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Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators - ELATE
Description:
The goal of the ELATE trial was to evaluate if, after ≥3 months of conventional-intensity warfarin therapy, low-intensity warfarin would result in less bleeding and still prevent recurrent venous thromboembolism compared with conventional intensity in patients with unprovoked venous thromboembolism.
Hypothesis:
Extended treatment with anticoagulant therapy at a lower intensity might be similarly effective, but associated with a lower risk of bleeding than conventional-intensity treatment in patients with unprovoked venous thromboembolism.
Study Design
Study Design:
Patients Screened: 1,455
Patients Enrolled: 738
Mean Follow Up: average 2.4 years
Mean Patient Age: mean age 57 years
Female: 45%
Patient Populations:
≥1 episode of unprovoked venous thromboembolism; and ≥3 months of oral anticoagulant therapy at the conventional intensity
Exclusions:
Other indications for warfarin therapy; a contraindication to long-term warfarin therapy, including a high risk of bleeding; antiphospholipid antibodies; an allergy to contrast medium; or a life expectancy of <2 years
Primary Endpoints:
Major bleeding episode, recurrent thromboembolism, death, and any bleeding episode
Drug/Procedures Used:
Patients who had completed ≥3 months of warfarin therapy for unprovoked venous thromboembolism were randomized in a double-blind manner to continue warfarin therapy with a target international normalized ratio (INR) of 2.0-3.0 (conventional-intensity, n=369) or a target INR of 1.5-1.9 (low-intensity, n=369). Randomization was stratified by clinical center and whether the patient had completed 3-4 months or >4 months of initial anticoagulant therapy.
Principal Findings:
Mean INR was 1.8 in the low-intensity therapy arm and 2.4 in the conventional-intensity therapy arm. During the mean 2.4-year follow-up, recurrent venous thromboembolism occurred in 16/369 patients in the low-intensity therapy arm (1.9 per 100 person-years) and 6/369 patients in the conventional-intensity therapy arm (0.7 per 100 person-years; hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.1-7.0, p=0.03).
Major bleeding occurred in nine patients in the low-intensity therapy arm (1.1 events per 100 person-years) and eight in the conventional-intensity therapy arm (0.9 event per 100 person-years; HR 1.2, 95% CI 0.4-3.0, p=0.76). The overall bleeding rate did not differ significantly between the two groups (4.9 vs. 3.7 events per 100 person-years; HR 1.3, 95% CI 0.8-2.1, p=0.26).
Mortality trended higher in the low-intensity arm (1.9 vs. 0.9 events per 100 person-years; HR 2.1, 95% CI 0.9-4.8, p=0.09). Recurrent venous thromboembolism occurred more frequently among patients enrolled 3-4 months after their most recent thrombosis than among those who had been treated for >4 months at the time of enrollment (HR 3.1, 95% CI 1.3-7.3).
Interpretation:
Among patients with unprovoked venous thromboembolism, treatment with conventional-intensity warfarin therapy was associated with less recurrent venous thromboembolism than low-intensity warfarin therapy, and no difference in the risk of major bleeding.
Bleeding and recurrent venous thromboembolism rates in the low-intensity warfarin arm in the present trial were similar to rates in the recent PREVENT study, which showed that extended low-intensity warfarin therapy was associated with a reduction in recurrent venous thromboembolism compared with placebo.
The authors note that recurrent thrombosis occurred more frequently in patients treated for a shorter period prior to enrollment (3-4 months) than those treated for a longer period (>4 months), suggesting that recurrences in patients receiving anticoagulant therapy tend to occur relatively early.
References:
Kearon C, Ginsberg JS, Kovacs MJ, et al., for the 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;349:631-9.
Keywords: Warfarin, Venous Thromboembolism, Peripheral Vascular Diseases
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