Anticoagulation for Stroke Prevention in Patients With Atrial Fibrillation and End-Stage Renal Disease—First, Do No Harm

Randhawa and colleagues¹ report the results of an updated meta-analysis of 15 observational studies reporting the outcomes of 47 480 patients with atrial fibrillation (AF) and end-stage renal disease (ESRD) according to whether or not they were treated with warfarin. Patients treated with warfarin (10 445 [22.0%]), compared with those not treated with warfarin, had similar rates of ischemic stroke (7.7% vs 7.1%; hazard ratio [HR], 0.96 [95% CI, 0.82-1.13]), major bleeding (16.1% vs 15.0%; HR, 1.20 [95% CI, 0.99-1.47]), and mortality (43.4% vs 52.5%; HR, 0.95 [95% CI, 0.83-1.09]), as well as a significantly higher risk of hemorrhagic stroke (2.4% vs 1.9%; HR, 1.49 [95% CI, 1.03-1.94]). Although these results are subject to confounding because they are nonrandomized, and although they demonstrate moderate or large amounts of heterogeneity, they suggest that warfarin may not be effective for the prevention of ischemic stroke in patients with AF and ESRD and instead may cause substantial harm. Similar results were recently reported in a network meta-analysis of observational studies that found no evidence of a reduction in thromboembolic events with warfarin or the direct oral anticoagulants apixaban, rivaroxaban, or dabigatran in patients with AF and ESRD.²

Randomized clinical trials of patients with AF who do not have ESRD have shown that warfarin is highly effective, reducing the risk of stroke by approximately two-thirds and mortality by approximately one-fourth.³ Patients with AF who also have ESRD are at even higher risk of stroke than those without ESRD,⁴ which makes effective stroke protection in these patients a very high priority. We believe that the signal of net harm in the updated meta-analysis by Randhawa et al¹ should dampen enthusiasm for the use of warfarin among patients with AF and ESRD. Other sobering findings of their analyses were that patients with ESRD have very high rates of major bleeding (approximately 15%), which, even in the absence of warfarin therapy, were double those of ischemic stroke, and mortality rates of 40% to 50% during a mean of 2.6 years of follow-up. These data underscore the eed for new approaches to reduce the burden of morbidity and mortality among patients with AF and ESRD.

If anticoagulation with warfarin is not a suitable option for stroke prevention in patients with AF who have ESRD, what are the alternatives? An increasingly popular approach in the United States is to use apixaban for stroke prevention among patients with AF and ESRD, but the evidence for this approach is of low quality. The US Food and Drug Administration approved apixaban for this indication based on limited pharmacokinetic data, but recent network meta-analysis data provide no evidence that it is effective.² The meta-analysis results raised the possibility that the lack of effectiveness of apixaban might be explained by the use of the dosage of 2.5 mg twice daily, which demonstrated no effectiveness, rather than the dosage of 5 mg twice daily, which produced more favorable results, but these data are potentially confounded because patients who received the higher dose are likely to have been more robust than those who received the lower dose. A separate potential benefit of using a direct oral anticoagulant is that dabigatran and rivaroxaban (but not apixaban) have been reported in both randomized clinical trials and observational studies to be associated with a reduced rate of deterioration of renal function compared with warfarin.⁵ However, neither dabigatran nor rivaroxaban is approved for patients with AF and ESRD.

A second approach to reduce the burden of stroke in patients with AF without ESRD without increasing bleeding might be to use a left atrial appendage occlusion device. These devices have not undergone randomized evaluation in patients with ESRD, but they appear to be noninferior to anticoagulation in patients with AF without ESRD who have a contraindication to long-term anticoagulation.⁶ A third potential option is to use aspirin or the combination of aspirin and clopidogrel, but antiplatelet therapy is of unproven effectiveness for stroke prevention in patients with AF and ESRD.

The lack of proven approaches to stroke prevention for patients with AF and ESRD highlights the urgent need for additional research in this population. The recently presented Renal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation trial (RENAL-AF; ClinicalTrials.gov identifier NCT02942407) compared the efficacy and safety of apixaban and warfarin for stroke prevention in patients with AF and ESRD, but the study was stopped early owing to lack of funding after 155 of a planned 760 patients were enrolled and produced inconclusive results.⁷ Currently ongoing studies include the Strategies for the Management of Atrial Fibrillation in Patients Receiving Hemodialysis (SAFE HD; ClinicalTrials.gov identifier NCT03987711) trial, comparing warfarin, apixaban, and no anticoagulation (with a planned enrollment of 150 patients), and the Compare Apixaban and Vitamin-K Antagonists in Patients with Atrial Fibrillation and End-Stage Kidney Disease (AXADIA; ClinicalTrials.gov identifier NCT02933697), comparing phenprocoumon and apixaban (with a planned enrollment of 222 patients).

While awaiting the results of randomized clinical trials, the management of stroke risk among patients with AF who have ESRD will remain challenging. We suggest that decisions to prescribe or withhold antithrombotic therapy or to use a left atrial appendage occlusion device in patients with AF and ESRD rely on clinical judgement, taking into account patient values and preferences and remembering the time-honored adage primum non nocere.

Published: April 6, 2020. doi:10.1001/jamanetworkopen.2020.2237

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Belley-Cote EP et al. JAMA Network Open.

Corresponding author: Emilie P. Belley-Cote, MD, PhD, Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, 20 Copeland Ave, Hamilton, ON L8L 2X2, Canada (emilie.belley-cote@phri.ca).

Conflict of Interest Disclosures: Dr Belley-Cote reported receiving a career award from the Department of Medicine at McMaster University; and grants from the Canadian Institutes for Health Research. Dr Eikelboom reported receiving a career award from the Heart and Stroke Foundation of Ontario; grants from the Canadian Institutes for Health Research; and honoraria and grant support from AstraZeneca, Bayer Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Sanofi-Aventis, and Servier.