Extended Oral Anticoagulant Therapy after a First Episode of Pulmonary Embolism

Context Optimal duration of anticoagulation after pulmonary embolism is uncertain, but physicians commonly prescribe 3 months of therapy for patients with transient risk factors for thrombosis and 6 months for patients with continuing or no known risk factors. Contribution After 3 months of successful anticoagulation, 326 patients were randomly assigned to stop therapy immediately or extend therapy to 6 months or 1 year. Regardless of duration of anticoagulation, 33 patients had recurrent thromboembolic events but only one event occurred in a patient still receiving therapy. Implications Extending the duration of anticoagulation does not seem to protect against recurrence once therapy has been discontinued. Patients at high risk for recurrence may require indefinite anticoagulation. The Editors Recent studies have shown that patients with a first episode of venous thromboembolism are protected from a recurrence while they are receiving anticoagulant treatment (1, 2). On the basis of differences in the risk for recurrence when anticoagulant treatment is discontinued, different durations of oral anticoagulation are currently recommended in different patient categories. A shorter period of anticoagulation is recommended for patients with venous thromboembolism associated with transient risk factors than for patients with idiopathic venous thromboembolism or venous thromboembolism associated with continuing risk factors (3-5). Current recommendations on the duration of oral anticoagulant treatment for venous thromboembolism are based on studies that mostly included patients presenting with deep venous thrombosis (1, 2, 5-7). Only a limited proportion of patients included in these studies presented with pulmonary embolism. Deep venous thrombosis and pulmonary embolism are generally considered to be two clinical manifestations of the same disease. However, patients presenting with pulmonary embolism are reported to have a higher incidence of fatal recurrent venous thromboembolism than patients presenting with deep venous thrombosis (8, 9). We performed a multicenter randomized trial 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. The primary outcome of the study was symptomatic, objectively confirmed recurrence of venous thromboembolism. Methods Study Patients Consecutive patients ranging from 15 to 85 years of age with a first episode of symptomatic, objectively confirmed pulmonary embolism were included in the study if they had completed 3 uninterrupted months of oral anticoagulant therapy without having a recurrence or bleeding. The diagnosis of pulmonary embolism was confirmed by pulmonary angiography or spiral computed tomography or by a lung scan indicating a high probability of pulmonary embolism or a lung scan indicating an intermediate probability of pulmonary embolism in a patient with objectively diagnosed deep venous thrombosis. Study patients were categorized as having idiopathic pulmonary embolism or pulmonary embolism associated with transient risk factors. Idiopathic pulmonary embolism was defined as pulmonary embolism occurring in the absence of known cancer, known thrombophilia, or any transient risk factor for venous thromboembolism. Pulmonary embolism associated with transient risk factors was pulmonary embolism occurring after recent trauma with or without bone fracture, recent surgery or childbirth, or prolonged immobilization (that is, lasting >7 days), or occurring during the use of oral contraceptives or pregnancy. Patients with pulmonary embolism associated with permanent risk factors (known cancer or known thrombophilia) were excluded from the study. Systematic screening for occult cancer or thrombophilia was not performed before enrollment. Patients who required prolonged anticoagulant therapy for reasons other than venous thromboembolism were excluded from the study, as were patients with major psychiatric disorders, patients with a life expectancy shorter than 2 years, those who could not return for the follow-up visits, and those who declined to participate. The institutional review boards of the participating hospitals approved the study; all patients gave informed consent. Study Design and Interventions The Warfarin Optimal Duration Italian Trial in patients with pulmonary embolism (WODIT-PE) was a multicenter randomized, open trial with independent, blinded assessment of the outcome events. The study was designed to evaluate the clinical benefit of extending the 3-month course of oral anticoagulant therapy after a first episode of pulmonary embolism. Patients who had completed 3 months of warfarin or acenocumarol therapy were randomly assigned to discontinue anticoagulation or to continue it for 3 additional months (pulmonary embolism associated with transient risk factors) or 9 additional months (idiopathic pulmonary embolism). Randomization was performed centrally in permuted blocks of six. The dose of warfarin or acenocumarol was adjusted to achieve a target international normalized ratio (INR) between 2.0 and 3.0. The therapy was monitored in anticoagulant clinics associated with the study centers, all in Italy. Outcome Measures The primary outcome of the study was the recurrence of symptomatic, objectively confirmed venous thromboembolism after the initial 3 months of anticoagulation. The secondary outcome was the cumulative incidence of adverse outcome events (recurrence of venous thromboembolism, death, or major bleeding). The criteria for the diagnosis of recurrence of pulmonary embolism were a new filling defect revealed by pulmonary angiography or spiral computed tomography or a new high-probability perfusion defect revealed by ventilation-perfusion lung scan. Sudden, otherwise unexplained death was also considered a recurrence of pulmonary embolism. The criteria for the diagnosis of deep venous thrombosis as an outcome for recurrence of venous thromboembolism in patients without deep venous thrombosis at baseline were the presence of a noncompressible proximal vein on ultrasonography or an intraluminal filling defect on venography. In patients with deep venous thrombosis at baseline, the criteria for the diagnosis of recurrent deep venous thrombosis were abnormal results on compression ultrasonography (proximal veins) or venography in the contralateral leg or, in the ipsilateral leg, an extension of an intraluminal filling defect on venography; a newly noncompressible venous segment; or an increase of 4 mm or more in the diameter of the thrombus (proximal veins) on ultrasonography (10). Bleeding was defined as major if it was clinically overt and associated with either a decrease in the hemoglobin level of at least 20 g/L or the need to transfuse two or more units of red blood cells, if it was retroperitoneal or intracranial, if it warranted the permanent discontinuation of therapy with the study drug, or if it required rehospitalization. Deaths were classified as the result of pulmonary embolism, bleeding, or another identifiable cause or as unexplained. All suspected outcome events (recurrent thromboembolism and bleeding episodes) and all deaths were reviewed centrally by an independent, external adjudication committee whose members were unaware of the treatment group assignments. Follow-up Patients were instructed to return for follow-up visits at 3, 6, and 12 months after randomization and every 6 months thereafter until the completion of the study. Patients were asked to return to the study center immediately if symptoms suggestive of recurrent venous thromboembolism or bleeding developed. For all patients who died during the follow-up period, the date and cause of death were documented. We attempted to gain permission for autopsies of all patients in whom pulmonary embolism could not be excluded as the cause of death. Statistical Analysis The primary analysis of efficacy was a comparison of the rates of symptomatic, objectively confirmed recurrence of venous thromboembolism in the two treatment groups. The analysis was performed on an intention-to-treat basis. It was assumed that the rate of recurrence of venous thromboembolism would be 12% in patients assigned to the discontinue oral anticoagulant therapy in the 2 years after discontinuation. We also assumed that the prolongation of oral anticoagulant therapy would produce a 50% reduction in the risk for recurrence. Given these assumptions, we needed 312 patients in each group to detect a difference of this magnitude between groups with a power of 80% and a type I error rate of 5%. To avoid the exposure of the study patients to an ineffective or dangerous therapeutic regimen, one prespecified interim analysis of efficacy and safety was planned after we randomly assigned 50% of planned patients. The following criteria for stopping the trial were defined a priori: an overall rate of recurrence of thromboembolic events lower than 7.5%, an unequivocal reduction in the rate of recurrent venous thromboembolism in the patients assigned to continue therapy (P < 0.001 by a one-sided test), a risk for recurrence in the continued therapy group that was less than 25% lower than that in the group assigned to discontinue therapy, or a rate of major bleeding higher than 5% in the continued therapy group. The cumulative hazard of recurrent venous thromboembolism was calculated according to the Kaplan-Meier life-table method (11). Rates of recurrence in the two groups were compared with the use of the log-rank test (12). Results Patients Patients were recruited between January 1997 and December 2000 when, after 326 patients were included, the results of the interim analysis showed a difference of less than 25% in the risk for recurrent venous thromboembolism between the two treatment groups. At the time of