Advanced

Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation - A Randomized trial

Albers, GW; Diener, HC; Frison, L; Grind, M; Nevinson, M; Partridge, S; Halperin, JL; Horrow, J; Olsson, Bertil LU and Petersen, P, et al. (2005) In JAMA: the journal of the American Medical Association 293(6). p.690-698
Abstract
Context Inpatients 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. Design, Setting, and Participants Double-blind, randomized, multicenter trial (20002001) conducted at 409 North American sites, involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors. Interventions Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily. Main Outcome Measures The primary end point was all strokes... (More)
Context Inpatients 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. Design, Setting, and Participants Double-blind, randomized, multicenter trial (20002001) conducted at 409 North American sites, involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors. Interventions Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily. Main Outcome Measures 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 pre-defined 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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
JAMA: the journal of the American Medical Association
volume
293
issue
6
pages
690 - 698
publisher
American Medical Association
external identifiers
  • pmid:15701910
  • wos:000226842200022
  • scopus:13444309949
ISSN
1538-3598
language
English
LU publication?
yes
id
9582c911-8344-43e3-acb9-46aadb446e2e (old id 254858)
alternative location
http://jama.ama-assn.org/cgi/content/abstract/293/6/690
date added to LUP
2007-08-24 08:04:26
date last changed
2017-11-19 04:12:20
@article{9582c911-8344-43e3-acb9-46aadb446e2e,
  abstract     = {Context Inpatients 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. Design, Setting, and Participants Double-blind, randomized, multicenter trial (20002001) conducted at 409 North American sites, involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors. Interventions Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily. Main Outcome Measures 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&lt;.001 for the pre-defined 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&lt;.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.},
  author       = {Albers, GW and Diener, HC and Frison, L and Grind, M and Nevinson, M and Partridge, S and Halperin, JL and Horrow, J and Olsson, Bertil and Petersen, P and Vahanian, A},
  issn         = {1538-3598},
  language     = {eng},
  number       = {6},
  pages        = {690--698},
  publisher    = {American Medical Association},
  series       = {JAMA: the journal of the American Medical Association},
  title        = {Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation - A Randomized trial},
  volume       = {293},
  year         = {2005},
}