Memantine for Premature Atrial Contractions: A Phase 2 Randomized Clinical Trial
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.
Article Details
Authors (59)
Yunli Shen
Chunyu Zeng
Yingxian Sun
Jian’an Wang
Bo Yu
Xiang Cheng
Xiaogang Guo
Dao Wen Wang
Department of Internal Medicine, Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (D.W.W., Y.W., J. Lai, L.W.).
Yue Li
Wei Han
Bingqing Zhou
Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China (C.Z., B. Zhou, J. Zeng, X.Y.).
Hongzhuan Sheng
Zhaoqi Huang
Department of Cardiology, The Third Affiliated Hospital of Guangzhou Medical University, China (Z.H.).
Yigang Li
Guosheng Fu
Jidong Zhang
Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China (J. Zhang).
Duanyang Xie
Dandan Liang
State Key Laboratory of Cardiovascular Diseases, Shanghai Arrhythmia Research Center, and Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, China (Y.S., W.H., D.X., D.L., Y. Liu, B. Yang, Q.Z., R.D., H.L., B. Zhang, Yizhang Wu, L.Z., S.L., K.X., G.W., Q.Z., B.S., Z.C., Yahan Wu, J. Leng, Y.-H.C.).
Yi Liu
Bing Yang
Qi Zhang
Ran Duan
Hongxiao Li
Baowei Zhang
Yizhang Wu
Department of Applied Physical Sciences, University of North Carolina
Liang Zheng
Jia He
Shenglin Liu
State Key Laboratory of Cardiovascular Diseases, Shanghai Arrhythmia Research Center, and Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, China (Y.S., W.H., D.X., D.L., Y. Liu, B. Yang, Q.Z., R.D., H.L., B. Zhang, Yizhang Wu, L.Z., S.L., K.X., G.W., Q.Z., B.S., Z.C., Yahan Wu, J. Leng, Y.-H.C.).
Dechun Yin
Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, China (Y. Li, D.Y.).
Guozhe Sun
Department of Cardiology, The First Hospital of China Medical University, Shenyang (Y.S., G.S., S.Z., X.G.).
Shu Zhang
Xiaofan Guo
Department of Neurology and Neurosurgery, UPMC Stroke Institute, University of Pittsburgh School of Medicine, Pittsburgh
Min Zhang
Yiyi Wang
Xiajun Hu
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.C., M.Z., Yiyi Wang, Xiajun Hu).
Jing Zeng
Xiaoli Yang
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Navy/Second Military Medical University
Shufeng Li
Ning Li
Feng Hu
Department of Chemistry, Engineering Research Center of Advanced Rare Earth Materials (Ministry of Education)
Haifeng Wang
Xinyang Hu
Yaping Wang
Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University
Cong Zeng
Kai Wang
Jian Yang
Yan Wang
Jinsheng Lai
Luyun Wang
Ke Xiong
Guanghua Wang
Qicheng Zou
Beihua Shao
Zhiwen Chen
Yahan Wu
State Key Laboratory of Cardiovascular Diseases, Shanghai Arrhythmia Research Center, and Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, China (Y.S., W.H., D.X., D.L., Y. Liu, B. Yang, Q.Z., R.D., H.L., B. Zhang, Yizhang Wu, L.Z., S.L., K.X., G.W., Q.Z., B.S., Z.C., Yahan Wu, J. Leng, Y.-H.C.).
Junwei Leng
State Key Laboratory of Cardiovascular Diseases, Shanghai Arrhythmia Research Center, and Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, China (Y.S., W.H., D.X., D.L., Y. Liu, B. Yang, Q.Z., R.D., H.L., B. Zhang, Yizhang Wu, L.Z., S.L., K.X., G.W., Q.Z., B.S., Z.C., Yahan Wu, J. Leng, Y.-H.C.).
Jun Pu
Changsheng Ma
Yi-Han Chen