While warfarin has served as the oral anticoagulant of choice for decades, its time in widespread clinical use may finally be drawing to a close.  A variety of new agents are in late stage development which hold several advantages: fewer interactions with other drugs, no need for therapeutic drug monitoring, and simpler dosing regimes.

The latest of these warfarin competitors to complete Phase III trials is the factor Xa inhibitor rivaroxaban. In the double-blind, double-dummy ROCKET AF trial, the investigators randomly assigned 14,264 patients with nonvalvular atrial fibrillation – who were at moderate to high risk of stroke – to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin.  Blinding was maintained through encrypted INR monitoring for all participants that allowed for sham adjustment of placebo for those in the rivaroxaban arm.  The primary clinical end-point was stroke or systemic embolism and the principal safety endpoint was a composite of major and non-major clinically relevant bleeding.  The study was powered to demonstrate non-inferiority of rivaroxaban and the median follow-up was 2 years. 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) (HR, 0.79; 95% CI, 0.66 to 0.96; P<0.001 for non-inferiority). In the safety analysis bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (HR, 1.03; 95% CI, 0.96 to 1.11; P=0.44). However, the important end-points of intracranial haemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) demonstrated significant reductions in favour of rivaroxaban therapy.

Conclusions

In patients with atrial fibrillation, the oral factor Xa inhibitor rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism. Rivaroxaban also demonstrated significant reductions in the important safety end-points of intracranial and fatal bleeding.

• Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.  N Engl J Med. 2011 Sep 8;365(10):883-91.