Effects of dabigatran versus warfarin on 2-year cognitive outcomes in old patients with atrial fibrillation: results from the GIRAF randomized clinical trial

Background Observational studies support a role for oral anticoagulation to reduce the risk of dementia in atrial fibrillation patients, but conclusive data are lacking. Since dabigatran offers a more stable anticoagulation, we hypothesized it would reduce cognitive decline when compared to warfarin in old patients with atrial fibrillation. Methods The GIRAF trial was a 24-month, randomized, parallel-group, controlled, open-label, hypothesis generating trial. The trial was done in six centers including a geriatric care unit, secondary and tertiary care cardiology hospitals in São Paulo, Brazil. We included patients aged [greater than or equal to] 70 years and CHA2DS2-VASc score > 1. The primary endpoint was the absolute difference in cognitive performance at 2 years. Patients were assigned 1:1 to take dabigatran (110 or 150 mg twice daily) or warfarin, controlled by INR and followed for 24 months. Patients were evaluated at baseline and at 2 years with a comprehensive and thorough cognitive evaluation protocol of tests for different cognitive domains including the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), a composite neuropsychological test battery (NTB), and computer-generated tests (CGNT). Results Between 2014 and 2019, 5523 participants were screened and 200 were assigned to dabigatran (N = 99) or warfarin (N = 101) treatment. After adjustment for age, log of years of education, and raw baseline score, the difference between the mean change from baseline in the dabigatran group minus warfarin group was - 0.12 for MMSE (95% confidence interval [CI] - 0.88 to 0.63; P = 0.75), 0.05 (95% CI - 0.07 to 0.18; P = 0.40) for NTB, - 0.15 (95% CI - 0.30 to 0.01; P = 0.06) for CGNT, and - 0.96 (95% CI - 1.80 to 0.13; P = 0.02) for MoCA, with higher values suggesting less cognitive decline in the warfarin group. Conclusions For elderly patients with atrial fibrillation, and without cognitive compromise at baseline that did not have stroke and were adequately treated with warfarin (TTR of 70%) or dabigatran for 2 years, there was no statistical difference at 5% significance level in any of the cognitive outcomes after adjusting for multiple comparisons. Trial registration Cognitive Impairment Related to Atrial Fibrillation Prevention Trial (GIRAF), NCT01994265. Keywords: Atrial fibrillation, Dementia, Cognitive scores, Dabigatran, Warfarin, Elderly