American Heart AssociationNov 18 2024

Prescribing anti-clotting medications to adults younger than age 65 who have atrial fibrillation (AFib) but no other risk factors for stroke did not reduce the risk of cognitive decline, stroke or transient ischemic attack (TIA), according to late-breaking science presented today at the American Heart Association's Scientific Sessions 2024. The meeting, Nov. 16-18, 2024, in Chicago, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science.

In Canada, anti-clotting medications such as rivaroxaban are prescribed to reduce the risk of stroke in people with AFib who are 65 years old or older or who have other stroke risk factors (such as diabetes, heart failure, high blood pressure, or a prior stroke or TIA). This study, the Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF), is the first large trial focused on assessing if anti-clotting medication can reduce the risk of cognitive decline, stroke or TIA among adults with AFib but no other risk factors for stroke.

Although numerous observational studies have reported an association between AFib and cognitive decline, we found that anticoagulation therapy initiated in relatively younger adults with AFib did not reduce this risk. Patients should adhere to standard recommendations for cognitive health, including adopting a healthy lifestyle, engaging in activities that stimulate their brains and maintaining regular physical activity."

Lena Rivard, M.D., M.Sc., study lead author, electrophysiologist at Montreal Heart Institute and associate professor of medicine at Université de Montréal, Canada

Although the trial was scheduled to allow for an average follow-up of 5 years, it was terminated early at an average follow-up of 3.7 years after the data safety and monitoring committee considered it futile to continue because of the clear lack of benefit from the study medication.

The trial included more than 1,200 adults, average age 53, who had AFib but none of the standard risk factors that would necessitate the prescription of blood thinner medication. Half of the study participants were randomly selected to receive 15 mg of rivaroxaban daily. The other half were randomly assigned to a placebo group. For the BRAIN-AF trial to include patients with vascular disease, i.e., a condition involving plaque build-up in blood vessels, a double-dummy design was used. Participants were monitored yearly for cognitive decline (a decline of two or more points on the Montreal Cognitive Assessment), stroke or TIA.

After an average of almost four years, the study found:

1 in 5 participants experienced cognitive decline, stroke or TIA. Cognitive decline accounted for 91% of the primary outcome; and 1 in 200 had major bleeding. The participants had a low incidence of stroke, at less than 1 in 100 (0.8%) per year. There were no differences in the outcomes of cognitive decline, stroke or TIA between those taking rivaroxaban and placebo. The rates of these conditions combined were 7% per year for those randomized to rivaroxaban versus 6.4% per year among those who received a placebo.

Rivard said she believes that "In clinical practice, people younger than age 65 with AFib tend to be overtreated with anticoagulant therapy, while older people who have indications for anticoagulation are under-treated." She also said, "Our study supports current guidelines by confirming that younger people with AFib but no other risk factors for stroke have a low rate of stroke, and anticoagulation is not useful in reducing the risk of cognitive decline, as assessed by the Montreal Cognitive Assessment score."

The researchers are also analyzing their results (more than 5,700 Montreal Cognitive tests were performed during the trial) using biomarkers and genetic tests collected from most BRAIN-AF participants to better understand cognitive decline in patients with AFib.

"The BRAIN-AF trial confirmed a high rate of cognitive decline during follow-up in younger adults. It is not known whether other interventions such as ablation of AFib could have a positive impact on cognition in this population," Rivard said.

To maximize safety, the trial used a low dose of rivaroxaban. It remains unknown whether a higher dose of rivaroxaban or a different molecule would have been effective when the study medication was not.

Study details, background and design:

BRAIN-AF included 1,235 adults with AFib being treated at one of 53 health centers in Canada. At enrollment in the study, participants' ages ranged from 30 to 62, with an average of 53. About 26% of participants were women, and 96% were white adults. None of the participants had current Canadian standard indications for someone with AFib to be prescribed anti-coagulation therapy (a prior stroke or TIA, high blood pressure, diabetes, heart failure or being age 65 or older). People were excluded from the trial if the Mini-Mental State Evaluation given at baseline indicated any level of dementia or if they were considered at high risk of bleeding because of another medical condition. Participants were randomly selected to receive either rivaroxaban (15 mg daily) or placebo; those who had vascular disease additionally received low-dose aspirin (100 mg daily) in a blinded fashion. Participants were recruited between April 2015 and November 2023; the last follow-up exams were completed in May 2024. Participants were followed for an average of 3.7 years. During that time, if they developed any of the standard indications for anti-coagulation therapy, they were withdrawn from their study medication and switched to standard anticoagulation therapy. Participants were monitored for cognitive decline, considered significant if there was a drop of 2 points or more on the Montreal Cognitive Assessment, stroke or TIA with difficulty moving or talking.

AFib is the most common heart rhythm disorder in the U.S., and the prevalence is expected to increase from about 5.2 million in 2010 to 12.1 million in 2030, according to the American Heart Association's 2024 Heart Disease and Stroke statistics. AFib is an irregular and often fast heartbeat in which the heart's upper chambers (atria) beat out of sync with the lower chambers (ventricles). Some people with AFib have no symptoms, while others have palpitations, light-headedness, dizziness or chest pain during episodes, which can be brief or persistent. It is well established that AFib raises the risk of stroke, and there is increasing evidence that it may contribute to cognitive decline.

American Heart Association