Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis of the 5 international randomized trials. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group.
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.


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


METHODS
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 x kg(-1) x min(-1); n=2012) by intravenous infusion for 7 continuous hours and via the cardioplegia solution.


METHODS
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.


RESULTS
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% Cl, 0.27-0.98; P=.04), and decreased the incidence of combined outcome (MI, stroke, or cardiac death) by 26% (OR, 0.73; 95% Cl, 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% Cl, 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.
Mangano
D T
DT
Department of Anesthesiology, Multicenter Study of Perioperative Ischemia, San Francisco, CA 94134, USA.
D000620:Aminoimidazole Carboxamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002561:Cerebrovascular Disorders / Q000209:etiology* / Q000401:mortality / Q000517:prevention & control; D001026:Coronary Artery Bypass / Q000401:mortality; D003402:Creatine Kinase / Q000378:metabolism; D004562:Electrocardiography; D006801:Humans; D007527:Isoenzymes; D015233:Models, Statistical; D015337:Multicenter Studies as Topic; D009203:Myocardial Infarction / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000401:mortality / Q000517:prevention & control; D011183:Postoperative Complications / Q000175:diagnosis / Q000401:mortality / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic; D012263:Ribonucleosides / Q000009:adverse effects / Q000627:therapeutic use*; D016019:Survival Analysis
D007527:Isoenzymes; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D003402:Creatine Kinase