Thrombin Inhibitor in Venous Thromboembolism - THRIVE
The goal of this trial was to evaluate the efficacy of ximelagatran compared with enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism after six months of anticoagulant therapy among patients with acute deep vein thrombosis.
Treatment with ximelagatran will be associated with a reduction in the frequency of recurrent venous thromboembolic events compared with enoxaparin/warfarin treatment among patients with acute deep vein thrombosis.
Patients Enrolled: 2,489
Mean Follow Up: 26 weeks
Mean Patient Age: Mean age 57 years
Acute, objectively confirmed deep vein thrombosis, with or without pulmonary embolism, for whom anticoagulant therapy was planned for at least six months; and age ≥18 years
Symptoms of deep vein thrombosis for >2 weeks; contraindications to anticoagulants; weight >140 kg; clinically significant bleeding disorder; stroke within the previous 30 days; hemodynamically unstable pulmonary embolism; platelet count <90 x 103/mcl; creatinine clearance <30 ml/min; clinically significant liver disease or levels of aminotransferases persistently increased to >twice the upper limit of normal; thoracic or central nervous system surgery within the previous two weeks or planned major surgery during the study; expected survival of <6 months; or treatment with thrombolytic agents within 14 days before randomization
Recurrent venous thromboembolism, assessed for noninferiority
Bleeding, composite of recurrent venous thromboembolism or major bleeding, and all-cause mortality
Patients were randomized to treatment with either ximelagatran (36 mg twice daily for six months; n=1,240) or enoxaparin (1 mg/kg twice daily for 5-20 days) followed by warfarin adjusted to maintain an international normalized ratio [INR] of 2.0-3.0 (n=1,249).
Baseline characteristics were similar between the two treatment groups. Treatment was completed through 24 weeks in 76% of the ximelagatran group and 82% of the enoxaparin/warfarin group. Target INR was met in 75% of the ximelagatran group (sham INR) and in 61% of the enoxaparin/warfarin group.
Recurrent venous thromboembolism, the primary endpoint, occurred in 2.1% of the ximelagatran arm (n=26) versus 2.0% of the enoxaparin/warfarin arm (n=24), for a difference of 0.2% (95% confidence interval -1.0 to 1.3), meeting the prespecified criteria for noninferiority. In the on-treatment analysis, recurrent venous thromboembolism occurred in 2.0% of the ximelagatran group and 1.5% of the enoxaparin/warfarin group. Major bleeding occurred in 1.3% of the ximelagatran group and 2.2% of the enoxaparin/warfarin group (p=0.07), while major or minor bleeding occurred in 6.1% and 7.6%, respectively (p=0.18; both on-treatment analyses).
All-cause mortality was reported in 2.3% of the ximelagatran group and 3.4% of the enoxaparin/warfarin group (p=0.09). Elevation of alanine aminotransferase levels to >3 times the upper limit of normal occurred more frequently in the ximelagatran group (9.6% and 2.0%). Serious coronary events as reported by the local investigator occurred more frequently in the ximelagatran group (n=10 vs. n=1, p=0.006).
Among patients with acute deep vein thrombosis, treatment with the novel, oral direct thrombin inhibitor ximelagatran was noninferior compared with initial treatment with enoxaparin followed by warfarin for the primary endpoint of recurrent venous thromboembolism. Unlike warfarin, ximelagatran does not require coagulation monitoring, and is delivered in a fixed oral dose. The elevations in liver enzymes would require monitoring in patients treated with ximelagatran.
The increase in investigator reported serious coronary events warrants close further evaluation. Ximelagatran is not commercially available.
Fiessinger JN, Huisman MV, Davidson BL, et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 2005;293:681-9.
Keywords: Pulmonary Embolism, Warfarin, Venous Thromboembolism, International Normalized Ratio, Azetidines, Benzylamines, Enoxaparin, Research Personnel, Liver, Venous Thrombosis, Confidence Intervals
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