Background: Acadesine (AICA riboside) (5-amino-1-[β-D- ribofuranosy]imidazole-4-carboxamide) is a purine nucleoside analog belonging to a new class of agents generally termed adenosine regulating agents (ARAs) that increase the availability of adenosine locally in ischemic tissues. The effects of acadesine on the incidence of fatal and nonfatal myocardial infarction (MI) and on the incidence of all adverse cardiovascular outcomes (cardiac death, MI, congestive heart failure, life-threatening dysrhythmia, or cerebrovascular accident) was investigated in patients undergoing coronary artery bypass graft (CABG) surgery. Methods: In 20 medical centers in the United States participating in the Multicenter Study of Perioperative Ischemia (McsPI), 633 patients undergoing CABG surgery were randomized in a double-blind fashion to receive either placebo (n = 212), low-dose acadesine (0.05 mg · kg-1 · min-1, n = 214), or high-dose acadesine (0.1 mg · kg-1 · min-1, n = 207) by intravenous infusion starting 15 min before anesthetic induction and continuing for 7 h, as well as added to the cardioplegic solution (final concentration of 5 μg/ml for those patients receiving acadesine). Anesthesia was standardized, and perioperative hemodynamics were to be strictly controlled. Twelve-lead electrocardiograms (ECGs), CK-MB isoenzyme concentrations, and autopsy were used to assess the occurrence of MI. Results: There was a similar incidence of adverse events in the acadesine groups and the placebo group, with the exception that serum uric acid transiently increased in the high-dose acadesine group. The incidence of perioperative MI, using the prespecified MI criterion (ECG Q wave, CK-MB elevation, or autopsy evidence), was not different between groups (24% versus 26% versus 21% [P = 0.574]), nor was the incidence of all cardiovascular outcomes (30% versus 30% versus 22% [P = 0.151]). After completion of the study, a post hoc analysis also was performed using the more specific definition of MI (ECG Q wave and CK-MB elevation, or autopsy evidence), and the incidence of MI was lower (P = 0.018, α = 0.017, corrected for multiple comparisons), as were adverse cardiovascular outcomes (P = 0.002) and CVA (P = 0.02) for patients treated with 0.1 mg · kg-1 · min-1 acadesine. In patients with Q-wave infarction, the high-dose acadesine group had a lower peak median CK-MB (P = 0.042) and area under the CK-MB curve (P = 0.021). No differences were found in the incidence or characteristics of MI (Holter or transesophageal echocardiography). Conclusions: The results of this trial did not demonstrate a statistically significant difference between acadesine and placebo using the prespecified criterion for MI. Of interest are the results of the post hoc analysis, using the more specific criterion for MI, which indicate that acadesine may reduce the incidence of larger Q-wave infarctions after coronary artery bypass surgery. A second trial is underway to evaluate this contention.