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Effect of Intravenous TRO40303 as an Adjunct to Primary Percutaneous Coronary Intervention for Acute ST-Elevation Myocardial Infarction: MITOCARE Study Results
Study Questions:
What is the efficacy and safety of TRO40303 for the reduction of reperfusion injury in patients undergoing revascularization for ST-segment elevation myocardial infarction (STEMI)?
Methods:
Patients in the MITOCARE study presenting with STEMI within 6 hours of onset of pain randomly received TRO40303 (n = 83) or placebo (n = 80) via intravenous bolus injection prior to balloon inflation during primary PCI in a double-blind manner. The primary endpoint was infarct size expressed as area under the curve (AUC) for creatine kinase (CK) and for troponin I (TnI) over 3 days. Secondary endpoints included measures of infarct size using cardiac magnetic resonance (CMR) and safety outcomes. The primary endpoint was compared between treatment groups using an analysis of covariance (ANCOVA) mixed model.
Results:
Median pain-to-balloon time was 180 minutes for both groups, and median (mean) door-to-balloon time was 60 (38) minutes for all sites. Infarct size, as measured by CK and TnI AUCs at 3 days, was not significantly different between treatment groups. There were no significant differences in CMR-assessed myocardial salvage index (1-infarct size/myocardium at risk) (mean 52% vs. 58% with placebo, p = 0.1000), mean CMR-assessed infarct size (21.9 g vs. 20.0 g, or 17% vs. 15% of left ventricular [LV] mass) or LV ejection fraction (LVEF) (46% vs. 48%), or in the mean 30-day echocardiographic LVEF (51.5% vs. 52.2%) between TRO40303 and placebo. A greater number of adjudicated safety events occurred in the TRO40303 group for unexplained reasons.
Conclusions:
The authors concluded that STEMI patients treated with contemporary mechanical revascularization principles did not show any effect of TRO40303 in limiting reperfusion injury of the ischemic myocardium.
Perspective:
This study reports that TRO40303, an inhibitor mitochondrial permeability transition pore (mPTP) opening, failed to show reductions in infarct size, as measured by the co-primary endpoints of reduction in AUC for cardiac biomarkers CK and TnI. Analysis of secondary endpoints, as measured by CMR and echocardiography, confirmed that there were no significant differences between TRO40303 and placebo in reducing reperfusion injury. These results, combined with the many prior failures in the field, raise an important issue of whether reperfusion injury occurs at all in humans, and if it does, whether this type of injury accounts for a significant part of the remaining infarct. Further research is needed to provide additional insight into the nature and true role of reperfusion injury.
Keywords: Myocardial Infarction, Creatine Kinase, Area Under Curve, Pain, Percutaneous Coronary Intervention, Mitochondrial Membrane Transport Proteins, Reperfusion Injury, Oximes, Biomarkers, Troponin I, Magnetic Resonance Spectroscopy, Echocardiography, Secosteroids
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