Efficacy and Safety of Vernakalant for Cardioversion of Atrial Fibrillation and Flutter: A Systematic Review and Meta-Analysis

Background/Objectives: Vernakalant is an atrial-selective antiarrhythmic used for rapid pharmacological cardioversion of recent-onset atrial fibrillation. This systematic review and meta-analysis evaluated the efficacy and safety of vernakalant compared with placebo, active antiarrhythmic therapy, and electrical cardioversion. Methods: PubMed, Embase, Google Scholar, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to August 2026. Randomized clinical trials, clinical trials, and comparative observational studies evaluating vernakalant in adults with atrial fibrillation or atrial flutter were included. Dichotomous outcomes were pooled as risk ratios (RRs) with 95% confidence intervals (CIs) using the Mantel–Haenszel random-effects model in RevMan 5.4. Results: Twenty controlled studies involving 4523 patients were included, of whom 2349 received vernakalant and 2174 received control therapy. Vernakalant significantly increased successful conversion to sinus rhythm compared with all controls (1234/2244 (55%) vs. 991/2147 (46.2%); RR = 1.63; 95% CI [1.34, 1.99]; p < 0.00001). The effect was strongest versus placebo (RR = 5.33; 95% CI [1.95, 14.60]; p = 0.001) and remained significant versus procainamide (111/178 (62.3%) vs. 83/172 (48.2%); RR = 1.29; 95% CI [1.07, 1.57]; p = 0.009) and flecainide (209/280 vs. 209/330 (63.3%); RR = 1.18; 95% CI [1.05, 1.33]; p = 0.007), but non-significant against amiodarone, propafenone, ibutilide, or electrical cardioversion. Safety outcomes did not differ significantly between groups, including all-cause mortality (RR = 1.23), drug discontinuation (RR = 0.98), serious adverse events (RR = 0.87), ventricular tachycardia (RR = 0.68), bradycardia (RR = 1.31), and hypotension (RR = 0.80). Conclusions: Vernakalant was associated with higher rates of conversion to sinus rhythm, while no statistically significant differences were observed in major safety outcomes. These findings support its use as a pharmacological option for rapid rhythm restoration in appropriately selected patients.