Prevention of Recurrent Venous Thromboembolism - PREVENT (Warfarin)

Description:

The goal of the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial was to evaluate treatment with long-term, low-intensity warfarin therapy for prevention of recurrent venous thromboembolism.

Hypothesis:

Long-term, low-intensity warfarin therapy (target international normalized ratio [INR], 1.5-2.0) might provide a safe and effective method of reducing the risk of recurrent venous thromboembolism among patients with a previous idiopathic venous thrombosis.

Study Design

Study Design:

Patients Screened: 578
Patients Enrolled: 508
Mean Follow Up: Up to 4.3 years (mean 2.1 years)
Mean Patient Age: Median 53 years
Female: 47%

Patient Populations:

Age ≥30 years, documented idiopathic venous thromboembolism, at least three uninterrupted months of oral anticoagulation therapy with full-dose warfarin.

Exclusions:

History of metastatic cancer, major gastrointestinal bleeding, or hemorrhagic stroke; a life expectancy of <3 years; use of dipyridamole, ticlopidine, clopidogrel, heparin, >325 mg of aspirin, or drugs that affect the prothrombin time; and patients with known lupus anticoagulant antibodies or antiphospholipid antibodies.

Primary Endpoints:

Recurrent venous thromboembolism; composite of recurrent venous thromboembolism, major hemorrhage, and death from any cause.

Secondary Endpoints:

Major hemorrhage; death from any cause.

Drug/Procedures Used:

In the PREVENT trial, eligible patients were treated for 28 days with open-label therapy to determine if their warfarin dose could be titrated to an INR of 1.5 to 2.0 without exceeding 10 mg per day, and to see if patients could maintain a compliance of 85%. Patients were randomized to placebo (n=253) or low-intensity warfarin (target INR, 1.5-2.0; n=255). The median dose of warfarin was 4 mg (IQ range, 3-6) in the warfarin arm. Patients returned for office visits every two months to determine their INR and adjust their dose.

Principal Findings:

The trial was discontinued early by the Data Safety Monitoring Board, due to a large, significant benefit with low-intensity warfarin therapy and the absence of any substantial evidence of any significant untoward side effects. The median INR was 1.0 in the placebo arm (IQ range, 1.0-1.1) versus 1.7 in the warfarin arm (IQ range, 1.4-2.0). Recurrent venous thromboembolism occurred in 37/253 placebo patients (7.2 per 100 person-years) versus 14/255 warfarin patients (2.6 per 100 person-years, hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.19-0.67, p<0.001). Benefit in the warfarin arm occurred early and was maintained throughout the follow-up. Similar benefit occurred in all of the prespecified subgroups, including those with and without inherited thrombophilia (HR 0.25 and HR 0.42, respectively). The composite end point of recurrent venous thromboembolism, major hemorrhage, or death was lower in the low-intensity warfarin arm versus placebo (HR=0.52, p=0.01). Major hemorrhage occurred in two patients in the placebo arm versus five in the low-intensity warfarin arm (p=0.25). There was no difference in mortality between the two arms (eight in the placebo arm vs. four in the low-intensity warfarin arm, p=0.26).

Interpretation:

Among patients with idiopathic venous thromboembolism who had received full-dose anticoagulation therapy for six months, treatment with low-intensity warfarin (target INR, 1.5-2.0) was associated with a reduction in recurrent venous thromboembolism and in the composite of recurrent venous thromboembolism, major hemorrhage, or death during follow-up. Additionally, no significant excess major bleeding occurred in the warfarin arm. Recurrent venous thromboembolism is a serious problem following discontinuation of anticoagulation therapy, and no prophylactic treatment without serious side effects is currently available. Prior observational studies had shown that while effective in reducing recurrent venous thromboembolism, long-term, full-dose warfarin therapy was associated with an increased risk of major bleeding. The present trial is the first randomized trial to examine the use of low-intensity warfarin therapy, rather than full-dose therapy in this population.

References:

Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-34.

Clinical Topics: Anticoagulation Management, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism

Keywords: International Normalized Ratio, Thromboembolism, Follow-Up Studies, Thrombophilia, Warfarin, Venous Thromboembolism, Venous Thrombosis, Confidence Intervals, Office Visits


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