Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.
The optimal duration of oral anticoagulant therapy for patients with acute proximal deep vein thrombosis (DVT) is uncertain. Based on the hypothesis that a normal impedance plethysmogram (IPG) following DVT defines a group of patients at low risk of recurrent venous thromboembolism (VTE), a trial was conducted to evaluate the efficacy of only four weeks of warfarin. Patients with venographically confirmed acute proximal DVT who had received four weeks of warfarin after initial heparin and whose four week IPG was normal were allocated to either continue warfarin (targeted International Normalized Ratio 2.0 to 3.0) for a further eight weeks or receive placebo. Patients with an abnormal four week IPG received warfarin for a further eight weeks. Based on clinical characteristics at the time of the qualifying thrombosis, all patients were classified as having either continuing or transient risk factors for recurrent VTE. During the eight weeks following randomization, nine (8.6%) of the 105 placebo patients developed recurrent VTE compared to one (0.9%) of the 109 warfarin patients, P = 0.009. Over the entire 11 months of follow-up, 12 placebo patients developed recurrence compared to seven warfarin patients, P = 0.3. Nineteen of the 192 patients with an abnormal four week IPG experienced recurrence during the nine months after discontinuing warfarin. In the 301 patients who received three months of warfarin in the randomized trial or in the cohort study, all 26 recurrent events were in the 212 patients with continuing risk factors.(ABSTRACT TRUNCATED AT 250 WORDS) The optimal duration of oral anticoagulant treatment after a first episode of pulmonary embolism remains uncertain.
                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.
                Multicenter randomized study with independent, blinded assessment of the outcome events.
                19 Italian hospitals.
                326 patients who had had 3 months of oral anticoagulant therapy without experiencing recurrence or bleeding.
                The primary study outcome was recurrence of symptomatic, objectively confirmed venous thromboembolism.
                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]).
                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. In patients with idiopathic deep venous thrombosis, continuing anticoagulant therapy beyond three months is associated with a reduced incidence of recurrent thrombosis during the period of therapy. Whether this benefit persists after anticoagulant therapy is discontinued is controversial.
                Patients with a first episode of idiopathic proximal deep venous thrombosis who had completed three months of oral anticoagulant therapy (with warfarin, in 97 percent of the cases and acenocoumarol in 3 percent) were randomly assigned to the discontinuation of oral anticoagulants or to their continuation for nine additional months. The primary study outcome was recurrence of symptomatic, objectively confirmed venous thromboembolism during at least two years of follow-up.
                The primary intention-to-treat analysis showed that of 134 patients assigned to continued oral anticoagulant therapy, 21 had a recurrence of venous thromboembolism (15.7 percent; average follow-up, 37.8 months), as compared with 21 of 133 patients assigned to the discontinuation of oral anticoagulant therapy (15.8 percent; average follow-up, 37.2 months), resulting in a relative risk of 0.99 (95 percent confidence interval, 0.57 to 1.73). During the initial nine months after randomization (after all patients received three months of therapy), 1 patient had a recurrence while receiving oral anticoagulant therapy (0.7 percent), as compared with 11 of the patients assigned to the discontinuation of oral anticoagulant therapy (8.3 percent; P=0.003). The incidence of recurrence after the discontinuation of treatment was 5.1 percent per patient-year in patients in whom oral anticoagulant therapy was discontinued after 3 months (95 percent confidence interval, 3.2 to 7.5 percent; average interval since discontinuation, 37.2 months) and 5.0 percent per patient-year in patients who received an additional 9 months of oral anticoagulant therapy (95 percent confidence interval, 3.1 to 7.8 percent; average interval since discontinuation, 29.4 months). None of the recurrences were fatal. Four patients had non-fatal major bleeding during the extended period of anticoagulant therapy (3.0 percent).
                In patients with idiopathic deep venous thrombosis, the clinical benefit associated with extending the duration of anticoagulant therapy to one year is not maintained after the therapy is discontinued. The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism remains controversial.
                We performed an open-label, randomized trial comparing a short oral anticoagulant course (3 months for proximal deep vein thrombosis [P-DVT] and/or pulmonary embolism [PE]; 6 weeks for isolated calf DVT [C-DVT]) with a long course of therapy (6 months for P-DVT/PE; 12 weeks for C-DVT). The outcome events were recurrences and major, minor, or fatal bleeding complications. A total of 736 patients were enrolled. There were 23 recurrences of venous thromboembolism in the short treatment group (6.4%) and 26 in the long treatment group (7.4%); the 2 treatment regimens had an equivalent effect. For the hemorrhage end point, the difference between the short and the long treatment groups was not significant: 15.5% versus 18.4% for all events (P=0.302), 1.7% versus 2.8% (P=0.291) for major events, and 13.9% versus 15.3% for minor bleeding. Subgroup analysis demonstrated that the rate of recurrence was lower for C-DVT than for P-DVT or PE.
                After isolated C-DVT, 6 weeks of oral anticoagulation is sufficient. For P-DVT or PE, we demonstrated an equivalence between 3 and 6 months of anticoagulant therapy. For patients with temporary risk factors who have a low risk of recurrence, 3 months of treatment seems to be sufficient. For patients with idiopathic venous thromboembolism or permanent risk factors who have a high risk of recurrence, other trials are necessary to assess prolonged therapy beyond 6 months. The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor.
                In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up.
                Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) - 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI - 3.8, 11.0). There were no major bleeds in either group.
                Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding. The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism is still a matter of debate.
                We performed a multicenter trial comparing six weeks of oral anticoagulant treatment with six months of such therapy in patients who had a first episode of venous thromboembolism. Anticoagulant therapy consisted of warfarin or dicumarol. Of the 902 patients enrolled, 5 were later excluded because they had congenital protein C deficiency; 443 were randomly assigned to receive six weeks of oral anticoagulant therapy with a targeted international normalized ratio (INR) of 2.0 to 2.85, and 454 were randomly assigned to receive six months of such therapy. The initial diagnoses were confirmed by means of venography in cases of deep-vein thromboses (n = 790) and with perfusion-ventilation scanning or angiography in cases of pulmonary embolism (n = 107); recurrences were confirmed in the same way.
                After two years of follow-up, there had been 123 recurrences of venous thromboembolism that met the diagnostic criteria, 80 in the six-week group (18.1 percent; 95 percent confidence interval, 14.5 to 21.6) and 43 in the six-month group (9.5 percent; 95 percent confidence interval, 6.8 to 12.2). The odds ratio for recurrence in the six-week group was 2.1 (95 percent confidence interval, 1.4 to 3.1). There was no difference in mortality or the rate of major hemorrhage between the six-week and six-month groups.
                Six months of prophylactic oral anticoagulation after a first episode of venous thromboembolism led to a lower recurrence rate than did treatment lasting for six weeks. The difference between the two groups occurred between 6 weeks and 6 months after the start of treatment, and the rates of recurrence remained nearly parallel for 1 1/2 years thereafter. A consensus has not been reached about the optimal duration of oral anticoagulant therapy after a second episode of venous thromboembolism.
                In a multicenter trial, we compared six months of oral anticoagulant therapy with anticoagulant therapy continued indefinitely in patients who had had a second episode of venous thromboembolism. Of 227 patients enrolled, 111 were randomly assigned to six months of anticoagulation and 116 were assigned to receive anticoagulant therapy indefinitely; for both groups, the target international normalized ratio was 2.0 to 2.85. The initial episodes of deep-vein thrombosis (n = 193) and pulmonary embolism (n = 34), as well as recurrent episodes, were all objectively confirmed.
                After four years of follow-up, there were 26 recurrences of venous thromboembolism that fulfilled the diagnostic criteria, 23 in the group assigned to six months of therapy (20.7 percent) and 3 in the group assigned to continuing therapy (2.6 percent). The relative risk of recurrence in the group assigned to six months of therapy, as compared with the group assigned to therapy of indefinite duration, was 8.0 (95 percent confidence interval, 2.5 to 25.9). There were 13 major hemorrhages, 3 in the six-month group, (2.7 percent) and 10 in the infinite-treatment group (8.6 percent). The relative risk of major hemorrhage in the six-month group, as compared with the infinite-treatment group was 0.3 (95 percent confidence interval, 0.1 to 1.1). There was no difference in mortality between the two groups.
                Prophylactic oral anticoagulation that was continued for an indefinite period after a second episode of venous thromboembolism was associated with a much lower rate of recurrence during four years of follow-up than treatment for six months. However, there was a trend toward a higher risk of major hemorrhage when anticoagulation was continued indefinitely. Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped.
                In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding.
                A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months. Of 83 patients assigned to continue to receive placebo, 17 had a recurrent episode of venous thromboembolism (27.4 percent per patient-year), as compared with 1 of 79 patients assigned to receive warfarin (1.3 percent per patient-year, P<0.001). Warfarin resulted in a 95 percent reduction in the risk of recurrent venous thromboembolism (95 percent confidence interval, 63 to 99 percent). Three patients assigned to the warfarin group had nonfatal major bleeding (two had gastrointestinal bleeding and one genitourinary bleeding), as compared with none of those assigned to the placebo group (3.8 vs. 0 percent per patient-year, P=0.09).
                Patients with a first episode of idiopathic venous thromboembolism should be treated with anticoagulant agents for longer than three months.