11/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Patients with high frailty Patients with prior life-threatening bleeding or recurrent bleeding Patients with poorly controlled hypertension AF is common in patients with CKD [51-56], with prevalence between 8 and 35 percent in patients on hemodialysis and approximately 7 percent in patients undergoing peritoneal dialysis [57-59]. This rate is significantly higher than in the general population [60-63]. Rates are even higher in studies which used prolonged/continuous monitoring for identifying AF ( figure 3) [51,52,64]. CKD significantly increases thromboembolic risk above baseline and is also associated with increased risk of bleeding [65-68]. Studies assessing the independent predictive value of presence of CKD for thromboembolic risk beyond the CHA DS -VASc score have yielded 2 2 mixed results [65,69,70]. The thromboembolic risk associated with CKD may be due to alterations in the normal hemostatic mechanisms. The increased bleeding risk, particularly from the gastrointestinal tract, is due to pathophysiologic mechanisms including impairment of normal platelet function secondary to factors such as uremic toxins, abnormal platelet arachidonic acid metabolism, altered von Willebrand factor, and reduction in intracellular adenosine diphosphate and serotonin, as well as an increase in the frequency of the need for invasive procedures [60]. (See "Uremic platelet dysfunction".) The evidence to support OAC (vitamin K antagonist [VKA] or DOAC) is less robust in individuals with creatinine clearance <30 mL/min, as many such patients were excluded from the important randomized trials [71]. However, we believe that the benefit outweighs the risk in most cases. The efficacy and safety of warfarin in patients with AF and CKD have been evaluated in observational studies which have come to differing conclusions [66,72-77]. A 2020 meta-analysis of 15 studies (with a total of 47,480 patients with AF and end-stage renal disease) found no difference in the risk of ischemic stroke (HR 0.96, 95% CI 0.82-1.13), a higher risk of hemorrhage stroke (HR 1.46, 95% CI 1.05-2.04), and no significant difference in mortality (HR 0.95, 95% CI 0.83-1.09) or major bleeding (HR 1.20, 95% CI 0.99-1.47) in comparing warfarin users with those not taking warfarin [78]. Many of the observational cohorts did not evaluate the quality of the OAC with warfarin, such as the time in the therapeutic range (TTR). This may be relevant since evidence suggests that higher TTR is associated with better outcomes. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) Hyperthyroidism The role of anticoagulant therapy is less well defined in patients in whom the underlying disease associated with AF can be corrected, as in hyperthyroidism. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 12/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with AF attributable to hyperthyroidism, we follow the general approach described above for identifying candidates for OAC. (See 'Approach to deciding whether to anticoagulate' above.) After successful treatment of the disorder, and after documentation that AF has not been present for at least three months, most of our experts suggest discontinuing anticoagulant treatment with periodic reassessment of the patient for recurrence of AF. We consider the absence of symptoms or signs of AF and two-week continuous monitoring showing no AF as adequate documentation. Some experts prefer additional documentation. However, some of our experts make a decision about continuing anticoagulant therapy based on the CHA DS -VASc 2 2 score independent of monitored rhythm in these patients. Hypertrophic cardiomyopathy The role of OAC in patients with hypertrophic cardiomyopathy and AF is discussed separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'Long-term management'.) Patients with cancer on chemotherapy Several chemotherapy drugs have been associated with AF and atrial flutter. Depending on severity, dose reduction or discontinuation of the offending chemotherapy agent may be indicated. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".) For most patients with AF and cancer who are on chemotherapy, we follow the general approach to selection of candidates for OACs described above. (See 'Approach to deciding whether to anticoagulate' above.). For patients who have AF in the setting of chemotherapy-related thrombocytopenia, OACs may require a dose reduction in order to prevent bleeding. (See "Anticoagulation in individuals with thrombocytopenia", section on 'Atrial fibrillation and acute coronary syndromes'.) ALTERNATIVES TO ANTICOAGULATION Left atrial appendage occlusion As discussed separately, left atrial appendage occlusion is the primary alternative for patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) who have an indication for anticoagulation but have a contraindication for long-term anticoagulation. (See 'Decision-making based upon risk assessment' above and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 13/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Pharmacologic agents For patients with AF, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic oral anticoagulation (OAC). In this setting, other antithrombotic regimens are less effective in lowering thromboembolic risk than standard therapeutic OAC and some antithrombotic regimens entail a bleeding risk similar to or greater than standard therapeutic OAC: Aspirin plus clopidogrel Dual antiplatelet therapy is preferred to aspirin alone in the occasional high-risk patient with AF who cannot be treated with any OAC for a reason other than risk of bleeding. Given the availability of the direct oral anticoagulant (DOAC) agents as alternatives to vitamin K antagonists (VKAs), this situation should be extremely uncommon. One possible example is a patient with contraindications to DOAC agents who cannot receive effective international normalized ratio (INR) monitoring for VKA. Of note, dual antiplatelet therapy and OAC have similar bleeding risks. Thus, a patient who would not be a candidate for OAC because of bleeding risk is also not a candidate for dual antiplatelet therapy. In patients with AF, dual antiplatelet therapy (with aspirin plus clopidogrel) reduces the risk of thromboembolism compared with aspirin monotherapy but offers less protection against thromboembolism than OAC (with VKA or DOAC). The safety and efficacy of dual antiplatelet therapy in patients with AF were investigated in the ACTIVE W and ACTIVE A trials. All patients in the two trials had AF and one or more risk factors for stroke. The primary endpoint in both trials was a composite outcome (the first occurrence of stroke, systemic [non-central nervous system] embolization, myocardial infarction, or vascular death). The ACTIVE W trial included 6706 patients who were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to OAC with a VKA (target INR 2.0 to 3.0) [79]. The trial was stopped at an interim analysis after a median follow-up of 1.3 years because VKA lowered the annual rate of the primary endpoint compared with combined antiplatelet therapy (3.9 versus 5.6 percent; relative risk [RR] 0.69, 95% CI 0.57-0.85). The ACTIVE A trial included 7554 patients with AF who were not candidates for warfarin OAC and were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to aspirin alone at the same dose [80]. After a median follow- up period of 3.6 years, patients treated with clopidogrel plus aspirin had a significantly lower annual rate of the primary combined endpoint (6.8 versus 7.8 percent; RR 0.89, 95% CI 0.81-0.98), which was primarily driven by a reduction in stroke (2.4 versus 3.3 percent; RR 0.72, 95% CI 0.62-0.83). On the other hand, dual antiplatelet therapy resulted in a higher rate of major bleeding (2.0 versus 1.3 percent/year; RR 1.57, 95% CI 1.29-1.92). https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 14/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Aspirin monotherapy Aspirin (or other antiplatelet agent) is not an effective therapy for preventing thromboembolic events in patients with AF. In patients with AF, some but not all meta-analyses of clinical trials comparing aspirin with placebo have found that aspirin reduced the risk of stroke and systemic embolism ( table 6) [14,38,81]. In contrast, clinical trials have demonstrated that OAC (with VKA or DOAC) lowers the risk of thromboembolism compared with aspirin ( table 6) [9,14-17,82-84]. Aspirin plus low-dose warfarin In contrast to therapeutic adjusted-dose warfarin (target INR 2.0 to 3.0), low-dose warfarin (1.25 mg/day or target INR between 1.2 and 1.5) in combination with aspirin (300 to 325 mg/day) should not be used to reduce stroke risk in patients with nonvalvular AF [17,85,86]. In the SPAF-III trial of 1044 patients with AF who were at high risk for embolism, low-dose warfarin plus aspirin had a much higher rate of ischemic stroke and systemic embolism than therapeutic adjusted-dose warfarin ( figure 4A-B) [85]. Aspirin plus full-dose warfarin Limited available data suggest that there is no benefit from adding aspirin to therapeutic OAC in patients with AF. In a post-hoc analysis of the SPORTIF trials in patients with AF, among patients taking aspirin plus warfarin (or aspirin plus the factor Xa inhibitor ximelagatran) experienced similar rates of stroke and systemic embolism as those taking warfarin alone (or ximelagatran alone) [87]. The risk of major bleeding was higher with aspirin plus warfarin compared with warfarin alone (3.9 versus 2.3 percent/year). The management of antithrombotic therapy for patients with AF treated with OAC who have a concurrent indication for antiplatelet therapy is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Concomitant antiplatelet therapy'.) RECOMMENDATIONS OF OTHERS Recommendations for choosing which patients with atrial fibrillation should be anticoagulated 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 [38,88-90]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 15/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 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".) 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 Role of oral anticoagulation (OAC) in atrial fibrillation (AF) In patients with AF, OAC reduces the risk of thromboembolism by approximately two-thirds across clinical risk factor profiles but also entails an increased risk of major bleeding. Deciding whether to anticoagulate For each patient, their estimated absolute risk reduction for thromboembolic events is weighed against their estimated increase in absolute risk of intracranial hemorrhage and other life-threatening or severely debilitating bleeding complications. (See 'Approach to deciding whether to anticoagulate' above.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 16/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate CHA DS -VASc risk score Our approach to deciding whether to prescribe anticoagulant 2 2 therapy for patients with AF (excluding those with rheumatic mitral stenosis that is severe 2 or clinically significant [mitral valve area 1.5 cm ], a bioprosthetic valve [surgical or transcatheter] within the first three to six months after implantation, or a mechanical heart valve) is as follows (see 'Approach to deciding whether to anticoagulate' above): For a CHA DS -VASc score 2 in males or 3 in females (calculator 1) ( table 1), we 2 2 recommend chronic OAC (Grade 1A). For a CHA DS -VASc score of 1 in males and 2 in females (calculator 1) ( table 1): 2 2 For patients with CHA DS -VASc score of 1 in males and 2 in females based on age 2 2 65 to 74 years, we recommend chronic OAC (Grade 1A). Age 65 to 74 years is a stronger risk factor than the other factors conferring one CHA DS -VASc score 2 2 point. For patients with other risk factors, the decision to anticoagulate is based upon the specific nonsex risk factor and the burden of AF. For patients with very low burden of AF (eg, AF that is well documented as limited to an isolated episode that may have been due to a reversible cause such as recent surgery, heavy alcohol ingestion, or sleep deprivation), it may be reasonable to forgo chronic OAC and institute close surveillance for recurrent AF, although it may not be possible to reliably estimate AF burden from surveying symptoms or infrequent monitoring. (See "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery' and "Atrial fibrillation and flutter after cardiac surgery", section on 'Anticoagulation'.) For patients with a CHA DS -VASc of 0 in males or 1 in females (calculator 1) ( table 1), 2 2 we suggest against OAC (Grade 2C). Patient values and preferences may impact the decision. For example, a patient who is particularly stroke averse and is not at increased risk for bleeding (see 'Bleeding risk' above) may reasonably choose anticoagulation, particularly if the patient is a candidate for treatment with a direct oral anticoagulant (DOAC). Bleeding risk For all potential candidates for OAC, bleeding risk and related possible contraindications to OAC should be reviewed ( table 2 and table 3). (See 'Bleeding risk' above.) The appropriate use of bleeding risk assessment is to draw attention to modifiable bleeding risk factors that can be mitigated to flag high-bleeding-risk patients for early https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 17/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate review and follow-up. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk'.) Specific patient groups Our approach to OAC for patients with AF who are older, have chronic kidney disease, hyperthyroidism, and hypertrophic cardiomyopathy can sometimes differ for patients who are younger or do not have these conditions. (See 'Specific patient groups' above.) Contraindication to OAC For patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a surgical bioprosthetic valve within the first three to six months after implantation, or a mechanical valve) with an indication for OAC but who have a contraindication for long-term OAC, the primary alternative is left atrial appendage occlusion. For such patients, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic OAC. (See 'Alternatives to anticoagulation' above and "Atrial fibrillation: Left atrial appendage occlusion".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lee CJ, Toft-Petersen AP, Ozenne B, et al. Assessing absolute stroke risk in patients with atrial fibrillation using a risk factor-based approach. Eur Heart J Cardiovasc Pharmacother 2021; 7:f3. 2. Borre ED, Goode A, Raitz G, et al. 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Topic 128998 Version 11.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 25/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2