Abstract Background Catheter ablation and antiarrhythmic drug therapy are utilized for rhythm control in atrial fibrillation (AF), but their comparative effectiveness, especially with contemporary treatment modalities, remains undefined. We conducted a systematic review and meta-analysis contrasting current ablation techniques against antiarrhythmic medications for AF. Methods We searched PubMed, SCOPUS, Cochrane CENTRAL, and Web of Science until November 2023 for randomized trials comparing AF catheter ablation with antiarrhythmics, against antiarrhythmic drug therapy alone, reporting outcomes for > 6 months. Four investigators extracted data and appraised risk of bias (ROB) with ROB 2 tool. Meta-analyses estimated pooled efficacy and safety outcomes using R software. Results Twelve trials (n = 3977) met the inclusion criteria. Catheter ablation was associated with lower AF recurrence (relative risk (RR) = 0.44, 95%CI (0.33, 0.59), P ˂ 0.0001) and hospitalizations (RR = 0.44, 95%CI (0.23, 0.82), P = 0.009) than antiarrhythmic medications. Catheter ablation also improved the physical quality of life component score (assessed by a 36-item Short Form survey) by 7.61 points (95%CI -0.70-15.92, P = 0.07); but, due to high heterogeneity, it was not statistically significant. Ablation was significantly associated with higher procedural-related complications [RR = 15.70, 95%CI (4.53, 54.38), P
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