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CLINICAL STATEMENTS AND GUIDELINES

January 2, 2024 Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 e38

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

subreference DOAC levels was significantly higher in patients receiving antiepileptic drugs compared to those not receiving any CYP3A4 inducers.4 The claim-based retrospective cohort study showed that CYP-inducing antiepileptic drug use was significantly associated with an 86% increase in thromboembolic and ischemic adverse events in patients receiving DOACs.6 A prospective multicenter cohort study corroborated that the patients receiving concomitant therapy of DOACs and antiepileptic drugs developed a higher rate of stroke/TIA/systemic embolism (5.7% patient-year).7

2 Warfarin remains the preferred agent in patients

with AF receiving CYP3A4/p-glycoprotein–inducing agents, or moderate-severe mitral stenosis or mechanical heart valve. Also, warfarin may be selected over DOACs in patients with AF due to higher cost or intolerances of DOACs. The optimal INR control, with a therapeutic INR goal of 2 to 3, needs to be achieved through the appropriate drug-drug interaction management, vitamin K dietary education, and routine INR monitoring. A systematic review of 47 studies found that time in therapeutic INR range showed negative correlation with risks of thromboembolism (R, –0.59; P=0.01) and major bleeding (R, –0.59; P=0.002).8 An RCT revealed that a weekly vitamin K dietary modification significantly achieved a therapeutic INR more frequently than a conventional group (74 versus 58%; P=0.04) at 90 days after randomization.9 A meta-analysis of 11 RCTs and 61 observational studies for warfarin drug interactions found that the concomitant use of APT (odds ratio [OR], 1.74 [95% CI, 1.56-1.94]), nonsteroidal anti-inflammatory drugs (OR, 1.83 [95% CI, 1.29-2.59]), selective serotonin reuptake inhibitors (OR, 1.62 [95% CI, 1.42-1.85]), or antimicrobial agents (OR, 1.63 [95% CI, 1.45-1.83]) was significantly associated with higher risks of clinically relevant bleeding.10 3 A significant number of patients with nonvalvu-

lar AF are receiving DOAC off-label doses not compliant with labeling.15–18 A meta-analysis of cohort studies showed that inappropriately lower DOAC doses are significantly associated with higher stroke or systemic embolism risks compared with the standard labeled doses (OR, 1.21 [95% CI, 1.02-1.43]; P=0.03), but no significant differences in bleeding risks were observed (OR, 1.03 [95% CI, 0.92-1.15]; P=0.62).11 Of note, 9 of 16 included studies were performed in Asia, while 4 studies in the United States, 2 studies in Europe, and 1 worldwide study were included. Another meta-analysis of observational studies found that inappropriately higher DOAC doses were significantly associated with higher risks of ischemic stroke/systemic embolism (hazard ratio [HR], 1.26 [95% CI, 1.11-1.43]; P=0.003) or major bleeding (HR, 1.30 [95% CI, 1.04-1.62]; P=0.025) compared with the standard doses.12 In this study, underdosing was also associated with a higher risk of net clinical outcome (HR, 1.19 [95% CI, 1.04-1.40]; P=0.04) and all-cause death (HR, 1.24 [95% CI, 1.04-1.48]; P=0.02). Off-label dosing should be avoided to optimize the efficacy and safety of DOACs.

6.4 Silent AF and Stroke of Undetermined

Cause Recommendation for Silent AF and Stroke of Undetermined Cause Referenced studies that support the recommendation are summarized in the Online Data Supplement. COR LOE Recommendation

2a B-R 1.	 In patients with stroke or TIA of undetermined cause,

initial cardiac monitoring and, if needed, extended monitoring with an implantable loop recorder are reasonable to improve detection of AF.1

Table 13.  Continued

Class VKA Direct Thrombin Inhibitor Factor Xa Inhibitor Name Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Appropriate use based on liver function (Child-Pugh score)† Child-Pugh A (mild) Not mentioned in the labeling No dose adjustment needed No dose adjustment needed No dose adjustment needed No dose adjustment needed Child-Pugh B (moderate) Use with caution Avoid use Use with caution Use with caution Child-Pugh C (severe) Avoid use Avoid use Avoid use Avoid use

Information obtained from manufacturer package inserts.13,14,20–22 Adapted with permission from pgs. 28-31 of Kido et al.23 Copyright 2021 American College of Clinical Pharmacy. *The effect of food (high-fat, high-calorie meal) on bioavailability for 10- and 20-mg tablet was evaluated in 24 subjects under fed and fasting conditions. After a single oral 20-mg dose, area under the curve was increased by 39%, and Cmax was increased by 76% under fed condition, but area under the curve and Cmax were similar between fasting and fed conditions.19 †Child-Pugh scoring: the severity of liver disease, primarily cirrhosis. Child-Pugh A (mild): 5 to 6 points; Child-Pugh B (moderate): 7 to 9 points; Child-Pugh C (severe): 10 to 15 points. The score is based on the 5 variables: encephalopathy (none=1 point, grade 1 and 2=2 points, grade 3 and 4=3 points); ascites (none=1 point, slight=2 points, moderate=3 points); total bilirubin (<2 mg/mL=1 point, 2-3 mg/mL=2 points, >3 mg/mL=3 points); albumin (>3.5 mg/mL=1 point, 2.8-3.5 mg/mL=2 points, <2.8 mg/mL=3 points); INR (<1.7=1 point, 1.7-2.2=2 points, >2.2=3 points).

CrCl indicates creatinine clearance; INR, international normalized ratio; OAC, oral anticoagulant; Scr, serum creatinine; and VKA, vitamin K antagonist.

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