Long-term, low-dose warfarin among venous thrombosis patients with and without factor V Leiden mutation: rationale and design for the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial

Abstract

Standard therapy for patients with deep venous thrombosis and pulmonary embolism typically includes anticoagulation for a 3-6-month period with full dose warfarin. However, patients following this regimen experience high rates of recurrent thrombosis, re-hospitalization and mortality in the years immediately following cessation of anticoagulation. This is true for patients at average risk of disease recurrence, and for patients at elevated risk due to the presence of inherited defects of anticoagulation such as factor V Leiden mutation. Unfortunately, no clinical regimen currently available has proven to have sufficient benefit to support long-term prophylaxis. In particular, full dose warfarin is associated with substantially increased risks of hemorrhage when used on a long term basis. In contrast, while targeted low-dose warfarin (INR 1.5-2.0) is safe for long-term therapy, the efficacy of this approach in the prevention of recurrent venous thromboembolic disease has remained untested. The Prevention of Recurrent Venous Thromboembolism (PREVENT) trial will evaluate the efficacy of prolonged treatment with low-dose warfarin in the secondary prevention of venous thromboembolism (VTE). Patients with a history of documented idiopathic venous thrombosis who have completed a standard course of anticoagulation therapy will be enrolled in a randomized, double-blind, placebo-controlled trial comparing usual care plus targeted low-dose warfarin to usual care plus placebo for a period of up to 4 years. Trial endpoints will include recurrent VTE, major bleeding episodes and all-cause mortality in the total patient population and separately in those patients with factor V Leiden. The potential clinical impact of the PREVENT trial is broad since a positive finding would strongly support chronic low-intensity anticoagulation among patients with venous thrombosis who are at risk for recurrence following cessation of standard outpatient anticoagulation.