Ximelagatran vs Low-Molecular-Weight Heparin and Warfarin for the Treatment of Deep Vein Thrombosis: A Randomized Trial

• Published in: JAMA : the journal of the American Medical Association 2005-02, Vol.293 (6), p.681-689
• Main Authors: Fiessinger, Jean-Noel, Huisman, Menno V, Davidson, Bruce L, Bounameaux, Henri, Francis, Charles W, Eriksson, Henry, Lundström, Torbjörn, Berkowitz, Scott D, Nyström, Per, Thorsén, Mona, Ginsberg, Jeffrey S, THRIVE Treatment Study Investigators, for the
• Format: Article
• Language: English
• Subjects: 80 and over; Adult; Aged; Aged, 80 and over; Alanine Transaminase - metabolism; Anticoagulants - administration & dosage; Anticoagulants - therapeutic use; Anticoagulants/administration & dosage/therapeutic use; Azetidines - administration & dosage; Azetidines - therapeutic use; Azetidines/administration & dosage/therapeutic use; Benzylamines; Biological and medical sciences; Blood clots; Cardiac arrhythmia; Clinical trials; Combination; Double-Blind Method; Drug Therapy; Drug Therapy, Combination; Female; General aspects; Heparin; Heparin, Low-Molecular-Weight - administration & dosage; Heparin, Low-Molecular-Weight - therapeutic use; Humans; Low-Molecular-Weight/administration & dosage/therapeutic use; Male; MEDICAL AND HEALTH SCIENCES; Medical sciences; Medical treatment; MEDICIN OCH HÄLSOVETENSKAP; Middle Aged; Prodrugs - administration & dosage; Prodrugs - therapeutic use; Prodrugs/administration & dosage/therapeutic use; Pulmonary Embolism - complications; Recurrence; Thrombolytic drugs; Treatment Outcome; Venous Thrombosis - complications; Venous Thrombosis - drug therapy; Venous Thrombosis - mortality; Venous Thrombosis/complications/drug therapy/mortality; Warfarin - administration & dosage; Warfarin - therapeutic use; Warfarin/administration & dosage/therapeutic use
• ISSN: 0098-7484; 1538-3598; 1538-3598
• DOI: 10.1001/jama.293.6.681

CONTEXT Ximelagatran, an oral direct thrombin inhibitor with a rapid onset of action and predictable antithrombotic effect, has the potential to be a simple therapeutic alternative to current standard treatment of acute venous thromboembolism. OBJECTIVE To compare the efficacy and safety of ximelagatran with standard enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism. DESIGN, SETTING, AND PATIENTS Randomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute deep vein thrombosis, of whom approximately one third had concomitant pulmonary embolism. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002. INTERVENTIONS Patients were randomized to receive 6 months of treatment with either oral ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0. MAIN OUTCOME MEASURES Recurrent venous thromboembolism, bleeding, and mortality. RESULTS Venous thromboembolism recurred in 26 of the 1240 patients assigned to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute difference between ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence interval [CI], –1.0% to 1.3%). This met the prespecified criterion for noninferiority. Corresponding values for major bleeding were 1.3% and 2.2% (difference, −1.0%; 95% CI, –2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, –1.1%; 95% CI, –2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients). CONCLUSIONS Oral ximelagatran administered in a fixed dose without coagulation monitoring, was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding. Increased levels of liver enzymes in 9.6% of ximelagatran-treated patients require regular monitoring;