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A Meta-analysis of the 5 International Randomized Trials

Dennis T. Mangano, PhD, MD

JAMA. 1997;277(4):325-332.

Abstract
Objective.
—To determine the effects of a purine nucleoside, acadesine, on the incidence of fatal and nonfatal cardiovascular and cerebrovascular complications following coronary artery bypass graft (CABG) surgery.

Data Sources.
—Individual patient data from 5 randomized, placebo-controlled, double-blind clinical trials, including 81 international medical centers of the United States, Canada, and Europe.

Study Selection.
—All patients from all clinical trials were included: a total of 4043 patients undergoing CABG surgery, evaluable for efficacy, and randomized to receive either placebo (n= 2031) or acadesine (0.1 mg.kg^-1.min^-1;n=2012) by intravenous infusion for 7 continuous hours and via the cardioplegia solution.

Data Extraction.
—Individual patient data were collected prospectively using standardized forms and methods and double-data entry. A general parametric approach and analysis-by-patient meta-analysis were used, including both fixed effects and random effects models. Inclusion and exclusion criteria, general methodology, and outcome assessment techniques were similar for all trials.

Data Synthesis.
—Acadesine decreased the incidence of the primary outcome, perioperative myocardial infarction (MI) by 27% (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.51-0.95; P=.02), decreased the incidence of cardiac death through postoperative day 4 by 50% (OR, 0.52; 95% CI, 0.27-0.98; P=.04), and decreased the incidence of combined outcome (MI, stroke, or cardiac death) by 26% (OR, 0.73; 95% CI, 0.57-0.93; P=.01). The random effects models for these outcomes also yielded significant results. The incidence of cerebrovascular accident was not significantly reduced by acadesine (OR, 0.69; 95% CI, 0.44-1.08; P=.10). A secondary analysis of cardiac death following MI through postoperative day 4 demonstrated that acadesine decreased by 89% the number of deaths from 13.3% (13 deaths/98 MIs) in the placebo group to 1.4% (1 death/71 MIs) in acadesine-treated patients (P=.003). Acadesine also reduced the use of ventricular-assistance devices for severe postoperative heart failure by approximately one third (P=.05). Finally, regarding safety, the incidence of adverse events was similar in the acadesine vs placebo groups, with the exception of a transient increase in serum uric acid in the acadesine group.

Conclusions.
—The results of this meta-analysis indicate that in patients undergoing CABG surgery, treatment with acadesine before and during surgery can reduce early cardiac death, MI, and combined adverse cardiovascular outcomes.

Author Affiliations
for The Multicenter Study of Perioperative Ischemia (McSPI) Research Group

From the Departments of Anesthesiology, Medicine, Surgery, Cardiology, and Epidemiology and Biostatistics of the Member Centers of the Multicenter Study of Perioperative Ischemia Research Group, United States, Canada, Europe, and the Ischemia Research and Education Foundation.

Footnotes
A complete list of the McSPI Research Group appears at the end of this article.

Reprints: Dennis T. Mangano, PhD, MD, Multicenter Study of Perioperative Ischemia, 250 Executive Park Blvd, Suite 3400, San Francisco, CA 94134.

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