Potentially Clinically Significant Drug-Drug Interactions in Older Adults with Atrial Fibrillation and Multimorbidity: Prevalence, Correlates, and Association with Adverse Clinical Outcomes in a Swedish National Register-Based Study

PURPOSE: Current research on potentially clinically significant drug-drug interactions (DDIs) in individuals with atrial fibrillation (AF) has predominantly focused on DDIs involving direct oral anticoagulants (DOACs), with limited evidence regarding other medications. Our study aimed to: (i) assess the overall prevalence of DDIs; (ii) investigate potential demographic correlates of DDIs; and (iii) examine the association of DDIs with adverse clinical outcomes in a nationwide cohort of older adults with AF and multimorbidity. METHODOLOGY: Data from the Swedish national registers were linked to establish a cohort with a 2-year follow-up of adults ≥ 65 years who, on 1 January 2017, had a diagnosis of AF, ≥ 1 comorbidity and were prescribed ≥ 2 medications (n = 192,716). This study describes the prevalence of 72 potentially clinically significant DDIs from an adapted explicit international consensus list and a review focused specifically on DDIs involving DOACs. Correlates of DDIs were assessed through logistic regressions. Cox regression analyses were conducted to examine the association between DDIs and adverse clinical outcomes: overall and cardiovascular (CV) mortality, overall and CV hospitalisation, stroke, bleeding, and falls. RESULTS: In the overall population, 37.5% presented with ≥ 1 potential DDI, with CV (33.8%) and central nervous system (CNS) drugs (12.4%) most frequently involved. Sex, age, and civil status were most consistently associated with DDIs. Individuals with ≥ 1 DDI had a higher hazard of CV death (hazard ratio 1.28 95% confidence interval (CI) [1.24-1.32]), CV hospitalisation (1.12 [1.10-1.15]) and falls (1.06 [1.02-1.09]). DDIs with DOACs were associated with gastrointestinal bleeding (2.80 [1.35-5.81]). DDIs with CNS drugs were associated with stroke (1.19 [1.09-1.29]) and falls (1.32 [1.27-1.39]). CONCLUSION: Potentially clinically significant DDIs were prevalent in older adults with AF and multimorbidity, with adverse clinical implications. Identifying these high-risk groups is essential for preventive strategies and effective clinical management.