Oral anticoagulation is a cornerstone of stroke prevention in atrial fibrillation (AF), and its benefit is well-established in patients at high risk for stroke, defined as a CHA₂DS₂-VASc score of 2 or more in men and 3 or more in women. Guidelines recommend anticoagulation in these patients without reservation. The picture is less clear for patients at intermediate risk (a score of 1 in men or 2 in women), where the annual stroke rate is low and the tradeoff with bleeding becomes more relevant. The 2023 AHA/ACC/ACCP/HRS guideline offers a measured Class 2a recommendation, stating that anticoagulation "is reasonable" in this group, and adds that patients who remain uncertain may benefit from consideration of factors that modify stroke risk (e.g., alcohol intake, physical activity, blood pressure control). That recommendation was based on observational data, as no randomized trial had specifically enrolled patients at intermediate risk. The SINGLE-AF trial was designed to address this gap.

SINGLE-AF was a multicenter, open-label, adjudicator-masked superiority trial conducted in South Korea. A total of 1,803 patients with AF and an intermediate risk of stroke (mean age 60.4 years, 23.7% women, 71.8% paroxysmal AF, mean CHA₂DS₂-VASc score 1.3, mean HAS-BLED score 0.5) were randomized 1:1 to DOAC therapy (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily) or no anticoagulation. In the no-anticoagulation group, antiplatelet therapy was permitted when clinically indicated and temporary anticoagulation was allowed around cardioversion or ablation. The primary endpoint was a composite of stroke, systemic embolism, major bleeding, or death from cardiovascular causes at 24 months. The primary endpoint occurred in 4 patients (0.5%) in the DOAC group and 13 patients (1.5%) in the no-anticoagulation group (difference −1.0 percentage points, 95% CI −2.0 to −0.1; P=0.03; HR 0.31, 95% CI 0.10–0.94). Stroke occurred in 3 patients (0.3%) and 10 patients (1.1%), respectively. Major bleeding was similar at 0.3% and 0.5% (HR 0.75, 95% CI 0.17–3.35), as was clinically relevant nonmajor bleeding (2.5% vs 1.6%). No cardiovascular deaths occurred in either group. Notably, 36.5% of the no-anticoagulation group received antiplatelet therapy during the trial, and 5.5% received a DOAC at some point.

Several limitations temper the findings. The trial was open-label, which can influence how symptoms are pursued and whether events are diagnosed, although outcome adjudication was masked. More importantly, the entire primary endpoint rested on 17 events across 1,803 patients. With numbers this small, a handful of reclassified events would erase significance, as reflected in the confidence interval for the hazard ratio, whose upper bound (0.94) sits just below 1. The relative risk reduction of 69% sounds impressive, but the absolute risk reduction was 1.0 percentage point over two years, a number needed to treat of approximately 100. In addition, more than a third of the control group received antiplatelet therapy, which does little to prevent AF-related stroke while still increasing bleeding risk, so the comparison was not truly DOAC versus no antithrombotic therapy. Finally, the trial was conducted entirely in South Korea, and East Asian populations have stroke and bleeding profiles that differ from other groups, limiting generalizability.

• Anticoagulation for Atrial Fibrillation with Intermediate Stroke Risk, N Engl J Med (2026) [PubMed abstract]
• Atrial fibrillation review