The phase IV ARTESiA trial (NCT01938248) found apixaban, a factor Xa inhibitor, to be more effective than aspirin in reducing the risk of stroke in patients with subclinical atrial fibrillation. However, apixaban was associated with a higher risk of major bleeding compared to aspirin.

Methodology

• The ARTESiA study was a randomized, double-blind, placebo-controlled phase IV clinical trial.
• Patients with a CHA2DS2-VASc score of 3 or higher who had at least one episode of subclinical atrial fibrillation lasting at least 6 minutes but no longer than 24 hours were eligible for the ARTESiA study. These episodes were identified by an implanted pacemaker, defibrillator or cardiac monitor. Patients were an average age of 76.8 years old, and had no history of major bleeding in the last six months. Participants were not permitted to take open-label dual-antiplatelet therapy.
• From 2015 – 2021, 4,012 patients were enrolled in the study. Of these, 2,015 were randomly assigned to receive apixaban (5 mg BID or 2.5 mg BID according to label) and 1,997 received aspirin (81 mg/day). The mean follow up was 3.5 years.
• The primary outcome measure was a composite of ischaemic stroke and systemic embolism, while the primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Haemostasis (ISTH).

Results

• The apixaban group had a lower rate of stroke or systemic embolism than the aspirin group (2.3% vs. 3.9%). This corresponds to a 37% relative risk reduction (95% CI, 12 to 55). Fatal and permanently disabling strokes (Mod. Rankin Score 3-6) were reduced by 49%.
• Apixaban was associated with a higher rate of major bleeding risk than aspirin (3.2% vs. 1.9%). This corresponds to an 80% relative risk increase (95% CI, 1.3 to 2.6). However, during the trial investigators did not detect fatal or intracranial bleeding.  In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). The primary safety outcome, major bleeding, was assessed in the on-treatment population. Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group.

Principal Investigator Jeff Healy emphasised the significance of these findings, stating "[this is] the first time we have shown that treating subclinical atrial fibrillation with an anticoagulant prevents stroke.” Findings from ARTESiA suggest that anticoagulation therapy should be considered for patients with subclinical atrial fibrillation who have additional stroke risk factor.

Funding

ARTESiA was managed by the Population Health Research Institute (PHRI) under the supervision of Jeff S Healy and Julia W Erath. The trial was supported by grants from the Canadian Institutes of Health Research (201610PTJ-378238), the Bristol-Myers Squibb–Pfizer Alliance, the Heart and Stroke Foundation of Canada, the Canadian Stroke Prevention Intervention Network, Hamilton Health Sciences, the Accelerating Clinical Trials Network, the Population Health Research Institute, and Medtronic. Findings were published on November 12, 2023, at NEJM.org.

References

Healey JS, Lopes RD, Granger CB, et al., on behalf of the ARTESIA Investigators. Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation. N Engl J Med 2023;Nov 12:[Epub ahead of print].

Svennberg E. Editorial: What Lies beneath the Surface — Treatment of Subclinical Atrial Fibrillation. N Engl J Med 2023;Nov 12:[Epub ahead of print].

Healy JS, Maqsood N: CardioNerds @AHA23: ARTESiA: Stroke Risk Reduction in Sub-Clinical AF: Apixaban vs Aspirin. Radcliffe Cardiology 2023. https://www.radcliffecardiology.com/video-index/cardionerds-aha23-artesia-stroke-risk-reduction-sub-clinical-af-apixaban-vs-aspirin