Circulation, Ahead of Print. BACKGROUND:Premature atrial contractions (PACs) are independently associated with atrial fibrillation, stroke, and heart failure, yet no pharmacological therapy is approved for PAC suppression. Experimental studies have identified a functional cardiac glutamatergic system in which N-methyl-D-aspartate receptors regulate atrial electrophysiology. Preclinical studies show that pharmacological antagonism of N-methyl-D-aspartate receptors with memantine suppresses atrial arrhythmias.METHODS:We conducted an investigator-initiated, phase 2, multicenter, randomized, double-blind, placebo-controlled trial. Symptomatic adults with frequent PACs (≥1000/24 h) were randomly assigned to receive memantine or placebo for 6 weeks. The primary end point was the percentage change in mean 24-hour PAC count from baseline to the end of treatment. The primary analysis was performed in the intention-to-treat population. Prespecified secondary end points included the responder rate (≥50% PAC reduction), percentage change in nonsustained atrial tachycardia burden, and cumulative incidence of new-onset atrial fibrillation.RESULTS:Among 241 patients included in the efficacy analysis, memantine resulted in a greater reduction in PAC count than placebo (between-group difference, 47.1 percentage points;P=0.0045). The responder rate was higher with memantine than with placebo (52.4% versus 23.1%;P<0.0001).
Circulation, Ahead of Print. BACKGROUND:Premature atrial contractions (PACs) are independently associated with atrial fibrillation, stroke, and heart failure, yet no pharmacological therapy is approved for PAC suppression. Experimental studies have identified a functional cardiac glutamatergic system in which N-methyl-D-aspartate receptors regulate atrial electrophysiology. Preclinical studies show that pharmacological antagonism of N-methyl-D-aspartate receptors with memantine suppresses atrial arrhythmias.METHODS:We conducted an investigator-initiated, phase 2, multicenter, randomized, double-blind, placebo-controlled trial. Symptomatic adults with frequent PACs (≥1000/24 h) were randomly assigned to receive memantine or placebo for 6 weeks. The primary end point was the percentage change in mean 24-hour PAC count from baseline to the end of treatment. The primary analysis was performed in the intention-to-treat population. Prespecified secondary end points included the responder rate (≥50% PAC reduction), percentage change in nonsustained atrial tachycardia burden, and cumulative incidence of new-onset atrial fibrillation.RESULTS:Among 241 patients included in the efficacy analysis, memantine resulted in a greater reduction in PAC count than placebo (between-group difference, 47.1 percentage points;P=0.0045). The responder rate was higher with memantine than with placebo (52.4% versus 23.1%;P<0.0001). Memantine also reduced nonsustained atrial tachycardia burden (between-group difference, 30.98 percentage points;P=0.0043) and was associated with a lower cumulative incidence of new-onset atrial fibrillation (4.8% versus 23.9%;P<0.0001). No clinically meaningful differences were observed in electrocardiographic intervals or left ventricular function, and no drug-related serious adverse events occurred.CONCLUSIONS:In patients with frequent symptomatic PACs, memantine reduced atrial ectopy and atrial tachyarrhythmia burden and demonstrated a favorable safety profile. These findings provide proof of concept for a novel, non–ion channel–based therapeutic strategy targeting the cardiac glutamatergic system.REGISTRATION:URL:https://www.clinicaltrials.gov; Unique identifier: NCT06501638.