MITOCARE: Novel Drug as Adjunct to PCI for STEMI Does Not Reduce Reperfusion Injury Risk

BARCELONA, Spain—In patients with ST-segment elevation myocardial infarction (STEMI), adjunctive TRO40303 does nothing to limit reperfusion injury after percutaneous coronary intervention (PCI), according to results presented on September 1, 2014, at the European Society of Cardiology Congress and simultaneously published online in the European Heart Journal.

“These results combined with the many failures in the field raise 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,” said presenter Dan Atar, MD, PhD, of the University of Oslo (Oslo, Norway).

TRO40303 is a compound that has been previously shown to reduce infarct size in animal MI models by inhibiting the opening of mitochondrial permeability transition pores.

Methods
For MITOCARE, Dr. Atar and colleagues randomized 163 STEMI patients within 6 hours of symptom onset to TRO40303 (6 mg/kg; n = 83) or placebo (n = 80) over a slow bolus injection after coronary angiography but before balloon inflation during PCI. All patients were treated at 10 European centers between October 2011 and September 2013.
Baseline characteristics between the study and control groups were well balanced, although TRO40303-treated patients tended to be older, more likely to have unsuccessful PCI, and have higher levels of mean CK levels on admission. Overall, median symptom-to-balloon and door-to-balloon times were 180 and 60 minutes, respectively.


There were no differences between the 2 groups in the co-primary efficacy endpoints of infarct size as measured by the mean area under the curve for creatine kinase (CK; 77,558.4 vs 74,455.3; P = .98) and troponin I (3,377.6 vs 3,084.9; P = .57) over 3 days. Cardiovascular magnetic resonance (n = 93) did not show any differences in infarct size normalized to the myocardium at risk (eg, myocardium salvage index) between the treatment and placebo arms (17% vs 15% of LV mass). Likewise, no differences in LVEF (46% vs 48%) or any other secondary outcome measures were observed, with the exception of infarct transmurality being higher in the TRO40303 group (P = .004).

Among 165 patients, including 2 additional patients who were treated with TRO40303 but did not receive PCI, the rate of experiencing at least 1 major adverse event was higher in the study arm than with placebo (24.7% vs 10.0%; P = .0131). The most common events were cardiogenic shock, ventricular arrhythmias, and revascularization. Of 102 serious adverse events, 72 occurred in 35 patients (41.2%) in the treatment arm and 30 occurred in 20 patients (25%) in the placebo arm. More than half of these events in both groups were cardiac disorders, which occurred twice as often in the TRO40303 group compared with in the placebo group.

Discussant Hans Erik Bøtker, MD, PhD, of Aarhus University Hospital, Skejby (Aarhus, Denmark), said that because reperfusion injury is “considered a major target for reproducing [preclinical] outcomes in STEMI patients,” MITOCARE was an important but disappointing study. He outlined 3 unanswered questions:

  • Whether the compound really does not work
  • Whether confounding factors or an inappropriate dose may have increased infarct size
  • Whether or not reperfusion injury really occurs in humans

“The dose-dependent response is not really convincing,” Dr. Bøtker said. “Also, the concentrations used in the rat models are significantly lower than those used in the [current] study.” Because of this, he concluded, “the MITOCARE study might have been a little premature.”

 


Source: 
Atar D, Arheden H, Berdeaux A, et al. Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results. Eur Heart J. 2014;Epub ahead of print.

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Disclosures
  • Dr. Atar reports no relevant conflicts of interest.

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