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J Am Coll Cardiol, 2006; 48:206-214, doi:10.1016/j.jacc.2006.04.044
(Published online 9 May 2006). © 2006 by the American College of Cardiology Foundation |
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Ischemia Research and Education Foundation (IREF), San Bruno, California
Manuscript received February 7, 2006; revised manuscript received March 30, 2006, accepted April 4, 2006.
* Reprint requests and correspondence: Dr. Dennis T. Mangano, Editorial Office, Ischemia Research and Education Foundation, 1111 Bayhill Drive, Suite 480, San Bruno, California 94066 (Email: dtb{at}iref.org).
OBJECTIVES: The purpose of this study was to assess the safety and efficacy of the adenosine regulating agent (ARA) acadesine for reducing long-term mortality among patients with post-reperfusion myocardial infarction (MI).
BACKGROUND: No prospectively applied therapy exists that improves long-term survival after MI associated with coronary artery bypass graft (CABG) surgery—a robust model of ischemia/reperfusion injury. Pretreatment with the purine nucleoside autocoid adenosine mitigates the extent of post-ischemic reperfusion injury in animal models. Therefore, we questioned whether use of the ARA acadesine—by increasing interstitial adenosine concentrations in ischemic tissue—would improve long-term survival after post-reperfusion MI.
METHODS: At 54 institutions, 2,698 patients undergoing CABG surgery were randomized to receive placebo (n = 1,346) or acadesine (n = 1,352) by intravenous infusion (0.1 mg/kg/min; 7 h) and in cardioplegia solution (placebo or acadesine; 5 µg/ml). Myocardial infarction was prospectively defined as: 1) new Q-wave and MB isoform of creatine kinase (CK-MB) elevation (daily electrocardiography; 16 serial CK-MB measurements); or 2) autopsy evidence. Vital status was assessed over 2 years, and outcomes were adjudicated centrally.
RESULTS: Perioperative MI occurred in 100 patients (3.7%), conferring a 4.2-fold increase in 2-year mortality (p < 0.001) compared with those not suffering MI. Acadesine treatment, however, reduced that mortality by 4.3-fold, from 27.8% (15 of 54; placebo) to 6.5% (3 of 46; acadesine) (p = 0.006), with the principal benefit occurring over the first 30 days after MI. The acadesine benefit was similar among diverse subsets, and multivariable analysis confirmed these findings.
CONCLUSIONS: Acadesine is the first therapy proven to be effective for reducing the severity of acute post-reperfusion MI, substantially reducing the risk of dying over the 2 years after infarction.
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