SINGLE-AF
(2026)Objective
To determine whether direct oral anticoagulant (DOAC) therapy reduces adverse clinical events compared with no anticoagulation in patients with atrial fibrillation at intermediate risk of stroke (CHA2DS2-VASc score of 1 in men or 2 in women).
Study Summary
• Stroke occurred in 0.3% (3 patients) with DOAC vs 1.1% (10 patients) with no anticoagulation (HR 0.30; 95% CI 0.08–1.08)
• Ischemic stroke or systemic embolism (post hoc): 0.1% vs 1.1% (HR 0.10; 95% CI 0.01–0.77)
• Major bleeding was similar: 0.3% vs 0.5% (HR 0.75; 95% CI 0.17–3.35); no cardiovascular deaths in either group
• Serious adverse events: 8.9% (DOAC) vs 9.3% (no anticoagulation)
Intervention
DOAC therapy (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily, with prespecified dose reductions) versus no oral anticoagulation
Inclusion Criteria
Age ≥19 years, atrial fibrillation, intermediate stroke risk (CHA2DS2-VASc score of 1 in men or 2 in women)
Study Design
Arms: DOAC therapy — apixaban 5 mg BID or rivaroxaban 20 mg daily (n=902) vs No anticoagulant therapy (n=901)
Patients per Arm: DOAC: 902; No anticoagulation: 901
Outcome
• Stroke: 0.3% vs 1.1% (HR 0.30; 95% CI 0.08–1.08); TIA: 0 vs 3 patients
• Major bleeding: 0.3% vs 0.5% (HR 0.75; 95% CI 0.17–3.35); clinically relevant nonmajor bleeding: 2.5% vs 1.6% (HR 1.58; 95% CI 0.81–3.08)
• Death from any cause: 0.3% vs 0.6% (HR 0.60; 95% CI 0.14–2.51); no cardiovascular deaths
• Win ratio for DOAC vs no anticoagulation: 3.31 (95% CI 1.15–9.54); effect consistent across subgroups
Bottom Line
In patients with atrial fibrillation at intermediate stroke risk, DOAC therapy reduced the composite of stroke, systemic embolism, major bleeding, or cardiovascular death at 24 months compared with no anticoagulation (0.5% vs 1.5%; HR 0.31), without an apparent increase in major bleeding — providing randomized-trial support for anticoagulating this class IIa population.
Major Points
- First randomized trial directly comparing DOAC therapy with no anticoagulation in intermediate-stroke-risk atrial fibrillation (CHA2DS2-VASc 1 in men, 2 in women).
- Primary composite end point (stroke, systemic embolism, major bleeding, or cardiovascular death) at 24 months: 0.5% with DOAC vs 1.5% with no anticoagulation (difference −1.0 pp; 95% CI −2.0 to −0.1; P=0.03; HR 0.31; 95% CI 0.10–0.94).
- Stroke: 0.3% vs 1.1% (HR 0.30; 95% CI 0.08–1.08); post hoc ischemic stroke or systemic embolism: 0.1% vs 1.1% (HR 0.10; 95% CI 0.01–0.77).
- Major bleeding was similar between groups (0.3% vs 0.5%; HR 0.75); no cardiovascular deaths occurred in either group.
- Win-ratio sensitivity analysis favored DOAC (3.31; 95% CI 1.15–9.54); treatment effect appeared consistent across subgroups.
- Event rates were far lower than the assumptions used for the power calculation (0.5%/1.5% observed vs 2.0%/4.5% assumed).
- Apixaban 5 mg was the most commonly used DOAC (67.4%); DOACs were full-dose in 81.6% of treated patients; 36.5% of the no-anticoagulant group received antiplatelet therapy.
Study Design
- Study Type
- Investigator-initiated, multicenter, open-label, randomized superiority trial with blinded (adjudicator-masked) outcome adjudication
- Randomization
- Yes
- Blinding
- Open-label with blinded adjudication of outcome events by an independent clinical-events committee
- Sample Size
- 1803
- Follow-up
- 24 months (median follow-up 730 days); assessments at baseline and 3, 6, 12, 18, and 24 months
- Centers
- 18
- Countries
- South Korea
Primary Outcome
Definition: Composite of stroke, systemic embolism, major bleeding (ISTH-defined), or death from cardiovascular causes (amended January 2025 from death from any cause, before unblinding, by the DSMB)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 13/901 (cumulative incidence 1.5%) | 4/902 (cumulative incidence 0.5%) | 0.31 (HR 0.10 to 0.94; risk difference −2.0 to −0.1) | P=0.03 |
Limitations & Criticisms
- Open-label design (though outcome adjudication was blinded)
- Conducted entirely in South Korea with a predominantly male (76%) population, limiting generalizability
- Observed event rates (0.5% vs 1.5%) were much lower than the assumed 2.0% vs 4.5%, yielding few events (4 vs 13) and wide confidence intervals
- Primary end point was amended during the trial (death from any cause narrowed to cardiovascular death), although this was done by the blinded DSMB and described previously
- 36.5% of the no-anticoagulant group received antiplatelet therapy and 5.5% crossed over to DOAC, which could attenuate or confound the comparison
- No multiplicity adjustment for secondary and subgroup analyses
Citation
Kim D, Lee YS, Shim J, et al. Anticoagulation for Atrial Fibrillation with Intermediate Stroke Risk. N Engl J Med. Published August 28, 2026. DOI: 10.1056/NEJMoa2607978