taking two antiplatelet agents and individuals taking prasugrel or ticagrelor were not enrolled. The following findings were noted: In the comparison of dabigatran 110 mg twice daily with warfarin for the prevention of ischemic events, antiplatelet therapy did not significantly change the relative risk (dabigatran noninferior to warfarin) of stroke and systemic embolism. With regard to the outcome of major bleeding, the relative risk did not change significantly, but the crude https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 12/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate rates of bleeding were higher in those receiving antiplatelet therapy (2.2 versus 2.8 and 3.8 versus 4.8 percent, comparing dabigatran 110 mg with warfarin in the no antiplatelet and antiplatelet groups, respectively). In the comparison of dabigatran 150 mg twice daily with warfarin for the endpoint of ischemic events, there was a nonsignificant decrease in the relative superiority of dabigatran compared with warfarin with the use of antiplatelet therapy (HR 0.52, 95% CI 0.38-0.72 and HR 0.80, 95% CI 0.59-1.08, comparing dabigatran with warfarin in the no antiplatelet and antiplatelet groups, respectively). With regard to the outcome of major bleeding, the relative risk did not change significantly comparing dabigatran 150 mg twice daily with warfarin, but the crude rates of bleeding were higher in those receiving antiplatelet therapy (2.7 versus 2.8 and 4.4 versus 4.8 percent, respectively). Concomitant use of a single antiplatelet agent significantly increased the risk of major bleeding (HR 1.6), while dual antiplatelet therapy further increased this risk (HR 2.3). This subgroup analysis from RE-LY raises the possibility that in patients with AF treated with both oral anticoagulant and antiplatelet therapy, dabigatran might be preferred to warfarin to reduce the absolute risk of major bleeding. As discussed separately, neither aspirin alone nor in combination with clopidogrel is as effective as warfarin in preventing stroke in patients with AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of antithrombotic agents in patients with AF are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [22,47-50]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 13/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Type of anticoagulation For most patients with atrial fibrillation (AF) with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA; eg, warfarin) (Grade 1A). (See 'Choice of anticoagulant' above.) Reasons to switch to a DOAC For patients with AF who have been treated with warfarin and are comfortable with periodic international normalized ratio (INR) measurement with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to DOAC (Grade 2B). However, it is reasonable to continue VKA in these patients for issues of patient cost and preference. When to use a VKA Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include (see 'Choice of anticoagulant' above): https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 14/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Definite reasons to use a VKA Clinical settings in which VKA (eg, warfarin; target INR 2.0 to 3.0; annual TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' above): Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Patients with mechanical heart valves of any type and any location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with a (surgical or transcatheter) bioprosthetic valve implanted within the prior three to six months. (See "Transcatheter aortic valve implantation: Periprocedural and postprocedural management" and "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.) Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump inducers, which can decrease the anticoagulant effect of DOACs) ( table 2A-C) or antivirals that may increase the anticoagulant effect of DOACs. (See 'Drug interactions' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Possible reasons to use a VKA Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose estimated glomerular filtration rate (Cockcroft-Gault creatinine clearance) is less than 30 mL/min/. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting. (See 'Chronic kidney disease' above.) Types of DOACs DOACs include the oral direct thrombin inhibitor dabigatran and direct factor Xa inhibitors (eg, apixaban, edoxaban, and rivaroxaban). DOACs are generally https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 15/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate administered at fixed doses without laboratory monitoring. Given differences in the characteristics and availability of DOACs, it is important for clinicians to be familiar with the clinical use of multiple DOAC agents ( table 2A and table 3). (See 'DOACs' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Clinician familiarity with dosing'.) Target INR For patients with AF treated with VKA (eg, warfarin), the target INR is between 2.0 and 3.0 with an average annual TTR 70 percent. This is based upon the increased risk of stroke observed with INR values significantly below 2 (four- to sixfold at an INR of 1.3 compared with an INR of 2 or above) and the increased risk of bleeding associated with INR above 3.0 ( figure 1). (See 'Vitamin K antagonist' above and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bellesini M, Bianchin M, Corradi C, et al. Drug-Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review. Clin Drug Investig 2020; 40:1001. 2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. 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Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients. Stroke 2018; 49:2933. 13. Graham DJ, Baro E, Zhang R, et al. Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation. Am J Med 2019; 132:596. 14. Andersson NW, Svanstr m H, Lund M, et al. Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation. Int J Cardiol 2018; 268:113. 15. Fralick M. Effectiveness and safety of apixaban. Ann Intern Med 2020; :463. 16. Ray WA, Chung CP, Stein CM, et al. Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Patients With Atrial Fibrillation. JAMA 2021; 326:2395. 17. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363:1875. 18. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation 2013; 128:237. 19. Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1735. 20. Yoshida T, Nakamura A, Funada J, et al. Efficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial. Circulation 2022; 145:718. 21. Fuster V, Ryd n LE, Asinger RW, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 17/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation 2001; 104:2118. 22. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e531S. 23. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:546S. 24. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335:540. 25. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019. 26. European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333:5. 27. Singer DE, Chang Y, Fang MC, et al. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. 28. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014; 129:1850. 29. Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. Thromb Haemost 2011; 106:572. 30. Huber K, Airaksinen KJ, Cuisset T, et al. Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: similarities and dissimilarities between North America and Europe. Thromb Haemost 2011; 106:569. 31. Bernhardt P, Schmidt H, Hammerstingl C, et al. Patients with atrial fibrillation and dense spontaneous echo contrast at high risk a prospective and serial follow-up over 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging. J Am Coll Cardiol 2005; 45:1807. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 18/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 32. Tang RB, Dong JZ, Liu XP, et al. Is CHA2DS2-VASc score a predictor of left atrial thrombus in patients with paroxysmal atrial fibrillation? Thromb Haemost 2011; 105:1107. 33. Reynolds MW, Fahrbach K, Hauch O, et al. Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. Chest 2004; 126:1938. 34. Sadanaga T, Sadanaga M, Ogawa S. Evidence that D-dimer levels predict subsequent thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy. J Am Coll Cardiol 2010; 55:2225. 35. Rold n V, Mar n F, Mui a B, et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J Am Coll Cardiol 2011; 57:2496. 36. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018; 154:1121. 37. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 143:e72. 38. Avezum A, Lopes RD, Schulte PJ, et al. Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation 2015; 132:624. 39. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. 40. Siontis KC, Zhang X, Eckard A, et al. Outcomes Associated With Apixaban Use in Patients With End-Stage Kidney Disease and Atrial Fibrillation in the United States. Circulation 2018; 138:1519. 41. Stanifer JW, Pokorney SD, Chertow GM, et al. Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease. Circulation 2020; 141:1384. 42. Weir MR, Ashton V, Moore KT, et al. Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and stage IV-V chronic kidney disease. Am Heart J 2020; 223:3. 43. Su X, Yan B, Wang L, et al. Oral Anticoagulant Agents in Patients With Atrial Fibrillation and CKD: A Systematic Review and Pairwise Network Meta-analysis. Am J Kidney Dis 2021; 78:678. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 19/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 44. Lip GYH, Keshishian AV, Zhang Y, et al. Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With High Risk of Gastrointestinal Bleeding. JAMA Netw Open 2021; 4:e2120064. 45. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012; 126:1185. 46. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127:634. 47. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 48. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non- valvular atrial fibrillation: Executive summary. Eur Heart J 2016. 49. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 50. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1031 Version 139.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 20/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate GRAPHICS Possible contraindications to anticoagulation Possible contraindication Factors to consider Active, clinically significant Site and degree of bleeding (eg, nosebleeds and menses generally bleeding are not a contraindication; active intracerebral bleeding is almost always an absolute contraindication), interval since bleeding stopped Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis Severe thrombocytopenia Absolute platelet count, platelet count trend, and platelet function (platelet count <50,000/microL) (eg, some individuals with ITP and a platelet count in the range of 30,000 to 50,000 may tolerate anticoagulation if needed) Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a mechanical heart valve it may be appropriate to anticoagulate sooner after trauma than a patient with a lesser indication) Invasive procedure or obstetric delivery (recent, emergency, or Type of procedure and associated bleeding risk, interval between procedure and anticoagulation planned) Previous intracranial Time interval since hemorrhage and underlying cause (eg, trauma hemorrhage or uncontrolled hypertension) Intracranial or spinal tumor Site and type of tumor, other comorbidities Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives for anesthesia; traumatic procedures are more concerning Severe, uncontrolled Absolute blood pressure and blood pressure trend hypertension This list does not take the place of clinical judgment in deciding whether or not to administer an anticoagulant. In any patient, the risk of bleeding from an anticoagulant must be weighed against the risk of thrombosis and its consequences. The greater the thromboembolic risk, the greater the tolerance for the possibility of bleeding and for shortening the time interval between an episode of bleeding and anticoagulant initiation. Refer to UpToDate content on the specific indication for the anticoagulant and the specific possible contraindication for discussions of these risks. ITP: immune thrombocytopenia. Graphic 107527 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 21/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Pharmacokinetics and drug interactions of direct oral anticoagulants Potential for Metabolism pharmacokinetic Anticoagulant Bioavailability and Half-life drug clearance* interactions* Dabigatran 3 to 7% bioavailable Over 80% cleared by the 12 to 17 hours P-gp inhibitors can increase (Pradaxa) kidney dabigatran effect Unaffected by Prolonged food P-gp with kidney P-gp inducers can substrate* impairment and in older decrease dabigatran Capsule must be taken intact and requires adults effect gastric acidity for absorption Avoidance of some combinations or dose adjustment may be needed Apixaban (Eliquis) 50% bioavailable 27% cleared by the kidney 12 hours Strong dual CYP3A4 and P-gp inhibitors can increase apixaban effect Prolonged in older adults Unaffected by food Metabolized, primarily by CYP3A4 Strong CYP3A4 P-gp substrate* inducers and/or P-gp inducers can decrease apixaban effect Avoidance of some combinations or dose adjustment may be needed Edoxaban 62% bioavailable 50% cleared by the kidney 10 to 14 hours P-gp inhibitors can increase (Savaysa, Lixiana) edoxaban effect Unaffected by Reduced Prolonged in food efficacy in renal P-gp inducers can patients with nonvalvular impairment decrease edoxaban effect atrial fibrillation Avoidance of some combinations or https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 22/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate and CrCl >95 dose adjustment mL/minute may be needed Undergoes minimal CYP metabolism P-gp substrate* Rivaroxaban (Xarelto) 10 mg dose: 36% cleared by the kidney 5 to 9 hours Strong dual CYP3A4 and P-gp 80 to 100% bioavailable Prolonged to 11 to 13 inhibitors can increase Metabolized, primarily by CYP3A4 hours in older adults Unaffected rivaroxaban effect by food P-gp substrate* 20 mg dose: Strong CYP3A4 66% inducers and/or P-gp inducers can decrease rivaroxaban bioavailable if taken when fasting; increased if taken with food effect Avoidance of some combinations or dose adjustment may be needed Refer to UpToDate for dosing in specific clinical settings, including nonvalvular AF, VTE treatment, and VTE prophylaxis. Data on clearance may help assess the potential for accumulation in patients with kidney impairment. Data on metabolism may help assess potential drug interactions through alteration of CYP3A4 metabolism and/or P-gp-mediated drug efflux. Refer to Lexi-Interact, the drug interactions tool included with UpToDate, for specific drug interactions. Tables of P-gp inhibitors and inducers and CYP3A4 inhibitors and inducers are available separately in UpToDate. P-gp: P-glycoprotein drug efflux pump; CYP3A4: cytochrome p450 3A4 isoform; CrCl: creatinine clearance estimated by the Cockcroft-Gault equation; AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant. Examples of P-gp inhibitors that reduce metabolism of DOACs, leading to increased DOAC levels, include clarithromycin, ombitasvir- or ritonavir-containing combinations, and verapamil. Examples of P-gp inducers that increase DOAC metabolism, leading to lower DOAC levels, include phenytoin, rifampin, and St. John's wort. Refer to list available as a separate table in UpToDate. Examples of strong CYP3A4 inhibitors that reduce metabolism of some DOACs, leading to increased DOAC levels, include clarithromycin and ombitasvir- or ritonavir-containing combinations. Examples of strong CYP3A4 inducers that increase metabolism of some DOACs, leading to lower https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 23/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate DOAC levels, include carbamazepine, phenytoin, and rifampin. Refer to list available as a separate table in UpToDate. In patients with AF, combined use of levetiracetam or valproate with dabigatran, apixaban, or rivaroxaban was associated with an increased risk of ischemic stroke or systemic embolism. The mechanism of this interaction is unknown. [1] Inhibition of CYP3A4 (ie, without P-gp inhibition) may also increase apixaban and rivaroxaban effect, but to a lesser extent than dual inhibition of CYP3A4 and P-gp. Examples of CYP3A4 inhibitors that do not also inhibit P-gp include diltiazem, fluconazole, and voriconazole. Increased monitoring is advised. Blood levels of edoxaban were reduced and a higher rate of ischemic stroke was observed in patients with AF and CrCl >95 mL/minute who were treated with edoxaban compared with those receiving warfarin. Refer to the UpToDate topic on anticoagulation in AF for additional information. Reference: 1. Gronich N, Stein N, Muszkat M. Association between use of pharmacokinetic-interacting drugs and e ectiveness and safety of direct acting oral anticoagulants: Nested case-control study. Clin Pharmacol Ther 2021; 110:1526. Prepared with data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. Drugs@FDA: FDA-Approved Drugs. U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (Accessed on December 9, 2021). Graphic 112756 Version 19.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 24/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate Strong inducers Moderate inducers inhibitors Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and cobicistat- Conivaptan Lumacaftor Dexamethasone Crizotinib Lumacaftor- ivacaftor Dipyrone containing coformulations Cyclosporine Efavirenz Mitotane Diltiazem Elagolix, estradiol, Darunavir Phenobarbital and norethindrone therapy pack Duvelisib Idelalisib Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin (rifampicin) Fedratinib Ketoconazole Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- palonosetron Mifepristone* Pexidartinib Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- ritonavir Sotorasib Isavuconazole (isavuconazonium sulfate) St. John's wort Ombitasvir- paritaprevir- ritonavir Lefamulin Letermovir Ombitasvir- paritaprevir- Netupitant Nilotinib ritonavir plus dasabuvir Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 25/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. [1,2] These classifications are based upon US Food and Drug Administration (FDA) guidance. sources may use a different classification system resulting in some agents being classified Other differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 26/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- Neratinib Lorlatinib containing coformulations Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- ivacaftor Tamoxifen* Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole Verapamil (isavuconazonium sulfate) Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 27/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. [1,2] These classifications are based upon US FDA guidance. classification system resulting in some agents being classified differently. Other sources may use a different Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 28/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 29/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]).