Memantine for Premature Atrial Contractions: A Phase 2 Randomized Clinical Trial

Clinical Snapshot

Key Findings

• P Value: P=0.0045 for primary endpoint

• Effect Size: Between-group difference of 47.1 percentage points in PAC reduction

• Primary Outcome: 47.1 percentage point greater reduction in PAC count with memantine versus placebo

• Nnt Or Sensitivity: NNT approximately 3.4 for achieving ≥50% PAC reduction (based on 52.4% vs 23.1% responder rates)

• Confidence Interval: Not reported in abstract

Clinical Application

Memantine is readily available, well-tolerated, with established dosing protocols from dementia treatment Memantine listed on PBS for dementia; off-label use would require specialist initiation. TGA approval for PACs would require Phase 3 confirmation. Aligns with RACGP emphasis on AF prevention strategies Australian patients with symptomatic frequent PACs (≥1000/24h) who have failed lifestyle modifications

Abstract

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.

References

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