Background:
The optimal duration of oral anticoagulant therapy in patients with deep venous thrombosis (DVT) of the lower extremities remains uncertain.
Objective:
To assess whether tailoring the duration of anticoagulation on the basis of the persistence of residual thrombi on ultrasonography reduces the rate of recurrent venous thromboembolism (VTE) compared with the administration of conventional fixed-duration treatment in adults with proximal DVT.
Design:
Parallel, randomized trial from 1999 to 2006. Trained physicians who assessed outcomes were blinded to patient assignment status, but patients and providers were not.
Setting:
9 university or hospital centers in Italy.
Patients:
538 consecutive outpatients with a first episode of acute proximal DVT at completion of an uneventful 3-month period of anticoagulation.
Intervention:
Patients were randomly assigned (stratified by center and secondary vs. unprovoked DVT by using a computer-generated list that was accessible only to a trial nurse) to fixed-duration anticoagulation (no further anticoagulation for secondary thrombosis and an extra 3 months for unprovoked thrombosis) or flexible-duration, ultrasonography-guided anticoagulation (no further anticoagulation in patients with recanalized veins and continued anticoagulation in all other patients for up to 9 months for secondary DVT and up to 21 months for unprovoked thrombosis). For the primary outcome assessment, 530 patients completed the trial.
Measurements:
The rate of confirmed recurrent VTE during 33 months of follow-up.
Results:
Overall, 46 (17.2%) of 268 patients allocated to fixed-duration anticoagulation and 32 (11.9%) of 270 patients allocated to flexible-duration anticoagulation developed recurrent VTE (adjusted hazard ratio [HR], 0.64 [95% CI, 0.39 to 0.99]). For patients with unprovoked DVT, the adjusted HR was 0.61 (CI, 0.36 to 1.02) and 0.81 (CI, 0.32 to 2.06) for those with secondary DVT. Major bleeding occurred in 2 (0.7%) patients in the fixed-duration group and 4 (1.5%) patients in the flexible-duration group (P = 0.67).
Limitations:
The trial lacked a double-blind design. The sample size was not powered to detect differences in bleeding between groups and to detect effectiveness of the intervention in the subgroups of patients with unprovoked and secondary DVT. Patients with previous thromboembolism, permanent risk factors for thrombosis, and thrombophilic abnormalities other than factor V Leiden and prothrombin mutation were excluded.
Conclusion:
Tailoring the duration of anticoagulation on the basis of ultrasonography findings reduces the rate of recurrent VTE in adults with proximal DVT.
Primary Funding Source:
None.
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Author, Article, and Disclosure Information
From University of Padua, Padua, Italy; University of Maastricht, Maastricht, and University of Amsterdam, Amsterdam, the Netherlands; and Santa Maria Nuova Hospital, Reggio Emilia, University of Insubria, Varese, Hospital of Piacenza, Piacenza, Treviso Healthcare Trust, Treviso, Civic Hospital of Venice, Venice, Civic Hospital, Castelfranco Veneto, Civic Hospital, Rovigo, Civic Hospital of Parma, Parma, and University of Perugia, Perugia, Italy.
Acknowledgment: The authors thank all of their patients, without whom this study would not have been possible.
Disclosures: None disclosed.
Reproducible Research Statement:Study protocol: Available from Dr. Prandoni (e-mail, [email protected]
Corresponding Author: Paolo Prandoni, MD, PhD, Department of Cardiothoracic and Vascular Sciences, Clinica Medica II, Thromboembolism Unit, University of Padua, Via Giustiniani 2, 35128 Padua, Italy; e-mail, [email protected]
Current Author Addresses: Dr. Prandoni: Department of Cardiothoracic and Vascular Sciences, Clinica Medica II, Thromboembolism Unit, University of Padua, Via Giustiniani 2, 35128 Padua, Italy.
Dr. Prins: Department of Clinical Epidemiology and Technology Assessment, University of Maastricht, PO Box 616, NL-6200 MD Maastricht, the Netherlands.
Dr. Lensing: Center for Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Box 22660, Amsterdam, the Netherlands.
Dr. Ghirarduzzi: Department of Internal Medicine, Angiology Unit, Arcispedale Santa Maria Nuova, Viale Risorgimento 80, I-42100 Reggio Emilia, Italy.
Dr. Ageno: Department of Clinical Medicine, University of Insubria, Viale Borri 57, 21100 Varese, Italy.
Dr. Imberti: Thrombosis and Haemostasis Center, Emergency Department, Hospital of Piacenza, Ospedale Civile, Via Taverna 49, I-29100 Piacenza, Italy.
Dr. Scannapieco: Committee for Thromboembolic Disease, Treviso Healthcare Trust, 31100 Treviso, Italy.
Dr. Ambrosio: Department of Internal Medicine, Civic Hospital of Venice, Venice, Italy.
Dr. Pesavento: Department of Angiology, Civic Hospital, Castelfranco Veneto, Italy.
Dr. Cuppini: Department of Internal Medicine, Civic Hospital, SOC of Medicine, ULSS 18-Rovigo, Viale Tre Martyrdoms 89, 45100 Rovigo, Italy.
Dr. Quintavalla: Azienda Ospedaliera-Universitaria di Parma, Via Gramsci 14, 43100 Parma, Italy.
Dr. Agnelli: Division of Internal and Cardiovascular Medicine, University of Perugia, Santa Maria della Misericordia Hospital, Via Dottori 1, 06129 Perugia, Italy.
Author Contributions: Conception and design: P. Prandoni, G. Agnelli.
Analysis and interpretation of the data: M.H. Prins, A.W.A. Lensing.
Drafting of the article: P. Prandoni, M.H. Prins, A.W.A. Lensing, G. Scannapieco, G.B. Ambrosio.
Critical revision of the article for important intellectual content: A.W.A. Lensing, A. Ghirarduzzi, W. Ageno, D. Imberti, G. Scannapieco, G.B. Ambrosio, R. Pesavento, S. Cuppini, R. Quintavalla, G. Agnelli.
Final approval of the article: P. Prandoni, M.H. Prins, A.W.A. Lensing, A. Ghirarduzzi, W. Ageno, D. Imberti, R. Pesavento, S. Cuppini, R. Quintavalla, G. Agnelli.
Provision of study materials or patients: P. Prandoni, A. Ghirarduzzi, W. Ageno, D. Imberti, G. Scannapieco, G.B. Ambrosio, R. Pesavento, S. Cuppini, R. Quintavalla.
Statistical expertise: M.H. Prins.
Administrative, technical, or logistic support: P. Prandoni.
Collection and assembly of data: P. Prandoni, A. Ghirarduzzi, W. Ageno, D. Imberti.
ClinicalTrials.gov registration number: NCT00380120.
* For additional AESOPUS investigators, see the Appendix.
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