Direct oral anticoagulants may be associated with fewer composite clinical events than no anticoagulation among patients with atrial fibrillation at intermediate risk of stroke.
In the multicenter, open-label, randomized superiority trial, researchers enrolled 1,803 patients aged 19 years or older at 18 centers in South Korea from July 2020 to June 2023, with outcome events adjudicated by a committee unaware of treatment assignments. Eligible patients had atrial fibrillation and intermediate stroke risk, defined as a CHA₂DS₂-VASc score of 1 in men or 2 in women. The patients were randomly assigned 1:1 to receive direct oral anticoagulants (DOAC) (n = 902) or no anticoagulation (n = 901).
The primary outcome was a composite of stroke, systemic embolism, major bleeding, or cardiovascular mortality at 24 months. Secondary outcomes included the individual components of the primary outcome, all-cause mortality, transient ischemic attack, clinically relevant nonmajor bleeding, myocardial infarction, and hospitalization. The primary outcome occurred in 4 patients assigned to DOACs and 13 assigned to no anticoagulation.
Stroke occurred in 3 patients receiving DOACs and 10 patients receiving no anticoagulation. Major bleeding occurred in 3 and 4 patients, respectively, while systemic embolism occurred in 0 and 1 patient. No cardiovascular mortality occurred in either group. Clinically relevant nonmajor bleeding occurred in 22 patients receiving DOACs and 14 receiving no anticoagulation.
The results were consistent in a sensitivity analysis that censored follow-up when patients reached a CHA₂DS₂-VASc score corresponding to a class I guideline indication for anticoagulation. The effect on the primary outcome also appeared generally consistent across the subgroups, including age, sex, heart failure, hypertension, diabetes, HAS-BLED score, and atrial fibrillation type. However, subgroup analyses were not adjusted for multiple comparisons, and the analysis by atrial fibrillation type was post hoc.
Serious adverse events occurred in 80 patients receiving DOACs and 84 receiving no anticoagulation. Intracranial hemorrhage occurred in 2 patients in the DOAC group, both of whom had hemorrhagic stroke, and 1 patient in the no-anticoagulation group, who did not have hemorrhagic stroke. The researchers noted that the small number of events precluded definitive conclusions regarding this numerical imbalance.
The trial had several limitations. Just 17 primary outcome events occurred, fewer than anticipated, which limited the precision of the treatment-effect estimate and may have resulted in an overestimate of the magnitude of benefit. The open-label design may have introduced bias despite blinded outcome adjudication, and about 5% of the patients in each group did not complete 2 years of follow-up. Antiplatelet therapy was used in about 33% of thosein the no-anticoagulation group, potentially affecting safety comparisons. Generalizability may also be limited because all participants wereenrolled in South Korea, and women and patients with nonparoxysmal atrial fibrillation may have been underrepresented.
“Given the lower-than-expected number of end-point events, the precision of the estimated treatment effect is limited, and these findings should be interpreted with caution,” wrote lead study author Daehoon Kim, MD, of the Division of Cardiology in the Department of Internal Medicine at Severance Hospital at the Yonsei University College of Medicine in South Korea, and colleagues.
The study was funded by the Ministry of Health and Welfare in South Korea, Samjin Pharmaceutical, and Hanmi Pharmaceutical. Full disclosures can be found in the study.
