Calcium/Calmodulin-Dependent Protein Kinase II Delta Inhibition and Ventricular Remodeling after Myocardial Infarction: A Randomized Clinical Trial

Andrew J. Boyle, Carl Schultz, Joseph B. Selvanayagam, Stuart Moir, Richard Kovacs, Nabil Dib, David Zlotnick, Mohammed Al-Omary, Stuart Sugito, Aravinda Selvarajah, Nicholas Collins, Grant McLachlan

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3 Citations (Scopus)

Abstract

Importance: After anterior ST-segment elevation myocardial infarction (STEMI), left ventricular (LV) remodeling results in heart failure and death. Calcium/calmodulin-dependent protein kinase II delta (CaMKIId) is a key molecular mediator of adverse LV remodeling. Objective: To determine whether NP202, an orally active inhibitor of CaMKIId, prevents LV remodeling in patients after anterior STEMI with early residual LV dysfunction. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled multicenter clinical trial of NP202 vs placebo in patients after primary percutaneous coronary intervention (PCI) for anterior STEMI was performed from November 19, 2015, to August 1, 2018. The study was performed at 32 sites across the US, Australia, and New Zealand. Patients presenting with anterior STEMI who underwent PCI within 12 hours of symptom onset and left ventricular ejection fraction (LVEF) less than 45% on screening echocardiogram 48 hours after primary PCI were included in the study. Baseline cardiovascular magnetic resonance (CMR) imaging was performed within 5 days of the STEMI and before administration of the study drug. Follow-up CMR was performed after 3 months. Data were analyzed from November 19, 2015, to August 1, 2018. Interventions: Patients were randomly assigned to NP202, 1000 mg, daily for 3 months vs corresponding placebo. Main Outcomes and Measures: The primary end point was change in LV end-systolic volume index (LVESVi) on CMR. Secondary end points were change in LV end-diastolic volume index, change in LVEF, change in infarct size, and change in diastolic function. Safety and tolerability were also assessed. Results: A total of 147 patients (mean [SD] age, 58 [11] years; 129 men [88%]; 130 White patients [88%]) who experienced anterior STEMI treated with primary PCI were randomized to receive NP202 (73 [49.7%]) or placebo (74 [50.3%]). Baseline LVEF was similar between groups. At baseline, patients randomized to NP202 had greater LVESVi (48.2 mL/m2) than that in the placebo group (41.3 mL/m2; P =.03). However, the groups were otherwise well matched. For the primary end point of change in LVESVi from baseline to 3 months, there was no significant difference between the placebo (median [interquartile range] change, -0.60 [-9.28 to 5.99] mL/m2) and NP202 groups (-3.53 [-9.24 to 4.81] mL/m2) (P =.78). There was also no difference in the secondary efficacy end points assessed by CMR. NP202 was well tolerated and demonstrated an acceptable safety profile. Major adverse cardiac and cerebrovascular event rates were similar between groups. Two deaths occurred in each group during the follow-up period. Conclusions and Relevance: Three months of treatment with NP202 after primary PCI for anterior STEMI with residual LV dysfunction did not improve LV remodeling. The drug was safe and well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT02557217.

Original languageEnglish
Pages (from-to)762-768
Number of pages7
JournalJAMA Cardiology
Volume6
Issue number7
DOIs
Publication statusPublished - Jul 2021

Bibliographical note

Funding Information:
receiving grants from Armaron Bio. Dr Schultz reported receiving grants from Abbott Vascular outside the submitted work. Dr Kovacs reported receiving clinical trial fees from Armaron Bio during the conduct of the study. Dr Dib reported receiving a grant from Armaron Bio and fees for services to Mercy Gilbert Hospital during the conduct of the study. Dr Zlotnick reported receiving consultant fees from Abiomed Speakers Bureau, AstraZeneca Speakers Bureau, Inari, and AngioDynamics Speakers Bureau outside the submitted work. Dr McLachlan reported being an employee of Armaron Bio and having a patent (8 017 649) issued by Armaron Bio during the conduct of the study. No other disclosures were reported.

Funding Information:
Funding/Support: The study was sponsored by

Publisher Copyright:
© 2021 American Medical Association. All rights reserved.

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