Effects of acadesine on myocardial infarction, stroke, and death following surgery - A meta-analysis of the 5 international randomized trials

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.