Although patients with atrial fibrillation (AF) and kidney impairment have an increased risk of thromboembolic events and bleeding complications, limited safety data exist to guide clinicians on the use of non–vitamin K antagonist oral anticoagulants (NOACs) in this patient population.
Fortunately, data are beginning to emerge. Recent findings from a post-hoc analysis of data from the Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial indicate that, among patients with AF and stage 4 CKD, apixaban was not only safe but also produced lower bleeding rates than warfarin. These study results were displayed in a poster presented by John W. Stanifer, MD, of Duke, at the American Society of Nephrology annual meeting held October 31 to November 5, 2017, in New Orleans, LA. Other Duke investigators involved in the study included Christopher B. Granger, MD, and Daniel Wojdyla, MS.
For safety reasons, those with severe kidney impairment (ie, those with a creatinine clearance [CrCl] less than 25 to 30 mL/min) are excluded from major randomized trials of NOACs. Because such patients are not included in clinical trials of these agents, 2 direct-acting oral anticoagulants, dabigatran and rivaroxaban, were approved by the United States Food and Drug Administration—based on their pharmacokinetic profiles alone—at a reduced dosage for patients with CrCl levels of 15 to 29 mL/min. Additionally, apixaban 5 mg was approved for use, without a dose reduction, in patients with severe renal impairment (CrCl < 30 mL/min), including those receiving chronic hemodialysis.
ARISTOTLE was a double-blind randomized controlled trial that compared apixaban with warfarin in 18,000 patients with AF. The trial demonstrated that apixaban was superior to warfarin in the prevention of stroke and systemic embolism and that those on apixaban had fewer bleeding events and lower mortality rates.
Although patients with serum creatinine levels above 2.5 mg/dL or CrCl lower than 25 mL/min were excluded from ARISTOTLE, the investigators conducting the post-hoc analysis identified 269 patients with CrCl less than 30 mL/min who were taking apixaban 5 mg or 2.5 mg twice daily. Among these individuals, researchers looked at primary efficacy outcomes of rates of stroke or systemic embolism and primary/secondary safety outcomes of major bleeding or a composite of major bleeding and clinically relevant non-major bleeding.
In this analysis, apixaban was found to have similar safety outcomes across CrCl categories. In patients with AF and stage 4 CKD, defined as a CrCl between 15 and 29 mL/min, apixaban yielded lower bleeding rates than warfarin—a finding that was consistent with the overall population.
This study is among the first of its kind, noted Stanifer. He explained that the results support the safety of the 2.5-mg dosage but are less conclusive for the 5-mg dosage, even though no statistical difference was found between the 2 groups. "The rate of adverse events was low in both groups, but there was a trend toward a few more in the 5-mg group, so that's probably an area that needs more study."
Stanifer added that Duke's Christopher B. Granger and Glenn M. Chertow, MD, MPH, of Stanford University, are currently conducting a study of NOAC treatment among patients on hemodialysis, which might provide additional safety data in this important new area of research.
Source: Stanifer JW, Granger CB, Chertow GM, et al. Apixaban vs. warfarin in patients with atrial fibrillation (AF) and stage 4 CKD. Presented at: American Society of Nephrology annual meeting, Kidney Week 2017; October 31-November 5, 2017; New Orleans, LA. Poster 460.