• Cardiology Clinical Trials
• Renal Insufficiency
• Arrhythmias
• Cerebrovascular Disease
• Renal Disease

Patients with atrial fibrillation (AF) and moderate renal dysfunction have a higher risk of stroke and bleeding than patients with normal renal function, but respond favorably to reduced-dose rivaroxaban compared with warfarin, according to new findings from the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF; NCT00403767].

Keith A. A. Fox, MD, University of Edinburgh, Edinburgh, United Kingdom, presented results from the ROCKET-AF prespecified renal impairment substudy.

The ROCKET-AF trial compared the safety and efficacy of rivaroxaban 20 mg daily (15 mg for patients with a calculated creatinine clearance [CrCl] 30 to 49 ml/min) to standard dose-adjusted warfarin in 14,264 patients with AF and additional risk factors for stroke. In the primary study analysis in the “per protocol” cohort, rivaroxaban was non-inferior to warfarin in reducing the risk of stroke or systemic embolism ([SSE]; 1.71% vs 2.16% per year; HR, 0.79; 95% CI, 0.66 to 0.96; p<0.001 for noninferiority) [Patel M et al. N Engl J Med 2011]. Of note, there was no statistically significant difference between the treatment groups when all events between randomization and the end of the study were analyzed in an intention-to-treat analysis (2.1% vs 2.4%; p=0.12 for superiority).

Rivaroxaban is predominantly metabolized by the liver, although one-third of the drug is cleared by the kidneys and excreted unchanged in the urine. The current substudy evaluated the 2950 patients in the “per protocol” cohort with a baseline CrCl of 30 to 49 ml/min who received a reduced-dose of rivaroxaban (15 mg/day) compared to those treated with dose-adjusted warfarin with a target INR of 2.0 to 3.0.

Compared with patients with normal renal function, patients in the renal dysfunction substudy were older, had a higher CHADS₂ risk score, and were more likely to have a history of SSE. Patients with renal impairment had higher rates of stroke and bleeding than patients with preserved renal function, regardless of study treatment.

There was no evidence of a statistical interaction between renal function and the effect of rivaroxaban on the primary efficacy (interaction p=0.45) or safety endpoint (interaction p=0.76; Table 1). Among patients with moderate renal dysfunction, patients randomized to rivaroxaban, compared with those randomized to warfarin, had annualized rates of SSE 2.32% and 2.77% respectively (HR, 0.84; 95% CI, 0.57 to 1.23). For the primary safety endpoint of major plus nonmajor clinically relevant bleeding, the corresponding rates were 17.8% and 18.3% (HR, 0.98; 0.84 to 1.14).

Fatal bleeding was reduced with rivaroxaban compared to warfarin among both patients with moderate renal dysfunction (0.28% vs 0.74%; HR, 0.39; 0.15 to 0.99) and in those with mild/normal renal function (0.23% vs 0.43%; HR, 0.55; 0.32 to 0.93), with no evidence of statistical heterogeneity (interaction p=0.53). The rates of intracranial hemorrhage in the rivaroxaban versus warfarin groups for patients with renal impairment were 0.71% versus 0.88% (HR, 0.81; 0.41 to 1.60) and among those with normal renal function 0.44% versus 0.71% (HR, 0.62; 0.42 to 0.92). Despite the numeric difference in the hazard ratios, the statistical test for interaction was not significant (p=0.51), in part related to the small absolute number of events in the former group. Gastrointestinal bleeding was more common with rivaroxaban than warfarin, both for patients with renal impairment (2.88% vs 1.77%; p=0.02) and normal renal function (1.79% vs 1.12%; p=0.0002).

Findings from this ROCKET-AF substudy were consistent with those from the overall trial. In patients with moderate renal impairment, reduced-dose rivaroxaban preserved the benefit of warfarin in preventing SSE, and in the “per protocol analysis” yielded lower rates than warfarin. The rates of bleeding and adverse events with reduced dose rivaroxaban compared with warfarin were similar, with fewer fatal bleeds.

• © 2011 MD Conference Express