Apixaban Reduced Risk of Stroke in Subclinical Afib Relative to Aspirin but with Greater Risk of Bleeding: ARTRESIA Trial

Treatment with the direct-acting oral anticoagulant (DOAC) apixaban, more effectively lowered risk of stroke or systemic embolism compared with aspirin in patients with subclinical atrial fibrillation; however, the treatment was associated with increased risk of major bleeding.1

Jeff Healy, MD

The findings, from the ATRESIA trial, led by Jeff Healey, MD, director of arrhythmia services and associate professor of medicine at McMaster University in Hamilton, Ontario, were published in the New England Journal of Medicine.

The study included 4012 adults with subclinical atrial fibrillation lasting 6 minutes to 24 hours who were randomly assigned to receive apixaban at a dose of 5 mg twice daily (n = 2015) or aspirin at a dose of 81 mg daily (n = 1997). If subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed, the apixaban or aspirin was stopped, follow-up was continued, and treatment with an open-label anticoagulant was initiated. The study included only participants with subclinical atrial fibrillation that was detected by an implanted pacemaker, defibrillator, or cardiac monitor.

The intent-to-treat population had a mean age of 76.8 (±7.6) years and a mean CHA₂DS₂-VASc score of 3.9 (±1.1). The median duration of the longest episode of subclinical atrial fibrillation in the 6 months before trial enrollment was 1.47 hours.

Healey et al reported that stroke or systemic embolism occurred in 55 patients assigned to receive apixaban (0.78% per patient-year [PPY]) and 86 patients assigned to receive aspirin (1.24% per patient-year )(HR, 0.63; 95% CI, 0.45-0.88; P = .007). For the second primary outcome, the risk of major bleeding, the result was 1.71% PPY with apixaban and 0.94% PPY with aspirin (HR, 1.80; 95% CI, 1.26-2.57; P = .001). Between-group differences were also observed in ischemic stroke (HR, 0.62; 95% CI, 0.43-0.91) and in stroke from any cause (HR, 0.64; 95% CI, 0.46-0.90).

During follow-up there were 457 (22.7%) deaths in the apixaban-treated group and 438 (21.9%) in the aspirin-treated group.

Among participants who experienced stroke, severity was assessed as being disabling or fatal in 33% (18 of 55) of those in the apixaban group and 43% (36 of 84) of those in the aspirin group (defined by modified Rankin Scale scores of 3-6). Despite a similar number of deaths in each group, the risk of fatal stroke was 49% lower in the apixaban group than with aspirin (HR, 0.51; 95% CI, 0.29-0.88). In terms of safety, fatal bleeding occurred in 5 patients with apixaban and 8 patients with aspirin.

Clinical Takeaways

Apixaban Superiority: Apixaban lowers stroke risk more effectively than aspirin in subclinical atrial fibrillation patients, with a noted bleeding risk.

Bleeding Concerns: Treatment with apixaban increases major bleeding risk compared to aspirin in subclinical atrial fibrillation patients.

Risk-Benefit Assessment: Clinicians must weigh the benefits of reduced stroke risk against the increased bleeding risk with apixaban therapy.

Sensitivity analyses were performed in the on-treatment population (all the patients who had undergone randomization and received at least 1 dose of the assigned trial drug) with follow-up censored 5 days after permanent discontinuation of trial medication for any reason. The mean duration of follow-up was 3.5 (±1.8) years for the intention-to-treat analysis and 2.5 (±1.8) years for the on-treatment analysis. In the on-treatment analysis, the risk of stroke or systemic embolism was 0.71% PPY with apixaban and 1.29% PPY with aspirin (HR, 0.55; 95% CI, 0.37-0.83; P = .004).

Healey et al wrote, "In considering the clinical benefit of apixaban therapy in patients with subclinical atrial fibrillation, one needs to assess both the benefits and risks. Simply counting strokes as compared with bleeding events might suggest a neutral overall effect."

The investigators noted that these results must be placed in the context of the NOAH-AFNET 6 trial, an event-driven study that was terminated early. Published in the New England Journal of Medicine in 2023,² the trial randomly assigned patients 65 years of age or older who had atrial high-rate episodes (AHREs) lasting for at least 6 minutes 1:1 to either edoxaban or placebo. All told, the study showed no significant between-group difference in the incidence of a composite of stroke, systemic embolism, or death from cardiovascular causes or the incidence of stroke.²

NOAH-AFNET 6, however, differed in several important ways from ARTESIA. The former had relatively few stroke events and was thus underpowered; the study also was stopped early.² Secondly, the primary outcome of NOAH-AFNET 6 included a composite of cardiovascular death in addition to stroke and systemic embolism.²

“The use of aspirin in the control group in the ARTESIA trial probably had little effect on the signal for reduction in stroke but almost certainly mitigated the signal for harm, because aspirin is known to increase bleeding. However, the difference in the control groups of the two trials does not explain the fact that the ARTESIA trial showed a significant reduction in stroke and the NOAH-AFNET 6 trial did not,” Healey et al noted.¹

This article originally appeared on partner website NeurologyLive and has been lightly edited.

REFERENCES
1. Healey JS, Lopes RD, Granger CB, et al. Apixaban for stroke prevention in subclinical atrial fibrillation. NEJM. 2024;390:107-117. doi:10.1056/NEJMoa2310234
2. Kirchof P, Toennis T, Goette A, et al. Anticoagulation with edoxaban in patients with atrial high-rate episodes. NEJM. 2023;389:1167-1179. doi:10.1056/NEJMoa2303062