BACKGROUND: Current U.S. and European guidelines recommend oral anticoagulation as a class IIa indication in patients with atrial fibrillation at intermediate risk for stroke; however, evidence from randomized trials is needed.
METHODS: We conducted a multicenter, open-label, adjudicator-masked superiority trial in South Korea involving patients with atrial fibrillation and an intermediate risk of stroke (a score of 1 in men and 2 in women on the CHA2DS2-VASc scale; range, 0 to 9, with higher scores indicating a greater risk of stroke). Patients were randomly assigned in a 1:1 ratio to receive either direct oral anticoagulant (DOAC) therapy or no anticoagulation. The primary end point was a composite of stroke, systemic embolism, major bleeding, or death from cardiovascular causes at 24 months.
RESULTS: Of 1803 patients who underwent randomization, 902 were assigned to receive DOAC therapy and 901 were assigned to receive no anticoagulant therapy. The mean age of the patients was 60.4 years, and 23.7% were women. At 24 months, a primary end-point event had occurred in 4 patients (cumulative incidence, 0.5%) in the DOAC group and in 13 (cumulative incidence, 1.5%) in the no-anticoagulant group (difference, -1.0 percentage points; 95% confidence interval [CI], -2.0 to -0.1; P = 0.03; hazard ratio, 0.31; 95% CI, 0.10 to 0.94). Stroke occurred in 3 patients (cumulative incidence, 0.3%) in the DOAC group and in 10 (cumulative incidence, 1.1%) in the no-anticoagulant group. The incidence of systemic embolism and major bleeding appeared to be similar in the two trial groups, and no deaths from cardiovascular causes occurred in either group. Serious adverse events occurred in 80 patients (8.9%) in the DOAC group and in 84 (9.3%) in the no-anticoagulant group.
CONCLUSIONS: Among patients with atrial fibrillation at intermediate risk for stroke, DOAC therapy led to a lower risk of stroke, systemic embolism, major bleeding, or death from cardiovascular causes at 24 months than no anticoagulation. (Funded by the Ministry of Health and Welfare, South Korea, and others; SINGLE-AF ClinicalTrials.gov number, NCT04437654.).
| Discipline Area | Score |
|---|---|
| Cardiology |  |
| Hemostasis and Thrombosis | |
| Internal Medicine | |
| Neurology | |
Overall, an important study focusing on a population of patients who have been under-represented to date. It provides additional data that support using anticoagulation for stroke prevention.
This study strengthens the recommendation to include DOAC in therapy for patients at intermediate risk with atrial fibrillation and lower risk for bleeding by showing benefit in stroke reduction and no significant difference in bleeding outcomes. The only concerns I identified were a low representation of women at 25% of the study population, and a significant number of patients with active cancer with serious events when active cancer was supposed to be an exclusion based on the full criteria in the appendix and associated bleeding risks. I would have liked to see the difference in bleeding events between those with apixaban vs rivaroxaban, but this was not included in the safety data in the supplementary section.
This randomized study is significant because it focuses on a population for which, until now, the recommendation for anticoagulation has been supported primarily by observational data. There are some limitations including: limited external validity, only asiatic population, a low mean age, and only 23.7% females. A low number of events occurred, which may have overestimated the effect. In the control group, a significant percentage compared with the DOAC group (36.5% vs. 0.4%) were taking antiplatelet drugs, which may have increased bleeding in the control group and thus apparently made the benefit of the DOAC more favorable. Therefore, the study is insufficient to support a strong recommendation for OAC in the study population.
The apparent safety of DOAC-anticoagulation is still impressive, so a net benefit results even when CHADS-Vascular Scores are low.
This trial suggests that patients with a low CHADS-VASC score may benefit from DOACs. The main limitation is the small number of events for efficacy and safety. A confirmatory trial would be helpful. Results of upcoming trials of FXIa inhibition in AF are pending. This alternative intervention may be associated with greater safety.
