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SAN DIEGO – Bendavia, a novel agent designed to prevent reperfusion injury by improving myocardial energetics, failed to reduce infarct size in ST-elevation MI patients in a phase II randomized trial.
Despite this disappointing result on the primary study endpoint, there was a silver lining. The study, known as the EMBRACE STEMI trial, generated two provocative findings in exploratory, hypothesis-generating secondary analyses: Bendavia appeared to reduce new-onset symptomatic heart failure early on after percutaneous coronary intervention, and the drug also had an apparent renal protective effect, Dr. C. Michael Gibson reported at the annual meeting of the American College of Cardiology.
These two potentially important findings are being studied more fully in three ongoing prospective, randomized, double-blind, placebo-controlled trials, added Dr. Gibson, professor of medicine at Harvard Medical School, Boston, and chairman of EMBRACE STEMI (Evaluation of Myocardial Effects of Bendavia for Reducing Reperfusion Injury in Patients With Acute Coronary Events).
As for the negative result in terms of the primary study hypothesis that Bendavia would reduce infarct size by preventing reperfusion injury in patients undergoing PCI for large STEMIs, as it had done successfully in animal models, the cardiologist said all indications are that the investigators targeted the right patients at the right time with the right dose of the medication.
“I think we conducted the experiment in such a way that if there was a ‘there’ there, we were going to see it,” Dr. Gibson said.
EMBRACE STEMI included 118 patients with large, first-time, anterior MIs featuring proximal or mid-left anterior descending coronary artery lesions. To be eligible for the study, patients had to arrive at the catheterization lab with a closed artery within 4 hours after symptom onset. They were then randomized in double-blind fashion to intravenous Bendavia at 0.05 mg/kg per hour for 1 hour beginning 15 minutes before PCI or to an equal volume of placebo.
The study, conducted by the PERFUSE study group at 24 sites in the United States and three European countries, was planned to be considerably larger, but to the surprise of investigators, 40% of patients arrived at the cath lab with an open artery.
“This is higher than the historical figure of 20%,” Dr. Gibson noted. “I think this is one of the notable findings in this study: Whether due to earlier presentation or better pharmacotherapy, it’s tougher to locate people with closed arteries for these kinds of studies in 2015.”
Bendavia did not significantly reduce infarct size as measured by the areas under the curve for creatine kinase MB (CK-MB) or troponin I over the initial 72 hours after PCI. Moreover, cardiac MRIs obtained at 4 and 30 days post PCI showed no significant difference between the Bendavia and placebo groups in infarct volume, left ventricular mass, edema volume, or left ventricular ejection fraction. Rates of ST-segment resolution immediately and 24 hours post PCI did not differ between the two groups, either. Nor did TIMI flow grade, frame count, or myocardial perfusion grade. Also, 30-day and 6-month rates of the composite clinical endpoint of death, new-onset heart failure beginning more than 24 hours post PCI, and heart failure rehospitalization did not differ in the Bendavia and control groups.
However, the incidence of new-onset heart failure within the first 8 hours post PCI was 8.6% in the Bendavia group compared with 18.3% in controls. This finding has prompted the two ongoing randomized trials where Bendavia is being tested in higher doses in patients with stable heart failure with reduced ejection fraction.
Bendavia is a peptide targeting the mitochondria, where it binds with cardiolipin and preserves the integrity of the electron transport system. In animal models of heart failure, it improves left ventricular function.
“It’s not an inotrope. It doesn’t change heart rate or blood pressure. Rather than increasing demands on the heart, it offers a supply side solution in improving myocardial energetics,” Dr. Gibson explained.
Bendavia was associated with renal preservation as reflected in a significantly smaller increase in creatinine level in the first 12 hours post PCI: 1.0 mcmol/L compared with 3.7 mcmol/L in controls.
This finding piqued the interest of discussant Dr. James B. McClurken , professor and vice chair of surgery at Temple University in Philadelphia.
“The renal protective findings have widespread potential application, including for coronary artery bypass surgery patients. What are your thoughts about the mechanism?” he asked.
Dr. Gibson replied that a small study done at the Mayo Clinic suggests a biologically plausible mechanism: Bendavia dramatically improved kidney hypoxia secondary to ischemia and the dye load entailed in longer PCI procedures.
Dr. Gibson reported receiving a research grant from Stealth BioTherapeutics to conduct the EMBRACE STEMI trial. He serves as a consultant to numerous pharmaceutical and medical device companies.