Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial.
BACKGROUND
In patients with nonvalvular atrial fibrillation, warfarin prevents ischemic stroke, but dose adjustment, coagulation monitoring, and bleeding limit its use.


OBJECTIVE
To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism.


METHODS
Double-blind, randomized, multicenter trial (2000-2001) conducted at 409 North American sites, involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors.


METHODS
Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily.


METHODS
The primary end point was all strokes (ischemic or hemorrhagic) and systemic embolic events. The primary analysis was based on demonstrating noninferiority within an absolute margin of 2.0% per year according to the intention-to-treat model.


RESULTS
During 6405 patient-years (mean 20 months) of follow-up, 88 patients experienced primary events. The mean (SD) INR with warfarin (2.4 [0.8]) was within target during 68% of the treatment period. The primary event rate with ximelagatran was 1.6% per year and with warfarin was 1.2% per year (absolute difference, 0.45% per year; 95% confidence interval, -0.13% to 1.03% per year; P<.001 for the predefined noninferiority hypothesis). When all-cause mortality was included in addition to stroke and systemic embolic events, the rate difference was 0.10% per year (95% confidence interval, -0.97% to 1.2% per year; P = .86). There was no difference between treatment groups in rates of major bleeding, but total bleeding (major and minor) was lower with ximelagatran (37% vs 47% per year; 95% confidence interval for the difference, -14% to -6.0% per year; P<.001). Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6.0% of patients treated with ximelagatran, usually within 6 months and typically declined whether or not treatment continued; however, one case of documented fatal liver disease and one other suggestive case occurred.


CONCLUSIONS
The results establish the efficacy of fixed-dose oral ximelagatran without coagulation monitoring compared with well-controlled warfarin for prevention of thromboembolism in patients with atrial fibrillation requiring chronic anticoagulant therapy, but the potential for hepatotoxicity requires further investigation.
Albers
Gregory W
GW
Stanford Stroke Center, Palo Alto, Calif, USA.
Diener
Hans-Christoph
HC
Frison
Lars
L
Grind
Margaretha
M
Nevinson
Mark
M
Partridge
Stephen
S
Halperin
Jonathan L
JL
Horrow
Jay
J
Olsson
S Bertil
SB
Petersen
Palle
P
Vahanian
Alec
A
D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy*; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001596:Benzylamines; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D016019:Survival Analysis; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D011355:Prodrugs; C426686:ximelagatran; D014859:Warfarin