Use of the direct oral anticoagulant (DOAC) apixaban was not superior to cardiac monitoring-guided aspirin for the prevention of new ischemic lesions in a patient population with an enriched embolic stroke of undetermined source (ESUS), according to results of the ATTICUS study published in NEJM Evidence.
In a multicenter, open-label, randomized study of patients with ESUS and at least one predictive factor for atrial fibrillation (AF) or a patent foramen ovale, the rate of any new ischemic lesion during 12-month follow-up was similar among patients assigned to apixaban or aspirin. Based on this futility, the ATTICUS study was terminated after a prespecified interim analysis.
Study researcher Tobias Geisler, MD, MHBA, of University Hospital Tübingen in Germany, said the neutral study result was somewhat surprising.
“Given the neutral results of two previous randomized trials investigating the effect of other DOACs versus aspirin in unselected patients with ESUS — RE-SPECT ESUS and NAVIGATE-ESUS — we expected ATTICUS, with its enriched ESUS population, to be a game-changing trial, that is, to pave the way to a more individualized secondary prevention after ESUS instead of the previous one-size-fits-all approach,” Dr. Geisler said. “Surprisingly, despite successful enrichment with AF detected in over a quarter of participants, the results were neutral.”
Dr. Geisler, co-primary investigator Sven Poli, MD, of University Hospital Tübingen, and colleagues enrolled 352 patients with ESUS and randomly assigned them to apixaban 5 mg twice daily (n=178) or aspirin 100 mg once daily (n=174). Treatment was initiated within 28 days after ESUS. Cardiac monitoring was mandatory, and aspirin treatment was switched to apixaban if AF was detected. The high proportion of participants with new ischemic lesions and embolic lesion pattern and the high incidence of recurrent stroke indicated successful enrichment.
The mean age of patients was 68.4 years, and 48.6% were female. More than one-third (36.6%) of participants had multiple cardioembolic enrichment factors, and AF was detected in 22.5% of patients assigned to apixaban and 28.2% of patients assigned to aspirin. Forty-five patients in the aspirin group were switched to apixaban because of AF.
The primary outcome, which was any new ischemic lesion, was assessable in the majority (92.3%) of patients. Any new lesion occurred in 13.6% of patients assigned apixaban compared with 16.0% of patients assigned aspirin (adjusted odds ratio = 0.79; 95% CI 0.42-1.48; p=0.57).
The secondary outcome of recurrent stroke incidence rate was similar between patients assigned apixaban and those assigned aspirin (one-year cumulative incidence rates 5.7 and 6.4, respectively). Major and clinically relevant nonmajor bleeding occurred in 2.8% of patients assigned apixaban and 4.0% of patients assigned aspirin; the one-year cumulative incidence rates were 2.9 and 4.2, respectively (hazard ratio = 0.68; 95% CI 0.22-2.16).
“Although ATTICUS did not reveal an increased bleeding rate under treatment with apixaban, we have to admit that the rather small sample size may limit interpretation,” Dr. Geisler said. “This is why we need to study efficacy and safety of apixaban in further high-quality trials before we can recommend its broader use in patients with ESUS.”
Finally, serious adverse events (AEs) occurred in 28.1% of patients assigned apixaban and 31.6% of patients assigned aspirin. Serious AE rates were 43.9 per 100 person-years for apixaban and 45.7 per 100 person-years for aspirin.
ATTICUS was limited by its open-label design, its use of new ischemic lesions on MRI as a surrogate for ischemic stroke, and its relatively short follow-up of 12 months. In addition, its small sample size “resulted in an insufficient power, which could also be a reason analyses had not reached statistical significance in favor of apixaban,” the researchers wrote.
According to Dr. Geisler, it is tempting to speculate that by preselecting patients with ESUS, one could define ESUS subgroups that may still benefit from DOACs without prior detection of AF.
“Like in the RE-SPECT ESUS trial with dabigatran, we could show that elderly ATTICUS participants may benefit from direct apixaban, most likely due to even higher rates of AF of over 40% in this subgroup,” Dr. Geisler said. “To confirm this most promising observation, Dr. Poli and I plan to move forward and plan the follow-up ATTICUS 75+ randomized trial that focuses on elderly patients with ESUS aged 75 years and older.”
This study was funded by Bristol-Myers Squibb and Medtronic Europe. Any conflicts of interest declared by the authors can be found in the original article.
Reference
Geisler T, Keller T, Martus P, et al. Apixaban versus aspirin for embolic stroke of undetermined source. NEJM Evid. 2024;3(1):EVIDoa2300235.
