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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 January 2, 2024 e55

Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

between patients on OAC monotherapy versus dual therapy (OAC plus APT). Major adverse cardiac or neurological events (HR, 1.5 [95% CI, 1.00-2.25]) did not differ significantly between mono- and dual therapy, while dual therapy was associated with an increased risk of bleeding (HR, 2.27 [95% CI, 1.38-3.73]; P=0.001).5

6.8.4 Chronic Kidney Disease (CKD)/Kidney Failure

Recommendations for CKD/Kidney Failure Referenced studies that support the recommendations are summarized in the Online Data Supplement. COR LOE Recommendations

1 B-R 1 For patients with AF at elevated risk for stroke and

CKD stage 3, treatment with warfarin or, preferably, evidence-based doses of direct thrombin or factor Xa inhibitors (Table 19) is recommended to reduce the risk of stroke.1–3

2a B-NR 2 For patients with AF at elevated risk for stroke and

CKD stage 4, treatment with warfarin or labeled doses of DOACs is reasonable to reduce the risk of stroke.4,5

2b B-NR 3 For patients with AF at elevated risk for stroke and

who have end-stage CKD (CrCl <15 mL/min) or are on dialysis, it might be reasonable to prescribe warfarin (INR 2.0-3.0) or an evidence-based dose of apixaban for oral anticoagulation to reduce the risk of stroke.6,7

Synopsis CKD is a risk factor for stroke in patients with AF, independent of other risk factors.8 The prevalence of AF among patients with renal failure on dialysis is high, including asymptomatic AF.9 Despite compelling evidence in the general population, conflicting data exist as to whether AF is a risk factor for stroke in patients on dialysis.10,11 Potential explanations for this discrepancy include competing risks of stroke and mortality, a high prevalence of undiagnosed AF in cohorts thought not to have AF, and the confounding effect of anticoagulation thrice weekly during hemodialysis.12 VKAs are limited by a markedly reduced time in therapeutic range in patients with severe CKD, including those on dialysis,13 and association with calciphylaxis.14 The pivotal DOAC trials excluded patients on dialysis, and recommendations for dosing are based on pharmacokinetic data only. Early experience with dabigatran and rivaroxaban in this population suggested an increased risk of bleeding relative to warfarin, driven by the higher dose of each.15 Only dabigatran is substantially removed by dialysis.16 A small RCT and a retrospective population-based cohort study found a lower risk of thromboembolism with rivaroxaban versus warfarin,17,18 but these findings await confirmation in larger studies. Limited data on LAAO exist in this group of patients, and prospective comparison to anticoagulation or no therapy is awaited.19 Recommendation-Specific Supportive Text 1.	 Early trials demonstrating the role of warfarin anti-

coagulation in preventing stroke did not enroll or separately report outcomes in patients with CKD. An analysis of the SPAF III trial showed that doseadjusted warfarin, compared with fixed low-dose warfarin plus aspirin, reduced the risk of stroke with a similar magnitude to patients with normal kidney function.3 In the AVERROES trial of apixaban versus aspirin in patients deemed unsuitable for warfarin, apixaban showed similar efficacy in patients with an estimated glomerular filtration rate (eGFR) of 25 to 50 mL/min as those with an eGFR >50 mL/min.20 Patients with CKD stage 3, which includes those with an eGFR of 30 to 60 mL/min, were enrolled in the pivotal trials of the DOACs and showed similar results compared with warfarin as seen in patients with normal kidney function.2

2 Evidence on the use of anticoagulation in patients

with AF and stage 4 CKD (eGFR, 15-30 mL/ min/1.73 m2) is largely observational. A prospective, multicenter cohort study of survivors of MI with AF found that warfarin prescription at discharge associated with a reduced risk of death, readmission due to MI, ischemic stroke, and bleeding.5 An analysis of patients with CrCl 25 to 30 mL/min at the time of enrollment in the ARISTOTLE trial found numerically fewer stroke and major bleeding events with apixaban than warfarin.4 Because CrCl overestimates eGFR, a proportion of the patients enrolled in the pivotal clinical trials of DOACs, which used CrCl cut-offs for enrollment, had CKD stage 4 as assessed by eGFR in current clinical practice. 3.	 The role of anticoagulation in patients with AF and

severe CKD, including those on dialysis, is controversial.6,7,21,22 Pending the results of RCTs comparing warfarin with no treatment, and warfarin with DOACs, SDM incorporating risks of bleeding and thromboembolism is encouraged. The pivotal clinical trials of apixaban excluded patients with CrCl <25 mL/min.23,24 Subsequently, the FDA-approved labeling was extended to include those with end-stage renal failure, including those on hemodialysis.25 A subsequent pharmacokinetic study found that drug levels with apixaban 2.5 mg twice daily approximate those seen with 5 mg twice daily in patients with normal renal function, suggesting 2.5 mg is a more appropriate dose in such patients.26 A large retrospective cohort study of Medicare beneficiaries found no difference in thromboembolism, but less major bleeding, in patients treated with apixaban versus warfarin.27 Another analysis found an increased risk of thromboembolism and of fatal or intracranial bleeding with apixaban 5 mg twice daily versus no anticoagulation but not with apixaban 2.5 mg twice daily.28 Two small trials of apixaban versus warfarin in patients with AF on hemodialysis could not show differences in safety or efficacy outcomes but significantly more bleeding than stroke events.29,30

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