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Oral anticoagulation (OAC) was no better than low-dose aspirin for secondary stroke prevention in people with left atrial cardiopathy absent evidence of atrial fibrillation (Afib or AF), the ARCADIA trial showed.

Recurrent strokes of any type occurred at a 4.4% annualized rate whether patients had been randomized to apixaban (Eliquis) or aspirin (HR 1.00, 95% CI 0.64-1.55), reported Hooman Kamel, MD, of Weill Cornell Medicine in New York City, and colleagues .

Thus OAC's proven benefits in Afib may not apply to survivors of cryptogenic stroke with atrial cardiopathy who had subclinical Afib extensively ruled out at baseline.

Notably, the trial had been stopped for futility after an interim analysis, and the investigators could not reach their target of 1,100 participants. They reported slow recruitment during the COVID-19 pandemic and more-than-expected patient withdrawals from the trial.

The available data showed no indication of safety concerns of apixaban in the study population, given the low rates of symptomatic intracranial hemorrhage (0% apixaban vs 1.1% aspirin) and other major hemorrhage (0.7% vs 0.8%) over nearly 2 years' follow-up.

Kamel's group noted that the ARCADIA results seem to contradict prior observational studies that had linked markers of atrial cardiopathy with the risk of ischemic stroke.

"Given the results of the current trial, these previously demonstrated links between atrial cardiopathy and stroke may have reflected unmeasured confounding by subclinical atrial fibrillation, which was probably more thoroughly ruled out by continuous heart rhythm monitoring in potential trial participants than in earlier cohort studies," the researchers wrote.

Atrial cardiopathy describes the subtle changes affecting the atria that have potential to manifest clinically. It is strongly associated with incident Afib and thought to explain some cryptogenic strokes (or embolic strokes of undetermined source [ESUS]).

"While the study benefited from appropriate scrutiny exercised by an engaged data and safety monitoring board adhering to a prespecified interim assessment, it remains possible that allowing for longer follow-up time and an analysis of more events may yet have revealed statistically significant differences," wrote Gregory Marcus, MD, MAS, and Bruce Ovbiagele, MD, MSc, MAS, both from the University of California San Francisco, in .

"For now, patients with ESUS should be treated with antiplatelet therapy and not anticoagulated," they suggested. However, 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."

Marcus and Ovbiagele pointed, for example, to NT-proBNP as a dubious way to label most study participants as having atrial cardiopathy in the trial. "[F]uture efforts to identify optimal therapeutic strategies for patients with atrial cardiopathy should focus on markers as directly reflective of left atrial pathology as possible," they urged.

ARCADIA was a multicenter phase III trial conducted at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium. Extensive entry criteria required that participants demonstrate:

• Cryptogenic stroke with brain CT or MRI to exclude lacunar infarcts, vascular imaging of the cervical and intracranial arteries to exclude large-artery atherosclerosis causing 50% or more stenosis of a relevant arterial lumen, and transthoracic or transesophageal echocardiography, a 12-lead ECG, and 24 hours or more of continuous heart rhythm monitoring to exclude cardioembolic sources
• Evidence of atrial cardiopathy: P-wave terminal force greater than 5000 μV × ms in ECG lead V1, serum NT-proBNP level greater than 250 pg/mL, or left atrial diameter index ≥ 3 cm/m² on echocardiogram
• No evidence of Afib

Investigators ultimately had 1,015 people randomized to apixaban 5 mg twice daily (n=507) versus aspirin 81 mg once daily (n=508). A dose reduction was allowed in the apixaban group if patients met certain criteria.

The overall cohort averaged 68 years of age, and 54.3% were women. Over three-quarters had documented hypertension, more than 30% diabetes, and approximately 10% known ischemic heart disease. The mean CHA₂DS₂-VASc score was 4.7 and the median NIH Stroke Scale score was 1. Time from stroke onset to randomization was a median 50 days.

Follow-up reached a mean of 1.8 years.

The 14.7% of participants diagnosed with Afib during the study crossed over to open-label apixaban therapy at their physician's discretion. Diagnosis occurred at a median 30 weeks after randomization.

In this subgroup, there was still no difference in stroke recurrence rates between apixaban and aspirin groups (annualized rate 1.8% vs 2.2%, HR 0.84, 95% CI 0.19-3.74), Kamel's team reported.

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