ROCKET AF: Rivaroxaban in Atrial Fibrillation

Chicago—Rivaroxaban, an investigational antithrombotic drug, was found to be at least as effective as warfarin in patients with paroxysmal atrial fibrillation (AF), with fewer dangerous side effects, such as intracranial hemorrhage and fatal bleeding, in a pivotal phase 3 trial reported at the AHA meeting. “Rivaroxaban is now a proven alternative to warfarin for moderate- or high-risk patients with AF,” stated Kenneth W. Mahaffey, MD, on behalf of the ROCKET AF (Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) investigators. Dr. Mahaffey is with Duke Clinical Research Institute in Durham, North Carolina. AF is the most common sustained cardiac rhythm, affecting >2.3 million people in the United States. People living with AF are at a 5-fold increased risk for stroke due to vulnerability to the formation of blood clots in the atria of the heart. Dose-adjusted warfarin is the mainstay of treatment, but warfarin has many drawbacks, including the risk of serious bleeding and the need for intensive monitoring. Rivaroxaban (Xarelto, Johnson & Johnson) is a novel oral anticoagulant under study for AF and other blood-clotting disorders. Rivaroxaban is a direct inhibitor of factor Xa that can be given once a day without the need for intensive monitoring. Thus far, the novel agent has been studied in >25,000 patients worldwide. ROCKET AF was an international, randomized, controlled trial in 45 countries that enrolled 14,264 patients with AF who were randomized 1:1 to rivaroxaban 20 mg/day or warfarin titrated to an international normalized ratio (INR) target of 2.5. Although monitoring is not needed for rivaroxaban, all patients were monitored for INR, because this was a double-blind, double-dummy trial. Mean age was 73 years. Patients were a high-risk group with multiple problems, including hypertension (90%), diabetes (40%), prior stroke/embolism/transient ischemic attack (55%), and prior myocardial infarction (18%). Rivaroxaban was noninferior to warfarin for the primary end point of the trial in the prespecified ontreatment population, with an incidence of stroke and non–central nervous system embolism of 1.71% versus 2.16% for warfarin (hazard ratio, 0.79; 95% confidence interval, 0.66-0.96; P=.015). While on study drug, rivaroxaban was superior to warfarin. An intent-to-treat analysis of all patients randomized in the trial whether they completed therapy or not found that rivaroxaban was noninferior to warfarin but was not statistically superior (2.12% vs 2.42%, respectively, for the primary end point; P=.117 for noninferiority). Similar rates of major and nonmajor clinically relevant bleeding events were found with both drugs: 14.91% with rivaroxaban versus 14.52% with warfarin. Rates of major bleeding were also comparable between treatment arms: 3.60% for the rivaroxaban group and 3.45% for the warfarin group. Fewer intracranial hemorrhages (0.49% vs 0.74%, respectively), critical organ bleeds (0.82% vs 1.18%, respectively), and bleeding-related deaths (0.24% vs 0.48%, respectively) were reported with rivaroxaban. “Intracranial hemorrhage and bleeding resulting in death are the adverse events we are most concerned about in patients with AF,” Dr. Mahaffey said. Patients treated with rivaroxaban had increased rates of ≥2 g/dL hemoglobin/hematocrit drop compared with warfarin (2.77% vs 2.26%, respectively) as well as increased rates of transfusion (1.65% vs 1.32%, respectively). No differences were seen between the 2 treatment arms for liver function abnormalities and rates of discontinuation due to adverse events.