CORRESPONDENCE: LETTER TO THE EDITOR
Role of Adenosine in Acute Myocardial Infarction
Mervyn B. Forman, MD, PhD, FACC and
Edwin K. Jackson, PhD
Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, 100 Technology Drive, Suite 450, Pittsburgh, Pennsylvania 15219-3130
The Acute Myocardial Infarction STudy of ADenosine (AMISTAD II) is a pivotal trial having major clinical implications for the treatment of patients with acute myocardial infarction (AMI) (1). The AMISTAD II study corroborates the findings of the first AMISTAD study (2); it verifies that, as in animals (3), myocardial reperfusion injury significantly contributes to final infarct size in humans, and demonstrates that reperfusion injury accounts for >50% of the final infarct size after reperfusion.
Several issues regarding the design of the AMISTAD II study should be addressed. First, the study was severely underpowered. This was further compounded by having a second treatment arm with low-dose adenosine. The rationale for the second arm is unclear as the first AMISTAD study clearly shows that high-dose adenosine (70 µg/kg/min) is efficacious with regard to reducing infarct size in patients with anterior AMI and does not cause serious adverse clinical events (2).
Second, because the beneficial effects of adenosine in experimental models occur only with reperfusion, adenosine should attenuate reperfusion injury only in reperfused patients. In the AMISTAD II study approximately 60% of the patients were treated with thrombolytic agents, with streptokinase used in almost 40% of these patients. This would result in only approximately 80% of patients undergoing successful reperfusion. A subset analysis of the primary clinical end points in the high-dose group who underwent successful reperfusion may show a significant difference. This hypothesis is supported by the observation, presented in abstract form, that the combined clinical end point of death and congestive heart failure was significantly reduced in the pooled adenosine group (low + high dose) who underwent successful reperfusion (placebo 15% vs. pooled adenosine 11%; p = 0.04), whereas no significant difference was found in patients who did not reperfuse (placebo 34% vs. pooled adenosine 33%; p = 0.7) (4).
Third, because animal studies demonstrate that adenosine’s beneficial effects are lost if myocardial ischemia occurs for more than 3 h (5), adenosine would prevent reperfusion injury only in patients receiving adenosine within the first 3 h after coronary occlusion. Therefore, a subset analysis of the high-dose group who were reperfused within 3 h may yield an even greater reduction in clinical end points. Indeed, data from the abstract presentation show strong trends in the combined end points in the pooled adenosine group treated within 2 h of symptoms (pooled adenosine 9% vs. placebo 13%) (4). This is further supported by the study of Marzilli et al. (6) in which patients undergoing mechanical reperfusion within 2 h of symptoms and who were treated with adenosine showed a significant improvement in ventricular function and a reduction in major adverse clinical end points.
Despite these shortcomings, the AMISTAD II study, taken in conjunction with other clinical studies with adenosine, has important implications for the treatment of AMI. Adenosine is the only agent that has been shown consistently to reduce infarct size and, in some studies, to improve clinical outcomes in AMI patients undergoing reperfusion therapy. Adenosine should therefore be added to the armamentarium of agents used to treat patients with AMI who are candidates for either pharmacologic or mechanical reperfusion strategies.
 |
Footnotes
|
|---|
Please note: Vanderbilt University owns intellectual property related to adenosine and myocardial infarction that was invented by Drs. Forman and Jackson some 15 years ago.
|
References
|
|---|
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 acute 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 acute 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. Forman MB, Velasco CE, Jackson EK. Adenosine attenuates reperfusion injury following regional myocardial ischaemia Cardiovasc Res 1993;27:9-17.[Free Full Text] 4. AMISTAD II: Acute Myocardial Infarction Study of Adenosine. Late breaking clinical trials in interventional cardiology. Medscape 2003. Available at: http://www.medscape.com/viewarticle/430267 and http://www.clinicaltrialresults.org/Files/shows/amistad2.ppt#1908,1,Slide%201. Accessed March 17, 2002.. 5. Babbitt DG, Virmani R, Vildibill Jr HD, Norton ED, Forman MB. Intracoronary adenosine administration during reperfusion following 3 hours of ischemiaeffects on infarct size, ventricular function, and regional myocardial blood flow. Am Heart J 1990;120:808-818.[CrossRef][Web of Science][Medline] 6. Marzilli M, Orsini E, Marraccini P, Testa R. Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction Circulation 2000;101:2154-2159.[Abstract/Free Full Text]
|
Top
References