Atrial fibrillation is the most common sustained cardiac rhythm disturbance seen in clinical practice. A number of trials have shown that the condition, which is most prevalent among the elderly, increases the chance of cerebrovascular accidents and of blood clots forming in the heart, increasing total mortality. These aspects are well-established, as is the use of anticoagulants to prevent thromboembolism in individuals with relevant risk scores. Yet although previous research has looked at the association between atrial fibrillation and cognitive decline, no studies to date have explored the effects of oral anticoagulants on the cognitive and functional aspects of patients.
But a Brazilian trial that brings to light the significant effects of anticoagulants on brain health was recently presented at the American Heart Association Scientific Sessions 2021.
The Cognitive Impairment Related to Atrial Fibrillation (GIRAF) study evaluated the effects of the anticoagulants warfarin and dabigatran on cognitive and functional impairment, bleeding occurrence, and cerebrovascular complications. It was led by cardiologist Bruno Caramelli, MD, PhD, associate professor and director of the interdisciplinary medicine in cardiology unit at the Heart Institute (InCor) of the University of São Paulo School of Medicine Clinics Hospital.
“There was no difference between the patients in the dabigatran group and the patients in the warfarin group,” he told Medscape Medical News.
The adequate use of anticoagulants can prevent cognitive decline in elderly patients with atrial fibrillation, Caramelli and his colleagues determined after 2 years of follow-up. This conclusion is based on data obtained from scales that measure memory, executive function, language, and attention. All participants completed a series of 90-minute cognitive and functional evaluations at baseline and during follow-up visits. Patients also underwent a brain MRI at baseline and after 2 years to identify possible stroke.
“There was no control group, as it would have been unethical to provide inadequate or incomplete treatment. That’s why I can’t say for certain that, if well treated, patients won’t develop cognitive decline. On the other hand, using historic control data from previous studies allows us to make this inference, which, while speculative, has a good chance of being correct,” Caramelli said.
The randomized, multicenter, prospective GIRAF trial evaluated 200 patients (62% male) older than 70 years with confirmed atrial fibrillation. Participants were randomly assigned to a 2-year course of dabigatran 110 mg or 150 mg twice daily, or to warfarin once daily at a dose sufficient to clot the blood. Most were treated at public hospitals in Brazil’s Unified Healthcare System.
When designing the study, the investigators were concerned whether they would find tools sensitive enough to assess higher cognitive function.
“We carried out tests that analyzed various cognitive domains in order to find out what was happening. They were quite labor-intensive, and took between 90 minutes and 2 hours to complete. Perhaps this helps to explain why, in the past, many studies only used tests that were much easier and quicker, and why they neglected to incorporate this type of assessment,” Caramelli explained.
The findings highlight the importance of adequate control of levels of anticoagulation. “The study rigorously controlled TTR [time in therapeutic range]. We aimed to keep it in the 70% range,” he said. This percentage is the current gold standard in the ideal therapeutic range, which is the way to assess long-term quality of anticoagulation management and the treatment’s risk–benefit profile. To get an idea of how difficult it is to reach these indices, he noted that at InCor, a top teaching and research hospital, real-world data show a TTR of around 45%.
“Every day, we hear about patients forgetting to take their medication. They stop taking it when they go to the dentist and then don’t go back to taking it…. Lots of things happen. So during the study, we called the patients to remind them to take the medication and perform the control tests,” Caramelli reported.
The investigators advised clinicians to aim to have patients maintain an anticoagulation status comparable to that in the study.
“At 2 years, we didn’t see any differences between the medications. But if you find that in 2 or 3 months the patient does not have a TTR of 70%, it’d be a good idea to consider changing medication,” he said. Warfarin, the older of the two study drugs, interacts with food and alcohol, so the patient’s anticoagulation status should be monitored every 3 weeks. Novel oral anticoagulants are more stable, they do not interact with food, and they do not need to be monitored in the same way; however, they are expensive.
Findings from GIRAF brought to light information that contradicts initial findings about the occurrence of cognitive decline after 1 or 2 years of anticoagulation therapy.
“Maybe these earlier studies weren’t totally correct because they weren’t prospective studies and, unlike ours, didn’t have as thorough and detailed results to analyze,” said Caramelli.
When a person does not have adequate anticoagulation, they can have clots that break off and travel to the brain, noticeably deteriorating cognitive function. “The other possibility is that there are small blood clots that also lead to cognitive deterioration. Our hypothesis is that they’ll keep on accumulating and end up leading to a reduction in the area of the brain responsible for higher cognitive functions,” he said, referring to functions such as joint attention, reasoning, working memory, and memory retention.
“Naturally, over time, these functions are going to decline. But in elderly patients with atrial fibrillation, the decline is likely more rapid,” he explained. To explore this possibility, the investigators are analyzing the baseline and 2-year MRIs that the study participants underwent. The conclusions will be the subject of a future publication.
GIRAF was the first trial outside of the United States to receive funding from Boehringer Ingelheim, the maker of dabigatran. Caramelli points out that the research is considered an investigator-initiated study and is independent.
American Heart Association (AHA) Scientific Sessions 2021: Abstract LBS.03. Presented November 14, 2021.
This article originally appeared in the Portuguese edition of Medscape.
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