DURHAM, NORTH CAROLINA. Although there is no evidence that otherwise healthy lone afibbers have an increased risk of ischemic stroke, it is clear that atrial fibrillation (AF) patients with heart failure, diabetes or hypertension have a significantly increased risk and this risk is further magnified if the patient has already suffered a heart attack or stroke. To date, oral anticoagulation with vitamin K antagonists such as warfarin (Coumadin) is still considered to be the best preventive therapy for patients at risk for stroke. Unfortunately, warfarin interacts with many foods and drugs and treatment requires constant, costly monitoring. Its use also substantially increases the risk of hemorrhagic stroke and major internal bleeding, particularly in older people, a group that, ironically, is also most at risk for an ischemic stroke. Effective warfarin therapy is based on maintaining an INR (international normalized ratio) between 2.0 and 3.0. In real life this ratio is only achieved on a continuous basis in about 50 to 60% of patients. Too low a ratio increases the risk of ischemic stroke, while too high a ratio increases the risk of hemorrhagic stroke and major bleeding.
Warfarin acts by inhibiting the activation of the vitamin K-dependent coagulation factors V, VII, and X in the extrinsic and common pathways of the coagulation cascade. Research aimed at replacing warfarin has focused on developing new pharmaceutical drugs which will inhibit specific coagulation factors. A new entry to the field is rivaroxaban (Xarelto) a direct inhibitor of factor Xa, the first member of the common pathway in the coagulation cascade.
Like dabigatran (Pradaxa), rivaroxaban was initially approved for temporary use following hip and knee operations. A very large study (ROCKET AF) evaluating rivaroxaban for stroke protection in AF patients has now been completed. The study included over 14,000 patients with nonvalvular AF treated at 1178 participating sites in 45 countries. The average (median) age of the patients was 73 years and 40% were female. Most of the study participants had persistent (probably including permanent) AF and had a CHADS2 score of at least 2 (mean score of 3.5). All in all, the trial involved a group of very sick people – in no way comparable to a group of otherwise healthy afibbers. Over 90% of the group had hypertension, 63% had heart failure, and 55% had experienced a prior stroke or transient ischemic attack (TIA).
The study participants were randomized to receive standard therapy with oral warfarin (INR range of 2.0 – 3.0) or 20 mg/day of rivaroxaban (15 mg/day for patients with kidney disorder). All patients also received a placebo pill and regular INR checks to blind them to the treatment received. The warfarin-treated patients were within INR target range 55% of the time. During an average follow-up of about 2 years, 188 patients (1.7%/year) in the rivaroxaban group experienced a stroke, TIA or systemic embolism as compared to 241 patients (2.2%/year) in the warfarin group. Major and non-major clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9%/year) and in 1449 patients (14.5%/year) in the warfarin group. The incidence of hemorrhagic stroke (intracranial hemorrhage) and fatal bleeding was significantly less in the rivaroxaban group (0.5% and 0.2%/year) than in the warfarin group (0.7% and 0.5%/year). However, the incidence of major gastrointestinal (GI) bleeding was higher in the rivaroxaban group (3.2%/year) than in the warfarin group (2.2%/year).
About 23% of participants dropped out of the study before its completion. The rate of ischemic stroke, TIA and systemic embolism during a median 117 days of follow-up was 4.7% in the rivaroxaban drop-out group and 4.3% in the warfarin drop-out group. The ROCKET AF investigators conclude that rivaroxaban is non-inferior to warfarin in the treatment of AF patients at moderate to high risk of stroke. NOTE: This study was funded by Johnson & Johnson and Bayer, and all the investigators had substantial financial ties to the pharmaceutical industry.
Patel, MR, Califf, RM, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine, August 10, 2011 [Epub ahead of print]
Editor's comment: Rivaroxaban is currently approved by the FDA for prevention of deep vein thrombosis after knee- or hip-replacement surgery. However, the FDA has asked for more data before approving the drug for stroke prevention in atrial fibrillation. Their main concern is that patients in the warfarin group were only within the specified INR range 55% of the time.