Memantine for Premature Atrial Contractions: Phase 2 Randomized Clinical Trial

19 Mar 20264 min read0 viewsJournal Feed

GIST (Key Takeaways)

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).

Premature atrial contractions (PACs) are linked with higher risk of atrial fibrillation, stroke, and heart failure, yet no approved pharmacologic PAC-suppressing therapy is available.
Preclinical data indicate a cardiac glutamatergic system with N-methyl-D-aspartate (NMDA) receptors that influence atrial electrophysiology; memantine, an NMDA receptor antagonist, has shown suppression of atrial arrhythmias in experimental models.

This was an investigator-initiated, phase 2, multicenter, randomized, double-blind, placebo-controlled trial.
Participants were symptomatic adults with frequent PACs defined as at least 1000 PACs per 24 hours.
Participants were randomized to memantine or placebo for a 6-week course.
The primary analysis adhered to the intention-to-treat principle.

Intervention: Memantine versus placebo for 6 weeks.
Primary outcome: Percentage change in mean 24-hour PAC count from baseline to end of treatment.
Prespecified secondary outcomes included: responder rate (≥50% reduction in PACs), percentage change in nonsustained atrial tachycardia burden, and cumulative incidence of new-onset atrial fibrillation.
Efficacy analyses focused on the efficacy population (n=241).

Memantine achieved a greater reduction in PAC count compared with placebo, with a between-group difference of 47.1 percentage points (P = 0.0045).
The responder rate favored memantine (52.4% vs 23.1%; P < 0.0001).
Reduction in nonsustained atrial tachycardia burden favored memantine (difference of 30.98 percentage points; P = 0.0043).
Cumulative incidence of new-onset atrial fibrillation was lower with memantine (4.8% vs 23.9%; P < 0.0001).
No clinically meaningful differences in electrocardiographic intervals or left ventricular function were detected, and no drug-related serious adverse events were reported.

The study provides proof-of-concept for a novel, non–ion channel–based strategy targeting the cardiac glutamatergic system to suppress atrial ectopy and tachyarrhythmias.