CORRESPONDENCE: LETTER TO THE EDITOR
AMISTAD Trials: Possible Reasons for Lack of Success
Michael V. Cohen, MD* and
James M. Downey, PhD
* Department of Physiology, MSB 3050, University of South Alabama, College of Medicine, Mobile, Alabama 36688 (Email: mcohen{at}usouthal.edu).
Results of the Acute Myocardial Infarction STudy of ADenosine (AMISTAD II) trial were recently reported by Ross et al. (1). As in the AMISTAD I trial (2), most of the conclusions were at best equivocal, although subgroup analysis each time suggested adenosine might be useful as an adjunct to reperfusion therapy in certain patients with acute myocardial infarction. Thus the hope was raised that a more targeted trial might yield a significant difference between placebo and treatment groups. Although this possibility is real, we would like to offer an alternative hypothesis. Contrary to the twice-repeated assertion by the investigators that "adenosine ... has consistently provided myocardial protection from ischemic injury in animal models," the ability of adenosine administered at or shortly before reperfusion to provide cardioprotection against infarction is indeed quite controversial. There are certainly some studies which report that adenosine at reperfusion can decrease infarct size in various animal models, and some of these experimental investigations are acknowledged by Ross et al. (1). However, it is notable that two of the references cited by the researchers to justify their conclusion have been misquoted. Yao and Gross (3) and Thornton et al. (4) found protection when adenosine or an adenosine agonist was used as a preconditioning agent.
Furthermore, Thornton et al. (4) actually observed that when N6-(2-phenylisopropyl) adenosine (PIA) was infused at reperfusion, it had no cardioprotective effect despite its effectiveness when applied as a pretreatment. Also, numerous other preclinical studies have been unable to document an effect of authentic adenosine (5–8) at reperfusion on infarct size. Therefore, it is possible that both the inability to demonstrate a significant effect of adenosine at reperfusion in patients and the inconsistent preclinical results are because adenosine given at reperfusion simply does not protect the heart.
In the two AMISTAD trials it was reported that infarct size was significantly diminished in those patients with anterior wall myocardial infarction who were treated with adenosine. Although this observation is potentially important and noteworthy, a technical limitation diminishes the significance of the data. It has been recognized for many years that a major determinant of infarct size is the size of the region at risk. In fact, no experimental study of infarct size limitation would be accepted for publication if the size of the risk region were not quantitated and used to normalize the measurement of infarct size. It is recognized that it is difficult, but not impossible, to obtain these data in clinical studies because scans must be recorded both before and after the intervention. Reliance on absolute infarct size as a percentage of the left ventricle—despite the many reasonable correlations between this parameter and measures of ventricular function and clinical outcome, without normalization for the size of the region at risk—can yield incorrect conclusions. And this difficulty is perhaps best highlighted by the very different measurements of infarction in patients treated with placebo: 45% in the AMISTAD I study and 27% in the AMISTAD II study.
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1. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW. A randomized, double-blinded placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of actue myocardial infarction (AMISTAD-II) J Am Coll Cardiol 2005;45:1775-1780.[Abstract/Free Full Text]2. Mahaffey KW, Puma JA, Barbagelata NA, et al. Adenosine as an adjunct to thrombolytic therapy for actue myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial J Am Coll Cardiol 1999;34:1711-1720.[Abstract/Free Full Text] 3. Yao Z, Gross GJ. A comparison of adenosine-induced cardioprotection and ischemic preconditioning in dogsefficacy, time course, and role of KATP channels. Circulation 1994;89:1229-1236.[Abstract/Free Full Text] 4. Thornton JD, Liu GS, Olsson RA, Downey JM. Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction Circulation 1992;85:659-665.[Abstract/Free Full Text] 5. Goto M, Miura T, Iliodoromitis EK, et al. Adenosine infusion during early reperfusion failed to limit myocardial infarct size in a collateral deficient species Cardiovasc Res 1991;25:943-949.[Abstract/Free Full Text] 6. Vander Heide RS, Reimer KA. Effect of adenosine therapy at reperfusion on myocardial infarct size in dogs Cardiovasc Res 1996;31:711-718.[CrossRef][Web of Science][Medline] 7. Budde JM, Velez DA, Zhao Z-Q, et al. Comparative study of AMP579 and adenosine in inhibition of neutrophil-mediated vascular and myocardial injury during 24 h of reperfusion Cardiovasc Res 2000;47:294-305.[Abstract/Free Full Text] 8. Xu Z, Downey JM, Cohen MV. AMP 579 reduces contracture and limits infarction in rabbit heart by activating adenosine A2 receptors J Cardiovasc Pharmacol 2001;38:474-481.[CrossRef][Web of Science][Medline]
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