Apixaban and Aspirin Appear Equal Against Recurrent Stroke in Individuals with Cardiopathy

In individuals with cryptogenic stroke and evidence of cardiopathy without atrial fibrillation (AF), anticoagulation with apixaban did not significantly reduce risk of recurrent stroke compared with aspirin therapy.

The findings, from the ARCADIA phase 3 randomized clinical trial, were published online February 7 in JAMA.¹

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Led by Hooman Kamel, MD, MS, vice chair for research and chief of neurocritical care in the department of neurology at Weill Cornell Medicine, researchers randomly assigned a cohort of more than 1000 participants with documented cryptogenic stroke and cardiopathy to receive either apixaban 5 mg or 2 mg twice daily or aspirin (81 mg) once daily. Kamel et al reported an identical annualized risk of recurrent stroke in both the aspirin- and apixaban-treated groups—4.4%. The investigators also found no significant increase in risk of symptomatic intracranial hemorrhage, other major bleeding, or death in the apixaban vs aspirin groups.¹

“Unrecognized atrial cardiopathy may explain some of the many ischemic strokes that are classified as cryptogenic…” wrote study authors.¹ “Given the proven role of anticoagulation in atrial fibrillation and the interrelationship between atrial fibrillation and atrial cardiopathy, anticoagulation may also reduce the risk of stroke in patients with atrial cardiopathy and no clinically apparent atrial fibrillation.”¹

Thus, ARCADIA was designed to test the hypothesis that anticoagulation in this population would be superior to antiplatelet therapy to prevent recurrent stroke.

Investigators recruited ARCADIA participants from 185 sites in the National Institutes of Health StrokeNet network and the Canadian Stroke Consortium. Inclusion criteria required age greater than 45 years, a clinical diagnosis of cryptogenic stroke, brain imaging to rule out hemorrhagic stroke and brain MRI and CT to rule out other etiologies. Key exclusion criteria, among other factors, included any history of AF or left ejection fraction less than 30%.¹

Eligible individuals were then screened for atrial cardiopathy, defined as at least one of 3 biomarkers known to be associated with a 2-fold greater risk of stroke: P-wave terminal force in ECG lead V₁ greater than 5000 μV × ms, serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m2 or greater on echocardiogram.

Of an initial pool of 3745 persons with cryptogenic stroke recruited between February 1, 2018, and December 14, 2022, 1015 were assessed as meeting at least 1 of the required criteria for cardiopathy. The final participants were randomly assigned in a 1:1 ratio to receive apixaban 5 mg twice daily (n = 507) or aspirin 81 mg once daily (n = 508).¹

The primary efficacy endpoint was recurrent stroke of any type, and the secondary endpoints were a composite of recurrent ischemic stroke or systemic embolism and the composite of recurrent stroke of any type or death from any cause, according to the study. Safety outcomes in the analysis were symptomatic intracranial hemorrhage and other major hemorrhage and death from any cause.¹

FINDINGS¹

The investigators reported that after a planned interim analysis in December 2022, the trial was stopped based on the finding that the hazard ratio (HR) for apixaban versus aspirin lay within the pre-specified interim boundaries for futility. There were no safety concerns identified at the time.

Participants had a mean age of 68.0 years, 54.3% were women, and 87.5% completed the full follow-up period.

After the mean follow-up period of 1.8 years, Kamel and colleagues identified the primary outcome of recurrent stroke in 40 participants in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (HR,1.00; 95% CI, 0.64 - 1.55). They also reported findings of a post-hoc analysis performed in 149 patients who had AF documented after randomization that revealed no significant difference in the rate of recurrent stroke between the group treated with apixaban (annualized rate, 1.8%) and with aspirin (annualized rate, 2.2%) (HR, 0.84; 95% CI, 0.19 - 3.74).

Analysis of secondary outcomes found recurrent stroke or death occurred in 67 patients in the apixaban group (annualized rate, 7.3%) and 62 patients in the aspirin group (annualized rate, 6.8%) (HR, 1.08; 95% CI, 0.76 - 1.52), according to the study results.

Based on the safety analysis, the researchers found no instances of symptomatic intracranial hemorrhage in participants receiving apixaban and in 7 patients receiving aspirin (annualized rate, 1.1%). Kamel and colleagues observed other major hemorrhages in 5 patients receiving apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (HR, 1.02; 95% CI, 0.29 - 3.52).¹

“Do the findings of the ARCADIA trial close the book on the promise of treating patients based on the presence of atrial cardiopathy (independent of evidence of AF)? We believe that would be premature…” wrote accompanying editorial authors Gregory Marcus, MD, MS, professor of medicine and Bruce Ovbiagele, MD, MSc, MAS, MBA, MLS, professor of neurology, both from the University of San Fransico.² “In particular, the NT-proBNP criterion, used to enroll more than half of all study participants, may not be sufficiently specific to the intended pathophysiology.”²

They emphasized that while the statistical analyses that focused on outcomes according to specific inclusion criteria returned no statistically significant findings, “the point estimates favored protection with apixaban among participants selected using the P-wave terminal force criterion and harm among those with an elevated NT-proBNP level."²

They believe the ARCADIA findings essentially set the stage for additional research and emphasize that future studies “to identify optimal therapeutic strategies for patients with atrial cardiopathy should focus on markers as directly reflective of left atrial pathology as possible.”²

References

1. Kamel H, Longstreth WT, Tirschwell DL, et al. Apixaban to prevent recurrence after cryptogenic stroke in patients with atrial cardiopathy: the ARCADIA randomized clinical trial. JAMA. Published online February 07, 2024. doi:10.1001/jama.2023.27188
2. Marcus GM, Ovbiagele B. Anticoagulation for atrial cardiopathy in cryptogenic stroke. [Editorial] JAMA. Published online February 07, 2024. doi:10.1001/jama.2023.23916