Prevention of Stroke and Systemic Embolism With Rivaroxaban Compared With Warfarin in Patients With Non-Valvular Atrial Fibrillation and Moderate Renal Impairment

Study Questions:

What are the risks and benefits of a lower dose of rivaroxaban versus standard warfarin for the prevention of embolic stroke in patients with atrial fibrillation (AF) and moderate renal insufficiency?

Methods:

The authors performed a prespecified secondary analysis of data from the ROCKET AF trial, a randomized, prospective, double-dummy study comparing warfarin with rivaroxaban for prevention of embolic stroke in nonvalvular AF. This secondary analysis was limited to those subjects with moderate renal insufficiency. Moderate renal insufficiency was defined as creatinine clearance of 30-49 ml/min at baseline, which constituted 20.7% of the original trial cohort. These subjects received 15 mg/day versus the standard 20 mg/day. The primary efficacy endpoint was a composite of all stroke (ischemic and hemorrhagic) and systemic embolism. Secondary endpoints added cardiovascular death and myocardial infarction to be primary endpoints. The principal safety endpoint was the composite of major and nonmajor clinically relevant bleeding events.

Results:

Of the original study cohort of 14,264 subjects with AF, the current study included 2,950 (20.7%) with moderate renal insufficiency. Subjects in this subgroup were older (79 years) and had higher event rates. The primary endpoint of stroke or systemic embolism occurred in 2.32 subjects per 100 patient-years with rivaroxaban versus 2.77 per 100 patient-years with warfarin (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.57-1.23) in the per-protocol population. Results were similar by intention-to-treat analysis (HR, 0.86; 95% CI, 0.63-1.17). Principal safety endpoint rates were similar between the two groups for major and nonmajor bleeding (17.82 vs. 18.28 per 100 patient-years; p = 0.76) and intracranial bleeding (0.71 vs. 0.88 per 100 patient-years; p = 0.54). Fatal bleeding was less frequent with rivaroxaban (0.28 vs. 0.74 per 100 patient-years; p = 0.047).

Conclusions:

The authors concluded that patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. They saw no evidence of heterogeneity in treatment effect across the dosing groups. The authors further concluded that dose adjustment in the ROCKET AF trial yielded results consistent with the overall trial in comparison with dose-adjusted warfarin.

Perspective:

This prespecified subanalysis of the landmark ROCKET AF study should reassure clinicians that rivaroxaban can be safely used in patients with moderate renal insufficiency, provided the dose is appropriately adjusted. This information is vital, as the renal insufficiency dose-adjustment for rivaroxaban was based solely on pharmacokinetic modeling and pharmacodynamic data, and rivaroxaban is partially renally excreted. One note of caution in interpreting these results, however, is that this subanalysis is not powered sufficiently to demonstrate either noninferiority or superiority. It should also be noted that, for reasons not yet clear, rivaroxaban appears to be associated with significantly lower rates of the most feared complications of anticoagulation: intracranial hemorrhage and fatal bleeding. So far, this appears to be true for the direct thrombin inhibitor dabigatran as well. This improved safety profile, along with the dramatically simplified administration compared with warfarin, makes the newer agents rivaroxaban and dabigatran very attractive for prophylaxis of thromboembolism in AF. Close attention should be paid to phase 4 or post-marketing studies to determine if, in real-world conditions, these differences result in improved outcomes for patients.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Lipid Metabolism, Novel Agents

Keywords: Stroke, Myocardial Infarction, Thrombin, Morpholines, Thiophenes, Warfarin, Thromboembolism, Renal Insufficiency, Intracranial Hemorrhages, Benzimidazoles, Factor Xa, Embolism


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