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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 January 2, 2024 e111

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

Synopsis No RCT has evaluated the use of OACs in patients with AF and liver disease. Three observational studies and 1 meta-analysis of observational studies have compared OAC therapy with no OAC therapy in patients with AF and active liver disease or a history of liver disease.1–4 In addition, 3 observational studies have compared OAC therapy in patients with liver disease to those without liver disease.5–7 In general, anticoagulation has been associated with lower risks of ischemic stroke or thromboembolism but was also associated with a significantly higher risk of major bleeding or ICH compared with no oral anticoagulation therapy in patients with AF and liver disease. Oral factor Xa inhibitors undergo hepatic metabolism, and impaired liver function may increase their plasma concentrations and the risk of bleeding. Pivotal clinical trials for DOACs excluded patients with active liver disease. Four postmarketing retrospective studies and 2 meta-analyses have evaluated the comparison between DOACs and VKAs in this population, and they showed DOACs were associated with a lower risk of major bleeding or ICH.1,7–11 Limited data exist on the safety of DOAC in severe liver disease. The uses of DOACs based on a Child-Pugh Score are summarized in Table 13 (Section 6.3.1.1. “Considerations in Managing Anticoagulation”). Recommendation-Specific Supportive Text 1.	 A meta-analysis showed that VKA use was sig-

nificantly associated with lower risks of ischemic stroke or thromboembolism but was also associated with significantly higher risks of major bleeding or ICH in patients with AF and liver disease compared with no oral anticoagulation therapy.7 A large-scale retrospective study also corroborated that OAC use was significantly associated with a lower risk of stroke or all-cause mortality in patients with AF and cirrhosis.3 VKA use in the liver fibrosis group was associated with a higher risk of the composite cardiovascular events and major bleeding than in the nonliver fibrosis group.4 However, no significant difference in the composite cardiovascular events and major bleeding between the 2 groups receiving DOACs was found. The efficacy and safety of VKAs or DOACs were not affected by nonalcohol fatty liver disease status.5 The subgroup analysis of the meta-analysis found that the risk of major bleeding was not affected by the presence of esophageal varices.13

2 A meta-analysis found no significant difference in

the risk of ischemic stroke and thromboembolism between DOACs and VKAs (OR, 0.82 [95% CI, 0.36- 1.88]; P=0.64) in patients with almost exclusively mildto-moderate liver disease (Child-Pugh class A-B), but DOAC use was associated with lower risks of major bleeding (OR, 0.54 [95% CI, 0.38-0.75]; P=0.0003) and ICH (OR, 0.35 [95% CI, 0.23-0.53]; P<0.0001) compared with the warfarin group.7 Another metaanalysis showed that, in patients with exclusively mild-to-moderate cirrhosis (Child-Pugh score A-B), DOAC use was associated with lower risks of ischemic stroke (HR, 0.62 [95% CI, 0.10-0.90]), major bleeding (HR, 0.64 [95% CI, 0.57-0.72]), or ICH (HR, 0.49 [95% CI, 0.40-0.59]) compared with warfarin.11 DOACs are reasonable oral anticoagulation agents in patients with AF and mild-to-moderate liver disease (Child-Pugh class A-B). However, data on DOACs are lacking on patients with AF and severe liver disease (Child-Pugh class C). 3.	 Rivaroxaban is currently avoided in patients with mod-

erate liver disease (Child-Pugh class B). Rivaroxaban AUC significantly increased by 2.27-fold after a single dose of rivaroxaban 10 mg in patients with moderate liver disease compared with healthy subjects.12 Although the FDA labeling recommends avoiding edoxaban in patients with moderate liver disease due to the concern of underlying coagulopathy, the edoxaban AUC was not significantly increased after a single dose of edoxaban 15 mg in patients with moderate liver disease compared with healthy subjects.14 Apixaban AUC was not significantly increased after a single dose of apixaban 5 mg in subjects with mild and moderate liver disease (Child-Pugh class A and B) compared with healthy subjects.15 Dabigatran AUC was also not significantly different after a single dose of dabigatran 150 mg in patients with moderate liver disease (Child-Pugh class B) compared with that in healthy subjects.16

11 FUTURE RESEARCH NEEDS

Enormous progress and important advances have been made in recent years on the understanding of mechanisms and on the prevention and management of AF, including substantial progress since the 2014 guideline, as well as the 2019 focused update. Although the writing committee has tried to make significant progress in this current guideline to address many of the gaps in the clinical management of AF, important gaps in knowledge remain and are listed below. 1.	 AF as a disease continuum: AF must be seen as a disease continuum, yet historically the emphasis has been on rhythm management. More evidence is needed on how to best improve in other aspects of AF care, such as prevention, modification of risk factors, and how to incorporate holistic approaches to AF management into daily clinical practice. 2.	 Downstream consequences: The downstream

consequences of AF over the long term must be better studied and defined. Most studies generally focus on short-term effects of therapy, usually 6 to 12 months. Many long-term consequences of AF

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