AN INITIAL MULTICENTER, RANDOMIZED CONTROLLED TRIAL ON THE SAFETY ANDEFFICACY OF ACADESINE IN PATIENTS UNDERGOING CORONARY-ARTERY BYPASS GRAFT-SURGERY

Acadesine (5-amino-4-imidazole carboxamide riboside) is a purine nucle oside analog that has been shown in animals to reduce myocardial ische mic injury by selectively increasing the availability of adenosine in ischemic tissues. Because patients undergoing coronary artery bypass g raft (CABG) surgery are especially vulnerable to developing myocardial ischemia, we investigated whether perioperative use of this adenosine -regulating drug with potential antiischemic properties could modify t he incidence and severity of perioperative myocardial ischemia. The go als of this study were to evaluate safety and the effects of acadesine on myocardial ischemia, left ventricular function, and, secondarily, on adverse clinical outcomes (myocardial infarction, heart failure, li fe-threatening dysrhythmias, and death) in patients undergoing CABG su rgery. One hundred sixteen patients were randomized to receive one of three continuous intravenous dosing regimens (placebo [control] or one of two doses of acadesine [high- and low-dose infusion]) in double-bl ind fashion intraoperatively and in the early postoperative period (to tal infusion time was 7 h). Multidose cold crystalloid cardioplegia (e ach containing either acadesine or placebo) was used for myocardial pr otection. All were monitored for potentially drug-related adverse even ts and the presence of myocardial ischemia was assessed by continuous Holter electrocardiography (ECG) and transesophageal echocardiography (TEE). All patients received standardized anesthetic, surgical, and he modynamic management during the intraoperative period. All research da ta (ECG, TEE, outcome data) were evaluated at the coordinating center (San Francisco) in blinded fashion to ensure that uniform data analysi s criteria were employed. The administration of acadesine was safe: mi ld increases in plasma uric acid (a metabolite of acadesine) occurred only in patients receiving high doses (mean increase 1.6 +/- 0.2 mg/dL ) and were without clinical sequelae. Before drug administration in th e preoperative period (baseline), the incidence and severity of ECG is chemia did not differ among the three groups (placebo = 18%; low-dose = 14%; high-dose = 14%). During prebypass, the incidence of ECG ischem ia was similar in all three groups (0%, 3%, 3%, respectively). The inc idence of TEE ischemia was numerically lower in the two acadesine grou ps (high-dose = 6%, low-dose = 15%) than in the control group (19%), b ut this was not statistically significant (P = 0.22). During postbypas s, the incidence of ECG ischemia was 11% in the high-dose group, 22% i n the low-dose group, and 18% in the control group (P = 0.42), and TEE ischemia was similar in incidence in all groups (placebo = 29%; low-d ose = 27%; high-dose = 24%) (P = 0.86). The mean duration of postbypas s ECG ischemic episodes was shorter in the high-dose group (36 +/- 20 min) than in the placebo (175 +/- 156 min) or low-dose (125 +/- 80 min ) groups (P = 0.04). The incidence of adverse cardiac outcome was 50/c in both the low- and high-dose groups, compared with 14% in the place bo group (P = 0.13). The incidence of creatine phosphokinase (CPK-MB) greater than or equal to 50 U/L in the placebo group was 47%, compared with 34% and 23% in the two acadesine groups (low- and high-dose grou ps, respectively; P = 0.09). The administration of intravenous acadesi ne for 7 h perioperatively is safe in patients undergoing CABG surgery . Acadesine limits the severity of postbypass myocardial ischemia as e videnced by shorter ischemic duration in patients receiving high-dose acadesine. Whether acadesine can definitively decease the frequency of myocardial infarction and the extent of myocardial injury remains to be determined.