Administration of regulating agent before CABG did not improve outcomes

Issue: August 2012

Intermediate- to high-risk patients undergoing CABG who were administered acadesine to regulate adenosine did not experience reductions in all-cause mortality, nonfatal stroke or need for mechanical support for ventricular dysfunction at 1 month after surgery, researchers reported in a new study.

The randomized, double blind, placebo-controlled Reduction in Cardiovascular Events by Acadesine in Patients Undergoing CABG (RED-CABG) study included intermediate- to high-risk patients (median age, 66 years) undergoing nonemergency, on-pump CABG at 300 sites in seven countries. Participants were enrolled from May 2009 to July 2012. Eligible participants were randomly assigned to acadesine (0.1 mg/kg per minute for 7 hours) or placebo beginning just before anesthesia induction. The trial was designed to evaluate whether acadesine could reduce the composite of all-cause mortality, nonfatal stroke and need for mechanical support for LV dysfunction occurring during and after CABG through postoperative day 28.

The trial was stopped after 3,080 of the originally projected 7,500 study participants were randomized because early findings showed a very low likelihood of a significant efficacious outcome, according to a press release. The final sample size comprised 2,986 patients in the intention-to-treat analysis.

Acadesine vs. placebo

Mark F. Newman, MD, chairman of the department of anesthesiology at Duke University Medical Center, and colleagues found that the primary efficacy outcome was observed in 5% of patients overall. Further, there was no significant difference between the acadesine and placebo groups, with incidence rates of 5.1% and 5%, respectively, according to the release.

“We expected about 10% of patients were at high risk for complication following CABG,” Newman stated in a release issued by Duke University Medical Center. “But the actual risk was 5%. What that means is cardiac surgery has gotten much safer, even for high-risk patients.”

The low complication rate is likely the result of improved surgical methods in recent years, including better anesthesia and advances in surgical and heart-lung machine management, the researchers said.

Additional efficacy endpoints, including length of mechanical ventilation, ICU and hospital stay, and quality of life, did not differ between the two groups.

Continued search for effective therapies

A previous meta-analysis of randomized controlled trials demonstrated that perioperative and postoperative acadesine infusion was associated with reductions in early cardiac death, MI and combined adverse cardiac outcomes in the same patient population studied in RED-CABG.

“These findings illustrate inherent risks of using promising meta-analysis results to plan ‘confirmatory’ clinical trials. There are several potential explanations for the negative results we observed. One consideration is the decision around study eligibility criteria and the overall primary endpoint of the trial,” the researchers wrote in the study. They added that the lack of benefit of acadesine may be related to the dosing regimen used.

The researchers concluded that the incidence of the primary composite endpoint of 5% indicates the need for continued investigation into therapies to reduce perioperative morbidity and mortality.

“Despite improvements in myocardial protection and perioperative care, the risk of death is still substantial in the first month after CABG surgery, averaging 3% to 6%, and can be even higher in patients with poor left ventricular function,” the researchers wrote. “Up to 50% of these deaths have been attributed to a cardiac cause, and this percentage has remained fairly constant over time.”

For more information:

Newman MF. JAMA. 2012;308:157-164.

Disclosure: The RED-CABG study was funded by Schering-Plough (subsequently Merck Sharp & Dohme Corp.). Dr. Newman reported receiving grant support and honoraria from Schering-Plough/Merck for activities related to the RED-CABG study and this article (all funds paid to the Duke Clinical Research Institute). See the full study for the other authors’ disclosures.