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Abstract

The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

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Most cited references 11

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Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study.

P A Wolf (1987)

Chronic atrial fibrillation without valvular disease has been associated with increased stroke incidence. The impact of atrial fibrillation on the risk of stroke with increasing age was examined in 5184 men and women in the Framingham Heart Study. After 30 years of follow-up, chronic atrial fibrillation appeared in 303 persons. Age-specific incidence rates steadily increased from 0.2 per 1000 for ages 30 to 39 years to 39.0 per 1000 for ages 80 to 89 years. The proportion of strokes associated with this arrhythmia was 14.7%, 68 of the total 462 initial strokes, increasing steadily with age from 6.7% for ages 50 to 59 years to 36.2% for ages 80 to 89 years. In contrast to the impact of cardiac failure, coronary heart disease, and hypertension, which declined with age, atrial fibrillation was a significant contributor to stroke at all ages.

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Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939--an oral, direct Factor Xa inhibitor--after multiple dosing in healthy male subjects.

Georg Wensing, Dagmar Kubitza, M Zuehlsdorf … (2005)

There is a clinical need for safe new oral anticoagulants. The safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939--a novel, oral, direct Factor Xa (FXa) inhibitor--were investigated in this single-center, placebo-controlled, single-blind, parallel-group, multiple-dose escalation study. Healthy male subjects (aged 20-45 years, body mass index 18.6-31.4 kg/m(2)) received oral BAY 59-7939 (n=8 per dose regimen) or placebo (n=4 per dose regimen) on days 0 and 3-7. Dosing regimens were 5 mg once, twice (bid), or three times daily, and 10 mg, 20 mg, or 30 mg bid. There were no clinically relevant changes in bleeding time or other safety variables across all doses and regimens. There was no dose-related increase in the frequency or severity of adverse events with BAY 59-7939. Maximum inhibition of FXa activity occurred after approximately 3 h, and inhibition was maintained for at least 12 h for all doses. Prothrombin time, activated partial thromboplastin time, and HepTest were prolonged to a similar extent to inhibition of FXa activity for all doses. Dose-proportional pharmacokinetics (AUC(tau, norm) and C(max, norm)) were observed at steady state (day 7). Maximum plasma concentrations were achieved after 3-4 h. The terminal half-life of BAY 59-7939 was 5.7-9.2 h at steady state. There was no relevant accumulation at any dose. BAY 59-7939 was safe and well tolerated across the wide dose range studied, with predictable, dose-proportional pharmacokinetics and pharmacodynamics and no relevant accumulation beyond steady state. These results support further investigation of BAY 59-7939 in phase II clinical trials.

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Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial.

Gregory W Albers, Thomas S. Partridge, Jay Horrow … (2005)

In patients with nonvalvular atrial fibrillation, warfarin prevents ischemic stroke, but dose adjustment, coagulation monitoring, and bleeding limit its use. To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism. 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. Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily. 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. 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. 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.