Failure of TRO40303 may question whether reperfusion injury actually occurs in man


Dan Atar (Department of Cardiology, Oslo University Hospital, Norway) told ESC delegates that the MITOCARE study indicates that the novel agent TRO40303 does not provide any protective effect compared with placebo in preventing reperfusion injury in STEMI patients undergoing primary PCI. This study, combined with many other failed trials, leads to new insights on how successful modern therapy of STEMI has become.

Atar reported: “The mitochondrial permeability transition pore is believed to be a promising target for preventing reperfusion injury. TRO40303 has been shown to inhibit the opening of this transition pore.” He added that the compound has been shown to reduce infarct size by 50% in rat and mouse models and also been shown to have protective effects on isolated human cells. Therefore, the aim of the multicentre, randomised, double-blind, placebo-controlled MITOCARE study was to assess whether these findings would be replicated in STEMI patients undergoing PCI. 

First-time STEMI patients (163) presenting within six hours of symptom onset and who had been assigned to undergo PCI were randomised to receive TRO40303 (83) or placebo (80) prior to balloon inflation. The primary endpoint was infarct size as measured by the area under the curve (AUC) for creatine kinase (CK) and for troponin I (TnI ) over three days; blood samples were taken at baseline and six, 12, 18, 24, 36, 48, 72 hours after PCI. The main secondary endpoint outcome was infarct size normalised to the myocardium at risk (expressed as the myocardium salvage index).

There were no significant differences between the TRO40303 group and the placebo group in the primary endpoint for either AUC72 CK (77558.4±50058.7 for TRO40303 vs. 74455.3±54601.9 for placebo; p=0.98) or for AUC72 for TnI  (3377.6±3031.7 vs.3084.9±2838.1; p=0.57). There were also no significant differences in any of secondary endpoints. For example, the mean myocardium salvage index was 0.52 in the TRO40303 group and 0.58 in the placebo group (p=0.1).

However, Atar and colleagues write in the report of MITOCARE, which was simultaneously published in the European Heart Journal at the time of the ESC presentation, that: “The study was not powered for safety analysis yet it revealed a higher rate of cardiac events [which occurred twice as often] in the TRO40303 group. Hence, the possibility that this imbalance in adverse events is linked to the study drug cannot be ruled out.”

Atar concluded that the MITOCARE trial did not show any protective effective of TRO40303, noting that a “high standard” of care accounted for the relatively small infarct sizes observed in both study arms after primary PCI and this left “little room for improvement”. He added: “These results [of MITOCARE] combined with many failures in the field raised a provocative issue: whether reperfusion injury occurs at all in man—and if it does, whether this type of injury really accounts for a significant part of the remaining infarct.”