Newer blood thinners significantly lower serious cardiovascular events in patients with atrial fibrillation who face an intermediate risk of stroke, according to findings from the SINGLE-AF trial. Presented during a Hot Line session at the ESC Congress 2026 and published simultaneously in the New England Journal of Medicine, the study shows that direct oral anticoagulants reduce adverse clinical outcomes without increasing major bleeding rates compared to receiving no treatment.
Evaluating Atrial Fibrillation at Intermediate Stroke Risk
Atrial fibrillation is a common heart rhythm disorder that can increase the risk of blood clots and stroke. Current European Society of Cardiology Guidelines strongly recommend oral anticoagulants for patients diagnosed with atrial fibrillation who face a high risk of stroke. For individuals categorized at intermediate risk, however, the clinical recommendation remains less definitive, listing anticoagulant therapy as an option that should be considered rather than a mandatory intervention.
This clinical uncertainty has persisted because earlier observational research produced mixed results, particularly when evaluating older vitamin K antagonist drugs. Professor Boyoung Joung from Yonsei University in Seoul, South Korea, served as principal investigator for the trial. “Evidence from observational studies with anticoagulants, particularly vitamin K antagonists, remains conflicting in those at intermediate risk,” Professor Joung noted regarding the motivation behind the research. The SINGLE-AF trial was designed to provide the first randomized evidence assessing whether newer direct oral anticoagulants offer a clear benefit for this specific patient population.
Design and Findings of the SINGLE-AF Trial
The SINGLE-AF trial operated as an open-label study across 18 medical centers in South Korea. Researchers enrolled 1,803 participants diagnosed with atrial fibrillation and an intermediate risk of stroke, defined as a CHA2DS2-VASc score of 1 for men or 2 for women. Participants were randomized in a 1:1 ratio into two distinct treatment paths. One group received direct oral anticoagulant therapy using either apixaban at 5 mg twice daily or rivaroxaban at 20 mg once daily, while the control group received no anticoagulation therapy.
After 24 months of observation, investigators recorded a 69% reduction in the trial’s primary composite endpoint among patients taking direct oral anticoagulators compared to those receiving no treatment. This primary endpoint combined stroke, systemic embolism, major bleeding, and cardiovascular death. Serious adverse events occurred in 0.5% of patients in the direct oral anticoagulant group, contrasted with 1.5% of patients in the untreated control group, yielding a statistically significant hazard ratio of 0.31.
| Clinical Outcome (24-Month Data) | Direct Oral Anticoagulants (DOAC) Group | No Anticoagulation Group |
|---|---|---|
| Primary Endpoint (Combined Events) | 0.5% | 1.5% |
| Ischemic Stroke Incidence | 0.1% | 1.1% |
| Major Bleeding Incidence | 0.3% | 0.5% |
The overall reduction in events was driven largely by a sharp decrease in ischemic strokes. Ischemic stroke occurred in just 0.1% of patients taking direct oral anticoagulants, compared to 1.1% of patients receiving no anticoagulation. Crucially, the trial tracked safety outcomes closely and found no accompanying increase in major bleeding. Major bleeding occurred in 0.3% of the active treatment group and 0.5% of the untreated group, confirming that the protective cardiovascular benefits came without a measurable penalty in bleeding risk.
Implications for Clinical Practice and Future Guidelines
The trial results provide randomized data supporting the use of direct oral anticoagulants in an intermediate-risk patient demographic where treatment efficacy was previously difficult to quantify. “We now have evidence from a randomized trial that patients with AF at intermediate stroke risk benefit from DOAC therapy, without an increase in major bleeding,” Professor Joung stated, highlighting the clinical relevance of the findings. Data from the research project are expected to influence future guideline recommendations and inform future health insurance reimbursement policies.