Varenicline and Ventricular Ectopy After Myocardial Infarction

BACKGROUND: Conventional antiarrhythmic drugs that target cardiac ion channels carry proarrhythmic risks, highlighting the need for alternative therapeutic approaches. Cardiac nicotinic acetylcholine receptors (nAChRs) represent a novel electrophysiological target. OBJECTIVES: The aim of this exploratory, proof-of-concept phase 2 trial was to evaluate the effect of varenicline, a partial nAChR agonist, on frequent premature ventricular complexes (PVCs) after myocardial infarction (MI) and to assess its short-term safety and biological target engagement. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, adults with frequent PVCs (≥1,000/24 h) assessed using 72-hour ambulatory electrocardiographic monitoring at ≥4 weeks post-MI were randomly assigned (1:1) to varenicline 0.5 mg twice daily or matching placebo for 45 days, in addition to guideline-directed medical therapy. The primary endpoint was the percentage change in 24-hour PVC count from baseline to week 6. Key secondary endpoints included responder rate (≥50% reduction in PVC count) and the incidence of nonsustained ventricular tachycardia (VT). RESULTS: Among 118 randomized patients, varenicline produced a 60.1 percentage point greater reduction in PVC burden compared with placebo (95% CI: 21.3-98.8 percentage points; P = 0.001). The responder rate was higher with varenicline (67.8% vs 30.5%; RR: 2.22; 95% CI: 1.46-3.39; P < 0.0001), and nonsustained VT incidence was lower (20.3% vs 37.3%; RR: 0.49; 95% CI: 0.29-0.85; P = 0.007). No deaths or malignant ventricular arrhythmias occurred in the varenicline group, with comparable adverse event rates between groups. CONCLUSIONS: In this phase 2 trial, varenicline significantly reduced PVC burden and nonsustained VT incidence in post-MI patients without evidence of a proarrhythmic effects. These findings support cardiac nAChRs as a potential antiarrhythmic target and justify further evaluation in larger outcome-driven trials. (Efficacy of Varenicline Tartrate in Treating Frequent Premature Ventricular Contractions: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial [Var-PVC]; NCT06780215).