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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 January 2, 2024 e37

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

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Table 13.  OACs Pharmacokinetic Characteristics and Dosing

Class VKA Direct Thrombin Inhibitor Factor Xa Inhibitor Name Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Metabolism S-isomer: CYP2C9 R-isomer: CYP1A2, CYP2C19, CYP3A4 Minimal CYP3A4/5 CYP3A4 Minimal CYP3A4 P-glycoprotein substrate No Yes Yes Yes Yes Excretion 0% renal; very little warfarin excreted unchanged in urine 80% renal 66% renal, 28% feces 27% renal, 73% biliary and intestinal 50% renal, 50% liver and biliary/intestinal Half-life 20-60 h 12-17 h 5-9 h 12 h 10-14 h Renal dosing adjustment based on actual body weight N/A CrCl >30 mL/min 150 mg twice daily CrCl >50 mL/min 20 mg daily with the biggest meal* 5 mg twice daily CrCl >50– ≤95 mL/ min 60 mg once daily

CrCl 15- 30 mL/ min 75 mg twice daily CrCl 15-50 mL/ min 15 mg daily with the biggest meal* If any 2 of the following: age ≥80y, body weight ≤60 kg, SCr ≥1.5 mg/dL 2.5 mg twice daily CrCl 15- 50 mL/ min 30 mg once daily

Drug interaction management based on concomitant therapy of CYP3A4 inhibitors/ p-glycoprotein inhibitors Adjust dose based on INR trends CrCl 30-50 mL/min with concomitant use of dronedarone or systemic ketoconazole: 75 mg twice daily CrCl <30 mL/min: avoid dabigatran use concomitantly with dronedarone or systemic ketoconazole Avoid rivaroxaban use with concomitant therapy of combined p-glycoprotein and strong CYP3A4 inhibitors (eg, systemic ketoconazole and ritonavir) No dose adjustment required with clarithromycin Avoid rivaroxaban use in patients with CrCl 15–<80 mL/min receiving combined p-glycoprotein and moderate CYP3A4 inhibitors (eg, erythromycin) In patients receiving apixaban 5 mg twice daily, reduce dose to 2.5 mg twice daily when combined p-glycoprotein and strong CYP3A4 inhibitors (eg, itraconazole, systemic ketoconazole, ritonavir) are used concomitantly If patients already receiving apixaban 2.5 mg twice daily, avoid apixaban use if combined p-glycoprotein and strong CYP3A4 inhibitors are concomitantly used No dose adjustment is required Drug interaction management based on concomitant therapy of p-glycoprotein/ CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) Adjust dose based on INR trends Avoid use Avoid use Avoid use Avoid use with rifampin. No study evaluated the effect of other p-glycoprotein/CYP3A4 inducers on edoxaban drug levels

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