Reduction in Cardiovascular Events by Acadesine in Patients Undergoing CABG - RED-CABG

Description:

The goal of the trial was to evaluate treatment with the adenosine-regulating agent acadesine compared with placebo among patients undergoing coronary artery bypass grafting (CABG).

Hypothesis:

Acadesine will improve clinical outcomes after CABG.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Stratified

Patient Populations:

  • Patients at least 50 years of age undergoing on-pump CABG with at least one of the following characteristics:
    - Women
    - Prior CABG
    - Prior myocardial infarction
    - Prior ischemic stroke
    - Left ventricular ejection fraction ≤30%
    - Diabetes mellitus

    Number of enrollees: 3,080
    Duration of follow-up: 28 days
    Mean patient age: 67 years
    Percentage female: 34%

Exclusions:

  • Planned valve replacement, carotid surgery, aortic surgery, or surgical ablation for arrhythmia
  • Planned major surgery within 30 days of CABG
  • Use of intermittent aortic cross clamping without cardioplegia
  • Use of minimally invasive surgery without cardiopulmonary bypass
  • Myocardial infarction within 5 days of CABG
  • Planned mechanical support device
  • Gout
  • Chronic kidney disease
  • Elevated liver enzymes
  • Ingestion of caffeine <12 hours before CABG
  • Use of adenosine <24 hours before CABG
  • Use of dipyridamole <2 days before CABG
  • Use of allopurinol <4 days before CABG

Primary Endpoints:

  • All-cause mortality, nonfatal stroke, or need for mechanical left ventricular support at 28 days

Drug/Procedures Used:

Patients undergoing CABG at high risk of adverse events were randomized to acadesine 0.1 mg/kg/min for 7 hours (n = 1,536) versus placebo (n = 1,544) just after induction of general anesthesia.

Principal Findings:

Overall 3,080 patients were randomized. The mean age was 67 years, 34% were women, mean body mass was 87 kg, 61% had diabetes, 48% had prior myocardial infarction, and 10% had prior stroke.

The trial was stopped early due to assessment of futility. The primary outcome occurred in 5.1% of the acadesine group versus 5.0% of the placebo group (p = 0.94).

All-cause mortality: 1.9% versus 1.8%
Nonfatal stroke: 1.7% versus 1.7%
Need for mechanical support: 2.3% versus 2.3%
Cardiovascular mortality: 1.7% versus 1.6%

Interpretation:

Among high-risk patients undergoing CABG, the use of perioperative acadesine for 7 hours was not beneficial. This agent did not reduce all-cause mortality, nonfatal stroke, or need for mechanical support compared with placebo. This contrasts the results of five previous studies in over 4,000 patients, which suggested benefit with acadesine. This medication joins the list of other disproven cardioprotective drugs during CABG: sodium-proton exchange inhibitor, purinergic receptor antagonist, and complement activation inhibitor.

References:

Newman MF, Ferguson TB, White JA, et al., on behalf of the RED-CABG Steering Committee and Investigators. Effect of Adenosine-Regulating Agent Acadesine on Morbidity and Mortality Associated With Coronary Artery Bypass Grafting. The RED-CABG Randomized Controlled Trial. JAMA 2012;308:157-64.

Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Cardiac Surgery and Heart Failure

Keywords: Myocardial Infarction, Stroke, Sodium, Ribonucleosides, Purinergic Antagonists, Medical Futility, Coronary Artery Bypass, Diabetes Mellitus


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