Sex differences in cognitive impairment and association with all-cause mortality: a report from a contemporary cohort of patients with atrial fibrillation

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Abstract Background Cognitive impairment (Cogn-Imp) in patients with atrial fibrillation (AF) has been associated with adverse outcomes. The impact of sex on the association between AF and Cogn-Imp is complex and there are limited data on specific sex-differences in AF patients with Cogn-Imp and association with outcomes. Purpose To investigate the impact of sex on Cogn-Imp, as well as the association of Cogn-Imp with adverse outcomes at follow-up in a contemporary cohort of patients with AF. Methods We analyzed patients enrolled in prospective observational study of AF patients. Cognitive status was evaluated by the Mini-Mental State Examination (MMSE). Patients were stratified according to MMSE scores obtained at baseline. A MMSE score <24 was considered suggestive of Cogn-Imp. All-cause mortality was the primary outcome. Results A total of 931 AF patients were included (median age 75 [IQR 66-82], CHA2DS2VASc score median 4 [2-5], HASBLED median 1 [1-2]). Almost ninenty percent (830/910, 89.2%) of the patients were treated with oral anticoagulants (OACs). Overall, 159/931 (17.1%) of the patients had a MMSE score <24 at baseline, indicative of Cogn-Imp. Female patients had a significant higher prevalence of Cogn-Imp compared to males (22.2% vs 14.0%, p=0.001). At the multivariable logistic regression analysis (adjusted for age, hypertension, previous stroke, coronary artery disease, diabetes, CKD, PAD, heart failure, AF type and use of OACs) female sex was independently associated with Cogn-Imp (adjusted OR 1.70, 95% CI 1.13-2.57). After a median follow-up of 633 [IQR 199-1503] days, all-cause mortality was 15.6% with a significant higher prevalence in patients with Cogn-Imp vs. No-Cogn-Imp, both for males (33.3% vs 15.8%, p<0.001) and females (29.6% vs 10.5%, p<0.001). Kaplan-Meier analysis showed a lower cumulative survival of patients with Cogn-Imp vs. No-Cogn-Imp (Log Rank p=0.01, Figure). At the adjusted Cox regression analysis, Cogn-Imp was associated with an independent higher risk of all-cause mortality both in males (adjusted HR 1.99, 95% CI 1.17-3.39) and females (adjusted HR 2.03, 95% CI 1.05-3.93). Stratifying the population by age, some differences in terms of association between Cogn-Imp and all-cause mortality were evident (Table). Cognitive impairment was associated with a higher risk of all-cause mortality in female patients aged 75-84 and ≥85 years old, but among males only in patients aged 75-84. Conclusions In a prospective observational real-world cohort of AF patients, female sex was independently associated with a higher occurrence of Cogn-Imp compared to male sex. Cognitive impairment was independently associated with a higher risk of all-cause mortality in both sexes with some differences across age categories suggesting peculiar pathophysiological interactions which warrant further investigations.