Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial.
BACKGROUND
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.


METHODS
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.


METHODS
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.


METHODS
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; the mechanism requires further evaluation. Prospective assessment of coronary events in future studies is warranted.
Fiessinger
Jean-Noel
JN
Department of Vascular Medicine, Hôpital Européen Georges Pompidou, Paris, France.
Huisman
Menno V
MV
Davidson
Bruce L
BL
Bounameaux
Henri
H
Francis
Charles W
CW
Eriksson
Henry
H
Lundström
Torbjörn
T
Berkowitz
Scott D
SD
Nyström
Per
P
Thorsén
Mona
M
Ginsberg
Jeffrey S
JS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000378:metabolism; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use*; D001384:Azetidines / Q000008:administration & dosage / Q000627:therapeutic use*; D001596:Benzylamines; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage / Q000627:therapeutic use*; D011655:Pulmonary Embolism / Q000150:complications; D012008:Recurrence; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D014859:Warfarin / Q000008:administration & dosage / Q000627:therapeutic use*
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D006495:Heparin, Low-Molecular-Weight; D011355:Prodrugs; C426686:ximelagatran; D014859:Warfarin; D000410:Alanine Transaminase