CHICAGO — A randomized, placebo-controlled trial testing a direct oral anticoagulant for the prevention of cognitive decline in patients with atrial fibrillation (AF) was stopped early due to futility.

After a median follow-up of 3.7 years, there was no difference between rivaroxaban 15 mg and placebo for a composite primary endpoint including cognitive decline, stroke and transient ischemic attack, said Léna Rivard, MD, electrophysiologist and associate professor at the Institute. Montreal Heart Institute in Montreal, Quebec, Canada.

When the BRAIN-AF trial was stopped by the data monitoring committee, 256 primary events had occurred, most of which involved cognitive decline. However, the rate of cognitive decline, defined as a reduction of at least 2 points from baseline on the validated Montreal Cognitive Assessment Test, was essentially identical.

“There was no difference between rivaroxaban and placebo, even with a very high rate of cognitive decline overall,” Rivard said during a late break from college. American Heart Association (AHA) Scientific Sessions 2024. At the end of follow-up, 18% of study participants met the definition of cognitive loss.

Cognitive decline in 18% of patients

One limitation of the BRAIN-AF study was that it enrolled patients at risk of stroke who did not meet guideline criteria for oral anticoagulation. This was necessary to allow study participants to be randomized to receive a placebo.

With this criterion, an age range of 30 to 62 years and exclusions for history of stroke, hypertension, diabetes and congestive heart failure, the study population had a low, but not zero, risk. , FA events. In addition to the observed rates of cognitive loss accumulated over a median follow-up of less than 4 years, the estimated stroke rate in this low-risk population was 0.5 to 1.0% per year. The observed incidence was 2.5%.

The data presented by Rivard were based on 1,235 patients randomized at 53 sites. The median age was 53 years, 78% of study participants had a history of paroxysmal AF, 96% were white, and approximately 25% were women.

There are a number of explanations for this study’s results, including that the patients were too young and too healthy, said Andrea M. Russo, MD, an electrophysiologist and professor of medicine at the Cooper Medical School of the Rowan University in Camden, New Jersey.

Additionally, although a 2-year history of AF was a study criterion, the burden of AF, which could be an independent risk factor for cognitive loss, was not described, Russo pointed out.

Overall, this result is unlikely to rule out the presence of microemboli in the pathophysiology of AF-related cognitive decline, but other mechanisms should be explored based on the trial results, he said. she pointed out.

The cognitive loss linked to AF “could be a hemodynamic effect,” Russo speculated. With fluctuations in blood flow due to abnormal rhythm, “hypoperfusion is a possibility.”

This study addresses a highly relevant clinical question that should serve as a basis for further work, given the substantial risk of cognitive decline related to AF in observational studies, and is reinforced by the BRAIN-AF data, she said. explain.

Relatively low dose of rivaroxaban

Due to concerns about increased bleeding in a group of patients without indication for anticoagulation, the dose of rivaroxaban in BRAIN-AF was 15 mg once daily, rather than the 20 mg typically used for stroke prophylaxis. cerebrovascular events in patients with AF. There were no fatal bleeding events in either group. Although numerically lower in the rivaroxaban group than in the placebo group, the differences in major bleeding (0.3% versus 0.8%) and stroke (2.5% versus 2.7% ) were not significant.

The study draws attention to the need for strategies to prevent cognitive decline in patients with AF, said Hooman Kamel, MD, vice chair of research and chief of neurocritical care at Weill Cornell Medical College in New York. , who was the study discussant for BRAIN. -AF. He called for much more attention to be given to this issue, including routinely measuring cognitive changes in trials of new AF treatments.

Kamel also expressed interest in looking elsewhere for modifiable mechanisms of cognitive decline in patients with AF. As an example, he cited a echocardiographic study which showed an association between cognitive decline and left atrial impairment. Although this study evaluated patients with atrial myopathy but not AF, it suggested a potential relationship between cardiovascular and cerebrovascular pathology that may be more complex than blood emboli.

He questioned whether a controlled trial exploring the ability of anticoagulation to prevent cognitive decline by blocking microemboli from reaching the brain was feasible, now that the benefits of anticoagulation are so well established in at-risk patients. higher.

“It may be too late to test anticoagulation to prevent dementia in AF,” Kamel said.