Long-term, low-intensity warfarin for the prevention of recurrent venous thromboembolism: the PREVENT trial

BACKGROUND:

Standard therapy for venous thromboembolism (VTE) includes 3-12 months of fulldose warfarin using a targeted international normalized ratio [INR] between 2.0 and 3.0. However, while recurrent VTE is common following cessation of this regimen, No therapeutic agent has shown an acceptable benefit-to-risk ratio for long-term management.

METHODS:

In this double-blind trial, patients with idiopathic VTE who had received standard full-dose anticoagulation for at least 3 months were randomly assigned to placebo or to long-term, low-intensity warfarin using a targeted INR of 1.5-2.0. All participants were followed for recurrent VTE, major bleeding events, and all-cause mortality.

RESULTS:

An interim review by the Independent Data and Safety Monitoring Board led to early termination of the trial after 508 patients had been randomized and followed for up to 4.3 years (mean 2.1 years). Of 253 patients assigned to placebo, 37 had recurrent VTE (7.3 per 100 person years) as compared to 14 of 255 assigned to lowintensity warfarin (2.6 per 100 person years), a risk reduction of 64% (hazard ratio 0.36, 95%CI = 0.20-0.67, P = 0.0007). Risk reductions were similar in magnitude for all prespecified subgroups, including those with and without factor V Leiden and the G20210A prothrombin polymorphism. Major bleeding complications occurred in 2 patients allocated to placebo and 5 allocated to low-intensity warfarin (P = 0.25). Death occurred in eight patients allocated to placebo and four allocated to lowintensity warfarin (P = 0.27). Two deaths were due to pulmonary embolism and 1 to hemorrhagic stroke, all in the placebo group. Low-intensity warfarin was thus associated with a 48% reduction in the prespecified composite study endpoint of recurrent VTE, major hemorrhage, or death (hazard ratio 0.52, 95%CI = 0.31-0.87, P = 0.011). In on-treatment analyses, the reduction in risk of recurrent VTE was between 77 and 81%.

CONCLUSIONS:

Low-intensity warfarin is a highly effective and safe method to prevent recurrent deep-vein thrombosis and pulmonary embolism