Author + information
- Michael Ragosta, MD∗ ()
- Cardiac Catheterization Laboratories, University of Virginia Health System, Charlottesville, Virginia
- ↵∗Reprint requests and correspondence:
Dr. Michael Ragosta, Cardiac Catheterization Laboratories, University of Virginia Health System, Charlottesville, Virginia 22909.
In the current era of translational research and evidence-based medicine, the published data abounds with examples of promising therapeutic strategies on the basis of brilliant theories that succeed in the laboratory and in pilot studies but fail in large-scale clinical trials. This has been particularly true for adjunctive therapies designed to reduce infarction in acute myocardial infarction (MI). Over the past several decades, numerous clever ideas have been proposed and tested. They succeeded primarily in enhancing the academic careers of basic scientists and cardiologists rather than the outcomes of patients with MI. Strategies such as therapeutic hypothermia, hyperbaric oxygen, stem cell injection, distal protection devices, aspiration thrombectomy, prophylactic intra-aortic balloon pumps, nitrates, magnesium, pexelizumab (an anti-C5 complement inhibitor), glucose/insulin/potassium infusion, and other drugs have been studied as methods to reduce infarction size or no-reflow. They were all on the basis of sound physiological principles and promising preliminary data, yet the expensive clinical trials that followed did not find clinical benefit.
In theory, adenosine is one of the most promising of these adjuncts. Several biological properties of adenosine could prove beneficial in patients with acute MI such as augmentation and preservation of microvascular flow, inhibition of oxidative stress, and inhibition of neutrophil-mediated reperfusion injury (1). Animal models demonstrated reductions in infarct size with adenosine, and small pilot studies in humans showed promising results (1); however, randomized clinical trials were mostly unsupportive. In a trial of 236 patients within 6 h of MI treated with lysis and randomized to a 3-h intravenous infusion of 70 μg/kg/min of adenosine versus placebo (AMISTAD [Acute Myocardial Infarction STudy of ADenosine]), only the subgroup with anterior MI had a reduction in infarct size compared with placebo (2). AMISTAD II, a larger trial enrolling >2,000 patients within 6 h of an anterior MI randomized to a 3-h infusion of either low-dose (50 μg/kg/min) or high-dose (70 μg/kg/min) adenosine or placebo, found no difference in the primary endpoint of the study (new heart failure or death within 6 months). A substudy consisting of 243 patients designed to measure infarct size observed no effect on infarct size in the pooled adenosine groups; however, the high-dose adenosine group had a significant reduction in infarct size versus placebo (3). Post-hoc analysis of AMISTAD II observed improved outcomes in the subset of patients undergoing reperfusion within the first 3 h of infarction (4). Other randomized clinical trials using an intracoronary bolus of adenosine found no benefit (5,6). Thus, despite some “positive” findings, these clinical trials were essentially negative. Adenosine is not used routinely for this purpose nor is it recommended by current practice guidelines.
So why not abandon adenosine to the trash heap of other good ideas that failed in clinical trials? The answer to this question is complex, and many critics consider the studies flawed and the question of adenosine’s benefit in MI unresolved. Studies designed to test whether a drug reduces reperfusion injury and infarction size must consider many variables. With such a very short half-life, the optimal dose, rate, duration, and route of adenosine administration are critical to get right. In addition, it is important to deliver the drug at the optimal time relative to the onset of infarction and reperfusion. It is very possible that the existing clinical trials simply got these parts wrong.
To add further complexity, the optimal window during which a therapy may reduce reperfusion injury and limit infarct size is likely very small. If reperfusion is accomplished very early, say within the first hour or 2 of symptom onset, the area at risk is mostly salvaged and the resulting infarction and area at risk of reperfusion injury will likely be very small. In such cases, a drug cannot be expected to show an improvement. Alternatively, if reperfusion is delayed, say 6 to 8 h after symptom onset, then the risk area is mostly infarcted. In such cases, there will be little additional injury from reperfusion and subsequently little benefit from agents that reduce reperfusion injury. Thus, agents such as adenosine may only prove effective during a very narrow time frame of only a few hours after symptom onset.
In this issue of JACC: Cardiovascular Interventions, Yetgin et al. (7) persevered in the face of negative trials and provide valuable insight into the role of adenosine in limiting infarct size. Their study design differed importantly from other work. They measured the size of infarction and no-reflow in pigs subject to 45 min of coronary occlusion followed by 2 h of reperfusion and compared the effect of 2 strategies of adenosine with control subjects: an intracoronary bolus of 3 mg adenosine administered over 1 min and a 2-h intracoronary infusion of 50 μg/kg/min of adenosine. The intracoronary bolus of adenosine had no effect. There was no increase in blood flow (beyond the expected reactive hyperemia caused by the infarction) and no reduction in infarction size, no-reflow area, or attenuation of neutrophil influx. In contrast, intracoronary infusion of high-dose adenosine increased blood flow and caused an absolute 13% reduction of infarct size and a 23% reduction in no-reflow along with a nonsignificant trend toward reduced neutrophil infiltration into the no-reflow area. They concluded that only high-dose, prolonged, intracoronary administration of adenosine is effective at reducing infarct size and no-reflow and that adenosine as an adjunctive therapy should be reconsidered.
Is it time then for another expensive trial? I believe that this would be very challenging and require extensive additional work to justify. The interesting work by Yetgin et al. (7) created more questions than answers. What is the optimal adenosine dose? Instead of using the same dose for all, should the dose be on the basis of the amount of adenosine needed to achieve a certain blood flow? Should we use a Doppler FloWire to dose adenosine and, if so, what is the optimal blood flow needed for benefit? Is a 3- to 4-fold increase needed or is 2-fold adequate? Is even higher better? For what duration should the infusion be administered? Is 2 h necessary or is 1 h enough? Clinicians will be faced with logistic problems to accomplish a prolonged intracoronary infusion. Infusion through the guide catheter is problematic as there is the potential to dislodge the catheter during a prolonged infusion or there may be reflux of drug into the aorta or noninfarct vessel during infusion, thus diminishing the amount of drug entering the infarct-related artery. This can be overcome by positioning a microcatheter, allowing selective infusion into the infarct-related artery, but there may be additional risk during a prolonged infusion. Prolonged infusion will also occupy the cardiac catheterization laboratory for many hours; it is unlikely that it will be safe to do this outside of the lab for fear of catheter dislodgment or vessel injury. Finally, the timing of adenosine administration relative to symptom onset and reperfusion remains to be determined. As alluded to earlier, there may be only a very narrow window of benefit limited to patients undergoing successful reperfusion 2 to 6 h after symptom onset, but this needs additional careful study. So, although I applaud the perseverance and excellent work of Yetgin et al. (7), I doubt that intracoronary adenosine will become routine therapy after successful reperfusion therapy during acute MI any time soon.
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Ragosta has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2015 American College of Cardiology Foundation
- Mahaffey K.W.,
- Puma J.A.,
- Barbagelata N.A.,
- et al.
- Ross A.M.,
- Gibbons R.J.,
- Stone G.W.,
- Kloner R.A.,
- Alexander R.W.
- Fokkema M.L.,
- Vlaar P.J.,
- Vogelzang M.,
- et al.
- Yetgin T.,
- Uitterdijk A.,
- te Lintel Hekkert M.,
- et al.