapy, surgical treatment). The results of the consensus reached are discussed herein from which it is clear that diagnostic and management approaches utilising personalised therapies tailored to the individual patient should be favoured. While it is clear that additional studies are needed on many aspects of diagnosis and management of CVD, the present Delphi survey provides some key recommendations for clinicians treating CVD that may be useful in daily practice.


304§
Riva, N., Righini, M., Camporese, G., Iotti, M., Bucherini, E., Kamphuisen, P.W., Verhamme, P., Douketis, J.D., Tonello, C., Prandoni, P., Ageno, W., PALLADIO Study Investigators

Accuracy of age-adjusted D-dimer to rule out deep vein thrombosis in the elderly
(2019) Thrombosis Research, 174, pp. 148-150.

PubMed ID: 30634165
DOI: 10.1016/j.thromres.2018.12.024


302§
Donà, M., Minotto, M., Bernardi, E., Saler, E., Verlato, N., da Porto, F.

Macro-modelling of combined in-plane and out-of-plane seismic response of thin strengthened masonry infills
(2019) COMPDYN Proceedings, 2, pp. 2449-2463.

Abstract
Some strengthening techniques, aimed to increase the infill Out-Of-Plane (OOP) resistance and its safety against OOP collapse, have been recently tested at the University of Padova. Based on this experimental work, a new infill macro-model consisting of two nonlinear fibre struts for each diagonal direction, able to predict the combined In-Plane/Out-Of-Plane (IP-OOP) seismic response of the panels, is proposed in this paper and calibrated on the above-mentioned experimental results for thin clay masonry panels strengthened by two external plaster layers, directly applied on the masonry surface, containing a biaxial basalt fibre grid. These macro-models were then used to carry-out parametric nonlinear static analyses on typical reinforced concrete infilled frames, designed both traditionally and seismically, with the aim of evaluating their lateral response both in the case of IP forces only (by assuming two force distributions applied to the frame) and in the case of IP-OOP combined forces (by applying OOP equivalent static forces to the panels). The main effects of the OOP forces are presented through pushover curves and drift profiles associated to the achievement of the various infill and frame limit states. Numerical results show the effectiveness of the infill strengthening in terms of improvement of the infills OOP performance and thus of the overall structural response.


302§
Jara-Palomares, L., Alfonso, M., Maestre, A., Jimenez, D., Garcia-Bragado, F., Font, C., Reyes, R.L., Blasco, L.H., Vidal, G., Otero, R., Monreal, M., Adarraga, M.ªD., Aibar, M.Á., Aibar, J., Amado, C., Arcelus, J.I., Ballaz, A., Barba, R., Barrón, M., Barrón-Andrés, B., Bascuñana, J., Blanco-Molina, Á., Camón, A.M., Cañas, I., Carrasco, C., Castro, J., de Ancos, C., Del Toro, J., Demelo, P., Díaz-Peromingo, J.A., Díaz-Simón, R., Falgá, C., Farfán, A.I., Fernández-Capitán, C., del Carmen Fernández-Criado, M., Fernández-Núñez, S., Fidalgo, Á., Font, L., García, M.A., García-Morillo, M., García-Raso, A., Gavín-Sebastián, O., del Carmen Gayol, M., Gil-Díaz, A., Gómez, V., Gómez-Cuervo, C., González-Martínez, J., Grau, E., Gutiérrez, J., Gutiérrez-González, S., Iglesias, M., Jaras, M.ªJ., Jou, I., Joya, M.D., Lalueza, A., Lima, J., Llamas, P., Lobo, J.L., López-Jiménez, L., López-Miguel, P., López-Núñez, J.J., López-Sáez, J.B., Lorente, M.A., Lorenzo, A., Loring, M., Madridano, O., Marchena, P.J., Martín, J.M., Mellado, M., Morales, M.ªV., Nieto, M.L., Nieto, J.A., Núñez, M.J., Olivares, M.C., Pedrajas, J.M., Pellejero, G., Pérez-Rus, G., Peris, M.ªL., Porras, J.A., Rivas, A., Rodríguez-Dávila, M.ªÁ., Adela Rodríguez-Hernández, A., Rubio, C.M., Ruiz-Artacho, P., Ruiz-Ruiz, J., Ruiz-Sada, P., Sahuquillo, J.C., Salazar, V., Sampériz, Á., Muñoz-Torrero, J.F.S., Sancho, T., Soler, S., Suriñach, J.M., Tapia, E., Tolosa, C., Torres, M.I., Trujillo-Santos, J., Uresandi, F., Valle, R., Villares, P., Gutiérrez, P., Vázquez, F.J., Vilaseca, A., Vanassche, T., Vandenbriele, C., Verhamme, P., Hirmerova, J., Malý, R., Celis, G., del Pozo, G., Salgado, E., Benzidia, I., Bertoletti, L., Bura-Riviere, A., Debourdeau, P., Farge-Bancel, D., Hij, A., Mahé, I., Moustafa, F., Schellong, S., Braester, A., Brenner, B., Tzoran, I., Sharif-Kashani, B., Barillari, G., Bilora, F., Bortoluzzi, C., Brandolin, B., Bucherini, E., Ciammaichella, M., Dentali, F., Di Micco, P., Maida, R., Mastroiacovo, D., Mumoli, N., Pace, F., Parisi, R., Pesavento, R., Prandoni, P., Quintavalla, R., Rocci, A., Romualdi, R., Sinicalchi, C., Tufano, A., Visonà, A., Hong, N.V., Zalunardo, B., Gibietis, V., Kigitovica, D., Skride, A., Bosevski, M., Bounameaux, H., Mazzolai, L., Caprini, J.A., Bui, H.M., Pham, K.Q., Reis, A., The RIETE investigators
Comparison of seven prognostic tools to identify low-risk pulmonary embolism in patients aged <50 years
(2019) Scientific Reports, 9 (1), art. no. 20064.

PubMed ID: 31882805
DOI: 10.1038/s41598-019-55213-8

Abstract
In young patients with acute pulmonary embolism (PE), the predictive value of currently available prognostic tools has not been evaluated. Our objective was to compare prognostic value of 7 available tools (GPS, PESI, sPESI, Prognostic Algorithm, PREP, shock index and RIETE) in patients aged <50 years. We used the RIETE database, including PE patients from 2001 to 2017. The major outcome was 30-day all-cause mortality. Of 34,651 patients with acute PE, 5,822 (17%) were aged <50 years. Of these, 83 (1.4%) died during the first 30 days. Number of patients deemed low risk with tools was: PREP (95.9%), GPS (89.6%), PESI (87.2%), Shock index (70.9%), sPESI (59.4%), Prognostic algorithm (58%) and RIETE score (48.6%). The tools with a highest sensitivity were: Prognostic Algorithm (91.6%; 95% CI: 85.6–97.5), RIETE score (90.4%; 95%CI: 84.0–96.7) and sPESI (88%; 95% CI: 81–95). The RIETE, Prognostic Algorithm and sPESI scores obtained the highest overall sensitivity estimates for also predicting 7- and 90-day all-cause mortality, 30-day PE-related mortality, 30-day major bleeding and 30-day VTE recurrences. The proportion of low-risk patients who died within the first 30 days was lowest using the Prognostic Algorithm (0.2%), RIETE (0.3%) or sPESI (0.3%) scores. In PE patients less 50 years, 30-day mortality was low. Although sPESI, RIETE and Prognostic Algorithm scores were the most sensitive tools to identify patients at low risk to die, other tools should be evaluated in this population to obtain more efficient results.


301§
Riera-Mestre, A., Mora-Luján, J.M., Trujillo-Santos, J., Del Toro, J., Nieto, J.A., Pedrajas, J.M., López-Reyes, R., Soler, S., Ballaz, A., Cerdà, P., Monreal, M., Monreal, M., Prandoni, P., Brenner, B., Farge-Bancel, D., Barba, R., Di Micco, P., Bertoletti, L., Schellong, S., Tzoran, I., Reis, A., Bosevski, M., Bounameaux, H., Malý, R., Verhamme, P., Caprini, J.A., Bui, H.M., Adarraga, M.D., Agud, M., Aibar, M.A., Alcalde-Manero, M., Alfonso, J., Amado, C., Arcelus, J.I., Ballaz, A., Barba, R., Barbagelata, C., Barrón, M., Barrón-Andrés, B., Blanco-Molina, A., Camon, A.M., Cañas, I., Castro, J., Cerdà, P., De Miguel, J., Del Toro, J., Demelo, P., Díaz-Pedroche, C., Díaz-Peromingo, J.A., Domínguez, I.M., Escribano, J.C., Falgá, C., Fernández-Capitán, C., Fernández-Criado, M.C., Fidalgo, M.A., Flores, K., Font, C., Font, L., Furest, I., García, M.A., García-Bragado, F., García-Raso, A., Gavín-Blanco, O., Gavín-Sebastián, O., Gil-Díaz, A., Godoy-Díaz, D., Gómez, V., Gómez-Cuervo, C., González-Martínez, J., Grau, E., Guirado, L., Gutiérrez, J., Hernández-Blasco, L.M., Jara-Palomares, L., Jaras, M.J., Jiménez, D., Joya, M.D., Jou, I., Lalueza, A., Lecumberri, R., Lima, J., Llamas, P., Lobo, J.L., López-Jiménez, L., López-Meseguer, M., López-Miguel, P., López-Núñez, J.J., López-Reyes, R., López-Sáez, J.B., Lorente, M.A., Loring, M., Lumbierres, M., Madridano, O., Maestre, A., Marchena, P.J., Martín-Martos, F., Martínez-Baquerizo, C., Martínez-García, M.A., Mellado, M., Moisés, J., Monreal, M., Morales, M.V., Muñoz-Blanco, A., Nieto, J.A., Núñez, M.J., Olivares, M.C., Olivera, P.E., Ortega, C., Osorio, J., Otalora, S., Otero, R., Panadero-Macia, M., Parra, V., Pedrajas, J.M., Pellejero, G., Pérez-Ductor, C., Pérez-Rus, G., Peris, M.L., Pesantez, D., Porras, J.A., Riera-Mestre, A., Rivas, A., Rodríguez-Cobo, A., Rodríguez-Matute, C., Rosa, V., Rubio, C.M., Ruiz-Artacho, P., Ruiz-Sada, P., Sahuquillo, J.C., Sala-Sainz, M.C., Salgueiro, G., Sampériz, A., Sánchez-Martínez, R., Sánchez-Muñoz-Torrero, J.F., Seguí, E., Soler, S., Suárez, S., Suriñach, J.M., Tolosa, C., Torres, M.I., Trujillo-Santos, J., Uresandi, F., Valero, B., Valle, R., Vidal, G., Vilar, C., Villares, P., Gutiérrez, P., Vázquez, F.J., Vilaseca, A., Vanassche, T., Vandenbriele, C., Verhamme, P., Hirmerova, J., Malý, R., Salgado, E., Benzidia, I., Bertoletti, L., Bura-Riviere, A., Debourdeau, P., Courtois, M.C., Farge-Bancel, D., Helfer, H., Hij, A., Mahé, I., Moustafa, F., Schellong, S., Braester, A., Brenner, B., Tzoran, I., Bilora, F., Bortoluzzi, C., Ciammaichella, M., Dentali, F., Di Micco, P., Ferrazzi, P., Imbalzano, E., Lodigiani, C., Maida, R., Mastroiacovo, D., Mumoli, N., Pace, F., Pesavento, R., Pomero, F., Prandoni, P., Quintavalla, R., Rocci, A., Rota, L., Siniscalchi, C., Tiraferri, E., Tufano, A., Visonà, A., Vo Hong, N., Zalunardo, B., Kalejs, R.V., Kigitovica, D., Skride, A., Bosevski, M., Zdraveska, M., Bounameaux, H., Mazzolai, L., Caprini, J.A., Tafur, A.J., Bui, H.M.

Natural history of patients with venous thromboembolism and hereditary hemorrhagic telangiectasia. Findings from the RIETE registry
(2019) Orphanet Journal of Rare Diseases, 14 (1), art. no. 196, .

PubMed ID: 31399146
DOI: 10.1186/s13023-019-1172-8

Abstract
Background: Limited data exist about the clinical presentation, ideal therapy and outcomes of patients with hereditary hemorrhagic telangiectasia (HHT) who develop venous thromboembolism (VTE). Methods: We used the data in the RIETE Registry to assess the clinical characteristics, therapeutic approaches and clinical outcomes during the course of anticoagulant therapy in patients with HHT according to initial presentation as pulmonary embolism (PE) or deep venous thrombosis (DVT). Results: Of 51,375 patients with acute VTE enrolled in RIETE from February 2009 to January 2019, 23 (0.04%) had HHT: 14 (61%) initially presented with PE and 9 (39%) with DVT alone. Almost half (47.8%) of the patients with VTE had a risk factor for VTE. Most PE and DVT patients received low-molecular-weight heparin for initial (71 and 100%, respectively) and long-term therapy (54 and 67%, respectively). During anticoagulation for VTE, the rate of bleeding events (major 2, non-major 6) far outweighed the rate of VTE recurrences (recurrent DVT 1): 50.1 bleeds per 100 patient-years (95%CI: 21.6-98.7) vs. 6.26 recurrences (95%CI: 0.31-30.9; p = 0.020). One major and three non-major bleeding were epistaxis. No patient died of bleeding. One patient died shortly after being diagnosed with acute PE. Conclusions: During anticoagulation for VTE in HHT patients, there were more bleeding events than VTE recurrences. Most bleeding episodes were non-major epistaxis.


300§
Pastore, G., Morani, G., Maines, M., Marcantoni, L., Bolzan, B., Zanon, F., Noventa, F., Corbucci, G., Baracca, E., Picariello, C., Lanza, D., Zuin, M., Roncon, L., Barold, S.S.

Patients with right bundle branch block and concomitant delayed left ventricular activation respond to cardiac resynchronization therapy
(2018) Europace, 20 (11), pp. E171-E178.

PubMed ID: 29294014
DOI: 10.1093/europace/eux362

Abstract
Aims: Right bundle branch block (RBBB) typically presents with only delayed right ventricular activation. However, some patients with RBBB develop concomitant delayed left ventricular (LV) activation. Such patients may show a specific electrocardiographic (ECG) pattern resembling RBBB in the precordial leads in association with an insignificant S-wave in lateral limb leads (atypical RBBB). We therefore postulated that the ECG pattern of atypical RBBB might be able to identify a subgroup of patients likely to respond to cardiac resynchronization therapy (CRT). The purpose of this study was to assess the impact of RBBB ECG morphology on CRT response in patients with heart failure (HF). Methods and results: We evaluated the echocardiographic clinical response of 66 patients with RBBB treated with CRT and followed up for almost 2 years. The patients were divided electrocardiographically into 2 groups: 31 with typical RBBB and 35 with atypical RBBB. Responders were classified in terms of reduction in LV end-systolic volume index (ESVi) ≥ 15% or reduction in the New York Heart Association (NYHA) Class ≥ 1 or Packer score variation (NYHA response with no HF-related hospitalization events or death). The atypical RBBB group presented a longer LV activation time compared with the typical RBBB group (111.9 ± 17.6 vs. 73.2 ± 15.4 ms; P < 0.001). In the atypical and typical RBBB groups, respectively, 71.4% and 19.4% of patients were ESVi responders (P = 0.001) 74.3% and 32.3% were NYHA responders (P = 0.002); similarly, 71.4% and 29.0% of patients exhibited a 2-year Packer score of 0 (P = 0.002). Conclusion: Patients with atypical RBBB, which is a pattern highly suggestive of concomitant delayed LV conduction, may show a satisfactory response to CRT.


299§
Zanon, F., Marcantoni, L., Baracca, E., Pastore, G., Giau, G., Rigatelli, G., Lanza, D., Picariello, C., Aggio, S., Giatti, S., Zuin, M., Roncon, L., Pacetta, D., Noventa, F., Prinzen, F.W.

Hemodynamic comparison of different multisites and multipoint pacing strategies in cardiac resynchronization therapies
(2018) Journal of Interventional Cardiac Electrophysiology, 53 (1), pp. 31-39.

PubMed ID: 29627954
DOI: 10.1007/s10840-018-0362-y

Abstract
Purpose: In order to increase the responder rate to CRT, stimulation of the left ventricular (LV) from multiple sites has been suggested as a promising alternative to standard biventricular pacing (BIV). The aim of the study was to compare, in a group of candidates for CRT, the effects of different pacing configurations—BIV, triple ventricular (TRIV) by means of two LV leads, multipoint (MPP), and multipoint plus a second LV lead (MPP + TRIV) pacing—on both hemodynamics and QRS duration. Methods: Fifteen patients (13 male) with permanent AF (mean age 76 ± 7 years; left ventricular ejection fraction 33 ± 7%; 7 with ischemic cardiomyopathy; mean QRS duration 178 ± 25 ms) were selected as candidates for CRT. Two LV leads were positioned in two different branches of the coronary sinus. Acute hemodynamic response was evaluated by means of a RADI pressure wire as the variation in LVdp/dtmax. Results: Per patient, 2.7 ± 0.7 veins and 5.2 ± 1.9 pacing sites were evaluated. From baseline values of 998 ± 186 mmHg/s, BIV, TRIV, MPP, and MPP-TRIV pacing increased LVdp/dtmax to 1200 ± 281 mmHg/s, 1226 ± 284 mmHg/s, 1274 ± 303 mmHg, and 1289 ± 298 mmHg, respectively (p < 0.001). Bonferroni post-hoc analysis showed significantly higher values during all pacing configurations in comparison with the baseline; moreover, higher values were recorded during MPP and MPP + TRIV than at the baseline or during BIV and also during MPP + TRIV than during TRIV. Mean QRS width decreased from 178 ± 25 ms at the baseline to 171 ± 21, 167 ± 20, 168 ± 20, and 164 ± 15 ms, during BIV, TRIV, MPP, and MPP-TRIV, respectively (p < 0.001). Conclusions: In patients with AF, the acute response to CRT improves as the size of the early activated LV region increases.


298§
Romano, A., Angeli, P., Piovesan, S., Noventa, F., Anastassopoulos, G., Chemello, L., Cavalletto, L., Gambato, M., Russo, F.P., Burra, P., Vincenzi, V., Scotton, P.G., Panese, S., Tempesta, D., Bertin, T., Carrara, M., Carlotto, A., Capra, F., Scroccaro, G., Alberti, A.

Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study
(2018) Journal of Hepatology, 69 (2), pp. 345-352.

PubMed ID: 29551707
DOI: 10.1016/j.jhep.2018.03.009

Abstract
Background & Aims: Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs. Methods: The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ± 197.6 days. Results: Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12–1.17) in F3, 1.49% (1.03–2.08) in CTP-A and 3.61% (1.86–6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14–3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24–12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2–16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment. Conclusions: These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of “de novo” hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors. Lay summary: Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon–free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure.


297§
Imberti, D., Becattini, C., Bernardi, E., Camporese, G., Cuccia, C., Dentali, F., Paretti, D.

Multidisciplinary approach to the management of patients with pulmonary embolism and deep vein thrombosis: a consensus on diagnosis, traditional therapy and therapy with rivaroxaban
(2018) Internal and Emergency Medicine, 13 (7), pp. 1037-1049.

PubMed ID: 29520700
DOI: 10.1007/s11739-018-1802-5

Abstract
Despite the availability of updated guidelines for the diagnosis and treatment of venous thromboembolism (VTE), the management of this disorder in clinical practice is often not standardized, given the different degree of compliance with official recommendations by the various involved specialists. The aim of this consensus paper, as a result of a board of experts in thromboembolism, is to define strategies to improve the quality of patients’ care and the efficiency of healthcare resources utilization, by means of: (a) analysis of the guidelines for diagnosis and treatment of VTE; (b) analysis of diagnostic and therapeutic algorithms currently used in clinical practice by different specialists; (c) agreement on a common algorithm for diagnosis and treatment of VTE in different clinical settings; (d) definition of the possible role of the new oral anticoagulant agents (NOAC), such as rivaroxaban, based on their potential benefits for both acute and chronic therapy. The so-called “single drug approach” (as opposed to the traditional heparin/VKA combination), which can be adopted with these drugs, makes anticoagulation more convenient for both patients and healthcare providers, without the need for a close monitoring of the hemocoagulative status, and with a concomitant reduction of length of hospitalization and treatment costs. Among NOACs, in this paper we focused on rivaroxaban only because it was the unique available NOAC in Italy for the treatment of VTE at the time the manuscript was written. Concerning rivaroxaban, the results of two phase III, randomized and controlled trials confirm the non-inferiority of this drug compared to standard therapy (enoxaparin/warfarin) for the treatment of patients with pulmonary embolism (EINSTEIN PE Study) or deep vein thrombosis (EINSTEIN DVT Study) in terms of both efficacy and safety, supporting its use as an effective therapeutic option for these disorders.


296§
Abbate, R., Camporese, G., Leonardo, G., Magnoni, F., Torregiani, A.

Chronic venous disease: A comparison of real-life experiences
(2018) Minerva Medica, 109 (4), pp. 334-336.

PubMed ID: 29947495
DOI: 10.23736/S0026-4806.18.05584-2


295§
Becattini, C., Dentali, F., Camporese, G., Sembolini, A., Rancan, E., Tonello, C., Manina, G., Padayattil, S., Agnelli, G.

Carotid atherosclerosis and risk for ischemic stroke in patients with atrial fibrillation on oral anticoagulant treatment
(2018) Atherosclerosis, 271, pp. 177-181.

PubMed ID: 29524860
DOI: 10.1016/j.atherosclerosis.2018.02.004

Abstract
Background and aims: Whether carotid atherosclerosis is associated with an increased risk for ischemic stroke in patients with atrial fibrillation (AF) on anticoagulant treatment is undefined. To explore this association, patients with AF on treatment with vitamin K antagonists were included in a multicenter, prospective study. Methods: At inclusion in the study, patients underwent Doppler-ultrasonography for the assessment of carotid atherosclerosis and then were prospectively followed. Ischemic stroke or transient ischemic attack (TIA) were the primary study outcomes; death and its causes were reported. Results: Overall, 587 patients were included in the study. At ultrasonography, 380 patients had carotid atherosclerosis (64.7%) and 45 internal carotid (ICA) stenosis ≥50% (7.7%). During a mean follow-up of 41 ± 15 months, 30 patients had an ischemic stroke or TIA (1.49% per patient-year, 95% CI 0.96–2.03) and 81 patients died (4.01% per patient-year, 95% CI 3.16–4.86). Carotid atherosclerosis was associated with a significant increase in the risk for the composite of ischemic stroke or TIA or death after adjusting for CHA2DS2VASc (6.0% vs. 3.1% patient-year; HR 1.60, 95% CI 0.99–2.59; p = 0.05). ICA ≥50% was associated with a not significant increase in the risk of ischemic stroke or TIA (2.05% vs. 1.45% patient-year; HR 1.39, 95% CI 0.42–4.58) or all-cause death (6.1% vs. 3.8% patient-year; HR 1.66, 95% CI 0.83–3.32). Conclusions: In patients with AF, carotid atherosclerosis is a predictor for the composite of cerebrovascular events or death while on anticoagulant therapy. In patients with AF and carotid atherosclerosis, the clinical benefit of a more intense antithrombotic treatment should be evaluated.

294§
Bernardi, E., Camporese, G.

Diagnosis of deep-vein thrombosis
(2018) Thrombosis Research, 163, pp. 201-206.

PubMed ID: 29050648
DOI: 10.1016/j.thromres.2017.10.006

Abstract
The diagnostic approach to suspected symptomatic deep-vein thrombosis of the lower extremities is usually based on non-invasive methods, including the estimation of clinical probability, the measurement of D-dimer levels, and ultrasonography. The present review discusses the evidence available from the literature about the management of the first episode of suspected deep-vein-thrombosis.


293§
Riva, N., Camporese, G., Iotti, M., Bucherini, E., Righini, M., Kamphuisen, P.W., Verhamme, P., Douketis, J.D., Tonello, C., Prandoni, P., Ageno, W., Ghirarduzzi, A., Veropalumbo, M.R., Donadini, M., the PALLADIO Study Investigators

Age-adjusted D-dimer to rule out deep vein thrombosis: findings from the PALLADIO algorithm
(2018) Journal of Thrombosis and Haemostasis, 16 (2), pp. 271-278.

PubMed ID: 29125695
DOI: 10.1111/jth.13905

Abstract
Essentials The accuracy of the age-adjusted D-dimer in suspected venous thromboembolism is still debated. We assessed the performance of age-adjusted D-dimer combined with the PALLADIO algorithm. The age-adjusted threshold can reduce the need for imaging tests compared to the fixed cut-off. The safety of this approach should be confirmed in large management studies. Summary: Background Age-adjusted D-dimer has been proposed to increase specificity for the diagnosis of venous thromboembolism (VTE). However, the accuracy of this threshold has been recently questioned. Objectives To assess the diagnostic performance of age-adjusted D-dimer combined with clinical pretest probability (PTP) in patients with suspected deep vein thrombosis (DVT). Methods PALLADIO (NCT01412242) was a multicenter management study that validated a new diagnostic algorithm, incorporating PTP, D-dimer (using the manufacturer's cut-off) and limited or extended compression ultrasonography (CUS) in outpatients with clinically suspected DVT. Patients with unlikely PTP and negative D-dimer had DVT ruled out without further testing (group 1); patients with likely PTP or positive D-dimer underwent limited CUS (group 2); patients with likely PTP and positive D-dimer underwent extended CUS (group 3). Patients with DVT ruled out at baseline had a 3-month follow-up. In this post-hoc analysis we evaluated age-adjusted D-dimer cut-off (defined as age times 10 μg L −1 , or age times 5 μg L −1 for D-dimers with a lower manufacturer's cut-off, in patients > 50 years). Results In total, 1162 patients were enrolled. At initial visit, DVT was detected in 4.0% of patients in group 2 and 53.0% in group 3. The age-adjusted D-dimer, compared with the fixed cut-off, resulted in 5.1% (95% CI, 4.0–6.5%) reduction of CUS. The incidence of symptomatic VTE during follow-up was: 0.24% (95% CI, 0.04–1.37) in group 1; 1.12% (95% CI, 0.44–2.85) in group 2; and 1.89% (95% CI, 0.64–5.40) in group 3. Conclusions The PALLADIO algorithm using age-adjusted D-dimer slightly decreased the number of required imaging tests, but this approach should be confirmed in large management studies.


292§
Camporese, G., Simioni, P., Bernardi, E.

Primo anno di edoxaban in Italia: Dati di sicurezza dalla Rete Nazionale di Farmacovigilanza
(2018) Patient Cardiovasc Risk, 2, pp. 3-10.


291§
Prandoni, P., Vedovetto, V., Ciammaichella, M., Bucherini, E., Corradini, S., Enea, I., Cosmi, B., Mumoli, N., Visonà, A., Barillari, G., Bova, C., Quintavalla, R., Zanatta, N., Pedrini, S., Villalta, S., Camporese, G., Testa, S., Parisi, R., Becattini, C., Cuppini, S., Pengo, V., Palareti, G., Morgagni Investigators

Residual vein thrombosis and serial D-dimer for the long-term management of patients with deep venous thrombosis
(2017) Thrombosis Research, 154, pp. 35-41.

PubMed ID: 28407492
DOI: 10.1016/j.thromres.2017.04.002

Abstract
Background The optimal long-term strategy for preventing recurrent venous thromboembolism (VTE) in patients with deep-vein thrombosis (DVT) is uncertain. Methods In 620 consecutive outpatients with a first proximal DVT who had completed at least three months of anticoagulation (unprovoked in 483, associated with minor risk factors in 137), the ultrasound presence of residual vein thrombosis (RVT) was assessed and defined as an incompressibility of at least 4 mm. In 517 patients without RVT and with negative D-dimer, anticoagulation was stopped and D-dimer was repeated after one and three months. Anticoagulation was resumed in 63 of the 72 patients in whom D-dimer reverted to positivity. Results During a mean follow-up of three years, recurrent VTE developed in 40 (7.7%) of the 517 patients, leading to an annual rate of 3.6% (95% CI, 2.6 to 4.9): 4.1% (95% CI, 2.9 to 5.7) in individuals with unprovoked DVT, and 2.2% (95% CI, 1.1 to 4.5) in those with DVT associated with minor risk factors. Of the 233 males with unprovoked DVT, 17 (7.3%) developed events in the first year of follow-up. Major bleeding complications occurred in 8 patients while on anticoagulation, leading to an annual rate of 1.2% (95% CI, 0.6 to 2.4). Conclusions Discontinuing anticoagulation in patients with a first episode of proximal DVT based on the assessment of RVT and serial D-dimer leads to an overall annual rate of recurrent VTE lower than 5.0%, which is the rate deemed as acceptable by the Subcommittee on Control of Anticoagulation of the ISTH. However, in males with unprovoked DVT there is room for further improving the long-term strategy of VTE prevention. (ClinicalTrials.gov number, NCT01285661).


290§
Bova, C., Vanni, S., Prandoni, P., Morello, F., Dentali, F., Bernardi, E., Mumoli, N., Bucherini, E., Barbar, S., Picariello, C., Enea, I., Pesavento, R., Bottino, F., Jiménez, D., Nazerian, P., Viviani, G., Crocco, F., De Morelli, G., Barrios, D., Quezada, A., Morello, F., Dentali, F., Dall’ Arche, A., Brescianini, S., Sardo, L., Stea, F., Bucherini, E., Vastola, M., Barbar, S., Roncon, L., Giatti, S., Enea, I., Puato, M., Spinazzè, A., Poggioni, C., the Bova Score Validation Study Investigators

A prospective validation of the Bova score in normotensive patients with acute pulmonary embolism
(2018) Thrombosis Research, 165, pp. 107-111.

PubMed ID: 29631073
DOI: 10.1016/j.thromres.2018.04.002

Abstract
Background: The Bova score has shown usefulness in the identification of intermediate-high risk patients with acute pulmonary embolism (PE), but lacks prospective validation. The aim of this study was to prospectively validate the Bova score in different settings from the original derivation cohort. Methods: Consecutive, normotensive patients with acute PE recruited at 13 academic or general hospitals were stratified, using their baseline data, into the three Bova risk stages (I–III). The primary outcome was the 30-day composite of PE-related mortality, hemodynamic collapse and non-fatal PE recurrences in the three risk categories. Results: In the study period, 639 patients were enrolled. The primary end point occurred in 45 patients (7.0%; 95% Confidence Intervals, 5.2%–9.3%). Risk stage correlated with the PE-related complication rate (stage I, 2.9%; stage II, 17%; stage III, 27%). Patients classified as stage III by the Bova score had a 6.5-fold increased risk for adverse outcomes (3.1–13.5, p < 0.001) compared with stages I and II combined. Rescue thrombolysis increased from stage I to stage III (0.6%, 12% and 15% respectively). All-cause mortality (5.3%) did not substantially differ among the stages. Conclusions: The Bova score accurately stratifies normotensive patients with acute PE into stages of increasing risk of 30-day PE-related complications.


289§
Weinberg, I., Giri, J., Kolluri, R., Arcelus, J.I., Falgá, C., Soler, S., Braester, A., Bascuñana, J., Gutiérrez-Guisado, J., Monreal, M., Adarraga, M.D., Agudo, P., Aibar, M.A., Aibar, J., Amado, C., Akasbi, M., Aranda, C., Arcelus, J.I., Arenas, A., Ballaz, A., Barba, R., Barrón, M., Barrón-Andrés, B., Bascuñana, J., Blanco-Molina, A., Camon, A.M., Carrasco, C., Castro, J., Cruz, A.J., de Ancos, C., del Toro, J., Demelo, P., Díaz-Pedroche, M.C., Díaz-Peromingo, J.A., Falgá, C., Farfán, A.I., Fernández-Capitán, C., Fidalgo, M.A., Font, C., Font, L., García, M.A., García-Bragado, F., García-Morillo, M., García-Raso, A., Gavín, O., Gayol, M.C., Gil-Díaz, A., Gómez, V., González-Martínez, J., Grau, E., Gutiérrez, J., Hernández-Blasco, L., Iglesias, M., Jara-Palomares, L., Jaras, M.J., Jiménez, D., Jou, I., Joya, M.D., Lalueza, A., Lima, J., Llamas, P., Lobo, J.L., López-Jiménez, L., López-Miguel, P., López-Nuñez, J.J., López-Reyes, R., López-Sáez, J.B., Lorente, M.A., Lorenzo, A., Loring, M., Loscos, S., Lumbierres, M., Marchena, P.J., Martín-Fernández, M., Martín-Guerra, J.M., Martín-Romero, M., Mellado, M., Modesto, M., Monreal, M., Morales, M.V., Nieto, J.A., Núñez, A., Núñez, M.J., Olivares, M.C., Otalora, S., Otero, R., Pedrajas, J.M., Pellejero, G., Pérez-Jacoiste, A., Pérez-Rus, G., Peris, M.L., Pesce, M.L., Porras, J.A., Rivas, A., Rodríguez-Dávila, M.A., Rodríguez-Fernández, L., Rodríguez-Hernández, A., Rosa, V., Rosillo-Hernández, E.M., Rubio, C.M., Ruiz-Alcaraz, S., Ruiz-Artacho, P., Ruiz-Ruiz, J., Ruiz-Sada, P., Sahuquillo, J.C., Sampériz, A., Sánchez-Muñoz-Torrero, J.F., Sancho, T., Sanoja, I.D., Soler, S., Soto, M.J., Suriñach, J.M., Tapia, E., Torres, M.I., Trujillo-Santos, J., Uresandi, F., Usandizaga, E., Valle, R., Vela, J.R., Vilar, C., Gutiérrez, P., Vázquez, F.J., Vilaseca, A., Vanassche, T., Vandenbriele, C., Verhamme, P., Yoo, H.H.B., Hirmerova, J., Malý, R., Salgado, E., Benzidia, I., Bertoletti, L., Bura-Riviere, A., Debourdeau, P., Falvo, N., Farge-Bancel, D., Hij, A., Mahé, I., Moustafa, F., Braester, A., Brenner, B., Ellis, M., Tzoran, I., Barillari, G., Bilora, F., Bortoluzzi, C., Brandolin, B., Bucherini, E., Camerota, A., Ciammaichella, M., Dentali, F., Di Micco, P., Grandone, E., Imbalzano, E., Lessiani, G., Maida, R., Mastroiacovo, D., Ngoc, V., Pace, F., Parisi, R., Pesavento, R., Pinelli, M., Prandoni, P., Quintavalla, R., Rocci, A., Siniscalchi, C., Sotgiu, P., Tufano, A., Visonà, A., Gibietis, V., Skride, A., Strautmane, S., Bosevski, M., Zdraveska, M., Bounameaux, H., Mazzolai, L., Caprini, J., Bui, H.M., RIETE Investigators

Characteristics, treatment patterns and outcomes of patients presenting with venous thromboembolic events after knee arthroscopy in the RIETE Registry
(2018) Journal of Thrombosis and Thrombolysis, 46 (4), pp. 551-558.

PubMed ID: 30196344
DOI: 10.1007/s11239-018-1736-9

Abstract
Knee arthroscopy is the most common orthopedic procedure worldwide. While incidence of post-arthroscopy venous thromboembolic events (VTE) is low, treatment patterns and patient outcomes have not been described. Patients from the “Registro Informatizado Enfermedad TromboEmbolica” who had confirmed post-arthroscopy VTE were compared to patients with provoked, post bone-fracture, and to patients with unprovoked VTE. Baseline characteristics, presenting signs and symptoms, treatment and outcomes including recurrent VTE, bleeds or death were compared. A total of 101 patients with post-arthroscopy VTE and 19,218 patients with unprovoked VTE were identified. Post-arthroscopy patients were younger (49.5 vs. 66 years, P < 0.0001) and had less history of VTE [5.9% vs. 20%, OR 0.26 (0.11–0.59)]. Among patients with isolated DVT, there were fewer proximal DVT in the post-arthroscopy group [40% vs. 86%, OR 0.11 (0.06–0.19)]. Treatment duration was shorter in the post-arthroscopy group (174 ± 140 vs. 311 ± 340 days, P < 0.0001) and more often with DOAC [OR 3.67 (1.95–6.89)]. Recurrent VTE occurred in 6.18 (1.96–14.9) and 11.9 (11.0–12.8) per 100 patient years [HR 0.52 (0.16–1.26)] after treatment in the post-arthroscopy and unprovoked groups, respectively. Recurrent VTE occurred in 5.17 (1.31–14.1) per 100 patient years in a separate post bone-fracture group (n = 147), also not statistically different than the post-arthroscopy recurrence rate. After anticoagulation cessation, some patients post-knee arthroscopy develop VTE. While our small sample size precludes drawing firm conclusions, this signal should warrant further research into the optimal treatment duration for these patients, as some patients may be at increased risk for long-term recurrence.


288§
Bikdeli, B., Lobo, J.L., Jiménez, D., Green, P., Fernández-Capitán, C., Bura-Riviere, A., Otero, R., Ditullio, M.R., Galindo, S., Ellis, M., Parikh, S.A., Monreal, M., Adarraga, M.D., Aibar, M.A., Aibar, J., Alfonso, M., Amado, C., Aranda, C., Arcelus, J.I., Asin, U., Azcarate-Agüero, P.M., Ballaz, A., Barba, R., Barrón, M., Barrón-Andrés, B., Bascuñana, J., Blanco-Molina, A., Camon, A.M., Carrasco, C., Castejón-Pina, N., Cruz, A.J., de Ancos, C., del Toro, J., Díaz-Pedroche, M.C., Díaz-Peromingo, J.A., Falgá, C., Farfán, A.I., Fernández-Capitán, C., Fidalgo, M.A., Font, C., Font, L., Furest, I., García, M.A., García-Bragado, F., García-Morillo, M., Gavín, O., Gil, A., Gómez, V., González-Martínez, J., Grau, E., Guijarro, R., Guirado, L., Gutiérrez, J., Hernández-Blasco, L., Iglesias, C., Jara-Palomares, L., Jaras, M.J., Jiménez, D., Jiménez, R., Jou, I., Joya, M.D., Lima, J., Lobo, J.L., López-Jiménez, L., López-Miguel, P., López-Nuñez, J.J., López-Reyes, R., López-Sáez, J.B., Lorente, M.A., Lorenzo, A., Loring, M., Loscos, S., Lumbierres, M., Marchena, P.J., Martínez-Baquerizo, C., Martín-Asenjo, M., Martín-Fernández, M., Martín-Guerra, J.M., Monreal, M., Morales, M.V., Nieto, J.A., Núñez, M.J., Olivares, M.C., Otalora, S., Otero, R., Pedrajas, J.M., Pellejero, G., Pérez-Ductor, C., Peris, M.L., Pesce, M.L., Porras, J.A., Riesco, D., Rivas, A., Rodríguez-Dávila, M.A., Rodríguez-Galán, I., Rodríguez-Hernández, A., Rosa, V., Rubio, C.M., Ruiz-Artacho, P., Ruiz-Ruiz, J., Sahuquillo, J.C., Sala-Sainz, M.C., Sampériz, A., Sánchez-Muñoz-Torrero, J.F., Sancho, T., Sanoja, I.D., Soler, S., Soto, M.J., Suriñach, J.M., Torres, M.I., Trujillo-Santos, J., Uresandi, F., Usandizaga, E., Valle, R., Vela, J., Vilar, C., Villalobos, A., Gutiérrez, P., Vázquez, F.J., Vilaseca, A., Vanassche, T., Vandenbriele, C., Verhamme, P., Yoo, H.H.B., Hirmerova, J., Malý, R., Salgado, E., Benzidia, I., Bertoletti, L., Bura-Riviere, A., Farge-Bancel, D., Hij, A., Merah, A., Mahé, I., Moustafa, F., Braester, A., Brenner, B., Ellis, M., Tzoran, I., Bilora, F., Bortoluzzi, C., Brandolin, B., Bucherini, E., Ciammaichella, M., Dentali, F., Di Micco, P., Grandone, E., Imbalzano, E., Lessiani, G., Maida, R., Mastroiacovo, D., Ngoc, V., Pace, F., Parisi, R., Pesavento, R., Pinelli, M., Prandoni, P., Quintavalla, R., Rocci, A., Romualdi, R., Siniscalchi, C., Sotgiu, P., Tiraferri, E., Tufano, A., Visonà, A., Zalunardo, B., Kalejs, R.V., Skride, A., Vitola, B., Bosevski, M., Zdraveska, M., Bounameaux, H., Mazzolai, L., Bikdeli, B., Caprini, J., Bui, H.M., RIETE Investigators

Early use of echocardiography in patients with acute pulmonary embolism: Findings from the RIETE registry
(2018) Journal of the American Heart Association, 7 (17), art. no. e009042, 7 p.

PubMed ID: 30371152
DOI: 10.1161/JAHA.118.009042

Abstract
Background—Transthoracic echocardiography (TTE) is often considered for risk stratification of patients with acute pulmonary embolism (PE). We sought to determine the contemporary utilization of early TTE (within 72 hours of PE diagnosis) and explored the association between TTE findings and PE-related mortality. Methods and Results—Data from the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry, a multicenter registry of consecutive patients with acute PE, were used (2001-July 2017). We used a generalized linear mixed model to determine predictors of early TTE performance. Moreover, the association between 3 TTE variables (right atrial enlargement, right ventricular hypokinesis, and presence of right heart thrombi) and 30-day PE-related mortality was assessed in generalized linear mixed models adjusted for PE severity index, and other comorbidities. Among 35 935 enrollees with acute PE, 15 375 (42.8%) underwent early TTE. There was an increase in early TTE utilization rate over time (P<0.001 for trend). Younger age, female sex, enrollment in countries other than Spain, history of coronary disease, heart failure, atrial fibrillation, tachycardia, and hypotension were the main predictors of early TTE (P<0.01 for all). In multivariable analyses, right atrial enlargement (adjusted odds ratio: 3.74; 95% confidence interval, 2.10-6.66), right ventricular hypokinesis (adjusted odds ratio: 3.11, 95% confidence interval: 1.85-5.21) and right heart thrombi (adjusted odds ratio: 4.39, 95% confidence interval, 1.99-9.71) were associated with increased odds for PErelated mortality. Conclusions—Early TTE is commonly performed for acute PE and utilization rates have increased over time. Right atrial enlargement, right ventricular hypokinesis, and right heart thrombi are predictive of worse outcomes. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02832245.


287§
Moustafa, F., Pesavento, R., di Micco, P., González-Martínez, J., Quintavalla, R., Peris, M.-L., Porras, J.A., Falvo, N., Baños, P., Monreal, M., the RIETE Investigators, Adarraga, M.D., Aibar, M.A., Alfonso, M., Arcelus, J.I., Ballaz, A., Baños, P., Barba, R., Barrón, M., Barrón-Andrés, B., Bascuñana, J., Blanco-Molina, A., Camón, A.M., Chasco, L., del Pozo, R., de Miguel, J., del Toro, J., Díaz-Pedroche, M.C., Díaz-Peromingo, J.A., Falgá, C., Fernández-Aracil, C., Fernández-Capitán, C., Fidalgo, M.A., Font, C., Font, L., Gallego, P., García, M.A., García-Bragado, M.F., García-Morillo, M., Garcıa-Raso, A., Gavín, O., Gil, F., Gómez, C., Gómez, V., González, J., Grau, E., Grimón, A., Guijarro, R., Gutiérrez, J., Hernández-Comes, H., Hernández-Blasco, G., Hernando, E., Jara-Palomares, L., Jaras, M.J., Jiménez, D., Joya, M.D., Llamas, P., Lobo, J.L., López-Jiménez, L., López-Reyes, R., López-Sáez, J.B., Lorente, M.A., Lorenzo, A., Lumbierres, M., Madridano, O., Maestre, A., Marchena, P.J., Martín-Asenjo, M., Martín-Martos, F., Martín-Romero, M., Miralles, M., Monreal, M., Morales, M.V., Moya, E.M., Muñoz, C., Nieto, J.A., Nieto, S., Núñez, A., Núñez, M.J., Odriozola, M., Otalora, S., Otero, R., Pedrajas, J.M., Pellejero, G., Pérez-Ductor, C., Peris, M.L., Pons, I., Porras, J.A., Ramírez, L., Riera-Mestre, A., Riesco, D., Rivas, A., Rodríguez, M., Rodríguez-Davila, M.A., Rosa, V., Rosillo-Hernández, E.M., Ruiz-Artacho, P., Sahuquillo, J.C., Sala-Sainz, M.C., Sampériz, A., Sánchez-Martínez, R., Soler, S., Suriñach, J.M., Tolosa, C., Torres, M.I., Trujillo-Santos, J., Uresandi, F., Usandizaga, E., Valero, B., Valle, R., Vela, J., Vela, L., Vidal, G., Villalobos, A., Vanassche, T., Verhamme, P., Yoo, H.H.B., Wells, P., Hirmerova, J., Malý, R., Salgado, E., Bertoletti, L., Bura-Riviere, A., Falvo, N., Farge-Bancel, D., Hij, A., Mahé, I., Merah, A., Moustafa, F., Quere, I., Braester, A., Brenner, B., Ellis, M., Tzoran, I., Andriulli, M., Antonucci, G., Barillari, G., Bortoluzzi, C., Brandolin, B., Bucherini, E., Cattabiani, C., Ciammaichella, M., Dentali, F., Di Micco, P., Duce, R., GiorgiPierfranceschi, M., Grandone, E., Imbalzano, E., Lessiani, G., Maida, R., Mastroiacovo, D., Pace, F., Pesavento, R., Pinelli, M., Poggio, R., Prandoni, P., Quintavalla, R., Rocci, A., Siniscalchi, C., Tiraferri, E., Visona, A., Zalunardo, B., Gibietis, V., Skride, A., Vitola, B., Zdraveska, M., Bounameaux, H., Mazzolai, L.
Real-life Use of Anticoagulants in Venous Thromboembolism With a Focus on Patients With Exclusion Criteria for Direct Oral Anticoagulants
(2018) Clinical Pharmacology and Therapeutics, 103 (4), pp. 684-691.

PubMed ID: 28675460
DOI: 10.1002/cpt.781

Abstract
We assessed the real-life use of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and exclusion criteria for randomized trials. From 2013 to 2016, 3,578 of 18,853 patients (19%) had exclusion criteria. Irrespective of which anticoagulant was chosen, they had more VTE recurrences (hazard ratio (HR): 3.10; 95% confidence interval (CI): 2.47–3.88), major bleeds (HR: 4.10; 95% CI: 3.38–4.96), and deaths (HR: 9.47; 95% CI: 8.46–10.6) than those without exclusion criteria. During initial therapy, no patient with exclusion criteria on DOACs (n = 115) recurred, but those on rivaroxaban bled less often (adjusted HR: 0.18; 95% CI: 0.04–0.79) than those on unfractionated heparin (n = 224) and similar to those (n = 3,172) on low-molecular-weight (LMWH) heparin. For long-term therapy, patients on rivaroxaban (n = 151) had nonsignificantly fewer VTE recurrences (adjusted HR: 0.74; 95% CI: 0.08–1.32) and major bleeds (adjusted HR: 0.41; 95% CI: 0.15–1.15) than those on LMWH (n = 2,071). The efficacy and safety of DOACs were similar to standard therapy.

286§
Prandoni, P., Lensing, A.W.A., Prins, M.H., Noventa, F., Villalta, S.

Does the presence of clinical symptoms of pulmonary embolism affect the outcome of patients with deep vein thrombosis?
(2017) Thrombosis Research, 157, pp. 134-135.

PubMed ID: 28743057
DOI: 10.1016/j.thromres.2017.07.021


285§
Prandoni, P., Ciammaichella, M., Mumoli, N., Zanatta, N., Visonà, A., Avruscio, G., Camporese, G., Bucherini, E., Bova, C., Imberti, D., Benedetti, R., Rossetto, V., Noventa, F., Milan, M., The Veritas Investigators

An association between residual vein thrombosis and subclinical atherosclerosis: Cross-sectional study
(2017) Thrombosis Research, 157, pp. 16-19.

PubMed ID: 28679112
DOI: 10.1016/j.thromres.2017.06.036

Abstract
Background The association between venous and arterial thrombotic disorders is still unclear. We assessed the association between residual vein thrombosis (RVT) and subclinical atherosclerosis in a cohort of patients with unprovoked (or associated with weak risk factors) proximal deep-vein thrombosis (DVT). Methods In a multicenter cross-sectional study, consecutive patients over 40 years free from atherosclerotic disorders received the ultrasound assessment of the leg vein system and that of carotid arteries approximately three months after an episode of proximal DVT. In each center the evaluation was done by two independent assessors. The presence of RVT was defined as the incompressibility of at least 4 mm in either the popliteal or the common femoral vein, and that of subclinical atherosclerosis as the presence of increased (> 0.9 mm) intima-media tickness (IMT) and/or carotid plaques. Results Out of 252 patients (mean age, 67; males, 53%; unprovoked, 77%), the presence of RVT was found in 139 (55.2%). An increased IMT was shown in 76 (54.7%) patients with and in 35 (31.0%) without RVT (p < 0.001). At least one carotid plaque was found in 80 (57.6%) patients with and in 36 (31.9%) without RVT (p < 0.001). After adjusting for the baseline characteristics, the odds ratio of subclinical atherosclerosis (increased IMT and/or carotid plaques) was 2.8 (95% CI, 1.6 to 4.7). Conclusion The ultrasound detection of RVT after an episode of proximal DVT that is either unprovoked or triggered by weak risk factors is associated with a higher prevalence of subclinical atherosclerosis. These findings may have implications for patient prognosis.


284§
Prandoni, P., Ageno, W., Mumoli, N., Zanatta, N., Imberti, D., Visonà, A., Ciammaichella, M., Simioni, L., Cappelli, R., Bucherini, E., Di Nisio, M., Avruscio, G., Camporese, G., Parisi, R., Cuppini, S., Turatti, G., Noventa, F., Sarolo, L.

Recanalization rate in patients with proximal vein thrombosis treated with the direct oral anticoagulants
(2017) Thrombosis Research, 153, pp. 97-100.

PubMed ID: 28364690
DOI: 10.1016/j.thromres.2017.03.022

Abstract
Background The recanalization rate in patients with deep venous thrombosis (DVT) of the legs treated with the direct oral anticoagulants (DOAC) is unknown. Methods In an Italian cohort, we investigated the rate of residual vein thrombosis (RVT) after three and/or six months in 352 patients with proximal DVT who had been treated with the DOACs as a stand-alone therapy or lead-in parenteral anticoagulants, and compared it to that recorded in a historical cohort of 1094 patients in which vitamin K antagonists (VKAs) had been employed. In both cohorts, RVT was defined as the ultrasound persistence of thrombotic material resulting in a diameter of at least 4 mm of incompressibility of the proximal veins. Results RVT was detected in 143 patients treated with DOACs (41.2%) after three months and in 58 patients (21.1%) after six months; the corresponding figure in patients treated with conventional anticoagulation was 52.3% and 54.5%, respectively. After adjusting for the baseline characteristics, the odds ratio of RVT in patients treated with the DOACs as compared with those treated with conventional anticoagulation was 0.63 (95% CI, 0.48–0.81) after three months, and 0.17 (95% CI; 0.11–0.26) after six months. Conclusions In patients with proximal DVT treated with the DOACs, the persistence of ultrasound detectable RVT is likely to occur less frequently than in patients treated with conventional anticoagulation. These results may have implications for the prognosis of patients with DVT.


283§
van Es, N., Bleker, S.M., Di Nisio, M., Kleinjan, A., Beyer-Westendorf, J., Camporese, G., Aggarwal, A., Verhamme, P., Righini, M., Büller, H.R., Bossuyt, P.M.

Improving the diagnostic management of upper extremity deep vein thrombosis
(2017) Journal of Thrombosis and Haemostasis, 15 (1), pp. 66-73.

PubMed ID: 27732764
DOI: 10.1111/jth.13536

Abstract
Essentials The Constans score and D-dimer can rule out upper extremity deep vein thrombosis without imaging. We evaluated the performance of an extended Constans score and an age-adjusted D-dimer threshold. The extended Constans score did not increase the efficiency compared to the original score. Age-adjusted D-dimer testing safely increased the efficiency by 4%, but this needs validation. Summary: Background Among patients with clinically suspected upper extremity deep vein thrombosis (UEDVT), a clinical decision rule based on the Constans score combined with D-dimer testing can safely rule out the diagnosis without imaging in approximately one-fifth of patients. Objectives To evaluate the performance of the original Constans score, an extended Constans score and an age-adjusted D-dimer positivity threshold. Methods Data of 406 patients with suspected UEDVT previously enrolled in a multinational diagnostic management study were used. The discriminatory performance, calibration and diagnostic accuracy of the Constans score were evaluated. The Constans score was extended by selecting clinical variables that may have incremental value in detecting UEDVT, conditional on the original Constans score items. The performance of the Constans rule was evaluated in combination with fixed and age-adjusted D-dimer thresholds. Results The original Constans score showed good discriminatory performance (c-statistic, 0.81; 95% confidence interval [CI], 0.76–0.85). An extended Constans score with five additional clinical items improved discriminatory performance and calibration, but this did not translate into a higher efficiency in avoiding imaging tests. Compared with a fixed threshold, age-adjusted D-dimer testing increased the proportion of patients for whom imaging and anticoagulation could be withheld from 21% to 25% (gain, 3.7%; 95% CI, 2.3–6.0%). Conclusions The Constans score has good discriminatory performance in the diagnosis of UEDVT. Age-adjusted D-dimer testing is likely to safely increase the efficiency of the diagnostic algorithm, but this approach needs prospective validation.


282§
Bernardi, E., Imberti, D., Ferrari, A.
Management Strategies for Vitamin K Antagonists Reversal in Patients with Major Bleeding:

A Survey of Italian Emergency Departments
(2017) Clinical and Applied Thrombosis/Hemostasis, 23 (1), pp. 40-44.

PubMed ID: 26239314
DOI: 10.1177/1076029615598219

Abstract
Objective: Emergency physicians frequently deal with patients on vitamin K antagonists (VKAs) suffering major bleeding events, and rapid reversal of anticoagulation in this setting is of paramount importance. In Italy, given the absence of specific national guidelines, local policies are likely to differ, possibly impacting on clinical outcomes. We decided to perform a telephone survey among Italian emergency physicians to evaluate management strategies for VKAs reversal in patients with major bleeding. Methods: We conducted a computer-assisted, 10-minute telephone survey of 15 questions, focusing on the local prevalence, assessment, and management strategies of major and intracranial hemorrhage (ICH) occurring in patients on VKAs. We planned to interview a sample of 320 Italian emergency physicians. Institutions from all geographic areas of Italy were to participate in the survey. Results: Of the 320 physicians contacted, 150 (47%) completed the survey, 95% being employed in public hospitals. Focusing on ICH, only 29% of the responders stated they would reverse anticoagulation irrespective of the international normalized ratio value, and only 27% would use prothrombin-complex concentrate as first-line agent. In patients needing urgent neurosurgical operation, less than 50% would administer prothrombin-complex concentrate before surgery. Conclusion: The average knowledge of management strategies for reversal of anticoagulation displayed by Italian emergency physicians appears to be unsatisfactory. The need for an extensive educational program and for the implementation of specific guidelines, possibly endorsed by Scientific Societies, cannot be underemphasized.


281§
Barrios, D., Chavant, J., Jiménez, D., Bertoletti, L., Rosa-Salazar, V., Muriel, A., Viallon, A., Fernández-Capitán, C., Yusen, R.D., Monreal, M., Decousus, H., Prandoni, P., Brenner, B., Barba, R., Di Micco, P., Tzoran, I., Reis, A., Bosevski, M., Bounameaux, H., Malý, R., Wells, P., Verhamme, P., Adarraga, M.D., Aibar, M.A., Alfonso, M., Arcelus, J.I., Azcarate-Agüero, P.M., Ballaz, A., Barrón, M., Barrón-Andrés, B., Bascuñana, J., Blanco-Molina, A., Cañada, G., Cañas, I., Casado, I., Chic, N., del Pozo, R., del Toro, J., Díaz-Pedroche, M.C., Díaz-Peromingo, J.A., Falgá, C., Fernández-Aracil, C., Fidalgo, M.A., Font, C., Font, L., Gallego, P., García, M.A., García-Bragado, F., García-Brotons, P., Gavín, O., Gómez, C., Gómez, V., González, J., Grau, E., Grimón, A., Guirado, L., Gutiérrez, J., Hernández-Comes, G., Hernández-Blasco, L., Jara-Palomares, L., Jaras, M.J., Jiménez, J., Joya, M.D., Llamas, P., Lobo, J.L., López, P., López-Jiménez, L., López-Reyes, R., López-Sáez, J.B., Lorente, M.A., Lorenzo, A., Luque, J.M., Marchena, P.J., Martínez, C., Martín-Martos, F., Nieto, J.A., Nieto, S., Núñez, A., Núñez, M.J., Otalora, S., Otero, R., Pedrajas, J.M., Pérez, G., Pérez-Ductor, C., Peris, M.L., Pons, I., Porras, J.A., Reig, O., Riera-Mestre, A., Riesco, D., Rivas, A., Rodríguez, M., Rodríguez-Dávila, M.A., Sahuquillo, J.C., Sala-Sainz, M.C., Sampériz, A., Sánchez-Martínez, R., Sanz, O., Soler, S., Sopeña, B., Suriñach, J.M., Tolosa, C., Torres, M.I., Trujillo-Santos, J., Uresandi, F., Usandizaga, E., Valero, B., Valle, R., Vela, J., Vidal, G., Vilar, C., Xifre, B., Vanassche, T., Yoo, H.H.B., Hirmerova, J., Salgado, E., Bura-Riviere, A., Farge-Bancel, D., Hij, A., Mahé, I., Merah, A., Moustafa, F., Braester, A., Antonucci, G., Barillari, G., Bilora, F., Bonanome, A., Bortoluzzi, C., Brandolin, B., Ciammaichella, M., De Ciantis, P., Dentali, F., Duce, R., Giorgi-Pierfranceschi, M., Grandone, E., Imbalzano, E., Lessiani, G., Maida, R., Mastroiacovo, D., Pace, F., Parisi, R., Pesavento, R., Pinelli, M., Poggio, R., Quintavalla, R., Rocci, A., Tiraferri, E., Tonello, D., Tufano, A., Venturelli, U., Visonà, A., Gibietis, V., Skride, A., Vitola, B., Zdraveska, M., Mazzolai, L.

Treatment of Right Heart Thrombi Associated with Acute Pulmonary Embolism
(2017) American Journal of Medicine, 130 (5), pp. 588-595.

PubMed ID: 28011316
DOI: 10.1016/j.amjmed.2016.11.027

Abstract
Background Evidence-based recommendations do not adequately address the treatment of right heart thrombi in patients who present with acute symptomatic pulmonary embolism. Methods This study included patients who had acute pulmonary embolism associated with right heart thrombi and participated in the Registro Informatizado de la Enfermedad TromboEmbólica registry. We assessed the effectiveness of anticoagulation versus reperfusion treatment for the outcomes of all-cause mortality, pulmonary embolism–related mortality, recurrent venous thromboembolism, and major bleeding rates through 30 days after initiation of pulmonary embolism treatment. We used propensity score matching to adjust for the likelihood of receiving reperfusion treatment. Results Of 325 patients with pulmonary embolism and right heart thrombi, 255 (78%; 95% confidence interval, 74-83) received anticoagulation and 70 (22%; 95% confidence interval, 17-26) also received reperfusion treatment. Propensity score–matched pairs analyses did not detect a statistically lower risk of all-cause death (6.2% vs 14%, P = .15) or pulmonary embolism–related mortality (4.7% vs 7.8%; P = .47) for reperfusion compared with anticoagulation. Of the patients who received reperfusion treatment, 6.2% had a recurrence during the study follow-up period, compared with 0% of those who received anticoagulation (P = .049). The incidence of major bleeding events was not statistically different between the 2 treatment groups (3.1% vs 3.1%; P = 1.00). Conclusions In patients with pulmonary embolism and right heart thrombi, no significant difference was found between reperfusion therapy and anticoagulant therapy for mortality and bleeding. The risk of recurrences was significantly higher for reperfusion therapy compared with anticoagulation. Right heart thrombi may not warrant riskier interventions than standard anticoagulation. © 2016 Elsevier Inc.


280§
Tzoran, I., Papadakis, M., Brenner, B., Fidalgo, Á., Rivas, A., Wells, P.S., Gavín, O., Adarraga, M.D., Moustafa, F., Monreal, M., Decousus, H., Prandoni, P., Barba, R., Di Micco, P., Bertoletti, L., Reis, A., Bosevski, M., Bounameaux, H., Malý, R., Wells, P., Aibar, M.A., Alfonso, M., Arcelus, J.I., Barrón, M., Barrón-Andrés, B., Bascuñana, J., Blanco-Molina, A., Bueso, T., Cañada, G., Cañas, I., Chic, N., del Pozo, R., del Toro, J., Díaz-Pedroche, M.C., Díaz-Peromingo, J.A., Falgá, C., Fernández-Capitán, C., Fidalgo, M.A., Font, C., Font, L., Gallego, P., García, A., García, M.A., García-Bragado, F., García-Brotons, P., Gómez, C., Gómez, V., González, J., González-Marcano, D., Grau, E., Grimón, A., Guijarro, R., Gutiérrez, J., Hernández-Comes, G., Hernández-Blasco, L., Hermosa-Los Arcos, M.J., Jara-Palomares, L., Jaras, M.J., Jiménez, D., Joya, M.D., Llamas, P., Lecumberri, R., Lobo, J.L., López, P., López-Jiménez, L., López-Reyes, R., López-Sáez, J.B., Lorente, M.A., Lorenzo, A., Maestre, A., Marchena, P.J., Martín-Martos, F., Nieto, J.A., Nieto, S., Núñez, A., Núñez, M.J., Odriozola, M., Otero, R., Pedrajas, J.M., Pérez, G., Pérez-Ductor, C., Peris, M.L., Porras, J.A., Reig, O., Riera-Mestre, A., Riesco, D., Rodríguez, C., Rodríguez-Dávila, M.A., Rosa, V., Ruiz-Giménez, N., Sahuquillo, J.C., Sala-Sainz, M.C., Sampériz, A., Sánchez-Martínez, R., Sánchez Simón-Talero, R., Sanz, O., Soler, S., Suriñach, J.M., Torres, M.I., Trujillo-Santos, J., Uresandi, F., Valero, B., Valle, R., Vela, J., Vicente, M.P., Villalobos, A., Vanassche, T., Verhamme, P., Hirmerova, J., Tomko, T., del Pozo, G., Salgado, E., Sánchez, G.T., Bura-Riviere, A., Mahé, I., Merah, A., Braester, A., Antonucci, G., Barillari, G., Bilora, F., Bortoluzzi, C., Cattabiani, C., Ciammaichella, M., Di Biase, J., Duce, R., Ferrazzi, P., Giorgi-Pierfranceschi, M., Grandone, E., Imbalzano, E., Lodigiani, C., Maida, R., Mastroiacovo, D., Pace, F., Pesavento, R., Pinelli, M., Poggio, R., Rota, L., Tiraferri, E., Tonello, D., Tufano, A., Visonà, A., Zalunardo, B., Gibietis, V., Skride, A., Vitola, B., Monteiro, P., Ribeiro, J.L., Sousa, M.S., Zdraveska, M., Calanca, L., Erdmann, A., Mazzolai, L.

Outcome of Patients with Venous Thromboembolism and Factor V Leiden or Prothrombin 20210 Carrier Mutations During the Course of Anticoagulation
(2017) American Journal of Medicine, 130 (4), pp. 482.e1-482.e9.

PubMed ID: 27986523
DOI: 10.1016/j.amjmed.2016.11.016

Abstract
Background Individuals with factor V Leiden or prothrombin G20210A mutations are at a higher risk to develop venous thromboembolism. However, the influence of these polymorphisms on patient outcome during anticoagulant therapy has not been consistently explored. Methods We used the Registro Informatizado de Enfermedad TromboEmbólica database to compare rates of venous thromboembolism recurrence and bleeding events occurring during the anticoagulation course in factor V Leiden carriers, prothrombin mutation carriers, and noncarriers. Results Between March 2001 and December 2015, 10,139 patients underwent thrombophilia testing. Of these, 1384 were factor V Leiden carriers, 1115 were prothrombin mutation carriers, and 7640 were noncarriers. During the anticoagulation course, 160 patients developed recurrent deep vein thrombosis and 94 patients developed pulmonary embolism (16 died); 154 patients had major bleeding (10 died), and 291 patients had nonmajor bleeding. On multivariable analysis, factor V Leiden carriers had a similar rate of venous thromboembolism recurrence (adjusted hazard ratio [HR], 1.16; 95% confidence interval [CI], 0.82-1.64), half the rate of major bleeding (adjusted HR, 0.50; 95% CI, 0.25-0.99) and a nonsignificantly lower rate of nonmajor bleeding (adjusted HR, 0.66; 95% CI, 0.43-1.01) than noncarriers. Prothrombin mutation carriers and noncarriers had a comparable rate of venous thromboembolism recurrence (adjusted HR, 1.00; 95% CI, 0.68-1.48), major bleeding (adjusted HR, 0.75; 95% CI, 0.42-1.34), and nonmajor bleeding events (adjusted HR, 1.10; 95% CI, 0.77-1.57). Conclusions During the anticoagulation course, factor V Leiden carriers had a similar risk for venous thromboembolism recurrence and half the risk for major bleeding compared with noncarriers. This finding may contribute to decision-making regarding anticoagulation duration in selected factor V Leiden carriers with venous thromboembolism. © 2017


279§
Trujillo-Santos, J., Bergmann, J.F., Bortoluzzi, C., López-Reyes, R., Giorgi-Pierfranceschi, M., López-Sáez, J.B., Ferrazzi, P., Bascuñana, J., Suriñach, J.M., Monreal, M.

Once versus twice daily enoxaparin for the initial treatment of acute venous thromboembolism
(2017) Journal of Thrombosis and Haemostasis, 15 (3), pp. 429-438.

PubMed ID: 28120516
DOI: 10.1111/jth.13616

Abstract
Essentials In venous thromboembolism (VTE), it is uncertain if enoxaparin should be given twice or once daily. We compared the 15- and 30-day outcomes in VTE patients on enoxaparin twice vs. once daily. Patients on enoxaparin once daily had fewer major bleeds and deaths than those on twice daily. The rate of VTE recurrences was similar in both subgroups. Summary: Background In patients with acute venous thromboembolism (VTE), it is uncertain whether enoxaparin should be administered twice or once daily. Methods We used the RIETE Registry data to compare the 15- and 30-day rates of VTE recurrence, major bleeding and death between patients receiving enoxaparin twice daily and those receiving it once daily. We used propensity score matching to adjust for confounding variables. Results The study included 4730 patients: 3786 (80%) received enoxaparin twice daily and 944 once daily. During the first 15 days, patients on enoxaparin once daily had a trend towards more VTE recurrences (odds ratio [OR], 1.79; 95% confidence interval [CI], 0.55–5.88), fewer major bleeds (OR, 0.42; 95% CI, 0.17–1.08) and fewer deaths (OR, 0.32; 95% CI, 0.13–0.78) than those on enoxaparin twice daily. At day 30, patients on enoxaparin once daily had more VTE recurrences (OR, 2.5; 95% CI, 1.03–5.88), fewer major bleeds (OR, 0.40; 95% CI, 0.17–0.94) and fewer deaths (OR, 0.58; 95% CI, 0.33–1.00). On propensity analysis, patients on enoxaparin once daily had fewer major bleeds at 15 (hazard ratio [HR], 0.30; 95% CI, 0.10–0.88) and at 30 days (HR, 0.16; 95% CI, 0.04–0.68) and also fewer deaths at 15 (HR, 0.37; 95% CI, 0.14–0.99) and at 30 days (HR, 0.19; 95% CI, 0.07–0.54) than those on enoxaparin twice daily. Conclusions Our findings confirm that enoxaparin prescribed once daily results in fewer major bleeds than enoxaparin twice daily, as suggested in a meta-analysis of controlled clinical trials. © 2017 International Society on Thrombosis and Haemostasis


278§
Tafur, A.J., Caprini, J.A., Cote, L., Trujillo-Santos, J., del Toro, J., Garcia-Bragado, F., Tolosa, C., Barillari, G., Visona, A., Monreal, M., Adarraga, M.D., Aibar, M.A., Alfonso, M., Arcelus, J.I., Ballaz, A., Barba, R., Barrón, M., Barŕn-Andrés, B., Bascuñana, J., Blanco-Molina, A., Cañas, I., Chic, N., del Pozo, R., Díaz-Pedroche, M.C., Díaz-Peromingo, J.A., Falgá, C., Fernández-Aracil, C., Fernández-Capitán, C., Fidalgo, M.A., Font, C., Font, L., Gallego, P., García, I., García, M.A., García-Ródenas, M., Gavín, O., Gómez, C., Gómez, V., González, J., Grau, E., Grimón, A., Guijarro, R., Guirado, L., Gutiérrez, J., Hernández-Comes, G., Hernández-Blasco, L., Jara-Palomares, L., Jaras, M.J., Jiménez, D., Jiménez, J., Joya, M.D., Llamas, P., Lobo, J.L., López, P., López-Jiménez, L., López-Reyes, R., López-Sáez, J.B., Lorente, M.A., Lorenzo, A., Lumbierres, M., Marchena, P.J., Martín-Martos, F., Mellado, M., Nieto, J.A., Nieto, S., Núñez, A., Núñez, M.J., Otalora, S., Otero, R., Ovejero, A., Pedrajas, J.M., Pérez, G., Pérez-Ductor, C., Peris, M.L., Pons, I., Porras, J.A., Reig, O., Riera-Mestre, A., Riesco, D., Rivas, A., Rodríguez, M., Rodríguez-Dávila, M.A., Rosa, V., Ruiz-Artacho, P., Ruiz-Giménez, N., Sahuquillo, J.C., Sala-Sainz, M.C., Sampériz, A., Sánchez-Martínez, R., Sanz, O., Soler, S., Sopeña, B., Suriñach, J.M., Torres, M.I., Uresandi, F., Usandizaga, E., Valero, B., Valle, R., Vela, J., Velez-Mendizábal, E., Vidal, G., Vila, M., Villalobos, A., Xifre, B., Vanassche, T., Verhamme, P., Yoo, H.H.B., Wells, P., Hirmerova, J., Malý, R., Salgado, E., Bertoletti, L., Bura-Riviere, A., Falvo, N., Farge-Bancel, D., Hij, A., Mahé, I., Moustafa, F., Braester, A., Brenner, B., Tzoran, I., Antonucci, G., Bilora, F., Bortoluzzi, C., Brandolin, B., Bucherini, E., Candeloro, G., Cattabiani, C., Ciammaichella, M., Dentali, F., Di Micco, P., Duce, R., Giorgi-Pierfranceschi, M., Grandone, E., Imbalzano, E., Lessiani, G., Maida, R., Mastroiacovo, D., Pace, F., Parisi, R., Pellegrinet, M., Pesavento, R., Pinelli, M., Poggio, R., Prandoni, P., Quintavalla, R., Rocci, A., Tiraferri, E., Tonello, D., Tufano, A., Visoná, A., Gibietis, V., Skride, A., Vitola, B., Bosevski, M., Zdraveska, M., Bounameaux, H., Mazzolai, L., RIETE Investigators

Predictors of active cancer thromboembolic outcomes: RIETE experience of the Khorana score in cancer-associated thrombosis
(2017) Thrombosis and Haemostasis, 117 (6), pp. 1192-1198.

PubMed ID: 28276571
DOI: 10.1160/TH16-11-0840

Abstract
Even though the Khorana risk score (KRS) has been validated to predict against the development of VTE among patients with cancer, it has a low positive predictive value. It is also unknown whether the score predicts outcomes in patients with cancer with established VTE. We selected a cohort of patients with active cancer from the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry to assess the prognostic value of the KRS at inception in predicting the likelihood of VTE recurrences, major bleeding and mortality during the course of anticoagulant therapy. We analysed 7948 consecutive patients with cancer-associated VTE. Of these, 2253 (28 %) scored 0 points, 4550 (57 %) 1-2 points and 1145 (14 %) scored ≥points. During the course of anticoagulation, amongst patient with low, moderate and high risk KRS, the rate of VTE recurrences was of 6.21 (95 %CI: 4.99-7.63), 11.2 (95 %CI: 9.91-12.7) and 19.4 (95 %CI: 15.4-24.1) events per 100 patient-years; the rate of major bleeding of 5.24 (95 %CI: 4.13-6.56), 10.3 (95 %CI: 9.02-11.7) and 19.4 (95 %CI: 15.4-24.1) bleeds per 100 patient-years and the mortality rate of 25.3 (95 %CI: 22.8-28.0), 58.5 (95 %CI: 55.5-61.7) and 120 (95 %CI: 110-131) deaths per 100 patient-years, respectively. The C-statistic was 0.53 (0.50-0.56) for recurrent VTE, 0.56 (95 %CI: 0.54-0.59) for major bleeding and 0.54 (95 %CI: 0.52-0.56) for death. In conclusion, most VTEs occur in patients with low or moderate risk scores. The KRS did not accurately predict VTE recurrence, major bleeding, or mortality among patients with cancer-associated thrombosis. © Schattauer 2017.


277§
Pastore, G., Maines, M., Marcantoni, L., Zanon, F., Noventa, F., Corbucci, G., Baracca, E., Aggio, S., Picariello, C., Lanza, D., Rigatelli, G., Carraro, M., Roncon, L., Barold, S.S.

ECG parameters predict left ventricular conduction delay in patients with left ventricular dysfunction
(2016) Heart Rhythm, 13 (12), pp. 2289-2296.

PubMed ID: 27424074
DOI: 10.1016/j.hrthm.2016.07.010

Abstract
Background Estimating left ventricular electrical delay (Q-LV) from a 12-lead ECG may be important in evaluating cardiac resynchronization therapy (CRT). Objective The purpose of this study was to assess the impact of Q-LV interval on ECG configuration. Methods One hundred ninety-two consecutive patients undergoing CRT implantation were divided electrocardiographically into 3 groups: left bundle branch block (LBBB), right bundle branch block (RBBB), and nonspecific intraventricular conduction delay (IVCD). The IVCD group was further subdivided into 81 patients with left (L)-IVCD and 15 patients with right (R)-IVCD (resembling RBBB, but without S wave in leads I and aVL). The Q-LV interval in the different groups and the relationship between ECG parameters and the maximum Q-LV interval were analyzed. Results Patients with LBBB presented a long Q-LV interval (147.7 ± 14.6 ms, all exceeding cutoff value of 110 ms), whereas RBBB patients presented a very short Q-LV interval (75.2 ± 16.3 ms, all <110 ms). Patients with an IVCD displayed a wide range of Q-LV intervals. In L-IVCD, mid-QRS notching/slurring showed the strongest correlation with a longer Q-LV interval, followed, in decreasing order, by QRS duration >150 ms and intrinsicoid deflection >60 ms. Isolated mid-QRS notching/slurring predicted Q-LV interval >110 ms in 68% of patients. The R-IVCD group presented an unexpectedly longer Q-LV interval (127.0 ± 12.5 ms; 13/15 patients had Q-LV >110 ms). Conclusion Patients with LBBB have a very prolonged Q-LV interval. Mid-QRS notching in lateral leads strongly predicts a longer Q-LV interval in L-IVCD patients. Patients with R-IVCD constitute a subgroup of patients with a long Q-LV interval. © 2016 Heart Rhythm Society


276§
Camporese, G., Bernardi, E., Noventa, F.

Reply to Nemeth et al. “The ERIKA trial: Still limited evidence on the efficacy of thromboprophylaxis after knee arthroscopy”
(2016) Thrombosis and Haemostasis, 116 (5), p. 1002.

DOI: 10.1160/TH16-08-0649


275§
Zanon, F., Marcantoni, L., Baracca, E., Pastore, G., Lanza, D., Fraccaro, C., Picariello, C., Conte, L., Aggio, S., Roncon, L., Pacetta, D., Badie, N., Noventa, F., Prinzen, F.W.

Optimization of left ventricular pacing site plus multipoint pacing improves remodeling and clinical response to cardiac resynchronization therapy at 1 year
(2016) Heart Rhythm, 13 (8), pp. 1644-1651.

PubMed ID: 27450156
DOI: 10.1016/j.hrthm.2016.05.015

Abstract
Background Approximately one-third of the patients with heart failure (HF) treated with cardiac resynchronization therapy (CRT) fail to respond. Positioning the left ventricular (LV) pacing lead in the area of the latest electrical delay may improve the response to CRT. Multipoint pacing (MPP) of the LV has been shown to improve the acute hemodynamic response. Objective The purpose of this study was to test the hypothesis that patients treated with MPP in whom LV pacing location is optimized have better long-term clinical outcomes than do patients treated with conventional CRT. Methods We evaluated the echocardiographic and clinical response of 110 patients with HF treated for nearly 1 year with either conventional CRT (standard [STD] group, n = 54, 49%), CRT with hemodynamic and electrical optimization of the LV pacing site (optimized [OPT] group, n = 36, 33%), or OPT combined with MPP (OPT + MPP group, n = 20, 18%). Responders were classified in terms of reduction in end-systolic volume index ≥15%, reduction in New York Heart Association (NYHA) class ≥1, and Packer score variation (NYHA response with no HF-related hospitalization events or death). Results In STD, OPT, and OPT + MPP groups, 56%, 72%, and 90% of patients, respectively, were end-systolic volume index responders (P = .004) and 67%, 78%, and 95% were NYHA class responders (P = .012); 59%, 67%, and 90% of patients exhibited a 1-year Packer score of 0 (P = .018). These trends remained significant after adjustment for confounding factors by multivariate logistic analysis. Conclusion Combining MPP with optimal positioning of the LV lead on the basis of electrical delay and hemodynamics enhances reverse remodeling and improves clinical outcomes beyond the effect due to conventional CRT. © 2016 The Authors

Author Keywords
Cardiac resynchronization therapy; Electrical delay; Heart failure; Hemodynamic response; Left ventricular pacing; Multipoint pacing


274§
Camporese, G., Bernardi, E., Noventa, F., Bosco, M., Monteleone, G., Santoro, L., Bortoluzzi, C., Freguja, S., Nardin, M., Marullo, M., Zanon, G., Mazzola, C., Damiani, G., Maniscalco, P., Imberti, D., Lodigiani, C., Becattini, C., Tonello, C., Agnelli, G., Santoliquido, A., Di Giorgio, A., Nicolardi, E., Biondi, G., Fieri, C., Dall’Acqua, D., De Matthaeis, A., Giannotta, L., Masciangelo, M., Taccardo, G., De Vitis, R., Militerno, A., Serpieri, S., Cilli, V., Parisi, R., Azzaretti, A., Gori, A., Cassola, P., Zabzuni, D., Volpi, P., Bait, C., Vitali, S., Vedovati, M.C., Di Micco, P., Dimaro, P., Ghirarduzzi, A., Veropalumbo, R., The ERIKA Study Group

Efficacy of rivaroxaban for thromboprophylaxis after knee arthroscopy (ERIKA): A phase ii, multicentre, double-blind, placebo-controlled randomised study
(2016) Thrombosis and Haemostasis, 116 (2), pp. 349-355.

PubMed ID: 27075710
DOI: 10.1160/TH16-02-0118

Abstract
Without thromboprophylaxis, knee arthroscopy (KA) carries a low to moderate risk of venous thromboembolism. Over 5 million arthroscopies are performed worldwide yearly. It was our study objective to assess the efficacy and safety of rivaroxaban for thromboprophylaxis after therapeutic KA. Patients undergoing KA in nine Italian teaching or community hospitals were allocated to once-daily rivaroxaban (10 mg) or placebo for seven days in a phase II, multicentre, double-blind, placebo-controlled randomised trial. The primary efficacy outcome was a composite of all-cause death, symptomatic thromboembolism and asymptomatic proximal DVT at three months; major bleeding represented the primary safety outcome. All patients underwent whole-leg ultrasonography at day 7(+1), or earlier if symptomatic. A total of 241 patients were randomised (122 rivaroxaban, 119 placebo), and 234 completed the study. The primary efficacy outcome occurred in 1/120 of the rivaroxaban group and in 7/114 of the placebo group (0.8% vs 6.1%, respectively, p=0.03; absolute risk difference, -5.3%, 95 °% CI, -11.4 to -0.8; crude relative risk 0.14, 95%> CI, 0.02 to 0.83; number-needed-to-treat=19). No major bleedings were observed. We found no association between different arthroscopic procedures and thrombotic events. Small sample size, high exclusion rate, and low number of anterior cruciate ligament reconstruction procedures are the main limitations of our study. In conclusion, a seven-day course of 10-mg rivaroxaban may be safely employed for thromboprophylaxis after KA. Whether prophylaxis after KA should be given to all patients, or to selected "high-risk" subjects, remains to be determined. A larger trial to verify our preliminary results is warranted. © Schattauer 2016.


273§
Prandoni, P., Noventa, F., Lensing, A.W.A., Prins, M.H., Villalta, S.

Post-thrombotic syndrome and the risk of subsequent recurrent thromboembolism
(2016) Thrombosis Research, 141, pp. 91-92.

PubMed ID: 26986754
DOI: 10.1016/j.thromres.2016.03.010


272§
Zilio, M., Mazzai, L., Sartori, M.T., Barbot, M., Ceccato, F., Daidone, V., Casonato, A., Saggiorato, G., Noventa, F., Trementino, L., Prandoni, P., Boscaro, M., Arnaldi, G., Scaroni, C.

A venous thromboembolism risk assessment model for patients with Cushing’s syndrome
(2016) Endocrine, 52 (2), pp. 322-332.

PubMed ID: 26113424
DOI: 10.1007/s12020-015-0665-z

Abstract
Cushing’s syndrome (CS) is associated with an incidence of venous thromboembolism (VTE) about ten times higher than in the normal population. The aim of our study was to develop a model for identifying CS patients at higher risk of VTE. We considered clinical, hormonal, and coagulation data from 176 active CS patients and used a forward stepwise logistic multivariate regression analysis to select the major independent risk factors for thrombosis. The risk of VTE was calculated as a ‘CS-VTE score’ from the sum of points of present risk factors. VTE developed in 20 patients (4 pulmonary embolism). The group of CS patients with VTE were older (p < 0.001) and had more cardiovascular events (p < 0.05), infections and reduced mobility (both p < 0.001), higher midnight plasma cortisol levels (p < 0.05), and shorter APTT (p < 0.01) than those without. We identified six major independent risk factors for VTE: age ≥69 years and reduced mobility were given two points each, whereas acute severe infections, previous cardiovascular events, midnight plasma cortisol level >3.15 times the normality and shortened APTT were given one point each. A CS-VTE score <2 anticipated no risk of VTE; a CS-VTE score of two mild risk (10 %); a CS-VTE score of three moderate risk (46 %); a CS-VTE score ≥4 high risk (85 %). Considering a score ≥3 as predictive of VTE, 94 % of the patients were correctly classified. A simple score helps stratify the VTE risk in CS patients and identify those who could benefit from thromboprophylaxis. © 2015, Springer Science+Business Media New York.


271§
Pastore, G., Zanon, F., Baracca, E., Aggio, S., Corbucci, G., Boaretto, G., Roncon, L., Noventa, F., Barold, S.S.

The risk of atrial fibrillation during right ventricular pacing
(2016) Europace, 18 (3), pp. 353-358.

PubMed ID: 26443444
DOI: 10.1093/europace/euv268

Abstract
Aims Right ventricular pacing adversely affects left atrial (LA) structure and function that may trigger atrial fibrillation (AF). This study compares the occurrence of persistent/permanent AF during long-term Hisian area (HA), right ventricular septal (RVS), and right ventricular apex (RVA) pacing in patients with complete/advanced atrioventricular block (AVB). Methods and results We collected retrospective data from 477 consecutive patients who underwent pacemaker implantation for complete/advanced AVB. Ventricular pacing leads were located in the HA, RVS, and RVA in 148, 140, and 189 patients, respectively. The occurrence of persistent/permanent AF was observed in 114 (23.9%) patients (follow-up 58.5 ± 26.5 months). Hisian area groups presented a lower rate of AF occurrence (16.9%) compared with RVS and RVA groups (25.7 and 28.0%, respectively), P = 0.049. Cox's proportional hazard model was used to estimate HR. The risk of persistent/permanent AF was significantly lower in the patients paced from HA compared with those paced from RVA, HR = 0.28 (95% CI 0.16-0.48, P = 0.0001). The RVS and RVA pacing groups showed a similar AF risk: HR 1.04 (95% CI 0.66-1.64, P = 0.856). Other independent predictors of persistent/permanent AF occurrence included previous (before device implantation) paroxysmal AF (HR = 4.08; 95% CI 3.15-7.31, P = 0.0001), LA diameter, and age, whereas baseline bundle-branch block was associated with a lower risk of AF occurrence (HR = 0.56; 95% CI 0.35-0.81, P = 0.003). Conclusions HA pacing compared with RVA or RVS pacing seems to be associated with a lower risk of persistent/permanent AF occurrence. The risk of persistent/permanent AF was similar in the RVA vs. RVS groups. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015.


270§
van Es, N., Bleker, S.M., Di Nisio, M., Kleinjan, A., Beyer-Westendorf, J., Camporese, G., Kamphuisen, P.W., Büller, H.R., Bossuyt, P.M., ARMOUR study investigators

A clinical decision rule and D-dimer testing to rule out upper extremity deep vein thrombosis in high-risk patients
(2016) Thrombosis Research, 148, pp. 59-62.

PubMed ID: 27815967
DOI: 10.1016/j.thromres.2016.10.019

Abstract
Introduction In a management study, a diagnostic algorithm consisting of a clinical decision rule, D-dimer, and ultrasonography was shown to safely exclude upper extremity deep vein thrombosis (UEDVT). Efficiency may be lower in high-risk subgroups: those with a central venous catheter or pacemaker, inpatients, cancer, and elderly patients. Methods Data of 406 patients with suspected UEDVT enrolled in a prospective management study were used for the present analysis. The aim was to evaluate the efficiency of the algorithm in subgroups, defined as the proportion of patients in whom imaging could be safely withheld based on the combination of a decision rule result indicating “UEDVT unlikely” and a normal D-dimer result. Results The strategy excluded UEDVT in 87 of 406 patients (21%); ultrasonography was withheld in these patients and none developed UEDVT during 3 months of follow-up. In contrast, ultrasonography could be withheld in only 4 of 92 patients with a catheter or pacemaker (4.3%; 95% CI: 1.7% to 11%) and in 4 of 83 inpatients (4.8%; 95% CI: 1.9% to 12%). The efficiency was 11% in patients with cancer and 13% in those older than 75 years. Conclusion Although the combination of a decision rule and D-dimer testing is safe in excluding UEDVT in the overall population of patients with suspected UEDVT, its efficiency appears limited in some subgroups, in particular those with a central venous catheter or pacemaker, and inpatients. © 2016 Elsevier Ltd


269§
Guercini, F., Mommi, V., Camporese, G., Tonello, C., Imberti, D., Benedetti, R., De Bartolomeo, G., Di Lecce, L., Romeo, F., Agnelli, G.

The management of patients with venous thromboembolism in Italy: insights from the PREFER in VTE registry
(2016) Internal and Emergency Medicine, 11 (8), pp. 1095-1102.

PubMed ID: 27448310
DOI: 10.1007/s11739-016-1507-6

Abstract
Venous thromboembolism (VTE) is the third most common cardiovascular disease. Real-life data on the clinical presentation, risk factors, diagnosis, and treatment of VTE in Italy and Europe are required to optimize the management of this disease. The PREFER in VTE registry, a prospective non-interventional real-life study, was designed to assess clinical characteristics and management of patients with VTE, use of health care resources, and on-treatment patient quality of life. Eligible consecutive patients with objectively diagnosed VTE were enrolled in the registry and followed up for 12 months. Between January and December 2013, 816 Italian and 1027 patients from 6 European countries other than Italy (European patients) were enrolled in the registry, and followed up until December 2014. Italian patients were the oldest (mean age 65.7 years) among the European patients. The Italian patients with a history of cancer were 24.6 % of whom 63.2 % had an active cancer (18.2 and 57.0 %, respectively, in Europe). Parenteral heparin was given, as initial treatment, in 73.8 % of Italian patients (66.4 % in Europe); VKA in combination with other treatments in 45.8 % (34.7 % in Europe); and VKA as the only anticoagulant treatment in 24.4 % (17.2 % in Europe). Of the Italian patients, 43.2 and 90.6 % of patients were hospitalized for deep vein thrombosis and pulmonary embolism, respectively; 65.4 % were admitted to the hospital through the emergency department. Following a real world approach, PREFER in VTE shows that the Italian patients, among and compared to the European patients, are the oldest, have a history of cancer more commonly, receive an initial treatment with heparin more commonly, and are more commonly hospitalized, particularly if affected by PE. © 2016, SIMI.


268§
Bleker, S.M., van Es, N., Kleinjan, A., Büller, H.R., Kamphuisen, P.W., Aggarwal, A., Beyer-Westendorf, J., Camporese, G., Cosmi, B., Gary, T., Ghirarduzzi, A., Kaasjager, K., Lerede, T., Marschang, P., Meijer, K., Otten, H.-M., Porreca, E., Righini, M., Verhamme, P., van Wissen, S., Di Nisio, M.

Current management strategies and long-term clinical outcomes of upper extremity venous thrombosis
(2016) Journal of Thrombosis and Haemostasis, 14 (5), pp. 973-981.

PubMed ID: 26866515
DOI: 10.1111/jth.13291

Abstract
Background: There is scant information on the optimal management and clinical outcome of deep and superficial vein thrombosis of the upper extremity (UEDVT and UESVT). Objectives: To explore treatment strategies and the incidence of recurrent venous thromboembolism (VTE), mortality, postthrombotic symptoms, and bleeding in patients with UEDVT and UESVT and to assess the prognosis of cancer patients with UEDVT. Patients/methods: Follow-up of patients with UEDVT or UESVT, who were enrolled previously in a diagnostic management study. Results: We followed 102 and 55 patients with UEDVT and UESVT, respectively, both for a median of 3.5 years. Anticoagulant treatment was started in 100 patients with UEDVT (98%) and in 40 (73%) with UESVT. Nine patients with UEDVT (9%) developed recurrent VTE, 26 (26%) died, 6 (8%) of 72 patients had moderate postthrombotic symptoms, and 5 (5%) experienced major bleeding. One patient with UESVT had a recurrent VTE, 18 (33%) died, none had moderate postthrombotic symptoms, and none had major bleeding. Of the cancer patients with UEDVT, 18% had recurrent VTE vs. 7.5% in non-cancer patients (adjusted hazard ratio 2.2, 95%CI 0.6-8.2). The survival rate was 50% in cancer patients with UEDVT vs. 60% in those without (adjusted HR 0.8, 95%CI 0.4-1.4). Conclusions: The risk of recurrent VTE was low in patients with UEDVT, and negligible for UESVT. Mortality was high for both diseases. Postthrombotic symptoms were infrequent and mild. Anticoagulant therapy of UEDVT carried a substantial risk of major bleeding. Cancer patients had a significant risk of recurrent VTE. © 2016 International Society on Thrombosis and Haemostasis.


267§
Prandoni, P., Bernardi, E., Valle, F.D., Visonà, A., Tropeano, P.F., Bova, C., Bucherini, E., Islam, M.S., Piccioli, A.

Extensive Computed Tomography versus Limited Screening for Detection of Occult Cancer in Unprovoked Venous Thromboembolism: A Multicenter, Controlled, Randomized Clinical Trial
(2016) Seminars in Thrombosis and Hemostasis, 42 (8), pp. 884-890.

PubMed ID: 27764880
DOI: 10.1055/s-0036-1592335

Abstract
Patients with unprovoked venous thromboembolism (VTE) may harbor occult cancer. Whether an extensive diagnostic work-up for cancer has additional value over a more limited screening for detection of underlying malignancy in these patients is controversial. We performed a randomized multicenter trial to assess if in patients with unprovoked VTE, a computed tomography (CT)-based diagnostic strategy including thoracic, abdominal, and pelvic CT in combination with fecal occult blood test yields a higher cancer detection rate than a nonstandardized testing approach based on physicians' clinical judgment and patients' preferences. Cancer-free patients were followed up for up to 24 months. Of the 195 consecutive patients with unprovoked VTE who were eligible for this investigation, an occult cancer was identified in 10 of the 98 patients (10.2%) randomized to the CT-based strategy, and in 8 of the 97 (8.2%) allocated to the personalized strategy (absolute difference, 2.0%; 95% confidence interval, −7.2-11.1; p = 0.81). During follow-up, cancer was identified in an additional 2 patients in each group. Overall, 7 (7.1%) patients of the CT-based strategy died, as compared with 11 (11.3%) of the personalized strategy, with 2 and 4, respectively, due to cancer. In conclusion, a CT-based strategy in combination with fecal occult blood test does not provide a clinically significant benefit over more limited cancer screening for detecting occult cancer in patients with unprovoked VTE. © Thieme Medical Publishers333 Seventh Avenue, New York, NY 10001, USA.


266§
Bernardi, E., Carbone, G., Dentali, F.

How to manage patients on rivaroxaban in the emergency department: A statement of the Italian society of emergency medicine advisory board
(2016) European Journal of Emergency Medicine, 23 (5), pp. 320-329.

PubMed ID: 26351974
DOI: 10.1097/MEJ.0000000000000322

Abstract
Rivaroxaban, a new oral anticoagulant, has been approved in many countries and its everyday use in clinical practice is increasing. Thus, the chances for an emergency physician to encounter rivaroxaban-treated patients in emergency situations have increased. Here, the authors address the main issues in terms of the prescription of rivaroxaban and the management of these patients in cases of minor or major bleeding, urgent surgery, atrial fibrillation requiring cardioversion, acute ischemic stroke, ST-elevation myocardial infarction, and new onset of atrial fibrillation in recent ST-elevation myocardial infarction. The recommendations reached are based on a literature review and a panel discussion of the advisory board of SIMEU, the Italian Society of Emergency Medicine. © Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.


265§
Prandoni, P., Lensing, A.W.A., Prins, M.H., Villalta, S., Harenberg, J., Noventa, F.

Residual vein thrombosis and the risk of subsequent serious complications
(2015) Thrombosis Research, 136 (1), pp. 178-179.

PubMed ID: 25981139
DOI: 10.1016/j.thromres.2015.04.038


264§
Zanon, F., Baracca, E., Pastore, G., Marcantoni, L., Fraccaro, C., Lanza, D., Picariello, C., Aggio, S., Roncon, L., Dell'Avvocata, F., Rigatelli, G., Pacetta, D., Noventa, F., Prinzen, F.W.

Multipoint pacing by a left ventricular quadripolar lead improves the acute hemodynamic response to CRT compared with conventional biventricular pacing at any site
(2015) Heart Rhythm, 12 (5), art. no. 6105, pp. 975-981.

PubMed ID: 25625721
DOI: 10.1016/j.hrthm.2015.01.034

Abstract
Background Response to cardiac resynchronization therapy (CRT) remains challenging. Pacing from multiple sites of the left ventricle (LV) has shown promising results. Objective The purpose of this study was to systematically compare the acute hemodynamic effects of multipoint pacing (MPP) by means of a quadripolar lead with conventional biventricular (BiV) pacing. Methods Twenty-nine patients (23 men; mean age 72 ± 12 years; LV ejection fraction 29% ± 7%; 15 with ischemic cardiomyopathy, 17 with left bundle branch block; mean QRS 183 ± 23 ms) underwent CRT implantation. Per patient, 3.2 ± 1.2 different veins and 6.3 ± 2.4 pacing sites were tested. LV electrical delay (Q-LV) was measured at each location, along with the increase in LV dP/dtmax (maximum rate of rise of LV pressure) obtained by BiV and MPP. The effect of MPP, by means of simultaneous pacing from distal and proximal dipoles, was investigated at all available sites. Results Overall, 3.2 ± 1.2 different MPP measurements were collected per patient. When all sites were considered, LV dP/dtmax increased from 951 ± 193 mm Hg/s at baseline to 1144 ± 255 and 1178 ± 259 mm Hg/s on BiV and MPP, respectively. When the best site was considered, LV dP/dtmax increased from a baseline value of 942 ± 202 mm Hg/s to 1200 ± 267 mm Hg/s (BiV) and 1231 ± 267 mm Hg/s (MPP). The mean QRS duration at any site during MPP and conventional CRT was 171 ± 18 and 175 ± 16 ms (P =.003), respectively. Conclusion Compared with BiV pacing at any LV site, MPP yielded a small but consistent increase in hemodynamic response. A correlation between the increase in hemodynamics and Q-LV on MPP was observed for all measurements, including those taken at the best and worst sites. The MPP-induced improvement in contractility was associated with significantly greater narrowing of the QRS complex than conventional BiV pacing. © 2015 Heart Rhythm Society. All rights reserved.


263§
Prandoni, P., Lensing, A.W.A., Prins, M.H., Villalta, S., Negri, S., Piccioli, A., Noventa, F.

Venous thrombotic burden and the risk of subsequent overt cancer
(2015) Thrombosis and Haemostasis, 114 (4), pp. 864-865.

PubMed ID: 26155830
DOI: 10.1160/TH15-02-0146


262§
Prandoni, P., Lensing, A.W.A., Prins, M.H., Pesavento, R., Piccioli, A., Sartori, M.T., Tormene, D., Milan, M., Vedovetto, V., Noventa, F., Villalta, S., Harenberg, J.

The impact of residual thrombosis on the long-term outcome of patients with deep venous thrombosis treated with conventional anticoagulation
(2015) Seminars in Thrombosis and Hemostasis, 41 (2), pp. 133-140.

PubMed ID: 25682083
DOI: 10.1055/s-0035-1544161

Abstract
The impact of residual vein thrombosis (RVT) on the long-term outcome of patients with deep vein thrombosis (DVT) is unknown. We assessed the incidence of recurrent venous thromboembolism (VTE), postthrombotic syndrome (PTS), arterial thrombotic events, and cancer in patients with DVT with and without RVT. For this purpose, we evaluated up to 3 years 869 consecutive patients with acute proximal DVT who had conventional anticoagulation. RVT, defined as ultrasound incompressibility of at least 4 mm in the common femoral and/or the popliteal vein after 3 months, was detected in 429 (49.4%) patients, and was more likely in males (adjusted odds ratio [OR], 1.82; 95% confidence interval [CI], 1.37-2.04), in patients with previous VTE (OR, 1.64; 95% CI, 1.06-2.54), and in those with extensive thrombosis (OR, 3.58; 95% CI, 2.19-5.86). During the 3-year follow-up, recurrent VTE developed in 84 (19.6%) patients with RVT and 43 (9.8%) patients without RVT (adjusted hazard ratio [HR], 2.03; 95% CI, 1.40-2.94); PTS in 225 (52.4%) and 118 (26.8%), respectively (HR, 2.34; 95% CI, 1.87-2.93); arterial thrombosis in 29 (6.7%) and 14 (3.2%), respectively (HR, 2.05; 95% CI, 1.08-3.88); and cancer in 21 (4.9%) and 8 (1.8%), respectively (HR, 3.09; 95% CI, 1.31-7.28). In conclusion, in patients treated with vitamin K antagonists for prevention of recurrent VTE, RVT doubles the risk of recurrent VTE, PTS, arterial thrombosis, and cancer. Males, patients with previous VTE, and those with extensive thrombosis are independent risk factors of RVT development. Studies addressing the impact of the novel direct anticoagulants on the development of RVT as well as the long-term complications of DVT are needed. © 2015 by Thieme Medical Publishers, Inc.


261§
Camporese, G., Bernardi, E., Noventa, F.

Efficacy of rivaroxaban for prevention of venous thromboembolism after knee arthroscopy: a randomized double-blind trial (ERIKA study)
(2015) J Thromb Haemost, 13, p. 204.


260§
Zilio, M., Mazzai, L., Sartori, M.T., Barbot, M., Ceccato, F., Daidone, V., Casonato, A., Saggiorato, G., Noventa, F., Trementino, L., Prandoni, P., Boscaro, M., Arnaldi, G., Scaroni, C.

A venous thromboembolism risk assessment model for patients with Cushing’s syndrome
(2015) Endocrine, 26, pp. 1-11.


259§
Agnelli, G., Gitt, A.K., Bauersachs, R., Fronk, E.-M., Laeis, P., Mismetti, P., Monreal, M., Willich, S.N., Wolf, W.-P., Cohen, A.T., Brodmann, M., Rief, P., Eischer, L., Stoshikj, S., Hirschl, M., Weinmann, S., Marschang, P., Abbadie, F., Achkar, A., Addala, A., Adnet, F., Alexandra, J.-F., Aquilanti, S., Belhassane, A., Benaroya, A., Berremili, T., Grenot, M.C., Birr, V., Holtea, D., Bonnin, C., Bosler, F., Durand, M.-G.B., Brisot, D., Brousse, C., De La Fuente, T., Cayman, R., Cazaubon, M., Champion, O., Chanut, M., Chevalet, P., Connault, J., Durant, C., Constans, J., Cordeanu, M., Couturaud, F., Lacut, K., De Dedker, L., Decoulx, E., Derrien, B., Diamand, J.-M., Diard, A., Douadi, Y., Dupas, S., Remond, S.S.M., Sevestre, M.-A., Edhery, S., Falvo, N., Taralunga, C.F., Ferrari, E., Gaillard, C., Garrigues, D., Gillet, J.L., Giordana, P., Grange, C., Vital-Durand, D., Grare, F., Henni, A.H., Heuser, S., Schmidt, J., Hidden-Henic, V., Hottin, D., Imbert, B., Pernod, G., Jakob, D., Jacquinandi, V., Jurus, C., Lacoste, A., Laroche, J.-P., Martin, M., Mazollier, C., Mersel, T., Miserey, G., Nedey, C., Nou, M., Quere, I., Ouvry, P., Peuch, B., Pichot, O., Poulain, V., Ray, P., Rifai, A., Roy, P.-M., Saby, J.-C., Simon, F., Simonot-Lalandec, E., Stephan, D., Tissot, A., Vodoungnon, H., Adamczyk, A., Schnabl, S., Ahmad, W.A., Weber, H., Axthelm, C., Bergmann, K., Beschorner, U., Knittel, M., Binias, K.-H., Pasligh, M., Boral, M., Friederike, G., Bratsch, H., Brauer, G., Burghard, S., Demann, C., Rennebaum, C., Demmig, A., Eberlein, U., Enger, F., Eschenburg, J., Forkmann, L., Frank, J., Freischmidt, H., Gassauer, M., Fritsche, I., Kubicek-Hofmann, C., Goebels, M.-C., Guggenbichler, S., Härtel, D., Hartmann, K., Heilberger, P., Heinsius, A., Held, M., Schnupp, S., Herman, G., Herold, J., Hertrich, F., Hommel, H., Hütte, G., Kalka, C., Jungandreas, K., Ramthor, M., Karcher, J., Werner, N., Karl-Wollweber, S., Keilhau, D.-A., Kittel, K., Knolinski, T., Köhler, C., Werth, S., Kopplin, U., Körner, I., Wittig, K., Kröger, K., Moysidis, T., Kroschel, U., Leschke, M., zur Nieden, T., Lübbert, G., Lutz, A., Wucherpfennig, P., Marencke, G.-H., Mortensen, K., Reppel, M., Nelles, H., Nestler, K., Neumeister, A., Schlosser, A., Oettler, W., Ott, I., Otto, A., Pertermann, A., Pfister, R., Pindur, L., Pourhassan, S., Predel, D., Pudollek, T., Reimer, D., Richter, C., Rieker, E., Rothenbücher, G., Rothhagen, B., Rudolff, S., Stücker, M., Schäfer, A., Sonnenschein, K., Schafnitzl, W., Schellong, S., Voigts, B., Schiller, M., Schmeink, T., Schneider, H., Schön, N., Schulze, M., Sechtem, U., Sedl, S., Werno, H.S., Stachowitz, J., Thieme, M., Tiefenbacher, C., Tsantilas, D., Vieth, P., vom Dahl, J., Grün-Himmelmann, K., von Bilderling, P., von Maltik, T., Weinrich, K., Weyer, M., Köln, E.K., Wirtz, P., Wittig, I., Zierock, P., Ageno, W., Caprioli, M., Rancan, E., Guercini, F., Mommi, V., Amitrano, M., Cannavacciuolo, F., Amore, M., D'Antoni, S., Angelini, E., Forgia, S.L., Antignani, P.L., Calandra, G., Arone, A., Perticone, F., Sciacqua, A., Asaro, G., Bellisi, M., Attanzio, M.T., Pinto, A., Attinasi, V., Cillari, E., Sorvillo, S., Balbarini, A., Santini, C., Violo, C., Banfi, E., Lodigiani, C., Barcellona, D., Delpin, S., Marongiu, S., Barillari, G., Pasca, S., Bartolini, C., Verdecchia, P., Bartone, M., Mancuso, G., Bellanuova, I., Felis, S., Bellizzi, A., Masotti, L., Bianchi, M., Carugati, A., Bianchini, G., Guarnera, G., Boari, B., Gallerani, M., Pasin, M., Bortoluzzi, C., Parisi, R., Brucoli, C., Palasciano, G., Camporese, G., Tonello, C., Canafoglia, L., Rupoli, S., Cancellieri, E., Paoletti, O., Testa, S., Carlizza, A., Carnovali, M., Sada, S., Samaden, A., Casarsa, C., Mearelli, F., Pivetti, G., Catalini, R., Zingaretti, O., Vascolare, M., Cavazza, S., Cosmi, B., Cenci, C., Prisco, D., Silvestri, E., Ceresa, F., Patanè, F., Ciampa, A., Siniscalchi, V., Ciarambino, T., De Bartolomeo, G., Clemente, M., Conti, F., Paiella, L., D'Avino, M., D'Alessandro, A., Placentino, M., Sollazzo, V., D'Angelo, A., Viganò, S., De Campora, P., Sangiuolo, R., De Franciscis, S., Serra, R., De Gaudenzi, E., De Santis, F., Piccinni, G.C., De Tommaso, I.D., Di Francesco, L., Vincentelli, G.M., Di Maggio, R., Saccullo, G., Siragusa, S., Di Micco, P., Fontanella, A., Di Michele, D., Di Minno, G., Tufano, A., Di Nisio, M., Porreca, E., Donadio, F., Imberti, D., Enea, I., Fabbian, F., Manfredini, R., Pala, M., Falanga, A., Milesi, V., Fiore, V., Franco, E., Giudice, G., Frausini, G., Rovinelli, M., Fuorlo, M., Landolfi, R., Morretti, T., Gamberini, S., Salmi, R., Ghirarduzzi, A., Veropalumbo, M.R., Ghizzi, M., Pepe, C., Gianniello, F., Martinelli, I., Iosub, D.I., Piovella, F., Iozzi, E., Talerico, A., Regina, M.L., Orlandini, F., Marconi, L., Palla, A., Marcucci, R., Poli, D., Margheriti, R., Sala, G., Marra, A., Marrocco, F., Montagna, E.S., Silvestris, F., Vallarelli, S., Mos, L., Rossetto, V., Mugno, F., Di Salvo, M., Nitti, C., Pennacchioni, M., Salvi, A., Olivieri, O., Tosi, F., Zorzi, F., Onesta, M., Pagliara, V., Villalta, S., Paolucci, G., Severino, S., Pierri, F., Russo, V., Pizzini, A.M., Quintavalla, R., Rubino, P., Ria, L., Schenone, A., Strafino, C., Tropeano, P., Vetrano, A., Zanatta, N., Cansino, M.D.A., Gutierrez, J.A., de las Revillas, F.A., Fernández, C.A., Mijares, N.C., Blanco-Molina, M.Á., Garcia, M.A., Seijo, D.J., Blazquez, R.A., López-Sáez, J.-B., Rodrigo, E.A., Blanch, J.V., Arxe, A.A., Dalmau, F.G.-B., Quincoces, A.B., Loizaga, A.G., Pérez, J.L.B., Díaz, P.B., Loaiza, A.Q., Castellote, M.C., Alcántara, I.C., Padierna, M.L., Expósito, M.C., Mas, A.C., Castro, F.C., Sanz, R.C., de Saracho, J.O., de la Fuente, E.C., de Ancos Aracil, C., Ruiz, J.R., de Daborenea González, M.D., Iglesias, A.F., de la Fuente Aguado, J., González, L.G., del Carmen Fernández-Capitán, M., Hernández, A.L., del Toro Cervera, J., Rus, G.P., Bregel, J.L.D., Fernández, F.D., Teresa Elias Hernández, Palomares, L.J., Bataler, R.F., Rodríguez, J.A.N., García, J.M.G., Porras, J.R.G., García, M.G., López, E.H., Lázaro, A.R., Jaras, M.J., Castro, D.J., Madridejos, R.J.-R., Navas, J.M.P., Lecumberri, R., Martínez, N., Castellanos, G.T.L., Espinosa, L.M., Jiménez, L.L., Cobo, O.M., Saiz, C.M., Pizarro, Y.R., Yglesias, P.J.M., Martín del Pozo, M., Melibovsky, L., Altarriba, E.S., Bosch, M.M., Secades, R.M., Luján, J.M.M., Mestre, A.R., Moral, P.M., Parra, J.A.T., Flores, A.M., Muñoz-Torrero, J.F.S., Rodríguez, F.J.M., Fernández, M.J.N., Sibajas, E.O., de Sedas, M.V., Caballero, P.P., del Campo, I.P.M., Sánchez, J.P., Gallego, A.R., álvarez, I.V., Beltrán, E.M.R., Fuentes, D.S., Schilling, V.R., álvarez, J.S., López, G.T., Caralt, J.M.S., Miranda, R.T., de Antonio, E.U., Banyai, M., Frank, U., Gian Reto Jörg, Jeanneret, C., Staub, D., Ackroyd, S., Agarwal, G., Mearns, B., Alikhan, R., Allameddine, A., Al-Refaie, F., Arden, C., Austin, A., Bakhai, A., Barton, T., Ewad, H., Body, R., Thachil, J., Chacko, J., Chandra, D., Charters, F., Church, A., McGrane, F., Clements, J., Clifford, P., Cox, D., Crouch, M., Crowther, M., Davies, E., Davies, M., Dimitri, S., Drebes, A., Franklin, S., George, J., Irvine, N., Gerofke, H., Gibbs, C., Goh, T., Gupta, S., Holmes, J., Jackson-Voyzey, E., Jones, N., Kallat, A., Kerr, P., Kesteven, P., Lench, T., Lester, W., Lowe, G., Lewis, M., McCormack, T., McCoye, A., Moriarty, A., Morris, W., Myers, B., Narayanan, M., Oo, N., Reed, M., Rose, P., Saja, K., Sivakumaran, M., Sohal, M., Solomons, G., Sultanzadeh, S.J., Venton, T., Wakeling, J., Walby, C., Waldron, M., Watt, S., Willcock, W., Zafar, A., On behalf of the PREFER in VTE investigators

The management of acute venous thromboembolism in clinical practice - study rationale and protocol of the European PREFER in VTE Registry
(2015) Thrombosis Journal, 13 (1), art. no. 41, .

DOI: 10.1186/s12959-015-0071-z

Abstract
Background: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. Methods/design: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. Results: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. Conclusion: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. Trial registration: Registered in DRKS register, ID number: DRKS00004795


258§
Imberti, D., Dentali, F., Ivaldo, N., Murena, L., Paladini, P., Castagna, A., Barillari, G., Guerra, E., Tonello, C., Castoldi, F., Lazzaro, F., Benedetti, R., Camporese, G., Porcellini, G.

Venous Thromboembolism in Patients Undergoing Shoulder Arthroscopy: Findings From the RECOS Registry
(2015) Clinical and Applied Thrombosis/Hemostasis, 21 (5), pp. 486-488.

PubMed ID: 25616489
DOI: 10.1177/1076029614567311


257§
Camporese, G., Avruscio, G.

Use of rivaroxaban for treatment of venous thromboembolism
(2015) Italian Journal of Vascular and Endovascular Surgery, 22 (2), pp. 97-107.


Abstract
Venous thromboembolism (VTE) is the third most common cardiovascular disease after myocardial infarction and stroke. Immediate and effective VTE treatment is mandatory to reduce the risks of thrombus extension and/or embolization in the early stage of the disease, and to limit the onset of the post-thrombotic syndrome, a complication potentially affecting deep veins of the leg in the late phase of the disease. For many years the standard of VTE therapy has been the association of heparins (unfractionated heparin or low-molecular-weight heparins) or fondaparinux, and the vitamin-K-antagonists (warfarin or acenocumarol). The limitations of these anticoagulant drugs stimulated the development of new anticoagulants. Rivaroxaban is a new oral active anticoagulant directly inhibiting the activated factor X for treatment of venous thromboembolism. The single-drug approach with rivaroxaban for treatment of acute deep-vein thrombosis and pulmonary embolism and for extended secondary prevention of VTE recurrence has been largely investigated along the EINSTEIN program with the EINSTEIN-DVT, EINSTEIN-PE and EINSTEIN-Extension randomized clinical trials. This article will review the pharmacokinetic and pharmacodynamic properties of rivaroxaban, its clinical efficacy and tolerability for the initial treatment of the acute phase of deep-vein thrombosis and pulmonary embolism and for the extended secondary prevention for VTE recurrence. Moreover, some practical considerations for its daily clinical use and the current pros and cons about the indications and the unresolved issues will be reported.


256§
Ageno, W., Camporese, G., Riva, N., Iotti, M., Bucherini, E., Righini, M., Kamphuisen, P.W., Verhamme, P., Douketis, J.D., Tonello, C., Prandoni, P., PALLADIO Study Investigators

Analysis of an algorithm incorporating limited and whole-leg assessment of the deep venous system in symptomatic outpatients with suspected deep-vein thrombosis (PALLADIO): A prospective, multicentre, cohort study
(2015) The Lancet Haematology, 2 (11), pp. e474-e480.

PubMed ID: 26686257
DOI: 10.1016/S2352-3026(15)00190-8

Abstract
Background: Compression ultrasonography is the mainstay of diagnosis of deep-vein thrombosis (DVT) of the legs. Compression ultrasonography can be extended to the entire deep venous system (whole-leg) or restricted to the proximal veins only (limited), and the two approaches are clinically equivalent. We aimed to assess the diagnostic value of an algorithm combining whole-leg and limited compression ultrasonography. Methods: We did a prospective, multicentre, cohort study at eight centres in five countries. Consecutive outpatients aged 18 years or older with suspected DVT underwent D-dimer measurement and pretest clinical probability assessment. DVT was ruled out without further testing if pretest probability was unlikely and D-dimer was negative (group 1). Patients in whom either pretest probability was likely or who were positive for D-dimer underwent limited compression ultrasonography only (group 2). Finally, patients in whom pretest probability was likely and who had a positive measurement for D-dimer underwent extended whole-leg compression ultrasonography (group 3). All patients in whom DVT was ruled out were followed up for 3 months. The primary outcome was the incidence of objectively recorded venous thromboembolism. The primary analysis included all patients managed according to the study protocol. This study is registered with ClinicalTrials.gov, number NCT01412242. The final results are reported here. Findings: Between March 1, 2011, and July 31, 2014, 1348 consecutive outpatients were referred for this study, of whom 1162 were eligible to participate. After pretest probability assessment and D-dimer testing, 351 were in group 1, 401 in group 2, and 410 in group 3. Limited compression ultrasonography was positive in 12 (3%) patients in group 2 and extended whole-leg compression ultrasonography was positive in 200 (49%) patients in group 3. 82 (39%) of all DVT diagnosed at baseline were isolated distal thromboses. 26 protocol violations were reported. Thus, 351 patients from group 1, 371 patients in group 2, and 202 patients in group 3 who had been excluded for DVT by the algorithm were included in the primary analysis at 3 months. One, four, and three DVTs were reported, respectively. Thus, the 3-month incidence of venous thromboembolism in untreated patients after a negative diagnostic strategy was 0·87% (95% CI 0·44-1·70). Interpretation: An algorithm combining limited and whole-leg compression ultrasonography could be a reliable, safe, and convenient method for diagnostic management of outpatients with clinically suspected DVT.


255§
Becattini, C., Rondelli, F., Vedovati, M.C., Camporese, G., Giustozzi, M., Boncompagni, M., Pucciarelli, S., Balzarotti, R., Mariani, E., Filippucci, E., Donini, A., Agnelli, G.

Incidence and risk factors for venous thromboembolism after laparoscopic surgery for colorectal cancer
(2015) Haematologica, 100 (1), pp. e35-e38.

PubMed ID: 25216684
DOI: 10.3324/haematol.2014.109843


254§
Piccioli, A., Bernardi, E., Prandoni, P.

Cancer screening in unprovoked venous thromboembolism
(2015) New England Journal of Medicine, 373 (25), p. 2473.

PubMed ID: 26672850
DOI: 10.1056/NEJMc1511798


253§
Spreafico, G., Bernardi, E., Pavei, P., Giraldi, E.

Factors influencing the success of endovenous laser ablation (EVLA)
(2015) Reviews in Vascular Medicine, 3 (4), pp. 31-34.

DOI: 10.1016/j.rvm.2015.10.001

Index Keywords
clinical effectiveness, endovenous laser ablation, energy yield, fiber optics, human, laser, laser surgery, priority journal, recanalization, Review, saphenous vein, surgical anatomy, treatment failure, treatment outcome, vein diameter, vein insufficiency


252§
Zanon, F., Baracca, E., Pastore, G., Fraccaro, C., Roncon, L., Aggio, S., Noventa, F., Mazza, A., Prinzen, F.

Determination of the longest intrapatient left ventricular electrical delay may predict acute hemodynamic improvement in patients after cardiac resynchronization therapy
(2014) Circulation: Arrhythmia and Electrophysiology, 7 (3), pp. 377-383.

PubMed ID: 24668162
DOI: 10.1161/CIRCEP.113.000850

Abstract
Background-One of the reasons for patient nonresponse to cardiac resynchronization therapy is a suboptimal left ventricular (LV) pacing site. LV electric delay (Q-LV interval) has been indicated as a prognostic parameter of cardiac resynchronization therapy response. This study evaluates the LV delay for the optimization of the LV pacing site. Methods and Results-Thirty-two consecutive patients (23 men; mean age, 71±11 years; LV ejection fraction, 30±6%; 18 with ischemic cardiomyopathy; QRS, 181±25 ms; all mean±SD) underwent cardiac resynchronization therapy device implantation. All available tributary veins of the coronary sinus were tested, and the Q-LV interval was measured at each pacing site. The hemodynamic effects of pacing at different sites were evaluated by invasive measurement of LV dP/dtmax at baseline and during pacing. Overall, 2.9±0.8 different veins and 6.4±2.3 pacing sites were tested. In 31 of max 32 (96.8%) patients, the highest LV dP/dtmax coincided with the maximum Q-LV interval. Q-LV interval correlated with the increase in LV dP/dt max in all patients at each site (AR1 p=0.98; P<0.001). A Q-LV value >95 ms corresponded to max ' a >10% in LV dP/dtmax. An inverse correlation between paced QRS duration and improvement in LV dP/dt max was seen max max in 24 patients (75%). Conclusions-Pacing the LV at the latest activated site is highly predictive of the maximum increase in contractility, expressed as LV dP/dtmax. A positive correlation between Q-LV interval and hemodynamic improvement was found in max all patients at every pacing site, a value of 95 ms corresponding to an increase in LV dP/dtmax of ≥10%.


251§
Pastore, G., Aggio, S., Baracca, E., Fraccaro, C., Picariello, C., Roncon, L., Corbucci, G., Noventa, F., Zanon, F.

Hisian area and right ventricular apical pacing differently affect left atrial function: An intra-patients evaluation
(2014) Europace, 16 (7), pp. 1033-1039.

PubMed ID: 24473501
DOI: 10.1093/europace/eut436

Abstract
Aims Right ventricular apex (RVA) pacing has adverse effects on left atrial (LA) function and may contribute to atrial arrhythmias. The effects of Hisian area (HA) pacing on LA function are still lacking. The objective of this study is to assess the left ventricular (LV) electromechanical activation/relaxation, systolic (S), diastolic (D) phases, and their effects on LA function during pacing from HA and RVA. Methods and results Thirty-seven patients with normal cardiac function underwent permanent HA pacing. In all patients, a RVA backup lead was added. The patients first underwent 3 months of HA pacing, followed by 3 months of RVA pacing. After each 3-month period, we compared by echocardiography: S-D LV electromechanical delay (S-D EMD), S-D intra-LV dyssynchrony, LV S-D phases, and their function evaluated by myocardial performance index (MPI) and mitral annular tissue Doppler early diastolic velocity (E′), pulmonary arterial systolic pressure (PASP), and LA function (LA phasic volumes and their emptying fraction). Right ventricular apex compared with HA pacing increased S-D EMD (P < 0.001) and intra-LV dyssynchrony (P < 0.001). As a consequence, a significant longer LV isovolumetric contraction time (P < 0.001) and LV isovolumetric relaxation time (P = 0.05) were measured during RVA compared with HA pacing, whereas LV ejection time was shorter (P = 0.033). Moreover, HA pacing resulted in significantly better MPI (P = 0.039), higher value of E′ (P = 0.049), and lower PASP (P < 0.001). Finally, RVA compared with HA pacing was associated to higher LA volumes pre-atrial contraction (P = 0.001) and minimal volume (P = 0.003) with reduction in passive emptying fraction (P < 0.001) and total emptying fraction (P = 0.005). Conclusion Hisian area compared with RVA pacing resulted in a more physiological LV electromechanical activation/relaxation and consequently better LA function.


250§
Kleinjan, A., Di Nisio, M., Beyer-Westendorf, J., Camporese, G., Cosmi, B., Ghirarduzzi, A., Kamphuisen, P.W., Otten, H.-M., Porreca, E., Aggarwal, A., Brodmann, M., Guglielmi, M.D., Iotti, M., Kaasjager, K., Kamvissi, V., Lerede, T., Marschang, P., Meijer, K., Palareti, G., Rickles, F.R., Righini, M., Rutjes, A.W.S., Tonello, C., Verhamme, P., Werth, S., Van Wissen, S., Büller, H.R.

Safety and feasibility of a diagnostic algorithm combining clinical probability, D-dimer testing, and ultrasonography for suspected upper extremity deep venous thrombosis: A prospective management study
(2014) Annals of Internal Medicine, 160 (7), pp. 451-457.

PubMed ID: 24687068
DOI: 10.7326/M13-2056

Abstract
Background: Although well-established for suspected lower limb deep venous thrombosis, an algorithm combining a clinical decision score, D-dimer testing, and ultrasonography has not been evaluated for suspected upper extremity deep venous thrombosis (UEDVT). Objective: To assess the safety and feasibility of a new diagnostic algorithm in patients with clinically suspected UEDVT. Design: Diagnostic management study. (ClinicalTrials.gov: NCT01324037) Setting: 16 hospitals in Europe and the United States. Patients: 406 inpatients and outpatients with suspected UEDVT. Measurements: The algorithm consisted of the sequential application of a clinical decision score, D-dimer testing, and ultrasonography. Patients were first categorized as likely or unlikely to have UEDVT; in those with an unlikely score and normal D-dimer levels, UEDVT was excluded. All other patients had (repeated) compression ultrasonography. The primary outcome was the 3-month incidence of symptomatic UEDVT and pulmonary embolism in patients with a normal diagnostic work-up. Results: The algorithm was feasible and completed in 390 of the 406 patients (96%). In 87 patients (21%), an unlikely score combined with normal D-dimer levels excluded UEDVT. Superficial venous thrombosis and UEDVT were diagnosed in 54 (13%) and 103 (25%) patients, respectively. All 249 patients with a normal diagnostic work-up, including those with protocol violations (n = 16), were followed for 3 months. One patient developed UEDVT during follow-up, for an overall failure rate of 0.4% (95% CI, 0.0% to 2.2%). Limitations: This study was not powered to show the safety of the substrategies. D-Dimer testing was done locally. Conclusion: The combination of a clinical decision score, D-dimer testing, and ultrasonography can safely and effectively exclude UEDVT. If confirmed by other studies, this algorithm has potential as a standard approach to suspected UEDVT.


249§
Kakkos, S.K., Nicolaides, A.N., Charalambous, I., Thomas, D., Giannopoulos, A., Naylor, A.R., Geroulakos, G., Abbott, A.L., Adovasio, R., Ziani, B., Alò, F.P., Cicilioni, C.G., Ambrosio, G., Andreev, A., Andreozzi, G.M., Verlato, F., Camporese, G., Arosio, E., Barkauskas, E., Barros D'Sa, A.A.B., Brannigan, P., Batchvarova, V., Dramov, A., Belardi, P., Novelli, G.P., Simoni, G., Bell, P., Biasi, G.M., Mingazzini, P., Bornstein, N.M., Bouchier-Hayes, D., Fitzgerald, P., Cairols, M.A., Cao, P.G., DeRango, P., Carboni, G.P., Geoffredo, C., Catalano, M., Chambers, B., Goetzmann, M., Dickinson, A., Clement, D., Bobelyn, M., Coccheri, S., Conti, E., Diamantopoulos, E., Andreadis, E.A., Dimakakos, P.B., Kotsis, T., Eikelboom, B., Entz, L., Ferrari-Bardile, A., Aloi, T., Salerno, M., Fernandes E Fernandes, J., Pedro, L., Fitzgerald, D.E., O'Shaughnessy, A.M., Fletcher, J., Forconi, S., Cappeli, R., Bicchi, M., Arrigucci, S., Gallai, V., Cardaiolli, G., Gomez-Isaza, L.F., Gorgoyannis, G., Liasis, N., Graf, M., Guarini, P., Hardy, S., Harris, P., Aston, S., Iosa, G., Katsamouris, A., Giannoukas, A., Krzanowski, M., Ladurner, G., Leal-Monedero, J., Lee, B.B., Liapis, C., Galanis, P., Liboni, W., Pavanelli, E., Mannarino, E., Vaudo, G., McCollum, P., Levison, R., Micieli, G., Bosone, D., Middleton, L., Pantziaris, M., Tyllis, T., Minar, E., Willfort, A., Moggi, L., Nenci, G., Radicchia, S., Norgren, L., Ribbe, E., Novo, S., Tantillo, R., Olinic, D., Paaske, W., Pagnan, A., Pauletto, P., Pagliara, V., Pettina, G., Pratesi, C., Matticari, S., Polivka, J., Sevcik, P., Poredos, P., Blinc, A., Videcnik, V., Pujia, A., Raso, A., Rispoli, P., Conforti, M., Robinson, T., Dennis, M.S.J., Rosfors, S., Rudofsky, G., Schroeder, T., Gronholdt, M.L., Simoni, G., Finocchi, C., Rodriguez, G., Spartera, C., Ventura, M., Scarpelli, P., Sprynger, M., Sadzot, B., Hottermans, C., Moonen, M., Taylor, P.R., Tovar-Pardo, A., Negreira, J., Vayssairat, M., Faintuch, J.M., Valaikiené, J., Walker, M.G., Wilkinson, A.R.

Predictors and clinical significance of progression or regression of asymptomatic carotid stenosis
(2014) Journal of Vascular Surgery, 59 (4), pp. 956-967.e1.

PubMed ID: 24377944
DOI: 10.1016/j.jvs.2013.10.073

Abstract
Objective: To determine baseline clinical and ultrasonographic plaque factors predictive of progression or regression of asymptomatic carotid stenosis and the predictive value of changes in stenosis severity on risk of first ipsilateral cerebral or retinal ischemic events (including stroke). Methods: A total of 1121 patients with asymptomatic carotid stenosis of 50% to 99% in relation to the bulb diameter (European Carotid Surgery Trial [ECST] method) underwent six monthly clinical assessments and carotid duplexes for up to 8 years (mean follow-up, 4 years). Progression or regression was considered present if there was a change of at least one grade higher or lower, respectively, persisting for at least two consecutive examinations. Results: Regression occurred in 43 (3.8%), no change in 856 (76.4%), and progression in 222 (19.8%) patients. Younger age, high grades of stenosis, absence of discrete white areas in the plaque, and taking lipid lowering therapy were independent baseline predictors of increased incidence of regression. High serum creatinine, male gender, not taking lipid lowering therapy, low grades of stenosis, and increased plaque area were independent baseline predictors of progression. One hundred and thirty first ipsilateral cerebral or retinal ischemic events, including 59 strokes, occurred. Forty (67.8%) of the strokes occurred in patients whose stenosis was unchanged, 19 (32.2%) in those with progression, and zero in those with regression. For the entire cohort, the 8-year cumulative ipsilateral cerebral ischemic stroke rate was zeroinpatients with regression, 9% if the stenosis was unchanged, and 16% if there was progression (average annual stroke rates of 0%, 1.1%, and 2.0%, respectively; log-rank, P = .05; relative risk in patients with progression, 1.92; 95% confidence interval, 1.14-3.25). For patients with baseline stenosis 70% to 99% in relation to the distal internal carotid (North American Symptomatic Carotid Endarterectomy Trial [NASCET] method), in the absence of progression (n = 349), the 8-year cumulative ipsilateral cerebral ischemic stroke rate was 12%. Inthe presence of progression (n = 77), it was 21% (average annual stroke rates of 1.5% and 2.6%, respectively; log-rank, P = .34). Only nine (30%) of the 30 strokes occurred in the progression group. Conclusions: Progressive asymptomatic carotid stenosis identified a subgroup with about twice the risk of ipsilateral stroke compared with those without progression. However, the clinical value of screening for progression simply for selecting patients for carotid procedures is limited because of the low frequency of progression and its relatively low associated stroke rate. The cost effectiveness of screening for change in stenosis severity to better direct current optimal medical treatment needs testing.


248§
Cosmi, B., Filippini, M., Campana, F., Avruscio, G., Ghirarduzzi, A., Bucherini, E., Camporese, G., Imberti, D., Legnani, C., Palareti, G.

Risk factors for recurrent events in subjects with superficial vein thrombosis in the randomized clinical trial SteFlux (Superficial Thromboembolism Fluxum)
(2014) Thrombosis Research, 133 (2), pp. 196-202.

PubMed ID: 24365043
DOI: 10.1016/j.thromres.2013.12.005

Abstract
Background/Aims To evaluate risk factors for recurrent events in patients enrolled in the SteFlux (Superficial Thromboembolism Fluxum) clinical trial which compared different doses and duration of low molecular weight heparin (parnaparin) for superficial vein thrombosis (SVT). Materials and Methods Outpatients with acute SVT of at least 4 cm in length of the internal or external saphenous veins or their collaterals were randomized in a double blind fashion to receive either parnaparin 8500 UI aXa od for ten days followed by placebo for 20 days or 8500 UI aXa od for ten days followed by 6400 UI aXa od for 20 days or 4250 UI aXa od for 30 days. Outcomes were the composite of symptomatic and asymptomatic deep vein thrombosis, pulmonary embolism and SVT recurrence or extension in the first 30 +/- 3 days with a 60 +/- 3 day follow-up. Results 98 outcomes (14.7%) were recorded during 93 days among 664 patients (M/F: 246/418, mean age 65). After correction for treatment, outcomes during 33 days were associated with previous venous thromboembolism (VTE) and/or SVT and/or family history of VTE (odds ratio-OR: 2.5; 95% confidence interval - CI: 1.4-4.8; p = 0.003). After stopping LMWH treatment, only the absence of varicose veins (OR: 2.5; 95% CI 1.3-5.0; p = 0.004) and previous VTE and/or SVT and/or family history of VTE (OR: 1.9; 95% CI:1.0-3.7; p = 0.048) were significantly associated with outcomes. Conclusions SVT patients with these factors may deserve a higher intensity and/or longer anticoagulant treatment. © 2013 Elsevier Ltd © 2013 Published by Elsevier Ltd.


247§
Vedovati, M.C., Becattini, C., Rondelli, F., Boncompagni, M., Camporese, G., Balzarotti, R., Mariani, E., Flamini, O., Pucciarelli, S., Donini, A., Agnelli, G.

A randomized study on 1-week versus 4-week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer
(2014) Annals of Surgery, 259 (4), pp. 665-669.

PubMed ID: 24253138
DOI: 10.1097/SLA.0000000000000340

Abstract
OBJECTIVE: To compare the efficacy and safety of antithrombotic prophylaxis given for 1 week or 4 weeks in patients undergoing laparoscopic surgery for colorectal cancer. BACKGROUND: Extending antithrombotic prophylaxis beyond 1 week reduces the incidence of venous thromboembolism (VTE) after open abdominal surgery for cancer. METHODS: In consecutive patients who underwent laparoscopic surgery for colorectal cancer, complete compression ultrasonography of the lower limbs was performed after 8 ± 2 days of antithrombotic prophylaxis. Patients with no evidence of VTE were randomized to short (heparin withdrawal) or to extended (heparin continued for 3 additional weeks) prophylaxis. Complete compression ultrasonography was repeated at day 28 ± 2 after surgery by investigators blinded to treatment allocation. The primary outcome of the study was the composite of symptomatic and ultrasonography-detected VTE at day 28 ± 2 after surgery. RESULTS: Overall, 301 patients were evaluated for inclusion in the study and 225 were randomized. VTE occurred in 11 of 113 patients randomized to short (9.7%) and in none of the 112 patients randomized to extended heparin prophylaxis (P = 0.001). The incidence of VTE at 3 months was 9.7% and 0.9% in patients randomized to short or to extended heparin prophylaxis, respectively (relative risk reduction: 91%, 95% confidence interval: 30%-99%; P = 0.005). The rate of bleeding was similar in the 2 treatment groups. Two patients died during the study period, 1 in each treatment group. CONCLUSIONS: After laparoscopic surgery for colorectal cancer, extended antithrombotic prophylaxis is safe and reduces the risk for VTE as compared with 1-week prophylaxis (NCT01589146). © 2013 by Lippincott Williams & Wilkins.


246§
Imberti, D., Ivaldo, N., Murena, L., Paladini, P., Castagna, A., Barillari, G., Guerra, E., Fama, G., Castoldi, F., Marelli, B., Pierfranceschi, M.G., Camporese, G., Dentali, F., Porcellini, G.

Venous thromboembolism in patients undergoing shoulder surgery: Findings from the RECOS Registry
(2014) Thrombosis Research, 134 (2), pp. 273-277.

PubMed ID: 24916548
DOI: 10.1016/j.thromres.2014.05.014

Abstract
Background Limited informations are available about venous thromboembolic (VTE) complications and thromboprophylaxis use after shoulder surgery. The primary end-point of the study was to determine the incidence of symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) within 90 days after shoulder surgery. Risk factors for VTE and thromboprophylaxis practices were also studied. Methods RECOS is a prospective multicenter registry of consecutive patients undergoing shoulder surgery recruited in nine hospitals in Italy. Cumulative rates of VTE were estimated according to the Kaplan-Meier method; a Cox regression model was used to calculate adjusted hazard ratio (HR) and 95% confidence interval (CI) for some variables that were identified as risk factors for VTE. Results From June 2009 to June 2011 1366 patients (males 54.4%; mean age 55,65 ± 15.3 years) were enrolled. The surgical procedures were: arthroscopy (71.9%), hemiarthroplasty (17.2%) total replacement (8.9%), fixation for proximal humeral fracture (2%). After 90 days, the incidence of symptomatic VTE was 0.66% (95CI% 0.2-1.12). Mean age was significantly higher in patient with than in patients without VTE (67,1 +/3.49 years vs 55,6 +/- 0,42 years, respectively; p = 0.024). Duration of surgery > 60 minutes (HR:10.99; 95CI% 1.26-95.89; p = 0.030) was found as independent risk factor for VTE, while cancer, medical disease, venous insufficiency and previous VTE were not. Pharmacological thromboprophylaxis was prescribed in 33.5% (n = 457) of the patients, in 95.8% of whom for a duration > 10 days. Conclusions The risk of symptomatic VTE in patients undergoing shoulder surgery is low. The potential need for thromboprophylaxis should be based on a case by case evaluation. © 2014 Elsevier Ltd.


245§
Spreafico, G., Piccioli, A., Bernardi, E., Giraldi, E., Pavei, P., Borgoni, R., Nosadini, A., Baccaglini, U.

Endovenous laser ablation of great and small saphenous vein incompetence with a 1470-nm laser and radial fiber
(2014) Journal of Vascular Surgery: Venous and Lymphatic Disorders, 2 (4), pp. 403-410.

DOI: 10.1016/j.jvsv.2014.04.012

Abstract
Objective: Endovenous laser ablation (EVLA) of great (GSV) and small saphenous vein (SSV) chronic insufficiency with 1470-nm diode laser and radial fiber yields good short-term results. The aim of this study was to assess its efficacy after at least 12 months of follow-up.

Methods: We performed a prospective interventional cohort study in an ambulatory care/day surgery setting. Consecutive patients with chronic, symptomatic GSV or SSV insufficiency were treated by EVLA with a 1470-nm diode laser and a radial fiberoptic. Patients were recruited between 2008 and 2011, and the follow-up was completed in 2012. All patients underwent clinical and echo color Doppler evaluations during follow-up. The primary outcome was the incidence of echo color Dopplerconfirmed failures during follow-up. We also investigated potential associations between failures and patients' characteristics, echo color Doppler findings, or surgical features. The secondary outcome was the postoperative pain course.

Results: The planned 12-month follow-up was completed in 372 patients. Echo color Doppler-confirmed failures occurred in 37 (12%) of 310 patients with GSV insufficiency, whereas none of 62 patients with SSVinsufficiency experienced a failure. Multiple Cox proportional hazards regression analysis showed a significant association of failures with a Clinical, Etiologic, Anatomic, and Pathologic class C ≥4 and a mean confluence of the superficial inguinal veins diameter ≥9mmin patients with GSV insufficiency. Postoperative pain coursewas favorable. More than two thirds of the patients were asymptomatic at 7 days.

Conclusions: EVLA with 1470-nm diode laser and radial fiberoptic is effective for treatment of GSV and especially SSV insufficiency and is well tolerated by the patients. Copyright © 2014 by the Society for Vascular Surgery.


244§
Piazza, M., Frigatti, P., Scrivere, P., Bonvini, S., Noventa, F., Ricotta II, J.J., Grego, F., Antonello, M.

Role of aneurysm sac embolization during endovascular aneurysm repair in the prevention of type II endoleak-related complications
(2013) Journal of Vascular Surgery, 57 (4), pp. 934-941.

PubMed ID: 23384494
DOI: 10.1016/j.jvs.2012.10.078

Abstract
Objective: The goal of this study was to evaluate the role of intraoperative aneurysm sac embolization during endovascular aneurysm repair (EVAR) using a standard dose of coils and fibrin glue in the prevention of type II endoleak (EII). Methods: Two groups were compared: 83 patients underwent standard EVAR during the period 2008-2009 (group A) and 79 patients underwent EVAR during the period 2010-2011 (group B). Computed tomography scans were evaluated with Osirix Pro 4.0 software to obtain aneurysm sac volume. EII rates at the first computed tomography scan follow-up, as well as midterm freedom from EII and freedom from related reintervention, were compared. Preoperative number of patent aortic side branches (inferior mesenteric artery, lumbar arteries, accessory renal arteries), sac thrombus, and sac volume were evaluated for their association with EII in the two groups using multiple logistic regressions. Results: Patient characteristics, Society for Vascular Surgery comorbidity scores (0.85 ± 0.44 vs 0.82 ± 0.46; P =.96), and operative time (185 ± 52 vs 179 ± 49; P =.92) were similar for groups A and B. The first computed tomography scan (≤3 months) revealed a significantly larger number of EIIs in group A than in group B (23% vs 10%; P =.02). Spontaneous EII resolution occurred in 65% of patients in group A and in 79% in group B (P = 1.0), whereas sac volume increased in 25% and 10% (P =.63) of cases, respectively. At 18 months (range, 6 months to 4.4 years), overall mean differences in sac volume shrinkage (27 ± 12 cm3 vs 25 ± 12 cm3; P =.19) and freedom from EII (92% vs 96%; P =.33) were similar, whereas freedom from reintervention was significantly lower in group A (93% vs 99%; P =.03) than in group B. Multivariate analysis showed preoperative aneurysm sac volume >125 cm3 to be the only independent significant predictor of EII (odds ratio, 4.0; 95% confidence interval, 1.5-10.5; P =.005). Conclusions: Although further confirmatory studies are needed, sac embolization during EVAR may be a valid approach to preventing EII and its complications during short- and midterm follow-up. More aggressive intraoperative embolization should be considered for patients with a preoperative aneurysm sac volume >125 cm3.


243§
Prandoni, P., Noventa, F., Milan, M.

Aspirin and recurrent venous thromboembolism
(2013) Phlebology, 28 (1_suppl), pp. 99-104.

PubMed ID: 23482543
DOI: 10.1177/0268355512475040

Abstract
While there is conclusive evidence that aspirin plays a role in reducing the risk of clinically relevant venous thromboembolism (VTE) arising in a number of surgical and non-surgical situations at risk, little is known of the potential of aspirin for the long/term prevention of recurrent VTE. In two recent multicentre, double-blind studies (WARFASA and ASPIRE), the efficacy and safety of a low dose of aspirin (100 mg per day) were assessed in patients with unprovoked VTE who had completed an initial period of conventional treatment with vitamin K antagonists. The two studies used identical aspirin regimens and had similar enrolment criteria and outcome measures. When data from these two trials were pooled, there was a 32% reduction in the rate of recurrence of VTE (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.51–0.90) and a 34% reduction in the rate of major vascular events (HR, 0.66; 95% CI, 0.51–0.86). Moreover, these benefits were achieved with a low risk of bleeding. As patients with previous symptomatic atherosclerosis were not enrolled in these two studies, whether these results apply also to this category of patients is uncertain. We recently had the opportunity to review the clinical charts of 1919 consecutive patients presented with a first episode of VTE, which was either unprovoked or triggered by transient risk factors, and were followed up for an average period of four years after discontinuing anticoagulation. The rate of recurrent VTE in the 256 patients with a history of symptomatic atherosclerosis who had been given 80–160 mg of aspirin once daily (17.2%) did not differ from that (19.9%) observed in those without atherosclerosis who were left without any antithrombotic treatments. The implication of this observation is that whenever patients with symptomatic atherosclerosis are deemed to require long-term protection against recurrent VTE, they are unlikely to benefit from (resuming) aspirin. Conversely, aspirin in low doses offers an appealing, safe and highly cost-effective option for the long-term prevention of recurrent events in patients with unprovoked VTE who are free from symptomatic atherosclerotic lesions.


242§
Kakkos, S.K., Griffin, M.B., Nicolaides, A.N., Kyriacou, E., Sabetai, M.M., Tegos, T., Makris, G.C., Thomas, D.J., Geroulakos, G., Adovasio, R., Ziani, B., Alò, F.P., Cicilioni, C.G., Ambrosio, G., Andreev, A., Andreozzi, G.M., Verlato, F., Camporese, G., Arosio, E., Barkauskas, E., Barros D'Sa, A.A.B., Brannigan, P., Batchvarova, V., Dramov, A., Belardi, P., Novelli, G.P., Simoni, G., Bell, P., Biasi, G.M., Mingazzini, P., Bornstein, N.M., Bouchier-Hayes, D., Fitzgerald, P., Cairols, M.A., Cao, P.G., DeRango, P., Carboni, G.P., Geoffredo, C., Catalano, M., Chambers, B., Goetzmann, M., Dickinson, A., Clement, D., Bobelyn, M., Coccheri, S., Conti, E., Diamantopoulos, E., Andreadis, E.A., Dimakakos, P.B., Kotsis, T., Eikelboom, B., Entz, L., Ferrari-Bardile, A., Aloi, T., Salerno, M., Fernandes E Fernandes, J., Pedro, L., Fitzgerald, D.E., O'Shaughnessy, A.M., Fletcher, J., Forconi, S., Cappeli, R., Bicchi, M., Arrigucci, S., Gallai, V., Cardaiolli, G., Geroulakos, G., Kakkos, S., Gomez-Isaza, L.F., Gorgoyannis, G., Liasis, N., Graf, M., Guarini, P., Hardy, S., Harris, P., Aston, S., Iosa, G., Katsamouris, A., Giannoukas, A., Krzanowski, M., Ladurner, G., Leal-Monedero, J., Lee, B.B., Liapis, C., Galanis, P., Liboni, W., Pavanelli, E., Mannarino, E., Vaudo, G., McCollum, P., Levison, R., Micieli, G., Bosone, D., Middleton, L., Pantziaris, M., Tyllis, T., Minar, E., Willfort, A., Moggi, L., DeRango, P., Nenci, G., Radicchia, S., Nicolaides, A., Kakkos, S., Thomas, D., Norgren, L., Ribbe, E., Novo, S., Tantillo, R., Olinic, D., Paaske, W., Pagnan, A., Pauletto, P., Pagliara, V., Pettina, G., Pratesi, C., Matticari, S., Polivka, J., Sevcik, P., Poredos, P., Blinc, A., Videcnik, V., Pujia, A., Raso, A., Rispoli, P., Conforti, M., Robinson, T., Dennis, M.S.J., Rosfors, S., Rudofsky, G., Schroeder, T., Gronholdt, M.L., Simoni, G., Finocchi, C., Rodriguez, G., Spartera, C., Ventura, M., Scarpelli, P., Sprynger, M., Sadzot, B., Hottermans, C., Moonen, M., Taylor, P.R., Tovar-Pardo, A., Negreira, J., Vayssairat, M., Faintuch, J.M., Valaikiené, J., Walker, M.G., Wilkinson, A.R.

The size of juxtaluminal hypoechoic area in ultrasound images of asymptomatic carotid plaques predicts the occurrence of stroke
(2013) Journal of Vascular Surgery, 57 (3), pp. 609-618.e1.

DOI: 10.1016/j.jvs.2012.09.045

Abstract
Objective: To test the hypothesis that the size of a juxtaluminal black (hypoechoic) area (JBA) in ultrasound images of asymptomatic carotid artery plaques predicts future ipsilateral ischemic stroke. Methods: A JBA was defined as an area of pixels with a grayscale value <25 adjacent to the lumen without a visible echogenic cap after image normalization. The size of a JBA was measured in the carotid plaque images of 1121 patients with asymptomatic carotid stenosis 50% to 99% in relation to the bulb (Asymptomatic Carotid Stenosis and Risk of Stroke study); the patients were followed for up to 8 years. Results: The JBA had a linear association with future stroke rate. The area under the receiver-operating characteristic curve was 0.816. Using Kaplan-Meier curves, the mean annual stroke rate was 0.4% in 706 patients with a JBA <4 mm 2, 1.4% in 171 patients with a JBA 4 to 8 mm2, 3.2% in 46 patients with a JBA 8 to 10 mm2, and 5% in 198 patients with a JBA >10 mm2 (P <.001). In a Cox model with ipsilateral ischemic events (amaurosis fugax, transient ischemic attack [TIA], or stroke) as the dependent variable, the JBA (<4 mm2, 4-8 mm2, >8 mm2) was still significant after adjusting for other plaque features known to be associated with increased risk, including stenosis, grayscale median, presence of discrete white areas without acoustic shadowing indicating neovascularization, plaque area, and history of contralateral TIA or stroke. Plaque area and grayscale median were not significant. Using the significant variables (stenosis, discrete white areas without acoustic shadowing, JBA, and history of contralateral TIA or stroke), this model predicted the annual risk of stroke for each patient (range, 0.1%-10.0%). The average annual stroke risk was <1% in 734 patients, 1% to 1.9% in 94 patients, 2% to 3.9% in 134 patients, 4% to 5.9% in 125 patients, and 6% to 10% in 34 patients. Conclusions: The size of a JBA is linearly related to the risk of stroke and can be used in risk stratification models. These findings need to be confirmed in future prospective studies or in the medical arm of randomized controlled studies in the presence of optimal medical therapy. In the meantime, the JBA may be used to select asymptomatic patients at high stroke risk for carotid endarterectomy and spare patients at low risk from an unnecessary operation. Copyright © 2013 by the Society for Vascular Surgery.


241§
Vedovati, M.C., Becattini, C., Rondelli, F., Boncompagni, M., Camporese, G., Balzarotti, R.

A randomized study on 1 vs. 4 weeks prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer.
(2013) Journal of Thrombosis and Haemostasis, 11, p. 214.


240§
Becattini, C., Vedovati, M.C., Rondelli, F., Boncompagni, M., Camporese, G., Balzarotti, R.

One week vs. four week heparin prophylaxis after laparoscopic surgery for colorectal cancer. The PRO-LAPS pilot feasibility study
(2013) Journal of Thrombosis and Haemostasis, 11, p. 11


239§
Spreafico, G., Piccioli, A., Bernardi, E., Giraldi, E., Pavei, P., Borgoni, R., Baccaglini, U.

Six-year follow-up of endovenous laser ablation for great saphenous vein incompetence
(2013) Journal of Vascular Surgery: Venous and Lymphatic Disorders, 1 (1), pp. 20-25.

DOI: 10.1016/j.jvsv.2012.05.004

Abstract
Objective: Treatment of chronic venous insufficiency of the great saphenous veins by endovenous laser ablation yields good short- and medium-term results, as assessed clinically and technically by echo-color-Doppler. At present, scarce data are available on the long-term results of endovenous laser ablation. We wanted to assess the long-term efficacy of endovenous laser ablation. Methods: We performed a prospective 6-year follow-up cohort study, with recruitment between 2003 and 2004, and the follow-up completed in 2010. The setting was an ambulatory care/day surgery. Of 209 consecutive patients who underwent endovenous laser ablation at our institution during the recruitment period, five (2.4%) did not complete the procedure due to technical reasons. Of 204 patients who successfully completed the intervention, 14 (6.8%) were lost for follow-up, and 190 completed the planned 6-year follow-up. The intervention was an endovenous laser ablation using a 980-nm laser diode. Clinical and echo-color-Doppler evaluations were regularly scheduled for all patients during the planned follow-up period. The incidence of clinical and echo-color-Doppler confirmed endovenous laser ablation failures over a 6-year follow-up period. Potential associations between failures and patients' characteristics, echo-color-Doppler findings, or surgical features were also investigated. Results: Symptomatic clinical endovenous laser ablation failures occurred in 22 (11.6%; 95% confidence interval [CI], 7.4-17.0%) patients; while 57 (30.0%; 95% CI, 23.6-37.1%) had echo-color-Doppler-confirmed failures. Only two patients (1.1%; 95% CI, 0.1%-3.8%) had both symptomatic clinical and echo-color-Doppler-confirmed failures. Three features of the great saphenous vein: an "atypical" junction, a junction diameter ≥8 mm, and a mean trunk diameter ≥8 mm, were independently associated with echo-color-Doppler-confirmed failures on multivariate logistic regression analysis. Conclusions: Six years after endovenous laser ablation, most patients were improved on clinical grounds, and more than two-thirds had no saphenous insufficiency at echo-color-Doppler. Only a minority had both clinical and echo-color-Doppler-confirmed failures. Anatomical features of the junction and the saphenous diameter both at the junction and at the trunk independently predicted echo-color-Doppler-confirmed failures. © 2013 Society for Vascular Surgery.


238§
Milan, M., Noventa, F., Ghirarduzzi, A., Pengo, V., Vedovetto, V., Filippi, L., Campello, E., Prandoni, P.

Aspirin and recurrent venous thromboembolism in patients with symptomatic atherosclerosis: Retrospective cohort study
(2012) Journal of Thrombosis and Haemostasis, 10 (10), pp. 2205-2206.

PubMed ID: 22827468
DOI: 10.1111/j.1538-7836.2012.04865.x


237§
Vujosevic, S., Tempesta, D., Noventa, F., Midena, E., Sebastiani, G.

Pegylated interferon-associated retinopathy is frequent in hepatitis C virus patients with hypertension and justifies ophthalmologic screening
(2012) Hepatology, 56 (2), pp. 455-463.

PubMed ID: 22331668
DOI: 10.1002/hep.25654

Abstract
Treatment with pegylated interferon alpha (PegIFNα) and ribavirin is still regarded as the standard of care for chronic hepatitis C virus (HCV). Retinopathy has been occasionally described but prospective, longitudinal data are lacking. We investigated the frequency and clinical significance of retinopathy during therapy with PegIFNα and ribavirin in 97 consecutive HCV patients. In all, 54 (55.7%) and 43 (44.3%) patients were treated with PegIFNα 2a and PegIFNα 2b, respectively. Ophthalmologic examination was performed before therapy (baseline), at 3 and 6 months (3T and 6T, respectively) of therapy, and 3 months after the end of therapy (3ET). All patients underwent the baseline and 3T examination, 95.9% and 90.7% of patients underwent 6T and 3ET examination, respectively. Overall, 30.9% of patients developed retinopathy, as defined by the presence of cotton wool spots and/or retinal hemorrhages. Variables significantly associated with retinopathy during treatment were age (P = 0.004), metabolic syndrome (P = 0.05), hypertension (P < 0.0001), cryoglobulinemia (P = 0.05), and preexisting intraocular lesions at baseline (P = 0.01). By multivariate analysis, the only variable independently associated with PegIFNα-associated retinopathy was hypertension (hazard ratio [HR] = 4.99, 95% confidence interval [CI] 2.29-10.89). The frequency of retinopathy was significantly higher in hypertensive patients versus those without hypertension at all timepoints (18.5% versus 5.7% at baseline, P = 0.05; 48.1% versus 15.7% at 3T, P = 0.0009; 68.0% versus 19.1% at 6T, P < 0.0001; 32.0% versus 6.2%, P = 0.0005 at 3ET). In one (1.1%) hypertensive patient, who developed bilateral branch retinal vein occlusion at 6T, the therapy was discontinued. A cost analysis showed that screening for PegIFNα-associated retinopathy was cost-effective as compared with thyroid-stimulating hormone screening. Conclusion: Retinopathy is frequent during treatment with PegIFNα and ribavirin, especially in hypertensive patients, who may develop serious complications. Screening for PegIFNα-associated retinopathy should be recommended for HCV patients with hypertension. © 2012 American Association for the Study of Liver Diseases.


236§
Prandoni, P., Noventa, F., Quintavalla, R., Bova, C., Cosmi, B., Siragusa, S., Bucherini, E., Astorri, F., Cuppini, S., Valle, F.D., Lensing, A.W.A., Prins, M.H., Villalta, S.

Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: A randomized trial
(2012) Blood, 119 (6), pp. 1561-1565.

PubMed ID: 22180438
DOI: 10.1182/blood-2011-11-391961

Abstract
Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present openlabel, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated. This study is registered as Clinical Trial number NCT00426075. © 2012 by The American Society of Hematology.


235§
Pastore, G., Aggio, S., Baracca, E., Rigatelli, G., Zanon, F., Roncon, L., Noventa, F., Barold, S.S.

A new integrated approach to improve left ventricular electromechanical activation during right ventricular septal pacing
(2012) Europace, 14 (1), pp. 92-98.

PubMed ID: 21868411
DOI: 10.1093/europace/eur270

Abstract
Aims: The deleterious effects of apical right ventricular pacing has fostered the utilization of alternative pacing sites. Although right ventricular septal (RVS) sites are commonly used, the results have been controversial because of poor standardization of lead position by fluoroscopy. This study investigated the utility of a new RVS pacing technique based on the combination of fluoroscopy (F), and electrophysiological mapping (F EP). Left ventricular (LV) electromechanical activation was determined in patients undergoing RVS pacing and the results of the F EP approach were compared with those derived from standard F alone. Methods and Results: Between December 2008 and November 2010 we enrolled 156 consecutive patients undergoing permanent RVS pacing. The standard F approach was used in 93 patients and the F EP technique was applied to 63 patients. Electromechanical activation was assessed by: (i) electromechanical latency (EML) interval measured from the QRS onset to the mechanical activation of the basal LV and (ii) intra-LV dyssynchrony measured as the interval from the earliest to the latest LV basal motion. Intra-LV dyssynchrony was found in 46.2 patients in the F group compared with 15.9 in the group F EP (P<0.001). The F group demonstrated a significantly higher degree of intra-LV dyssynchrony than F EP group (43.9 ± 24.3 vs. 26.5 ± 15.4 ms;P< 0.001). The F group exhibited a significantly higher EML duration compared with the F EP group (215.8 ± 25.3 vs. 195.1 ± 17.4 ms; P< 0.001). Conclusion: During RVS pacing, the F EP approach provides a more physiological LV activation than the standard F technique. The prognostic significance of these short-term findings needs to be correlated with long-term data. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please.


234§
Prandoni, P., Prins, M.H., Ghirarduzzi, A., Pengo, V., Sartori, M.T., Ugolotti, M.C., Bracco, A., Veropalumbo, M.R., Noventa, F., Lensing, A.W.

Family history of venous thrombosis or sudden death as a risk factor for venous thromboembolism.
(2012) Thrombosis and haemostasis, 107 (6), pp. 1191-1192.

PubMed ID: 22436905
DOI: 10.1160/TH11-12-0845


233§
Camporese, G., Bernardi, E., Scarano, L., Ghirarduzzi, A., Imberti, D., Prandoni, P.

Outcome of patients with suspected lower limb symptomatic deep vein thrombosis and a normal ultrasound-based initial diagnostic workup: A prospective study
(2012) Journal of Thrombosis and Haemostasis, 10 (12), pp. 2605-2606.

PubMed ID: 23025495
DOI: 10.1111/jth.12015

Index Keywords
clinical feature, clinical trial (topic), human, leg thrombosis, letter, mortality, nuclear magnetic resonance imaging, priority journal, prognosis, treatment outcome, ultrasound, X ray; Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Leg, Male, Middle Aged, Prospective Studies, Venous Thrombosis, Young Adult


232§
Milan, A., Freato, F., Vanzo, V., Camporese, G., Baraldi, M., Chiandetti, L., Zaramella, P.

Near-infrared spectroscopy measure of limb peripheral perfusion in neonatal arterial thromboembolic disease
(2012) Minerva Pediatrica, 64 (6), pp. 633-639.

PubMed ID: 23108325

Abstract
Aim. In critically ill neonates, peripheral perfusion and oxygenation assessment may provide indirect information on circulatory failure in limb arterial thromboembolic emergencies. Aims of our study were: 1) to evaluate the changes on tissue oxygenation index, oxyhemoglobin, deoxyhemoglobin and blood volume obtained by near-infrared spectroscopy (NIRS) on the infants legs; 2) to compare them with ultrasonographic data. Methods. Tissue oxygenation index (TOI), oxyhemoglobin (O2Hb), deoxyhemoglobin (HHb) and blood volume (BV) differences were assessed by NIRS on the calf of 8 newborn infants (median weight 1995, range 585-3010 g; median gestational age 32.5, range 26-40 wks). An ultrasonographic scan of the arterial system was performed before the NIRS measurements, to validate the site of arterial occlusion. Results. A t-test for independent samples showed lower values in the affected limb for all NIRS measurements. TOI measurements displayed lower values in the thromboembolic limb (mean 44.79±12%) versus unaffected (mean 47.95±17.08%) (P=0.0001). Mean (SD) peak systolic velocity in the patent artery below the occlusion decreased from 108±25 cm/s in the normal limb to 25.6±28 cm/s in the thrombus site (P=0.02). Conclusion. In neonatal intensive care units, measurement of limb peripheral perfusion and oxygenation seems to be clinically useful in arterial thromboembolic emergencies.


231§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of the intracranial circulation
(2012) International Angiology, 31 (5 SUPPL1), pp. 1-9.


230§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the surveillance of patients with stents
(2012) International Angiology, 31 (5 SUPPL1), pp. 57-62.


229§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of female pelvic congestion syndrome
(2012) International Angiology, 31 (5 SUPPL1), pp. 41-43.


228§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the surveillance of patients with prosthesis or aortic-iliac-femoral endograft
(2012) International Angiology, 31 (5 SUPPL1), pp. 62-69.


227§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of the visceral arteries and veins and of the renal artery
(2012) International Angiology, 31 (5 SUPPL1), pp. 32-36.


226§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of diagnosis of superficial vein thrombosis and diagnosis of deep vein thrombosis
(2012) International Angiology, 31 (5 SUPPL1), pp. 49-52.


225§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of the venous circulation of the lower limbs
(2012) International Angiology, 31 (5 SUPPL1), pp. 52-56.


224§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of the arterial circulation of the lower limbs
(2012) International Angiology, 31 (5 SUPPL1), pp. 43-49.


223§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of male varicocele
(2012) International Angiology, 31 (5 SUPPL1), pp. 39-41.


222§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of the circulation of the upper limbs and of the thoracic outlet syndrome
(2012) International Angiology, 31 (5 SUPPL1), pp. 24-30.


221§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of the vasculogenig erectile dysfunction
(2012) International Angiology, 31 (5 SUPPL1), pp. 36-39.


220§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for assessment of the lymphoedema of the limbs
(2012) International Angiology, 31 (5 SUPPL1), pp. 69-77.


219§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of the aorta and iliac arteries
(2012) International Angiology, 31 (5 SUPPL1), pp. 30-32.


218§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F.

Guidelines for the assessment of the supra-aortic trunks
(2012) International Angiology, 31 (5 SUPPL1), pp. 9-24.


217§
Antignani, P.L., Benedetti-Valentini, F., Aluigi, L., Baroncelli, T.A., Camporese, G., Failla, G., Martinelli, O., Palasciano, G.C., Pulli, R., Rispoli, P., Amato, A., Amitrano, M., Dorigo, W., Gossetti, B., Irace, L., Laurito, A., Magnoni, F., Minucci, S., Pedrini, L., Righi, D., Verlato, F., Italian Society for Vascular Investigation

Diagnosis of vascular diseases. Ultrasound investigations--guidelines.
(2012) International angiology : a journal of the International Union of Angiology, 31 (5 Suppl 1), pp. 1-77.

PubMed ID: 23470846


216§
Cosmi, B., Filippini, M., Tonti, D., Ghirarduzzi, A., Avruscio, G., Imberti, D., Andreozzi, G.M., Camporese, G., Palareti, G.

Risk factors for relapses in patients with superficial vein thrombosis in the randomized clinical study STEFLUX (Superficial Thromboembolism Fluxum) [Risikofaktoren für rezidive bei menschen mit oberflächlicher venenthrombose bei der randomisierten klinischen studie STEFLUX (Superficial Thromboembolism Fluxum)]
(2012) Vasomed, 24 (3), pp. 130-131.


215§
Cosmi, B., Filippini, M., Tonti, D., Avruscio, G., Ghirarduzzi, A., Bucherini, E., Camporese, G., Imberti, D., Palareti, G., Favaretto, E., Campana, F., Ragazzo, S., Ceccato, F., Rondinello, S., Veropalumbo, M.R., Iotti, M., Andreozzi Giuseppe, M., Verlato, F., Imberti, D., Prisco, V., Greco, R., Aluigi, L., Visoná, A., Zalunardo, B., Laura, Z., Diego, T., Amico, C., Benin, P., Vella, V., Boccoli, G., Chiodi, L., Aloisi, D., Angeloni, L., Postacchini, D., Cruciani, G., Macchiati, I., Grossi, A., La Placa, S., Renzi, C., Kontothanassis, D.

A randomized double-blind study of low-molecular-weight heparin (parnaparin) for superficial vein thrombosis: STEFLUX (Superficial ThromboEmbolism and Fluxum)
(2012) Journal of Thrombosis and Haemostasis, 10 (6), pp. 1026-1035.

PubMed ID: 22487001
DOI: 10.1111/j.1538-7836.2012.04727.x

Abstract
Background: Optimal doses and duration of low-molecular-weight heparin (LMWH) for the treatment of superficial vein thrombosis (SVT) are still uncertain. Objectives: To compare the efficacy and safety of different doses and durations of LMWH parnaparin for symptomatic lower limb SVT. Patients and methods: Outpatients with at least a 4-cm-long SVT of long or short saphenous veins or their collaterals were randomized to receive parnaparin either 8500UIonce daily (o.d.) for 10days followed by placebo for 20days (group A) or 8500UIo.d. for 10days followed by 6400UIonce daily (o.d.) for 20days (group B) or 4250UIo.d. for 30days (group C) in a double-blind fashion in 16 clinics. Primary outcome was the composite of symptomatic and asymptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE) and relapse and/or symptomatic or asymptomatic SVT recurrence in the first 33days with 60days follow-up. Results: Among 664 patients, primary outcome occurred in 33/212 (15.6%), 4/219 (1.8%) and 16/217 (7.3%) subjects in groups A, B and C, respectively (B vs. A: absolute risk reduction [ARR]: 13.7%, 95% confidence intervals [CI]: 8-18.9 P<0.001; B vs. C: ARR: 5.5%; 95% CI: 1.6-9.4 P= 0.011; C vs. A: ARR: 8.2%, 95% CI: 2-14 P=0.012). During days 0-93, the event rate was higher in group A (22.6%) than either in group B (8.7%; P=0.001) or C (14.3%, P=0.034). No major hemorrhages occurred. Conclusions: An intermediate dose of parnaparin for 30days is superior to either a 30-day prophylactic dose or a 10-day intermediate dose for lower limb SVT treatment. © 2012 International Society on Thrombosis and Haemostasis.


214§
Pengo, V., Noventa, F., Denas, G., Pengo, M.F., Gallo, U., Grion, A.M., Iliceto, S., Prandoni, P.

Long-term use of vitamin K antagonists and incidence of cancer: A population-based study
(2011) Blood, 117 (5), pp. 1707-1709.

PubMed ID: 21127176
DOI: 10.1182/blood-2010-08-304758

Abstract
Whether long-term use of vitamin K antagonists (VKAs) might affect the incidence of cancer is a longstanding hypothesis. We conducted a population-based study including all cancer- and thromboembolism-free patients of our health area; study groups were defined according to chronic anticoagulant use to VKA-exposed and control groups. Cancer incidence and cancerrelated and overall mortality was assessed in both groups. 76 008 patients (3231 VKAexposed and 72 777 control subjects) were followed-up for 8.2 (± 3.2) years. After adjusting for age, sex, and time-to-event, the hazard ratio of newly diagnosed cancer in the exposed group was 0.88 (95% confidence interval [95% CI] 0.80-0.98; P < .015). VKA-exposed patients were less likely to develop prostate cancer, 0.69 (95% CI 0.50-0.97; P = .008). The adjusted hazard ratio for cancer-related and overall mortalitywas1.07 (95% CI 0.92-1.24) and 1.12 (95% CI 1.05-1.19), respectively. These results support the hypothesis that anticoagulation might have a protective effect on cancer development, especially prostate cancer. © 2011 by The American Society of Hematology.


213§
Camporese, G., Bernardi, E., Noventa, F.

Efficacy of rivaroxaban for prevention of venous thromboembolism after knee arthroscopy: A randomized double-blind trial (Erika study)
(2011) J Thromb Haemost, 9, pp. 156-157.


212§
Camporese, G., Labropoulos, N., Verlato, F., Bernardi, E., Ragazzi, R., Salmistraro, G., Kontothanassis, D., Andreozzi, G.M.

Benign outcome of objectively proven spontaneous recanalization of internal carotid artery occlusion
(2011) Journal of Vascular Surgery, 53 (2), pp. 323-329.

PubMed ID: 21050696
DOI: 10.1016/j.jvs.2010.07.066

Abstract
Objective Spontaneous recanalization of intracranial internal carotid artery (ICA) occlusion is frequent in embolic strokes. Spontaneous recanalization of the extracranial portion of the ICA occlusion of atherosclerotic or embolic origin is only anecdotally reported, and data are lacking about its incidence, natural history, and outcome in long-term follow-up. Methods Consecutive patients with ICA occlusion were prospectively identified and followed-up to detect the incidence of a spontaneous recanalization. Patients with objectively confirmed recanalization were prospectively followed-up to observe their natural history and the onset of new cerebrovascular events. ICA occlusion and spontaneous recanalization were diagnosed by means of color-coded Doppler ultrasound imaging or selective contrast angiography, or both. All patients were evaluated and treated for atherosclerotic risk factors. Results Spontaneous recanalization occurred in 16 of 696 patients (2.3%; 95% confidence interval, 1.3%-3.7%) with ICA occlusion after a mean interval of 38 months from the diagnosis of occlusion. Spontaneous recanalization was detected with color-coded Doppler ultrasound imaging and with selective contrast angiography, with a complete agreement of diagnostic findings. Two patients presented with symptomatic spontaneous recanalization. All patients with spontaneous recanalization were asymptomatic after a mean follow-up of 66.2 months. Conclusions Spontaneous recanalization of previously occluded extracranial ICAs is more frequent than anticipated. Once it occurs, spontaneous recanalization seems to have a benign long-term course. © 2011 Society for Vascular Surgery.


211§
Barbar, S., Noventa, F., Rossetto, V., Ferrari, A., Brandolin, B., Perlati, M., De Bon, E., Tormene, D., Pagnan, A., Prandoni, P.

A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: The Padua Prediction Score
(2010) Journal of Thrombosis and Haemostasis, 8 (11), pp. 2450-2457.

PubMed ID: 20738765
DOI: 10.1111/j.1538-7836.2010.04044.x

Abstract
Prophylaxis of venous thromboembolism (VTE) in hospitalized medical patients is largely underused. We sought to assess the value of a simple risk assessment model (RAM) for the identification of patients at risk of VTE. Methods: In a prospective cohort study, 1180 consecutive patients admitted to a department of internal medicine in a 2-year period were classified as having a high or low risk of VTE according to a predefined RAM. They were followed-up for up to 90 days to assess the occurrence of symptomatic VTE complications. The primary study outcome was to assess the adjusted hazard ratio (HR) of VTE in high-risk patients who had adequate in-hospital thromboprophylaxis in comparison with those who did not, and that of VTE in the latter group in comparison with low-risk patients. Results: Four hundred and sixty-nine patients (39.7%) were labelled as having a high risk of thrombosis. VTE developed in four of the 186 (2.2%) who received thromboprophylaxis, and in 31 of the 283 (11.0%) who did not (HR of VTE, 0.13; 95% CI, 0.04-0.40). VTE developed also in two of the 711 (0.3%) low-risk patients (HR of VTE in high-risk patients without prophylaxis as compared with low-risk patients, 32.0; 95% CI, 4.1-251.0). Bleeding occurred in three of the 186 (1.6%) high-risk patients who had thromboprophylaxis. Conclusions: Our RAM can help discriminate between medical patients at high and low risk of VTE. The adoption of adequate thromboprophylaxis in high-risk patients during hospitalization leads to longstanding protection against thromboembolic events with a low risk of bleeding. © 2010 International Society on Thrombosis and Haemostasis.


210§
Sebastiani, G., Tempesta, D., Fattovich, G., Castera, L., Halfon, P., Bourliere, M., Noventa, F., Angeli, P., Saggioro, A., Alberti, A.

Prediction of oesophageal varices in hepatic cirrhosis by simple serum non-invasive markers: Results of a multicenter, large-scale study
(2010) Journal of Hepatology, 53 (4), pp. 630-638.

PubMed ID: 20615567
DOI: 10.1016/j.jhep.2010.04.019

Abstract
Background & Aims: Preliminary data suggest that non-invasive methods could be useful to assess presence of oesophageal varices (OV) in cirrhotic patients. We aimed to further investigate simple serum non-invasive markers for diagnosing and grading OV. Methods: A retrospective set of 510 cirrhotics and a prospective set of 110 cirrhotics were enrolled consecutively in five centers. Platelets, AST-to-ALT ratio, AST-to-platelet-ratio index, Forns' index, Lok index, Fib-4, and Fibroindex were measured within 2 months from upper endoscopy, taken as a gold standard. Performance was expressed as sensitivity, specificity, positive, and negative predictive values (PPV, NPV), accuracy, and area under the curve (AUC). Results: A combination of Lok index (cutoff = 1.5) and Forns' index (cutoff = 8.8) had 0.80 AUC (0.76-0.84, 95% CI), and high NPV (>90%) to exclude clinically relevant OV, defined as large OV or small OV with red signs or in Child-Pugh C cirrhosis. By applying this combination, upper endoscopy would have been avoided in 1/3 of our cirrhotics. Large OV could be excluded with 96% NPV by Lok index (cutoff = 1.5). A combination of Lok index (cutoff = 0.9) and Forns' index (cutoff = 8.5) predicted presence of any grade OV with good performance: 0.82 AUC (0.76-0.88, 95% CI), 88% PPV. Conclusions: Serum non-invasive markers may be useful as a first line tool to identify cirrhotic patients in which the risk of clinically relevant OV is trivial, and to reduce the number of upper endoscopies. However, we are still far from the possibility of replacing upper endoscopy by simple serum non-invasive markers in the vast majority of patients. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


209§
Pastore, G., Zanon, F., Noventa, F., Baracca, E., Aggio, S., Corbucci, G., Cazzin, R., Roncon, L., Barold, S.S.

Variability of left ventricular electromechanical activation during right ventricular pacing: Implications for the selection of the optimal pacing site
(2010) PACE - Pacing and Clinical Electrophysiology, 33 (5), pp. 566-574.

PubMed ID: 20025705
DOI: 10.1111/j.1540-8159.2009.02647.x

Abstract
Background: The right ventricular septum (RVS) and Hisian area (HA) are considered more "physiological" pacing sites than right ventricular apex (RVA). Studies comparing RVS to RVA sites have produced controversial results. There are no data about variability of electromechanical activation obtained by an approach using fluoroscopy and electrophysiological markers. This study compared the variability of left ventricular (LV) electromechanical activation in patients undergoing short-term RVA and RVS with that measured during HA pacing based on fluoroscopy and electrophysiological markers. Methods: Tissue Doppler echocardiography was performed in 142 patients before and after RVA (54), RVS (44), and HA (44) pacing. Electromechanical activation was assessed by: (1) electromechanical latency (EML)-interval between QRS onset and mechanical activation of basal LV; (2) intra-LV dyssynchrony (intra-LV)-interval between earliest to the latest LV basal motion. The intra- and interpatients variability among pacing groups were assessed. Results: Pacing from RVA showed longer EML and higher degree of intra-LV than RVS and HA pacing. RVA and RVS showed a higher variability than HA pacing with regard to intrapatient changes of EML (RVA vs RVS, P = 0.4; RVS vs HA, P = 0.01, RVA vs HA, P = 0.0002) and intra-LV (RVA vs RVS, P = 0.2; RVS vs HA, P = 0.04; RVA vs HA, P = 0.005). Similar results were found in interpatients variability from paced-values. Conclusions: RVA and RVS pacing produce a variable effect on LV electromechanical activation that is significantly more pronounced than HA pacing. A pacing site such as HA selected by fluoroscopic and electrophysiological markers maintains baseline and homogeneous LV activation pattern. © 2010 Wiley Periodicals, Inc.


208§
Bortoletto, G., Scribano, L., Realdon, S., Marcolongo, M., Mirandola, S., Franceschini, L., Bonisegna, S., Noventa, F., Plebani, M., Martines, D., Alberti, A.

Hyperinsulinaemia reduces the 24-h virological response to PEG-interferon therapy in patients with chronic hepatitis C and insulin resistance
(2010) Journal of Viral Hepatitis, 17 (7), pp. 475-480.

PubMed ID: 19878535
DOI: 10.1111/j.1365-2893.2009.01204.x

Abstract
Insulin resistance (IR) reduces response to pegylated-interferon (PEG-IFN)/ribavirin in chronic hepatitis C (CHC), but the mechanisms are still undefined. We examined the relationship between baseline insulin levels, the main component affecting homeostasis model of assessment - insulin resistance (HOMA-IR) for assessment of IR in non-diabetic patients, and the 'acute' virological response to PEG-IFN measured 24 h after the first injection and taken as correlate of intracellular interferon signalling. In 62 patients treated with PEG-IFN/Ribavirin, serum insulin and HOMA-IR were assessed at baseline, while hepatitis C virus (HCV)-RNA was measured at baseline and 24 h, 1, 2, 4 and 12 weeks after treatment initiation. Sustained virological response was examined 24 weeks after therapy discontinuation. Mean baseline insulin was 11.52 ± 8.51 U/L and mean HOMA-IR was 2.65 ± 2.01 both being significantly higher with advanced liver fibrosis. Hepatitis C virus-RNA decay observed 24 h after the first injection of PEG-IFN was significantly lower (0.7 ± 0.8 log) in patients with HOMA ≥3 compared with those with HOMA <3 (1.7 ± 0.8, P = 0.001). A highly significant (r = -0.42) inverse correlation was observed between baseline insulin levels and the 24-h HCV-RNA decay. The difference in early viral kinetics between patients with HOMA ≥3 or <3 resulted in a significant difference in the percentage of patients achieving rapid (week 4) and sustained virological response. Multivariate analysis, inclusive of patient age, HCV genotype and fibrosis stage, identified baseline insulin levels as the main independent variable affecting the 24-h response to PEG-IFN. Hyperinsulinaemia reduces the cellular response to Pegylated-interferon in CHC with IR. Strategies to reduce insulin levels before initiation of treatment should be pursued to improve efficacy of anti-viral treatment. © 2009 Blackwell Publishing Ltd.


207§
Prandoni, P., Noventa, F., Milan, M. Quere I, Presles E, POST Study Group, et al.

Superficial venous thrombosis and venous thromboembolism: A large, prospective epidemiologic study
(2010) Ann Intern Med, 152 (4), p. 218.


206§
Nicolaides, A.N., Kakkos, S.K., Kyriacou, E., Griffin, M., Sabetai, M., Thomas, D.J., Tegos, T., Geroulakos, G., Labropoulos, N., Dor, C.J., Morris, T.P., Naylor, R., Abbott, A.L., Adovasio, R., Ziani, B., Alò, F.P., Cicilioni, C.G., Ambrosio, G., Andreev, A., Andreozzi, G.M., Verlato, F., Camporese, G., Arosio, E., Barkauskas, E., Barros D'Sa, A.A.B., Brannigan, P., Batchvarova, V., Dramov, A., Belardi, P., Novelli, GP, Simoni, G., Bell, P., Biasi, G.M., Mingazzini, P., Bornstein, N.M., Bouchier-Hayes, D., Fitzgerald, P., Cairols, M.A., Cao, P.G., DeRango, P., Carboni, G.P., Geoffredo, C., Catalano, M., Chambers, B., Goetzmann, M., Dickinson, A., Clement, D., Bobelyn, M., Coccheri, S., Conti, E., Diamantopoulos, E., Andreadis, E.A., Dimakakos, P.B., Kotsis, T., Eikelboom, B., Entz, L., Ferrari-Bardile, Aloi, T., Salerno, M., Fernandes e Fernandes, J., Pedro, L., Fitzgerald, D.E., O'Shaunnersy, Anne, Fletcher, J., Forconi, S., Cappeli, R., Bicchi, M., Arrigucci, S., Gallai, V., Cardaiolli, G., Geroulakos, G., Kakkos, S., Gomez-Isaza, L.F., Gorgoyannis, G., Liasis, N., Graf, M., Guarini, P., Hardy, S., Harris, P., Aston, S., Iosa, G., Katsamouris, A., Giannoukas, A., Krzanowski, M., Ladurner, G., Leal-Monedero, J., Lee, B.B., Liapis, C., Galanis, P., Liboni, W., Pavanelli, E., Mannarino, E., Vaudo, G., McCollum, P., Levison, R., Micieli, G., Bosone, D., Middleton, L., Pantziaris, M., Tyllis, T., Minar, E., Willfort, A., Moggi, L., Nenci, G., Radicchia, S., Nicolaides, A., Thomas, D, Norgren, L., Ribbe, E., Novo, S., Tantillo, R., Olinic, D., Paaske, W., Pagnan, A., Pauletto, P., Pagliara, V., Pettina, G., Pratesi, C., Matticari, S., Polivka, J., Sevcik, P., Poredos, P., Blinc, A., Videcnik, V., Pujia, A., Raso, A., Rispoli, P., Conforti, M., Robinson, T., Dennis, M.S.J., Rosfors, S., Rudofsky, G., Schroeder, T., Gronholdt, M.L., Simoni, G., Finocchi, C., Rodriguez, G., Spartera, C., Ventura, M., Scarpelli, P., Sprynger, M., Sadzot, B., Hottermans, C., Moonen, Taylor, P.R., Tovar-Pardo, A., Negreira, J., Vayssairat, M., Faintuch, J.M., Valaikiené, J., Walker, M.G., Wilkinson, A.R.

Asymptomatic internal carotid artery stenosis and cerebrovascular risk stratification
Journal of Vascular Surgery, 52 (2010) (6), pp. 1486-1496.E5.

DOI: 10.1016/j.jvs.2010.07.021

Abstract
Background The purpose of this study was to determine the cerebrovascular risk stratification potential of baseline degree of stenosis, clinical features, and ultrasonic plaque characteristics in patients with asymptomatic internal carotid artery (ICA) stenosis. Methods This was a prospective, multicenter, cohort study of patients undergoing medical intervention for vascular disease. Hazard ratios for ICA stenosis, clinical features, and plaque texture features associated with ipsilateral cerebrovascular or retinal ischemic (CORI) events were calculated using proportional hazards models. Results A total of 1121 patients with 50% to 99% asymptomatic ICA stenosis in relation to the bulb (European Carotid Surgery Trial [ECST] method) were followed-up for 6 to 96 months (mean, 48). A total of 130 ipsilateral CORI events occurred. Severity of stenosis, age, systolic blood pressure, increased serum creatinine, smoking history of more than 10 pack-years, history of contralateral transient ischemic attacks (TIAs) or stroke, low grayscale median (GSM), increased plaque area, plaque types 1, 2, and 3, and the presence of discrete white areas (DWAs) without acoustic shadowing were associated with increased risk. Receiver operating characteristic (ROC) curves were constructed for predicted risk versus observed CORI events as a measure of model validity. The areas under the ROC curves for a model of stenosis alone, a model of stenosis combined with clinical features and a model of stenosis combined with clinical, and plaque features were 0.59 (95% confidence interval [CI] 0.54-0.64), 0.66 (0.62-0.72), and 0.82 (0.78-0.86), respectively. In the last model, stenosis, history of contralateral TIAs or stroke, GSM, plaque area, and DWAs were independent predictors of ipsilateral CORI events. Combinations of these could stratify patients into different levels of risk for ipsilateral CORI and stroke, with predicted risk close to observed risk. Of the 923 patients with <70% stenosis, the predicted cumulative 5-year stroke rate was <5% in 495, 5% to 9.9% in 202, 10% to 19.9% in 142, and <20% in 84 patients. Conclusion Cerebrovascular risk stratification is possible using a combination of clinical and ultrasonic plaque features. These findings need to be validated in additional prospective studies of patients receiving optimal medical intervention alone. Copyright © 2010 by the Society for Vascular Surgery.


205§
Camporese, G., Bernardi, E., Noventa, F.

Update on the clinical use of the low-molecular-weight heparin, parnaparin
(2009) Vascular Health and Risk Management, 5, pp. 819-831.

PubMed ID: 19851520

Abstract
Parnaparin is a low-molecular-weight heparin that has widely shown its efficacy and safety in prevention of venous thromboembolism, in the treatment of chronic venous disorders, and in the treatment of venous and arterial (stable and unstable angina, acute ST-segment elevation myocardial infarction) thrombosis. Parnaparin at the respective dosages of 3200, 4250, 6400, or 12800 IUaXa for a period ranging from 3 to 5 days to 6 months, is usually administered subcutaneously by means of once-daily regimen and is better tolerated than unfractionated heparin at the injection site. In the variety of commercially available low-molecular-weight heparins, parnaparin represents a useful therapeutic option, even though little evidence is available comparing the superiority or the equivalent efficacy and safety of parnaparin to that of the unfractionated heparin or placebo. This review summarizes the available literature on the use of parnaparin in different settings of cardiovascular diseases, including papers published during the past year and ongoing studies. © 2009 Camporese et al, publisher and licensee Dove Medical Press Ltd.


204§
Sebastiani, G., Halfon, P., Castera, L., Pol, S., Thomas, D.L., Mangia, A., Di Marco, V., Pirisi, M., Voiculescu, M., Guido, M., Bourliere, M., Noventa, F., Alberti, A.

SAFE biopsy: A validated method for large-scale staging of liver fibrosis in chronic hepatitis C
(2009) Hepatology, 49 (6), pp. 1821-1827.

PubMed ID: 19291784
DOI: 10.1002/hep.22859

Abstract
The staging of liver fibrosis is pivotal for defining the prognosis and indications for therapy in hepatitis C. Although liver biopsy remains the gold standard, several noninvasive methods are under evaluation for clinical use. The aim of this study was to validate the recently described sequential algorithm for fibrosis evaluation (SAFE) biopsy, which detects significant fibrosis (≥F2 by METAVIR) and cirrhosis (F4) by combining the AST-to-platelet ratio index and Fibrotest-Fibrosure, thereby limiting liver biopsy to cases not adequately classifiable by noninvasive markers. Hepatitis C virus (HCV) patients (2035) were enrolled in nine locations in Europe and the United States. The diagnostic accuracy of SAFE biopsy versus histology, which is the gold standard, was investigated. The reduction in the need for liver biopsies achieved with SAFE biopsy was also assessed. SAFE biopsy identified significant fibrosis with 90.1% accuracy (area under the receiver operating characteristic curve = 0.89; 95% confidence interval, 0.87-0.90) and reduced by 46.5% the number of liver biopsies needed. SAFE biopsy had 92.5% accuracy (area under the receiver operating characteristic curve = 0.92; 95% confidence interval, 0.89-0.94) for the detection of cirrhosis, obviating 81.5% of liver biopsies. A third algorithm identified significant fibrosis and cirrhosis simultaneously with high accuracy and a 36% reduction in the need for liver biopsy. The patient's age and body mass index influenced the performance of SAFE biopsy, which was improved with adjusted Fibrotest-Fibrosure cutoffs. Two hundred two cases (9.9%) had discordant results for significant fibrosis with SAFE biopsy versus histology, whereas 153 cases (7.5%) were discordant for cirrhosis detection; 71 of the former cases and 56 of the latter cases had a Fibroscan measurement within 2 months of histological evaluation. Fibroscan confirmed SAFE biopsy findings in 83.1% and 75%, respectively. Conclusion: SAFE biopsy is a rational and validated method for staging liver fibrosis in hepatitis C with a marked reduction in the need for liver biopsy. It is an attractive tool for large-scale screening of HCV carriers. Copyright © 2009 by the American Association for the Study of Liver Diseases.


203§
Camporese, G., Bernardi, E., Noventa, F.

Prevention of deep venous thrombosis after knee arthroscopy. Recent advances [Recenti acquisizioni sulla tromboprofilassi dopo artroscopia del ginocchio]
(2009) Recenti Progressi in Medicina, 100 (5), pp. 227-232.

PubMed ID: 19772212
DOI: 10.1701/427.5078

Abstract
In absence of prophylaxis, the incidence of deep vein thrombosis after knee arthroscopy is reported to be as high as 18%. Recommendations for thromboprophylaxis after knee arthroscopy have actually been updated. The results of the largest randomized clinical trial (KANT study) in this setting are reported together with a review of the literature.

§
Cavazzana, A., Pengo, V., Tonello, M., Noventa, F., Grossi, C., Borghi, M.O., De Moerloose, P., Reber, G., Ruffatti, A.

Anti-β2-glycoprotein I ELISA assay: The influence of different antigen preparations
(2009) Thrombosis and Haemostasis, 101 (4), pp. 789-791.

PubMed ID: 19350132
DOI: 10.1160/TH08-02-0082


202§
Bernardi, E., Camporese, G., Noventa, F.

Ultrasound-based diagnostic strategies for deep vein thrombosis reply
(2009) JAMA - Journal of the American Medical Association, 301 (9), pp. 934-935.

DOI: 10.1001/jama.2009.186


201§
Antonello, M., Frigatti, P., Maturi, C., Lepidi, S., Noventa, F., Pittoni, G., Deriu, G.P., Grego, F.

Open Repair for Ruptured Abdominal Aortic Aneurysm: Is It Possible to Predict Survival?
(2009) Annals of Vascular Surgery, 23 (2), pp. 159-166.

PubMed ID: 18834704
DOI: 10.1016/j.avsg.2008.05.011

Abstract
The aim of the study was to determine variables that could be used to predict survival in patients with ruptured abdominal aortic aneurysm (RAAA) and to assess the accuracy of the Glasgow Aneurysm Score (GAS) and the Acute Physiology Chronic Health Evaluation II (APACHE-II). From January 1998 to July 2006, 103 patients underwent operations for RAAA. For each patient, 44 variables were retrospectively recorded in a database. Data were analyzed with univariate and multivariate methods. In the univariate analysis significant predictors of death were hypotension (p = 0.001), preexisting peripheral vascular disease (p < 0.001), renal insufficiency (p = 0.037), chronic obstructive pulmonary disease (p = 0.028), level of HCO3- (p < 0.001), intraperitoneal rupture (p = 0.001), blood transfused (p < 0.001), cardiac complications (p < 0.001), and APACHE-II score (p = 0.001). Multivariate analysis confirmed statistical significance for coexisting peripheral vascular disease (p < 0.001), diastolic blood pressure at admission <60 mm Hg (p = 0.039), APACHE-II score >18.5 (p = 0.025), HCO3- <21 mg/dL (p < 0.001), and intraperitoneal rupture of the aneurysm (p = 0.011) as predictors of death. Results of the study suggested that different factors can be helpful in identifying those patients whose operative risk is prohibitive. APACHE-II, contrary to GAS, is an accurate system to predict postoperative death after repair for RAAA. © 2009 Annals of Vascular Surgery Inc.


200§
Camporese, G., Bernardi, E.

Low-molecular-weight heparin for thromboprophylaxis
(2009) Current Opinion in Pulmonary Medicine, 15 (5), pp. 443-454.

PubMed ID: 19593139
DOI: 10.1097/MCP.0b013e32832f5d9d

Abstract
Purpose of review: Venous thromboembolism represents a potentially threatening complication in surgical and medical patients. Thromboprophylaxis showed a significant reduction of venous thromboembolic events, and low-molecular-weight heparins have been considered the standardized prophylactic regimen for a long time. The purpose of this review is to provide updated evidence on the use of low-molecular-weight heparins for prevention of venous thromboembolism after the publication of the latest American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on antithrombotic and thrombolytic therapy. RECENT FINDINGS: Low-molecular-weight heparins, used as comparator or investigational drug, have been investigated in several studies not included in the analysis of the latest American College of Chest Physicians Guidelines on Antithrombotic and Thrombolytic Therapy. Data gathered from studies published from December 2007 up to May 2009 dealing with surgical and medical patients have been collected and discussed. SUMMARY: Low-molecular-weight heparins are expanding their application, but progressively they will be replaced by other new antithrombotics for the prophylaxis of venous thromboembolism. Surgical patients undergo a more concerted approach to thromboprophylaxis than medical patients. Future research should aim at improving prophylaxis in the latter setting in order to significantly reduce the rate of venous thromboembolic events. Copyright © 2009 Lippincott Williams & Wilkins.


199§
Parisi, R., Visonà, A., Camporese, G., Verlato, F., Lessiani, G., Antignani, P.L., Palareti, G.

Isolated distal deep vein thrombosis: Efficacy and safety of a protocol of treatment. Treatment of Isolated Calf Thrombosis (TICT) study
(2009) International Angiology, 28 (1), pp. 68-72.

PubMed ID: 19190559

Abstract
Aim. The optimal treatment of isolated distal deep vein thrombosis (ID-DVT) is still controversial. A complete anticoagulation as soon as the diagnosis is made is recommended by some authors. Alternatively, other authors suggest to perform serial ultrasonography assessments to detect the possible extension of DVT towards proximal veins. Only in this case the treatment should be initiated. Furthermore, the optimal duration of treatment is far from established. The Treatment of Isolated Calf Thrombosis (TICT) study was set up to assess the efficacy and safety of a particular treatment regimen of ID-DVT based on low molecular weight heparins (LMWH). Methods. The drug treatment consisted of a twice-daily subcutaneous administration of a full dose of weight-adjusted LMWH for one week, followed by a half dose of LMWH administered once-daily for another three weeks. At the end of the four-week period of treatment, a colour-coded Doppler ultrasonography (CCDU) assessment was scheduled and after three months a follow-up visit was performed. If a patient was unable to attend the visit, he was contacted by a phone-call to assess if any adverse events occurred. The study enrolled 192 outpatients with ID-DVT confirmed by CCDU. Twenty-one out of 192 patients (10.9%) were excluded for violation of protocol. Thus 171 (39.9% men, mean age of 60.45 years) were eligible and were included in the study. Sixty-one patients (36.6%) presented an unprovoked ID-DVT. Results. Events during the period of treatment (4 weeks). Ten out of 171 patients (5.8%) had complications: five patients showed an extension proximal to the knee (2.9%) all with an unprovoked ID-DVT; two showed an extension of thrombus within the distal veins. Three patients (1.7%) suffered from minor bleeding; there was no major bleeding. Further events during three months of observation occurred. Five patients had thrombus recurrences: four patients showed a proximal DVT (3 with a previous unprovoked ID-DVT, 1 with a previous ID-DVT secondary to a traumatic leg fracture, with persistent difficulty of deambulation); one, with a previous secondary thrombosis, showed a ID-DVT. Conclusion. In our study only 2.9% of patients with ID-DVT showed a progression of thrombosis to proximal deep veins; the majority of thrombus progression, during the treatment period, was observed in patients with unprovoked ID-DVT. Our results support the usefulness of a prolonged treatment in unprovoked ID-DVT.


198§
Kontothanassis, D., Di Mitri, R., Ferrari Ruffino, S., Zambrini, E., Camporese, G., Gerard, J.L.

Endovenous laser treatment of the small saphenous vein with a 980-nm diode laser: early results
(2009) J Vasc Surg, 49 (4), pp. 817-1092.


197§
Kontothanassis, D., Di Mitri, R., Ferrari Ruffino, S., Zambrini, E., Camporese, G., Gerard, J.L., Labropoulos, N.

Endovenous laser treatment of the small saphenous vein
(2009) Journal of Vascular Surgery, 49 (4), pp. 973-979.e1.

PubMed ID: 19341887
DOI: 10.1016/j.jvs.2008.11.019

Abstract
Purpose: Endovenous laser treatment is a minimally invasive technique for ablation of the incompetent great (GSV) and small saphenous vein (SSV). Compared with the GSV, fewer data are available on SSV laser ablation and are not validated. This multicenter prospective study evaluated the feasibility, safety, and efficacy of endovenous laser ablation to treat SSVs. Methods: Between January 2003 and January 2007, 204 patients (229 limbs) with CVD and incompetent SSVs (evaluated by the CEAP classification) who were eligible for surgery underwent consecutive laser ablation procedures. Many required additional treatment for varicose tributaries and perforator veins with phlebectomy and foam sclerotherapy, Energy was delivered to the vein wall by a 600-μm optical fiber using 810-nm or 980-nm diode laser. Ablations were performed with duplex ultrasound (DU) guidance and tumescent anesthesia. Follow-up was with clinical examination and DU imaging. Results: DU imaging showed immediate occlusion of the SSV with no thrombosis in the proximal veins. No complications occurred intraoperatively. All patients had postoperative ecchymosis, but it was minimal. Three patients had distal thrombotic complications. Superficial phlebitis after complementary surgery occurred in three cases. Complete occlusion with absence of flow ≤2 months of follow-up was detected in 226 SSV (98.7%). It occurred 22 in patients with large SSV diameter. Recanalization was found in one patient at 12 months and in two patients at 24 months. Seven limbs had reflux in previously treated areas, treated segments, and segments in continuity with them. Three underwent an intervention to correct symptomatic reflux. The other four had no symptoms. After 1 year, eight limbs developed reflux in new locations and four underwent treatment. Symptoms resolved in most patients soon after the operation. The mean follow-up was 16 months (range, 2-39 months). After 8 to 12 months postprocedurally, the laser-treated veins were fibrotic and almost indistinguishable on DU imaging from the surrounding tissues. In five patients (2.25%) postoperative paresthesia occurred >2 to 3 days postoperatively and persisted in the follow-up. No paresthesia occurred in our last series whenever a larger amount of tumescent cold saline was infused around the vein. Conclusion: Endovenous laser ablation of the SSV has excellent early and midterm results. The prevalence of thrombosis and paresthesia is very low. Symptom relief is very good. © 2009 The Society for Vascular Surgery.


196§
Ghirarduzzi, A., Camporese, G., Siragusa, S., Imberti, D., Bucherini, E., Landini, F.

A randomized, prospective, open-label study on distal vein thrombosis (low-molecular-weight-heparin vs warfarin for 6 weeks): The Todi study
(2009) J Thromb Haemost, 7 (SUPPL. 2),


195§
Marzolo, M., Verlato, F., Zotta, L., Guadagnin, M.L., Borgese, L., Cravatari, M., Nardi, M., Camporese, G., Andreozzi, G.M.

Occult atherosclerosis and physical vascular examination: A simple strategy to avoid inadequate cardiovascular prevention and under-use of diagnostic vascular guidelines in outpatients. A multicenter study by Angiology Care Units in North-Eastern Italy
(2008) International Angiology, 27 (5), pp. 426-432.

PubMed ID: 18974707

Abstract
Aim. Recent studies show a high prevalence of inadequate secondary prevention in a subset of the US population at highest risk for stroke and acute myocardial infarction. Methods. The present investigation evaluated subjects older than 50 years of age attending four Angiology Care Units in Northern Italy. The adequacy of risk factor (hypertension, body weight, cigarette smoking and hypercholesterolemia) control was in particular analyzed, and a search was made for occult atherosclerotic lesions during a thorough physical examination. Finally, adherence to diagnostic vascular guidelines was also evaluated. Results. Twenty-two percent out of 483 patients enrolled in this study were found to have unexpected atherosclerotic lesions, 61.9% of the patients with a history of hypertension, 10.6% showed an inadequate control of blood pressure levels, 55% presented poor lipid control, 16.6% had not stopped smoking and 45.7% were overweight. The physical examination revealed that 13.8% of the patients had cervical bruits, 6.3% had aortic hyperpulsatility and 8.5% were lacking lower limb pulses, not previously diagnosed. It was found that in almost half of the participating patients diagnostic vascular guidelines were not being followed. Conclusion. This study shows a high prevalence of inadequate primary and secondary prevention and under-use of diagnostic vascular guidelines in the care of high-risk patients (older than 50 years with diabetes, smokers, etc.). Considerable efforts are required to effectively implement risk factor modification strategies and, with regard to Angiology Care Units, to correctly search for occult atherosclerotic lesions in high-risk patients.


194§
Camporese, G., Noventa, F., Bernardi, E.

In response
(2008) Annals of Internal Medicine, 149 (9), pp. 687-688.


193§
Pastore, G., Noventa, F., Piovesana, P., Cazzin, R., Aggio, S., Verlato, R., Zanon, F., Baracca, E., Roncon, L., Padeletti, L., Barold, S.S.

Left ventricular dyssynchrony resulting from right ventricular apical pacing: Relevance of baseline assessment
(2008) PACE - Pacing and Clinical Electrophysiology, 31 (11), pp. 1456-1462.

PubMed ID: 18950303
DOI: 10.1111/j.1540-8159.2008.01209.x

Abstract
Objectives: Evaluation of left ventricular (LV) dyssynchrony in patients undergoing short-term right ventricular apical (RVA) pacing and correlation with baseline echocardiographic and clinical characteristics. Background: RVA pacing causes abnormal ventricular depolarization that may lead to mechanical LV dyssynchrony. The relationships between pacing-induced LV dyssynchrony and baseline echocardiographic and clinical variables have not been fully clarified. Methods: Tissue Doppler echocardiography was performed in 153 patients before and after RVA pacing. LV dyssynchrony was measured by the time between the shortest and longest electromechanical delays in the five basal LV segments (intra-LV). The prevalence and degree of LV dyssynchrony after RVA pacing was evaluated in three groups: baseline LV ejection fraction (LVEF) <35%, 35-55%, and ≥55%. The intrapatient effect of RVA pacing was determined as the percent increase in intra-LV value (Δintra-LV%). The pacing-induced intra-LV was correlated with baseline variables. Results: The prevalence and degree of LV dyssynchrony after RVA pacing was significantly higher in patients with lower LVEF (P < 0.001). ΔIntra-LV% was inversely correlated with baseline intra-LV and LVEF (B = -2.6, B = -4.2, P < 0.001). Baseline intra-LV and LV end-systolic volume correlated positively with intra-LV after RVA pacing (B = 0.49, B = 0.6, P < 0.001), whereas LVEF showed an inverse correlation. Conclusions: The degree of LV dyssynchrony induced by RVA is variable. Patients with higher baseline LV dyssynchrony, more dilated LV, and more depressed LVEF showed a higher degree of LV dyssynchrony during pacing. These findings may assume importance in predicting the risk of heart failure in pacemaker patients. © 2008, The Authors.


192§
Bernardi, E., Camporese, G., Büller, H.R., Siragusa, S., Imberti, D., Berchio, A., Ghirarduzzi, A., Verlato, F., Anastasio, R., Prati, C., Piccioli, A., Pesavento, R., Bova, C., Maltempi, P., Zanatta, N., Cogo, A., Cappelli, R., Bucherini, E., Cuppini, S., Noventa, F., Prandoni, P.

Serial 2-point ultrasonography plus D-dimer vs whole-leg color-coded Doppler ultrasonography for diagnosing suspected symptomatic deep vein thrombosis: A randomized controlled trial
(2008) JAMA - Journal of the American Medical Association, 300 (14), pp. 1653-1659.

PubMed ID: 18840838
DOI: 10.1001/jama.300.14.1653

Abstract
Context: Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. Objective: To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. Design, Setting, and Patients: A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n=2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. Main Outcome Measure: Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. Results: Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n=1045) or whole-leg (n=1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%; 95% CI, -1.4% to 0.8%). Conclusion: The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. Trial Registration: clinicaltrials.gov Identifier: NCT00353093 ©2008 American Medical Association. All rights reserved.


191§
Camporese, G., Bernardi, E., Prandoni, P., Noventa, F., Verlato, F., Simioni, P., Ntita, K., Salmistraro, G., Frangos, C., Rossi, F., Cordova, R., Franz, F., Zucchetta, P., Kontothanassis, D., Andreozzi, G.M.

Low-molecular-weight heparin versus compression stockings for thromboprophylaxis after knee arthroscopy: A randomized trial
(2008) Annals of Internal Medicine, 149 (2), pp. 73-82.

PubMed ID: 18626046
DOI: 10.7326/0003-4819-149-2-200807150-00003

Abstract
Background: Knee arthroscopy, the most common orthopedic operation worldwide, carries a definite risk for deep venous thrombosis; however, postsurgical thromboprophylaxis is not routinely recommended. Objective: To evaluate whether low-molecular-weight heparin (LMWH) better prevents deep venous thrombosis and does not cause more complications than graduated compression stockings in adults having knee arthroscopy. Design: Assessor-blind, randomized, controlled trial. Setting: The Department of Knee Surgery, Abano Terme Clinic, Abano Terme (knee surgery, random assignment, and bleeding event survey), and the Unit of Angiology, University Hospital of Padua, Padua (efficacy outcomes evaluation, follow-up, data management, and analysis), Italy. Patients: 1761 consecutive patients undergoing knee arthroscopy between March 2002 and January 2006. Intervention: Patients were randomly assigned to wear full-length graduated compression stocking for 7 days (660 patients) or to receive a once-daily subcutaneous injection of LMWH (nadroparin, 3800 anti-Xa IU) for 7 days (657 patients) or 14 days (444 patients). The data and safety monitoring board prematurely stopped the 14-day heparin group after the second interim analysis. Measurements: Combined incidence of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality (primary efficacy end point) and combined incidence of major and clinically relevant bleeding events (primary safety end point). All patients had bilateral whole-leg ultrasonography at the end of the allocated prophylactic regimen or earlier if indicated. All patients with normal findings were followed for 3 months, and none was lost to follow-up. Results: The 3-month cumulative incidence of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality was 3.2% (21 of 660 patients) in the stockings group, 0.9% (6 of 657 patients) in the 7-day LMWH group (absolute difference, 2.3 percentage points [95% CI, 0.7 to 4.0 percentage points]; P = 0.005), and 0.9% (4 of 444 patients) in the prematurely stopped 14-day LMWH group. The cumulative incidence of major or clinically relevant bleeding events was 0.3% (2 of 660 patients) in the stockings group, 0.9% (6 of 657 patients) in the 7-day LMWH group (absolute difference, -0.6 percentage point [CI, -1.5 to 0.2 percentage points]), and 0.5% (2 of 444 patients) in the 14-day LMWH group. Limitations: The study was not double-blind or double-dummy. Almost half of the events making up the composite outcome measure were distal deep venous thromboses. Stockings were used instead of placebo because of local prophylaxis policies. Conclusion: In patients undergoing knee arthroscopy, prophylactic LMWH for 1 week reduced a composite end point of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality more than did graduated compression stockings. © 2008 American College of Physicians.


190§
Antonello, M., Frigatti, P., Maturi, C., Lepidi, S., Noventa, F., Pittoni, G.

Open repair for ruptured abdominal aortic aneurysm
(2008) Ann Vasc Surg.


189§
Gensini, G.F., Bonifacio, M., Camporese, G.

(2008) TVP: Guida per la diagnosi e il trattamento della trombosi venosa profonda in medicina generale,


188§
Camporese, G., Bernardi, E., Prandoni, P.

Low-molecular weight heparin for 7 days was more effective than compression stockings for preventing DVT in knee arthroscopy
(2008) Ann Intern Med, 149, pp. 6-10.


187§
Prandoni, P., Noventa, F., Ghirarduzzi, A., Pengo, V., Bernardi, E., Pesavento, R., Iotti, M., Tormene, D., Simioni, P., Pagnan, A.

The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients
(2007) Haematologica, 92 (2), pp. 199-205+III-IV.

PubMed ID: 17296569
DOI: 10.3324/haematol.10516

Abstract
Background and Objectives: While it has long been recognized that patients with acute unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) have a higher risk of recurrent venous thromboembolism (VTE) than that of patients with secondary thrombosis, whether other clinical parameters can help predict the development of recurrent events is controversial. The aim of this investigation was to assess the rate of recurrent VTE after withdrawal of vitamin K antagonists, and to identify clinical parameters associated with a higher likelihood of recurrence. Design and Methods: We followed, up to a maximum of 10 years, 1626 consecutive patients who had discontinued anticoagulation after a first episode of clinically symptomatic proximal DVT and/or PE. All patients with clinically suspected recurrent VTE underwent objective tests to confirm or rule out the clinical suspicion. Results: After a median follow-up of 50 months, 373 patients (22.9%) had had recurrent episodes of VTE. The cumulative incidence of recurrent VTE was 11.0% (95% CI, 9.5-12.5) after 1 year, 19.6% (17.5-21.7) after 3 years, 29.1% (26.3-31.9) after 5 years, and 39.9% (35.4-44.4) after 10 years. The adjusted hazard ratio for recurrent VTE was 2.30 (95% CI, 1.82-2.90) in patients whose first VTE was unprovoked, 2.02 (1.52-2.69) in those with thrombophilia, 1.44 (1.03-2.03) in those presenting with primary DVT, 1.39 (1.08-1.80) for patients who received a shorter (up to 6 months) duration of anticoagulation, and 1.14 (1.06-1.12) for every 10-year increase of age. When the analysis was confined to patients with unprovoked VTE the results did not change. Interpretation and Conclusions: Besides unprovoked presentation, other factors independently associated with a statistically significant increased risk of recurrent VTE are thrombophilia, clinical presentation with primary DVT, shorter duration of anticoagulation, and increasing age. ©2007 Ferrata Storti Foundation.


186§
Scquizzato, E., Teramo, A., Miorin, M., Facco, M., Piazza, F., Noventa, F., Trentin, L., Agostini, C., Zambello, R., Semenzato, G.

Genotypic evaluation of killer immunoglobulin-like receptors in NK-type lymphoproliferative disease of granular lymphocytes
(2007) Leukemia, 21 (5), pp. 1060-1069.

PubMed ID: 17361229
DOI: 10.1038/sj.leu.2404634

Abstract
Using polymerase chain reaction (PCR)-based sequence-specific primers, the killer immunoglobulin-like receptor (KIR) genotypes of 35 patients with natural killer (NK)-type lymphoproliferative disease of granular lymphocytes and of 50 normal subjects were investigated to evaluate whether genes coding for activating KIRs were more frequently detected in patients with NK-lymphoproliferative disease of granular lymphocytes (LDGL). Genotype frequency indicated that the most frequently found gene content was eight genes in controls and 14 in patients (P < 0.05). The KIR genotype analysis revealed that patient and, surprisingly, control KIR genotypes preferentially consisted of type B haplotypes characterized by the presence of multiple-activating KIRs. Evidence was also provided that the same KIR genotype was shared by a variable number of patients. Interestingly, the recurrent genotypes observed in the patient group were not found in controls. Concerning inhibitory genes, KIR2DL5a and 2DL5b were more frequently detected in patients than in controls (P < 0.01), likely representing a discrete feature of the genetic repertoire of the patients. KIR gene repertoire analysis in patients suggests that the susceptibility to NK-LDGL might be related to the presence of activating KIR genes and supports the concept that these receptors may be involved in the priming of granular lymphocytes (GL) proliferation. Population analysis might disclose a genetic background predisposing to this disease.


185§
Terrin, L., Trentin, L., Degan, M., Corradini, I., Bertorelle, R., Carli, P., Maschio, N., Bo, M.D., Noventa, F., Gattei, V., Semenzato, G., De Rossi, A.

Telomerase expression in B-cell chronic lymphocytic leukemia predicts survival and delineates subgroups of patients with the same igVH mutation status and different outcome
(2007) Leukemia, 21 (5), pp. 965-972.

PubMed ID: 17344921
DOI: 10.1038/sj.leu.2404607

Abstract
Activation of telomerase reverse transcriptase (hTERT) is essential for unlimited cell growth and plays a critical role in tumorigenesis. We investigated hTERT gene expression in 134 B-cell chronic lymphocytic leukemia (B-CLL) cases and evaluated its prognostic value with other prognostic markers (IgVH mutation status, CD38 and ZAP-70 expression). Real-time PCR assays to quantify either all hTERT transcripts (AT) or only the full length (FL) transcript encoding the functional protein were developed. hTERT-AT levels strongly correlated with hTERT-FT levels (r = 0.743, P < 0.0001); both inversely correlated with the percentage of IgVH mutation (P < 0.005) and were significantly higher in unmutated than in mutated cases (P = 0.004 and P = 0.001, respectively). The hTERT values which best discriminated between the unmutated and mutated IgVH cases were 150 and 40 copies for hTERT-AT and hTERT-FL, respectively. Using these cut-off values, there was a significant difference in the survival of patients with high or low hTERT levels (P < 0.0001). Unmutated cases with low hTERT levels had an overall survival close to mutated cases with high hTERT levels. Thus, this work identifies hTERT-RNA level as a new prognostic marker in B-CLL, and may be used to identify previously unrecognized patient groups with the same IgVH mutation status and different disease outcomes.


184§
Ageno, W., Manfredi, E., Dentali, F., Silingardi, M., Ghezzi, F., Camporese, G., Bolis, P., Venco, A.

The incidence of venous thromboembolism following gynecologic laparoscopy: A multicenter, prospective cohort study
(2007) Journal of Thrombosis and Haemostasis, 5 (3), pp. 503-506.

PubMed ID: 17092300
DOI: 10.1111/j.1538-7836.2007.02312.x

Abstract
Background: Information on the incidence of venous thromboembolism (VTE) following laparoscopic procedures is inadequate and there is currently no solid evidence to guide the use of thromboprophylaxis in this setting. Gynecologic laparoscopy is a common procedure, and is frequently performed in low-risk patients. To our knowledge, there are no clinical studies specifically designed to assess the incidence of VTE in this setting. Methods: In a prospective cohort study, consecutive patients undergoing gynecologic laparoscopy underwent compression ultrasonography (CUS) and clinical assessment to evaluate the incidence of clinically relevant VTE. CUS was performed 7 ± 1 and 14 ± days postoperatively. A subsequent telephone contact was scheduled at 30 and 90 days. No patient received pharmacologic or mechanical prophylaxis. Patients with malignancy or previous VTE were excluded from the study. Results: We enrolled 266 consecutive patients; mean age was 36.3 years, range: 18-72. The most common indications for laparoscopy were ovarian cysts in 25.6% of patients, endometriosis in 21.0% of patients, unexplained adnexal masses in 12.4% of patients, and infertility in 7.5% of patients. The mean duration of the procedure was 60.5 min (range: 10-300 min). In particular, in 55.6% of patients the duration exceeded 45 min. There were neither episodes of CUS detected DVT (0/247; 0%, 95% CI 0-1.51%) or clinically relevant VTE after follow-up (0/256; 0%, 95% CI 0-1.48%). No patient died of fatal pulmonary embolism (0/266; 0%, 95% CI 0-1.42%). Conclusions: Gynecologic laparoscopy in non-cancer patients is a low-risk procedure for postoperative VTE. © 2007 International Society on Thrombosis and Haemostasis.


183§
Camporese, G., Bernardi, E., Prandoni, P., Verlato, F., Cordova, R., Simioni, P.

The KANT Study Group. Graduated compression stockings (GCS) versus low-molecular-weight heparin (LMWH) for prevention of deep vein thrombosis (DVT) after knee arthroscopy (KA). A randomized study [Abstract]
(2007) J Thromb Haemost, p. 5.


182§
Bernardi, E., Camporese, G., Buller, H.R.

Limited versus extended ultrasonography for the diagnosis of clinically suspected deep vein thrombosis. A randomized study [abstract O-M-055].
(2007) J Thromb Haemost, 5 (SUPPL. 1),


181§
Camporese, G., Bernardi, E., Prandoni, P.

Graduated compression stocking (GCS) versus low-molecular-weight heparin (LMWH) for prevention of deep vein thrombosis (DVT) after knee arthroscopy (KA): A randomized study (KANT)
(2007) J Thromb Haemost, 5 (SUPPL. 2), pp. OT-052.


180§
Biffi, R., Pittiruti, M., Campisi, C., Agnelli, G., Aldrighetti, L., Bernardi, E., Bertoglio, S., De Cicco, M., Moia, M., Palareti, G., Sandrucci, S., Zanon, G.F.

Catheter-related central venous thrombosis: The development of an Italian nationwide Consensus Paper
(2007) Nutritional Therapy and Metabolism, 25 (4), pp. 173-182.

Abstract
Catheter-related central venous thrombosis is a serious complication in patients who need long-term venous access. Though scientific data and clinical experience are steadily increasing, many uncertainties still exist about several aspects concerning etiology, pathogenesis, diagnosis, management, and prevention of this complication. The GAVeCeLT (the Italian Study Group for Long-Term Central Venous Access) promoted a nationwide Consensus, and 12 experts systematically reviewed all of the available literature. A preliminary document was presented and discussed during a specific Consensus Meeting before an enlarged panel of more than 80 experts (representing different health professions and disciplines). This led to a pre-final document, which was presented to more than 800 health professionals. After a peer review by an external board of experts, a final document was prepared. In this paper, methodology and results of the Consensus are presented. © SINPE-GASAPE.


179§
Ruffatti, A., Tonello, M., Del Ross, T., Cavazzana, A., Grava, C., Noventa, F., Tona, F., Iliceto, S., Pengo, V.

Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity
(2006) Thrombosis and Haemostasis, 96 (3), pp. 337-341.

PubMed ID: 16953276
DOI: 10.1160/TH06-05-0287

Abstract
In women diagnosed as having category I primary obstetric anti-phospholipid syndrome, clinical characteristics and the risk of subsequent thromboembolic events and further unsuccessful pregnancy has not been clearly documented. Women with unexplained obstetric complications and no definite autoimmune systemic diseases were tested for lupus anticoagulant (LA), IgG/IgM anticardiolipin (aCL) and IgG/IgM anti-human β2-Glycoprotein I (aβ2GPI) antibodies and diagnosed as having primary antiphospholipid syndrome (APS) in classification category I on the basis of more than one laboratory criteria present in any combination. Characteristics at the time of diagnosis and risk factors for subsequent clinical events during a mean follow-up of 6.3 years were evaluated. Fifty-three of 600 women studied were found to fulfil obstetric criteria and had more than one positive laboratory test at the time of diagnosis.All the women were aCL and aβ2GPI positive, and 16 were also LA positive. This latter group (triple positivity) had distinct features and had more frequently experienced previous thromboembolism (OR= 122.5, 95% CI 16-957, p<0.001).They also had an increased rate of late pregnancy loss (OR= 16.2, 95% CI 0.9-292, p=0.01), and a higher IgG aβ2GPI titer at diagnosis (median, 25th and 75th percentile were 118, 37-962, vs. 23, 18-32, respectively, p<0.0001). During follow-up, the rate of thromboembolic events was significantly higher in the group of women with triple positivity and/or previous thromboembolism (OR=57.5, 95% CI 2.7-1160, p=0.0004) which were the only independent predictors ofTE in the multivariate model. Recurrent pregnancy loss took place in seven out of 47 women who had a new pregnancy. Triple positivity and/or previous thromboembolism were again the only independent markers (OR=34.4, 95% CI 3.5-335.1, p=0.003) of an unsuccessful new pregnancy. In conclusion, in primary APS with pregnancy morbidity in classification category 1, quite different groups of patients may be identified on the basis of laboratory tests. Triple positivity and/or a history of thromboemlism predict new TE events and new unsuccessful pregnancies. © 2006 Schattauer GmbH, Stuttgart.


178§
Boccato, S., Pistis, R., Noventa, F., Guido, M., Benvegnù, L., Alberti, A.

Fibrosis progression in initially mild chronic hepatitis C
(2006) Journal of Viral Hepatitis, 13 (5), pp. 297-302.

PubMed ID: 16637859
DOI: 10.1111/j.1365-2893.2005.00683.x

Abstract
The natural history of chronic hepatitis C presenting with no/minimal liver fibrosis is uncertain with controversies on risk of progression and need for antiviral treatment. We studied rates and determinants of fibrosis progression in initially mild chronic hepatitis C. One hundred and six patients (mean age 41.65 ± 12.83 years) with chronic hepatitis C virus infection and no/minimal fibrosis in the initial liver biopsy (F0/F1 by METAVIR score) were followed prospectively while untreated with repeated biopsy after 5 or more years (mean interval 7.8 ± 1.51 years). Patients showing fibrosis progression were compared with nonprogressors for baseline and follow-up parameters. Sixty-four patients (60.4%) showed fibrosis progression including 13 of 27 (49%) with F0 and 51 of 79 (65%) with F1. Progression to F3 or cirrhosis was seen in 36% of those with F1 initially. Fibrosis progression (ΔF/year) was associated with age (P < 0.0001), baseline and follow-up alanine aminotransferase (ALT) (P = 0.005), histological activity (P = 0.004) and steatosis (P = 0.002) in the initial biopsy and use of alcohol (P = 0.008). Thus liver fibrosis progression occurs in two-thirds of patients with initially mild chronic hepatitis C within 5-10 years and advanced fibrosis/cirrhosis develops in one-third of those with F1 initially. Fibrosis is facilitated by older age and alcohol and associated with inflammatory activity and ALT levels. Antiviral therapy should be considered in mild chronic hepatitis C. © 2005 Blackwell Publishing Ltd.


177§
Sebastiani, G., Vario, A., Guido, M., Noventa, F., Plebani, M., Pistis, R., Ferrari, A., Alberti, A.

Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C
(2006) Journal of Hepatology, 44 (4), pp. 686-693.

PubMed ID: 16490278
DOI: 10.1016/j.jhep.2006.01.007

Abstract
Background/Aims: In chronic hepatitis C, biopsy is the gold standard for assessment of liver fibrosis. Non-invasive markers have been proposed but their use is limited by diagnostic accuracy. Our aim was to increase the diagnostic performance of non-invasive markers of liver fibrosis by combining them in sequential algorithms. Methods: One hundred and ninety patients with chronic hepatitis C were evaluated for AST to platelets ratio (APRI), Forns' index and Fibrotest at the time of liver biopsy and stepwise combination algorithms were developed and validated prospectively in 100 additional patients. Results: Three algorithms were developed: (1) significant fibrosis (F≥2 by METAVIR) was identified with high diagnostic performance (>94% accuracy) using APRI as screening test, followed by Fibrotest in APRI non-classified cases and restricting liver biopsy to patients classified F0-F1 by non-invasive tests. (2) A slightly modified algorithm had similar performance when applied to hepatitis C carriers with normal ALT. (3) Identification of cirrhosis (95% accuracy) was achieved using a dedicated algorithm with different cut-off, reducing by 60-70% the liver biopsies needed. Conclusions: Stepwise combination of non-invasive markers of liver fibrosis improves the diagnostic performance in chronic hepatitis C. Need for liver biopsy is reduced by 50-70% but cannot be completely avoided. © 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


176§
Sebastiani, G., Vario, A., Ferrari, A., Pistis, R., Noventa, F., Alberti, A.

Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C
(2006) Journal of Viral Hepatitis, 13 (3), pp. 199-205.

PubMed ID: 16475996
DOI: 10.1111/j.1365-2893.2005.00662.x

Abstract
Hepatic iron has been described in hepatitis C virus (HCV) infection as an important cofactor of disease outcome. The mechanisms leading to hepatic iron deposits (HIDs) in HCV patients are partially understood. We investigated HIDs in the liver biopsies of a consecutive series of 242 HCV-infected patients with well-compensated liver disease. Serum ferritin was elevated in 20.7% and transferrin saturation in 19.0%, while 38.8% had stainable HIDs indicating that serum markers of systemic iron overload have low sensitivity in predicting HIDs in hepatitis C. A cut-off value of serum ferritin (350 μg/L in females and 450 μg/L in males) had good negative predictive value in excluding presence of mild-moderate HIDs (grade II-III). Hepatic iron deposits correlated by multivariate analysis with serum ferritin [odds ratio (OR) 1.008, 95% confidence interval (CI) 1.005-1.011] and albumin (OR 1.15, 95% CI 1.02-1.297). Hepatic iron deposits were more frequent in HCV-3-infected cases than in other genotypes (P = 0.027) while raised serum iron indices were more frequent in non-HCV-3 genotypes (P = 0.02). Furthermore, advanced fibrosis (F3-F4 by METAVIR) was more frequent in non-HCV-3 genotypes (P = 0.04). In HCV-3 cases there was a close association between HIDs and severe (grade II-III) steatosis (P < 0.00001). These results indicate that in well-compensated chronic hepatitis C HIDs are strongly associated with HCV-3 and viral-induced hepatic steatosis, while in the presence of other genotypes they might merely reflect a more advanced stage of liver disease and/or a systemic iron overload. Serum ferritin could identify a subgroup of patients in which the need of venesection could be excluded without liver biopsy. © 2005 Blackwell Publishing Ltd.


175§
Bortolotti, F., Guido, M., Bartolacci, S., Cadrobbi, P., Crivellaro, C., Noventa, F., Morsica, G., Moriondo, M., Gatta, A.

Chronic hepatitis B in children after e antigen seroclearance: Final report of a 29-year longitudinal study
(2006) Hepatology, 43 (3), pp. 556-562.

PubMed ID: 16496323
DOI: 10.1002/hep.21077

Abstract
Chronic hepatitis B is usually a benign disease in Caucasian children; however, the long-term prognosis remains unsettled. This report describes the results of a 29-year longitudinal study including 99 white children with chronic hepatitis B, mainly acquired horizontally: 91 were hepatitis B e antigen (HBeAg) positive (4 had cirrhosis), and 8 were HBeAg negative at presentation. Of the 91 HBeAg-positive children, 89 underwent HBeAg seroconversion after a mean period of 5.2 ± 4.0 years and were included in the study. Of the 85 children without cirrhosis, one had HBeAg-negative hepatitis and the other 84 became inactive carriers. During a mean follow-up of 14.5 ± 6.1 years after HBeAg seroclearance, 4 carriers experienced reactivation, and 3 of them had HBeAg-negative hepatitis at the last follow-up. Of the 8 initially HBeAg-negative children, 2 had HBeAg-negative hepatitis, and 6 were inactive carriers. Of the 4 children with cirrhosis, 2 had hepatocellular carcinoma (HCC) and remained alive and 2 lost the histological features of cirrhosis in adulthood. Two patients with HBeAg-negative hepatitis and 1 with cirrhosis had experienced drug abuse. At the end of follow-up, 15 of the 89 initially HBeAg-positive patients and 2 of 8 initially HBeAg-negative children had cleared hepatitis B surface antigen. In conclusion, the overall prognosis for chronic hepatitis B in horizontally infected Caucasian children is favorable; however, some patients progress to HCC and HBeAg-negative hepatitis. Long-term monitoring is important, as is counseling on cofactors of liver damage, such as alcohol and drug abuse.


174§
Sebastiani, G., Vario, A., Noventa, F., Guido, M., Pistis, R., Ferrari, A.

Diagnosis performance of non-invasive biomarkers of liver fibrosis and cirrhosis in chronic hepatitis B (abstract)
(2006) J. Hepatol., 44 (SUPPL. 2).


173§
Bernardi, E., Pesavento, R., Prandoni, P.

Upper extremity deep venous thrombosis
(2006) Seminars in Thrombosis and Hemostasis, 32 (7), pp. 729-736.

PubMed ID: 17024601
DOI: 10.1055/s-2006-951458

Abstract
About 10% of all episodes of venous thrombosis are due to upper extremity deep vein thrombosis (UEDVT). Associated risk factors are indwelling central venous catheters, cancer, and coagulation defects; 20% of the episodes are unexplained. The onset of UEDVT is usually heralded by complaints such as arm swelling and pain, but may also be completely asymptomatic, especially in carriers of central venous lines. Objective confirmation is mandatory prior to instituting anticoagulation because the clinical diagnosis is unreliable; ultrasound-based methods represent the preferred diagnostic approach. Prophylaxis with low-dose heparin or low-dose warfarin may be used, especially in carriers of central venous catheters, although its efficacy is still uncertain. Unfractionated or low molecular weight heparins followed by oral anticoagulants should be regarded as the treatment of choice, whereas thrombolysis and surgery may be indicated in selected cases. Up to one third of the patients develop pulmonary embolism that may be fatal; postthrombotic syndrome and recurrent thromboembolism are also frequent complications. UEDVT should no longer be regarded as a rare and benign disease, as reported previously. Copyright © 2006 by Thieme Medical Publishers, Inc.


172§
Pesavento, R., Bernardi, E., Concolato, A., Dalla Valle, F., Pagnan, A., Prandoni, P.

Postthrombotic syndrome
(2006) Seminars in Thrombosis and Hemostasis, 32 (7), pp. 744-751.

PubMed ID: 17024603
DOI: 10.1055/s-2006-951460

Abstract
Despite considerable progress in the diagnosis and treatment of deep vein thrombosis (DVT) of the lower extremities, one of every three patients will develop postthrombotic sequelae within 2 years; these sequelae are severe in ∼20% of cases and produce considerable socioeconomic consequences. Among factors potentially related to the development of the postthrombotic syndrome (PTS) are older age, obesity, insufficient oral anticoagulant therapy, and recurrent ipsilateral thrombosis. Whether the extent and location of the initial thrombosis are associated with the development of PTS is controversial. Based on recent findings, the lack of vein recanalization within the first 6 months appears to be an important predictor of PTS, whereas the development of transpopliteal venous reflux is not. The diagnosis of PTS can be made on clinical grounds for patients with a history of DVT. The combination of a standardized clinical evaluation with the results of compression ultrasonography and Doppler ultrasound helps diagnose or exclude a previous proximal vein thrombosis. According to the results of recent clinical studies, the prompt administration of adequate compression elastic stockings in patients with symptomatic DVT has the potential to reduce the frequency of late PTS development by half. The management of this condition is demanding and often frustrating. However, when carefully supervised and instructed to wear proper elastic stockings, more than 50% of patients will either remain stable or improve during long-term follow-up. Clinical presentation helps predict the prognosis; the outcome of patients who refer with initially severe manifestations is more favorable than that of patients whose symptoms deteriorate progressively over time. Copyright © 2006 by Thieme Medical Publishers, Inc.


171§
Pengo, V., Biasiolo, A., Pegoraro, C., Cucchini, U., Noventa, F., Iliceto, S.

Antibody profiles for the diagnosis of antiphospholipid syndrome
(2005) Thrombosis and Haemostasis, 93 (6), pp. 1147-1152.

PubMed ID: 15968401
DOI: 10.1160/TH04-12-0839

Abstract
Among the so called 'antiphospholipid antibodies', the presence of Lupus Anticoagulant (LA) is associated with thrombosis-related events and defines the antiphospholipid syndrome. The role of anti-cardiolipin (aCL) antibodies and anti-human β2-glycoprotein I (aβ2GPI) antibodies is less striking. Since the problem of standardization for these tests is far from resolved, we evaluated whether the combination of results (antiphospholipid laboratory profiles) could help to better classify these patients. Over a 6-year period, 618 consecutive subjects (55% of whom had previous documented thrombosis-related events) were referred to our clinic for Antiphospholipid antibody detection. LA was detected according to internationally accepted recommendations. ACL and aβ2GPI antibodies were detected by Enzyme-Linked-Immunosorbent Assay (ELISA). Patients' records were reviewed for the presence of previous thromboembolic events or obstetric complications according to Sapporo's clinical criteria for the diagnosis of antiphospholipid syndrome (APS) and each patient underwent a physical examination. When individual tests were considered in a multivariate analysis which took into account age, gender, the presence of SLE or other autoimmune diseases and established risk factors for venous and arterial thromboembolism, LA (Odds Ratio 4.4, Confidence Interval 1.5-13.3) and aβ2GPI antibodies (Odds Ratio 2.9, Confidence Interval 1.1-7.5) but not aCL antibodies (Odds Ratio 1.2, Confidence Interval 0.5-2.7) were found to be independent risk factors for thrombosis-related events. When antiphospholipid antibody profiles instead of individual test positivity were analyzed in the above mentioned model, triple positivity resulted a strong independent risk factor (Odds Ratio 33.3, Confidence Interval 7.0-157.6), retaining its significance when the association with venous or arterial thromboembolism was considered. Double positivity with negative LA was close to significance for thrombosis-related events (Odds Ratio 2.2, Confidence Interval 1.0-5.2, p=0.056) and highly significant risk factor for obstetric complications (Odds Ratio 10.8, Confidence Interval 2.9-40.8). Other combinations did not reach statistical significance. The mean level of IgG aβ2GPI antibodies was statistically higher in triple positive profile and might account for positive LA. As compared to a single test, the analysis of a complete antiphospholipid antibody profile can better determine patients at risk. © 2005 Schattauer GmbH, Stuttgart.


170§
Bortolotti, F., Resti, M., Marcellini, M., Giacchino, R., Verucchi, G., Nebbia, G., Zancan, L., Marazzi, M.G., Barbera, C., Maccabruni, A., Zuin, G., Maggiore, G., Balli, F., Vajro, P., Lepore, L., Molesini, M., Guido, M., Bartolacci, S., Noventa, F.

Hepatitis C virus (HCV) genotypes in 373 Italian children with HCV infection: Changing distribution and correlation with clinical features and outcome
(2005) Gut, 54 (6), pp. 852-857.

PubMed ID: 15888796
DOI: 10.1136/gut.2004.053744

Abstract
Background and aim: Little is known of hepatitis C virus (HCV) genotypes in HCV infected children. This retrospective, multicentre study investigated genotype distribution and correlation with clinical features and outcome in a large series of Italian children. Methods: Between 1990 and 2002, 373 HCV RNA positive children, consecutively recruited in 15 centres, were assayed for genotypes by a commercial line probe assay. Results: The following genotype distribution pattern was recorded: genotype 1b = 41%; 1a = 20%; 2 = 17%; 3 = 14.5%; 4 = 5%; other = 2.5%. The prevalence of genotypes 1b and 2 decreased significantly (p<0.001) among children born from 1990 onwards compared with older children (46% v 70%) while the rate of genotypes 3 and 4 increased significantly (from 8% to 30%). Children infected with genotype 3 had the highest alanine aminotransferase levels and the highest rate of spontaneous viraemia clearance within the first three years of life (32% v 3% in children with genotype 1; p<0.001). Of 96 children enrolled in interferon trials during the survey, 22% definitely lost HCV RNA, including 57% of those with genotypes 2 and 3. Conclusion: HCV genotypes 1 and 2 are still prevalent among infected adolescents and young adults in Italy but rates of infection with genotypes 3 and 4 are rapidly increasing among children. These changes could modify the clinical pattern of hepatitis C in forthcoming years as children infected with genotype 3 have the best chance of spontaneous viraemia clearance early in life, and respond to interferon in a high proportion of cases.


169§
Prandoni, P., Ghirarduzzi, A., Pengo, V., Noventa, F., Bernardi, E.

The risk of recurrent venous thromboembolism after stopping anticoagulation in patients with acute deep vein thrombosis or pulmonary embolism
(2005) J Thromb Haemost, 3.


168§
Boccato, S., Pistis, R., Noventa, F., Benvegnù, L., Alberti, A.

(2005) Fibrosis Progression in Initially Mild Chronic Hepatitis C.


167§
Kakkos, S.K., Nicolaides, A.N., Griffin, M., Sabetai, M., Dhanjil, S., Thomas, D.J., Sonecha, T., Salmasi, A.M., Geroulakos, G., Georgiou, N., Francis, S., Ioannidou, E., Dore, C.J., Adovasio, R., Ziani, B., Alò, F.P., Cicilioni, C.G., Ambrosio, G., Andreev, A., Andreozzi, G.M., Verlato, F., Camporese, G., Arosio, E., Barkauskas, E., Barros D'Sa, A.A.B., Brannigan, P., Batchvarova, V., Dramov, A., Belardi, P., Novelli, G.P., Simoni, G., Bell, P., Biasi, G.M., Mingazzini, P., Bornstein, N.M., Bouchier-Hayes, D., Fitzgerald, P., Cairols, M.A., Cao, P.G., DeRango, P., Carboni, G.P., Geoffredo, C., Catalano, M., Chambers, B., Goetzmann, M., Dickinson, A., Clement, D., Bobelyn, M., Coccheri, S., Conti, E., Diamantopolous, E., Andreadis, E.A., Dimakakos, P.B., Kotsis, T., Eikelboom, B., Entz, L., Ferrari-Bardile, Aloi, T., Salerno, M., Fernandez e Fernandez, J., Pedro, L., Fitzgerald, D.E., O'Shaunnersy, A., Fletcher, J., Forconi, S., Cappeli, R., Bicchi, M., Arigucci, S., Gallai, V., Cardaiolli, G., Geroulakos, G., Kakkos, S., Gomez-Isaza, L.F., Gorgoyannis, G., Liasis, N., Graf, M., Guarini, P., Hardy, S., Harris, P., Aston, S., Iosa, G., Katsamouris, A., Glannoukas, A., Krzanowski, M., Ladurner, G., Leal-Monedero, J., Lee, B.B., Liapis, C., Galanis, P., Liboni, W., Pavanelli, E., Mannarino, E., Vaudo, G., McCollum, P., Levison, R., Micieli, G., Bosone, D., Middleton, L., Pantziaris, M.

Factors associated with mortality in patients with asymptomatic carotid stenosis: Results from the ACSRS study
(2005) International Angiology, 24 (3), pp. 221-230.

PubMed ID: 16158030

Abstract
Aim. This study determines the factors associated with mortality in patients with asymptomatic carotid stenosis. Methods. Patients (n=1 101) with asymptomatic internal carotid artery stenosis greater than 50% in relation to the bulb diameter were followed up for a period of 6 to 84 (median 38) months. Stenosis was graded using duplex scanning and expressed as a percentage of the carotid bulb diameter. Clinical and biochemical risk factors were recorded. The end-points were ipsilateral ischemic stroke, cardiovascular death and all cause mortality. Results. In a Cox multivariate analysis 6 factors emerged as independent predictors of risk. Age, male gender, cardiac failure, left ventricular hypertrophy on electrocardiogram (ECG) and myocardial ischemia on ECG were associated with increased risk. Antiplatelet therapy was associated with decreased risk. Based on these risk factors a high-risk group consisting of one third of the population with a 40% cumulative cardiovascular death rate and a 66% all cause death rate at 7 years could be identified. The remaining 2/3 consisted of a low-risk group with a 10% cumulative cardiovascular death rate and a 21% all cause death rate at 7 years (P<0.0001 compared to the high risk group). There was not any significant difference in the cumulative ipsilateral stroke rate, which was 12% in the low and 13% in the high cardiovascular risk group (Log Rank P>0.05). Conclusion. The methodology and findings from the ACSRS natural history study need to be applied to randomized controlled trials on the value of carotid endarterectomy or stenting in patients with asymptomatic carotid stenosis. They may help refine the indications for intervention in patients with carotid endarterectomy.


166§
Nicolaides, A.N., Kakkos, S.K., Griffin, M., Sabetai, M., Dhanjil, S., Tegos, T., Thomas, D.J., Giannoukas, A., Geroulakos, G., Georgiou, N., Francis, S., Ioannidou, E., Doré, C.J., Adovasio, R., Ziani, B., Aló, E.P., Cicilioni, C.G., Ambrosio, G., Andreev, A., Andreozzi, G.M., Verlato, F., Camporese, G., Arosio, E., Barkauskas, E., Barros D'Sa, A.A.B., Brannigan, P., Batchvarova, V., Dramov, A., Belardi, P., Novelli, G.P., Simoni, G., Bell, P., Biasi, G.M., Mingazzini, P., Bornstein, N.M., Bouchier-Hayes, D., Fitzgerald, P., Cairols, M.A., Cao, P.G., DeRango, P., Carboni, G.P., Geoffredo, C., Catalano, M., Chambers, B., Goetzmann, M., Dickinson, A., Clement, D., Bobelyn, M., Coccheri, S., Conti, E., Diamantopolous, E., Andreadis, E.A., Middleton, L., Pantziaris, M., Tyllis, T., Minar, E., Willfort, A., Moggi, L., Nenci, G., Radicchia, S., Norgren, L., Ribbie, E., Novo, S., Tantillo, R., Olinic, D., Paaske, W., Pagnan, A., Pauletto, P., Pagliara, V., Pettina, G., Pratesi, C., Matticari, S., Polivka, J., Sevcik, P., Poredos, P., Blinc, A., Videcnik, V., Pujia, A., Raso, A., Rispoli, P., Conforti, M., Robinson, T., Dennis, M.S.J., Rosfors, S., Rudofsky, G., Schroeder, T., Gronholdt, M.L., Simoni, G., Finocchi, C., Rodriguez, G., Dimakakos, P.B., Kotsis, T., Eikelboom, B., Entz, L., Ferrari-Bardille, Aloi, T., Salerno, M., Fernandes e Fernandes, J.

Severity of asymptomatic carotid stenosis and risk of ipsilateral hemispheric ischaemic events: Results from the ACSRS study
(2005) European Journal of Vascular and Endovascular Surgery, 30 (3), pp. 275-284.

PubMed ID: 16130207
DOI: 10.1016/j.ejvs.2005.04.031

Abstract
Objectives. This study determines the risk of ipsilateral ischaemic neurological events in relation to the degree of asymptomatic carotid stenosis and other risk factors. Methods. Patients (n = 1115) with asymptomatic internal carotid artery (ICA) stenosis greater than 50% in relation to the bulb diameter were followed up for a period of 6-84 (mean 37.1) months. Stenosis was graded using duplex, and clinical and biochemical risk factors were recorded. Results. The relationship between ICA stenosis and event rate is linear when stenosis is expressed by the ECST method, but S-shaped if expressed by the NASCET method. In addition to the ECST grade of stenosis (RR 1.6; 95% CI 1.21-2.15), history of contralateral TIAs (RR 3.0; 95% CI 1.90-4.73) and creatinine in excess of 85 μmol/L (RR 2.1; 95% CI 1.23-3.65) were independent risk predictors. The combination of these three risk factors can identify a high-risk group (7.3% annual event rate and 4.3% annual stroke rate) and a low risk group (2.3% annual event rate and 0.7% annual stroke rate). Conclusions. Linearity between ECST percent stenosis and risk makes this method for grading stenosis more amenable to risk prediction without any transformation not only in clinical practice but also when multivariable analysis is to be used. Identification of additional risk factors provides a new approach to risk stratification and should help refine the indications for carotid endarterectomy. © 2005 Elsevier Ltd. All rights reserved.


165§
Girolami, A., Prandoni, P., Marchiori, A., Bernardi, E., Cogo, A., Cuppini, S., Rudelli, G., Alvino, S., Recchia, G., Stragliotto, E., Zerbini, O., Gonsalvi, M., Morelli, P., Bucherini, E., Tormene, D., Mosena, L., Rosi, G., Lu Priore, A., Ambrosio, G., Parisi, R., Bortoluzzi, C., Contavalli, C., Andreozzi, G.M., Verlato, F., Camporese, G., Aluigi, L., Astorino, G., Pagnan, A., Salsa, F., Bullo, C., Visonà, A., Lusiani, L., Bonanome, A., Pesavento, R., Patrassi, G.M., Scarano, L., Marcon, L., Faresin, F., Frausini, G., Francolini, G., Imberti, D., Prati, C., Santonastaso, M., Zanatta, N., Viani, M.P., Malacarne, Z., Pinto, A., Prestipino, F., Ghirarduzzi, A., Iotti, M., Cattabiani, M., Todini, A.R., Paiella, M.L., Allegra, C., Carlizza, A., Venco, A., Dentali, F., Scannapieco, G., Villalta, S., Di Salvo, M.M., The Vesalio Investigators Group

High vs. low doses of low-molecular-weight heparin for the treatment of superficial vein thrombosis of the legs: A double-blind, randomized trial
(2005) Journal of Thrombosis and Haemostasis, 3 (6), pp. 1152-1157.

PubMed ID: 15946202
DOI: 10.1111/j.1538-7836.2005.01391.x

Abstract
In contrast with extensive information on the management of deep vein thrombosis of the lower extremities, little is known on the most appropriate treatment of the superficial vein thrombosis (SVT). In a multicenter, prospective, controlled, double-blind, double-dummy clinical trial, 164 consecutive patients with acute SVT of the great saphenous vein were randomized to receive the s.c. administration of either fixed prophylactic doses (2850 a-Xa IU) or body-weight adjusted therapeutic doses of nadroparin once daily for 1 month. The main study outcome was to compare the rate of asymptomatic and symptomatic extension of SVT and/or venous thromboembolic (VTE) complications during a 3-month follow-up period. Of the 81 patients randomized to the prophylactic doses, seven [8.6%; 95% confidence interval (CI), 3.5-17.0] developed SVT progression or VTE complications as compared with six of the 83 (7.2%; 95% CI, 2.8-15.1) allocated to the treatment group (absolute difference, 1.4; 96% CI, -6.9 to 9.7; P = 0.74). No patient in either group developed major bleeding. Our findings suggest that therapeutic doses of low-molecular-weight heparin, administered for 1 month in patients with SVT of the greater saphenous vein do not improve results obtained by prophylactic doses, administered for the same period, over a 3-month follow-up period. © 2005 International Society on Thrombosis and Haemostasis.


164§
Camporese, G., Bernardi, E., N'Tita, K., Verlato, F., Salmistraro, G., Cordova, R.

Different thromboprophylaxis approaches in patients undergoing knee arthroscopy (KANT Study): A prospective randomized study
(2005) Journal of Thrombosis and Haemostasis, 3.


163§
Kontothanassis, D., Camporese, G., Scuro, A., Ramazzo, L., Fagioli, M., Zotta, L.

Endovascular vein treatment (ELVeS™) for chronic venous insufficiency from varicose disease of lower limbs with reviparin sodium thromboprophylaxis
(2005) J Clin Med, 4, pp. 3-6.


162§
Bernardi, E., Prandoni, P.

Subcutaneous unfractionated heparin compared with low-molecular-weight heparin for the initial treatment of venous thromboembolism
(2005) Current Opinion in Pulmonary Medicine, 11 (5), pp. 363-367.

PubMed ID: 16093806
DOI: 10.1097/01.mcp.0000174228.47725.79

Abstract
Purpose of review: Low-molecular-weight heparin is the preferred choice for the initial treatment of acute, uncomplicated venous thromboembolism. In this context, unfractionated heparin is as safe and effective as low-molecular-weight heparin but requires strict laboratory monitoring. Twice-daily subcutaneous unfractionated heparin is more effective than, and as safe as, intravenous unfractionated heparin and may simplify patient treatment in or out of the hospital, being possibly cost saving, especially if it is used in weight-based, fixed, unadjusted doses. The present review focuses on the relative values of low-molecular-weight heparin and subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism. Recent findings: The major advantages of low-molecular-weight heparin over unfractionated heparin seem to be ease of administration and cost savings associated with home therapy or early hospital discharge; however, many patients with venous thromboembolism are still admitted to the hospital for treatment, and unfractionated heparin is extensively used to this purpose, especially in the United States. Subcutaneous unfractionated heparin, adjusted according to activated partial thromboplastin time algorithms, is as safe and effective as low-molecular-weight heparin for the treatment of venous thromboembolism, allows for quick mobilization and early discharge of suitable patients, and represents a cost-effective strategy. Fixed-dose unfractionated heparin, like low-molecular-weight heparin, may be used for the home treatment of deep vein thrombosis. Summary: Subcutaneous unfractionated heparin, targeted on activated partial thromboplastin time results or in fixed doses, may be used in or out of the hospital for the treatment of venous thromboembolism, being possibly cost effective; however, these findings need confirmation through appropriate, large-sample, randomized clinical trials. © 2005 Lippincott Williams & Wilkins.


161§
Fattovich, G., Zagni, I., Ribero, M.L., Castagnetti, E., Minola, E., Lomonaco, L., Scattolini, C., Fabris, P., Boccia, S., Giusti, M., Abbati, G., Felder, M., Rovere, P., Redaelli, A., Tonon, A., Tomba, A., Montanari, R., Paternoster, C., Distasi, M., Fornaciari, G., Tositti, G., Rizzo, C., Suppressa, S., Pantalena, M., Noventa, F., Tagger, A.

A randomized trial of prolonged high dose of interferon plus ribavirin for hepatitis C patients nonresponders to interferon alone
(2004) Journal of Viral Hepatitis, 11 (6), pp. 543-551.

PubMed ID: 15500555
DOI: 10.1111/j.1365-2893.2004.00538.x

Abstract
Retreatment of chronic hepatitis C patients nonresponders to interferon (IFN) alone with the standard dose of IFN [3 million units (MU) thrice weekly (TIW)] plus ribavirin for 24 weeks has yielded low sustained virological response (SVR), averaging 8%. The aim of the present, open-labelled, randomized study was to evaluate the efficacy of IFN induction therapy followed by prolonged high dose of IFN plus ribavirin in nonresponders. One hundred and fifty-one patients were randomized to receive 5 MU daily of IFN alfa-2b (group 1, n = 73) or 5 MU TIW of IFN alfa 2b (group 2, n = 78) for 4 weeks followed by IFN (5 MU TIW) plus ribavirin (1000/1200 mg/daily) for 48 weeks in both groups. In an intention-to-treat analysis, the sustained virological response (SVR) at 24-week follow-up was 33 and 23% for group 1 and 2, respectively (P = 0.17). The overall SVR was 52 and 18% in patients with genotype 2/3 and 1/ 4, respectively. Among genotype 1/4 patients the SVR was 29 and 11% for age younger or older than 40 years. Compared with genotype 2/3 patients, the risk (95% confidence interval) of nonresponse to retreatment was 3.0-fold (1.17-8.0) in younger genotype 1/4 patients and 8.4-fold (3.0-23.29) in older genotype 1/4 patients. In conclusion these results suggest that retreatment with a reinforced regimen should be focused in nonresponder genotype 2/3 patients and younger genotype 1/4 patients, who are most likely to benefit. Induction therapy does not improve SVR.


160§
Marcolongo, R., Tavolini, I.M., Laveder, F., Busa, M., Noventa, F., Bassi, P., Semenzato, G.

Immunosuppressive therapy for idiopathic retroperitoneal fibrosis: A retrospective analysis of 26 cases
(2004) American Journal of Medicine, 116 (3), pp. 194-197.

PubMed ID: 14749165
DOI: 10.1016/j.amjmed.2003.08.033


159§
Becattini, C., Rondelli, F., Vedovati, M.C., Camporese, G., Giustozzi, M., Boncompagni, M.

Incidence and risk factors for venous thromboembolism after laparoscopic surgery for colorectal cancer
(2004) Haematologica.


158§
Prandoni, P., Bernardi, E., Marchiori, A., Lensing, A.W.A., Prins, M.H., Villalta, S., Bagatella, P., Sartor, D., Piccioli, A., Simioni, P., Pagnan, A., Girolami, A.

The long term clinical course of acute deep vein thrombosis of the arm: Prospective cohort study
(2004) British Medical Journal, 329 (7464), pp. 484-485.

PubMed ID: 15256419
DOI: 10.1136/bmj.38167.684444.3A


157§
Prandoni, P., Lensing, A.W.A., Prins, M.H., Frulla, M., Marchiori, A., Bernardi, E., Tormene, D., Mosena, L., Pagnan, A., Girolami, A.

Below-knee elastic compression stockings to prevent the post-thrombotic syndrome. A randomized, controlled trial
(2004) Annals of Internal Medicine, 141 (4), pp. 249-256+I-12.

PubMed ID: 15313740
DOI: 10.7326/0003-4819-141-4-200408170-00004

Abstract
Background: Because only limited evidence suggests that elastic stockings prevent the post-thrombotic syndrome in patients with symptomatic deep venous thrombosis (DVT), these stockings are not widely used. Objective: To evaluate the efficacy of compression elastic stockings for prevention of the post-thrombotic syndrome in patients with proximal DVT. Design: Randomized, controlled clinical trial. Setting: University hospital. Patients: 180 consecutive patients with a first episode of symptomatic proximal DVT who received conventional anticoagulant treatment. Interventions: Before discharge, patients were randomly assigned to wear or not wear below-knee compression elastic stockings (30 to 40 mm Hg at the ankle) for 2 years. Follow-up was performed for up to 5 years. Measurements: The presence and severity of the post-thrombotic syndrome were scored by using a standardized scale. Results: Post-thrombotic sequelae developed in 44 of 90 controls (severe in 10) and in 23 of 90 patients wearing elastic stockings (severe in 3). All but 1 event developed in the first 2 years. The cumulative incidence of the post-thrombotic syndrome in the control group versus the elastic stockings group was 40.0% (95% CI, 29.9% to 50.1%) versus 21.1% (CI, 12.7% to 29.5%) after 6 months, 46.7% (CI, 36.4% to 57.0%) versus 22.2% (CI, 13.8% to 30.7%) after 1 year, and 49.1% (CI, 38.7% to 59.4%) versus 24.5% (CI, 15.6% to 33.4%) after 2 years. After adjustment for baseline characteristics, the hazard ratio for the post-thrombotic syndrome in the elastic stockings group compared with controls was 0.49 (CI, 0.29 to 0.84; P = 0.011). Limitations: This study lacked a double-blind design. Conclusions: Post-thrombotic sequelae develop in almost half of patients with proximal DVT. Below-knee compression elastic stockings reduce this rate by approximately 50%.


156§
Piccioli, A., Lensing, A.W.A., Prins, M.H., Falanga, A., Scannapieco, G.L., Ieran, M., Cigolini, M., Ambrosio, G.B., Monreal, M., Girolami, A., Prandoni, P., Girolami, B., Bernardi, E., Bagatella, P., Marchiori, A., Marchetti, M., Vignoli, A., Doria, S., Parisi, R., Bortoluzzi, C., Paolicelli, M., Filippi, F., Baggio, E., Lipari, G.

Extensive screening for occult malignant disease in idiopathic venous thromboembolism: A prospective randomized clinical trial
(2004) Journal of Thrombosis and Haemostasis, 2 (6), pp. 884-889.

PubMed ID: 15140122
DOI: 10.1111/j.1538-7836.2004.00720.x

Abstract
Patients with symptomatic idiopathic venous thromboembolism and apparently cancer-free have an approximate 10% incidence of subsequent cancer. Apparently cancer-free patients with acute idiopathic venous thromboembolism were randomized to either the strategy of extensive screening for occult cancer or to no further testing. Patients had a 2-year follow-up period. Of the 201 patients, 99 were allocated to the extensive screening group and 102 to the control group. In 13 (13.1%) patients, the extensive screening identified occult cancer. In the extensive screening group, a single (1.0%) malignancy became apparent during follow-up, whereas in the control group a total of 10 (9.8%) malignancies became symptomatic [relative risk, 9.7 (95% CI, 1.3-36.8; P < 0.01]. Overall, malignancies identified in the extensive screening group were at an earlier stage and the mean delay to diagnosis was reduced from 11.6 to 1.0 months (P < 0.001). Cancer-related mortality during the 2 years follow-up period occurred in two (2.0%) of the 99 patients of the extensive screening group vs. four (3.9%) of the 102 control patients [absolute difference, 1.9% (95% CI, -5.5-10.9)]. Although early detection of occult cancers may be associated with improved treatment possibilities, it is uncertain whether this improves the prognosis.


155§
Pengo, V., Biasiolo, A., Pegoraro, C., Cucchini, U., Noventa, F., Iliceto, S.

Antibody profiles for the diagnosis of antiphospholipid syndrome
(2005) Thrombosis and Haemostasis, 93 (6), pp. 1147-1152.

PubMed ID: 15968401
DOI: 10.1160/TH04-12-0839

Abstract
Among the so called 'antiphospholipid antibodies', the presence of Lupus Anticoagulant (LA) is associated with thrombosis-related events and defines the antiphospholipid syndrome. The role of anti-cardiolipin (aCL) antibodies and anti-human β2-glycoprotein I (aβ2GPI) antibodies is less striking. Since the problem of standardization for these tests is far from resolved, we evaluated whether the combination of results (antiphospholipid laboratory profiles) could help to better classify these patients. Over a 6-year period, 618 consecutive subjects (55% of whom had previous documented thrombosis-related events) were referred to our clinic for Antiphospholipid antibody detection. LA was detected according to internationally accepted recommendations. ACL and aβ2GPI antibodies were detected by Enzyme-Linked-Immunosorbent Assay (ELISA). Patients' records were reviewed for the presence of previous thromboembolic events or obstetric complications according to Sapporo's clinical criteria for the diagnosis of antiphospholipid syndrome (APS) and each patient underwent a physical examination. When individual tests were considered in a multivariate analysis which took into account age, gender, the presence of SLE or other autoimmune diseases and established risk factors for venous and arterial thromboembolism, LA (Odds Ratio 4.4, Confidence Interval 1.5-13.3) and aβ2GPI antibodies (Odds Ratio 2.9, Confidence Interval 1.1-7.5) but not aCL antibodies (Odds Ratio 1.2, Confidence Interval 0.5-2.7) were found to be independent risk factors for thrombosis-related events. When antiphospholipid antibody profiles instead of individual test positivity were analyzed in the above mentioned model, triple positivity resulted a strong independent risk factor (Odds Ratio 33.3, Confidence Interval 7.0-157.6), retaining its significance when the association with venous or arterial thromboembolism was considered. Double positivity with negative LA was close to significance for thrombosis-related events (Odds Ratio 2.2, Confidence Interval 1.0-5.2, p=0.056) and highly significant risk factor for obstetric complications (Odds Ratio 10.8, Confidence Interval 2.9-40.8). Other combinations did not reach statistical significance. The mean level of IgG aβ2GPI antibodies was statistically higher in triple positive profile and might account for positive LA. As compared to a single test, the analysis of a complete antiphospholipid antibody profile can better determine patients at risk. © 2005 Schattauer GmbH, Stuttgart.


154§
Bortolotti, F., Resti, M., Marcellini, M., Giacchino, R., Verucchi, G., Nebbia, G., Zancan, L., Marazzi, M.G., Barbera, C., Maccabruni, A., Zuin, G., Maggiore, G., Balli, F., Vajro, P., Lepore, L., Molesini, M., Guido, M., Bartolacci, S., Noventa, F.

Hepatitis C virus (HCV) genotypes in 373 Italian children with HCV infection: Changing distribution and correlation with clinical features and outcome
(2005) Gut, 54 (6), pp. 852-857.

PubMed ID: 15888796
DOI: 10.1136/gut.2004.053744

Abstract
Background and aim: Little is known of hepatitis C virus (HCV) genotypes in HCV infected children. This retrospective, multicentre study investigated genotype distribution and correlation with clinical features and outcome in a large series of Italian children. Methods: Between 1990 and 2002, 373 HCV RNA positive children, consecutively recruited in 15 centres, were assayed for genotypes by a commercial line probe assay. Results: The following genotype distribution pattern was recorded: genotype 1b = 41%; 1a = 20%; 2 = 17%; 3 = 14.5%; 4 = 5%; other = 2.5%. The prevalence of genotypes 1b and 2 decreased significantly (p<0.001) among children born from 1990 onwards compared with older children (46% v 70%) while the rate of genotypes 3 and 4 increased significantly (from 8% to 30%). Children infected with genotype 3 had the highest alanine aminotransferase levels and the highest rate of spontaneous viraemia clearance within the first three years of life (32% v 3% in children with genotype 1; p<0.001). Of 96 children enrolled in interferon trials during the survey, 22% definitely lost HCV RNA, including 57% of those with genotypes 2 and 3. Conclusion: HCV genotypes 1 and 2 are still prevalent among infected adolescents and young adults in Italy but rates of infection with genotypes 3 and 4 are rapidly increasing among children. These changes could modify the clinical pattern of hepatitis C in forthcoming years as children infected with genotype 3 have the best chance of spontaneous viraemia clearance early in life, and respond to interferon in a high proportion of cases.


153§
Prandoni, P., Ghirarduzzi, A., Pengo, V., Noventa, F., Bernardi, E.

The risk of recurrent venous thromboembolism after stopping anticoagulation in patients with acute deep vein thrombosis or pulmonary embolism
(2005) J Thromb Haemost, 3.


152§
Boccato, S., Pistis, R., Noventa, F., Benvegnù, L., Alberti, A.

(2005) Fibrosis Progression in Initially Mild Chronic Hepatitis C.


151§
Kakkos, S.K., Nicolaides, A.N., Griffin, M., Sabetai, M., Dhanjil, S., Thomas, D.J., Sonecha, T., Salmasi, A.M., Geroulakos, G., Georgiou, N., Francis, S., Ioannidou, E., Dore, C.J., Adovasio, R., Ziani, B., Alò, F.P., Cicilioni, C.G., Ambrosio, G., Andreev, A., Andreozzi, G.M., Verlato, F., Camporese, G., Arosio, E., Barkauskas, E., Barros D'Sa, A.A.B., Brannigan, P., Batchvarova, V., Dramov, A., Belardi, P., Novelli, G.P., Simoni, G., Bell, P., Biasi, G.M., Mingazzini, P., Bornstein, N.M., Bouchier-Hayes, D., Fitzgerald, P., Cairols, M.A., Cao, P.G., DeRango, P., Carboni, G.P., Geoffredo, C., Catalano, M., Chambers, B., Goetzmann, M., Dickinson, A., Clement, D., Bobelyn, M., Coccheri, S., Conti, E., Diamantopolous, E., Andreadis, E.A., Dimakakos, P.B., Kotsis, T., Eikelboom, B., Entz, L., Ferrari-Bardile, Aloi, T., Salerno, M., Fernandez e Fernandez, J., Pedro, L., Fitzgerald, D.E., O'Shaunnersy, A., Fletcher, J., Forconi, S., Cappeli, R., Bicchi, M., Arigucci, S., Gallai, V., Cardaiolli, G., Geroulakos, G., Kakkos, S., Gomez-Isaza, L.F., Gorgoyannis, G., Liasis, N., Graf, M., Guarini, P., Hardy, S., Harris, P., Aston, S., Iosa, G., Katsamouris, A., Glannoukas, A., Krzanowski, M., Ladurner, G., Leal-Monedero, J., Lee, B.B., Liapis, C., Galanis, P., Liboni, W., Pavanelli, E., Mannarino, E., Vaudo, G., McCollum, P., Levison, R., Micieli, G., Bosone, D., Middleton, L., Pantziaris, M.

Factors associated with mortality in patients with asymptomatic carotid stenosis: Results from the ACSRS study
(2005) International Angiology, 24 (3), pp. 221-230.

PubMed ID: 16158030

Abstract
Aim. This study determines the factors associated with mortality in patients with asymptomatic carotid stenosis. Methods. Patients (n=1 101) with asymptomatic internal carotid artery stenosis greater than 50% in relation to the bulb diameter were followed up for a period of 6 to 84 (median 38) months. Stenosis was graded using duplex scanning and expressed as a percentage of the carotid bulb diameter. Clinical and biochemical risk factors were recorded. The end-points were ipsilateral ischemic stroke, cardiovascular death and all cause mortality. Results. In a Cox multivariate analysis 6 factors emerged as independent predictors of risk. Age, male gender, cardiac failure, left ventricular hypertrophy on electrocardiogram (ECG) and myocardial ischemia on ECG were associated with increased risk. Antiplatelet therapy was associated with decreased risk. Based on these risk factors a high-risk group consisting of one third of the population with a 40% cumulative cardiovascular death rate and a 66% all cause death rate at 7 years could be identified. The remaining 2/3 consisted of a low-risk group with a 10% cumulative cardiovascular death rate and a 21% all cause death rate at 7 years (P<0.0001 compared to the high risk group). There was not any significant difference in the cumulative ipsilateral stroke rate, which was 12% in the low and 13% in the high cardiovascular risk group (Log Rank P>0.05). Conclusion. The methodology and findings from the ACSRS natural history study need to be applied to randomized controlled trials on the value of carotid endarterectomy or stenting in patients with asymptomatic carotid stenosis. They may help refine the indications for intervention in patients with carotid endarterectomy.


150§
Nicolaides, A.N., Kakkos, S.K., Griffin, M., Sabetai, M., Dhanjil, S., Tegos, T., Thomas, D.J., Giannoukas, A., Geroulakos, G., Georgiou, N., Francis, S., Ioannidou, E., Doré, C.J., Adovasio, R., Ziani, B., Aló, E.P., Cicilioni, C.G., Ambrosio, G., Andreev, A., Andreozzi, G.M., Verlato, F., Camporese, G., Arosio, E., Barkauskas, E., Barros D'Sa, A.A.B., Brannigan, P., Batchvarova, V., Dramov, A., Belardi, P., Novelli, G.P., Simoni, G., Bell, P., Biasi, G.M., Mingazzini, P., Bornstein, N.M., Bouchier-Hayes, D., Fitzgerald, P., Cairols, M.A., Cao, P.G., DeRango, P., Carboni, G.P., Geoffredo, C., Catalano, M., Chambers, B., Goetzmann, M., Dickinson, A., Clement, D., Bobelyn, M., Coccheri, S., Conti, E., Diamantopolous, E., Andreadis, E.A., Middleton, L., Pantziaris, M., Tyllis, T., Minar, E., Willfort, A., Moggi, L., Nenci, G., Radicchia, S., Norgren, L., Ribbie, E., Novo, S., Tantillo, R., Olinic, D., Paaske, W., Pagnan, A., Pauletto, P., Pagliara, V., Pettina, G., Pratesi, C., Matticari, S., Polivka, J., Sevcik, P., Poredos, P., Blinc, A., Videcnik, V., Pujia, A., Raso, A., Rispoli, P., Conforti, M., Robinson, T., Dennis, M.S.J., Rosfors, S., Rudofsky, G., Schroeder, T., Gronholdt, M.L., Simoni, G., Finocchi, C., Rodriguez, G., Dimakakos, P.B., Kotsis, T., Eikelboom, B., Entz, L., Ferrari-Bardille, Aloi, T., Salerno, M., Fernandes e Fernandes, J.

Severity of asymptomatic carotid stenosis and risk of ipsilateral hemispheric ischaemic events: Results from the ACSRS study
(2005) European Journal of Vascular and Endovascular Surgery, 30 (3), pp. 275-284.

PubMed ID: 16130207
DOI: 10.1016/j.ejvs.2005.04.031

Abstract
Objectives. This study determines the risk of ipsilateral ischaemic neurological events in relation to the degree of asymptomatic carotid stenosis and other risk factors. Methods. Patients (n = 1115) with asymptomatic internal carotid artery (ICA) stenosis greater than 50% in relation to the bulb diameter were followed up for a period of 6-84 (mean 37.1) months. Stenosis was graded using duplex, and clinical and biochemical risk factors were recorded. Results. The relationship between ICA stenosis and event rate is linear when stenosis is expressed by the ECST method, but S-shaped if expressed by the NASCET method. In addition to the ECST grade of stenosis (RR 1.6; 95% CI 1.21-2.15), history of contralateral TIAs (RR 3.0; 95% CI 1.90-4.73) and creatinine in excess of 85 μmol/L (RR 2.1; 95% CI 1.23-3.65) were independent risk predictors. The combination of these three risk factors can identify a high-risk group (7.3% annual event rate and 4.3% annual stroke rate) and a low risk group (2.3% annual event rate and 0.7% annual stroke rate). Conclusions. Linearity between ECST percent stenosis and risk makes this method for grading stenosis more amenable to risk prediction without any transformation not only in clinical practice but also when multivariable analysis is to be used. Identification of additional risk factors provides a new approach to risk stratification and should help refine the indications for carotid endarterectomy. © 2005 Elsevier Ltd. All rights reserved.


149§
Girolami, A., Prandoni, P., Marchiori, A., Bernardi, E., Cogo, A., Cuppini, S., Rudelli, G., Alvino, S., Recchia, G., Stragliotto, E., Zerbini, O., Gonsalvi, M., Morelli, P., Bucherini, E., Tormene, D., Mosena, L., Rosi, G., Lu Priore, A., Ambrosio, G., Parisi, R., Bortoluzzi, C., Contavalli, C., Andreozzi, G.M., Verlato, F., Camporese, G., Aluigi, L., Astorino, G., Pagnan, A., Salsa, F., Bullo, C., Visonà, A., Lusiani, L., Bonanome, A., Pesavento, R., Patrassi, G.M., Scarano, L., Marcon, L., Faresin, F., Frausini, G., Francolini, G., Imberti, D., Prati, C., Santonastaso, M., Zanatta, N., Viani, M.P., Malacarne, Z., Pinto, A., Prestipino, F., Ghirarduzzi, A., Iotti, M., Cattabiani, M., Todini, A.R., Paiella, M.L., Allegra, C., Carlizza, A., Venco, A., Dentali, F., Scannapieco, G., Villalta, S., Di Salvo, M.M., The Vesalio Investigators Group

High vs. low doses of low-molecular-weight heparin for the treatment of superficial vein thrombosis of the legs: A double-blind, randomized trial
(2005) Journal of Thrombosis and Haemostasis, 3 (6), pp. 1152-1157.

PubMed ID: 15946202
DOI: 10.1111/j.1538-7836.2005.01391.x

Abstract
In contrast with extensive information on the management of deep vein thrombosis of the lower extremities, little is known on the most appropriate treatment of the superficial vein thrombosis (SVT). In a multicenter, prospective, controlled, double-blind, double-dummy clinical trial, 164 consecutive patients with acute SVT of the great saphenous vein were randomized to receive the s.c. administration of either fixed prophylactic doses (2850 a-Xa IU) or body-weight adjusted therapeutic doses of nadroparin once daily for 1 month. The main study outcome was to compare the rate of asymptomatic and symptomatic extension of SVT and/or venous thromboembolic (VTE) complications during a 3-month follow-up period. Of the 81 patients randomized to the prophylactic doses, seven [8.6%; 95% confidence interval (CI), 3.5-17.0] developed SVT progression or VTE complications as compared with six of the 83 (7.2%; 95% CI, 2.8-15.1) allocated to the treatment group (absolute difference, 1.4; 96% CI, -6.9 to 9.7; P = 0.74). No patient in either group developed major bleeding. Our findings suggest that therapeutic doses of low-molecular-weight heparin, administered for 1 month in patients with SVT of the greater saphenous vein do not improve results obtained by prophylactic doses, administered for the same period, over a 3-month follow-up period. © 2005 International Society on Thrombosis and Haemostasis.


148§
Camporese, G., Bernardi, E., N'Tita, K., Verlato, F., Salmistraro, G., Cordova, R.

Different thromboprophylaxis approaches in patients undergoing knee arthroscopy (KANT Study): A prospective randomized study
(2005) Journal of Thrombosis and Haemostasis, 3.


147§
Kontothanassis, D., Camporese, G., Scuro, A., Ramazzo, L., Fagioli, M., Zotta, L.

Endovascular vein treatment (ELVeS™) for chronic venous insufficiency from varicose disease of lower limbs with reviparin sodium thromboprophylaxis
(2005) J Clin Med, 4, pp. 3-6.


146§
Bernardi, E., Prandoni, P.

Subcutaneous unfractionated heparin compared with low-molecular-weight heparin for the initial treatment of venous thromboembolism
(2005) Current Opinion in Pulmonary Medicine, 11 (5), pp. 363-367.

PubMed ID: 16093806
DOI: 10.1097/01.mcp.0000174228.47725.79

Abstract
Purpose of review: Low-molecular-weight heparin is the preferred choice for the initial treatment of acute, uncomplicated venous thromboembolism. In this context, unfractionated heparin is as safe and effective as low-molecular-weight heparin but requires strict laboratory monitoring. Twice-daily subcutaneous unfractionated heparin is more effective than, and as safe as, intravenous unfractionated heparin and may simplify patient treatment in or out of the hospital, being possibly cost saving, especially if it is used in weight-based, fixed, unadjusted doses. The present review focuses on the relative values of low-molecular-weight heparin and subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism. Recent findings: The major advantages of low-molecular-weight heparin over unfractionated heparin seem to be ease of administration and cost savings associated with home therapy or early hospital discharge; however, many patients with venous thromboembolism are still admitted to the hospital for treatment, and unfractionated heparin is extensively used to this purpose, especially in the United States. Subcutaneous unfractionated heparin, adjusted according to activated partial thromboplastin time algorithms, is as safe and effective as low-molecular-weight heparin for the treatment of venous thromboembolism, allows for quick mobilization and early discharge of suitable patients, and represents a cost-effective strategy. Fixed-dose unfractionated heparin, like low-molecular-weight heparin, may be used for the home treatment of deep vein thrombosis. Summary: Subcutaneous unfractionated heparin, targeted on activated partial thromboplastin time results or in fixed doses, may be used in or out of the hospital for the treatment of venous thromboembolism, being possibly cost effective; however, these findings need confirmation through appropriate, large-sample, randomized clinical trials. © 2005 Lippincott Williams & Wilkins.


145§
Fattovich, G., Zagni, I., Ribero, M.L., Castagnetti, E., Minola, E., Lomonaco, L., Scattolini, C., Fabris, P., Boccia, S., Giusti, M., Abbati, G., Felder, M., Rovere, P., Redaelli, A., Tonon, A., Tomba, A., Montanari, R., Paternoster, C., Distasi, M., Fornaciari, G., Tositti, G., Rizzo, C., Suppressa, S., Pantalena, M., Noventa, F., Tagger, A.

A randomized trial of prolonged high dose of interferon plus ribavirin for hepatitis C patients nonresponders to interferon alone
(2004) Journal of Viral Hepatitis, 11 (6), pp. 543-551.

PubMed ID: 15500555
DOI: 10.1111/j.1365-2893.2004.00538.x

Abstract
Retreatment of chronic hepatitis C patients nonresponders to interferon (IFN) alone with the standard dose of IFN [3 million units (MU) thrice weekly (TIW)] plus ribavirin for 24 weeks has yielded low sustained virological response (SVR), averaging 8%. The aim of the present, open-labelled, randomized study was to evaluate the efficacy of IFN induction therapy followed by prolonged high dose of IFN plus ribavirin in nonresponders. One hundred and fifty-one patients were randomized to receive 5 MU daily of IFN alfa-2b (group 1, n = 73) or 5 MU TIW of IFN alfa 2b (group 2, n = 78) for 4 weeks followed by IFN (5 MU TIW) plus ribavirin (1000/1200 mg/daily) for 48 weeks in both groups. In an intention-to-treat analysis, the sustained virological response (SVR) at 24-week follow-up was 33 and 23% for group 1 and 2, respectively (P = 0.17). The overall SVR was 52 and 18% in patients with genotype 2/3 and 1/ 4, respectively. Among genotype 1/4 patients the SVR was 29 and 11% for age younger or older than 40 years. Compared with genotype 2/3 patients, the risk (95% confidence interval) of nonresponse to retreatment was 3.0-fold (1.17-8.0) in younger genotype 1/4 patients and 8.4-fold (3.0-23.29) in older genotype 1/4 patients. In conclusion these results suggest that retreatment with a reinforced regimen should be focused in nonresponder genotype 2/3 patients and younger genotype 1/4 patients, who are most likely to benefit. Induction therapy does not improve SVR.


144§
Marcolongo, R., Tavolini, I.M., Laveder, F., Busa, M., Noventa, F., Bassi, P., Semenzato, G.

Immunosuppressive therapy for idiopathic retroperitoneal fibrosis: A retrospective analysis of 26 cases
(2004) American Journal of Medicine, 116 (3), pp. 194-197.

PubMed ID: 14749165
DOI: 10.1016/j.amjmed.2003.08.033


143§
Becattini, C., Rondelli, F., Vedovati, M.C., Camporese, G., Giustozzi, M., Boncompagni, M.

Incidence and risk factors for venous thromboembolism after laparoscopic surgery for colorectal cancer
(2004) Haematologica.


142§
Prandoni, P., Bernardi, E., Marchiori, A., Lensing, A.W.A., Prins, M.H., Villalta, S., Bagatella, P., Sartor, D., Piccioli, A., Simioni, P., Pagnan, A., Girolami, A.

The long term clinical course of acute deep vein thrombosis of the arm: Prospective cohort study
(2004) British Medical Journal, 329 (7464), pp. 484-485.

PubMed ID: 15256419
DOI: 10.1136/bmj.38167.684444.3A


141§
Prandoni, P., Lensing, A.W.A., Prins, M.H., Frulla, M., Marchiori, A., Bernardi, E., Tormene, D., Mosena, L., Pagnan, A., Girolami, A.

Below-knee elastic compression stockings to prevent the post-thrombotic syndrome. A randomized, controlled trial
(2004) Annals of Internal Medicine, 141 (4), pp. 249-256+I-12.

PubMed ID: 15313740
DOI: 10.7326/0003-4819-141-4-200408170-00004

Abstract
Background: Because only limited evidence suggests that elastic stockings prevent the post-thrombotic syndrome in patients with symptomatic deep venous thrombosis (DVT), these stockings are not widely used. Objective: To evaluate the efficacy of compression elastic stockings for prevention of the post-thrombotic syndrome in patients with proximal DVT. Design: Randomized, controlled clinical trial. Setting: University hospital. Patients: 180 consecutive patients with a first episode of symptomatic proximal DVT who received conventional anticoagulant treatment. Interventions: Before discharge, patients were randomly assigned to wear or not wear below-knee compression elastic stockings (30 to 40 mm Hg at the ankle) for 2 years. Follow-up was performed for up to 5 years. Measurements: The presence and severity of the post-thrombotic syndrome were scored by using a standardized scale. Results: Post-thrombotic sequelae developed in 44 of 90 controls (severe in 10) and in 23 of 90 patients wearing elastic stockings (severe in 3). All but 1 event developed in the first 2 years. The cumulative incidence of the post-thrombotic syndrome in the control group versus the elastic stockings group was 40.0% (95% CI, 29.9% to 50.1%) versus 21.1% (CI, 12.7% to 29.5%) after 6 months, 46.7% (CI, 36.4% to 57.0%) versus 22.2% (CI, 13.8% to 30.7%) after 1 year, and 49.1% (CI, 38.7% to 59.4%) versus 24.5% (CI, 15.6% to 33.4%) after 2 years. After adjustment for baseline characteristics, the hazard ratio for the post-thrombotic syndrome in the elastic stockings group compared with controls was 0.49 (CI, 0.29 to 0.84; P = 0.011). Limitations: This study lacked a double-blind design. Conclusions: Post-thrombotic sequelae develop in almost half of patients with proximal DVT. Below-knee compression elastic stockings reduce this rate by approximately 50%.


140§
Piccioli, A., Lensing, A.W.A., Prins, M.H., Falanga, A., Scannapieco, G.L., Ieran, M., Cigolini, M., Ambrosio, G.B., Monreal, M., Girolami, A., Prandoni, P., Girolami, B., Bernardi, E., Bagatella, P., Marchiori, A., Marchetti, M., Vignoli, A., Doria, S., Parisi, R., Bortoluzzi, C., Paolicelli, M., Filippi, F., Baggio, E., Lipari, G.

Extensive screening for occult malignant disease in idiopathic venous thromboembolism: A prospective randomized clinical trial
(2004) Journal of Thrombosis and Haemostasis, 2 (6), pp. 884-889.

PubMed ID: 15140122
DOI: 10.1111/j.1538-7836.2004.00720.x

Abstract
Patients with symptomatic idiopathic venous thromboembolism and apparently cancer-free have an approximate 10% incidence of subsequent cancer. Apparently cancer-free patients with acute idiopathic venous thromboembolism were randomized to either the strategy of extensive screening for occult cancer or to no further testing. Patients had a 2-year follow-up period. Of the 201 patients, 99 were allocated to the extensive screening group and 102 to the control group. In 13 (13.1%) patients, the extensive screening identified occult cancer. In the extensive screening group, a single (1.0%) malignancy became apparent during follow-up, whereas in the control group a total of 10 (9.8%) malignancies became symptomatic [relative risk, 9.7 (95% CI, 1.3-36.8; P < 0.01]. Overall, malignancies identified in the extensive screening group were at an earlier stage and the mean delay to diagnosis was reduced from 11.6 to 1.0 months (P < 0.001). Cancer-related mortality during the 2 years follow-up period occurred in two (2.0%) of the 99 patients of the extensive screening group vs. four (3.9%) of the 102 control patients [absolute difference, 1.9% (95% CI, -5.5-10.9)]. Although early detection of occult cancers may be associated with improved treatment possibilities, it is uncertain whether this improves the prognosis. © 2004 International Society on Thrombosis and Haemostasis.


139§
Pengo, V., Barbero, F., Biasiolo, A., Pegoraro, C., Noventa, F., Iliceto, S.

Prevention of thromboembolism in patients with mitral stenosis and associated atrial fibrillation: Effectiveness of low intensity (INR target 2) oral anticoagulant treatment
(2003) Thrombosis and Haemostasis, 89 (4), pp. 760-764.

PubMed ID: 12669133

Abstract
Mitral stenosis (MS) in association with atrial fibrillation (AF) is a clinical condition at high risk for systemic thromboembolism. Although oral anticoagulants greatly reduce the incidence of thromboembolism in these patients, the optimal intensity of treatment has never been tested in specific clinical trials, and current recommendations are derived from studies of nonrheumatic AF. In this study we tested the effectiveness of two different intensities. The study design was carried out as an open randomized prospective study in an anticoagulation clinic. We randomized 103 patients with MS and AF to a low (target INR = 2) or moderate (target INR = 3) anticoagulation regimen. The primary end points were systemic thromboembolism, major bleeding and vascular death. During a mean follow-up of 4.5 years, I systemic embolism occurred in the low intensity group (0.41 per 100 pt/yrs, CI 0.01-2.3), and I minor stroke occurred in the moderate intensity group (0.40 per 100 pt/yrs, CI 0.01-2.3; p = ns). Major bleeding occurred in 8 patients, with 3 in the low intensity (1.25 per 100 pt/yrs) and 5 in the moderate intensity group (2.0 per 100 pt/yrs, Incidence Rate Ratio 0.6, CI 0.1 -3.1; p = ns). Total events (systemic embolism, major bleeding and vascular death) occurred in 7 low intensity patients and 8 moderate intensity patients. As expected, minor bleeding was more frequent in the moderate intensity group of patients, who actually had more intense treatment and required closer monitoring of oral anticoagulant treatment. These data suggest that low intensity anticoagulation, as performed in an anticoagulation clinic, is effective and safe in high risk patients with MS and AF.


138§
Grego, F., Lepidi, S., Bassi, P., Tavolini, I.M., Noventa, F., Pagano, F., Deriu, G.P.

Simultaneous surgical treatment of abdominal aortic aneurysm and carcinoma of the bladder
(2003) Journal of Vascular Surgery, 37 (3), pp. 607-614.

PubMed ID: 12618700
DOI: 10.1067/mva.2003.26

Abstract
Objective: The purpose of this study was to evaluate the short-term and long-term results of simultaneous surgical treatment of coexisting abdominal aortic aneurysm and bladder carcinoma. Methods: A prospective study was carried out to compare patients undergoing simultaneous surgical treatment of abdominal aneurysm and bladder carcinoma with control patients undergoing surgery for either one of the two diseases alone. From January 1995 to December 2000, 16 consecutive patients were seen with concomitant abdominal aortic aneurysm and bladder carcinoma at our institutional referral center. All patients underwent a standard operative protocol that included aneurysm graft replacement, radical cystoprostatectomy, and urinary reconstruction. Endovascular treatment of the aneurysm was considered in the last 2 years of the study. After each simultaneous treatment case, two control patients were selected according to the same type of vascular or urinary procedure, respectively, and pathologic staging. The analyzed endpoint was mortality, and confounder variables included common and disease-specific risk factors. Frequencies of vascular, urologic, and systemic complications were carefully considered with special attention to graft infection and tumor recurrence. Results: Endovascular treatment was not performed for morphologic reasons. No perioperative mortality was observed. A trend toward inferior survival rates in simultaneously treated patients was observed in the early follow-up period, but survival analysis with log-rank test showed no statistical difference among the groups (P = .19). Cox proportional hazard model results proved no influence of the different group treatments on survival (P = .49) and no influence of age and risk factors, except for preoperative renal status (P = .015). The increased mortality rate of the simultaneous treatment group could be ascribed to the presence of preoperative moderate renal insufficiency in two study group patients. Long-term survival of treated patients is mainly dependent on cancer progression. Graft infection and other vascular complications were not observed. Systemic and urologic complications were similar in study and control groups. Conclusion: This study shows that the simultaneous surgical approach to coexisting abdominal aortic aneurysm and transitional cell carcinoma of the bladder represents a suitable choice of treatment in highly specialized centers, but patients with preoperative renal insufficiency should be carefully evaluated. Endovascular treatment represents an appealing alternative whenever indicated.


137§
Fallo, F., Camporese, G., Capitelli, E., Andreozzi, G.M., Mantero, F., Lumachi, F.

Ultrasound evaluation of carotid artery in primary hyperparathyroidism
(2003) Journal of Clinical Endocrinology and Metabolism, 88 (5), pp. 2096-2099.

PubMed ID: 12727960
DOI: 10.1210/jc.2002-021837

Abstract
Patients with primary hyperparathyroidism (PHPT) have an increased cardiovascular morbidity and mortality. Elevated serum calcium and/or PTH may directly contribute to vascular tissue damage, but the role of classic factors for atherosclerosis has not fully been evaluated in this disease. The aim of our study was to dissect the potential effect of hypercalcemia and/or high PTH from that of major cardiovascular risk factors (i.e. diabetes mellitus, hyperlipidemia, hypertension, obesity, smoking habit) on the carotid artery structure of patients with PHPT. Twenty-six consecutive patients with PHPT [subdivided into two groups according to the absence (n = 10) or the presence (n = 16) of one or more risk factors] and 15 normocalcemic healthy subjects as controls were studied. At ultrasonography, a significant increase (P < 0.001) of carotid mean and maximum intima-media thickness, as well as a significant reduction of lumen diameter (P < 0.05) were found in the PHPT group with risk factors, compared with the other two groups. This suggests that hypercalcemia and/or PTH elevation per se are not determinant of carotid atherosclerosis in PHPT, and that increased cardiovascular mortality and morbiUty in this disease is attributable to the combined presence of classic cardiovascular risk factors.


136§
Camporese, G., Verlato, F., Salmistraro, G., Ragazzi, R., Andreozzi, G.M.

Spontaneous recanalization of internal carotid artery occlusion evaluated with color flow imaging and contrast arteriography
(2003) International Angiology, 22 (1), pp. 64-71.

PubMed ID: 12771859

Abstract
Aim. In strokes of embolic origin a partial recanalization of the intracranial occluded vessel occurs with a high incidence (as high as 80%). In the literature, we find few cases of revascularization, detected with color flow imaging (CFI) or with arteriography (AGF), at carotid siphon or at the origin of an occluded internal carotid artery (ICA). Up to now there have been no reliable data on the incidence and clinical consequences of SR of an extracranial ICA occlusion. In this case-report we document 8 cases of SR of occluded ICA observed in the last 10 years in our Care Unit. Methods. We observed 8 complete ICA occlusion at the origin, detected with CFI (8 of 8) and with AGF (7 of 8). All symptomatic patients and 2 of 5 asymptomatic patients underwent CT scan in the acute phase of stroke. All patients underwent CFI follow-up (every 6-12 monhts) to evaluate contralateral CCA and ICA and the presence of new focal neurological symptoms. All patients assumed BMT (antiplatelet or anticoagulant therapy). Results. SR occurred in 6 patients between 24 and 96 months, in 1 patient within 8 months and 1 patient within 6 months from the diagnosis of ICA occlusion. Diagnosis of SR was based in all patients with CFI and in 4 patients confirmed with AGF. Five patients underwent CT scan that excluded haemorrhagic transformation of previous ischemic areas or new ischemic events (2 patients did CT scan only after SR). All patients underwent CFI follow-up in a 3-88 months period. There were no new focal neurological symptoms in 7 of 8 patients, 1 patient presented aspecific neurological symptoms. Conclusion. Diagnosing SR of occluded extracranical ICA seems to be more frequent than expected. SR is an event that has to be researched in follow-up of these patients; besides, it seems to have a relatively benign outcome with respect to the onset of new neurological symptoms.


135§
Camporese, G., N'Tita, K., Rossi, F., Bernardi, E., Verlato, F., Salmistraro, G.

Different thromboprophylaxis approaches in patients undergoing knee arthroscopy (KANT study): interim report of prospective randomized study
(2003) Journal of Thrombosis and Haemostasis, 1,


134§
Marchiori, A., Verlato, F., Sabbion, P., Camporese, G., Rosso, F., Mosena, L., Andreozzi, G.M., Prandoni, P.

High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study
(2002) Haematologica, 87 (5), pp. 523-527.

PubMed ID: 12010667

Abstract
Background and Objectives. The optimal treatment of superficial thrombophlebitis of the leg is undefined. The main study objective was to assess the efficacy and safety of unmonitored high doses as compared to low doses of unfractionated heparin (UFH) for prevention of venous thromboembolic complications in patients with superficial thrombophlebitis of the thigh. Design and Methods. Sixty consecutive patients with acute thrombophlebitis of the great saphenous vein, as assessed by ultrasonography, were randomized to subcutaneous injection twice daily of UFH in high unmonitored doses (12,500 IU for one week followed by 10,000 IU) or prophylactic doses (5,000 IU) for four weeks. The rate of asymptomatic involvement of the deep venous system and/or symptomatic thromboembolic events during a six-month follow-up period was assessed and compared between the two study groups. Results. Six of the 30 patients (20.0 %; 95% Cl, 7.7 to 38.6) randomized to low-dose UFH developed symptomatic or asymptomatic events as compared to 1 of the 30 patients (3.3%; 95% Cl, 0.07 to 17.2) who received high-dose UFH (p=0.05 by one-sided Fisher's exact test). No patient experienced major bleeding complications in either group. Interpretation and Conclusions. The results of this study suggest that in patients with acute thrombophlebitis of the thigh unmonitored high doses of UFH are more effective than prophylactic doses of UFH for prevention of venous thromboembolic complications and do not enhance the risk of bleeding complications. © 2002, Ferrata Storti Foundation.


133§
Bernardi, E.

Extended versus rapid analysis of the leg vein system: A multicenter ultrasound study (The ERASMUS Study) - An interim analysis
(2003) Pathophysiology of Haemostasis and Thrombosis, 33 (5-6), pp. 314-318.

PubMed ID: 15692235
DOI: 10.1159/000083820

Abstract
The reliability of diagnostic strategies based on compression ultrasonography (CUS) for the diagnosis of proximal deep venous thrombosis (DVT) in symptomatic (out)patients is well documented; however these approaches never gained widespread application. Echo-color-Doppler (ECD), is regularly adopted by vascular laboratories as first line test in case of clinically suspected DVT, although the specificity of calf veins imaging is uncertain, as is the negative predictive value of a normal ECD workup. To date, no direct comparison of these strategies is available in the literature. We designed a randomised prospective study to compare the safety and feasibility of two diagnostic approaches: a "rapid" (CUS + D-dimer), and an "extended" strategy (ECD of the whole-leg). All consecutive patients with suspected symptomatic DVT of the legs, if at their first episode, and if not meeting exclusion criteria, will be enrolled in the study. The primary outcome of the study will be the rate of symptomatic VTE during a 3-month follow-up, after a normal diagnostic workup with either of the two proposed strategies. All events will be adjudicated by a blind and independent committee, based on the results of objective testing. An interim data analysis will be presented during the congress session. Copyright © 2004 S. Karger AG, Basel.


132§
Spiezia, L., Bernardi, E., Tormene, D., Simioni, P., Girolami, A., Prandoni, P.

Recurrent thromboembolism in fertile women with venous thrombosis: Incidence and risk factors
(2003) Thrombosis and Haemostasis, 90 (5), pp. 964-966.

PubMed ID: 14597998


131§
Prandoni, P., Bilora, F., Marchiori, A., Bernardi, E., Petrobelli, F., Lensing, A.W.A., Prins, M.H., Girolami, A.

An association between atherosclerosis and venous thrombosis
(2003) New England Journal of Medicine, 348 (15), pp. 1435-1441.

PubMed ID: 12686699
DOI: 10.1056/NEJMoa022157

Abstract
BACKGROUND: In about a third of patients with venous thromboembolism, the cause of the disorder is unexplained. In patients with atherosclerosis, activation of both platelets and blood coagulation and an increase in fibrin turnover are detectable, which may lead to thrombotic complications. Whether atherosclerosis is associated with an increased risk of venous thrombosis is unknown. METHODS: We performed ultrasonography of the carotid arteries in 299 unselected patients who had deep venous thrombosis of the legs without symptomatic atherosclerosis and in 150 control subjects. Patients with spontaneous thrombosis, patients with secondary thrombosis from acquired risk factors, and control subjects were assessed for plaques. RESULTS: At least one carotid plaque was detected in 72 of the 153 patients with spontaneous thrombosis (47.1 percent; 95 percent confidence interval, 39.1 to 55.0), 40 of the 146 with secondary thrombosis (27.4 percent; 95 percent confidence interval, 20.2 to 34.6), and 48 of the 150 control subjects (32.0 percent; 95 percent confidence interval, 24.5 to 39.5). The odds ratios for carotid plaques in patients with spontaneous thrombosis, as compared with patients with secondary thrombosis and with controls, were 2.3 (95 percent confidence interval, 1.4 to 3.7) and 1.8 (95 percent confidence interval, 1.1 to 2.9), respectively. In a multivariate analysis that accounted for risk factors for atherosclerosis, the strength of this association did not change. CONCLUSIONS: There is an association between atherosclerotic disease and spontaneous venous thrombosis. Atherosclerosis may induce venous thrombosis, or the two conditions may share common risk factors.


130§
Bernardi, E., Prandoni, P.

Safety of low molecular weight heparins in the treatment of venous thromboembolism
(2003) Expert Opinion on Drug Safety, 2 (1), pp. 87-94.

PubMed ID: 12904127
DOI: 10.1517/14740338.2.1.87

Abstract
Low molecular weight heparins (LMWHs) are commonly employed as a substitute for unfractionated heparin (UFH) in the treatment of venous thromboembolic events. Despite their higher cost, the preferential use of LMWHs seemed justified initially as, based on the results of earlier meta-analyses, these compounds were deemed to be more effective and safer than UFH. Although, in this respect, their purported superiority over UFH could not be confirmed by subsequent large, randomised trials and updated meta-analyses, other peculiar features of LMWHs were highlighted, favouring their preferential utilisation in patients with venous thromboembolism. Among these, the possibility of once-daily administration on an out-patient basis, the lower incidence of Type II heparin-induced thrombocytopenia and the lower likelihood of osteoporosis after prolonged treatment periods, appear to be especially prominent. This review attempts to evaluate the available evidence focusing on the safety of LMWHs for the treatment of venous thromboembolism and the current therapeutic options and potential advantages of LMWHs, either in general or in selected patient populations. © 2003 Ashley Publications Ltd.


129§
Alberti, A., Noventa, F., Benvegnù, L., Boccato, S., Gatta, A.

Prevalence of liver disease in a population of asymptomatic persons with hepatitis C virus infection
(2002) Annals of Internal Medicine, 137 (12), pp. 961-964.

PubMed ID: 12484711
DOI: 10.7326/0003-4819-137-12-200212170-00009

Abstract
Background: The prevalence of significant liver disease in persons with asymptomatic hepatitis C virus (HCV) infection is unclear. Objective: To determine the prevalence and severity of HCV infection in asymptomatic persons. Design: Population-based cross-sectional study. Setting: Northeastern Italy. Patients: 4820 apparently healthy Telecom Italy employees or their relatives who underwent screening for cardiovascular risk factors. Measurements: Initial screening for anti-HCV by enzyme-linked immunosorbent assay followed by HCV RNA testing by polymerase chain reaction and monitoring of alanine aminotransferase levels in viremic persons (92% of viremic persons also had liver biopsies to assess their METAVIR scores). Results: 116 persons (2.4% [95% CI, 1.97% to 2.84%]) were positive for anti-HCV and 85 (1.76% [CI, 1.39% to 2.14%]) were also viremic. The ALT level was persistently normal in 39 (46%) of viremic patients and elevated in 46 (54%). Significant hepatic histologic abnormalities were detected in 19% (CI, 7.21% to 36.4%) of persons with persistently normal ALT levels and in 61% (CI, 45.4% to 74.9%) of viremic persons who had elevated ALT levels (P < 0.001). The prevalence of HCV infection and number of persons with chronic liver fibrosis increased with age (P = 0.003). Conclusions: Hepatitis C is histologically active and progressive in up to 40% of asymptomatic persons with HCV infection. The severity of liver disease correlates with abnormal ALT levels and increases with age.


128§
Prandoni, P., Lensing, A.W.A., Piccioli, A., Bernardi, E., Simioni, P., Girolami, B., Marchiori, A., Sabbion, P., Prins, M.H., Noventa, F., Girolami, A.

Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis
(2002) Blood, 100 (10), pp. 3484-3488.

PubMed ID: 12393647
DOI: 10.1182/blood-2002-01-0108

Abstract
A small proportion of patients with deep vein thrombosis develop recurrent venous thromboembolic complications or bleeding during anticoagulant treatment. These complications may occur more frequently if these patients have concomitant cancer. This prospective follow-up study sought to determine whether in thrombosis patients those with cancer have a higher risk for recurrent venous thromboembolism or bleeding during anticoagulant treatment than those without cancer. Of the 842 included patients, 181 had known cancer at entry. The 12-month cumulative incidence of recurrent thromboembolism in cancer patients was 20.7% (95% CI, 15.6%-25.8%) versus 6.8% (95% CI, 3.9%-9.7%) in patients without cancer, for a hazard ratio of 3.2 (95% CI, 1.9-5.4) The 12-month cumulative incidence of major bleeding was 12.4% (95% CI, 6.5%-18.2%) in patients with cancer and 4.9% (95% CI, 2.5%-7.4%) in patients without cancer, for a hazard ratio of 2.2 (95% CI, 1.2-4.1). Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy but could not be explained by sub- or overanticoagulation. Cancer patients with venous thrombosis are more likely to develop recurrent thromboembolic complications and major bleeding during anticoagulant treatment than those without malignancy. These risks correlate with the extent of cancer. Possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed. © 2002 by The American Society of Hematology.


127§
Pengo, V., Filippi, B., Biasiolo, A., Pegoraro, C., Noventa, F., Iliceto, S.

Association of the G20210A mutation in the factor II gene with systemic embolism in nonvalvular atrial fibrillation
(2002) American Journal of Cardiology, 90 (5), pp. 545-547.

PubMed ID: 12208422
DOI: 10.1016/S0002-9149(02)02534-1

Abstract
Inherited thrombophilias are a relevant risk factor in venous thromboemblism, and therefore, might be also relevant in systemic thromboembo-lism in nonvalvular AF. To test this hypothesis, the factor V Leiden and G20210A factor II gene mutations were evaluated in patients with AF complicated by systemic thromboembolism and in age-and sex-matched controls with uncomplicated AF. The factor II gene mutation was significantly associated with systemic thromboembolism independently from other clinical risk factors. Screening for this mutation may help in identifying patients at risk and in deciding the antithrombotic strategy.


126§
Kraaijenhagen, R.A., Piovella, F., Bernardi, E., Verlato, F., Beckers, E.A.M., Koopman, M.M.W., Barone, M., Camporese, G., Van Loon, B.J.P., Prins, M.H., Prandoni, P., Büller, H.R.

Simplification of the diagnostic management of suspected deep vein thrombosis
(2002) Archives of Internal Medicine, 162 (8), pp. 907-911.

PubMed ID: 11966342
DOI: 10.1001/archinte.162.8.907

Abstract
Background: The standard diagnostic approach in patients with suspected deep vein thrombosis is to repeat the compression ultrasonography after 1 week in all patients with an initial normal result. We hypothesized that a normal finding of a D-dimer assay safely obviates the need for repeated ultrasonography. In addition, we evaluated the potential value of a pretest probability assessment for this purpose. Methods: At presentation, consecutive outpatients with suspected thrombosis underwent independent assessment by means of ultrasonography of the proximal veins, a wholeblood D-dimer assay, and a pretest clinical model. Patients with normal ultrasonographic findings and an abnormal D-dimer assay result were scheduled for repeated ultrasonography. We evaluated the incidence of symptomatic venous thromboembolic complications during a 3-month follow-up, and the value of clinical pretest probability with ultrasonography or D-dimer assay in scenario analyses. Results: We studied 1756 patients with prevalence of thrombosis of 22%. At entry, results of the D-dimer assay and ultrasonography were normal in 828 patients (47%). Of these, 6 returned with confirmed symptomatic venous thromboembolism (complication rate, 0.7%; 95% confidence interval [ CI ], 0.3% - 1.6%). Repeated ultrasonography was avoided in 61% of the patients with an initial normal test result. Scenario analyses disclosed that the complication rate was 1.6% (95% CI, 0.8%-2.6%) in those with a low clinical pretest probability and a normal result of ultrasonography at referral, whereas this figure was 1.8% (95% CI, 0.9%-3.3%) in patients with a low clinical probability result and a normal result of the D-dimer assay at referral. Conclusions: It is safe to withhold repeated ultrasonography in patients with suspected deep vein thrombosis who have normal results of ultrasonograpy and the SimpliRED D-dimer assay at presentation. The combination of a low clinical pretest probability with a normal result of compression ultrasonography or the D-dimer assay appears to be equally safe in refuting the diagnosis of deep vein thrombosis.


125§
Kraaijenhagen, R.A., Piovella, F., Bernardi, E., Veralto, F., Beckers, E.A.M., Koopman, M.M.W., Barone, M., Camporese, G., van Loon, B.J.P., Prins, M.H., Prandoni, P., Buller, H.R.

The optimal diagnostic management strategy in patients with suspected deep vein thrombosis (abst)
(2002) Thromb Haemost,


124§
Prandoni, P., Lensing, A.W.A., Prins, M.H., Bernardi, E., Marchiori, A., Bagatella, P., Frulla, M., Mosena, L., Tormene, D., Piccioli, A., Simioni, P., Girolami, A.

Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism
(2002) Annals of Internal Medicine, 137 (12), pp. 955-960.

PubMed ID: 12484710
DOI: 10.7326/0003-4819-137-12-200212170-00008

Abstract
Background: The optimum duration of anticoagulant therapy after an episode of deep venous thrombosis (DVT) is controversial. Contributing to the controversy is uncertainty about whether residual venous thrombosis, as assessed by repeated ultrasonography over time, increases the risk for recurrent thromboembolism. Objective: To determine the risk for recurrent thromboembolism in patients who have persistent residual thrombosis compared with patients who have early vein recanalization. Design: Prospective cohort study. Setting: A university hospital in Padua, Italy. Patients: 313 consecutive symptomatic outpatients with proximal DVT who received conventional short-term anticoagulation. Measurements: Ultrasonographic assessment of the common femoral and popliteal veins was performed 3 months after acute DVT in all patients and at 6, 12, 24, and 36 months in patients found to have residual venous thrombosis. Veins were considered recanalized if they were 2.0 mm or less in diameter on a single test or 3.0 mm or less in diameter on two consecutive tests. Recurrent thromboembolism was assessed during a 6-year period. Results: The cumulative incidence of normal results on ultrasonography was 38.8% at 6 months, 58.1% at 12 months, 69.3% at 24 months, and 73.8% at 36 months. Of 58 recurrent episodes, 41 occurred while the patient had residual thrombosis. The hazard ratio for recurrent thromboembolism was 2.4 (95% CI, 1.3 to 4.4; P = 0.004) for patients with persistent residual thrombosis versus those with early vein recanalization. Conclusions: Residual venous thrombosis is an important risk factor for recurrent thromboembolism. Ultrasonographic assessment of residual venous thrombosis may help clinicians modify the duration of anticoagulation in patients with DVT.


123§
Prandoni, P., Lensing, A.W.A., Bernardi, E., Villalta, S., Bagatella, P., Girolami, A.

The diagnostic value of compression ultrasonography in patients with suspected recurrent deep vein thrombosis
(2002) Thrombosis and Haemostasis, 88 (3), pp. 402-406.

PubMed ID: 12353067

Abstract
Diagnosis of recurrent deep-vein thrombosis (DVT) is difficult because of limitations in distinguishing acute from old thrombi. In the past, an ultrasound method for diagnosis of recurrent ipsilateral DVT was developed, which relies on repeated measurements of the diameters of the common femoral and popliteal veins. To assess the safety of withholding anticoagulation from patients with improved or stable compression vein diameters, 205 consecutive patients presenting with suspected recurrent ipsilateral DVT were evaluated. The vein diameter was measured under compression with the transducer and compared with earlier ultrasound results. Patients with stable or improved ultrasound findings had repeat ultrasound assessments after 2 (± 1) and 7 (± 1) days. Patients with repeatedly normal ultrasound results were followed-up for six months to determine the incidence of symptomatic recurrent venous thromboembolism. Of the 205 patients, 153 had stable or improved ultrasound findings. Repeat ultrasound assessment became abnormal in 3, and recurrence was confirmed by venography in all. A six months follow-up was done in the remaining 150 patients with repeatedly normal ultrasound tests and showed 2 (1.3%; 95% CI, 0.02 to 4.7%) confirmed non-fatal venous thromboembolic complications. The positive predictive value of a stable or improved ultrasound was 90% (95% CI, 77 to 97%). In conclusion, it is safe to withhold anticoagulant treatment from patients with suspected recurrent ipsilateral DVT in whom compression ultrasonography showed improved or stable vein diameters.


122§
Realdon, S., Pontisso, P., Adami, F., Trentin, L., Noventa, F., Ferrari, A., Migliorato, I., Gatta, A., Alberti, A.

High levels of soluble tumor necrosis factor superfamily receptors in patients with hepatitis C virus infection and lymphoproliferative disorders
(2001) Journal of Hepatology, 34 (5), pp. 723-729.

PubMed ID: 11434619
DOI: 10.1016/S0168-8278(00)00063-5

Abstract
Background: Chronic hepatitis C virus (HCV) infection is associated with a variety of extrahepatic disorders that may relate to direct or indirect effects of virus infection. Increased levels of soluble forms of tumor necrosis factor (TNF) receptors I and II, found in lymphoproliferative and infectious diseases, can interfere with TNF induced apoptotic cell death. The aim of the present study was to evaluate soluble TNF family receptors levels in lymphoproliferative disorders associated with HCV infection. Methods: One hundred and forty-nine subjects were studied, including 120 anti-HCV positive patients (60 without lymphoproliferative manifestations, 47 with type II cryoglobulinemia and 13 with low-grade B-cell non-Hodgkin's lymphoma (B-NHL)) and 29 anti-HCV negative subjects (19 with low-grade B-NHLs and ten normal controls). Results: Soluble forms of TNF receptor I, TNF receptor II and Fas were significantly higher in HCV positive patients compared with normal controls. The highest levels were found in patients affected by type II cryoglobulinemia or HCV positive lymphoplasmacytoid lymphomas (LP-NHLs), while HCV positive patients without type II cryoglobulinemia or with other B-NHLs had lower values (P < 0.01). Conclusions: Among HCV infected individuals, very high levels of soluble TNF receptors are significantly associated with type II cryoglobulinemia and LP-NHLs, suggesting that they may be involved in these proliferative disorders. © 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V.


121§
Pengo, V., Legnani, C., Noventa, F., Palarenti, G.

Oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding: A multicenter inception cohort study
(2001) Thrombosis and Haemostasis, 85 (3), pp. 418-422.

PubMed ID: 11307807

Abstract
Oral anticoagulants (OA) are the drug of choice for stroke prevention in patients with non-rheumatic atrial fibrillation (NRAF). This clear benefit/risk ratio comes from several randomized clinical trials (RCT) in which highly selected patients were strictly monitored. The aim of this study was to ascertain whether the safety of OA was also obtained outside the setting of clinical trials in consecutive patients starting treatment and routinely followed at Italian anticoagulation clinics. A total of 433 patients with NRAF were enrolled in the ISCOAT study and followed up for a mean of 1.4 years. Two patients (0.3% per year) suffered from a complete non-fatal ischemic stroke, 8 patients (1.3% per year) died of thrombosis-related vascular death, and 11 patients (11 events, 1.8% per year) suffered from major bleedings (2 fatal). Major bleeding occurred more frequently in patients >75 years of age (6 events, 5.1% per year) than in younger patients (5 events, 1.0% per year). The cumulative incidence of major bleeding in patients over 75 years of age (10.8%; 95% CI, 1.8-19.8) was significantly higher than in younger patients (2.8%; 95% CI, 0.3-5.3, p = 0.006). Major primary bleeding unrelated to organic lesions (7 patients, 1 male and 6 females) occurred in 5 elderly patients (>75 years old) with a cumulative incidence (9.6%; 95% CI 0.8-18.4) significantly higher than in younger patients (1.2%; 95% CI, 0-3.0, p = 0.0003). Univariate analysis revealed a higher frequency of major primary bleeding in females, in diabetic patients and in in those who had suffered a previous thromboembolic event. Multivariate analysis revealed that only age greater than 75 years was independently related to major primary bleedings (RR 6.6; 95% CI 1.2-37, p = 0.032). Minor bleedings (n = 27) were not more frequent in elderly patients (6% vs 4% per year, p = ns). Patients were kept at optimal intensity of treatment for 63% of the time. These data confirm the efficacy of OA but identify elderly patients as a high risk group of major bleeding.


120§
Benvegnù, L., Noventa, F., Bernardinello, E., Pontisso, P., Gatta, A., Alberti, A.

Evidence for an association between the aetiology of cirrhosis and pattern of hepatocellular carcinoma development
(2001) Gut, 48 (1), pp. 110-115.

PubMed ID: 11115831
DOI: 10.1136/gut.48.1.110

Abstract
Background - Patients with liver cirrhosis are at significant risk of hepatocellular carcinoma (HCC) that may develop as well defined nodular lesions or as more aggressive infiltrating tumours. Aim - To compare prospectively risk factors associated with nodular or infiltrating HCC in cirrhotic patients. Patients and methods - We studied 370 patients with cirrhosis, followed prospectively by periodic ultrasound (US) of the liver, for a mean period of 74.6 (SD 32.4) months to define the incidence and patterns of HCC development. Patients who developed HCC were compared according to tumour pattern using univariate and multivariate analysis. Results - Sixty one (16.5%) patients developed HCC: HCC was classified as nodular in 49 (80.3%) and infiltrating in 12 (19.7%) according to US and computerised tomography (CT) imaging. The five and 10 year cumulative probabilities were 8.1% (95% confidence interval (CI) 5.2%-11%) and 25.2% (15.0-35.4%) for nodular HCC and 2.1% (0.5-3.7%) and 6.9% (2.1-11.7%) for infiltrating HCC. Patients with infiltrating HCC were younger than those with nodular HCC (59.5 v 66.2 years, 95% CI 55.2-63.8 and 64.1-68.3 years; p=0.014). Using multivariate analysis, development of nodular HCC was associated with older age (p=0.0002; relative risk (RR) 3.1; 95% CI 1.6-5.2), longer duration (p=0.09; RR 2.6; 95% CI 1.8-3.4), and more advanced stage (p=0.002; RR 2.5; 95% CI 1.3-4.5) of cirrhosis but not with the aetiology of liver disease. In contrast, development of infiltrating HCC appeared to be unrelated to age or disease duration or stage, while it was associated with hepatitis B virus infection (p=0.07; RR 3.96; 95% CI 1.1-5.2) and with hepatitis B/hepatitis C virus coinfection (p=0.0007; RR 16.9; 95% CI 3.8-36.7). Conclusions - In liver cirrhosis, we identified two patterns of HCC developing with distinct risk factors. Nodular HCC was related to the cirrhotic process per se independent of aetiological factors and may depend on the proliferative activity within regenerative nodules, while the infiltrating form of HCC was linked to hepatitis B virus infection and may reflect more direct virus induced carcinogenesis.


119§
Fattovich, G., Ribero, M.L., Pantalena, M., Diodati, G., Almasio, P., Nevens, F., Tremolada, F., Degos, F., Rai, J., Solinas, A., Mura, D., Tocco, A., Zagni, I., Fabris, F., Lomonaco, L., Noventa, F., Realdi, G., Schalm, S.W., Tagger, A.

Hepatitis C virus genotypes: Distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe
(2001) Journal of Viral Hepatitis, 8 (3), pp. 206-216.

PubMed ID: 11380799
DOI: 10.1046/j.1365-2893.2001.00291.x

Abstract
The aim of this study was to evaluate the distribution and clinical significance of hepatitis C virus (HCV) genotypes in European patients with compensated cirrhosis due to hepatitis C (Child class A) seen at tertiary referral centres. HCV genotypes were determined by genotype-specific primer PCR in 255 stored serum samples obtained from cirrhotics followed for a median period of 7 years. Inclusion criteria were biopsy-proven cirrhosis, absence of complications of cirrhosis and exclusion of all other potential causes of chronic liver disease. The proportion of patients with types 1b, 2, 3a, 1a, 4 and 5 were 69%, 19%, 6%, 5%, 0.5% and 0.5%, respectively. Kaplan-Meier 5-year risk of hepatocellular carcinoma (HCC) was 6% and 4% for patients infected by type 1b and non-1b, respectively (P = 0.8); the corresponding figures for decompensation were 18% and 7% (P = 0.0009) and for event-free survival were 79% and 89% (P = 0.09), respectively. After adjustment for baseline clinical and serological features. HCV type 1b did not increase the risk for HCC [adjusted relative risk = 1.0 (95% confidence interval = 0.47-2.34)], whereas it increased the risk for decompensation by a factor of 3 (1.2-7.4) and decreased event-free survival by a factor of 1.7 (0.9-3.10). In conclusion, type 1b and, to a lesser extent, type 2, are the most common HCV genotypes in European patients with cirrhosis. HCV type 1b is not associated with a greater risk for HCC, but increases the risk for decompensation by threefold in patients with cirrhosis.


118§
Verlato, F., Bruchi, O., Prandoni, P., Camporese, G., Maso, G., Busonera, F., Girolami, A., Andreozzi, G.M.

The value of ultrasound screening for proximal vein thrombosis after total hip arthroplasty: A prospective cohort study
(2001) Thrombosis and Haemostasis, 86 (2), pp. 534-537.

PubMed ID: 11521999

Abstract
The role of ultrasound screening for proximal deep-vein thrombosis (DVT) following major hip surgery is controversial. 202 consecutive patients, who had received warfarin prophylaxis after total hip arthroplasty underwent a bilateral ultrasound assessment of the proximal vein system (using the criterion of vein compressibility) before hospital discharge. In the 9 patients (4.5%; 95% CI, 2.1-8.3%) with positive test anticoagulant treatment was successfully continued for three months. In all the remaining 193 patients the warfarin treatment was withdrawn. A second ultrasound test was performed 15 days later, and showed a new (asymptomatic) abnormality compatible with proximal DVT in 2 patients (1.0%; 95% CI, 0.1-3.7%). All other 191 patients remained asymptomatic until the completion of a 3-month follow-up period (rate of symptomatic thromboembolism, 0/191, 0%; 95% CI, 0-1.9%). Because of the relatively high incidence of proximal DVT in patients undergoing major orthopaedic surgery under warfarin prophylaxis, screening for proximal DVT at hospital discharge in these patients is indicated. The negativity of this test has the potential of safely preventing the extension of anticoagulation beyond hospital stay. A larger controlled study in which the value of this strategy is tested against the prolongation of oral anticoagulation in patients with a negative ultrasound screening at discharge is indicated.


117§
Camporese, G.

Angiological evalutation of patients with suspected venous thrombosis [La valutazione angiologica del paziente con sospetto di trombosi venosa]
(2001) Impegno Ospedaliero, Sezione Scientifica, 22 (5), pp. 87-97.

Abstract
The thromboembolic venous (TVE) disease is a serious and potentially fatal illness. Both Physicians and Public Health Service had to be awaken to the necessity that every citizen presenting symptoms of deep venous thrombosis (DVT) should be urgently sent to a timely and appropriate diagnostic procedure to check as soon as possible presence or not of such disease. Patients with suspect DVT may present very particular characteristics and may require specific diagnostic procedures, according to their source (out-patient or in-patient). There are some predisposing conditions to the developing of TVE, but also diagnostic and therapeutic procedures aimed to the solution of such disease. Infact, besides diagnostic flow-charts enforceable to the different categories of patients, treatment of DVT can also be customized, thanks to the introduction of low-molecolar weight heparins (LMWH) and to the following opportunity to treat DVT at home. However, not all patients can be treated at home and a great many of them is still necessary hospitalization. Finally, a particular mention to the diagnosis of thrombofilia, acknowleged to be still more involved in the pathogenesis of DVT, as scientific research provide statistically significant data about their prevalence in all people, about their penetration and about their tight correlation with all predisposing factors that support the onset of DVT.


116§
Prandoni, P., Bernardi, E., Bagatella, P., Piccioli, A., Marchiori, A.

The optimal treatment of venous thrombosis: Current status and future perspectives
(2001) Clinical Laboratory, 47 (3-4), pp. 151-154.

PubMed ID: 11294578


115§
Bernardi, E., Piccioli, A., Marchiori, A., Girolami, B., Prandoni, P.

Upper extremity deep vein thrombosis: risk factors, diagnosis, and management.
(2001) Seminars in vascular medicine, 1 (1), pp. 105-110.

PubMed ID: 15199520
DOI: 10.1055/s-2001-14547

Abstract
Upper extremity deep vein thrombosis (UEDVT) should no longer be regarded as an uncommon and benign disease, as previously reported. It is usually associated with risk factors, as central venous lines, malignancy, and coagulation defects; however, up to 20% of UEDVTs are apparently spontaneous. The clinical picture is characterized by swelling, pain, and functional impairment, albeit UEDVT may be completely asymptomatic. Objective testing is mandatory prior to instituting anticoagulation because the prevalence of UEDVT is less than 50% in symptomatic subjects, and compression ultrasound or color Doppler represents the preferred diagnostic methods. Up to 36% of the patients develop pulmonary embolism, which may be fatal; postthrombotic sequelae and recurrent thromboembolism are also frequent complications. Unfractionated or low-molecular-weight heparin followed by oral anticoagulation should be regarded as the treatment of choice; thrombolysis and surgery may be indicated in selected cases. Prophylaxis with low-dose heparin or low-dose warfarin is necessary whenever central venous catheters are positioned.


114§
Bernardi, E., Bagatella, P., Frulla, M., Simioni, P., Prandoni, P.

Postthrombotic syndrome: incidence, prevention, and management.
(2001) Seminars in vascular medicine, 1 (1), pp. 71-80.

PubMed ID: 15199516

Abstract
Mild to severe postthrombotic sequelae, including chronic pain, edema, and ulceration, arise in one third of patients short after deep vein thrombosis (DVT). Recurrent DVT is closely associated with the development of postthrombotic syndrome (PTS), whereas if the extent and location of DVT might be relevant remains unclear. Chronic venous hypertension and abnormal microvessel or lymphatic function also correlates with PTS. The diagnosis of PTS is based on clinical grounds only if patients report a history of documented DVT; otherwise, objective testing is required. To abate the prevalence of PTS, the best policy is represented by prevention of recurrent thrombosis and use of stockings. Despite a plenty of surgical options, conservative treatment is preferable because half of the patients improve or remain stable during follow-up, provided they wear elastic stockings. Clinical presentation has a prognostic value, as patients with initially severe symptoms enjoy a more favorable outcome than those who progressively deteriorate over time.


113§
Prandoni, P., Bernardi, E., Tormene, D., Mosena, L., Sartor, D., Girolami, A.

Diagnosis of recurrent deep vein thrombosis.
(2001) Seminars in vascular medicine, 1 (1), pp. 55-60.

PubMed ID: 15199514

Abstract
Long-term follow-up studies demonstrated that venous thromboembolism is a chronic disease, as the rate of recurrent deep vein thrombosis (DVT) continuously increases after the primitive thrombotic episode. Objective testing is mandatory to confirm or refute the presence of recurrent DVT, as only 30% of patients with suspected recurrence have a new documented thrombotic episode. There is no consensus on the preferred diagnostic procedure; furthermore, both invasive and noninvasive methods are limited in this context. Venography, the established gold standard, is invasive, costly, inconvenient and requires high technical skills. Among noninvasive techniques, serial impedance plethysmography, alone or in combination with leg scanning and venography, and serial compression ultrasound (CUS), were adequately investigated. At present, the recommended approach is represented by a quantitative CUS method that possesses an excellent reproducibility and accuracy. The safety of withholding anticoagulants from patients with a normal quantitative CUS work-up has been recently demonstrated in a prospective management study.


112§
Prandoni, P., Sabbion, P., Tanduo, C., Errigo, G., Zanon, E., Bernardi, E.

Prevention of venous thromboembolism in high-risk surgical and medical patients.
(2001) Seminars in vascular medicine, 1 (1), pp. 61-70.

PubMed ID: 15199515

Abstract
Although pharmacologic prophylaxis against venous thromboembolism has become the standard of care following total hip and knee replacement, prophylaxis among patients undergoing surgery for hip fracture and other lower extremity trauma remains underutilized. Available experience consistently supports the view that low-molecular-weight heparins are more effective than unfractionated heparin for prevention of proximal deep vein thrombosis (DVT) with no additional hemorrhagic risk and more effective than oral anticoagulants for prevention of in-hospital (mostly distal) venous thrombosis at the price of a higher surgical site bleeding and wound hematoma. The choice between low-molecular-weight heparin and warfarin should be tailored to the individual patients based on the clinical assessment of postoperative thrombosis and bleeding risk as well as the prophylaxis-specific cost and convenience. Whether thromboprophylaxis should be continued for a few additional weeks after hospital discharge is controversial. The overall incidence of postoperative DVT in patients with cancer is about twice as high as that of patients free of malignancy. Accordingly, they require prophylactic measures comparable with those usually recommended for major orthopedic surgery. In this setting, dermatan sulfate shows promise. In contrast to surgical patients, prevention of venous thromboembolism is less well studied in hospitalized medical patients. In a recent controlled randomized trial, enoxaparin in high prophylactic doses was an effective and safe measure of thromboprophylaxis in ordinary bedridden patients.

111§
Gerotto, M., Dal Pero, F., Pontisso, P., Noventa, F., Gatta, A., Alberti, A.

Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon
(2000) Gastroenterology, 119 (6), pp. 1649-1655.

PubMed ID: 11113086
DOI: 10.1053/gast.2000.20230

Abstract
Background & Aims: The NS5A and the E2 proteins of hepatitis C virus (HCV)-1b can bind and inhibit in vitro the interferon (IFN)-induced cellular kinase PKR. The role of such interaction in modulating the antiviral effect of IFN is still controversial. We have analyzed the E2 and the NS5A sequences in HCV-1b-infected patients treated with IFN to assess whether and how different combinations of wild-type and mutant proteins correlated with early and long-term virological response. Methods: In 30 patients, sequences of pretreatment and on-treatment E2-PePHD and NS5A-PKR binding domain (including the putative ISDR) were analyzed in parallel by sequencing cDNA-polymerase chain reaction products and up to 25 independent clones. Results: The E2-PePHD sequence was highly conserved with a homogeneous quasispecies and was identical in 29 of 30 cases with no association with the pattern of response and no evidence of evolution during therapy. Patients with a mutated NS5A-ISDR had a higher rate of early virological response (67%) than cases with wild-type ISDR (17%). This association was lost in long-term responders (33% vs. 17%). Conclusions: Although the highly conserved E2-PePHD motif might contribute to reduce IFN responsiveness, variations within this region do not seem to play a role in modulating IFN sensitivity. The NS5A-ISDR sequence influenced the early, but not the sustained response, to IFN, suggesting that other factors may be more important for the long-term outcome of therapy.


110§
De Franceschi, L., Fattovich, G., Turrini, F., Ayi, K., Brugnara, C., Manzato, F., Noventa, F., Stanzial, A.M., Solero, P., Corrocher, R.

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage
(2000) Hepatology, 31 (4), pp. 997-1004.

PubMed ID: 10733558
DOI: 10.1053/he.2000.5789

Abstract
The antiviral drug ribavirin (RBV) is widely used in combination with interferon (IFN) in the treatment of chronic hepatitis C virus (HCV) infection. A major side effect of RBV is a reversible hemolytic anemia. We have evaluated the in vitro effects of RBV on erythrocyte adenosine triphosphate (ATP) content and on hexosemonophosphate shunt (HMS). The ATP levels were significantly decreased in the presence of RBV and the HMS was increased, suggesting the presence of red cell susceptibility to oxidation. In vivo, we have studied the hematologic effects of treatment with RBV alone or in combination with IFN in 11 patients with chronic hepatitis C: 6 were treated with RBV (1,000-1,200 mg/d) and 5 were treated with a combination of RBV and IFN (5 million U thrice weekly). Patients were studied at semi- monthly intervals from 0 to day 60 of therapy. Both treatments were associated with a significant reduction in hemoglobin levels (steady state level at day 45) and a marked increase in absolute reticulocyte counts. Erythrocyte Na-K pump activity was significantly diminished, whereas K-Cl cotransport and its dithiotreitol-sensitive fraction, malondialdehyde and methemoglobin levels were significantly increased. RBV-treated patients showed an increase in aggregated band 3, which was associated with a significantly increased binding of autologous antibodies and complement C3 fragments indicating an erithrophagocytic removal by reticuloendothelial system.


109§
Verlato, F., Camporese, G., Bernardi, E., Salmistraro, G., Rocco, S., Mayellaro, V., Busonera, F., Andreozzi, G.M.

Clinical outcome of patients with internal carotid artery occlusion: A prospective follow-up study
(2000) Journal of Vascular Surgery, 32 (2), pp. 293-298.

DOI: 10.1067/mva.2000.106953

Abstract
Purpose: We prospectively evaluated whether, and to what extent, different clinical presentations (symptomatic or asymptomatic) or the presence of atherosclerotic narrowing of the contralateral carotid system modifies the mortality rate and the incidence of non-fatal cerebrovascular events in patients with internal carotid artery (ICA) occlusion. Methods: A prospective cohort study was conducted in the Unit Care of Angiology at the University Hospital of Padua in Italy. Consecutive patients with ICA occlusion were eligible for the study. Between 1990 and 1991, 41 such patients were identified at our center. All patients were observed prospectively for a mean of 44.5 months, except for one patient who was lost to follow-up after 12 months. Patients with severe (ie, more than 75%) stenosis of the contralateral internal carotid artery were scheduled for thromboendarterectomy. ICA occlusion was objectively documented in all patients by using a combination of echo-color Doppler scanning and continuous-wave Doppler scanning (periorbital flow). Results: The overall mortality rate was 22.0% (95% CI, 10.6-37.6), and the stroke-related mortality rate was 7.3% (95% CI, 1.5-19.9). No differences in overall and stroke-related mortality rates were observed between asymptomatic and symptomatic patients. None of the patients experienced nonfatal cerebrovascular events. Conclusion: ICA occlusion seems to represent a relatively benign condition, in both its symptomatic and asymptomatic presentation. The presence of an atherosclerotic stenosis less than 75% of the contralateral ICA does not seem to worsen the prognosis of this condition.

Index Keywords
adult, aged, article, cerebrovascular accident, clinical article, clinical trial, controlled clinical trial, controlled study, Doppler echography, female, follow up, human, human cell, human tissue, incidence, internal carotid artery occlusion, Italy, male, priority journal, prognosis, randomized controlled trial, treatment outcome


108§
Verlato, F., Rosso, F., Verlato, G., Camporese, G., Sartor, D., Andreozzi, G.M.

Probability of carotid artery stenosis based on a simple clinical model
Int Ang, 19 (2000) (SUPPL. 1), p. 46.


107§
Bernardi, E., Piccioli, A., Oliboni, G., Zuin, R., Girolami, A., Prandoni, P.

Nomograms for the administration of unfractionated heparin in the initial treatment of acute thromboembolism - An overview
(2000) Thrombosis and Haemostasis, 84 (1), pp. 22-26.

PubMed ID: 10928464

Abstract
Despite the availability of low-molecular-weight heparins, unfractionated heparin (UFH) still remains the drug of choice for the initial treatment of acute venous thromboembolism in many countries. When appropriately employed, UFH treatment results in a degree of efficacy and safety that is fully comparable with that obtained with the use of heparin derivatives. The use of nomograms for the intravenous or subcutaneous administration of UFH assures that virtually all patients will promptly achieve adequate levels of anticoagulation, thus decreasing the likelihood of recurrent venous thromboembolism without extra bleeding-risk. In this article we reviewed clinical studies on the implementation and validation of UFH dosing nomograms, and attempted a quantitative analysis of their performance. According to the results of our analysis, a statistically significantly higher proportion of patients treated on the basis of a nomogram reached a therapeutic anticoagulant level within 24 h of treatment, as compared to patients treated following the standard practice (odds ratio, 3.6; 95% CI, 2.6 to 4.9). The rate of recurrent thromboembolic events was significantly lower for patients treated according to a nomogram (odds ratio, 0.3; 95% CI, 0.1 to 0.8), while no significant differences in terms of either major or minor bleedings were detected between nomogram patients and controls.


106§
Bernardi, E., Prandoni, P.

The post-thrombotic syndrome
(2000) Current Opinion in Pulmonary Medicine, 6 (4), pp. 335-342.

PubMed ID: 10912643
DOI: 10.1097/00063198-200007000-00015

Abstract
One of every three patients with deep-vein thrombosis of the lower extremities will develop, within 5 years, post-thrombotic sequelae that vary from minor signs to severe manifestations such as chronic pain, intractable edema, and leg ulceration. The post-thrombotic syndrome (PTS) develops as a result of the combination of venous hypertension due to persistent outflow obstruction or valvular incompetence and abnormal microvasculature or lymphatic function. Among factors potentially related to the development of PTS, recurrent ipsilateral thrombosis plays a major role. Whether the extent and the location of the initial thrombosis are associated with the development of PTS is still controversial. The diagnosis of PTS can be accepted on clinical grounds for patients with a history of venous thrombosis. The combination of a standardized clinical evaluation with the results of compression ultrasonography and Doppler ultrasonography helps diagnose or exclude a previous proximal-vein thrombosis. Prevention of recurrent thrombosis and use of compression elastic stockings are the cornerstones of PTS prevention. The management of this condition is demanding and often frustrating. Although several surgical procedures have been tested, conservative treatment is largely preferable, as more than 50% of patients either remain stable or improve during long-term follow-up, if carefully supervised and instructed to wear proper elastic stockings. Clinical presentation helps predict the prognosis, being the outcome of patients who refer with initially severe manifestations more favorable than that of patients whose symptoms progressively deteriorate over time. (C) 2000 Lippincott Williams and Wilkins, Inc.


105§
Bernardi, E., Prins, M.H., Ten Cate, J.W., Prandoni, P., Simioni, P., Andreozzi, G.M., Girolami, A., Büller, H.R.

Antiplatelet therapy and other interventions after revascularisation procedures in patients with peripheral arterial disease: A meta-analysis
(2000) European Journal of Vascular and Endovascular Surgery, 19 (4), pp. 370-380.

PubMed ID: 10801370
DOI: 10.1053/ejvs.1999.1034

Abstract
Objectives: to evaluate the efficacy of conservative adjuvant therapy after revascularisation procedures in patients with peripheral arterial disease. Design: meta-analysis. Materials: English-language studies published from 1976 to 1997. Methods: reports on conservative therapies in patients with peripheral arterial disease after percutaneous transluminal angioplasty, endarterectomy, thromboendarterectomy or bypass grafting were eligible. Uncontrolled or retrospective studies, double reports or trials without clinical outcomes were excluded. Included studies were graded as level 1 (randomised and double- or assessor-blind), level 2 (open randomised), or level 3 (non-randomised comparative). (Loss of) patency, amputation, vascular events and mortality were the outcomes considered. When feasible, end-of-treatment results, either continuous or binary, were combined with appropriate statistical methods. Results: thirty-two studies were included. Compared to non-active control, aspirin with dipyridamole improved (loss of) patency (odds ratio (OX) 0.69, 95% confidence interval (CI) 0.53 to 0.90) and mortality (OX 0.80, 95% CI, 0.57 to 1.14); ticlopidine improved (loss of) patency (OR 0.53, 95% CI, 0.33 to 0.85) and amputation (OX 0.29, 95% CI, 0.08 to 1.01). Data on the effectiveness of vitamin-K inhibitors were not conclusive. Conclusions: patients with peripheral arterial disease improve their outcome by receiving aspirin with dipyridamole or ticlopidine after a revascularisation procedure.


104§
Martini, R., Camporese, G., Salmistraro, G., Scomparin, M.A., Verlato, F., Andreozzi, G.M.

Short term treatment with prostanoids in critical limb ischaemia: Three months follow-up
(1999) Minerva Cardioangiologica, 47 (12), pp. 656-657.

PubMed ID: 10670248


103§
Camporese, G., Verlato, F., Salmistraro, G., Andreozzi, G.M.

Casi di ricanalizzazione spontanea di occlusioni carotidee valutate con eco color-Doppler ed arteriografia
(1999) Minerva Cardioangiologica, 47 (11), pp. 451-453.


102§
Verlato, F., Zucchetta, P., Prandoni, P., Camporese, G., Marzola, M.C., Salmistraro, G., Bui, F., Martini, R., Rosso, F., Andreozzi, G.M.

An unexpectedly high rate of pulmonary embolism in patients with superficial thrombophlebitis of the thigh
(1999) Journal of Vascular Surgery, 30 (6), pp. 1113-1115.

PubMed ID: 10587397
DOI: 10.1016/S0741-5214(99)70051-0

Abstract
Purpose: The rate of objectively proven pulmonary embolism in patients with thrombophlebitis of the greater saphenous vein was studied. Methods: Consecutive ambulant patients with thrombophlebitis of the greater saphenous vein, involving the above-knee segment, underwent a complete venous echo color Doppler examination of the lower limbs, perfusion lung scanning, and chest radiography. A high probability of pulmonary embolism was defined as the presence of two or more large segmental defects, one large and two or more moderate perfusion defects, or four or more moderate perfusion defects, with no corresponding abnormality found by means of chest radiography. Results: Of the 21 patients included in the study, findings compatible with a high probability of pulmonary embolism were detected in seven patients (33.3%; 95% CI, 14.6 to 57.0), although clinical symptoms of pulmonary embolism were present only in one patient. No association was found between the presence of thrombosis at the saphenofemoral junction and the risk for pulmonary embolism. Conclusion: The rate of pulmonary embolism in patients with thrombophlebitis of the greater saphenous vein is unexpectedly high. This risk is similarly high in patients with thrombosis at the saphenofemoral junction and in patients without thrombosis at the saphenofemoral junction. Our results are consistent with those of other recent investigations and suggest that superficial thrombophlebitis of the thigh is not as benign a disease entity as previously described.

Index Keywords
adult, aged, article, cardiovascular risk, clinical article, color ultrasound flowmetry, female, human, lung embolism, lung perfusion, male, priority journal, saphenous vein, scintigraphy, thorax radiography, thrombophlebitis


101§
Hiatt, W.R., Girolami, B., Bernardi, E., Prins, M., Girolami, A.

Intermittent claudication revisited: The value of medical therapy [3] (multiple letters)
(1999) Archives of Internal Medicine, 159 (16), pp. 1955-1957.

PubMed ID: 10493329
DOI: 10.1001/archinte.159.16.1955


100§
Girolami, B., Bernardi, E., Prins, M.H., Cate X, J.W., Prandoni, P., Hettiarachchi, R., Marras, E., Stefani, P.M., Girolami, A., Büller, H.R.

Antithrombotic drugs in the primary medical management of intermittent claudication: A meta-analysis
(1999) Thrombosis and Haemostasis, 81 (5), pp. 715-722.

PubMed ID: 10365743

Abstract
Background. There is no consensus on the efficacy of the antithrombotic drugs available for patients with intermittent claudication. Methods. A Medline and manual search was used to identify relevant publications. Uncontrolled or retrospective studies, double reports or trials without clinical outcomes were excluded. Included studies were graded as level 1 (randomised and double- or assessor-blind), level 2 (open randomised), or level 3 (non-randomised comparative). Mortality, cerebro- or cardiovascular events, amputations, arterial occlusions or number of revascularization procedures performed in the lower limbs, pain-free and total walking distance, ankle brachial index and calf blood flow, were the main outcomes considered. When feasible, end of treatment results, either continuous or binary, were combined with appropriate statistical methods. Results. Mortality was significantly decreased by ticlopidine compared to placebo (common odds ratio 0.68, 95% C.I., 0.49-0.95); clopidogrel decreased vascular events in comparison to aspirin (odds ratio 0.76, 95% C.I., 0.63-0.92) in level 1 studies. Arterial occlusions and the number of revascularization procedures performed were statistically significantly decreased by aspirin and ticlopidine, respectively. A small but statistically significant improvement in pain-free walking distance was determined by picotamide, indobufen, low molecular weight heparins, sulodexide and defibrotide, in small studies. Conclusions. Clopidogrel and ticlopidine do reduce clinically important events in patients with intermittent claudication and could be added to the primary medical treatment of these patients. The use of aspirin in these patients cannot be based on direct evidence, but only on analogy with coronary and cerebral atherosclerosis, where it has documented efficacy. Other antithrombotic drugs were not properly evaluated in patients with intermittent claudication.


99§
Girolami, B., Bernardi, E., Prins, M.H., Ten Cate, J.W., Hettiarachchi, R., Prandoni, P., Girolami, A., Büller, H.R.

Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl: A meta-analysis
(1999) Archives of Internal Medicine, 159 (4), pp. 337-345.

PubMed ID: 10030306
DOI: 10.1001/archinte.159.4.337

Abstract
Background: There is no consensus on the efficacy of physical training, smoking cessation, and pharmacological therapy (pentoxifylline or nafronyl oxalate) in the treatment of patients with intermittent claudication at Fontaine stage II of disease. Methods: A MEDLINE and manual search was used to identify relevant publications. Uncontrolled or retrospective studies, double reports, and trials without clinically meaningful outcomes were excluded. Included studies were graded level 1 (randomized and double- or assessor-blind), level 2 (open randomized), or level 3 (nonrandomized). Pain- free and total walking distance were the main outcomes considered; when feasible, end-of-treatment results were combined with appropriate meta- analytical procedures. Results: In 5 level 2 studies, physical training increased pain-free and total walking distance significantly (139.0 m [95% confidence interval {CI}, 31.0 to 246.9 m] and 179.1 m [95% CI, 60.2 to 298.1 m], respectively). In a level 3 study, smoking cessation resulted in a nonsignificant increase in total walking distance of 46.7 m (95% CI, -19.3 to 112.7 m). In 6 level 1 studies, pentoxifylline increased both pain-free and total walking distance by 21.0 m (95% CI, 0.7 to 41.3 m) and 43.8 m (95% CI, 14.1 to 73.6 m), respectively. In 4 level 1 trials, nafronyl significantly increased pain-free walking distance (58.6 m [95% CI, 30.4 to 86.8 m]) and total walking distance (71.2 m [95% CI, 13.3 to 129.0 m]). Conclusions: Physical training increased pain-free and total walking distance in level 2 studies. Only level 3 studies support the usefulness of smoking cessation. In level I studies, pentoxifylline and nafronyl increased pain-free and total walking distance, but the average effects were relatively small.

Index Keywords
naftidrofuryl, pentoxifylline; adult, blood viscosity, drug effect, drug efficacy, female, human, intermittent claudication, major clinical study, male, meta analysis, outcomes research, peripheral occlusive artery disease, priority journal, quality of life, review, smoking cessation, training, walking; Clinical Trials, Exercise Therapy, Humans, Intermittent Claudication, Nafronyl, Pentoxifylline, Smoking Cessation, Treatment Outcome, Vasodilator Agents


98§
Scannapieco, G., Parisi, R., Bortoluzzi, C., Doria, S., Puato, M., Ambrosio, G.B.

Fattori di rischio aterogeno in pazienti con arteriopatia obliterante degli arti inferiori
Minerva Cardioangiologica, 47 (1999) (12), pp. 579-580.

PubMed ID: 10670212


97§
Pengo, V., Zasso, A., Barbero, F., Banzato, A., Nante, G., Parissenti, L., John, N., Noventa, F., Volta, S.D.

Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation
(1998) American Journal of Cardiology, 82 (4), pp. 433-437.

PubMed ID: 9723629
DOI: 10.1016/S0002-9149(98)00357-9

Abstract
Adjusted-dose warfarin is effective for stroke prevention in patients with nonrheumatic atrial fibrillation (AF), but the risk of bleeding is high, especially among the elderly. Fixed minidose warfarin is effective in preventing venous thromboembolism with low risk of bleeding and no need for frequent clinical monitoring. Patients >60 years with nonrheumatic AF were randomized in an open-labeled trial to receive fixed minidose warfarin (1.25 mg/day) or standard adjusted-dose warfarin (International Normalized Ratio [INR] between 2.0 and 3.0). Primary outcome events were ischemic stroke, peripheral or visceral embolism, cerebral or fatal bleeding, and vascular death. Secondary end points were major bleeding, myocardial infarction, and death. This study was discontinued before completion in light of publication of the Stroke Prevention in Atrial Fibrillation III trial, which indicated that low-intensity fixed-dose warfarin treatment (i.e., INR < 1.5) was insufficient for stroke prevention in high-risk patients with nonrheumatic AF. From a total of 1,209 considered patients, 303 were randomized to be studied (150 in the minidose group and 153 in the adjusted-dose group). Mean follow-up was 14.5 months. The rate of cumulative primary events was 11.1% (95% confidence intervals [CI] 4.0 to 18.2) in the fixed minidose group and 6.1% (95% CI 1.1 to 11.1) in the adjusted-dose group (p = 0.29). The rate of ischemic stroke was significantly higher in the minidose group (3.7% vs 0% per year, p = 0.025). Major bleedings were more frequent in standard treatment group (2.6% vs 1% per year, p = 0.19). Most thromboembolic complications occurred at INRs < 1.2, whereas the majority of hemorrhages occurred at INRs >3.0. No significant difference in primary outcome events was observed in the abbreviated study. However, the significantly increased occurrence of ischemic stroke in the fixed minidose warfarin group suggests that this regimen does not protect patients with nonrheumatic AF.


96§
Benvegnù, L., Chemello, L., Noventa, F., Fattovich, G., Pontisso, P., Alberti, A.

Retrospective analysis of the effect of interferon therapy on the clinical outcome of patients with viral cirrhosis
(1998) Cancer, 83 (5), pp. 901-909.

PubMed ID: 9731893
DOI: 10.1002/(SICI)1097-0142(19980901)83:5<901::AID-CNCR15>3.0.CO;2-Z

Abstract
BACKGROUND. Recent data suggest that interferon therapy (IFN) can reduce the risk of progression to hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related cirrhosis. METHODS. A cohort of 189 patients with Child's Stage A cirrhosis of viral etiology followed prospectively were analyzed retrospectively to assess the effects of IFN on the clinical course and development of HCC. RESULTS. During a mean follow-up of 71.5 ± 23.6 months, 7.9% of 88 treated and 21.8% of 101 untreated patients showed worsening of the Child's disease stage (P < 0.01); 5.6% of treated and 26.7% of untreated patients developed HCC (P < 0.001); and 3.4% of treated and 19.8% of untreated patients died of liver disease or underwent orthotopic liver transplantation (OLT) (P < 0.005). Using Cox's regression analysis, no treatment with IFN, high bilirubin and alkaline phosphatase (ALP) levels, and low leukocyte counts and prothrombin activity (PT) were associated significantly with worsening of Child's disease stage; no treatment with IFN, long term disease, low albumin and PT, and high γ-glutamyl transpeptidase (GGT) were related significantly to HCC development; and no treatment with IFN, low albumin and PT, and high GGT and ALP were associated significantly with reduced survival. After adjustment for independent risk factors identified by multivariate analysis, the estimated cumulative probability of worsening of cirrhosis (P < 0.05), development of HCC (P < 0.001), and death or OLT (P < 0.006) was significantly lower in IFN-treated patients compared with untreated patients. This beneficial effect of therapy was statistically evident only in HCV positive patients. CONCLUSIONS. These results support the hypothesis that IFN improves clinical outcomes and reduces progression to HCC in patients with HCV-related cirrhosis. These conclusions, based on retrospective data, should be confirmed prospective.


95§
Bortolotti, F., Jara, P., Crivellaro, C., Hierro, L., Cadrobbi, P., Frauca, E., Camarena, C., De La Vega, A., Diaz, C., De Moliner, L., Noventa, F.

Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period
(1998) Journal of Hepatology, 29 (2), pp. 184-190.

PubMed ID: 9722198
DOI: 10.1016/S0168-8278(98)80002-0

Abstract
Background/Aims: Chronic hepatitis B virus infection can lead to cirrhosis and hepatocellular carcinoma, particularly in men over 40 years of age and in areas where childhood-onset infection is common. The sequence of events from paediatric infection to severe disease in adults is only partially known. The aim of this study was to evaluate the evolution of chronic hepatitis B acquired in childhood during 20 years of follow-up. Patients: One hundred and eighty-five consecutive, otherwise healthy, Caucasian children were enrolled in Padua (Italy) and in Madrid (Spain) between 1975 and 1985, and followed for an average period of 13 years; 168 were hepatitis B e antigen (HBeAg) positive and five had cirrhosis. Results: Thirty patients received steroids or levamisole and 21 interferon, but treatment did not significantly influence HBeAg clearance. Overall, two (1.1%) children, with initial cirrhosis, developed hepatocellular carcinoma and the other three (1.6%) cirrhotic patients became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; 14 (7.5%) children maintained HBeAg positive hepatitis; 155 (83.8%) became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; six (3.2%) experienced reactivation of liver disease and viral replication after remission and five (2.7%) maintained biochemical features of liver damage after HBeAg clearance. Only 6% cleared hepatitis B surface antigen. Conclusions: Even considering the bias of treatment, the large majority of Caucasian children with chronic hepatitis B became asymptomatic carriers of infection with normal alanine amino-transferase during the first 20 years of observation. Cirrhosis is an early, rare complication, and a risk factor for hepatocellular carcinoma. A subgroup of patients who experienced reactivation or maintained liver damage after HBeAg clearance seems to be at greater risk for disease progression during adult life.


94§
Benvegnu, L., Fattovich, G., Noventa, F.

Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis: A prospective study
(1998) Hepatology.


93§
Bernardi, E., Prandoni, P., Lensing, A.W.A., Agnelli, G., Guazzaloca, G., Scannapieco, G., Piovella, F., Verlato, F., Tomasi, C., Moia, M., Scarano, L., Girolami, A.

D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: Prospective cohort study
(1998) British Medical Journal, 317 (7165), pp. 1037-1040.

PubMed ID: 9774286

Abstract
Objective. To investigate the efficacy of using a rapid plasma D-dimer test as an adjunct to compression ultrasound for diagnosing clinically suspected deep vein thrombosis. Design. D-dimer concentrations were determined in all patients with a normal ultrasonogram at presentation. Repeat ultrasonography was performed 1 week later only in patients with abnormal D-dimer test results. Main outcome measure. Patients with normal ultrasonograms were not treated with anticoagulants and were followed for 3 months for thromboembolic complications. Setting. University research and affiliated centres. Subjects. 946 patients with clinically suspected deep vein thrombosis. Results. Ultrasonograms were abnormal at presentation in 260 (27.5%) patients. Of the remaining 686 patients tested for D-dimer, 88 (12.8%) had abnormal concentrations. During follow up venous thromboembolic complications occurred in one of the 598 patients who were not treated with anticoagulants and who had an initial normal ultrasonogram and D-dimer concentration, whereas thromboembolic complications occurred in two of the 83 untreated patients who had abnormal D-dimer concentrations but a normal repeat ultrasonogram. The cumulative incidence of venous thromboembolic complications during follow up was 0.4% (95% cofidence interval O% to 0.9%). The rapid plasma D-dimer test used as an adjunct to compression ultrasonography resulted in a reduction in the mean number of repeat ultrasound examinations and additional hospital visits from 0.7 to 0.1 per patient. Conclusions. Testing for D-dimer as an adjunct to a normal baseline ultrasound examination decreased the number of subsequent ultrasound examinations considerably without any increased risk of venous thromboembolic complications in patients not receiving anticoagulants. The use of ultrasound and testing for D-dimer enabled treatment decisions to be made at the time of presentation in most patients.


92§
Verlato, F., Prandoni, P., Bernardi, E., Andreozzi, G.M.

Diagnosi di trombosi venosa profonda nel paziente ambulatoriale: Eco-Doppler e D-Dimero
(1998) Minerva Cardioangiologica, 46 (10), pp. 366-368.

PubMed ID: 10021811


91§
Prandoni, P., Bagatella, P., Bernardi, E., Girolami, B., Rossi, L., Scarano, L., Marchiori, A., Piccioli, A., Girolami, A.

Use of an algorithm for administering subcutaneous heparin in the treatment of deep venous thrombosis
(1998) Annals of Internal Medicine, 129 (4), pp. 299-302.

PubMed ID: 9729183
DOI: 10.7326/0003-4819-129-4-199808150-00006

Abstract
Background: Despite the widespread use of subcutaneous heparin in the initial treatment of deep venous thrombosis, there are no guidelines for achieving adequate anticoagulation with this drug. Objective: To implement a weight-based algorithm for the administration of subcutaneous unfractionated heparin after an intravenous loading dose. Design: Prospective cohort study. Setting: University hospital. Participants: 70 outpatients with proximal venous thrombosis. Intervention: An intravenous bolus of heparin followed by a subcutaneous injection of heparin in doses adjusted for body weight. Subsequent adjustments of the subcutaneous heparin dose were scheduled twice daily according to the algorithm; the activated partial thromboplastin time (aPTT) was measured in the mid-interval (target range, 50 to 90 seconds). Results: The therapeutic threshold aPTT (≤50 seconds) was achieved in 61 patients (87%) within 24 hours and in 69 patients (99%) within 48 hours. In 7 patients (10%), a supratherapeutic aPTT lasted more than 12 hours. No major bleeding episodes or cases of heparin-induced thrombocytopenia were seen. Three patients (4.3% [95% CI, 0.9% to 12.0%]) had recurrent thromboembolism during 3 months of follow-up. Conclusion: The administration of subcutaneous heparin according to a weight-based algorithm allows the rapid achievement of effective and safe anticoagulation in patients with deep venous thrombosis.


90§
Locasciulli, A., Testa, M., Pontisso, P., Benvegnù, L., Fraschini, D., Corbetta, A., Noventa, F., Masera, G., Alberti, A.

Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia
(1997) Blood, 90 (11), pp. 4628-4633.

PubMed ID: 9373275

Abstract
The aim of this study was to ascertain prevalence and natural history of hepatitis C virus (HCV) infection in a large cohort of patients cured of childhood leukemia who had been followed prospectively for liver disease for at least 10 years since chemotherapy withdrawal: 114 consecutive patients entered the study. Liver function tests and ultrasonography were used to assess presence of liver disease. Patients were tested for antibody to HCV and for serum HCV-RNA at the end of chemotherapy and at the end of follow- up. At chemotherapy withdrawal, 56 patients (49%} were HCV-RNA positive, often without detectable anti-HCV, and in these cases, transaminase levels were more elevated during (P = .08) and after (P = .04) chemotherapy compared with HCV-RNA negative cases. Patients were then followed-up 13 to 27 years (mean, 17) after chemotherapy withdrawal. During this period, 38 initially anti-HCV negative patients seroconverted to anti-HCV and 17 initially anti- HCV positive cases lost reactivity. Forty patients were persistently HCV-RNA positive in serum, while 16 initially viremic patients became HCV-RNA negative during follow-up. At the end of the observation period, a persistent transaminase elevation was detected only in four HCV-RNA positive and anti- HCV positive cases, while no patient developed signs or symptoms of decompensated liver disease. Thus, hepatitis C was a frequent finding in long-term survivors after chemotherapy. It was associated with an atypical serologic profile and did not cause severe liver impairment over a period of 13 to 27 years.


89§
Alberti, A., Chemello, L., Noventa, F., Cavalletto, L., De Salvo, G.

Therapy of hepatitis C: Re-treatment with alpha interferon
(1997) Hepatology, 26 (3 SUPPL.), pp. 137S-142S.

PubMed ID: 9305679

Abstract
The long-term benefit of interferon therapy in chronic hepatitis C is limited. During therapy, serum alanine aminotransferase (ALT) levels decrease to normal and hepatitis C virus (HCV) RNA decreases in 40% to 60% of patients. However, most patients relapse after therapy withdrawal, so that no more than 15% to 25% achieve a sustained response. Re-treatment has been evaluated in studies using different regimens and forms of alpha interferon in different cohorts of patients at different times after initial therapy. Both end-of-treatment and sustained responses to re-treatment correlate with the type of response achieved during the initial course. Patients who do not respond or have only a partial response to the initial course of interferon have an extremely low rate of sustained response when re-treated, independently of the regimen used. Combining data from 13 studies, sustained responses occurred in no patients who were re-treated with 3 million units (MU) three times weekly for 6 months, and in only 2% to 3% of patients re- treated with higher doses and/or for longer periods. In contrast, a significant number of patients who responded during the initial course but subsequently relapsed have a sustained response when re-treated with interferon alone. Combining data from 11 published studies on patients who relapsed after an initial course, sustained responses occurred in 15% (95% confidence interval [CI], 10%-20%) of patients re-treated with 3 MU three times weekly for 6 months, in 29% (CI, 17%-40%) re-treated with a higher dose for 6 months, and in 43% (CI, 34%-50%) re-treated for at least 12 months. On the other hand, patients who relapsed after a 12-month course of interferon had only 4% rate (range, 0%-8%) of sustained response when re-treated. The best predictor of sustained response to re-treatment in patients who had relapsed was a negative serum HCV-RNA test by polymerase chain reaction at the end of the first course. These results, which have been confirmed in a recent prospective, randomized controlled trial, indicate that nonresponders to interferon should not be re-treated with interferon alone, whereas patients who relapse after a 6-month course of alpha interferon therapy have an indication to be re-treated for at least 12 months, especially if serum HCV RNA was negative at the end of the first course of treatment.


88§
Faronato, P.P., Maioli, M., Tonolo, G., Brocco, E., Noventa, F., Piarulli, F., Abaterusso, C., Modena, F., De Bigontina, G., Velussi, M., Inchiostro, S., Santeusanio, F., Bueti, A., Nosadini, R.

Clustering of albumin excretion rate abnormalities in caucasian patients with NIDDM
(1997) Diabetologia, 40 (7), pp. 816-823.

PubMed ID: 9243103
DOI: 10.1007/s001250050754

Abstract
Proteinuria and nephropathy have been found to cluster in families of non-insulin-dependent diabetic (NIDDM) Pima Indian, and in Caucasian insulin-dependent diabetic (IDDM) patients. No information is at present available for Caucasian NIDDM patients. The aim of the present study was to determine whether micro-macroalbuminuria (AER +) is associated with albumin excretion rate abnormalities in diabetic and non-diabetic siblings of probands with NIDDM and AER +. We identified 169 Caucasian families with one NIDDM proband (the patient with longest known NIDDM duration) (101 families with only NIDDM siblings, 33 families with both NIDDM and non-NIDDM siblings and 35 families with only non-NIDDM siblings). Of the probands 56 had AER + [Prob-NIDDM-(AER+)], 78 had AER- [Prob-NIDDM-(AER-)], 74 siblings of Prob- NIDDM-(AER+), and 113 siblings of Prob-NIDDM-(AER-) also had NIDDM. Data on albuminuria and retinopathy from multiple sibling pairs when the size of the sibship was more than two was adjusted according to a weighting factor. The odds ratio for AER+, in siblings of Prob-NIDDM-(AER +) adjusted for age, hypertension, glycated haemoglobin A(1c) and other confounding variables was 3.94 (95% confidence intervals: 1.93-9.01) as compared to siblings of Prob- NIDDM-(AER -). The 74 siblings of Prob-NIDDM-(AER +) had higher prevalence of proliferative retinopathy than siblings of Prob-NIDDM-(AER-) (14 vs 2%; p < 0.01). We also identified 66 non-diabetic siblings of 41 NIDDM probands with AER + and 36 non-diabetic siblings of 27 NIDDM probands with AER-. Albumin excretion was two times higher, although still within the normal range, in the non-diabetic siblings of Prob-NIDDM-(AER+) than in siblings of Prob-NIDDM-(AER) [median = 13.5 (range 0.5-148) vs 6.6 (range 1-17) pg/min (p < 0.05)]. In conclusion higher rates of albumin excretion aggregate in Caucasian families with NIDDM. Proliferative retinopathy is more frequently observed in families showing a clustering of AER + and NIDDM. These findings suggest that familial factors play a role in the pathogenesis of renal and retinal complications in NIDDM.


87§
Mingardi, R., Avogaro, A., Noventa, F., Strazzabosco, M., Stocchiero, C., Tiengo, A., Erle, G.

Alcohol intake is associated with a lower prevalence of peripheral vascular disease in non-insulin dependent diabetic women
(1997) Nutrition, Metabolism and Cardiovascular Diseases, 7 (4), pp. 301-308.


Abstract
Background and Aim: We sought to separately determine in men and women: 1) the prevalence of peripheral vascular disease (PVD) among patients with NIDDM; 2) the impact of alcohol consumption on peripheral vascular disease (PVD). Methods and Results: A cross sectional study in a cohort of 340 diabetic men and 310 diabetic women in whom the most common risk factors for PVD and drinking habits were documented. The overall prevalence of PVD was 33%. The prevalence of PVD was 41% in males and 24% in females. The prevalence of PVD was similar among men who drank regularly and among those who did not, whereas PVD was significantly lower in women with a moderate alcohol consumption ( χ2 (1) = 5.77; p<0.022). Among males, increased alcohol consumption was associated with significantly higher total cholesterol as well as HDL cholesterol levels. Significantly older age was observed in patients with PVD among those who were heavy drinkers. Among women, moderate alcohol consumption was associated with significantly higher triglyceride concentrations. The logistic regression model demonstrates that in men, strong independent predictors for PVD were age (odd ratio 1.09; 1.06-1.12 95% confidence interval), smoking (2.8; 1.33-5.88), hypertension (2.02; 1.15-3.54) and microvascular complications (3.13; 1.86-5.27); PVD was inversely related to HDL-cholesterol (0.97; 0.96-1.00). In females, strong independent predictors for PVD were age (1.05; 1.03-1.08), long term diabetic complications (2.17; 1.32-3.56), trigliceride levels (1.00; 1.00-1.01), hypertension (1.67; 1.01-2.75), and smoking (1.88; 1.14-3.09) whereas, alcohol intake was inversely associated to the presence of PVD (0.11; 0.06-0.20). Conclusions: We conclude that in men, alcohol intake is not associated with an increased prevalence of PVD, whereas in women it is significantly inversely related. Long term microvascular complications are related to PVD in both men and women. ©1997, Medikal Press.


86§
Pengo, V., Barbero, F., Banzato, A., Garelli, E., Noventa, F., Biasiolo, A., Zasso, A., Dalla Volta, S.

A comparison of a moderate with moderate-high intensity oral anticoagulant treatment in patients with mechanical heart valve prostheses
(1997) Thrombosis and Haemostasis, 77 (5), pp. 839-844.

PubMed ID: 9184389

Abstract
Background. The long-term administration of oral anticoagulants to patients with mechanical heart valve prostheses is generally accepted. However, the appropriate intensity of oral anticoagulant treatment in these patients is still controversial. Methods and Results. From March 1991 to March 1994, patients referred to the Padova Thrombosis Center who had undergone mechanical heart valve substitution at least 6 months earlier were randomly assigned to receive oral anticoagulants at moderate intensity (target INR = 3) or moderate-high intensity (target INR = 4). Principal end points were major bleeding, thromboembolism and vascular death. Minor bleeding was a secondary end-point. A total of 104 patients were assigned to the target 3 group and 101 to the target 4 group; they were followed for from 1.5 years to up 4.5 years (mean, 3 years). Principal end-points occurred in 13 patients in the target 3 group (4 per 100 patient-years) and in 20 patients in the target 4 group (6.9 per 100 patient-years). Major hemorrhagic events occurred in 15 patients, 4 in the target 3 group (1.2 per 100 patient-years) and 11 in the target 4 group (3.8 per 100 patient-years) (p = 0.019). The 12 recorded episodes of thromboembolism, 4 of which consisted of a visual deficit, were all transient ischemic attacks, 6 in the target 3 group (1.8 per 100 patient-years) and 6 in the target 4 group (2.1 per 100 patient-years). There were 3 vascular deaths in each group (0.9 and 1 per 100 patient-years for target 3 and target 4 groups, respectively). Minor bleeding episodes occurred 85 times (26 per 100 patient-years) in the target 3 group and 123 times (43 per 100 patient-years) in the target 4 group (p = 0.001). Conclusions. Mechanical heart valve patients on anticoagulant treatment who had been operated on at least 6 months earlier experienced fewer bleeding complications when maintained on a moderate intensity regimen (target INR = 3) than those on a moderate-high intensity regimen (target INR = 4). The number of thromboembolic events and vascular deaths did not differ between the two groups.


85§
Noventa, F., De Salvo, G.L., Chemello, L., Pontisso, P., Alberti, A.

A model to predict long-term sustained response to interferon therapy in chronic hepatitis C
(1997) Journal of Viral Hepatitis, 4 (3), pp. 193-198.

PubMed ID: 9181528
DOI: 10.1046/j.1365-2893.1997.00137.x

Abstract
Interferon therapy is used widely for chronic hepatitis C but only a minority of treated patients achieve a long-lasting sustained response. We have developed, by logistic regression, a mathematical model to estimate the probability of sustained response in an individual patient with chronic hepatitis C when treated with interferon-α (IFN-α). The model, which includes age, sex, disease duration, pretreatment serum γ-glutamyl-transpeptidase, alanine aminotransferase and virus genotype, was developed from a database of 307 patients and validated in a new set of 200 patients. It performed well as goodness-of-fit (P = 0.71 and P = 0.15 in the development and test sample, respectively) and discrimination (area under receiver operating curve = 0.79 in the development and 0.78 in the test sample, respectively). This model may provide decision support in the treatment of chronic hepatitis C with IFN-α. © 1997 Blackwell Science Ltd.


84§
Benvegnù, L., Noventa, F., Chemello, L., Fattovich, G., Alberti, A.

Prevalence and incidence of cholecystolithiasis in cirrhosis and relation to the etiology of liver disease
(1997) Digestion, 58 (3), pp. 293-298.

PubMed ID: 9243126
DOI: 10.1159/000201457

Abstract
To assess prevalence and incidence of cholecystolithiasis in cirrhosis, 356 consecutive cirrhotics and 247 consecutive cases of chronic hepatitis without cirrhosis were studied by ultrasonography. Cholecystolithiasis was significantly more frequent in cirrhotics than in patients with chronic hepatitis (p < 0.001) after stratification for age and for alcohol abuse, and its prevalence in the former was affected by Child’s class (p < 0.001) and duration (p < 0.001) of cirrhosis and was higher in HBsAg-negative as compared with HBsAg-positive cases (36.2 vs. 11.9%) and in patients with previous alcohol abuse (41.5 vs. 28.3%), while no difference was noted in relation to sex. By multivariate analysis, duration and Child’s class of cirrhosis and HBsAg-negative status were statistically associated with cholecystolithiasis. One hundred and eighty-two of the 356 cirrhotic patients without gallstones at inclusion were followed prospectively, and 21 (11.5%) of them developed cholecystolithiasis, and duration of cirrhosis and past alcohol abuse were found to be independent risk factors for gallstone development by multivariate analysis. Cirrhosis is a significant risk factor for cholecystolithiasis, except for HBsAg-positive patients who have prevalence and incidence similar to noncirrhotics. Severity and duration of cirrhosis and previous alcohol abuse are associated with an increased risk of gallstone formation. © 1997 S. Karger AG, Basel.


83§
De Salvo, G.L., Noventa, F., Chemello, L., Pontisso, P., Alberti, A.

Variables that influence response to different interferon schedules in chronic hepatitis C and predictive models.
(1997) Journal of viral hepatitis, 4 Suppl 1, pp. 79-83.

PubMed ID: 9097283

Abstract
In chronic hepatitis C (HCV), standard interferon therapy with 3 MU three times weekly for 6 months is associated with sustained response in about 10-20% of patients while another 10-15% respond only when higher dosages or/and longer periods of treatment are used. Different variables have been described that are associated with sustained response and may also identify patients requiring low- or high-dose regimens. We have analysed a large data base of 442 patients with chronic hepatitis C treated with interferon-alpha to define rates of sustained response in different patient subgroups treated with different schedules. The rate of sustained response was increased with higher dose regimens in most patient categories, defined according to age, pre-treatment liver histology and HCV genotype, while the amount of interferon per one sustained response remained the same or was reduced. The use of higher dose regimen was particularly cost-effective in patients with cirrhosis. Using the same data base, different models of prediction of sustained response in the individual patient were developed and compared. Inclusion of the HCV genotype in these models was found to increase significantly specificity and sensitivity, confirming that this parameter has a major influence on sustained response to interferon therapy in chronic HCV.


82§
Benvegnù, L., Pontisso, P., Cavalletto, D., Noventa, F., Chemello, L., Alberti, A.

Lack of correlation between hepatitis C virus genotypes and clinical course of hepatitis C virus-related cirrhosis
(1997) Hepatology, 25 (1), pp. 211-215.

PubMed ID: 8985292
DOI: 10.1053/jhep.1997.v25.pm0008985292

Abstract
The influence of the hepatitis C virus (HCV)-genotype on liver disease severity was evaluated in 429 consecutive patients with chronic hepatitis C, including 109 with cirrhosis who were followed up prospectively, allowing for the assessment of the role of the HCV-genotype on disease outcome and on the development of hepatocellular carcinoma (HCC). HCV-1 was detected in 147 (46%) patients without cirrhosis and in 47 (43%) with cirrhosis (P: not significant), being mainly HCV-1b. HCV-2 was found in 103 (32%) cases without cirrhosis and in 30 (27.5) with cirrhosis (P: not significant), being mainly HCV-2a. HCV-3 was detected in 32 (10%) patients without cirrhosis and in 2 (2%) with cirrhosis (P < 0.005). Infection with more than one genotype (HCV- 1/HCV-2 and HCV-1/HCV-3) was observed only in cirrhotic patients (6 of 109; 5.5%). During a mean follow-up of 67 ± 22 months, 21 (19%) patients with cirrhosis showed worsening in Child's stage, 5 (4.5%) underwent liver transplantation, 23 (21%) developed HCC, and 24 (22%) died of complication of liver disease; the overall incidence of at least one of these events was 38.5%. By the Kaplan-Meier method and log-rank test, the cumulative probability of developing each or at least one of the above events did not differ in relation to the genotype of infecting HCV, apart from patients with mixed genotype infection who showed a significantly higher incidence of death (P < .05). These data indicate that HCV-genotypes do not have a significant effect on the severity and outcome of liver disease in patients with chronic HCV-infection. Patients with cirrhosis who are also infected by HCV-1 and HCV-2 had a similar prognosis and progression to HCC, while patients infected by more than one genotype showed the most unfavorable course of disease.


81§
Fattovich, G., Giustina, G., Degos, F., Tremolada, F., Diodati, G., Almasio, P., Nevens, F., Solinas, A., Mura, D., Brouwer, J.T., Thomas, H., Njapoum, C., Casarin, C., Bonetti, P., Fuschi, P., Basho, J., Tocco, A., Bhalla, A., Galassini, R., Noventa, F., Schalm, S.W., Realdi, G.

Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients
(1997) Gastroenterology, 112 (2), pp. 463-472.

PubMed ID: 9024300
DOI: 10.1053/gast.1997.v112.pm9024300

Abstract
Background and Aims: Few data are available concerning the long-term prognosis of chronic liver disease associated with hepatitis C virus infection. This study examined the morbidity and survival of patients with compensated cirrhosis type C. Methods: A cohort of 384 European cirrhotic patients was enrolled at seven tertiary referral hospitals and followed up for a mean period of 5 years. Inclusion criteria were biopsy-proven cirrhosis, abnormal serum aminotransferase levels, absence of complications of cirrhosis, and exclusion of hepatitis A and B viruses and of metabolic, toxic, or autoimmune liver diseases. Results: Antibodies against hepatitis C virus were positive in 98% of 361 patients tested. The 5-year risk of hepatocellular carcinoma was 7% and that of decompensation was 18%. Death occurred in 51 patients (13%), with 70% dying of liver disease. Survival probability was 91% and 79% at 5 and 10 years, respectively. Two hundred five patients (53%) were treated with interferon alfa. After adjustment for clinical and serological differences at baseline between patients treated or not treated with interferon, the 5-year estimated survival probability was 96% and 95% for treated and untreated patients, respectively. Conclusions: in this cohort of patients, life expectancy is relatively long, in agreement with the morbidity data showing a slowly progressive disease.


80§
Benvegnu, L., Fattovich, G., Chemello, L., Noventa, F., Alberti, A.

Retrospective analysis of the effect of interferon therapy on hepatocellular carcinoma development in cirrhosis
(1996) Hepatology, 24,


79§
Pontisso, P., Urso, M., Noventa, F., Moroni, M., Colombo, M., Barbara, L.

Multicentric study on HCV genotypes in Italian patients with chronic HCV infection
(1996) IX Triennial International Symposium on Viral Hepatitis and Liver Disease, p. 181.


78§
Verlato, F., Camporese, G., Rocco, S., Bernardi, F., Mayellaro, V., Salmistraro, G.

Clinical outcome of patients with internal carotid artery occlusion: A prospective follow-up study
(1997) XVI Congress of the International Society of Thrombosis and Haemostasis, PS-539, p. 132.


77§
Prandoni, P., Villalta, S., Bagatella, P., Rossi, L., Marchiori, A., Piccioli, A., Bernardi, E., Girolami, B., Simioni, P., Girolami, A.

The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients
(1997) Haematologica, 82 (4), pp. 423-428.

PubMed ID: 9299855

Abstract
Background and Objective. In contrast to the extensive documentation on the short-term outcome of patients with acute deep vein thrombosis (DVT) of the lower extremities, little is known about the long-term clinical course of this disease. To determine the clinical course of patients with a first episode of symptomatic DVTn over an 8-year follow-up period. The primary aims were to assess the long-term incidence of recurrent venous thromboembolism and that of the post-thrombotic syndrome. In addition, we determined mortality and evaluated potential risk factors for all these outcomes. Methods. This was designed as a prospective cohort follow-up study. Consecutive symptomatic outpatients with a first episode of venography proven DVT were treated with an initial course of furl-dose (low molecular weight) heparin, followed by at least three months of oral anticoagulants. After discharge, they were instructed to wear compression elastic stockings for at least two years. Follow-up assessments were scheduled at three and six months, and then every six months up to eight years. Diagnosis of recurrent venous thromboembolism was made according to standard criteria. The presence of post-thrombotic syndrome was evaluated using a standardized scale. Results. A total of 528 consecutive patients with a first episode of venography confirmed DVT were included in the study. The cumulative incidence of recurrent venous thromboembolism after two, five and eight years was 17.2, 24.3 and 29.7% respectively. Malignancy and impaired coagulation inhibition increased the risk of recurrent venous thromboembolism (RR=1.48 and 2.0, respectively). In contrast, surgery and recent trauma or fracture were associated with a diminished risk of recurrent venous thromboembolism (RR- 0.65 and 0.39, respectively). The cumulative incidence of post-thrombotic syndrome after two, five and eight years was 24.5, 29.6 and 29.8%, respectively. The development of ipsilateral recurrent DVT was strongly associated with the risk for post-thrombotic syndrome (risk ratio, 2.4). Survival after eight years was 69%. The presence of malignancy increased the risk of death remarkably (risk ratio, 7.1). Interpretation and Conclusions. Symptomatic DVT carries a high risk for recurrent venous thromboembolism that persists for many years especially in patients without transient risk factors for DVT. The post-thrombotic syndrome occurs in almost one-third of patients and is strongly related to recurrent ipsilateral DVT. Our findings challenge the widely adopted short course of anticoagulation in patients with symptomatic DVT.


76§
Scarano, L., Bernardi, E., Prandoni, P., Sardella, C., Rossi, L., Carraro, P., Simioni, P., Girolami, A.

Accuracy of two newly described D-dimer tests in patients with suspected deep venous thrombosis
(1997) Thrombosis Research, 86 (2), pp. 93-99.

PubMed ID: 9175231
DOI: 10.1016/S0049-3848(97)00053-4

Abstract
Accumulating evidence suggests that the ELISA determination of D-Dimer might be a useful tool for the exclusion of deep vein thrombosis (DVT) of lower extremities, because of its high sensitivity and negative predictive value. However, conventional ELISA assay is time-consuming and, therefore, is not suitable for emergency use. To evaluate the accuracy of two rapid assays recently described, 126 consecutive outpatients with the clinical suspicion of DVT underwent the NycoCard D-Dimer and the Instant I.A. D-Dimer determination, using venography as the reference test. In all patients, the conventional ELISA assay was also performed. Venography confirmed the presence of DVT in 30 patients (23.8%), and ruled out the diagnosis in the remaining 96. Instant I.A D-Dimer was positive in 28 patients with DVT (sensitivity, 93.3%), and negative in 90 subjects free from thrombosis (specificity, 93.8%). Nycocard D-Dimer correctly identified 27 patients with DVT (sensitivity 90.0%), and was negative in 77 subjects free from thrombosis (specificity, 80.2%). Sensitivity, specificity, negative and positive predictive values of both tests did not differ from those found with the classic ELISA method. In conclusion, both Instant I.A. D-Dimer and Nycocard D-Dimer.


75§
Prandoni, P., Polistena, P., Bernardi, E., Cogo, A., Casara, D., Verlato, F., Angelini, F., Simioni, P., Signorini, G.P., Benedetti, L., Girolami, A.

Upper-extremity deep vein thrombosis: Risk factors, diagnosis, and complications
(1997) Archives of Internal Medicine, 157 (1), pp. 57-62.

PubMed ID: 8996041

Abstract
Background: Little is known about the clinical, diagnostic, and prognostic aspects of upper-extremity deep vein thrombosis (UEDVT). Objectives: To identify the clinical and laboratory parameters associated with this disease, to assess the diagnostic accuracy of ultrasonographic methods for its detection, and to establish the frequency of both early and late complications. Patients and Methods: After a careful history was taken, 58 consecutive patients with signs and symptoms that were clinically suggestive of UEDVT underwent the determination of antithrombin III and protein C and S levels and resistance to activated protein C and lupuslike anticoagulants. Compression ultrasonography, color flow Doppler imaging, and Doppler ultrasonography were performed prior to venography. Patients with confirmed UEDVT underwent objective tests to detect a pulmonary embolism and were followed up prospectively to record recurrent thromboembolic events and postthrombotic sequelae. Results: Findings from venography confirmed UEDVT in 27 patients (47%). Central venous catheters, thrombophilic states, and a previous leg vein thrombosis were statistically significantly associated with UEDVT. Sensitivity and specificity of compression ultrasonography (96% and 93.5%, respectively) and color flow Doppler imaging (100% and 93%, respectively) were comparable and better than those of Doppler ultrasonography (81% and 77%, respectively). Objective findings suggestive of a pulmonary embolism were recorded in 36% of the patients with UEDVT. After a mean follow-up of 2 years, 2 patients with UEDVT experienced recurrent thromboembolic events, and 4 had postthrombotic sequelae. Conclusions: Symptomatic UEDVT is associated with central venous catheters, thrombophilic states, and a previous leg vein thrombosis. Both compression ultrasonography and color flow Doppler imaging are accurate methods for its detection. A pulmonary embolism is a common complication of the disease. Finally, this disorder may recur and may be followed by postthrombotic sequelae.


74§
Verlato, F., Zanon, G.F., Gamba, P.G., Verlato, G., Rocco, S., Orzali, A., Camporese, G., Signorini, G.P.

Echo doppler color flow (EDCF) evaluation of vascular pathology in pediatric age groups
(1996) International Angiology, 15 (4), pp. 321-327.

PubMed ID: 9127773

Abstract
Although rarely observed, vascular diseases in children constitute a complex clinical problem. Until recently the diagnostic approach to infant vascular diseases was based on invasive methods such as arteriography, but now the use of ultrasonographic methods such as Doppler c.w. and Echo Doppler Color Flow (EDCF) in angiology can offer new and interesting application even in the pediatric age range. In the present study 15 children affected by vascular diseases (eight with arteriovenous fistulas (AVF), two with pseudoaneurysms, and five with angiomas or cysts) either of iatrogenic or congenital etiology, were examined by Doppler c.w and EDCF. In three additional cases a suspected vascular disease was not confirmed. The data obtained by Doppler c.w. and EDCF proved useful to perform a preoperative diagnosis; however some diagnostic criteria differed from those described in adulthood, as in the AVF cases, for instance, we observed the prevalence of indirect signs such as alterations of venous flow, and the presence of 'multicolored speckled mass' and of 'the spreading of the color in extravasal space' rather than a direct connection between an artery and a vein. Also pseudoaneurisms were easily detected by EDCF. In two cases of congenital AVF, the diagnosis was confirmed by arteriography. Surgery was performed in 9 children, 7 with AVF and 2 with pseudoaneurysm; in all cases, the vascular defect detected by ultrasonography was visualized and corrected. In 7 cases EDCF was also used in the follow-up. In conclusion this study suggests a possible more extensive use of ultrasonographic methods in the diagnostic approach to vascular diseases in pediatric age groups, and points out their validity in screening very young patients and in their surgical follow-up.

Author Keywords
Arteriovenous fistulas; Pediatrics; Ultrasonography; Vascular disesases


73§
Verlato, F., Camporese, G., Rocco, S., Salmistraro, G., Signorini, G.P.

Carotid kinks - Relationship to atherosclerosis and cerebral ischemia
(1996) Journal of Vascular Investigation, 2 (2), pp. 65-69.

Abstract
Carotid kinking (CK) prevalence in patients with suspected cerebrovascular disease seems quite high (10-15%). However, the potential for these lesions to produce cerebral ischemia is not well established. The aim of our study is to evaluate CK (defined as a sharp bend of the vessel producing an angle ≤ 90°) in its relationship to the presence of ipsilateral neurological signs, its association with atherosclerosis and those factors considered to place the patient at risk for the development of atherosclerosis, Ipsilateral neurological signs were evaluated by clinical history and neurological examination. We studied 1447 patients with color now duplex scanning; 241 patients (17%) had hemispheric symptoms and 1192 (83%) were asymptomatic or with non-localizing symptoms. We found 150 patients (10.4%) With CK: 48 on the right side, 56 on the left side and 46 bilateral. The presence of CK on the side of hemispheric symptoms (5.7% on the right and 6% on the left) did not differ significantly from asymptomatic patients (6.6% on the right and 7.2% on the left). In our study, the presence of CK does not appear to be of clinical significance for the development of cerebrovascular ischaemia. Also, atherosclerosis does not seem to play a role in the pathogenesis of the kink itself. The only factors that correlated with the presence of kinking were age and hypertension. Body weight, sex and cigarette smoking had an inverse correlation; no correlation was found with the levels of serum cholesterol.


72§
Cogo, A., Lensing, A.W.A., Prandoni, P., Simioni, P., Bernardi, E., Girolami, B., Piccioli, A., Villalta, S., Ten Cate, J.W., Girolami, A.

Relevance of inherited risk factors in young patients with deep-vein thrombosis
(1996) Clinical and Applied Thrombosis/Hemostasis, 2 (1), pp. 55-59.

DOI: 10.1177/107602969600200111

Abstract
The relevance of congenital thrombophilia in the pathogenesis of venous thromboembolism in young patients is still debated. In a case-control study, plasma antigen and activity of antithrombin, protein C, and plasminogen, as well as total and free protein S were measured in a series of 166 consecutive outpatients aged less than 50 years, who underwent contrast venography because of clinically suspected deep-vein thrombosis (DVT). The presence of major acquired risk factors for venous thrombosis was also recorded. The association between DVT and inherited thrombophilia or acquired risk factors was initially described using crude odds ratios (OR). Subsequently, a logistic regression model was used to test their independence. Of the 166 patients included, venography showed an acute DVT in 73 (cases), whereas it was normal in the remaining 93 (controls). Major acquired risk factors were identified in 51 cases and in 20 controls (crude OR: 8.5; 95% CI: 4.1-17.1). Inherited thrombophilia was detected in seven cases and in one control (crude OR: 9.8; 95% CI: 1.2-81.2). Inherited thrombophilia was equally distributed between patients with secondary and idiopathic DVT and was proved to be independent from acquired risk factors in the regression model. Inherited thrombophilia is an independent risk factor for DVT in young patients. However, its prevalence in unselected cases with the first episode of DVT is low. © 1996 Lippincott-Raven Publishers.


71§
Prandoni, P., Lensing, A.W.A., Cogo, A., Cuppini, S., Villalta, S., Carta, M., Cattelan, A.M., Polistena, P., Bernardi, E., Prins, M.H.

The long-term clinical course of acute deep venous thrombosis
(1996) Annals of Internal Medicine, 125 (1), pp. 1-7.

PubMed ID: 8644983
DOI: 10.7326/0003-4819-125-1-199607010-00001

Abstract
Background: In patients who have symptomatic deep venous thrombosis, the Long-Term risk for recurrent venous thromboembolism and the incidence and severity of post-thrombotic sequelae have not been well documented. Objective: To determine the clinical course of patients during the 8 years after their first episode of symptomatic deep venous thrombosis. Design: Prospective cohort study. Setting: University outpatient thrombosis clinic. Patients: 355 consecutive patients with a first episode of symptomatic deep venous thrombosis. Measurements: Recurrent venous thromboembolism, the post-thrombotic syndrome, and death. Potential risk factors for these outcomes were also evaluated. Results: The cumulative incidence of recurrent venous thromboembolism was 17.5% after 2 years of follow-up (95% Cl, 13.6% to 22.2%), 24.6% after 5 years (Cl, 19.6% to 29.7%), and 30.3% after 8 years (Cl, 23.6% to 37.0%). The presence of cancer and of impaired coagulation inhibition increased the risk for recurrent venous thromboembolism (hazard ratios, 1.72 [Cl, 1.31 to 2.25] and 1.44 [Cl, 1.02 to 2.01], respectively). In contrast, surgery and recent trauma or fracture were associated with a decreased risk for recurrent venous thromboembolism (hazard ratios, 0.36 [Cl, 0.21 to 0.62] and 0.51 [Cl, 0.32 to 0.87], respectively). The cumulative incidence of the post-thrombotic syndrome was 22.8% after 2 years (Cl, 18.0% to 27.5%), 28.0% after 5 years (Cl, 22.7% to 33.3%), and 29.1 % after 8 years (Cl, 23.4% to 34.7%). The development of ipsilateral recurrent deep venous thrombosis was strongly associated with the risk for the post-thrombotic syndrome (hazard ratio, 6.4; Cl, 3.1 to 13.3). Survival after 8 years was 70.2% (Cl, 64.7% to 75.6%). The presence of cancer increased the risk for death (hazard ratio, 8.1; Cl, 3.6 to 18.1). Conclusion: Patients with symptomatic deep venous thrombosis, especially those without transient risk factors for deep venous thrombosis, have a high risk for recurrent venous thromboembolism that persists for many years. The post-thrombotic syndrome occurs in almost one third of these patients and is strongly related to ipsilateral recurrent deep venous thrombosis. These findings challenge the widely adopted use of short-course anticoagulation therapy in patients with symptomatic deep venous thrombosis.


70§
Marcolongo, R., Russo, R., Laveder, F., Noventa, F., Agostini, C.

Immunosuppressive therapy prevents recurrent pericarditis
(1995) Journal of the American College of Cardiology, 26 (5), pp. 1276-1279.

PubMed ID: 7594043
DOI: 10.1016/0735-1097(95)00302-9

Abstract
Objectives.: This study reviews the clinical outcome of a series of patients with recurrent pericarditis before and after immunosuppressive therapy. Background.: Despite anti-inflammatory treatment, some patients with acute pericarditis experience repeated relapses of the disease. The use of steroids for the treatment of recurrent pericarditis remains controversial. Methods.: Twelve patients (4 women, 8 men; mean [±SD] age 35.9 ± 17.2 years, range 15 to 65) with recurrent pericarditis unrelated to any systemic disease were selected. All 12 patients previously received ineffective short-term courses of low dose steroids and had a total of 39 relapses during a mean follow-up period of 14.2 months (range 4 to 50). A 3-month course of treatment with prednisone, at an immunosuppressive dosage, was started (1 to 1.5 mg/kg body weight per day for 4 weeks, then gradually withdrawn). When prednisone reduction was undertaken, all patients started a 5-month course of treatment with aspirin (1.6 g/day until steroid suspension, then reduced to 0.8 g/day). Results.: During a mean follow-up period of 41.6 months (range 7 to 104), immunosuppressive treatment with high dose prednisone resulted in stable remission in all except one patient, who experienced one relapse. In this patient, the addition of azathioprine to prednisone induced a persistent remission, which remained after 1-year follow-up. During treatment, three patients had severe steroid-related adverse effects that in two patients required replacement of prednisone with azathioprine and cyclophosphamide, respectively. This variation in the immunosuppressive regimen did not modify the favorable clinical outcome. Conclusions.: The dose and duration of steroid treatment are critical factors in preventing recurrent pericarditis. High dose prednisone with aspirin should be considered in the treatment of recurrent pericarditis resistant to anti-inflammatory therapy. Cyclophosphamide or azathioprine should be reserved for patients who do not respond to high dose prednisone or who experience severe complications related to steroid therapy. © 1995 American College of Cardiology.


69§
Parenti, A.R., Rugge, M., Frizzera, E., Ruol, A., Noventa, F., Ancona, E., Ninfo, V.

p53 Overexpression in the multistep process of esophageal carcinogenesis
(1995) American Journal of Surgical Pathology, 19 (12), pp. 1418-1422.

PubMed ID: 7503363
DOI: 10.1097/00000478-199512000-00008

Abstract
The timing of p53 mutation in the multistep process of esophageal carcinogenesis is still under debate. We tested p53 expression in 16 samples of low-grade and 29 samples of high-grade esophageal dysplasia (ED) coexisting with esophageal squamous cancer (ESC) in 31 patients who underwent total esophagectomy. In normal mucosa, a positive immunoreaction was detected in 10 of 31 cases, always restricted to the lower half of the epithelial thickness. We detected p53-positive nuclei in 11 of 16, 23 of 29, and 23 of 31 samples of low-grade ED, high-grade ED, and ESC, respectively. Cases exhibiting positive staining in dysplastic samples also demonstrated positive immunoreaction in the carcinomatous tissue. Immunoreactivity in cancer cells was never found in the absence of positive dysplastic nuclei. A significantly higher score of immunoreactive nuclei was detected in high-grade versus low- grade and in low-grade compared with normal mucosa. These data suggest that p53 mutation may represent an early event in esophageal oncogenesis.


68§
Chemello, L., Cavalletto, L., Noventa, F., Bonetti, P., Casarin, C., Bernardinello, E., Pontisso, P., Donada, C., Casarin, P., Belussi, E., Frezza, M., Alberti, A.

Predictors of sustained response, relapse and no response in patients with chronic hepatitis C treated with interferon‐α
(1995) Journal of Viral Hepatitis, 2 (2), pp. 91-96.

PubMed ID: 7493303
DOI: 10.1111/j.1365-2893.1995.tb00012.x

Abstract
Summary. Three main patterns of response are seen when interferon‐α (IFN‐α) is used for the treatment of chronic hepatitis C: 1 sustained response with alanine‐aminotransferase (ALT) normalization that is maintained after cessation of therapy, with or without clearance of serum hepatitis C virus (HCV) RNA; 2 transient response with ALT normalization during therapy followed by relapse after its withdrawal, and 3 no response with no or only partial reduction in ALT levels. In order to define variables that could predict each of these three types of response we studied 321 cases of chronic hepatitis C treated with IFN‐α in two consecutive trials conducted in our Unit. By univariate analysis, age < 45 years (P < 0.01), known disease duration < 60 months (P < 0.01), normal gamma‐glutamyltranspeptidase (γGT) levels (P < 0.01) and infection by HCV genotype 2 or HCV genotype 3 (P < 0.01) were found to be statistically associated with sustained response while age > 45 years (P < 0.01), body weight (P= 0.05), cirrhosis (P < 0.01) and elevated γGT levels (P < 0.01) were associated with no response. By multivariate analysis sustained response was predicted by HCV genotype 2 (P < 0.01) and HCV genotype 3 (P < 0.01), known disease duration (P < 0.01), patient's age (P < 0.05) and associated with the use of a more aggressive treatment schedule (P < 0.05). Transient response with relapse was predicted by known duration of disease (P < 0.05), HCV genotype 1 (P < 0.05) and female sex (P < 0.05). No response was statistically associated with elevated γGT levels (P < 0.01), higher body weight (P < 0.05) and with the less aggressive regimen of 3 MU of natural IFN‐α given three times weekly for 6 months (P < 0.05). These results indicate that the HCV genotype as well as the schedule of treatment greatly affect the pattern of response to IFN in chronic hepatitis C and allow us to define criteria to predict which type of response is more likely in individual patients. Copyright © 1995, Wiley Blackwell. All rights reserved


67§
Chemello, L., Bonetti, P., Cavalletto, L., Talato, F., Donadon, V., Casarin, P., Belussi, F., Frezza, M., Noventa, F., Pontisso, P., Benvegnu, L., Casarin, C., Alberti, A.

Randomized trial comparing three different regimens of alpha-2a-interferon in chronic hepatitis C
(1995) Hepatology, 22 (3), pp. 700-706.

PubMed ID: 7657272
DOI: 10.1016/0270-9139(95)90286-4

Abstract
Alpha-interferon (IFN-α) is an effective treatment for chronic hepatitis C, but only 20% to 30% of patients are apparently cured with the currently recommended schedule of 3 MU given three times a week for 6 months. To evaluate the efficacy of more aggressive treatment regimens, we have conducted a randomized trial in 174 patients with chronic hepatitis C using three different schedules: (1) 12-month treatment starting with 6 MU/three times a week and decreasing the dose on the basis of serum alanine transaminase (ALT) activities (group A: 59 cases); (2) fixed dose of 3 MU three times a week for 12 months (Group B: 61 cases), (3) fixed dose of 6 MU three times a week for 6 months (Group C: 54 cases). Patients were evaluated during therapy for biochemical and virological response and followed for at least 12 months after therapy to assess long-term efficacy and liver histological outcome. The genotype of infecting HCV was also analyzed in all patients, and predictors of response were determined by multivariate analysis. Serum ALT became normal during therapy in 76% of patients (95% confidence interval [CI]: 63 to 86), 65% (CI: 52 to 77), and 74% (CI: 60 to 85) in groups A, B, and C, respectively (P = NS). The corresponding figures for sustained response 12 months after therapy were 49% (CI: 36 to 62), 31% (CI: 20 to 44), and 28% (CI: 16 to 42) (A vs. B, P = .06; A vs. C, P = 0.03). Eighty-six percent of patients with sustained response cleared HCV-RNA from serum and 72% improved histologically. Patients infected with HCV genotypes 2a and 3 had higher sustained response rates than those with 1b, independent of treatment schedule. In patients infected with genotype 1b, the rate of sustained response was related to dose and duration of therapy being 28% with schedule A, 16% with schedule B, and 9% with schedule C. Multivariate analysis indicated that younger age (P = .016), shorter disease duration (P = .003), and infection with HCV genotypes 2a (P = .0017) and 3 (P = .0083) were independent predictors of sustained response. These results indicate that sustained response to IFN-α in chronic hepatitis C is affected by dose and duration of therapy, particularly in patients infected with HCV genotype 1b. © 1995.


66§
Fattovich, G., Giustina, G., Schalm, S.W., Hadziyannis, S., Sanchez-Tapias, J., Almasio, P., Christensen, E., Krogsgaard, K., Degos, F., de Moura, M.C., Solinas, A., Noventa, F., Realdi, G.

Occurrence of hepatocellular carcinoma and decompensation in Western European patients with cirrhosis type B
(1995) Hepatology, 21 (1), pp. 77-82.

PubMed ID: 7806171
DOI: 10.1016/0270-9139(95)90411-5

Abstract
To examine the morbidity of compensated cirrhosis type B, a cohort of 349 Western European, white patients (86% men; mean age, 44 years) with biopsy-proven cirrhosis was followed up for a mean period of 73 months and was studied for occurrence of hepatocellular carcinoma (HCC) and decompensation. At entry into the study all patients were tested for hepatitis B e antigen (HBeAg; 34% of patients were HBeAg-positive) and antibody to hepatitis delta virus (anti-HDV; 20% of patients were anti-HDV-positive); 48% of 252 patients tested were hepatitis B virus (HBV)-DNA-positive. During follow-up HCC developed in 32 (9%) of the 349 patients and decompensation was observed in 88 (28%) of 317 tumor-free patients. Five years after diagnosis, the probability of HCC appearance was 6% and the probability of decompensation was 23%. After the first episode of decompensation the probability of survival was 35% at 5 years. Cox's regression analysis identified three variables that independently correlated with HCC: age, serum levels of platelets, and liver firmness on physical examination. HBV (HBeAg or HBV-DNA) and HDV (anti-HDV) markers at presentation had no prognostic value for the development of HCC. In conclusion, a high proportion of patients with HBsAg-positive compensated cirrhosis do not experience worsening of their condition for several years, but once decompensation occurs life expectancy is poor. European, white patients with compensated cirrhosis type B are at consistent risk for HCC. Prognostic factors for HCC reflect an advanced stage of cirrhosis and support the hypothesis that development of a tumor could be the likely consequence of long-standing hepatic disease. © 1995.


65§
De Salvo, G.L., Noventa, F., Chemello, L., Casarin, C., Pontisso, P., Bonetti, P., Urso, M., Crisara, D., Alberti, A.

A model to predict sustained response to therapy and to optimize the dose of interferon in chronic hepatitis C
(1995) J Hepatol, 23, pp. 67-72.


64§
Benvegnù, L., Pontisso, P., Cavalletto, D., Chemello, L., Noventa, F., Borri, A., Donadon, V., Alberti, A.

Lack of correlation between hepatitis C virus (HCV) genotypes and clinical course of hepatitis C
(1995) J Hepatol, 23 (1 SUPPL.), p. 87.


63§
Mingardi, R., Avogaro, A., Noventa, F.

Alcohol intake is associated with a lower prevalence of peripheral vascular disease in non-insulin dependent diabetic women
(1995) Diabetologia, 38,


62§
Alberti, A., Chemello, L., Pontisso, P., Noventa, F., Casarin, C., Bonetti, P., Benvegnù, L., Cavalletto, L.

Predictors of response to interferon in chronic hepatitis C
(1995) Proceeding of the Second International Symposium on Lymphoblastoid Alpha-interferon, pp. 27-32.


61§
Fattowich, G., Giustina, G., Degos, F., Tremolada, F., Diodati, P., Almasio, P., Nevens, F., Solinas, A., Mura, D., Brouwer, J.T., Thomas, H.C., Niapoum, C., Bonetti, P., Casarin, C., Fuschi, P., Basho, J., Tocco, A., Bhalla, A., Galassini, R., Noventa, F., Schalm, S.W., Realdi, G.

Survival and prognostic indicators in cryptogenic compensated cirrhosis: A multicenter study.
(1995) J Hepatol, 23, p. 122.


60§
Villalta, S., Prandoni, P., Cogo, A., Bagatella, P., Piccioli, A., Bernardi, E., Simioni, P., Scarano, L., Girolami, A.

The utility of non-invasive tests for detection of previous proximal-vein thrombosis
(1995) Thrombosis and Haemostasis, 73 (4), pp. 592-596.

PubMed ID: 7495064

Abstract
Background. Despite the availability of several diagnostic methods for the detection of deep-vein thrombosis (DVT), the identification of previous episodes of DVT remains a diagnostic challenge. Study objective. To assess the reliability of a combination of a standardized clinical score with three non-invasive tests: compression ultrasonography (CUS), Doppler ultrasound (DUS), and photoplethysmography (PPG), in determining the presence or the absence of previous proximal DVT. Methods. One hundred consecutive unselected outpatients were identified, who had undergone contrast venography six to nine years previously because of the clinical suspicion of DVT (confirmed in 43). They were blindly reinvestigated by a panel of trained operators unaware of venography results. They underwent a clinical evaluation of the lower limb, by applying a standardized score to five symptoms and six signs (grading each item from 0 to 3); a PPG test to determine the venous refilling time; a DUS test to determine the venous reflux separately in the common femoral and the popliteal vein; and a CUS test to determine vein compressibility in the same regions. Results. An abnormal CUS test and/or the demonstration of venous reflux in the popliteal region and/or a high clinical score (≥ 8) identified twenty-four of the 43 (56%) DVT+ patients with a specificity of 89%. The combination of normal CUS with the absence of venous reflux in both the common femoral and popliteal vein and a low clinical score excluded previous thrombosis in 45 (79%) of the 57 DVT-patients (negative predictive value, 78%). Abnormal venous reflux in the isolated common femoral vein did not reliably predict the presence or absence of previous DVT. However, this occurred in only 13 (13%) patients. The PPG determination of venous refilling time did not improve the results obtained with the other tests. Conclusions. The combination of a standardized clinical evaluation with the results of CUS and DUS can reliably diagnose or exclude previous proximal-vein thrombosis in almost 90% of patients with previous episodes of suspected DVT.


59§
Prandoni, P., Villalta, S., Polistena, P., Bernardi, E., Cogo, A., Girolami, A.

Symptomatic deep-vein thrombosis and the post-thrombotic syndrome
(1995) Haematologica, 80 (2 SUPPL.), pp. 42-48.

PubMed ID: 7628770


58§
Diodati, G., Bonetti, P., Tagger, A., Casarin, C., Noventa, F., Ribero, M., Fasola, M., Ruol, A., Realdi, G.

Relationship between serum HCV markers and response to interferon therapy in chronic hepatitis C - Evaluation of HCV genotypes during and after long-term follow-up
(1994) Digestive Diseases and Sciences, 39 (11), pp. 2497-2502.

PubMed ID: 7525169
DOI: 10.1007/BF02087672

Abstract
Hepatitis C virus is the most frequent cause of chronic non-A, non-B hepatitis, and the antibodies to structural and nonstructural proteins encoded by viral genome have been suggested to be markers of ongoing HCV infection. We studied the behavior of these antibodies during interferon therapy in 18 patients with chronic hepatitis C and also during a follow-up period of at least four years. A significant decrease of anti-HCV titer was found only in patients who had shown positive response to therapy and all of them were anti-HCV negative at the end of follow-up. Analysis by recombinant immunoblotting assay showed that only anti-c100 were affected by interferon therapy, whereas anti-c22 and anti-c33 were not modified. Using polymerase chain reaction to detect small amounts of HCV genome in serum, we could confirm that the behavior of HCV-RNA during and after interferon therapy is similar to that of anti-HCV and the loss of anti-c100 seems to be closely related to HCV-RNA disappearance from serum. Our patients with chronic hepatitis C were found to be of type 1b and 2, according to the recent score of Simmonds, and the clearance of serum HCV-RNA during treatment and its sustained negative status are closely related to genotype 2 and to long-term positive response to interferon. © 1994 Plenum Publishing Corporation.


57§
Bortolotti, F., Bertolini, A., Barbierato, E., Noventa, F., Crivellaro, C., Carretta, M., Cadrobbi, P., Tagger, A., Ribero, M.

Acute non-A, non-B hepatitis in Italy: A 16-year prospective epidemiological study. The possible role of hepatitis C virus
(1994) Infection, 22 (5), pp. 321-325.

PubMed ID: 7843809
DOI: 10.1007/BF01715537

Abstract
During a survey of acute symptomatic viral hepatitis conducted in Padua over the last 16 years, 404 (20%) cases of non-A, non-B hepatitis were observed, including 55% with overt parenteral exposure (35% drug abusers) and 45% with unknown exposure. Between 1978 and 1982 the attack rate of the disease increased significantly (p < 0.01) in males, (from 3.8 to 17.3/105 inhabitants), in adolescents and in youths. The prevalence of drug abusers rose up to 58% in 1982 suggesting the occurrence of an outbreak in this risk group. In subsequent years the attack rate returned to initial levels in males, although drug abuse still remains the single most important route of infection, and declined in females, especially after the disappearance of post-transfusion hepatitis since 1991. Retrospective anti-HCV testing of patients seen up to 1990 and prospective investigation of patients hospitalized later have shown an antibody prevalence of 88% among parenterally transmitted cases, and of 29% in the other patients, without significant differences between the prospective and the retrospective study. These findings suggest that an outbreak of hepatitis C occurred in our area in the early eighties and that drug abuse is still the most important mode of transmission of acute hepatitis C.


56§
Cogo, A., Bernardi, E., Prandoni, P., Girolami, B., Noventa, F., Simioni, P., Girolami, A.

Acquired risk factors for deep-vein thrombosis in symptomatic outpatients
(1994) Archives of Internal Medicine, 154 (2), pp. 164-168.

PubMed ID: 8285811
DOI: 10.1001/archinte.154.2.164

Abstract
Background: Epidemiologic studies on deep-vein thrombosis (DVT) have been mainly confined to the inpatient population. The aim of this study was to investigate the association between DVT and acquired risk factors in a large cohort of outpatients with clinically suspected DVT. Methods: Consecutive outpatients with clinically suspected DVT were enrolled in the study. Before objective testing, all patients were interviewed by a trained physician for the presence of risk factors for DVT development. Subsequently, the presence or absence of DVT was assessed with venography. Results: Approximately 30% of cases of DVT were considered to be secondary to a major risk factor (immobilization, trauma, and/or recent surgery). Among additional risk factors, only increased age (over 60 years), male gender, malignant neoplasm, heart failure, systemic lupus erythematosus, and arteriopathy were independently associated with the risk of acute DVT. Conclusion: Major risk factors for venous thromboembolism are a common cause of DVT among symptomatic outpatients; therefore, the usefulness of extending DVT prophylaxis in the outpatient setting should be tested. The role of additional risk factors in the development of DVT needs to be established by properly designed studies.


55§
Benvegnù, L., Fattovich, G., Noventa, F., Tremolada, F., Chemello, L., Cecchetto, A., Alberti, A.

Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study
(1994) Cancer, 74 (9), pp. 2442-2448.

PubMed ID: 7922998
DOI: 10.1002/1097-0142(19941101)74:9<2442::AID-CNCR2820740909>3.0.CO;2-#

Abstract
Background. Patients with cirrhosis have a high risk of hepatocellular carcinoma (HCC) but it is unclear how the etiology of liver disease influences tumor development. The authors evaluated hepatitis B and C virus (HBV, HCV) infection in cirrhosis in relation to the risk of HCC. Methods. Two hundred and ninety consecutive cirrhotic patients were followed prospectively with periodic ultrasound examination. At entry, patients were tested for markers of HBV and HCV to assess relation to tumor development during follow‐up. Results. Twenty and five‐tenths percent of patients were hepatitis B surface antigen (HBsAg) positive and 68.9% were positive for HCV antibodies. Previous alcohol abuse was present in 26.2%. During follow‐up (46.3 ± 21.4 months), HCC developed in 32 patients (11.0%) (annual incidence approximately 3%) including 19.6% of HBsAg‐positive patients, 12.2% of HCV antibody positive patients and 14.4% of patients with a history of alcohol abuse. The highest rate of HCC was in patients with dual HBsAg and anti‐HCV positivity with or without previous alcohol abuse, whereas the lowest incidence (0%) was in cases without risk factors. By univariate analysis, age older than 59 years (P < 0.005), longer duration of cirrhosis (P < 0.005), serum alpha‐fetoprotein levels higher than 20 ng/ml (P < 0.05), and dual HBsAg and HCV positivity (P < 0.02) appeared to be associated with HCC. By multivariate analysis, age (P < 0.01), positivity for HBsAg and HCV antibodies (P < 0.05), male sex (P < 0.05), and previous alcohol abuse (P < 0.08) were independently related to tumor appearance. Conclusions. These results, although confirming that male sex and previous alcohol abuse are risk factors for hepatocellular carcinoma in cirrhosis, indicate that concurrent hepatitis B and C virus infection determines the highest risk of developing hepatocellular carcinoma. Copyright © 1994 American Cancer Society


54§
Guido, M., Rugge, M., Fattovich, G., Rocchetto, P., Cassaro, M., Chemello, L., Noventa, F., Giustina, G., Alberti, A.

Human immunodeficiency virus infection and hepatitis C pathology
(1994) Liver, 14 (6), pp. 314-319.

PubMed ID: 7877436
DOI: 10.1111/j.1600-0676.1994.tb00095.x

Abstract
ABSTRACT: To investigate the possible influence of human immunodeficiency virus (HIV) infection on hepatitis C virus‐related liver disease, liver morphology was evaluated in 160 HBsAg‐negative patients with chronic hepatitis C, including 68 HIV‐positive and 92 HIV‐negative cases. No differences were detected in the severity of necro‐inflammatory hepatic lesions between HIV‐negative and HIV‐positive patients when the CD4+ lymphocytes count exceeded 400 cells/mm3. In contrast, HIV‐positive patients with CD4+ lymphocytes below 400/mm3 showed a significantly lower grade of portal inflammation and piecemeal necrosis. These results suggest that liver lesions in hepatitis C may largely depend on immunomediated mechanisms. Copyright © 1994 Munksgaard


53§
Realdi, G., Fattovich, G., Hadziyannis, S., Schalm, S.W., Almasio, P., Sanchez-Tapias, J., Christensen, E., Giustina, G., Noventa, F., The Investigators of the European Concerted Action on Viral Hepatitis (EUROHEP)

Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study
(1994) Journal of Hepatology, 21 (4), pp. 656-666.

PubMed ID: 7814813
DOI: 10.1016/S0168-8278(94)80115-0

Abstract
A multicenter longitudinal study was performed to assess the survival of hepatitis B surface antigen positive compensated cirrhosis, primarily in relation to hepatitis B virus replication and hepatitis delta virus infection, and to construct a prognostic index based on entry characteristics. This cohort study involved nine university medical centers in Europe. Three hundred and sixty-six Caucasian HBsAg positive patients with cirrhosis who had never had clinical manifestations of hepatic decompensation were enrolled and followed for a mean period of 72 months (6 to 202 months). Inclusion criteria were biopsy-proven cirrhosis, information on serum hepatitis B e antigen and antibody to hepatitis D virus at the time of diagnosis and absence of complications of cirrhosis. At entry 35% of the patients were HBeAg positive, 48% of the patients tested were HBV-DNA positive and 20% anti-HDV positive. Death occurred in 84 (23%) patients, mainly due to liver failure (45 cases) or hepatocellular carcinoma (23 cases). The cumulative probability of survival was 84% and 68% at 5 and 10 years, respectively. Cox's regression analysis identified six variables that independently correlated with survival: age, albumin, platelets, splenomegaly, bilirubin and HBeAg positivity at time of diagnosis. According to the contribution of each of these factors to the final model, a prognostic index was constructed that allows calculation of the estimated survival probability. No difference in survival of hepatitis D virus infected and uninfected patients was observed. Termination of hepatitis B virus replication and/or biochemical remission during follow up correlated with a highly significant better survival. These data show that in compensated cirrhosis B, hepatitis B virus replication, age and indirect indicators of poor hepatic reserve and established portal hypertension significantly worsen the clinical course of the disease, whereas hepatitis D virus infection does not influence the prognosis. The highly significant improvement in life expectancy following cessation of hepatitis B virus replication and biochemical remission favors antiviral therapy in those patients with a guarded prognosis, as estimated by a prognostic index. © 1994 Journal of Hepatology.


52§
Diodati, G., Bonetti, P., Noventa, F., Casarin, C., Rugge, M., Scaccabarozzi, S., Tagger, A., Pollice, L., Tremolada, F., Davite, C., Realdi, G., Ruol, A.

Treatment of chronic hepatitis C with recombinant human interferon‐α2a: Results of a randomized controlled clinical trial
(1994) Hepatology, 19 (1), pp. 1-5.

PubMed ID: 7506223
DOI: 10.1002/hep.1840190102

Abstract
Sixty consecutive patients with chronic hepatitis C were included in a randomized controlled trial of recombinant human interferon‐α2a vs. no treatment. Treated patients received tapering doses of interferon thrice weekly for 1 yr. Twenty treated cases (66.7) normalized serum aminotransferase levels within the first 4 mo of treatment, but reactivation or breakthrough frequently occurred afterward (20 in both cases). Only one of the untreated patients showed spontaneous normalization of serum aminotransferase levels. Liver histology did not improve in patients without a biochemical response or with breakthrough during therapy, whereas it did not worsen in long‐term responders and reactivating patients. Lack of response does not appear to be related to serum interferon antibodies, although their early appearance is more frequent in patients who showed reactivation later on. No biochemical parameter was found to be predictive for positive response to treatment. Antibody to c100 became negative in 62.5 of long‐term responders, whereas no change was recorded in other treated patients or controls. Reactivation and breakthrough often occur during treatment, and further studies are needed to determine the most effective schedule (dose and time) of interferon treatment. Loss of c100 antibody during therapy may be a marker of long‐term maintenance of response to interferon therapy. (Hepatology 1994;19:1–5). Copyright © 1994 American Association for the Study of Liver Diseases


51§
Gatta, A., Merkel, C., Amodio, P., Bellon, S., Bellumat, A., Bolognesi, M., Borsato, L., Buttò, M., Casson, F.F., Cavallarin, G., Cielo, R., Cristina, P., Cucci, E., Donada, C., Donadon, V., Enzo, E., Marin, R., Mazzaro, C., Miori, R., Noventa, F., Torboli, P., Ruol, A.

Development and Validation of a Prognostic Index Predicting Death After Upper Gastrointestinal Bleeding in Patients with Liver Cirrhosis: A Multicenter Study
(1994) The American Journal of Gastroenterology, 89 (9), pp. 1528-1536.

PubMed ID: 8079932
DOI: 10.1111/j.1572-0241.1994.tb09173.x

Abstract
Prognostic factors of the outcome of upper gastrointestinal bleeding in patients with cirrhosis are insufficiently deflned. Pertinent clinical, biochemical, and endoscopic data of 332 upper gastrointestinal bleedings in 268 patients with cirrhosis observed in the participating centers during 31 months were recorded. Clinical data were analyzed until 40 days after bleeding. A f'urther set of 82 bleedings was used as a validation group. Ninety‐two of the 268 patients died within the time of the study, and 28 of the 82 patients of the validation group died. According to a stepwise logistic regression analysis, s‐creatinine, ascites on admission, previous diagnosis of hepatocellular carcinoma, s‐bilirubin, prothrombin index, varices as definite or probable source of bleeding, gender, and presentation with hemathemesis were the best set of covariates for predicting outcome. From them a prognostic index was developed and validated in the 82 further bleedings. Sensitivity and specificity in the cumulated training and test sets were 75 and 80%, respectively. In the present material, the prognostic index was significantly more efficient than Cbild‐Pugh score or the prognostic index proposed by Garden et al. These data show that it is possible to predict the outcome of upper gastrointestinal bleeding in cirrhosis on the basis of few easily available data. The prognostic index we proposed and validated may become useful to predict the outcome of a bleeding and to select or stratify patients in clinical trials. Copyright © 1994, Wiley Blackwell. All rights reserved


50§
Alberti, A., Chemello, L., Pontiso, P., Noventa, F., Casarin, C., Boneti, P.

Predictors of response to interferon in chronic hepatitis C
(1994) Lymphoblastoid Alpha-Interferon, pp. 27-31.


49§
Chemello, L., Alberti, A., Bonetti, P., Casarin, C., Pontisso, P., Noventa, F., Gerotto, M., Tisminesky, S., Simmonds, P., Cavalletto, L.

Multivariate analysis of response predictors to Interferon-alfa in chronic hepatitis C
(1994) VI. International Symposium on Viral Hepatitis, p. 26.


48§
Cogo, A., Prandoni, P., Villalta, S., Polistena, P., Bernardi, E., Simioni, P., Vigo, M., Benedetti, L., Girolami, A.

Changing Features of Proximal Vein Thrombosis Over Time
(1994) Angiology, 45 (5), pp. 377-382.

PubMed ID: 8172385
DOI: 10.1177/000331979404500507

Abstract
Recently, the sensitivity of impedance plethysmography (IPG) for the diagnosis of acute deep-vein thrombosis (DVT) in symptomatic outpatients has been questioned. In order to verify whether a change in the venographic pattern of DVT has occurred over years, accounting for the decreased sensitivity of IPG, the authors compared two series of consecutive venograms demonstrating proximal DVT, performed between 1984-1988 (166 patients) and 1990-1992 (140 patients). They evaluated both the extension and the occlusiveness of deep-vein thrombi in the two series. Moreover, changes in the referral characteristics of patients were investigated. In the second series of venograms a signif icant decrease in thrombi extension, expressed by a lower prevalence of iliac vein throm bosis (29% versus 43%; P = 0.0074) was observed; moreover, a significant increase in the prevalence of nonocclusive thrombi (22% versus 8%; P = 0.0004) was also recorded in the second series when compared with the first. During the study period, among the referral characteristics of patients, the authors observed both a significant decrease in the prevalence of proximal DVT (from 31% to 24%; P < 0.01) and a slight and not statistically significant decrease in the median time elapsed between onset of symptoms and referral for objective testing (from eight and a half to seven days). In conclusion, proximal deep- vein thrombi are currently less extensive and occlusive than observed in the past. These results might depend on earlier referral of less symptomatic patients and might explain the recently reported decrease in IPG sensitivity for proximal DVT. © 1994, Sage Publications. All rights reserved.


47§
Prandoni, P., Cogo, A., Bernardi, E., Villalta, S., Polistena, P., Simioni, P., Noventa, F., Benedetti, L., Girolami, A.

A simple ultrasound approach for detection of recurrent proximal-vein thrombosis
(1993) Circulation, 88 (4), pp. 1730-1735.

PubMed ID: 8403319
DOI: 10.1161/01.CIR.88.4.1730

Abstract
Background. The objective of this study was to develop a simple ultrasound method for measuring thrombus regression in patients with proximal deep-vein thrombosis (DVT) and to test its utility for the detection of DVT recurrence. Methods and Results. The study comprised a cross-sectional survey and a prospective investigation (149 and 145 patients, respectively). In both phases, the normalization rate of a previously abnormal ultrasound test, applying the criterion of full compressibility of the common femoral and popliteal veins (C-US method), was assessed. In the prospective study, the vein diameter under maximum compression (thrombus thickness) was measured in the abnormal venous segments at scheduled times (1, 3, 6, and 12 months). In patients presenting with suspected DVT recurrence, the procedure was repeated and results were compared with those available from the previous examination. Noncompressibility of a previously normal(ized) venous segment and enlargement of thrombus thickness (≥2 mm) were considered diagnostic of proximal DVT recurrence. The diagnostic accuracy of the C-US method alone, as well as of the combined ultrasound methods (C-US + thrombus thickness), was assessed against contrast phlebography. C-US test normalization occurred in only 30% of patients within 1 year. A significant reduction of the thrombus mass (P <.0001) was recorded throughout the entire study period. However, a major decrease in thrombus mass (>50%) was recorded within the first 3 months. Of 29 patients who developed a suspected recurrent DVT, phlebography confirmed diagnosis in 11. The C-US method alone showed an excellent accuracy (100%) but was applicable in only 6 patients (21%). Both the sensitivity and the specificity for proximal DVT recurrence of the combined ultrasound methods were 100% (95% confidence interval, 69% to 100% and 81% to 100%, respectively) and were applicable in all patients. Conclusions. The serial ultrasound measurement of thrombus mass after an acute episode of DVT may allow the correct identification of patients who develop a recurrent proximal-vein thrombosis.


46§
Bortolotti, F., Stivanello, A., Noventa, F., Bertolini, A., Pavanello, N.

AIDS related practices of family physicians in an urban area of Northern Italy
(1993) Proceedings of the IXth Conference on AIDS, .


45§
Benvegnù, L., Fattovich, G., Diodati, G., Noventa, F., Pontisso, P., Tremolada, F., Alberti, A.

Hepatitis C virus infection and replication in patients with hepatocellular carcinoma
(1993) Viral Hepatitis and Liver Disease, pp. 706-709.


44§
Prandoni, P., Lensing, A.W.A., Büller, H.R., Cogo, A., Prins, M.H., Cattelan, A.M., Cuppini, S., Noventa, F., Ten Cate, J.W.

Deep-Vein Thrombosis and the Incidence of Subsequent Symptomatic Cancer
(1992) New England Journal of Medicine, 327 (16), pp. 1128-1133.

PubMed ID: 1528208
DOI: 10.1056/NEJM199210153271604

Abstract
In contrast to the established relation between overt cancer and subsequent venous thromboembolism, it is unclear whether symptomatic deep-vein thrombosis is associated with a risk of subsequent overt malignant disease. Two hundred sixty consecutive patients with symptomatic, venographically proved deep-vein thrombosis were enrolled in a study, of whom 250 were followed during a two-year period. Among those assessed during follow-up, the incidence of subsequently detected cancer in the 105 patients with secondary venous thrombosis (i.e., thrombosis associated with a well-recognized risk factor other than cancer) was compared with the incidence of cancer in the 145 patients with idiopathic venous thrombosis. Routine examination at the time of diagnosis of the venous thrombosis revealed cancer in 5 of the 153 enrolled patients with idiopathic venous thrombosis (3.3 percent) and in none of the 107 enrolled patients with secondary venous thrombosis. During follow-up, overt cancer developed in 2 of the 105 patients with secondary venous thrombosis (1.9 percent) and in 11 of the 145 patients with idiopathic venous thrombosis (7.6 percent; odds ratio, 2.3; 95 percent confidence interval, 1.0 to 5.2; P = 0.043). Of the 145 patients with idiopathic venous thrombosis, 35 had confirmed recurrent thromboembolism. Overt cancer subsequently developed in 6 of the 35 (17.1 percent). The incidence of cancer in the patients with recurrent idiopathic venous thrombosis was higher than that in the patients with secondary venous thrombosis (P = 0.008; odds ratio, 9.8; 95 percent confidence interval, 1.8 to 52.2) or in the patients with idiopathic venous thrombosis that did not recur (P = 0.024; odds ratio, 4.3; 95 percent confidence interval, 1.2 to 15.3). There is a statistically significant and clinically important association between idiopathic venous thrombosis and the subsequent development of clinically overt cancer, especially among patients in whom venous thromboembolism recurs during follow-up. (N Engl J Med 1992;327:1128–33.), SINCE the initial observation by Trousseau in 1868 relating thrombotic phenomena to cancer,1 numerous studies have addressed the relation between malignant disease and venous thromboembolism. An increased incidence of venous thromboembolism in patients with known cancers has been convincingly demonstrated. Thus, cohort studies of surgical patients that used mandatory objective tests to confirm the presence of postoperative venous thrombosis showed that the incidence of venous thrombosis was markedly higher in patients with malignant disorders than in patients with other (nonmalignant) diseases.2 , 3 Furthermore, an increased risk of venous thromboembolism is suggested by the high incidence of pulmonary embolism and subclinical activation… © 1992, Massachusetts Medical Society. All rights reserved.


43§
Alberti, A., Morsica, G., Chemello, L., Cavalletto, D., Noventa, F., Pontisso, P., Ruol, A.

Hepatitis C viraemia and liver disease in symptom-free individuals with anti-HCV
(1992) The Lancet, 340 (8821), pp. 697-698.

PubMed ID: 1355801
DOI: 10.1016/0140-6736(92)92234-7

Abstract
There is controversy about clinical management of patients who persistently have antibodies to hepatitis C virus (anti-HCV) but who have no symptoms and signs of liver disease. We have taken liver biopsy samples from 23 such patients (16 of whom had normal alanine aminotransferase [ALT] values) to assess prevalence of liver disease and to see whether anti-HCV and HCV-RNA correlated with histological findings. 16 patients had histological evidence of chronic hepatitis, which was not predicted by serum ALT or by the pattern of specificity of anti-HCV. All 16 cases with hepatitis C viraemia (HCV-RNA detected by polymerase chain reaction), including 9 with normal ALT, had chronic hepatitis on biopsy (p<0·001), whereas 7 HCV-RNA-negative cases had normal liver histology. These findings indicate that serum HCV-RNA is a sensitive and specific marker of liver disease in anti-HCV-positive subjects, independent of ALT values, and challenge the idea of the existence of "true" healthy carriers of HCV. © 1992.


42§
Bortolotti, F., Stivanello, A., Noventa, F., Forza, G., Pavanello, N., Bertolini, A.

Sustained aids education campaigns and behavioural changes in Italian drug abusers
(1992) European Journal of Epidemiology, 8 (2), pp. 264-267.

PubMed ID: 1644146
DOI: 10.1007/BF00144811

Abstract
In the area of Padua, northern Italy, fear of AIDS along with AIDS educational campaigns had reduced risk behaviours for HIV among intravenous drug abusers (IVDA) as early as 1987, although at that time 38% of seropositive cases still shared needles and only 22% of subjects used condoms. The present study has been conducted in the same area and with similar criteria to evaluate the effectiveness and limits of a sustained education campaign. Drug related and sexual risk behaviours and motivations preventing behavioural changes were investigated by direct interview in 190 IVDA. Fourteen percent of the participants, including 16% of the seropositive, were still sharing needles, mainly because they did not have works available at the time they were needed. Demographic features, drug-related characteristics and anti-HIV seroprevalence did not differ significantly between needlesharers and other drug abusers. Condom use was reported by 46% of subjects, but encouragingly enough this figure included 80% of the seropositives. While knowledge of seropositivity seemed to encourage condom use, a higher selectivity about partners and a negative attitude towards condoms were the most frequent motivations preventing safer sex. These results suggest that sustained AIDS education campaigns are being successful in maintaining and reinforcing the trend to risk reduction previously observed among drug abusers in this area. Nevertheless the persistence of risk behaviours in a consistent proportion of participants emphasizes the urgency of additional prevention strategies, such as syringe exchange or supply to the limited number of sharers and counselling to encourage safer sex. © 1992 Gustav Fischer.


41§
Benvegnu, L., Cecchetto, A., Noventa, F., Tremolada, F., Ruol, A., Alberti, A.

Space‐occupying lesions of the liver detected by ultrasonography and their relation to hepatocellular carcinoma in cirrhosis
(1992) Liver, 12 (2), pp. 80-83.

PubMed ID: 1320176
DOI: 10.1111/j.1600-0676.1992.tb00561.x

Abstract
Abstract: Fifty‐four patients with cirrhosis, found to have a space‐occupying lesion in the liver by ultrasound (US), underwent US‐assisted biopsy of the lesion and were then followed prospectively to define outcome and survival. Histologic examination revealed hepatocellular carcinoma in 26 patients, while five had liver cell dysplasia without hepatocellular carcinoma and 23 had no evidence of tumor or of dysplasia. All five patients with an initial diagnosis of dysplasia developed hepatocellular carcinoma during follow‐up and their survival curve was similar to that of patients with liver cancer and significantly worse than that of patients without dysplasia or tumor. There were five false‐negative cases of hepatocellular carcinoma among the patients with negative histology. Overall, US‐assisted liver biopsy diagnosed malignancy with a sensitivity of 72%, which increased to 86% when dysplasia was considered a pre‐neoplastic lesion. © 1992 Blackwell Munksgaard

Author Keywords
hepatocellular carcinoma; liver cell dysplasia; ultrasonography


40§
Fattovich, G., Giustina, G., Brollo, L., Guido, M., Pontisso, P., Noventa, F., Alberti, A.

Therapy for chronic hepatitis B with lymphoblastoid interferon‐α and levamisole
(1992) Hepatology, 16 (5), pp. 1115-1119.

PubMed ID: 1427652
DOI: 10.1002/hep.1840160503

Abstract
About one third of patients with chronic hepatitis B show a sustained response when treated with interferon‐α. Combining interferon‐α with immunomodulators might be a way to increase response rate. The aim of this study was to compare the efficacy of lymphoblastoid interferon‐α given alone with its efficacy when combined with levamisole in chronic hepatitis B. Forty‐five patients with HBeAg‐positive chronic hepatitis were randomly selected (with stratification for ALT levels) to receive a 6‐mo course of combination therapy with lymphoblastoid interferon‐α (5 million units/m2 three times per week) and levamisole (150 mg three times per week) or lymphoblastoid interferon at the same dose regimen and a matching placebo. Final evaluation 18 mo after randomization revealed a loss of both HBeAg and hepatitis B virus DNA with ALT normalization in 38% of patients treated with interferon‐α alone and in 10% of patients receiving combination therapy. The higher response rate observed in patients treated with interferon‐α alone was maintained after stratification for basal ALT levels (i.e., higher [45% vs. 10%] or lower [31% vs. 9%] than three times the upper normal value). The length of time to sustained HBeAg clearance was significantly (p < 0.05) shorter in patients receiving monotherapy than in patients receiving combination therapy. Blinded histological assessment revealed improvement in 44% of patients treated with interferon‐α alone compared with improvement in 6% of patients receiving combination therapy. These results indicate that levamisole has no additive effects when combined with interferon‐α in the treatment of HBeAg‐positive chronic hepatitis. (HEPATOLOGY 1992;16:1115–1119.) Copyright © 1992 American Association for the Study of Liver Diseases


39§
Bizzaro, N., Tremolada, F., Casarin, C., Bonetti, P., Noventa, F., Diodati, G., Drago, C., Realdi, G.

Serum alanine aminotransferase levels among volunteer blood donors: Effect of sex, alcohol intake and obesity
(1992) Italian Journal of Gastroenterology, 24 (5), pp. 237-241.

PubMed ID: 1623221

Abstract
Serum alanine aminotransferase (ALT) activity and antibody to hepatitis B core antigen (anti-HBc) were proposed as surrogate markers of non-A, non-B (NANB) infection. In this study we analyzed 649 consecutive repeat blood donors to define the possible exclusion rate if both surrogate markers were implemented in our Blood Service, and to assess risk factors associated with elevated ALT levels. One hundred and seven blood donors (16.5%) had slightly elevated ALT levels (higher than the upper reference value, but less than twice this level), but only 15 (2.3%) had a level higher than mean log+ 2.25 SD. Seventy-seven (11.8%) resulted anti-HBc positive. Blood donors with elevated ALT levels and those who were anti-HBc positive belonged to different populations, being only 6 (0.9%) positive for both surrugate markers. Only two known donors (0.3%) resulted anti-HCV positive, and each of them was implicated in one of the four post-transfusion hepatitis (PTH) cases observed in 200 recipients of blood from these 649 donors. Both were negative for anti-HBc but one had elevated ALT levels. Male sex, age, alcohol use and obesity resulted all independently and significantly associated with elevated ALT levels. For both alcohol use and body weight we observed a significant linear relationship with serum ALT levels. These findings suggest that in our Region the exclusion of blood donors with ALT levels above the reference value, or those anti-HBc positive, would exclude an unacceptably high rate of blood donors without proven evidence of post-transfusion hepatitis prevention. The observed association between alcohol use and body weight to elevated ALT levels may be helpful in counseling blood donors.


38§
Merkel, C., Bolognesi, M., Bellon, S., Zuin, R., Noventa, F., Finucci, G., Sacerdoti, D., Angeli, P., Gatta, A.

Prognostic usefulness of hepatic vein catheterization in patients with cirrhosis and esophageal varices
(1992) Gastroenterology, 102 (3), pp. 973-979.

PubMed ID: 1537533
DOI: 10.1016/0016-5085(92)90185-2

Abstract
Clinical and anamnestic data, Pugh score, and size of esophageal varices were obtained in 129 cirrhotics. Hepatic vein catheterization was performed to measure hepatic venous pressure gradient (HVPG), indocyanine green (ICG) intrinsic hepatic clearance, and hepatic plasma flow. During a follow-up period of up to 60 months, 44 patients experienced gastrointestinal bleeding and 54 died. Applying Cox regression analysis, ICG intrinsic hepatic clearance, Pugh score, previous variceal bleeding, and HVPG were the only significant prognostic determinants of survival. In addition, Cox's regression analysis showed that HVPG, Pugh score, size of varices, and previous variceal bleeding all contained significant prognostic information regarding risk of gastrointestinal bleeding. The models were validated using a split-sample technique, and prognostic indexes for death and gastrointestinal bleeding were calculated. The prognostic index predicting death had significantly improved prognostic accuracy over a prognostic index calculated excluding the data obtained from hepatic vein catheterization (P < 0.05). In conclusion, prognostic accuracy in cirrhosis with portal hypertension is significantly improved by information obtained from hepatic vein catheterization. © 1992.


37§
Prandoni, P., Lensing, A., Buller, H., Cogo, A., Carta, M., Polistena, P., Villalta, S., Noventa, F., Ruol, A., ten Cate, J.

Symptomatic deep-vein thrombosis and the post-thrombotic syndrome
(1992) PhD thesis, University of Amsterdam, pp. 181-196.


36§
Cuppini, S; Noventa, F; Cogo, A; Canal, S; Polistena, P;

Clinical findings and the probability of proximal-vein thrombosis
(1991) THROMBOSIS AND HAEMOSTASIS, 65, (6), pp. 1176-1176.


35§
Rugge, M., Guido, M., Bortolotti, F., Cassaro, M., Cadrobbi, P., Noventa, F., Realdi, G.

Histology and virus expression in the liver: A prognostic puzzle in chronic hepatitis B
(1991) Virchows Archiv A Pathological Anatomy and Histopathology, 419 (2), pp. 93-97.

PubMed ID: 1871961
DOI: 10.1007/BF01600222

Abstract
Forty chronic untreated paediatric carriers of hepatitis B virus (HBV) infection, with no other causes of liver disease, were biopsied on presentation, when the disease was in the active viral replication phase. After a period ranging from 1 to 13 years, all patients underwent a control biopsy. At the time of the last biopsy, 31 of the patients were anti-HBe positive, whereas 9 persisted in the active replication phase. In this latter phase, necrotic and inflammatory lesions and the presence of nuclear HBcAg were found significantly more frequently than when replication had terminated. The necrotic and inflammatory lesions detected in the first biopsy of patients who subsequently underwent antiHBe seroconversion were significantly more severe than in patients failing to reach seroconversion. All patients who maintained viral replication showed generalized nuclear reactivity for HBcAg on presentation; such reactivity was also found in 16 of 31 (52%) patients who reached anti-HBeAg seroconversion. All these cases had piecemeal necrosis (PMN) in the biopsy. PMN may therefore be considered as a positive prognostic factor in that it identifies those patients who may seroconvert with significant remission of liver disease © 1991 Springer-Verlag.


34§
Fattovich, G., Brollo, L., Giustina, G., Noventa, F., Pontisso, P., Alberti, A., Realdi, G., Ruol, A.

Natural history and prognostic factors for chronic hepatitis type B
(1991) Gut, 32 (3), pp. 294-298.

PubMed ID: 2013423
DOI: 10.1136/gut.32.3.294

Abstract
One hundred and five hepatitis B surface antigen (HBsAg) positive patients presenting with chronic persistent hepatitis (n = 46) or chronic active hepatitis without cirrhosis (n = 59) were followed longitudinally for one to 16 years (mean 5.5 years) and underwent follow up biopsy. During a mean histological follow up of 3.7 years, active cirrhosis developed in 21 (20%) patients one to 13 years after entry to the study with a calculated annual incidence of 5.9%. The probability of evolution to cirrhosis was significantly higher in patients with chronic active hepatitis and bridging hepatic necrosis than in those with moderate chronic active hepatitis or chronic persistent hepatitis (p<0.0001). Cox multiple regression analysis showed that the following three variables independently implied poor prognosis: older age, presence of bridging hepatic necrosis, and persistence of hepatitis B virus DNA in serum (p<0.0001). These findings indicate that patients with severe chronic active hepatitis and persistent hepatitis B virus replication are at very high risk of rapid progression to cirrhosis.


33§
Prandoni, P; Cattelan, AM; Noventa, F; Brogini, A; Ruol, A;

Risk of subsequent malignant neoplasms in patients with deep-vein thrombosis
(1990) Fibrinolysis, 4, , pp. 54.


32§
Realdi, G; Fattovich, G; Noventa, F; Santantonio, TERESA ANTONIA; Caredda, F; Pastore, G; Moroni, M; Maladorno, D; Ruol, A;

A multicentric controlled trial of alpha-2a interferon in HBeAg/HBV-DNA positive chronic hepatitis
The 1990 International Symposium on Viral Hepatitis and Liver Disease, 127


31§
Bortolotti, F., Cadrobbi, P., Crivellaro, C., Guido, M., Rugge, M., Noventa, F., Calzia, R., Realdi, G.

Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood
(1990) Gastroenterology, 99 (3), pp. 805-810.

PubMed ID: 2379783
DOI: 10.1016/0016-5085(90)90972-4

Abstract
Seventy-six children aged 1-13 years who were known to be positive for hepatitis B surface antigen and hepatitis B e antigen in serum for at least 6 months and who had biopsy-proven chronic hepatitis have been followed longitudinally for 1-12 years (mean, 5 years). Twenty-three of them are now young adults. Eight patients had acute type B hepatitis 12-24 months before entering the study, while 68 patients came to observation during a chronic phase. At the beginning of follow-up, all 76 children were positive in serum for hepatitis B virus DNA, and 44 (58%) had chronic active hepatitis, associated with cirrhosis in two cases. During follow-up, 23 (30%) patients remained hepatitis B e antigen-positive, most with unchanged biochemical and histological features. The other 53 (70%) cases seroconverted to hepatitis B e antibody and cleared hepatitis B virus DNA from serum, including 7 of 8 (87%) patients with acute hepatitis at presentation. After seroconversion, alanine aminotransferase levels normalized in all patients and remained normal in 49 patients (92.5%) throughout a mean observation period of 3 years. Five of these children, including 2 of 7 (29%) with previous acute hepatitis, eventually cleared hepatitis B surface antigen from their sera. Finally, 4 (7.5%) patients experienced a mild increase of alanine aminotransferase levels several months after seroconversion in the absence of hepatitis B virus replication or of delta virus superinfection. Clinical and virological parameters did not significantly differ between patients with or without acute onset; however, seroconversion occurred earlier, and the rate of hepatitis B surface antigen clearance was greater in the former than in the latter group. The present data indicate that approximately two thirds of children with hepatitis B e antigen- and hepatitis B virus DNA-positive chronic hepatitis clear hepatitis B virus DNA from their sera before reaching adulthood. After termination of viral replication, most patients achieve a sustained biochemical remission, suggesting the disappearance of disease activity. Reactivation of virus replication after hepatitis B e antibody seroconversion has never been observed in this series, although mild alanine aminotransferase level abnormalities could be detected in a minority of cases. © 1990.


30§
Realdi, G., Fattovich, G., Pastore, G., Caredda, F., Noventa, F., Santantonio, T., Moroni, M., Criscuolo, D., Maladorno, D., Rugge, M., Dienes, H.P.

Problems in the management of chronic hepatitis B with interferon: experience in a randomized, multicentre study
(1990) Journal of Hepatology, 11 (SUPPL. 1), pp. S129-S132.

PubMed ID: 2079570
DOI: 10.1016/0168-8278(90)90179-U

Abstract
In a multicentre trial, 82 patients known to be hepatitis B e antigen and hepatitis B virus DNA positive for at least 1 year, with elevated serum alanine aminotransferase levels and chronic liver lesions on biopsy, were randomized to receive either recombinant interferon alfa-2a at a dose of 4.5 million units thrice weekly for 4 months or no treatment. At the end of therapy, viral DNA clearance and aminotransferase normalization were significantly (p < 0.05) more frequent in treated patients than in controls. After 16 months' follow up, the difference was still significant for hepatitis B e antigen clearance and transaminase normalization. Hepatitis B virus DNA reactivation was observed during follow up in 43% of treated patients and 50% of controls. Improvements in liver inflammation were observed in patients on interferon. High pre-treatment serum aminotransferase levels, female sex and a low score for fibrosis in the initial biopsy were predictive factors significantly (p < 0.05) associated with termination of hepatitis R virus replication in treated cases. These results indicate that interferon is effective in inducing clearance of HBV from serum and improvement of biochemical and histological parameters of liver disease. However, a more prolonged regimen of therapy may be required to obtain stable suppression of hepatitis B virus replication. © 1990.


29§
Merkel, C., Bolognesi, M., Angeli, P., Noventa, F., Caregaro, L., Sacerdoti, D., Gatta, A.

Prognostic Indicators of Survival in Patients with Cirrhosis and Esophageal Varices, without Previous Bleeding
(1989) The American Journal of Gastroenterology, 84 (7), pp. 717-722.

PubMed ID: 2787099
DOI: 10.1111/j.1572-0241.1989.tb02640.x

Abstract
Sixty‐one patients with cirrhosis with varices without previous bleeding were admitted to our Department over a period of 2 yr. Fifty had alcoholic cirrhosis. Child‐Turcotte‐Pugh class was A in 11 patients, B in 30, and C in 20. Varices were Fl in 18, and F2‐F3 in 43. During follow‐up of up to 40 months, one patient was lost to follow‐up and 22 patients died, seven of gastrointestinal bleeding and 15 of liver failure. The probability of death from any cause was significantly related to Child‐Turcotte‐Pugh class, ascites, encephalopathy, s‐albumin, s‐bilirubin, prothrombin index, and galactose elimination capacity. Independent prognostic variables according to Cox's model resulted s‐albumin, s‐bilirubin, encephalopathy, and varices. Considering only patients who died from liver failure, survival was univariately related to the same determinants, whereas the Cox's model individuated s‐bilirubin, s‐albumin, ascites, and galactose elimination capacity as independent prognostic indicators. Considering only patients who died from gastrointestinal bleeding no Cox model could be performed due to the small number of deaths. In patients with Fl varices, the probability of death from liver failure was 5 times higher than that from gastrointestinal bleeding; in patients with F2‐F3 varices, liver failure and gastrointestinal bleeding each accounted for approximately half of the deaths. These data could become useful when programming a clinical trial of prophylaxis which considers reduction in mortality as the main end‐point. Copyright © 1989, Wiley Blackwell. All rights reserved


28§
Tremolada, F., Bizzaro, N., Noventa, F., Realdi, G.

Non-A, non-B post-transfusion hepatitis. Epidemiological features and results of prospective studies including preventive measures
(1988) Annali dell'Istituto Superiore di Sanita, 24 (2), pp. 293-301.

PubMed ID: 3134838

Abstract
Despite a decade of intensive investigation, the nature of the non-A, non-B agents remains elusive. Transmission of non-A, non-B hepatitis occurs primarly by percutaneous routes, and also by apparently non percutaneous routes. In this setting the epidemiology resembles that of hepatitis B. At least two blood-borne agents seems responsible of non-A, non-B hepatitis blood-transmitted. A third type, a fecal-orally transmitted and epidemic non-A, non-B hepatitis with epidemiologic characteristics of hepatitis A, but serologically unrelated to HAV, have been described. Post-transfusion remains the most commonly recognzied form of non-A, non-B hepatitis with an incidence variable from 2 to 17% according to donor sources, number of blood units transfused and possible geographical variability of a carrier rate of chronic infection. Non-A, non-B hepatitis in recipients of clotting-factor concentrates, such as haemophiliac patients, is also well known. These blood products, even if heat treated, showed a very high hepatitis risk, with an attack rate in recipients ranging from 65 to 80%. Other groups at risk for parenterally acquired non-A, non-B hepatitis were represented by drug addicts, haemodialysis and plasmapheresis patients and organ transplant recipients. Finally sporadic non-A, non-B hepatitis occurs in absence of parenteral exposure and unassociated with a specific epidemic or outbreak. This type represents approximately 15-30% of hepatitis cases among hospitalized adult patients. In a prospective study of 709 cardiac surgery patients we observed a significant higher hepatitis incidence in 58 who received blood units and clotting-factor concentrates (56.9%) than in 651 who received only blood units (10.3%). In this latter group the incidence of hepatitis appear related to the number of blood units transfused ranging from 2% in recipients of 1-3 blood units to 18.75 in recipients 10 or more blood units. In another group of 205 patients submitted to orthopedic or gynecologic surgery and who received a mean of 3.0 + 1.6 blood units, we observed a significant lower post-transfusion hepatitis incidence (2%). In a control group of 200 cardiac patients submitted to cardiac catheterization and neither operated or transfused hepatitis incidence was very low (0.5%). In cardiac surgery patients a 75% reduction of post-transfusion hepatitis incidence was obtained after the introduction of two ancillary measures for prevention of post-transfusion hepatitis, such as the exclusion of commercial blood products and reduction of the number of omologous blood units obtained with autotransfusion techniques.


27§
Realdi, G., Fattovich, G., Noventa, F., Boscaro, S., Alberti, A.

Determinants of disease activity and evolution of chronic hepatitis type B
(1988) Annali dell'Istituto Superiore di Sanita, 24 (2), pp. 211-215.

PubMed ID: 3331067

Abstract
Hepatitis B virus (HBV) is not a cytophatic agent and liver disease is considered the consequence of the host immune response to viral antigens expressed in the liver during active viral replication. Cellular immunity appears to play a major role in the clearance of infected hepatocytes, while humoral immunity may contribute to neutralization of viral particles and virions released by the liver. An inadequate immune response to viral antigens seems to be the major component in the evolution to chronic infection and in the persistence of liver damage. During chronic infection two main distinct phases of the biology of the virus are recognized. An early phase is characterized by persistence of HBV-DNA replication with production of complete virions, while in a later phase integration of viral genome into the host genome can occur. In this latter situation active viral replication ceases and only HBsAg particles are detected in serum. Specific markers in liver and serum are available to identify these two virological phases. Evolution of chronic persistent or active hepatitis is deeply influenced by the change of the biology of the virus from episomic to integrated state, during the natural course of chronic infection. Several outcomes of liver disease can be observed in relation to the timing of this event on one side, and to the severity of liver damage on the other. After termination of viral replication and anti-HBe seroconversion, about 80% of patients underwent a permanent remission of disease activity and clearance of complete virions. A second group of patients (about 20% of prospective cases) do not benefit from anti-HBe seroconversion, as shown by persistence of viral replication, or by its reactivation, detected by HBV-DNA testing in serum or HBcAg in the liver. All these patients had persistence of inflammatory activity in the liver. The evolution of the disease in these cases is related to the duration of persistent viral replication, but often a progressive deterioration occurs. Environmental, genetic and etnic factors seem to be involved in modulating the outcome of chronic liver disease due to HBV. Identification of these factors is of primary importance in predicting the outcome of the disease as well as the response to antiviral therapy.


26§
Tremolada, F., Loreggian, M., Antona, C., Cirillo, F., Noventa, F., Realdi, G.

Blood-transmitted and clotting-factor-transmitted non-A, non-B hepatitis: Clinical differences and evolution
(1988) Journal of Clinical Gastroenterology, 10 (4), pp. 413-418.

PubMed ID: 3138304
DOI: 10.1097/00004836-198808000-00014

Abstract
In a prospective study of post-transfusion hepatitis (PTH) in open-heart surgery patients, non-A, non-B hepatitis was diagnosed by exclusion criteria in 100 patients (14.1%). The frequency of hepatitis was significantly higher (56.9%; p < 0.001) in patients receiving blood units and clotting-factor concentrates of commercial origin, which were administered for the occurrence of bleeding complications during surgery, as compared to patients treated with blood units alone (10.3%). When clinical features of hepatitis at presentation were compared in the two groups of patients, a shorter incubation period (p < 0.05) and a higher prevalence of jaundice (p < 0.01) were found in patients receiving blood and clotting-factors. Persistence of abnormal alanine aminotransferase (ALT) levels after 12 months from onset were found in more than 70% of patients in both groups. Late biochemical remission, however, was observed in 21 % of patients receiving blood units alone, but in none of those who received clotting factors. All these latter patients had histologic features of active liver disease during the chronic phase of the illness, as compared to only 46% of patients receiving blood units alone (p = 0.02). Our results show significant differences in the clinical course of non-A, non-B hepatitis transmitted by blood as compared to clotting factors, supporting the hypothesis of different etiological non-A, non-B agents. © Lippincott-Raven Publishers.

Author Keywords
Clotting-factor concentrates; Non-A, non-B hepatitis; Post-transfusion hepatitis


25§
Diodati, G., Pontisso, P., Bonetti, P., Stenico, D., Noventa, F., Alberti, A., Realdi, G.

Cryptogenic chronic liver disease and serum or liver hepatitis b virus markers: Their possible correlations and etiologic significance
(1988) Digestion, 39 (4), pp. 251-256.

PubMed ID: 3065100
DOI: 10.1159/000199633

Abstract
In an attempt to evaluate a possible correlation between cryptogenic chronic liver disease and a present or past hepatitis B virus (HBV) infection, we studied 17 patients with hepatitis B surface antigen (HBsAg)-negative, nonalcoholic chronic liver disease; 9 of them were positive for serum HBsAg detected by a solid-phase enzyme immunoassay with monoclonal antibody (M-EIA) and 8 were negative for the same marker. Liver hepatitis B core antigen (HBcAg), studied by an indirect immunofluorescence technique, was present in 55.5% of the patients positive for serum HBsAg by M-EIA. In the same group of patients, liver HBV-DNA was found in 66.6% of the patients. On the other hand, only 1 patient without serum positivity for HBsAg by M-EIA was positive for liver HBcAg and HBV-DNA. None of our patients showed serum positivity for HBV-DNA sequences. We conclude that HBV infection may be a possible cause of cryptogenic chronic liver disease; this HBV-related, HBsAg-negative chronic liver disease seems to have no viral replication or undetectable levels of HBV-DNA in serum. HBsAg, detected by a monoclonal assay, seems to be a suitable marker to identify this subgroup of patients with HBsAg-negative chronic liver disease. © 1988 S. Karger AG, Basel.

Author Keywords
Cryptogenic chronic liver disease; HBV markers; HBV-DNA; Monoclonal antibody


24§
Sorrentino, P., Baccaglini, U., Ruffatto, M.T., Noventa, F., Schoos, E., Melloni, M.C., Castoro, C., Boccanegra, T., Mazzoleni, F., Tremolada, C., Peracchia, A.

Mastectomized woman's acquired knowledge about and attitude toward breast reconstruction. A prospective study on 100 cases
(1988) Italian Journal of Surgical Sciences, 18 (1), pp. 17-23.

PubMed ID: 3372211

Abstract
A prospective study was carried out on 100 mastectomized women. Each patient was given a questionnaire concerning her awareness of the diagnosis, reaction to the operation, relationship with her own body, cosmetic solution chosen, feminine ideal, sources of information about breast reconstruction, acquired knowledge about it, attitude and motivation towards a possible plastic operation. This survey underlines that the relationship between the doctor and the neoplastic patient is hindered by the patient's lack of knowledge about her disease and about the possibility of rehabilitation by means of reconstructive surgery. 42% of the patients actually ignored the reason for their mutilation, and 53% of the women interviewed were shown not to be sufficiently informed about the possibility of plastic surgery, even though this kind of information has been recognised by many authors as fundamental for the patient's physical, psychological and esthetic welfare. 59% reported to have been informed by sources other than physicians although they are the most qualified. However 8% of all women showed a positive attitude towards the possibility of breast reconstruction: the mutilation experienced seemed to be such a strong motivation that factors such as sociocultural background and acquired knowledge about reconstruction itself were apparently unimportant.


23§
Tremolada, F; Bizzaro, N; Noventa, F; Realdi, G;

Non-A, non-B post-transfusion hepatitis. Epidemiological features and results of prospective studies including preventive measures.
(1987) Annali dell'Istituto superiore di sanità, 24, (2), pp. 293-301


22§
Fattovich, G., Boscaro, S., Noventa, F., Pornaro, E., Stenico, D., Alberti, A., Ruol, A., Realdi, G.

Influence of Hepatitis Delta Virus Infection on Progression to Cirrhosis in Chronic Hepatitis Type B
(1987) Journal of Infectious Diseases, 155 (5), pp. 931-935.

PubMed ID: 3559292
DOI: 10.1093/infdis/155.5.931

Abstract
Serological markers of hepatitis delta virus (H D V) infection were found in 18 (12%) of 146 consecutive patients with chronic hepatitis B, and the characteristics of patients who had antibody to H D V (anti- H D V-positive) were analyzed. During one to 15 years of follow-up, histological deterioration was documented in 77% of anti- H D V—positive patients; however, in hepatitis B surface antigen (H B sAg) carriers without H D V infection, histology deteriorated in 30% but improved or remained unchanged in the majority of patients (P `.01). In seven (70%) of the 10 anti- H D V—positive patients who showed transition from chronic active hepatitis to cirrhosis, this event was observed within the first two years of follow-up. The probability of evolution to cirrhosis was significantly higher in anti- H D V—positive patients than in patients without antibody to H D V (P `.001). These findings indicate that H D V infection in patients with chronic hepatitis B is associated with a more-rapid progression to cirrhosis compared with H B sAg carriers with chronic hepatitis and no evidence of H D V infection. © 1987 by The University of Chicago.


21§
Armigliato, M., Bortolotti, F., Noventa, F., Realdi, G., Bertaggia, A., Carretta, M., Meneghetti, F.

Epidemiology of hepatitis A in northern Italy: A seven-year survey
(1986) Infection, 14 (6), pp. 283-285.

PubMed ID: 3818106
DOI: 10.1007/BF01643963

Abstract
During a seven-year survey of acute symptomatic viral hepatitis in Padua (Northern Italy), the epidemiological features of hepatitis A were evaluated in 207 consecutive patients (120 males, mean age 22.7 ± 11.4 years). The annual attack rate of the disease decreased significantly (p <0.05) between 1978 and 1979 (0.11/1000 inhabitants) and 1981 and 1984 (0.04-0.03/1000 inhabitants), mainly due to its declining prevalence in the pediatric age. In parallel with the shifting of hepatitis A towards adulthood, single sources of infection, mainly associated with adult life-style such as foreign travel and raw shellfish ingestion, have become more and more prominent. The spread of drug abuse has not influenced the epidemiology of hepatitis A in our area. © 1986 MMV Medizin Verlag GmbH München.


20§
Fattovich, G., Brollo, L., Noventa, F.

The clinical course of chronic active hepatitis type B [EVOLUZIONE CLINICA DELL'EPATITE CRONICA ATTIVA HBSAG POSITIVA]
(1986) Giornale di Malattie Infettive e Parassitarie, 38 (12), pp. 1344-1346.


19§
Fattovich, G., Rugge, M., Brollo, L., Pontisso, P., Noventa, F., Guido, M., Alberti, A., Realdi, G.

Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti‐HBe in chronic hepatitis type B
(1986) Hepatology, 6 (2), pp. 167-171.

PubMed ID: 3957228
DOI: 10.1002/hep.1840060203

Abstract
Seventy consecutive HBsAg‐ and HBeAg‐positive patients with biopsy‐proven chronic hepatitis were followed prospectively with serial determinations of SGPT levels and hepatitis B virus serum markers including HBsAg, HBeAg, anti‐HBeand hepatitis B virus DNA. During a period of 1 to 11 years (mean ± S.D.: 5.0 ± 2.3 years), 28 patients remained persistently HBeAg positive, most with continuing biochemical and histologic activity, while 41 cases seroconverted to anti‐HBe. One patient became HBeAg and anti‐HBe negative. After seroconversion, 87.8% ofthe cases showed sustained normalization of SGPT, and clearance of hepatitis B virus DNA from serum and histologic improvement was documented in 79% of the cases who had a control liver biopsy, while 15.8% developed cirrhosis. In two patients (4.9%), the disease remained active despite seroconversion, and both cases had evidence of continuing hepatitis B virus replication. Finally, reactivation of liver damage and of hepatitis B virus replication was observed in three additional patients (7.3%) who had transiently normalized SGPT after seroconversion. All 70 patients were analyzed for hepatitis delta virus markers, and only two persistently HBeAg‐positive cases were found positivefor antibody to hepatitis delta virus in serum, one also having hepatitis delta antigenin the liver. These findings indicate that, in chronic hepatitis type B, termination ofvirus replication is associated in most patients with biochemical and histologic regression of inflammatory activity. After anti‐HBe seroconversion has occurred, virusreplication and liver disease may persist or reactivate in a small proportion of patients thus giving origin to the well‐recognized group of anti‐HBe positive, hepatitis B virus DNA‐positive chronic hepatitis type B. Copyright © 1986 American Association for the Study of Liver Diseases


18§
Tremolada, F., Realdi, G., Noventa, F., Antona, C., Ruol, A.

Experience with immunosuppressive treatment of chronic active hepatitis with a chronopluricorticoid [ESPERIENZA DI TERAPIA IMMUNOSOPPRESSIVA DELL'EPATITE CRONICA ATTIVA CON IMPIEGO DI CRONOPLURICORTICOIDE]
(1985) Clinica Terapeutica, 112 (2), pp. 121-130.

PubMed ID: 4017455


17§
D’Angelo, A., Noventa, F., Volpe, A.

CORAL: An A.I. Approach to the Problem-Oriented. Medical Record.
(1985) AIMIA Global Conference.


16§
Realdi, G., Tremolada, F., Chiappetta, F., Antona, C., Noventa, F., Loreggian, M., Chemello, L., Alberti, A.

Clinical aspects and risk factors in posttransfusion hepatitis [Aspetti clinici e fattori di rischio dell'epatite post-trasfusionale.]
(1984) Ricerca in Clinica e in Laboratorio, 14 Suppl 1, pp. 17-35.

PubMed ID: 6330858


15§
Fattovich, G, Alberti, A, Tremolada, F, Rigoli, AM, Bortolotti, F, Noventa, F, Rugge, M, Readi, G

Liver disease in chronic hepatitis B virus infect- tion: Relation to HBeAg and anti HBe status
(1984) Liver, 4.


14§
Pontisso, P; Alberti, A; Schiavon, E; Noventa, F; Bortolotti, F; Realdi, G;

Virus receptors for polymerized human-serum albumin (PHSA) in hepatitis-b virus (HBV) infection-detection by a solid-phase radioimmunoassay (RIA)
(1983) Italian Journal of Gastroenterology and Hepatology, 15, (1), pp. 72-73.


13§
Realdi, G., Tremolada, F., Bortolotti, F., Alberti, A., Rigoli, A.M., Noventa, F., Busachi, C.A., Rugge, M.

The natural history of post-transfusion and sporadic non-A, non-B, hepatitis in Italy.
(1983) Progress in clinical and biological research, 143, pp. 55-66.

PubMed ID: 6322202


12§
Fattovich, G., Alberti, A., Crivellaro, C., Pontisso, P., Noventa, F., Realdi, G.

Cellular immunity to the hepatitis B virion in acute hepatitis type B
(1983) Clinical and Experimental Immunology, 53 (3), pp. 645-650.

PubMed ID: 6616959

Abstract
Ten patients were studied serially during acute hepatitis type B for lymphocyte sensitization to the hepatitis B surface antigen (HBsAg) and to the complete hepatitis B virion (Dane particle). Using the lymphocyte transformation test, sensitization to purified HBsAg was not observed during the first 10 days of illness but became detectable later, being particularly evident during convalescence, while sensitization to antigens of the complete virion, other than HBsAg, was demonstrable as soon as at the onset of symptoms, often at the time of maximum liver cell damage. These results indicate that in the course of acute hepatitis type B, lymphocyte sensitization to other antigens of the complete virion precedes that to HBsAg and may be of greater pathogenetic importance.


11§
Tremolada, F., Chiappetta, F., Noventa, F., Valfrè, C., Ongaro, G., Realdi, G.

Prospective Study of Posttransfusion Hepatitis in Cardiac Surgery Patients Receiving only Blood or also Blood Products
(1983) Vox Sanguinis, 44 (1), pp. 25-30.

PubMed ID: 6299010
DOI: 10.1111/j.1423-0410.1983.tb04099.x

Abstract
Abstract. The incidence, etiology and risk factors of posttransfusion (PT) hepatitis were evaluated in a prospective study of 297 consecutive open‐heart surgery patients. PT hepatitis occurred in 63 (21.2%) patients with a significantly higher hepatitis attack rate in 51 recipients of commercial clotting factor concentrates (56.8%) compared to 246 recipients of blood units from single volunteer donors (13.8% p<0.001). Among the concentrates, Prothrombin‐complex showed the highest relative hepatitis risk (24) while in patients receiving only blood, the incidence PT hepatitis was correlated with the blood volume transfused. Of the 63 patients with PT hepatitis, 2 (3%) had hepatitis B, 8 (13%) showed evidence of cytomegalovirus infection and 53 (84%) had non‐A, non‐B hepatitis. These results show that in Italy, as elsewhere, non‐A, non‐B PT hepatitis is frequent, particularly when commercial blood products are used. © 1983 S. Karger AG, Basel


10§
Trevisan, A., Cavigli, R., Meliconi, R., Stefanini, G.F., Zotti, S., Rugge, M., Noventa, F., Betterle, C., Realdi, G.

Detection of immunoglobulins G and A on the cell membrane of hepatocytes from patients with alcoholic liver disease
(1983) Journal of Clinical Pathology, 36 (5), pp. 530-534.

DOI: 10.1136/jcp.36.5.530

Abstract
The presence of immunoglobulins (Ig) G, A, and M and of complement fractions (C3-C4) on the liver cell surface was investigated by direct immunofluorescence in 40 patients with alcoholic liver disease. IgG was detected on the liver cell membrane with a linear staining pattern in 29 patients. The percentage of IgG-positive hepatocytes correlated with transaminase activities, independently of the histological findings. IgA was demonstrable with a coarse granular staining pattern in 11 of the 14 cases with established cirrhosis. The finding of IgG bound to the hepatocyte surface in patients with alcohol-induced liver damage suggests that alcohol could be responsible for antigenic modifications of hepatocyte membrane with consequent triggering of a humoral immune response.


9§
Tremolada, F; Loreggian, M; Pornaro, E; Schivazappa, L; Noventa, F; Valfre, C; Realdi, G;

Cytomegalovirus (CMV) infection in post-transfusion hepatitis (PTH)
(1982) Gastroenterologie Clinique Et Biologique, 6, (10), 828-829.


8§
Tremolada, F., Realdi, G., Noventa, F., Alberti, A., Pornada, E., Valfre, C., Gallucci, V.

POST-TRANSFUSION HEPATITIS IN ITALY
(1982) The Lancet, 319 (8276), pp. 853-854.

PubMed ID: 6122080
DOI: 10.1016/S0140-6736(82)91900-6


7§
Fattovich, G; Alberti, A; Antona, C; Pontisso, P; Crivellaro, C; Noventa, F; Realdi, G;

Cellular-immunity to the hepatitis-b virion in acute and chronic infection
(1982) Gastroenterologie Clinique Et Biologique, 6, (10), pp. 819-820.


6§
Trevisan, A., Reali, G., Alberti, A., Noventa, F.

Changes in liver membrane antigenicity and intracellular viral antigens expression in hepatitis B virus-infected hepatocytes
(1982) La Ricerca in Clinica e in Laboratorio, 12 (2), pp. 401-408.

PubMed ID: 7051255
DOI: 10.1007/BF02909425

Abstract
In this paper we studied the presence of HBsAg and immunoglobulin G on the liver cell surface in patients with chronic HBV infection. For this purpose we developed a double immunofluorescence technique which allowed the contemporary detection of membrane antigens and the intracellular expression of HBV antigens (HBsAg and HBcAg) within the same hepatocyte. In 16 selected patients (10 with CAH and 6 with normal liver or NSRH) we found that the presence of membranous HBsAg is associated to the healthy carrier state of the infection and it correlates with the presence of abundant HBsAg in the cytoplasm of liver cells. On the contrary, membrane-bound IgG was found in patients with active virus replication and its presence correlates with nuclear HBcAg. On the basis of these results a modulatory effect of the cytophilic IgG on HBV cellular expression is proposed. © 1982 Springer-Verlag.

Author Keywords
Antigenic modulation; Chronic active hepatitis; Healthy carriers; Hepatitis B virus antigens; Hepatocyte membrane-bound IgG


5§
Realdi, G., Trevisan, A., Alberti, A., Noventa, F.

Heterogeneity of antigenic expression at the liver cell surface in hepatitis B virus infection
(1982) Liver, 2 (3), pp. 279-284.

DOI: 10.1111/j.1600-0676.1982.tb00211.x


4§
Trevisan, A., Realdi, G., Noventa, F., Zotti, S., Meliconi, R., Gludd, C., Tage-Jensen, U.

Antigenic alterations of liver cell membrane in alcoholics
(1981) The Lancet, 318 (8258), p. 1285.

PubMed ID: 6118695
DOI: 10.1016/S0140-6736(81)91519-1


3§
Tremolada, F; Realdi, G; Noventa, F; Antona, C; Schivazappa, L; Valfre, C;

Prospective-study of post-transfusion hepatitis (PTH) in patients receiving blood and blood products.
(1981) Italian Journal of Gastroenterology and Hepatology, 13, (3), pp. 217-218.


2§
Trevisan, A., Realdi, G., Alberti, A., Noventa, F.

Relationship between membrane-bound immunoglobulin and viral antigens in liver cells from patients with hepatitis B virus infection
(1979) Gastroenterology, 77 (2), pp. 209-214.

PubMed ID: 376391

Abstract
In an attempt to define further the significance of immunoglobulin G (IgG) fixed in vivo to the hepatocyte membrane in hepatitis B virus (HBV) infection, we have studied the relationship between presence of membrane-bound IgG and that of intracellular hepatitis B surface (HBsAg) and core (HBcAg) antigens in hepatocytes from 25 HBsAg chronic carriers. For this purpose, we have used a double immuno-fluorescence technique that is able to detect IgG and viral antigens within the same liver cell. In 15 patients with HBsAg-positive chronic active hepatitis, we found a statistically significant association between detection of membrane-bound IgG and that of intranuclear HBcAg within the same liver cells. On the contrary HBsAg containing hepatocytes generally did not show IgG fixed on their surface. IgG was not detected on the liver cell surface in 10 other HBsAg carriers without active disease and with large amounts of HBsAg containing hepatocytes. These results suggest that in HBsAg-positive chronic active hepatitis membrane-bound IgG is directed against viral antigens or virus-induced neoantigens that appear on the surface of infected cells at the time of active virus replication. Modulation of virus expression by this IgG could play a role in the pathogenesis of the disease. © 1979.


1§
Trevisan, A; Losi, C; Noventa, F; Diodati, G; Realdi, G;

Relationship between membrane-bound immunoglobulins and antigenic expression in hepatitis-b virus (HBV) infected hepatocytes
(1978) Italian Journal of Gastroenterology and Hepatology, 10, (3), pp. 157-159.