Study EMBRACEs Novel Drug, But Fails to Reduce Infarct Size in Anterior STEMI

SAN DIEGO, CA— In first-time STEMI patients undergoing PCI after a proximal or mid LAD occlusion, the administration of a novel mitochondrial targeting peptide failed to reduce infarct size, according to results of the EMBRACE STEMI trial presented March 15, 2015, at the American College of Cardiology/i2 Scientific Session.Take Home: Study EMBRACEs Novel Drug, But Fails to Reduce Infarct Size in Anterior STEMI

Bendavia (Stealth BioTherapeutics; Newton, MA)—a cell-permeable peptide—targets cardiolipin, a phospholipid found exclusively in the inner mitochondrial membrane. By doing so, it “preserves the integrity of the electron transport system” resulting in infarct size reductions ranging from 10% to 40% in prior animal studies, according to C. Michael Gibson, MD, of Harvard Medical School (Boston, MA).

For the study, researchers from 24 hospitals in 4 countries randomized 297 first-time STEMI patients with anterior lesions in the proximal or mid LAD to Bendavia infusion (0.05 mg/kg/hr; n = 150) or placebo (n = 147) administered 15 minutes prior to and 1 hour after PCI. Surprisingly, about 40% of patients presented with open arteries and confirmed STEMIs and were excluded from the study, bringing the primary analysis population down to 118. Notably, Dr. Gibson said, Bendavia did not change the rate of artery opening.

Patients assigned to placebo were more likely to present with hypertension than those slated to receive Bendavia (60% vs 37.9%; P = .02). However, all other clinical and angiographic characteristics were well matched between the groups.

No Difference in Infarct Size

Infarct size, as measured by serum CK-MB at 6 hours, was similar between the study drug and placebo groups (217.4 ± 41.1 vs 266.6 ± 37.7 ng/ml; P = NS), as was the area under the curve (AUC) for the measurement (5,570 vs 5,785 ng*h/ml; P = NS). Results were maintained when more sensitive troponins were measured at 6 hours.

There were no differences between the treatment strategies with regard to infarct volume, edema, or LVEF, but there was a trend toward slightly larger cardiac mass with placebo compared with the study drug on cardiac MRI at 4 days, consistent with the higher history of hypertension in the placebo arm (162.2 vs 141.5 g; P = .08). Angiographic outcomes related to flow or perfusion also were similar, as were procedural success rates.

The clinical composite endpoint (death, new-onset congestive heart failure after 24 hours of PCI, or heart failure rehospitalization) was similar between the study arms at 30 days and 6 months (P = NS for both). However, given that three-quarters of new-onset heart failure occurred within 24 hours of PCI, researchers noticed trends within these patients for decreased events with the study drug, with most events occurring within the first 8 hours (table 1).

Table 1. Congestive HF Events Within 24 Hours by Time from Balloon Deflation to HF Onset

In a non-prespecified exploratory analysis of patients with hypertension, infarct volume was smaller with the study drug compared with placebo (35.8 vs 52.6 ml; P = .03) and edema volume trended smaller (49 vs 61 ml; P = .053). There were no differences in the rate of any treatment-related adverse events or ST-segment resolution.

Bendavia was associated with less change in creatinine over the first 12 hours compared with placebo (1.0 vs 3.7 µmol/L; P = .03). Over the first 48 hours after PCI, the AUC for creatinine was again lower for the study drug compared with placebo after adjusting for baseline creatinine and PCI duration as a surrogate for dye load (P = .04).

In summary, Dr. Gibson said, while the primary endpoint is neutral, the “hypothesis-generating data” related to heart failure is now being prospectively tested in 2 ongoing studies and the “provocative information about renal preservation” is now being prospectively evaluated in an ongoing trial.”

Not Giving Up

Discussing the study, Eric D. Peterson, MD, MPH, of the Duke Clinical Research Institute (Durham, NC), congratulated the researchers for “joining the venerable club of drugs that work very well in animal models but don't unfortunately work in reperfusion models in humans.”

In response, Dr. Gibson said, “For something to work, you have to give the right drug to the right patient at the right time at the right dose.”

Given that the EMBRACE STEMI patients had by far the largest MIs possible, he said the study enrolled the right patients. “What is interesting is in those people who had the thickest heart muscles, the hypertensive patients, [is] where we may have seen a signal,” Dr. Gibson commented, adding that they also had the right dose and the right timing. “We conducted the experiment in a way that if there was an [issue] there, we would have seen it.”

Panelist Sotirios Tsimikas, MD, of the University of California, San Diego (La Jolla, CA), said, “This is still an area of cardiology with unmet need.” He questioned Dr. Gibson on the mechanism of potential benefit associated with the study drug. 

“In other reperfusion injury trials, we have given the drug distally,” Dr. Gibson responded. “What if the artery is open but the drug can't get to the area that you need to get it to? That is still one of the residual unsolved issues.”

With regard to renal protectiveness, panelist James B. McClurken, MD, of Doylestown Hospital (Philadelphia, PA), said Bendavia may have “widespread potential application, including in coronary surgical revascularization.”

 

 

 


Source:
Gibson CM. The EMBRACE STEMI Study: a phase 2a, randomized, double-blind, placebo controlled trial to evaluate the safety, tolerability and efficacy of intravenous Bendavia on reperfusion injury in patients treated with standard therapy including primary PCI and stenting for ST-segment elevation myocardial infarction. Presented at: American College of Cardiology/i2 Scientific Session; March 15, 2015; San Diego, CA.

Disclosure:

  • EMBRACE STEMI was sponsored by Stealth BioTherapeutics.
  • Dr. Gibson reports receiving institutional research support from Stealth BioTherapeutics.
  • Dr. Peterson reports receiving consulting fees/honoraria from AstraZeneca, Boehringer Ingelheim, Genentech, Janssen, and Sanofi and research support from Eli Lilly and Janssen.
  • Dr. Tsimikas reports receiving consulting fees/honoraria from Pfizer, serving in a fiduciary role at Isis, and holding patents via UCSD.
  • Dr. McClurken reports no relevant conflicts of interest.

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