Extended Oral Anticoagulant Therapy after a First Episode of Pulmonary Embolism

Extended Oral Anticoagulant Therapy after a First Episode of Pulmonary Embolism

Giancarlo Agnelli, MD;
Paolo Prandoni, MD, PhD;
Cecilia Becattini, MD;
Mauro Silingardi, MD;
Maria Rita Taliani, MD;
Maddalena Miccio, MD;
Davide Imberti, MD;
Renzo Poggio, MD;
Walter Ageno, MD;
Enrico Pogliani, MD;
Fernando Porro, MD;
Pietro Zonzin, MD; and
for the Warfarin Optimal Duration Italian Trial Investigators*

From Università di Perugia, Perugia; Istituto di Clinica Medica II, Università di Padova, Padua; Arcispedale S. Maria Nuova, Reggio Emilia; Ospedale Maggiore, Trieste; Centro Trombosi, Ospedale Galliera, Genoa; Ospedale di Piacenza, Piacenza; Università di Milano-Bicocca, Ospedale San Gerardo, Monza; Università d'nsubria, Varese; Ospedale Maggiore di Milano IRCCS, Milan; and Ospedale S. Maria della Misericordia, Rovigo, Italy.

Abstract

Background: The optimal duration of oral anticoagulant treatment after a first episode of pulmonary embolism remains uncertain.

Objective: To evaluate the long-term clinical benefit of extending a 3-month course of oral anticoagulant therapy to 6 months (pulmonary embolism associated with temporary risk factors) or to 1 year (idiopathic pulmonary embolism) in patients with a first episode of pulmonary embolism.

Design: Multicenter randomized study with independent, blinded assessment of the outcome events.

Setting: 19 Italian hospitals.

Patients: 326 patients who had had 3 months of oral anticoagulant therapy without experiencing recurrence or bleeding.

Measurements: The primary study outcome was recurrence of symptomatic, objectively confirmed venous thromboembolism.

Results: Among 165 patients assigned to extended anticoagulant therapy, 15 patients (9.1%) had a recurrence of venous thromboembolism (3.1% per patient-year; average follow-up, 34.9 months), as compared with 18 of 161 patients (11.2%) assigned to discontinue treatment (4.1% per patient-year; average follow-up, 32.7 months); the rate ratio was 0.81 (95% CI, 0.42 to 1.56). All but one of the recurrences occurred after anticoagulant treatment was discontinued. Nineteen recurrences (57.6%) were episodes of pulmonary embolism, two of which were fatal. Three major bleeding episodes were observed during extended anticoagulation (1.8%). Among patients with idiopathic venous thromboembolism, 11 of 90 patients assigned to extended anticoagulation and 11 of 91 patients assigned to discontinue treatment experienced a recurrence (relative risk, 0.99 [CI, 0.45 to 2.16]).

Conclusion: Patients with pulmonary embolism have a substantial risk for recurrence after discontinuation of oral anticoagulation, regardless of treatment duration. Physicians should try to identify patients who are at high risk for recurrent venous thromboembolism and are therefore potential candidates for indefinite oral anticoagulant therapy.

*For a list of the Warfarin Optimal Duration Italian Trial Investigators, see Appendix.

Article and Author Information

Presented in part at the 21st Congress of the International Society of Thrombosis and Haemostasis, Paris, France, 10 July 2001.
Acknowledgment: The authors thank Eva Tikotin for her editorial assistance, the nursing and laboratory staff of the participating centers for their enthusiastic cooperation, and the patients included in the study for their trust and support.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Giancarlo Agnelli, MD, Sezione di Medicina Interna e Cardiovascolare, Dipartimento di Medicina Interna, Università di Perugia, Via Enrico Dal Pozzo, 06123 Perugia, Italy; e-mail, agnellig{at}unipg.it.
Current Author Addresses: Drs. Agnelli, Becattini, and Taliani: Sezione di Medicina Interna e Cardiovascolare, Dipartimento di Medicina Interna, Università di Perugia, Via Enrico Dal Pozzo, 06123 Perugia, Italy.
Dr. Prandoni: Istituto di Clinica Medica II, Università di Padova, Via Ospedale Civile 105, 35100 Padua, Italy.
Dr. Silingardi: Divisione di Medicina Interna I, Arcispedale S. Maria Nuova, Viale Umberto I 50, 42100 Reggio Emilia, Italy.
Dr. Miccio: Medicina d'Urgenza, Ospedale Maggiore, Piazza Ospedale 2, 34100 Trieste, Italy.
Dr. Imberti: III Unità Operativa di Medicina Interna, Ospedale di Piacenza, Via Taverna 49, 29100 Piacenza, Italy.
Dr. Poggio: II Divisione Medicina Generale-Centro Trombosi, Ospedale Galliera, Via Volta 4, 16128 Genoa, Italy.
Dr. Ageno: Dipartimento di Medicina Interna e Terapia Medica, Università d'nsubria, Viale Borri 57, 21100 Varese, Italy.
Dr. Pogliani: Divisione di Ematologia, Dipartimento di Medicina Interna, Università di Milano-Bicocca, Ospedale San Gerardo, Via Donizetti 106, Monza, Italy.
Dr. Porro: Medicina d'Urgenza, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100 Milan, Italy.
Dr. Zonzin: Divisione di Cardiologia, Ospedale S. Maria della Misericordia, Via tre Martiri 140, 45100 Rovigo, Italy.
Author Contributions: Conception and design: P. Prandoni, C. Becattini, M.R. Taliani.
Analysis and interpretation of the data: G. Agnelli, C. Becattini.
Drafting of the article: G. Agnelli, P. Prandoni, C. Becattini, M. Silingardi, M.R. Taliani, M. Miccio, D. Imberti, R. Poggio, W. Ageno, E. Pogliani, F. Porro, P. Zonzin.
Final approval of the article: G. Agnelli, P. Prandoni, C. Becattini, M. Silingardi, M.R. Taliani, M. Miccio, D. Imberti, R. Poggio, W. Ageno, E. Pogliani, F. Porro, P. Zonzin.
Provision of study materials or patients: P. Prandoni, M. Silingardi, M.R. Taliani, M. Miccio, D. Imberti, R. Poggio, W. Ageno, E. Pogliani, F. Porro, P. Zonzin.