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Original Investigation
April 14, 2021

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

Author Affiliations
  • 1Department of Cardiovascular Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia
  • 2University of Newcastle, Newcastle, New South Wales, Australia
  • 3Hunter Medical Research Institute, Newcastle, New South Wales, Australia
  • 4University of Western Australia School of Medicine, Perth, Australia
  • 5Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia
  • 6Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia
  • 7South Australian Health and Medical Research Institute, Adelaide, Australia
  • 8MonashHeart, Melbourne, Victoria, Australia
  • 9Monash University, Melbourne, Victoria, Australia
  • 10Krannert Institute of Cardiology, Indianapolis, Indiana
  • 11Dignity Healthcare, Gilbert, Arizona
  • 12University of Buffalo, Buffalo, New York
  • 13Armaron Bio, Melbourne, Victoria, Australia
JAMA Cardiol. 2021;6(7):762-768. doi:10.1001/jamacardio.2021.0676
Key Points

Question  Does inhibition of calcium/calmodulin-dependent protein kinase II delta with NP202 after anterior ST-segment elevation myocardial infarction prevent left ventricular (LV) remodeling?

Findings  This randomized clinical trial including 147 patients found no significant difference in the primary end point of change in LV end-systolic volume index over 3 months of treatment with drug NP202 compared with placebo. The drug was safe and well tolerated.

Meaning  Oral NP202 after anterior ST-segment elevation myocardial infarction with residual LV dysfunction does not attenuate LV remodeling.

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

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