Premature atrial contractions (PACs) are associated with increased risks of atrial fibrillation (AF), stroke, and heart failure (HF), yet no approved pharmacologic therapy exists for PAC suppression.

A phase 2, multicenter, randomized, double-blind, placebo-controlled trial published in the Circulation assessed the efficacy and safety of memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, in this population. Symptomatic adults with frequent PACs (≥1000 per 24 hours) were enrolled and randomly assigned to receive memantine or placebo for 6 weeks. The primary endpoint was percentage change in mean 24-hour PAC count from baseline to treatment completion, analyzed in the intention-to-treat population.

A total of 241 participants were included in the efficacy analysis. Memantine demonstrated a significantly greater reduction in PAC count compared with placebo (between-group difference: 47.1 percentage points; P=0.0045). The responder rate, defined as ≥50% reduction in PACs, was higher with memantine (52.4%) versus placebo (23.1%; P<0.0001). Secondary endpoints showed reductions in non-sustained atrial tachycardia burden (between-group difference: 30.98 percentage points; P=0.0043) and lower cumulative incidence of new-onset AF (4.8% vs 23.9%; P<0.0001). No clinically meaningful changes were observed in electrocardiographic intervals or left ventricular function, and no drug-related serious adverse events were reported.

Memantine reduced atrial ectopy and arrhythmia burden with a favorable safety profile. These findings support targeting the cardiac glutamatergic system as a novel therapeutic approach.