Cardiopathy No Basis for Choosing Anticoagulation in ESUS

MUNICH — Anticoagulation using apixaban (Eliquis) offers no benefit over aspirin in patients with embolic stroke of undetermined source (ESUS) who have atrial cardiopathy but no overt atrial fibrillation, suggest findings from the ARCADIA trial.

The trial, which was halted early, randomized more than 1000 ESUS patients with atrial cardiomyopathy to apixaban or placebo. Results showed that apixaban did not improve rates of recurrent stroke of any kind nor safety outcomes such as major hemorrhage and all-cause mortality.

The results were presented May 24 at the 9th European Stroke Organisation Conference (ESOC).

“We found no benefit of apixaban over aspirin in patients with ESUS who had evidence of atrial cardiopathy, at least based on the criteria in our trial,” said study presenter Hooman Kamel, MD, MS, vice chair for research and chief of neurocritical care in the Department of Neurology, Weill Cornell Medicine, New York City.

“It could be that this concept of thrombogenic atrial cardiopathy really isn’t present unless there is also atrial fibrillation,” he continued, suggesting alternatively that results may be due to the “incorrect choice of atrial cardiopathy biomarkers or thresholds.”

“We chose these because they were clinically scalable and usable in a multicenter design,” Kamel explained, adding that there are a number of different proposed biomarkers that could be used in a future study.

The team will now perform secondary analyses over the coming months to “try to help sort out some of these potential explanations.”

Kamel concluded, however, that, “as of now, no strategy of anticoagulation has been found to be better than antiplatelet therapy for secondary stroke prevention after ESUS.”

Similar Results

Approached for comment, session co-chair Robin Lemmens, MD, PhD, a neurologist in the Department of Neurosciences, UZ Leuven, Leuven, Belgium, noted that this is the third ESUS trial, after the NAVIGATE and RE-SPECT trials, and they have all showed “similar results.”

He told Medscape Medical News, however, that there “could be various reasons for that, and it’s good that they mentioned looking into the subgroups,” as has been done for those other studies.

“Most of these trials were initiated under the concept that most of these patients would have had underlying atrial fibrillation, and then of course there would have been a benefit for anticoagulation.”

“It turns out that that’s not the case,” Lemmens said, “probably because there’s a lot of heterogeneity in these patients,” with different reasons for developing stroke, “not just only potentially underlying atrial fibrillation.”

Session co-chair Arthur Liesz, MD, PhD, Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany, added that it is important to consider the definition of atrial cardiopathy in this context.

If this was limited only to structural cardiopathy, then this “was a rather small subpopulation in this study,” he told Medscape Medical News.

Liesz said that it could instead have been conducted with “more stringent cutoffs,” and could have considered blood biomarkers, “which then would have delivered more overlap with structural cardiopathy,” and allowed those patients to be analyzed separately.

Heterogeneous Etiologies?

Kamel began by noting that the failure of NAVIGATE and RESPECT to show a benefit from anticoagulation in the prevention of recurrent stroke in patients with ESUS led to the hypothesis that this is “perhaps due to heterogeneous underlying etiologies.”

Moreover, these etiologies “may require different types of antithrombotic therapy to best prevent recurrence, and one such underlying etiology may be atrial cardiopathy.”

He explained that several observational studies have found, in the absence of atrial fibrillation, associations between stroke and different markers of atrial cardiopathy and, “given the proven benefit of anticoagulation in preventing strokes in patients with atrial fibrillation, it seems plausible” that they may also benefit.

To investigate further, the team conducted ARCADIA, an investigator-initiated, multicenter, randomized trial involving patients aged 45 years and older from 185 sites in the US and Canada with a clinical diagnosis of stroke that met the consensus criteria for ESUS.

They also were required to have undergone brain imaging to rule out hemorrhagic stroke, and to have a modified Rankin Scale score ≤4, indicating up to a moderately severe degree of disability.

They also had atrial cardiopathy, as determined by P-wave terminal force in V1 >5000µV*ms on electrocardiography, serum N-terminal prohormone of brain natriuretic peptide levels >250 pg/mL, or a left atrium diameter ≥3 cm/m2.

The patients were randomly assigned to apixaban 5 mg or 2.5 mg twice daily plus aspirin placebo, or apixaban placebo plus aspirin 81 mg daily. Those diagnosed with atrial fibrillation after randomization crossed over to open-label anticoagulant therapy at physician discretion.

Kamel reported that in 2022, after enrollment of 1015 patients with a mean follow-up of 1.8 years, the trial was halted at the planned interim efficacy/futility analysis, adding that there were “no safety concerns.”

The apixaban and aspirin groups were well balanced in terms of their baseline characteristics. The mean age was 68 years, and 54% were female. Three quarters of the participants were White, 21.1% Black.

Prior stroke was reported in 19% of patients. Hypertension was common, in about 77%, and type 2 diabetes was seen in 31%. There were relatively few cases of ischemic heart disease, heart failure, and peripheral arterial disease.

The primary efficacy outcome of recurrent stroke of any type occurred in 4.4% of both patients treated with apixaban and those given aspirin, at a hazard ratio (HR) of 1.00 (95% CI, 0.64 – 1.55). Similar findings were seen when looking individually at ischemic and hemorrhagic stroke, and stroke of undetermined type.

There was also no significant difference in the secondary outcomes of recurrent ischemic stroke or systemic embolism, at 4.1% vs 4.4% (HR, 0.92; 95% CI, 0.59 – 1.44), and recurrent stroke of any type or death from any cause, at 7.3% v 6.8% (HR, 1.08; 95% CI, 0.76 – 1.52).

In terms of safety, rates of major hemorrhage were low and almost identical between the groups, at 0.7% with apixaban and 0.8% for aspirin (HR, 1.02; 95% CI, 0.29 – 3.51), and were similar for all-cause mortality, at 1.8% vs 1.2% (HR, 1.53; 95% CI, 0.63 – 3.74).

Proportionately more patients treated with aspirin experienced symptomatic intracranial hemorrhage, at 1.1% vs 0%.

The trial results generated a flurry of interest on Twitter.

Thomas Ford, MD, a vascular neurology fellow from Boston Medical Center, described the results as “disappointing,” although he was “curious to see if there was any signal of benefit in subgroup analyses.”

Shadi Yaghi, co-director of the Comprehensive Stroke Center at Brown University, Providence, Rhode Island, added that the trial “begs the question [as to] whether all device-detected atrial fibrillation warrants anticoagulation.”

Replying, Mitchell Elkind, MD, MD, MPhil, professor of neurology and epidemiology at Columbia University Irving Medical Center, New York City, said that he agrees with this interpretation.

“Maybe the issue is not with the concept of atrial cardiopathy but with the need to [anticoagulate] all patients with low AF burden or incidental AF after stroke.”

The study was funded by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. The study drug was provided in kind by BMS-Pfizer, and ancillary funding for the NT.proBNP assays was provided by Roche. No relevant financial relationships were reported.

9th European Stroke Organisation Conference (ESOC) 2023: Abstract 2709. Presented May 24, 2023.