Lowered Stroke Rates and Increased Risk of Bleeding With Apixaban as Preventive for Subclinical Atrial Fibrillation

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For patients on apixaban, the risk of stroke or systemic embolism was lowered by 37% and the risk of disability or fatal stroke was lessened by 49%.

Jeff Healey, MD, director of arrhythmia services and associate professor of medicine at McMaster University in Hamilton, Ontario

Jeff Healey, MD

The ARTESIA trial (NCT01938248) published in the New England Journal of Medicine revealed that treatment with apixaban, a direct-acting oral anticoagulant, can more effectively lower the risk of stroke or systemic embolism than aspirin in patients with subclinical atrial fibrillation; however, the treatment was associated with increased risk of major bleeding.1

The study included 4012 patients 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 those with subclinical atrial fibrillation that was detected by an implanted pacemaker, defibrillator, or cardiac monitor.

Led by Jeff Healey, MD, director of arrhythmia services and associate professor of medicine at McMaster University in Hamilton, Ontario, stroke or systemic embolism occurred in 55 patients assigned to receive apixaban (0.78% per patient-year) and 86 patients assigned to receive aspirin (1.24% per patient-year)(HR, 0.63; 95% CI, 0.45-0.88; P = .007). In terms of the second primary outcome, the risk of major bleeding was 1.71% per patient-year with apixaban and 0.94% per patient-year 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 death occurred in 457 patients (22.7%) in the apixaban group and in 438 patients (21.9%) in the aspirin group. 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 (interquartile range, 0.20-4.95).

For patients who experienced stroke, 33% (18 of 55) of those in the apixaban group and 43% (36 of 84) of those in the aspirin group had their severity assessed as being disabling or fatal, defined by modified Rankin Scale scores of 3-6. Despite a similar number of deaths between the groups, 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

  1. Apixaban Superiority: Apixaban lowers stroke risk more effectively than aspirin in subclinical atrial fibrillation patients, with a noted bleeding risk.
  2. Bleeding Concerns: Treatment with apixaban increases major bleeding risk compared to aspirin in subclinical atrial fibrillation patients.
  3. 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% per patient-year with apixaban and 1.29% per patient-year 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 (NCT02618577), an event-driven study that was terminated early. Published in the New England Journal of Medicine in 2023, 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 was different from ARTESIA in that it was stopped early, had relatively few stroke events, and was thus underpowered. Secondly, the primary outcome of NOAH-AFNET 6 included a composite of cardiovascular death in addition to stroke and systemic embolism. “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

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
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