EFFECTS OF ACADESINE ON THE INCIDENCE OF MYOCARDIAL-INFARCTION AND ADVERSE CARDIAC OUTCOMES AFTER CORONARY-ARTERY BYPASS GRAFT-SURGERY

Background: Acadesine (AICA riboside) no-1-[beta-D-ribofuranosy]imidaz ole-4-carboxamide) is a purine nucleoside analog belonging to a new cl ass of agents generally termed adenosine regulating agents (ARAs) that increase the availability of adenosine locally in ischemic tissues, T he effects of acadesine on the incidence of fatal and nonfatal myocard ial infarction (MI) and on the incidence of all adverse cardiovascular outcomes (cardiac death, MI, congestive heart failure, Life-threateni ng dysrhythmia, or cerebrovascular accident) was investigated in patie nts undergoing coronary artery bypass graft (CABG) surgery. Methods: I n 20 medical centers in the United States participating in the Multice nter Study of Perioperative Ischemia (McSPI), 633 patients undergoing CABG surgery were randomized in a double-blind fashion to receive eith er 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 an d continuing for 7 h, as well as added to the cardioplegic solution (f inal concentration of 5 mu g/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 occurren ce of MI. Results: There was a similar incidence of adverse events in the acadesine groups and the placebo group, with the exception that se rum 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 i ncidence 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, alpha = 0.017, corrected for multiple comparisons), as we re 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 pea k 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 o f this trial did not demonstrate a statistically significant differenc e between acadesine and placebo using the prespecified criterion for M I. Of interest are the results of the post hoc analysis, using the mor e specific criterion for MI, which indicate that acadesine may reduce the incidence of larger Q-wave infarctions after coronary artery bypas s surgery. A second trial is underway to evaluate this contention.