7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation in adults: Use of oral anticoagulants : Warren J Manning, MD, Daniel E Singer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC : Peter J Zimetbaum, MD, Scott E Kasner, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 16, 2022. INTRODUCTION Most patients with atrial fibrillation (AF) should receive long-term oral anticoagulation to decrease the risk of ischemic stroke and other embolic events. For most patients, the benefit from anticoagulation outweighs the associated increase in the risk of bleeding. The use of anticoagulant therapy for patients with AF who are not pregnant (excluding those 2 with rheumatic mitral stenosis that is moderate or severe [mitral valve area 1.5 cm ], a bioprosthetic valve within three to six months of implantation, or a mechanical heart valve) will be reviewed here. Management for patients with valve disease is briefly discussed in a section below that provides links to related topics on these specific valve conditions. (See 'Patients with valvular heart disease' below.) Related topics include: (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Anticoagulation for atrial fibrillation during pregnancy. (See "Supraventricular arrhythmias during pregnancy", section on 'Atrial fibrillation and flutter' and "Use of anticoagulants during pregnancy and postpartum".) (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Stroke in patients with atrial fibrillation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 1/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate (See "Atrial fibrillation: Left atrial appendage occlusion".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) APPROACH TO ANTICOAGULATION Choice of anticoagulant For patients with AF, we suggest the following sequential steps (related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation): Determine if anticoagulation is indicated. The identification of patients who should receive long-term oral anticoagulation is discussed separately. Prior to initiation of anticoagulant therapy, possible contraindications should be weighed ( table 1). (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Select an anticoagulant. The following discussion applies to patients who are not pregnant. Selection of anticoagulant for use during pregnancy is discussed separately. (See "Supraventricular arrhythmias during pregnancy", section on 'Anticoagulation' and "Use of anticoagulants during pregnancy and postpartum".) For most patients with AF with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than vitamin K antagonist (VKA; eg, warfarin). For most patients with AF who have been treated with warfarin with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to a DOAC. However, it is reasonable to continue VKA in these patients for financial or other preferences. Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include: Clinical settings in which VKA (eg, warfarin; target international normalized ratio [INR] 2.0 to 3.0; TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' below): Patients with a mechanical heart valve of any type and location. (See "Antithrombotic therapy for mechanical heart valves".) 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'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 2/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump [P-gp] inducers, which can decrease the anticoagulant effect of DOACs and chronic antiviral agents, which may increase the anticoagulant effect of DOACs) ( table 2A-C) [1]. (See 'Drug interactions' below and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) 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 creatinine clearance (CrCl by Cockcroft-Gault equation) is less than 25 to 30 mL/min. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting, as described below. (See 'Chronic kidney disease' below.) Evidence supporting this approach comes from randomized trials in patients with nonvalvular AF in which DOAC use resulted in similar or lower rates of both ischemic stroke and major bleeding compared with treatment with adjusted-dose warfarin (INR of 2.0 to 3.0) ( table 3) [2-8]. Important additional advantages of the DOAC agents include a high relative but small absolute reduction in the risk of intracranial hemorrhage (ICH), convenience (no requirement for routine testing of the INR), lack of susceptibility to dietary interactions, and markedly reduced susceptibility to drug interactions [3-6]. Disadvantages of DOAC include lack of efficacy and safety data in patients with severe chronic kidney disease, lack of easily available monitoring of blood levels and compliance, and higher patient cost in some health care settings. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) A meta-analysis including the RE-LY (dabigatran) [3,9], ARISTOTLE (apixaban) [5], ROCKET AF (rivaroxaban) [4], and ENGAGE AF-TIMI 48 (edoxaban) [10] trials supports the broad conclusion that DOAC agents are preferable to adjusted-dose VKA for most patients [2]. Compared with VKA (warfarin), DOAC reduced rates of mortality, stroke or systemic embolic event, and hemorrhagic stroke ( table 3). https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 3/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Regarding the relative efficacy and safety of the DOAC agents, no randomized controlled trials (RCTs) directly comparing the DOACs have been published. Published observational studies have many limitations and are no substitute for head to head RCTs [11-16]. Initiation DOAC For patients with AF starting DOAC, effective anticoagulation is achieved within a few hours. We do not use heparin to bridge patients starting DOAC. For patients prescribed one of the DOACs, we suggest that clinicians review dosing recommendations from regulatory agencies and available in drug information compendia such as Lexicomp. (See 'Dosing' below.) Vitamin K antagonist Protocols for initiating VKA (eg, warfarin) are discussed separately. All patients should have an INR measured before starting therapy. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration' and 'Dosing' below.) For patients with AF starting VKA (eg, warfarin): With no intracardiac thrombus or prior history of thromboembolism, the risk of a thromboembolic event during the several days typically required to achieve therapeutic anticoagulation with warfarin is generally very low. Thus, it is reasonable for outpatients to initiate warfarin without low molecular weight heparin bridging. (See "Warfarin and other VKAs: Dosing and adverse effects".) With high risk of thromboembolism (eg, prior cerebrovascular event/transient ischemic attack or current intracardiac thrombus) and low risk of ICH, initiation of warfarin with a heparin bridging regimen may be reasonable in some clinical settings (eg, patient who is hospitalized for another condition such as heart failure and has no acute stroke) although there is no high quality evidence to support this approach. Management for patients with acute stroke is discussed below. (See 'Acute stroke' below.) Dosing DOACs Dosing recommendations for DOACs are largely derived from the doses tested in the randomized clinical trials ( table 3) [3-5,10,17,18]. Given differences in the characteristics and availability of DOACs, it is important for practitioners to develop familiarity with the clinical use of multiple DOAC agents. DOACs are generally administered at fixed doses without laboratory monitoring. Use in patients with chronic kidney disease is discussed below. (See 'Chronic kidney disease' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 4/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Use of these agents including drug interactions ( table 2A-C) and dosing in patients with chronic renal insufficiency is presented separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct thrombin inhibitors'.): Apixaban The dose of apixaban is 5 mg twice daily (approximately 12 hours apart) unless the patient has two or more of the following: age 80 years, body weight 60 kg, or serum creatinine level 1.5 mg/dL [133 micromol/L]). Then the dose of apixaban is 2.5 mg twice daily. This dose adjustment is for moderate renal impairment. Data are lacking to inform use in patients with CrCL <15 mL/min or on dialysis. (See 'Chronic kidney disease' below.) Dabigatran For patients with CrCl >30 mL/min, the dose is 150 mg twice daily (approximately 12 hours apart). For most patients prescribed dabigatran, we suggest the 150 mg twice daily dose, as opposed to the 110 mg dose, based upon the results of the RE-LY trial. Where available, the 110 mg twice daily dose may be preferred in patients assessed to be at increased risk of bleeding or who are particularly concerned about the risk of bleeding. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) For patients with CrCL 15 to 30 mL/min, the dose is 75 mg orally, twice daily. Concomitant use of a P-gp inhibitor or antiviral should be avoided. We generally avoid use of dabigatran in this setting. (See 'Choice of anticoagulant' below.) For patients with CrCl <15 mL/min or on dialysis, no dosing recommendations are available. We avoid use of dabigatran in this setting. (See 'Choice of anticoagulant' below.) Edoxaban dosing varies according to the estimated glomerular filtration rate: For patients with a Cockcroft-Gault equation CrCl >95 mL/min, edoxaban should not be used due to lesser efficacy compared with warfarin in preventing stroke in this group due to high renal clearance. For such patients, another DOAC is an alternative. For patients with a CrCl of >50 to 95 mL/min, an edoxaban dose of 60 mg once daily is used. For patients with a CrCl of 15 to 50 mL/min, the dose is 30 mg once daily. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 5/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate For patients with a CrCl of <15 mL/min, there are limited data, so edoxaban is avoided in these patients. For patients 65 years of age and with at least one of the following characteristics, the dose is 30 mg once daily: weight 60 kg or concomitant use of potent P-glycoprotein inhibitors (eg, verapamil, quinidine). For patients with advanced age ( 80 years) and low body weight (ie, 45 kg or 60 kg plus an additional risk factor), a lower dose of edoxaban (15 mg once daily) may be safe and effective. This approach is supported by the results of the ELDERCARE-AF trial in which 984 Japanese patients age 80 years or older were randomly assigned to receive edoxaban 15 mg or placebo daily [19]. The mean body weight of participants was low (50.6 11 kg). All patients were considered inappropriate candidates for standard oral anticoagulant regimens due to one or more of the following concerns: a low CrCL ( 15 and <30 mL/min), a history of bleeding, low body weight ( 45 kg), or use of a nonsteroidal antiinflammatory drug or an antiplatelet drug. The annualized rate of stroke or systemic embolism was 2.3 and 6.7 percent in the two groups, respectively (hazard ratio [HR] 0.34, 95% CI 0.19-0.61), and the rate of major bleeding was 3.3 and 1.8 percent, respectively (HR 1.87, 95% CI 0.90-3.89). ICH was rare in both groups (0.3 and 0.6 percent). In a prespecified subanalysis of this trial, findings were largely similar across different categories of renal dysfunction (ie, mild, moderate, and severe) [20]. (See 'Older adults' below.) Rivaroxaban If the CrCl is >50 mL/min, the rivaroxaban dose is 20 mg once daily with the largest meal of the day (>500 calories), usually the evening meal. If the CrCl is 15 to 50 mL/min, the rivaroxaban dose is 15 mg once daily with the largest meal of the day (>500 calories). If the CrCl <15 mL/min, avoid use of rivaroxaban. (See 'Chronic kidney disease' below.) Vitamin K antagonist For patients with AF treated with VKA (eg, warfarin), an INR between 2.0 and 3.0 is recommended with an average annual TTR >70 percent [21,22]. 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) [23-27]. Dosing of warfarin is discussed in detail separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 6/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Advanced age (over 74 years) is an independent risk factor for bleeding during anticoagulation as well as a risk factor for stroke. However, we recommend an INR between 2.0 and 3.0 for these patients as well [27]. Temporary interruption of anticoagulation Temporary interruption of oral anticoagulation for reasons of bleeding or urgent/elective surgery/invasive procedure results in an increased risk of thromboembolism after the period of effective anticoagulation has ended [28]. The optimal approach to such patients is unclear and likely depends on issues such as baseline thromboembolic risk, duration of anticoagulant interruption, and bleeding risk. These issues are discussed in detail separately. (See "Perioperative management of patients receiving anticoagulants" and "Management of anticoagulants in patients undergoing endoscopic procedures" and "Use of anticoagulants during pregnancy and postpartum" and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Urgent surgery/procedure'.) The discussion of the management of anticoagulant therapy in the patient undergoing percutaneous coronary intervention is found separately [29,30]. (See "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.) The reversal of the anticoagulant effect of warfarin and DOAC agents is discussed separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Anticoagulant reversal'.) Anticoagulant failure Thromboembolic events occur despite adequate anticoagulation in patients with AF. Predictors of these events include (see "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'): Transesophageal echocardiographic (TEE) evidence of dense spontaneous echo contrast and low left atrial appendage ejection velocity [31]. TEE evidence of complex aortic plaque [31]. TEE-detected thrombi can be related to clinical risk factors [32]. (See "Pathophysiology of ischemic stroke", section on 'Stroke subtypes'.) Subtherapeutic INR on VKA [33] or noncompliance in patients taking DOAC agents. Elevated D-dimer levels. In a single-center, prospective, observational study of 269 patients, D-dimer levels were elevated (at least 0.5 mcg/mL) in 23 percent, and elevated levels were significantly associated with a higher rate of thromboembolism (HR 15.8, 95% CI 3.33-75.5) [34]. Similarly, in a study of 829 patients with AF, elevated von Willebrand factor levels were associated with risk of thrombotic events [35]. However, we do not recommend routine https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 7/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate testing of D-dimer or von Willebrand factor in patients with AF, as incorporating such testing in anticoagulation decision-making has not been shown to alter outcomes in this setting. There are no studies of the optimal anticoagulation strategy for those experiencing a thromboembolic event. For those patients with a subtherapeutic INR with warfarin at the time of the event, an attempt should be made to identify the cause (compliance, drug/food interaction) and to consider switching to a DOAC if the annual TTR has been less than 70 percent [36]. For those on a twice-a-day DOAC, consideration of a once-a-day DOAC should be made if noncompliance is an issue. For those on a once-a-day DOAC, a different once-daily agent may be considered (eg, another once-daily DOAC or possibly warfarin because the INR can be followed). Though reasonable, none of these approaches is of proven benefit. Ischemic strokes with nonembolic causes occur in patients with AF as in patients without AF. These are not the target of anticoagulants. Occurrence of such a stroke is not a "failure" of anticoagulation. Other reasons for switching agents Some patients with AF may need to be switched from DOAC agent to VKA, from VKA to DOAC, or between DOAC agents for reasons other than anticoagulant failure (which is discussed above). (See 'Anticoagulant failure' above.) Reasons for switching from VKA to DOAC: As discussed above, most patients with AF treated with VKA should be switched to DOAC. (See 'Choice of anticoagulant' above.) Need for repeated invasive procedures, annual TTR <70 percent, convenience. Possible reasons for switching from DOAC to VKA: Out-of-pocket cost Development of severe kidney disease (see 'Chronic kidney disease' below) Development of a contraindication to DOAC use, as discussed above (see 'Choice of anticoagulant' above) Information on switching oral agents is provided separately ( table 4). (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.) Recommendations for transitioning between DOACs and parenteral anticoagulants, including unfractionated heparin and low molecular weight heparin, are available in the individual drug https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 8/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate monographs for each DOAC. Drug interactions The individual DOACs are in varying degrees eliminated by CYP3A4 metabolism or are substrates of P-glycoprotein (P-gp) efflux pump and subject to pharmacokinetic drug interactions, although fewer in number than warfarin interactions. Drugs that inhibit CYP3A4 metabolism or P-gp efflux can increase DOAC levels (ie, greater anticoagulant effect and bleeding), whereas drugs that are inducers can decrease DOAC effect, which can lead to therapeutic failure. A detailed review of the different drug interactions can be found in tables ( table 2A-C) and the Lexicomp drug interaction program within UpToDate. Additional related content is discussed separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) SPECIFIC PATIENT GROUPS Patients with valvular heart disease The above general considerations regarding choice of anticoagulant (DOAC versus VKA) apply to patients with valvular heart disease (excluding patients with rheumatic mitral stenosis that is severe or clinically significant [mitral valve area 2 1.5 cm ], a bioprosthetic valve within three to six months of implantation, or a mechanical heart valve in any location), although the evidence in patients with severe native valve disease is more limited than for the general population of AF patients [37]. (See 'Choice of anticoagulant' above.) Some patients with valvular lesions (without heart failure), such as mitral valve prolapse, nonrheumatic moderate or severe mitral regurgitation, mitral valve repair (except for the first three to six months postoperatively), or moderate or less aortic valvular conditions, have been enrolled in clinical trials of the DOACs. These trials also included a few patients (with or without heart failure) with severe native valvular conditions who were not scheduled to undergo valve replacement. As an example, in the ARISTOTLE trial, which compared apixaban with warfarin ( table 3), approximately 26 percent of the patients had a history of moderate or severe valvular heart disease or previous valve surgery (not including placement of a mechanical heart valve) [38]. While these patients had higher rates of stroke and systemic embolism than those without, the benefits of a lower rate of stroke/systemic embolism and major bleeding with apixaban (compared with warfarin) were similar to those without valvular heart disease. Approaches to antithrombotic therapy (including anticoagulation) in patients with AF with the following specific valve conditions are discussed separately: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 9/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 2 Rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ). (See "Antithrombotic therapy for mechanical heart valves" and "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Mechanical heart valve in any location. (See "Antithrombotic therapy for mechanical heart valves".) Surgically implanted bioprosthetic valve. The choice of anticoagulant after surgical valve procedures is discussed separately. (See "Antithrombotic therapy for mechanical heart valves" and 'Choice of anticoagulant' above.) Transcatheter bioprosthetic valve. The choice of anticoagulant after transcatheter valve procedures is discussed separately. (See 'Choice of anticoagulant' above and "Transcatheter aortic valve implantation: Antithrombotic therapy", section on 'General approach' and "Transcatheter mitral valve repair", section on 'Antithrombotic therapy'.) Older adults For most older patients, including those over the age of 75 years, we prefer DOACs (also referred to as non-vitamin K oral anticoagulants [NOACs]) to warfarin because of the reduced risk of intracranial hemorrhage versus warfarin. Since there are no head to head randomized trials comparing DOACs in this patient group, we do not have a preference for a specific DOAC. Dose adjustment should be made if the patient meets relevant criteria such as renal function for the DOAC. The results of the ELDERCARE-AF trial are discussed separately. (See 'Dosing' above and 'Chronic kidney disease' below.) Chronic kidney disease Who to anticoagulate Our approach to deciding which AF patients with chronic kidney disease (CKD) to anticoagulate is presented separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) Choice of anticoagulant For patients with AF and CKD stage G2 or G3 ( figure 2) treated with oral anticoagulation, most of our contributors choose a DOAC rather than VKA. However, the evidence to support this choice in patients with CKD is limited [39-43]. One contributor prefers VKA in this setting given wider clinical experience. For patients with AF and severe kidney disease (stage G4 or G5; estimated glomerular filtration 2 rate <30 mL/min/1.73 m ), on dialysis, or with acute renal injury, DOAC is generally avoided and VKA is generally the preferred long-term anticoagulant. Patients with stage 4 and 5 CKD are at higher risk of having unpredictable sudden deterioration in renal function than patients with https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 10/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate normal renal function, and such deterioration could cause an abrupt reduction in clearance of a DOAC that depends on renal metabolism. In such a setting, use of an agent such as warfarin that allows for therapeutic drug monitoring may be preferred. An annual time in the therapeutic range of >70 percent is desirable. (See "Direct oral anticoagulants (DOACs) and parenteral direct- acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease' and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) If a DOAC is chosen for a patient with stage 4 or 5 CKD or on dialysis, our contributors prefer apixaban, in part because apixaban is less dependent on kidney function for clearance than other DOACs available in the US ( table 2A). The support for use of apixaban in these patients is largely based upon our clinical experience and observational studies [40,41]. In a subgroup analysis of the ARISTOTLE trial in patients with creatinine clearance (CrCl) 25 to 30 mL/min, the risk of major bleeding was significantly less with apixaban compared with warfarin (hazard ratio [HR] 0.34, 95% CI 0.14-0.80) [41]. We avoid dabigatran in patients with stage 4 or 5 CKD because a high percentage of the drug is renally cleared. These issues are discussed further separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease'.) Based upon pharmacokinetic modeling, the US Food and Drug Administration approved DOAC dosing for use in selected patients with CKD based upon Cockcroft-Gault CrCl as described above (see 'Dosing' above). Patients at risk for gastrointestinal bleeding Risk factors for gastrointestinal bleeding in patients on oral anticoagulants have been identified. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Gastrointestinal'.) Choosing apixaban or dabigatran over rivaroxaban or warfarin may be prudent to prevent major bleeding outcomes in AF patients at high risk of gastrointestinal bleeding. In a subgroup analysis of the ARISTOPHANES observational study, 381,054 individuals anticoagulated for nonvalvular AF and who were at high risk of gastrointestinal bleeding were followed for major bleeding outcomes [44]. Compared with warfarin, apixaban and dabigatran were associated with a lower risk of major bleeding (apixaban: HR 0.59, 95% CI 0.56-0.63; dabigatran: HR 0.78, 95% CI 0.70-0.86), whereas rivaroxaban was associated with a higher gastrointestinal bleeding risk (HR 1.11, 95% CI 1.05-1.16). Acute stroke Recommendations for the management (including the role of antithrombotic therapy) of patients with AF with an acute stroke are presented separately. Patients with AF for whom anticoagulant therapy is being considered and who have had an ischemic stroke within 30 days should be referred to a neurologist or other clinician who is experienced in managing https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 11/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate antithrombotic care in such patients. Although once widely practiced, early treatment with heparin for patients with AF who have an acute cardioembolic stroke is generally avoided as studies have shown that such treatment causes more harm than good (See "Stroke in patients with atrial fibrillation" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'.) AF after surgery Approaches to OAC in patients with AF after cardiac surgery and after noncardiac surgery are discussed separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Our approach to postoperative anticoagulation' and "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery'.) Concomitant antiplatelet therapy For patients with indications for both anticoagulant for AF and for antiplatelet therapy (for a concurrent condition), any potential benefit must take into account an increased risk of bleeding with concomitant antiplatelet and anticoagulant therapy. The combination of antiplatelet and anticoagulant increases the risk of bleeding compared with either alone [45]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) The potential use of both anticoagulant and antiplatelet therapies in patients with AF is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Efficacy and safety' and "Acute coronary syndrome: Oral anticoagulation in medically treated patients" and "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.) The issue of whether aspirin is necessary for secondary prevention of cardiovascular disease in patients treated with anticoagulant for AF is discussed in detail separately. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) The impact of antiplatelet therapy on bleeding (and efficacy) outcomes in patients taking either warfarin or dabigatran was evaluated in a post-hoc subgroup analysis of the RE-LY trial (see 'Choice of anticoagulant' above) in which approximately 40 percent of patients were taking concomitant aspirin or clopidogrel at some point during the study [46]. Very few patients were 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, 12:58 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, 12:58 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, 12:58 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