Clinical Phenotype Classification of Atrial Fibrillation Patients Using Cluster Analysis and Associations with Trial-Adjudicated Outcomes

Background and purpose: Given the great clinical heterogeneity of atrial fibrillation (AF) patients, conventional classification only based on disease subtype or arrhythmia patterns may not adequately characterize this population. We aimed to identify different groups of AF patients who shared common clinical phenotypes using cluster analysis and evaluate the association between identified clusters and clinical outcomes. Methods: We performed a hierarchical cluster analysis in AF patients from AMADEUS and BOREALIS trials. The primary outcome was a composite of stroke/thromboembolism (TE), cardiovascular (CV) death, myocardial infarction, and/or all-cause death. Individual components of the primary outcome and major bleeding were also assessed. Results: We included 3980 AF patients treated with the Vitamin-K Antagonist from the AMADEUS and BOREALIS studies. The analysis identified four clusters in which patients varied significantly among clinical characteristics. Cluster 1 was characterized by patients with low rates of CV risk factors and comorbidities; Cluster 2 was characterized by patients with a high burden of CV risk factors; Cluster 3 consisted of patients with a high burden of CV comorbidities; Cluster 4 was characterized by the highest rates of non-CV comorbidities. After a mean follow-up of 365 (standard deviation 187) days, Cluster 4 had the highest cumulative risk of outcomes. Compared with Cluster 1, Cluster 4 was independently associated with an increased risk for the composite outcome (hazard ratio (HR) 2.43, 95% confidence interval (CI) 1.70–3.46), all-cause death (HR 2.35, 95% CI 1.58–3.49) and major bleeding (HR 2.18, 95% CI 1.19–3.96). Conclusions: Cluster analysis identified four different clinically relevant phenotypes of AF patients that had unique clinical characteristics and different outcomes. Cluster analysis highlights the high degree of heterogeneity in patients with AF, suggesting the need for a phenotype-driven approach to comorbidities, which could provide a more holistic approach to management aimed to improve patients’ outcomes.