An Initial Multicenter, Randomized Controlled Trial on the Safety and Efficacy of Acadesine in Patients Undergoing Coronary Artery Bypass Graft Surgery

Acadesine (5-amino-4-imidazole carboxamide riboside) is a purine nucleoside analog that has been shown in animals to reduce myocardial ischemic injury by selectively increasing the availability of adenosine in ischemic tissues. Because patients undergoing coronary artery bypass graft (CABG) surgery are especially vulnerable to developing myocardial ischemia, we investigated whether perioperative use of this adenosine-regulating drug with potential anti-ischemic properties could modify the incidence and severity of perioperative myocardial ischemia. The goals 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, life-threatening dysrhythmias, and death) in patients undergoing CABG surgery. 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-blind fashion intraoperatively and in the early postoperative period (total infusion time was 7 h). Multidose cold crystalloid cardioplegia (each containing either acadesine or placebo) was used for myocardial protection. All were monitored for potentially drug-related adverse events and the presence of myocardial ischemia was assessed by continuous Holter electrocardiography (ECG) and transesophageal echocardiography (TEE). All patients received standardized anesthetic, surgical, and hemodynamic management during the intraoperative period. All research data (ECG, TEE, outcome data) were evaluated at the coordinating center (San Francisco) in blinded fashion to ensure that uniform data analysis criteria were employed. The administration of acadesine was safe: mild 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 the preoperative period (baseline), the incidence and severity of ECG ischemia did not differ among the three groups (placebo = 18%; low-dose = 14%; high-dose = 14%). During prebypass, the incidence of ECG ischemia was similar in all three groups (0%, 3%, 3%, respectively). The incidence of TEE ischemia was numerically lower in the two acadesine groups (high-dose = 6%, low-dose = 15%) than in the control group (19%), but this was not statistically significant (P = 0.22). During postbypass, the incidence of ECG ischemia was 11% in the high-dose group, 22% in 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-dose = 27%; high-dose = 24%) (P = 0.86). The mean duration of postbypass 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 5% in both the low- and high-dose groups, compared with 14% in the placebo group (P = 0.13). The incidence of creatine phosphokinase (CPK-MB) >50 U/L in the placebo group was 47%, compared with 34% and 23% in the two acadesine groups (low- and high-dose groups, respectively; P = 0.09). The administration of intravenous acadesine for 7 h perioperatively is safe in patients undergoing CABG surgery. Acadesine limits the severity of postbypass myocardial ischemia as evidenced by shorter ischemic duration in patients receiving high-dose acadesine. Whether acadesine can definitively decrease the frequency of myocardial infarction and the extent of myocardial injury remains to be determined.