Coumadin No Worse for Mental Function Than Pradaxa, When Well Administered

It has been hypothesized that patients with atrial fibrillation (AF) receiving direct oral anticoagulants (DOACs) would have less cognitive decline than those on vitamin K antagonists, such as Coumadin (warfarin). Findings reported recently in BMC Medicine found otherwise.¹

The findings were from the GIRAF study conducted in São Paulo, Brazil. Two hundred patientes were randomized to take either Pradaxa (dabigatran), which targets thrombin, Coumadin. Use of Coumadin requires careful timing and monitoring, and patients may be at higher risk for microbleeds in the brain and other conditions that promote cognitive decline. But no overall cognition advantage was observed for patients with atrial fibrillation or atrial flutter in Pradaxa compared with those in the Coumadin group, investigators concluded.

“The results of the analysis of the mean change from baseline in the [mental test scores] did not support our hypothesis that [Pradaxa] would attenuate cognitive decline compared to [Coumadin], as no evidence of a beneficial effect of [Pradaxa] was found between the groups," wrote lead author Bruno Caramelli, of the cardiology unit at University ofSão Paulo.

This was the first randomized prospective study to compare a vitamin K antagonist with a DOAC for the goal of collecting evidence about a difference in cognitive abilities. The study volunteers were older — ages 70 and older. The investigators employed a battery of mental tests to establish baseline cognitive function. These tests were repeated at 24 months and outcomes were analyzed for changes in executive function, attention, language and memory.

“Cognitive evaluations lasted approximately 90 minutes and were performed by two neurologists, blinded to group assignments,” Caramelli wrote. Patients with previous stroke or dementia were excluded from the trial. Patients who received Coumadin had better cognitive outcomes based on one of the tests, the Montreal Cognitive Assessmeny. and the difference met the statistical standard for being significant and not by chance.

“This was not confirmed in the more exhaustive and comprehensive cognitive tests (neuropsychological test battery and computer-generated tests), nor in the exploratory outcomes of cognitive domains (memory, executive function, language, and attention),” wrote Caramelli and his co-investigators, advising caution in interpreting this one result.

Pradaxa has more stable and predictable pharmacokinetics than Coumadi.n The lack of difference in cognition between the two drugs may have to do with the high level of clinical control exercised during the trial, Caramelli wrote.

“The lack of benefit from Pradaxa in our trial might be related to a very well-managed [Coumadin] administration.” The international normalized ratio (INR), or time it takes for blood to clot, must be monitored closely to find the appropriate treatment window, and in the case of trial participants, the time in treatment range (TTR) was roughly 70%, which higher than in previous pivotal studies, he wrote.

“Indeed, observational studies suggest an association of [Coumadin] therapy quality and cognition: Both poor control and supratherapeutic INRs are associated with an increased risk of dementia. The very adequate anticoagulation regimen with [Coumadin] in the GIRAF trial could have an effect, protecting patients against greater cognitive decline,” Caramelli wrote.

The authors noted potential limitations of their study, including that two-year window of observation was too short to spot changes in mental function. Also, many patients with low educational attainment, a known risk factor for early dementia, were included in this study.

This article originally appeared on Managed Healthcare Executive.

Reference

1. Caramelli B, Yu PC, Cardozo FAM, et al. Effects of dabigatran versus warfarin on 2-year cognitive outcomes in old patients with atrial fibrillation: results from the GIRAF randomized clinical trial. BMC Med. 2022 Oct 26;20(1):374. doi: 10.1186/s12916-022-02563-2.