Six months versus two years of oral anticoagulation after a first episode of unprovoked deep-vein thrombosis. The PADIS-DVT randomized clinical trial

Abstract

The optimal duration of anticoagulation after a first episode of unprovoked deep-vein thrombosis is uncertain. We aimed to assess the benefits and risks of an additional 18 months of treatment with warfarin versus placebo, after an initial 6 months of anticoagulation for a first unprovoked proximal deep-vein thrombosis. We conducted a multicenter, randomized, double-blind, controlled trial comparing an additional 18 months of warfarin with placebo in patients with a unprovoked proximal deep-vein thrombosis initially treated for 6 months (treatment period: 18 months; follow up after treatment period: 24 months). The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months. Secondary outcomes were the composite at 42 months, as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. All outcomes were centrally adjudicated. A total of 104 patients, enrolled between July 2007 and October 2013 were analyzed on an intention-to-treat basis; no patient was lost to follow-up. During the 18-month treatment period, the primary outcome occurred in none of the 50 patients in the warfarin group and in 16 out of 54 patients (cumulative risk, 29.6%) in the placebo group (hazard ratio, 0.03; 95% confidence interval: 0.01 to 0.09; P<0.001). During the entire 42-month study period, the composite outcome occurred in 14 patients (cumulative risk, 36.8%) in the warfarin group and 17 patients (cumulative risk, 31.5%) in the placebo group (hazard ratio, 0.72; 95% confidence interval: 0.35-1.46). In conclusion, after a first unprovoked proximal deep-vein thrombosis initially treated for 6 months, an additional 18 months of warfarin therapy reduced the composite of recurrent venous thrombosis and major bleeding compared to placebo. However, this benefit was not maintained after stopping anticoagulation. Clinical registration: this trial was registered at www.clinicaltrials.gov as #NCT00740493.

Figure 1.

Patients’ flow through the study.

Figure 2.

Kaplan-Meier estimates of the probability of the composite outcome of recurrent venous thromboembolism and major bleeding during the entire study period, according to study group. The unadjusted hazard ratios (95% confidence interval) warfarin/placebo were 0.03 (0.01 to 0.51) during the treatment period and 0.72 (0.35 to 1.46) during the entire study period.

Figure 3.

Meta-analysis of the PADIS-PE and PADIS-DVT studies. Pooled hazard ratios were calculated for the composite of recurrent venous thromboembolism and major bleeding and for the recurrent venous thromboembolism component. The pooled hazard ratio for the component of major bleeding is not reported as there was no major bleeding in the placebo group of the PADIS-DVT trial. HR: hazard ratio; 95% CI: 95% confidence interval; PE: pulmonary embolism; DVT: deep-vein thrombosis.