EXPEDITED REVIEW
Post-Reperfusion Myocardial Infarction
Long-Term Survival Improvement Using Adenosine Regulation With Acadesine
Dennis T. Mangano, PhD, MD*,
Yinghui Miao, MD, MS,
Iulia C. Tudor, PhD,
Cynthia Dietzel, MDfor the for the Investigators of the Multicenter Study of Perioperative Ischemia (McSPI) Research Group the Ischemia Research and Education Foundation (IREF)
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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Abbreviations and Acronyms
| | ARA = adenosine regulating agent | | CABG = coronary artery bypass graft | | CK-MB = MB isoform of creatine kinase | | MI = myocardial infarction | | PCI = percutaneous coronary intervention |
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