Varenicline and Ventricular Ectopy After Myocardial Infarction: A Randomized Phase 2 Study
Yunli Shen1, Xiaogang Guo2, Chunyu Zeng3
1State Key Laboratory of Cardiovascular Diseases, Department of Cardiology, and Shanghai Arrhythmia Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
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).
Insights
Varenicline significantly reduced premature ventricular complexes (PVCs) and ventricular tachycardia in post-MI patients. This novel approach targeting cardiac nicotinic acetylcholine receptors (nAChRs) shows promise as a safe antiarrhythmic therapy.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Conventional antiarrhythmic drugs pose proarrhythmic risks.
- Cardiac nicotinic acetylcholine receptors (nAChRs) offer a novel therapeutic target.
Purpose of the Study:
- To evaluate varenicline's efficacy and safety in reducing premature ventricular complexes (PVCs) post-myocardial infarction (MI).
- To assess varenicline's biological target engagement and antiarrhythmic potential.
Main Methods:
- A multicenter, randomized, double-blind, placebo-controlled phase 2 trial.
- 118 adults with frequent PVCs post-MI received varenicline or placebo for 45 days.
- Primary endpoint: percentage change in 24-hour PVC count; secondary endpoints: responder rate and nonsustained ventricular tachycardia (VT) incidence.
Main Results:
- Varenicline significantly reduced PVC burden by 60.1% compared to placebo (P = 0.001).
- Higher responder rates (67.8% vs 30.5%) and lower nonsustained VT incidence (20.3% vs 37.3%) were observed with varenicline.
- Adverse event rates were comparable, with no deaths or malignant ventricular arrhythmias in the varenicline group.
Conclusions:
- Varenicline effectively reduces PVC burden and VT incidence in post-MI patients without proarrhythmic effects.
- Cardiac nAChRs are a viable antiarrhythmic target.
- Further large-scale outcome trials are warranted to confirm these findings.
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