Exploring the safety and efficacy of DOACs in clinically complex phenotypes of patients with atrial fibrillation: focus on frailty, multimorbidity and polypharmacy

INTRODUCTION: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation (AF); however, patients encountered in real-world practice frequently exhibit frailty, multimorbidity, and polypharmacy, phenotypes underrepresented in randomized clinical trials. AREAS COVERED: This narrative review addresses the safety and efficacy of DOACs in clinically complex AF populations. Targeted searches of PubMed/MEDLINE, Embase, and major cardiology society documents (ESC/EHRA) were performed from inception to May 2025, prioritizing randomized trials and complemented by large observational studies and registries. Available evidence indicates that DOACs demonstrate similar or superior efficacy and safety compared with vitamin K antagonists in frail and multimorbid patients. Although polypharmacy increases the risk of drug - drug interactions, DOACs are associated with fewer interactions and simplified dosing strategies. Observational data support the real-world effectiveness of DOACs when treatment is individualized according to frailty status, comorbidity burden, renal function, and medication review. EXPERT OPINION: DOACs can be used safely and effectively in complex AF patients when care is individualized. Integration of frailty screening, structured polypharmacy review, and holistic management approaches, such as the ABC pathway, may improve outcomes. Future research should focus on prospective studies and implementation strategies in underrepresented high-risk populations.