Administering the adenosine-regulating agent acadesine to intermediate- and high-risk patients undergoing CABG did not reduce their risk of all-cause mortality, stroke or left ventricular dysfunction, according to the results of the RED-CABG trial published July 10 in the Journal of the American Medical Association .
“Ischemia/reperfusion injury remains an important cause of morbidity and mortality after coronary artery bypass graft (CABG) surgery,” Mark F. Newman, MD, of the Duke University Medical Center in Durham, N.C., and colleagues wrote.
To better understand whether patients undergoing CABG surgery and administered an adenosine-regulating agent saw better results, including reduced cardiac death, Newman et al conducted the RED-CABG (Cardiovascular Events by Acadesine in Patients Undergoing CABG) trial. The randomized trial enrolled 2,986 intermediate- to high-risk patients undergoing CABG between May 6, 2009, and July 30, 2010.
The study participants were randomized at a 1:1 ratio to receive a 0.1 mg/kg per minute dose of acadesine for seven hours or placebo. The authors reported all-cause mortality, cases of nonfatal stroke and the need for mechanical support for severe left ventricular dysfunction through post-op day 28.
The median age of the study cohort was 66, and the majority of patients were white males with a history of hyperlipidemia, diabetes and a family history of cardiovascular disease.
Newman and colleagues reported that the primary outcomes were in 5 percent of the study population with no significant differences found between the placebo and acadesine groups, 5 percent vs. 5.1 percent, respectively.
“The incidence of the primary composite endpoint in the overall study population (including the placebo group) was substantially below that projected from the previous studies and historical data,” the authors wrote. “These findings illustrate inherent risks of using promising meta-analysis results to plan 'confirmatory' clinical trials.”
The authors attributed the negative findings to the study eligibility criteria and the endpoints chosen for the trial. The researchers said that the overall mortality risk based on Society of Thoracic Surgeons criteria was lower than what was originally projected.
“We cannot exclude the possibility that a more favorable result might have been obtained in patients deemed to be at higher risk of intraoperative ischemic events, such as those undergoing long and complex combined valve and coronary procedures,” Newman et al wrote.
The authors added that the lack of results seen with acadesine could be due to the dosing regimen used.
“The RED-CABG study demonstrates that among intermediate- to high-risk patients undergoing CABG surgery, acadesine did not reduce all-cause mortality, nonfatal stroke, or need for mechanical support for SLVD [severe left ventricular dysfunction] through postoperative day 28,” the authors summed. “The incidence of the primary composite endpoint was 5 percent, indicating the need for continued investigation into therapies to reduce perioperative morbidity and mortality.”