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Evidence summaries

Low-Intensity Warfarin for Long-Term Prevention of Venous Thromboembolism

Long-term, low-intensity warfarin therapy appears to be far more effective than placebo but less effective than conventional warfarin therapy in preventing recurrent venous thromboembolism. Level of evidence: "B"

In a study on the effectiveness of low-intensity warfarin in preventing recurrent venous thromboembolism 1, 508 subjects were randomized to either placebo or low-intensity warfarin. The patients with idiopathic venous thromboembolism had received full-dose anticoagulation therapy for a median of 6.5 months before randomization (target INR, 1.5 to 2.0). The trial was terminated early when the 508 patients had been followed for up to 4.3 years. The incidence of recurrent venous thromboembolism was 7.2 per 100 person-years in the placebo group as compared with 2.6 per 100 person-years in the group on low-intensity warfarin, a risk reduction of 64 percent (hazard ratio 0.36; 95% CI 0.19 to 0.67; p<0.001). Risk reductions were similar for all subgroups. Low-intensity warfarin was associated with a 48 percent reduction in the composite end point of recurrent venous thromboembolism, major hemorrhage, or death. According to per-protocol and as-treated analyses, the reduction in the risk of recurrent venous thromboembolism was between 76 and 81 percent.

In another randomized, double-blind study 2 738 patients who had completed at least three months of warfarin therapy for unprovoked venous thromboembolism were randomly assigned to continue warfarin therapy with a target INR of 2.0 to 3.0 (conventional intensity) or a target INR of 1.5 to 1.9 (low intensity). Patients were followed for an average of 2.4 years. The incidence of recurrent venous thromboembolism was 1.9 per 100 person-years in the low-intensity therapy group as compared with 0.7 per 100 person-years in the conventional-intensity therapy group (hazard ratio 2.8; 95% CI 1.1 to 7.0). The incidence of major bleeding episodes was 1.1 events per 100 person-years and 0.9 event per 100 person-years, respectively (hazard ratio 1.2; 95% CI 0.4 to 3.0). There was no significant difference in the frequency of overall bleeding between the two groups (hazard ratio 1.3; 95% CI 0.8 to 2.1).

Comment: The quality of evidence is downgraded by imprecise results (limited study size for each comparison).

    References

    • Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ, PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003 Apr 10;348(15):1425-34. [PubMed]
    • Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, MacKinnon B, Weitz JI, Crowther MA, Dolan S, Turpie AG, Geerts W, Solymoss S, van Nguyen P, Demers C, Kahn SR, Kassis J, Rodger M, Hambleton J, Gent M, Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003 Aug 14;349(7):631-9. [PubMed]

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