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Thrombin Inhibitor in Venous Thromboembolism III - THRIVE III
Description:
The goal of this trial was to evaluate the efficacy of ximelagatran compared with placebo for the extended secondary prevention of venous thromboembolism after six months of anticoagulant therapy.
Hypothesis:
Treatment with ximelagatran would be associated with a reduction in the frequency of new venous thromboembolic events compared with placebo.
Study Design
Study Design:
Patients Enrolled: 1,233
Mean Follow Up: 18 months
Mean Patient Age: mean age 57 years
Female: 47
Patient Populations:
Age ≥18 years; symptomatic, objectively confirmed deep venous thrombosis of the leg or pulmonary embolism; and treated with anticoagulant therapy for six months without subsequent recurrence
Exclusions:
Indication for continuous anticoagulant treatment; a condition associated with an increased risk of bleeding; hemoglobin concentration of <9.0 g/dl; platelet count of <90,000 per cubic millimeter; pregnancy or lactation; serious illness with expected survival <18 months; renal impairment; clinically significant liver disease; or persistent elevation of aminotransferase level to >3 times the upper limit of normal
Primary Endpoints:
Recurrence of venous thromboembolism
Secondary Endpoints:
Overall mortality, and other measures of safety, including major and minor bleeding
Drug/Procedures Used:
Patients were randomized to either ximelagatran (24 mg; n=612) or placebo (n=611) orally twice daily.
Principal Findings:
Symptomatic recurrent venous thromboembolism, the primary endpoint, occurred less frequently in the ximelagatran arm (2.8%, n=12) versus placebo (12.6%, n=71) (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.09-0.30, p<0.001). There was no difference in all-cause mortality (1.1%, n=6 in the ximelagatran arm vs. 1.4%, n=7 in the placebo arm, HR 0.83, 95% CI 0.28–2.46).
Bleeding occurred in 134 patients in the ximelagatran arm (23.9%) versus 111 patients in placebo arm (21.0%, HR 1.19, 95% CI 0.93-1.53, p=0.17). Major hemorrhage occurred in six patients in the ximelagatran arm and five in the placebo arm, none of which were fatal. Transient elevation of the alanine aminotransferase level to >3 times the upper limit of normal occurred more frequently in the ximelagatran versus placebo arm (6.4% vs. 1.2%, p<0.001).
Interpretation:
Among patients with venous thromboembolism treated with six months of anticoagulant therapy, additional treatment with the direct thrombin inhibitor ximelagatran was associated with a reduction in the primary endpoint of recurrent venous thromboembolism compared with placebo without an increase in bleeding through 18 months of follow-up.
Prior studies have shown that treatment with warfarin reduces recurrent venous thromboembolism, but has been associated with an increased risk of major hemorrhage when continued beyond six months. Despite the benefits associated with ximelagatran therapy over placebo in the present trial, elevations in aminotransferase levels were more common, although transient.
References:
Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H, for the THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-21.
Keywords: Follow-Up Studies, Benzylamines, Secondary Prevention, Azetidines, Pulmonary Embolism, Warfarin, Venous Thromboembolism, Venous Thrombosis, Confidence Intervals
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