Rivaroxaban Tablets (Xarelto®)
Rivaroxaban Tablets (Xarelto®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
Rivaroxaban, an oral factor XA inhibitor, has been approved for reducing the risk of stroke in patients with atrial fibrillation (AF). The drug joins dabigatran (Pradaxa) as the second "nonwarfarin" oral anticoagulant approved for this indication. Rivaroxaban was previously approved for the prophylaxis of deep vein thrombosis (DVT) in patients undergoing hip or knee replacement (see Pharmacology Update, August 15, 2011, page 117). The drug is marketed by Janssen Pharmaceuticals as Xarelto.
Rivaroxaban is indicated for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF and for the prophylaxis of DVT in patients undergoing knee or hip replacement.1
The recommended dose for patients with AF is 20 mg once daily with the evening meal, as food increases the bioavailability of rivaroxaban. For patients with creatinine clearance between 15 and 50 mL/min, the recommended dose is 15 mg. For the prophylaxis of DVT, the dose is 10 mg daily. The duration of therapy is 12 days for knee replacement and 35 days for hip replacement.1
Rivaroxaban is dosed once daily compared to twice daily for dabigatran. Similar to dabigatran, laboratory monitoring is not required.
The drug should not be co-administered with combined P-gp and strong CYP3A4 inhibitors (e.g., ritonavir, intraconazole, ketoconazole).1 P-gp and strong CYP3A4 inducers may reduce the effectiveness of rivaroxaban while combined P-gp and weak or moderate inhibitor may increase systemic exposure. Discontinuation of rivaroxaban may increase the risk of thrombotic events.1 Patients on rivaroxaban may develop epidural or spinal hematomas if they receive neuraxial anesthesia or undergo spinal puncture.1 Currently there is no antidote for rivaroxaban (see Clinical Implications).
Rivaroxaban is an orally active factor Xa inhibitor. Its efficacy for stroke prevention in AF was based on a multinational, double-blind, randomized, noninferiority comparative trial to warfarin (ROCKET AF),1,2 which enrolled 14,264 patients with nonvalvular AF with moderate-to-high risk for stroke. The median age was 73 years, 60% were male, 90% had hypertension, and the median CHADS2 score was 3.0 (87% equal to or higher than 3). Patients were randomized to rivaroxaban 20 mg (15 mg with reduced renal function) or dose-adjusted warfarin. The median duration of treatment exposure was 707 days. The primary efficacy outcome was stroke or systemic embolism and the primary safety outcome was a composite of major and nonmajor bleeding events. The rate of stroke or systemic embolism based on intention-to-treat was 2.1% per year for rivaroxaban and 2.4% per year for warfarin (hazard ratio, 0.88; 95% confidence interval 0.75 to 1.03). Noninferiority was demonstrated but not superiority. There were no differences in composite major and nonmajor bleeding events (14.9% vs 14.5% per year) or major bleeding events (3.6% vs 3.4% per year). However, intracranial hemorrhage was lower for rivaroxaban (0.5% vs 0.7% per year, P = 0.02). Major gastrointestinal (GI) bleeding events were higher with rivaroxaban (3.2% vs 2.2%, P < 0.001). A higher percent of patients on rivaroxaban discontinued participation in the clinical trial due to bleeding events (4.3% vs 3.1%).
This is the second nonwarfarin drug approved for stroke prevention in nonvalvular AF. The first was the thrombin inhibitor dabigatran. A third drug, also a factor Xa inhibitor, apixaban, is awaiting FDA approval. While the new agents were all compared to dose-adjusted warfarin, it is difficult to compare across studies by applying transitive logic due to study differences. In RE-LY (dabigatran), 32.7% had a CHADS2 score above 3 while in ARISTOTLE (apixaban), those above CHADS2 score of 3 were 30.2%, compared to 87% for (ROCKET AF).2-4 Other differences included the effective dosing of warfarin. For the dabigatran study, the median percent time in therapeutic range (%TTR) for warfarin was about 65% compared to 55% for rivaroxaban and 66% for apixaban. Other observations among these studies: dabigatran and apixaban were superior to warfarin, apixaban showed a lower risk of major bleeds, all three drugs showed a lower risk of intracranial hemorrhage, dabigatran and rivorxaban showed a higher risk of GI bleeds, and dabigatran showed a higher risk of myocardial infarction. Currently there is no antidote for these agents, although a recent report suggests that prothrombin complex concentrate may be able to reverse rivaroxaban but not dabigatran.5 Reversal of these drugs may be an important clinical issue, as a total of 256 fatal bleedings have been reported with dabigatran worldwide as of November 6, 2011.6 Boehringer Ingelheim indicated that the number of deaths was within expectations. More clinical experience in practice will determine if one or more of these agents emerges as the preferred agent.
1. Xarelto Prescribing Information. Titusville, NJ: Janssen Pharmaceuticals; November 2011.
2. Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.
3. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: 1139-1151.
4. Granger CB, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992.
5. Eerenberg ES, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-1579.
6. http://www.reuters.com/article/2011/11/18/boehringer-pradaxa-idUSL5E7MI1VK20111118. Accessed November 21, 2011.Rivaroxaban, an oral factor XA inhibitor, has been approved for reducing the risk of stroke in patients with atrial fibrillation (AF). The drug joins dabigatran (Pradaxa) as the second "nonwarfarin" oral anticoagulant approved for this indication.
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