A stroke may be preventable even when atrial fibrillation falls below the high-risk threshold, with blood-thinning drugs reducing serious complications without increasing major bleeding.
The SINGLE-AF trial provides the first randomized evidence that direct oral anticoagulants (DOACs) can benefit people with atrial fibrillation and an intermediate risk of stroke. Over two years, these medications reduced the combined risk of stroke, systemic embolism, major bleeding, or cardiovascular death by 69% compared with no anticoagulation.
The results were presented during a Hot Line session at ESC Congress 2026 and simultaneously published in the New England Journal of Medicine.
The Anticoagulation Gray Area
Atrial fibrillation (AF) causes the heart’s upper chambers to beat irregularly, allowing blood to pool and potentially form clots. If a clot travels to the brain, it can block an artery and cause an ischemic stroke. Anticoagulants lower that risk, but physicians must weigh the benefit against the possibility of serious bleeding.
ESC Guidelines strongly recommend oral anticoagulants for patients with AF and a high risk of stroke. For those at intermediate risk, anticoagulation receives a Class IIa recommendation, meaning it should be considered but is not advised as firmly.
“Evidence from observational studies with anticoagulants, particularly vitamin K antagonists, remains conflicting in those at intermediate risk. SINGLE-AF was conducted to provide the first evidence from a randomized trial on whether newer direct oral anticoagulants (DOACs) are beneficial in patients with AF at intermediate risk of stroke,” said principal investigator Professor Boyoung Joung of Yonsei University in Seoul, South Korea.
Testing DOACs Against No Treatment
The open-label trial included 1,803 people treated at 18 centers in South Korea. Each participant had AF and an intermediate stroke risk (defined as a CHA₂DS₂-VASc score of 1 in men or 2 in women).
Researchers randomly assigned participants (1:1) either to receive no anticoagulant or to take a DOAC (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily). Unlike older vitamin K antagonists, these medications act directly on specific proteins involved in blood clotting.
After 24 months, the primary outcome occurred in 0.5% of patients taking a DOAC and 1.5% of those receiving no anticoagulation (0.5% and 1.5%, respectively; p=0.028; hazard ratio 0.31; 95% confidence interval 0.10 to 0.94). That represents a 69% relative reduction and an absolute difference of 1 percentage point.
Fewer Ischemic Strokes
The overall benefit appeared to be driven largely by ischemic stroke, which affected 0.1% of patients receiving DOAC therapy and 1.1% of those taking no anticoagulant. The primary outcome also included systemic embolism, major bleeding, and cardiovascular death.
Crucially, the reduction in adverse events was not accompanied by more major bleeding. Major bleeding occurred in 0.3% of the DOAC group and 0.5% of the group receiving no anticoagulation.
“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. Data from the SINGLE-AF trial may be used to inform future guideline recommendations and reimbursement policies,” Professor Joung concluded.
Reference: “Anticoagulation for Atrial Fibrillation with Intermediate Stroke Risk” by Daehoon Kim, Young Soo Lee, Jaemin Shim, Hee Tae Yu, Junbeom Park, Jin-Kyu Park, Il-Young Oh, Ki-Woon Kang, Eue-Keun Choi, Kyoung-Min Park, Hyoung-Seob Park, Dae-Hyeok Kim, Hyung Wook Park, Jun Kim, Jum-Suk Ko, Dongmin Kim, Jong-Youn Kim, Jin-Bae Kim, Jung-Hoon Sung, Tae-Hoon Kim, Jae-Sun Uhm, Hui-Nam Pak and Boyoung Joung, 27 August 2026, New England Journal of Medicine.
DOI: 10.1056/NEJMoa2607978
The trial was funded by the Ministry of Health and Welfare, Republic of Korea, Samjin Pharmaceutical and Hanmi Pharmaceutical.
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