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CLINICAL STATEMENTS AND GUIDELINES

January 2, 2024 Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 e36

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

5 Aspirin therapy was compared with no treatment in

patients with low stroke risk in a multicenter RCT in Japan, the Japan Atrial Fibrillation Stroke Trial.10 This trial was stopped early when an interim analysis showed that aspirin gave a marginally higher risk of major bleeding and was unlikely to prevent primary or secondary endpoints. The primary endpoint was noncardiovascular death, ICH, major bleeding, and peripheral embolization. A meta-analysis of 7 trials that studied aspirin versus placebo found that aspirin reduced stroke by 19%, which did not reach statistical significance with a CI that included 0 (–1% to 35%). Four of these were primary prevention trials and showed an absolute risk reduction with aspirin of 0.8% per year, with a number needed to treat of 125.11 Although aspirin has not been studied in patients without any risk factors for stroke, patients without stroke risk may derive no benefit from aspirin therapy. In fact, 1 study that analyzed stroke mechanisms in the SPAF (Stroke Prevention in Atrial Fibrillation) I-III trials demonstrated that aspirin did not decrease the rate of cardioembolic stroke and that AF patients at highest risk for stroke are those with the highest rates of cardioembolic stroke and have the greatest reduction in stroke with anticoagulants.19 Thus, modest reduction in stroke observed in some trials may have been related to noncardioembolic stroke in patients with additional risk factors.

6.3.1.1 Considerations in Managing Anticoagulants

Recommendations for Considerations in Managing Anticoagulants Referenced studies that support the recommendations are summarized in the Online Data Supplement. COR LOE Recommendations

1 C-LD 1 For patients with AF receiving DOACs, optimal man-

agement of drug interactions is recommended for those receiving concomitant therapy with interacting drugs, especially CYP3A4 and/or p-glycoprotein inhibitors or inducers (Table 13).1–7

1 B-R 2 For patients with AF receiving warfarin,* a target INR

between 2 and 3 is recommended, as well as optimal management of drug-drug interactions, consistency in vitamin K dietary intake, and routine INR monitoring to improve time in therapeutic range and to minimize risks of preventable thromboembolism or major bleeding.8–10

3: Harm B-NR 3 For patients with AF, nonevidence-based doses of

DOACs should be avoided to minimize risks of preventable thromboembolism or major bleeding and to improve survival.11,12

*Excludes patients with mechanical valves. Synopsis Multiple factors need to be considered to select an optimal OAC in patients with AF. Efficacy, safety, insurance coverage, renal/hepatic function, drug interaction screening, medication adherence, and patient preferences are the major factors for consideration. Dosing of DOACs in patients with AF should be selected based on age, renal function, weight, and concomitant medications. The hepatic function also needs to be evaluated for the appropriateness of DOACs. Characteristics and dosing of OACs are summarized in Table 13. Although DOAC drug interactions occur in practice less frequently than with warfarin, clinically significant drug interactions through CYP3A4 and/or p-glycoprotein should be carefully evaluated. Strong CYP3A4 and/or p-glycoprotein inhibitors such as ketoconazole, itraconazole, and ritonavir may significantly increase DOAC plasma levels and the risk of bleeding, while strong CYP3A4 and/or p-glycoprotein inducers such as rifampin, phenytoin, phenobarbital, primidone, carbamazepine, or St. John’s wort may lower DOAC plasma levels and increase the risks of stroke or systemic embolism. The routine measurement of DOAC plasma concentrations is not indicated in practice due to the lack of well-established therapeutic ranges in the literature. DOAC levels may be indicated when clinicians assess DOAC adherence for potentially noncompliant patients, quantify residual anticoagulation levels before emergency invasive procedures/surgeries, or evaluate the absorption of DOAC after bariatric surgery. Regular monitoring is recommended to optimize indications, ensure appropriate dosing, and avoid adverse effects. Suggested laboratory monitoring is summarized in Figure 11.

If warfarin is selected over DOACs, achievement of higher time in therapeutic range (eg, ≥70%), and thorough consideration of drug-drug interactions, vitamin K food intake advice, and patient education on adherence to dosing instructions are important to reduce adverse effects.

Recommendation-Specific Supportive Text 1.	 Rivaroxaban is contraindicated for patients receiving

ketoconazole or ritonavir, because ketoconazole or ritonavir coadministration significantly increased rivaroxaban plasma levels by 158% or 153%, respectively.1 Apixaban also requires dose adjustment to 2.5 mg twice daily for patients receiving apixaban 5 mg twice daily when ketoconazole, itraconazole, or ritonavir is started.13 Apixaban plasma level was significantly increased by 99% when ketoconazole was coadministered in healthy subjects.2 The concomitant therapy of dronedarone or ketoconazole for patients with creatinine clearance (CrCl) 30 to 50 mL/min receiving dabigatran requires dose adjustment to dabigatran 75 mg twice daily because it produced comparable dabigatran exposure in patients with CrCl 30 to 50 mL/min receiving the concomitant therapy to patients with CrCl 15 to 29 mL/min receiving only dabigatran.14 A retrospective study revealed that the probability of patients with

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