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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 January 2, 2024 e35

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

gave a stroke rate of 2.59 in ATRIA14 and 3.5 in the Swedish cohort.13 Therefore, the stroke risk of patients in the rivaroxaban2 and edoxaban4 trials was likely >2% given a required minimum CHADS2 score of 2, and lower in the apixaban3 and dabigatran1 trials that included scores of 0 and 1. A Markov state transition decision model16 concluded that anticoagulation was preferred for a stroke rate of 1.7%. Therefore, a stroke and systemic embolism risk threshold of 2% is likely to yield a benefit that far exceeds risk. In some conditions, such as hypertrophic cardiomyopathy, the risk of stroke is high enough independent of risk score to indicate anticoagulation.17

2 In the randomized DOAC trials, all DOACs

achieved noninferiority1–4 and in 2 trials (for dabigatran, RE-LY, and for apixaban, ARISTOTLE) were superior to warfarin. With warfarin, regular assessment of the INR is necessary to maintain a therapeutic value. In the RCTs, the mean time in therapeutic range was only 55% in ROCKET AF2 and highest at 66% in ARISTOTLE.3 In a metaanalysis,6 DOACs, compared with warfarin, had a relative risk of stroke of 0.81 (95% CI, 0.73-0.91; P<0.0001), a relative risk of mortality of 0.90 (95% CI, 0.85-0.95; P=0.0003), relative risk of ICH of 0.48 (95% CI, 0.39-0.59; P<0.0001), and increased relative risk of bleeding of 1.25 (95% CI, 1.01-1.55; P=0.043). Although patients with moderate to severe mitral stenosis or mechanical valve were excluded from DOAC trials (and subsequently shown they may have worse outcomes with DOACS), other forms of VHD were allowed, such as aortic stenosis or regurgitation or mitral regurgitation. Bioprosthetic valves and valve repair were allowed in the edoxaban (ENGAGE AF) and apixaban (ARISTOTLE) trials, and valve repair in the rivaroxaban (ROCKET AF) trial. A systematic review18 of patients with VHD (other than mitral stenosis or mechanical valve) concluded that DOACs were safe. 3.	 As the DOAC trials1–4 demonstrated improved

safety compared with warfarin, the threshold of using a DOAC might be different than for warfarin.16 A Markov decision model found the tipping point for warfarin to be at 1.7%/year stroke risk.16 Considering the improved ICH and mortality risk of DOACs compared with warfarin in meta-analyses of the DOAC trials,5–7 it is appropriate to designate a lower stroke risk threshold if a DOAC is utilized. The dabigatran1 and apixaban3 trials included lower risk patients and about one-third of patients had a CHADS2 score of 0 or 1. This likely corresponds to an estimated annual stroke risk of about 1%, considering more recent cohorts.13,14 This is further supported by meta-analyses that showed a consistent benefit of DOACs across a broad range of vulnerable patients, including as classified by CHADS2 scores.6,7

4 A meta-analysis of AF trials from the 1990s and

early 2000s found that while antiplatelet therapy (APT), most commonly aspirin, reduced stroke and systemic embolism compared with placebo, APT was inferior to warfarin in patients with AF.11 Aspirin was studied compared to apixaban in the AVERROES trial (Apixaban Versus ASA to Prevent Stroke In AF Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment)9 for patients unsuitable for VKAs; this trial was stopped early due to the benefit of apixaban over aspirin to prevent stroke or systemic embolism, while major bleeding was similar between the 2 arms. The combination of clopidogrel and aspirin was compared to VKAs in ACTIVEW (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events),8 and this trial was stopped prematurely due to the superiority of anticoagulation with VKAs to prevent stroke, non–central nervous system systemic embolus, MI, or vascular death. Unless there is an indication for antiplatelet therapy, such as coronary artery disease (CAD) or vascular disease, patients with AF should not be prescribed antiplatelet therapy to reduce stroke risk.

Figure 10. Antithrombotic Options in Patients With AF. Colors correspond to Table 2. AF indicates atrial fibrillation; and DOAC, direct oral anticoagulant.

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