The Impact of a Single Study: Single-AF
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EP LAB DIGEST. 2026;26(10):5.
Bradley P Knight, MD, FACC, FHRS
Dear Readers,
Not all patients with atrial fibrillation (AF) are treated with oral anticoagulation (OAC) to prevent a stroke because, in some patients, the risk of stroke is considered to be lower than the risk of severe bleeding from OAC. Cost is also a consideration. In the modern era, OAC means treatment with a direct oral anticoagulant (DOAC), most commonly apixaban or dabigatran. Because there is a small risk of intracranial hemorrhage with OAC, it has been felt that a patient’s annual risk of stroke must exceed 1% to justify treating AF with a DOAC. Therefore, most patients with AF are treated with a DOAC only if they have more than one risk factor for stroke.
A study just published in the New England Journal of Medicine1 provides new information about the use of a DOAC in patients with AF whom most would consider at low risk for stroke. Interestingly, the study is titled “Anticoagulation for Atrial Fibrillation with Intermediate Stroke Risk,” even though most people would consider patients in the trial to be at low risk. Investigators randomized 1800 patients with a CHA2DS2-VASc score of 1 for men and 2 for women to receive either a DOAC or no DOAC. Nearly three-quarters of the patients receiving DOAC therapy received apixaban, and the remainder received dabigatran (except for one patient who received dabigatran). One limitation of the study is that antiplatelet therapy was used in one-third of the patients in the no-DOAC group. Patients were followed for 2 years.
The primary end point (a composite of stroke, systemic embolism, major bleeding, or death from cardiovascular causes) occurred in only 4 patients in the DOAC group (0.5%) versus 13 patients in the no-DOAC group (1.5%). A stroke occurred in 3 patients in the DOAC group (1 ischemic and 2 hemorrhagic) and in 10 patients in the no-DOAC group (all ischemic). There was no difference in serious adverse events between groups. During the course of the study, about 15% of patients in each group had an increase in their CHA2DS2-VASc score of at least 1 during follow-up. A sensitivity analysis censoring follow-up when the CHA₂DS₂-VASc score increased during the study was performed and did not appear to have a material impact on the results.
The investigators performed a subgroup analysis, but because the event rate was so low, the findings are not particularly useful. However, other studies have shown that not each of the factors included in the CHA2DS2-VASc score are equally predictive. For example, age is probably the strongest predictor of stroke. It is also likely that the risks associated with some factors exist along a continuum. For example, a 60-year-old patient is likely at higher risk of stroke than a 30-year-old patient. It is also increasingly recognized that AF burden is a predictor of stroke that is not included in the CHA2DS2-VASc score. Therefore, it would not be unreasonable to advise a 60-year-old man with advanced heart failure and permanent AF to take a DOAC, even though his CHA2DS2-VASc score is only 1.
How will the results of the SINGLE-AF study affect the use of OAC in patients with AF? What can patients now be told? One message is that the risk of an ischemic stroke from AF in a man with a CHA2DS2-VASc score of 1—or a woman with a score of 2—is very low, at approximately 0.5% per year. Taking a DOAC reduces that risk even further, to almost zero, but carries a very small increased risk of hemorrhagic stroke—approximately 0.1% per year. Because these outcomes were so infrequent in the SINGLE-AF study, the statistical power of the findings is limited. However, it is likely that these small numbers will still have a big impact on patient care.
Disclosures: Dr Knight has served as a paid consultant to Medtronic and was an investigator in the PULSED AF trial. He has served as a consultant, speaker, investigator, and/or has received EP fellowship grant support from Abbott, AltaThera, AtriCure, Baylis Medical, Biosense Webster, Biotronik, Boston Scientific, CVRx, Philips, and Sanofi; he has no equity or ownership in any of these companies. Dr Knight reports payment or honoraria from Convatec for a lecture.
