Latent Class Analysis to Identify Phenotype-Specific Treatment Effects of Catheter Ablation Versus Drug Therapy in Patients with Atrial Fibrillation: A Secondary Analysis of the CABANA Trial

BACKGROUND: The risk profile of patients with atrial fibrillation (AF) is heterogeneous, and treatment responses to catheter ablation versus drug therapy may vary across clinical phenotypes. Latent class analysis (LCA) identifies unobserved subgroups from baseline characteristics. OBJECTIVES: To apply LCA to CABANA data to define AF phenotypes and assess whether treatment effects differed across latent classes. METHODS: This secondary analysis of the CABANA trial included 2,204 patients randomized to catheter ablation or drug therapy. Twenty baseline variables covering demographics, comorbidities, AF history, symptom burden, and echocardiographic measures were used for LCA. The primary outcome was a composite of all-cause death, disabling stroke, serious bleeding, or cardiac arrest. Treatment effects across latent classes were evaluated under intention-to-treat (ITT) and per-protocol (PP) frameworks using Cox models with a treatment-by-class interaction term. RESULTS: Three latent classes were identified: Class 1 (n = 558), an older multimorbid symptomatic phenotype; Class 2 (n = 739), an older preserved-function lower-comorbidity phenotype; and Class 3 (n = 905), a younger male metabolic-risk phenotype. In ITT, treatment-effect estimates for catheter ablation versus drug therapy were most favorable in Class 2 (adjusted hazard ratio 0.56, 95% CI 0.34-0.92), whereas estimates in other classes were less distinct; interaction p = 0.070. PP analysis showed similar patterns, with the most favorable estimates observed in Class 2; interaction p = 0.047. CONCLUSIONS: LCA identified three AF phenotypes with differential responses to catheter ablation versus drug therapy. These findings suggest treatment heterogeneity across AF phenotypes and support further evaluation of phenotype-guided rhythm-control strategies. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/; Unique Identifier: NCT00911508.