Despite the fact that numerous clinical trials investigating infarct size have been completed over the last two to three decades, the methods for treating lethal reperfusion injury efficiently have only become established very recently. After several years of accumulating evidence in experimental preparations that lethal reperfusion injury might exist, the description of the phenomenon of ischaemic post-conditioning in animal models has fully convinced us of the existence and importance of irreversible myocardial damage occuring after reflow. Transfer to the clinics was possible in small phase II trials, provided care was taken to assess the determinants of infarct size and, most importantly, to consider the timing of drug administration with respect to the time of reflow. Technical questions remain to be resolved regarding the assessment of the area at risk in the difficult setting of emergency care for reperfusion therapy. Nevertheless, convincing pharmacological trials are being performed that mark the start of a new era that will, in the future, improve the prognosis of patients with ST-segment elevation myocardial infarction through the prevention of lethal myocardial reperfusion injury. At present, while erythropoietin and adenosine have not proved efficient for alleviation of lethal reperfusion injury, a significant benefit has been reported for cyclosporin and exenatide. New pharmacological agents need to be identified and tested in phase II trials. In the meantime, clinical outcome studies are currently being conducted for cyclosporin.
ST elevation myocardial infarction
Over the last two decades, improvement of reperfusion therapy has clearly contributed to the amelioration of the prognosis of acute myocardial infarction (MI) patients. Major progress has been made in the organization of pre-hospital care, technical devices and catheterization techniques. The combination of faster access to reperfusion therapy, thromboaspiration, prevention of embolization and stenting, and optimized antiplatelet therapy to prevent acute thrombotic reocclusion have reduced the ischaemic time (and subsequent ischaemia-related damage).1 All these improvements in treatment of the atherothrombotic lesion have contributed to reduce infarct size dramatically, limit adverse left ventricular (LV) remodelling, and ameliorate the quality of life and prognosis of ST-segment elevation myocardial infarction (STEMI) patients.2–4 This optimized reperfusion therapy has allowed rapid and maximal coronary artery reflow in more than 90% of STEMI patients. Paradoxically, this success comes with a price, namely, ‘reperfusion injury’.
It has long been known that reperfusion per se can irreversibly damage the previously ischaemic myocardium.5 This lethal reperfusion injury refers to cell death associated with prolonged ischaemia that can be prevented by an intervention applied at the time of reperfusion.6,7 Various in vitro as well as in vivo studies, e.g. using gap junction uncouplers, Na+–H+ exchanger inhibitors, and inhibitors of the contractile apparatus, have indicated that pharmacological agents may alleviate lethal reperfusion injury. Rodriguez-Sinovas et al. reported that reduction of cell coupling during initial reperfusion was consistently associated with attenuation of reperfusion injury.8 Harper et al. showed that inhibition of the Na+–H+ exchanger can preserve cardiomyocyte viability in the hypoxic neonatal rat cardiomyocyte.9 Inserte et al. demonstrated that stimulation of particulate guanylyl cyclase may improve cardiomyocyte survival during reperfusion.10 Schlack et al. showed that administration of the contractile inhibitor 2,3-Butanedione monoxime at the onset of reperfusion prevented extension of necrosis after reflow in a dog model.11 However, little, if anything, has been done to prevent reperfusion-induced muscle damage, and no drug is currently being used in STEMI patients to protect the myocardium from reperfusion injury. This is likely to be the major chance for improving the prognosis of STEMI patients in forthcoming years. This review analyses the current clinical evidence that pharmacological treatment may attenuate lethal myocardial reperfusion damage in STEMI patients, with attention to those studies that specifically addressed the issue of reperfusion injury.
2. Pharmacological treatment of reperfusion injury: a new clinical challenge
Pharmacological approaches to reperfusion injury represent a new clinical challenge that is different from infarct size reduction therapy, which is a global approach. The specificity of the pharmacological therapy of reperfusion injury is twofold. First, it implies that the timing of reperfusion is a central issue with respect to the success of the treatment, whereas this aspect has seldom been taken into account in most of the previous infarct size reduction clinical trials. Second, its target (i.e. reperfusion injury) is clearly defined. Although it encompasses several pathophysiological and clinical features, including myocardial stunning, ventricular arrhythmias, no reflow (microvascular obstruction) and lethal reperfusion injury (reperfusion infarction), only the last of these will be considered here, because it clearly corresponds to an irreversible myocyte damage that is a key therapeutic target with anticipated significant impact on the patient's prognosis.
The concept of lethal reperfusion injury has been validated in various experimental preparations and subsequently in patients with acute MI.12–19 This major conceptual breakthrough was a result of the demonstration by Vinten-Johanssen's group that a therapeutic intervention performed at the time of reperfusion was able to reduce infarct size in the dog model of acute MI.12 It is noteworthy that it was not a pharmacological treatment that was used by these authors to attenuate lethal reperfusion injury; rather, they demonstrated that brief episodes of ischaemia with intervening short phases of reflow applied immediately after a prolonged ischaemic insult could, paradoxically, attenuate lethal reperfusion injury. They termed this ‘ischaemic post-conditioning’. Furthermore, they showed that this protection was lost when the treatment application was delayed by a few minutes, thereby indicating that the therapeutic window to prevent lethal reperfusion injury is very narrow.20 The description of ischaemic post-conditioning therefore supports the concept that the overall irreversible damage to the heart following a prolonged ischaemia/reperfusion insult is the sum of two different types of irreversible damage, with the first one occuring during ischaemia and the second one during reperfusion.7 With respect to the pharmacological therapy of reperfusion injury, this simple demonstration opened major perspectives, on the one hand for the mechanistic understanding of cardiomyocyte death, and on the other hand, for our strategy regarding clinical care of acute STEMI patients.
Although some aspects of the biology of reperfusion have been known for a long time and are considered to be involved in some features of reperfusion injury (e.g. the overproduction of reactive oxygen species or the cytosolic accumulation of calcium), the discovery of post-conditioning provided, for the first time, a tool to modulate lethal reperfusion injury and analyse subsequent alterations in molecular and cellular functions. The above-mentioned preliminary studies, together with ischaemic post-conditioning, have allowed the identification of signalling pathways and molecular targets involved in cell death triggered by reperfusion.8–11 This offers future pharmacological targets to develop new treatments of acute MI. Among others, activation of the phosphatidylinositol 3′ Kinase/Akt/endothelial nitric oxide synthase/glycogene synthase kinase3β or the extracellular signal-regulated kinase 1/2 signalling pathways have been identified as important players in reperfusion injury.21–26 Likewise, rapid recovery of pH after reflow has been shown to be an important cofactor for cardiomyocyte and endothelial cell damage during reperfusion in various animal species.27–30 A better characterization of such molecular targets will probably help in the development of new pharmacological treatments to prevent lethal reperfusion injury.
As it clearly designated the onset of reperfusion as a major event for the fate of ischaemic cells, post-conditioning further helped to refine our research and improve the quality of specific treatments of lethal reperfusion injury. The sharp timing and the narrow time window for myocardial protection against reperfusion necrosis has two important consequences. First, it makes mandatory that the therapeutic intervention be performed before reopening of the culprit coronary artery. In terms of practical aspects, administration of the pharmacological treatment must therefore be started at any time before angioplasty (or thrombolysis), i.e. as early as first medical care but no later than before coronary reflow. It is likely that, in the future, many treatments aimed at preventing reperfusion injury will be started in the ambulance, before hospital admission. Second, it imposes that we consider the pharmacokinetics of the drug with specific attention to its availability at an optimal concentration within the reperfused myocardium at the onset of reperfusion. However, while we know that the drug must be active during the first minute of reperfusion, we do not yet know how long after reflow the exposure to this protective treatment should continue in order to optimize the prevention of myocardial injury.
3. Study design for pharmacological therapy of reperfusion injury
While preconditioning remained a ‘laboratory concept’ for most cardiologists, except during surgical procedures, the demonstration of post-conditioning, and the theoretical ability to attenuate lethal reperfusion injury by modifying the conditions of reperfusion, was clearly a great opportunity for interventional cardiologists to improve the treatment of patients with acute MI. A prerequisite for pharmacological therapy of reperfusion injury was to demonstrate that lethal reperfusion does exist in acute MI patients and to convince interventional cardiologists that they could act on it easily in the difficult conditions of emergency care for patients with an acute life-threatening disease. Fortunately, our group could show that ischaemic post-conditioning, performed by four cycles of 1min balloon inflation and deflation starting within the first minute following reopening of the culprit coronary artery, was able to reduce infarct size in a safe and quite simple manner.31 We chose to apply to STEMI patients the experimental procedure described by Vinten-Johansen's group, rather than looking for a pharmacological agent that would possibly mimic this protection. External vascular clamping of the coronary artery (as done in animal models) was replaced in patients by brief inflations and deflations of the angioplasty balloon to create short episodes of myocardial ischaemia and reperfusion. The main reason for choosing ischaemic post-conditioning to treat lethal reperfusion injury was that there was no strong experimental evidence at that time that any drug could mimic ischaemic post-conditioning and be applicable to STEMI patients. We found that infarct size (as assessed by cardiac enzyme release) was reduced by 36% following a regime of four cycles of 1min ischaemia and 1min reperfusion by angioplasty balloon inflation and deflation performed immediately after reflow.31 In a second small trial, we reported that this protection was still present at 6 months after MI, and resulted in an improvement in contractile function at 1year post-MI.32 These two small proof-of-concept studies suggested that lethal reperfusion injury represents a significant amount of the global irreversible myocardial damage in STEMI patients and that it could be alleviated by a feasible, timely intervention. Taking into consideration previous studies showing that infarct size is a major determinant of mortality after acute MI, and that adverse LV remodelling and subsequent evolution to heart failure are determined by infarct size, it now appears reasonable to hypothesize that such a near 30% reduction in infarct size by a therapeutic intervention targeting reperfusion injury should improve clinical outcome and open a clinically relevant field for cardioprotection in STEMI patients.33–38 This is a major challenge for the future.
Beyond the demonstration that lethal reperfusion injury was important and could be efficiently reduced in acute MI patients, these initial studies carried major information for future pharmacological treatment of reperfusion injury. The critical importance of the timing of intervention, together with the restrictions imposed by the emergency clinical setting, force us to define an appropriate experimental design thoroughly. This is, in fact, nothing other than transferral to the clinical situation of emergency coronary artery angioplasty what had been defined decades ago by Reimer and Jennings and others for infarct size experiments in animal models, recently revisited by Vinten-Johansen and colleagues.7,39,40 Briefly, the objective was to build a human model that would allow the demonstration that a therapeutic intervention performed at the time of reflow could reduce infarct size in acute MI patients. Several aspects have to be taken into consideration in order to ensure optimal conditions to conclude that a given drug does attenuate lethal reperfusion injury.41 The following conditions appear to be mandatory: (i) to administer the treatment at the latest before the end of the first minute of reflow; (ii) to assess the determinants of infarct size (size of the area at risk, duration of ischaemia); (iii) not to include patients with visible collaterals to the risk region (or assess collateral flow when possible), because they are endogenously protected; (iv) not to include patients with an opened culprit coronary artery at the time of admission (initial thrombolysis in myocardial infarction flow grade >1) because, by definition, they have already experienced spontaneous reperfusion, i.e. have already been exposed to reperfusion injury; (v) to prefer patients with a large area at risk, i.e. patients with anterior infarcts, because the larger the area at risk, the greater the potential benefit of post-conditioning; (vi) to use myocardial infarct size-related end-points (e.g. infarct size, LV remodelling, heart failure, death) as opposed to coronary vessel-related end-points (e.g. recurrent ischaemia, need for revascularization; Figure 1). Although not specifically studied, it appears that patients with low ejection fraction at hospital admission (often corresponding to a large area at risk) do benefit the most from ischaemic post-conditioning.31,32
Schematic flow chart for treating lethal reperfusion injury in ST-segment elevation myocardial infarction (STEMI) patients in phase II clinical trials. Treatment of lethal reperfusion injury in STEMI patients must start before reperfusion, from first medical care to (at the latest) coronary angioplasty. Most of the damage occurs during the first minute of reflow; therefore, the treatment must be active at that time. In order to assess the efficiency of the treatment accurately, end-points and determinants of infarct size or surrogate end-points should be measured at specific time points. Determinants of infarct size ought to be assessed before reperfusion. According to the technique used, infarct size may be measured before hospital discharge (cardiac enzyme release, magnetic resonance imaging) or within weeks after myocardial infarction (magnetic resonance imaging or single photon emission tomography). Left ventricular (LV) remodelling and clinical end-points are better assessed from 6 to 12 months after myocardial infarction. TIMI, thrombolysis in myocardial infarction.
Integrating these conditions into the study design helps to limit the heterogeneity of the population and increase the statistiscal power, i.e. to set optimal conditions to be able to draw conclusions regarding the efficiency of a given drug to alleviate lethal reperfusion injury.
It is important to note that these study design conditions have not been taken into account in most of the past infarct size reduction studies that were designed before the ‘post-conditioning era’. In many of them, the timing of study drug administration was not clearly defined or was set several hours after reperfusion (when reperfusion injury has already occurred). The admission TIMI flow grade was not considered, so that patients with an opened (TIMI flow grade >1) coronary artery at admission were included while, by definition, they had undergone spontaneous reperfusion injury before any protective intervention could be completed. Importantly, neither the collateral circulation nor the size of the area at risk was measured in most cases. This may be responsible for some negative results, or at least did not permit conclusions regarding whether a given intervention would be an efficient treatment of lethal reperfusion injury.
4. First attempts at a pharmacological treatment to prevent lethal reperfusion injury
The next step was to determine whether a pharmacological treament would be as efficient as angioplasty post-conditioning to prevent lethal reperfusion injury. The candidate drug has to comply with what has been learned with respect to the signalling pathways involved in ischaemic post-conditioning. Indeed, a number of pharmacological agents, commercialy available for clinical use in various indications, have now been shown able to reduce infarct size in well-controlled experimental models of ischaemia/reperfusion injury, including adenosine, atrial natriuretic peptides, morphine, halogenated anaesthetics, erythropoietin (EPO), nicorandil, and cyclosporin.14,22,41–45 In the meantime, new agents are being developed that target specific molecular entities or pathways involved in post-conditioning protection, with encouraging preliminary in vitro results.
A few clinical phase II trials of the new ‘post-conditioning era’ have recently been completed. Piot et al. performed a proof-of-concept study using cyclosporin as a treatment of lethal reperfusion injury.46 The rationale for that study was a strong record (from 1991 to 2005) of in vitro and in vivo experimental data showing that cyclosporin can reduce ischaemia/reperfusion damage.47–52 Cyclosporin, a potent immunosuppressor through its binding to cyclophilin A and the subsequent inhibition of the calcineurin–nuclear transcription factor of activated T cells pathway, has also been recognized as an inhibitor of the opening of the mitochondrial permeability transition pore, via its binding to the mitochondrial D isoform of cyclophilin. Many investigations have shown that the permeability transition pore opens at the time of reperfusion and plays a key role in cell death in these circumstances.50
We then decided to examine whether cyclosporin would be as protective as angioplasty post-conditioning in STEMI patients. Cyclosporin was a good candidate because it is commercially available for clinical use and can be injected as an intravenous bolus. Its pharmacokinetic profile fits with what is known of the time scale of lethal reperfusion injury, i.e. it reaches a high concentration during the first minutes of reperfusion. We used the same experimental design as that in the two initial angioplasty post-conditioning studies and controlled collateral flow, ischaemia time, and the size of the area at risk. Care was taken to administer cyclosporin before reopening of the culprit coronary artery in order to ensure a high blood concentration of the drug at the time of reperfusion. An intravenous bolus of cyclosporin was administered in a peripheral vein within 10 min before angioplasty. We observed no adverse clinical events, nor did we detect any biological abnormalities. In the end, infarct size was significantly reduced, by nearly 30%, in the group of patients who received cyclosporin.46 We later reported that this treatment did not have any adverse effect on LV remodelling at 1year post-infarction, but rather confirmed that infarct size reduction was persistent and was associated with a limitation of LV dilatation.53 This was a proof-of-concept study, using a surrogate end-point. Much more information is needed before one can propose that type of treatment on a daily basis for STEMI patients. A positive point, however, is that one can expect that an average infarct size reduction over 25% of the area at risk is likely to represent a solid background for any clinically useful drug. Clinical outcome studies have to be completed and will hopefully demonstrate a significant benefit. As for cyclosporin, a phase III trial is already ongoing; the CIRCUS study (does Cyclosporine ImpRove Clinical oUtcome in STEMI patients?). This is an international, multicentre randomized placebo-controlled study that aims to determine whether an intravenous bolus administration of 2.5 mg/kg of cyclosporin can reduce the incidence of a combined end-point (mortality/hospitalization for heart failure/LV remodelling) at 1year in STEMI patients with a full occlusion of the left anterior descending coronary artery treated by angioplasty within 12 h of onset of chest pain.
Since the beginning of the ‘post-conditioning era’, other pharmacological agents have been evaluated in phase II clinical trials. The erythropoietin story is of interest in several respects. In vitro studies have suggested that EPO displays anti-inflammatory properties, promotes neovascularization, and induces mobilization of endothelial progenitor cells from bone marrow. EPO has been shown to activate the reperfusion-induced salvage kinases pathway and reduce infarct size in animal models of myocardial ischaemia/reperfusion injury.54 However, phase II clinical studies have yielded conflicting results. In a small monocentre study, 20 STEMI patients received either a single intravenous bolus of darbopoietin alfa (300 µg) or placebo prior to primary angioplasty.55 The authors reported a non-significant change in creatine kinase (CK) and CK-muscle brain (MB) release in the darbopoietin group when compared with the control group. Binbreck et al. administered a single intravenous dose of EPO (30 000 IU) immediately before the administration of a fibrinolytic agent in 236 STEMI patients.56 They failed to see a reduction in infarct size in the treated group. In the study by Ferrario et al., 30 STEMI patients received a single intravenous perfusion of EPO (33 000 IU) immediately before coronary angioplasty.57 Although the CK-MB release was significantly smaller in the EPO group, magnetic resonance imaging did not show any difference in infarct size in the group of patients who received EPO. Thus, despite the fact that these authors took into consideration the timing of administration of EPO with respect to reperfusion, they did not convincingly demonstrate that EPO is able to reduce infarct size in acute MI patients. Overall, it appears that EPO cannot reduce lethal reperfusion injury in STEMI patients. The discrepancy with pre-clinical studies is unclear, but these observations indicate that one must be cautious with the interpretation of pre-clinical data, and that well-designed phase II clinical trials bring essential information as a first step in the development of pharmacological therapies against lethal reperfusion injury.
As a counter-example, some studies do not bring interesting information concerning the ability of EPO to attenuate lethal reperfusion injury owing to inappropriate experimental design. In the HEBE III trial, 60 000 IU of EPO was injected in patients with STEMI and reduced enzymatic infarct size by 6.7% (P= 0.06).58 However, the drug administration was performed within 3 h of angioplasty, i.e. in most cases well after reperfusion injury had occurred. Similar interpretation applies to the recently published REVEAL study, in which EPO was administered within 4 h of coronary angioplasty.59 Whatever the final (positive or negative) effect on infarct size, these two studies unfortunately do not allow conclusions to be drawn regarding the efficiency of EPO with respect to lethal reperfusion injury. Overall, the consensus is that EPO may not be used to treat lethal reperfusion injury in STEMI patients.
In the APEX-AMI trial, inhibition of complement activation by the humanized monoclonal antibody pexelizumab was tested in 5745 STEMI patients with high-risk ECG findings, referred to percutaneous coronary intervention within 6 h of onset of symptoms.60 Pexelizumab did not improve clinical outcome at 30 or 90 days. This large-scale study addressed to some extent the capacity of complement inhibition after reperfusion to improve clinical outcome. However, it was performed while the same group had previously reported, in a large phase II trial with 960 patients, that pexelizumab failed to reduce infarct size (as assessed by release of cardiac enzymes), but could improve the 90 day mortality.61 This indicates how difficult it is to extrapolate data from phase II studies, and possibily, that infarct size reduction in a phase II study might need to be a prerequesite for a clinical outcome (phase III) study in this type of clinical scenario.
The adenosine story is also unclear, but for different reasons. Adenosine is a known to be powerful coronary vasodilator, and an inhibitor of platelet aggregation and leucocyte adherence to the endothelium. At the cardiomyocyte level, adenosine might protect from lethal reperfusion injury through different mechanisms, including activation of the reperfusion-induced salvage kinases pathway and subsequent inhibition of the opening of the mitochondrial permeability transition pore. There is a large body of evidence showing that adenosine can reduce infarct size in some experimental preparations.62–64 In addition, there are conflicing pre-clinical data concerning the cardioprotective effects of adenosine analogues, owing to the respective specificity of action on A1, A2, and A3 adenosine receptor subtypes. Clinical trials have been performed in the past, i.e. before the post-conditioning era. In the AMISTAD-I (Acute Myocardial Infarction STudy of ADenosine) trial, 236 STEMI patients received a 3 hour intravenous infusion of 70 µg/kg/min of adenosine that was started prior to the administration of the thrombolytic therapy, i.e. before the onset of reperfusion.65 A subgroup analysis showed that only patients with an anterior wall infarction displayed a significant 67% reduction in infarct size. In the ADMIRE study, the mixed A1/A2 adenosine agonist AMP579 was administered before angioplasty in 311 acute MI patients.66 The authors did not report any infarct size reduction in the treated group. In these two studies, although the timing of drug administration was appropriate, other important points can be criticized, including the absence of assessment of the size of the area at risk, and the inclusion of patients with coronary collateral or with a TIMI flow grade >1 at admission. Thus, these two studies do not bring conclusive information concerning the ability of adenosine to attenuate lethal reperfusion injury. In a more recent article, Desmet et al. reported that high-dose intracoronary adenosine cannot improve myocardial salvage in STEMI patients.67 Unfortunately, despite randomization, the control and adenosine-treated subgroups exhibited unbalanced profiles, with significantly different heart rate, incidence of diabetes, or previous revascularization. Also, there was a significantly different incidence of the 0–1 TIMI flow grade in the adenosine group (80%) vs. the placebo group (63%). Additionally, the size of the area at risk was not assessed. These problems in the study design weaken the data and do not permit the conclusion that adenosine may not be able to attenuate lethal reperfusion injury in STEMI patients. Additional phase II studies are ongoing to investigate this issue.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates glucose homeostasis, and its analogues are currently used for the treatment of type 2 diabetes. GLP-1 receptors are expressed in the heart and vessels, and recent studies suggest that they may attenuate lethal reperfusion injury in an animal model, possibly via the activation of several signalling pathways.68–71 Yet, Ban et al. reported that the GLP-1-related improvement of cardiomyocyte viability after ischaemia/reperfusion injury was preserved in Glp1r−/− mice, suggesting a more complex mechanism of action.72 Very recently, Lonborg et al. sought to determine whether exenatide might reduce infarct size when administered at the time of reperfusion in STEMI patients.73 Exenatide was administered as an intravenous infusion starting 15 min before angioplasty and continued over 6 h after reperfusion. When the area at risk was taken into consideration, analysis of covariance showed that exenatide could reduce infarct size, as measured by cardiac magnetic resonance imaging 90 days after acute MI (Figure 2). In this well-designed study, one might question whether, owing to the 6 h infusion, exenatide reached the optimal blood concentration in all patients. In addition, one cannot exclude the possibility that exenatide, like most infarct size-reducing agents, might have reduced oedema, leading to an underestimation of the oedema-based T2-weighted area at risk only in the treated group, hence an underestimation of the infarct size reduction effect of this drug. Nevertheless, this is a new example of an interesting phase II study that is required in the cardioprotection field of research to investigate new pharmacological treatments of reperfusion injury.
Exenatide reduces infarct size when administered at reperfusion. Lonborg et al. administered the glucagon-like peptide-1 analogue exenatide to STEMI patients. Infusion was strated 15 min before reperfusion and continued over the next 6 h. Infarct size (in grams) was plotted against the myocardial area at risk (in grams), as measured by T2-weighted cardiac magnetic resonance techniques. The regression line for the exenatide group lies significantly below the line for the placebo group, indicating that for any size of area at risk the patients who received exenatide developed significantly smaller infarcts than control patients. Reproduced with permission from the European Society of Cardiology from Lonborg et al.73
Following the description of postconditioning and the demonstration of its clinical application in STEMI patients, a new clinical era has begun for the pharmacological therapy of lethal reperfusion injury. Cardiologists are now aware that, beyond the coronary vessel, the cardiac muscle can and must be protected. In addition to cyclosporin and exenatide, new agents will soon be tested, and clinical outcome trials (e.g. with cyclosporin or its analogues) are needed to determine whether the reduction of infarct size at reperfusion may prevent heart failure and improve survival in patients with acute myocardial infarction.
Conflict of interest: none declared.
This article is part of the Spotlight Issue on: Reducing the Impact of Myocardial Ischaemia/Reperfusion Injury
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. A single bolus of a long-acting erythropoietin analogue darbepoetin alfa in patients with acute myocardial infarction: a randomized feasibility and safety study. Cardiovasc Drugs Ther 2006;20:135-141.
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. AMP579 Delivery for Myocardial Infarction REduction study. A randomized, double-blinded, placebo-controlled, dose-ranging study measuring the effect of an adenosine agonist on infarct size reduction in patients undergoing primary percutaneous transluminal coronary angioplasty: the ADMIRE (AmP579 Delivery for Myocardial Infarction REduction) study. Am Heart J 2003;146:146-152.
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