CHICAGO — Researchers failed to prevent cognitive impairment in people with existing atrial fibrillation (Afib) by taking anticoagulation to mitigate subclinical brain infarctions, according to the BRAIN-AF study.

Stopped early for futility, BRAIN-AF suggested a similar risk of cognitive decline, stroke, or transient ischemic attack (TIA) whether AF patients at low risk of stroke — a group with no existing indication for anticoagulation — were allocated lower-dose rivaroxaban (Xarelto) or placebo (7% vs 6.4%, HR 1.10, 95% CI 0.86-1.40). The lack of between-group difference in the primary outcome was consistent across prespecified patient subgroups.

At least no harm was detected for rivaroxaban in this setting: major bleeding was 0.3% with rivaroxaban versus 0.8% with placebo, Lena Rivard, MD, MSc, of the Montreal Heart Institute reported at American Heart Association (AHA) annual meeting.

She noted that the trial was terminated early for futility after an interim review; originally scheduled for 5 years, the investigators ended up tracking an average of 3.7 years of regular cognitive testing.

Subsequently, it remains unclear how cognition relates to Fib—whether one causes the other or whether it simply coexists due to shared risk factors.

If the mechanism of cognitive decline in Fib was indeed related to microemboli passing from the heart to the brain, then anticoagulation would be expected to work for prevention, commented Andrea Russo, MD, of Cooper University Health Care in Camden. New Jersey, which was not involved in the lawsuit.

“The presence of microemboli is just one mechanism. We need to study other mechanisms, such as cerebral hypoperfusion, perhaps the impact of drugs used to treat Afib,” Russo said at an AHA news conference.

However, AHA session discussant Hooman Kamel, MD, of Weill Cornell Medicine/NewYork-Presbyterian in New York City, pointed out that BRAIN-AF may not be enough to rule out cerebral infarctions as a major mechanism of cognitive decline in Afib.

The study population was fairly young and healthy, he noted, citing the average age of the participants to be just over 53.

In particular, the study excluded people with an indication for anticoagulation or antithrombotic therapy, previous stroke or TIA, hypertension, diabetes, congestive heart failure, or a condition associated with bleeding risk.

Rivard acknowledged that the BRAIN-AF results cannot be extrapolated to these other populations.

BRAIN-AF was conducted across Canada and randomized patients at 53 sites from 2015 to 2023. 1,235 patients with Afib, aged 30 to 62 years, at low risk of stroke were enrolled brain according to Canadian guidelines.

About a quarter of the cohort were female and over 95% were white. The Fib pattern was paroxysmal in over 78% of cases, persistent in 11%, and long-lasting persistent in approximately 11%.

The study protocol had participants randomized to rivaroxaban 15 mg or placebo. Patients who developed any of the standard indications for anticoagulant therapy were withdrawn from study medication and switched to standard anticoagulant therapy.

As expected, there was a low incidence of stroke (0.8%) in the entire study cohort.

Among those with endpoint events, cognitive decline was by far the most common outcome (91.4%), with stroke (5.1%) and TIA (3.5%) less common.

For their cognitive testing, all patients underwent a Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (dawdling) at the initial time. The MoCA was repeated annually, while the final visit had participants take a final MMSE and MoCA. Cognitive decline was defined as a 2+ point reduction in MoCA from baseline.

This reliance on the MoCA alone for cognitive assessment was a major limitation of the study, the authors acknowledged. Furthermore, the results are specific to low-dose rivaroxaban and may not apply to another oral anticoagulant.

“(BRAIN-AF) should really set the stage for future studies that look at … cognitive decline or dementia as an important study endpoint going forward, in addition to our classic endpoints of things like hospitalization and stroke cerebral,” Russo said.

“Emerging (Afib) treatment strategies should include measures of cognition from the start,” agreed Kamel.