Summary
Background
Several trials investigating erythropoietin as a novel cytoprotective agent in myocardial infarction (MI) failed to translate promising preclinical results into the clinical setting. These trials could have missed crucial events occurring in the first few minutes of reperfusion. Our study differs by earlier intracoronary administration of a longer-acting erythropoietin analogue at the onset of reperfusion.
Aim
To evaluate the ability of intracoronary administration of darbepoetin-alpha (DA) at the very onset of the reperfusion, to decrease infarct size (IS).
Methods
We randomly assigned 56 patients with acute ST-segment elevation MI to receive an intracoronary bolus of DA 150 μg (DA group) or normal saline (control group) at the onset of reflow obtained by primary percutaneous coronary intervention (PCI). IS and area at risk (AAR) were evaluated by biomarkers, cardiac magnetic resonance (CMR) and validated angiographical scores.
Results
There was no difference between groups regarding duration of ischemia, Thrombolysis in Myocardial Infarction flow grade at admission and after PCI, AAR size and extent of the collateral circulation, which are the main determinants of IS. The release of creatine kinase was not significantly different between the two groups even when adjusted to AAR size. Between 3–7 days and at 3 months, the area of hyperenhancement on CMR expressed as a percentage of the left ventricular myocardium was not significantly reduced in the DA group even when adjusted to AAR size.
Conclusion
Early intracoronary administration of a longer-acting erythropoietin analogue in patients with acute MI at the time of reperfusion does not significantly reduce IS.
Résumé
Contexte
Plusieurs essais qui ont étudié l’érythropoïétine (EPO) comme un nouvel agent protecteur lors de l’infarctus du myocarde (IDM), ont échoué à traduire en clinique les études précliniques prometteuses. Ces essais pourraient avoir laissé de côté des évènements cruciaux au cours des premières minutes de la reperfusion. Notre étude diffère par une administration plus précoce, intracoronaire d’une EPO à longue durée d’action, au moment de la reperfusion.
Objectifs
L’objectif de cet essai était d’évaluer l’intérêt de la darbépoétine-alpha (DA) intracoronaire administrée précocement à la reperfusion pour diminuer la taille de l’IDM.
Méthodes
Nous avons randomisé 56 patients avec IDM aigu avec sus-élévation du segment ST, pour recevoir soit un bolus intracoronaire de 150 μg de darbépoétine-alpha (groupe DA) ou du sérum physiologique (groupe témoin) au moment de la reperfusion obtenue par angioplastie primaire (PCI). L’aire à risque et la taille de l’infarctus ont été évalués par des biomarqueurs, une imagerie par résonance magnétique (IRM) et des scores angiographiques validés.
Résultats
Il n’y avait pas de différence entre les deux groupes en termes de durée d’ischémie, de flow TIMI à l’admission et après angioplastie, d’aire à risque ou encore de collatéralité, qui sont les principaux déterminants de la taille de l’infarctus. La libération de CK n’était pas significativement différente entre les deux groupes même après ajustement sur la taille de l’aire à risque. Après trois à sept jours et à trois mois, l’aire du rehaussement à l’IRM exprimée comme un pourcentage du ventricule gauche n’était pas significativement réduit dans le groupe DS, même après ajustement sur l’aire à risque.
Conclusions
L’administration précoce intracoronaire d’une EPO de longue durée d’action chez de patients avec IDM aigu, au moment de la reperfusion ne réduit pas significativement la taille de l’IDM.
Background
Acute myocardial infarction (MI) is a leading cause of death worldwide. In patients that survive the immediate event, infarct size (IS) is the main determinant of further prognosis . Rapid reperfusion of the ischemic myocardium remains the best treatment for limiting IS and further complications . However, recent evidence supports the idea that reperfusion itself has the potential to initiate additional lethal injury . New strategies that directly target the reperfusion phase by adding adjunct reperfusion therapies could further reduce IS and improve clinical outcomes of acute MI .
Erythropoietin (EPO), a cytokine synthesized by the kidney in response to hypoxia, is commonly used in the treatment of the anaemia of chronic renal failure . Beyond its well-known haematopoietic action, EPO inhibits apoptosis and activates prosurvival kinases, such as PI3 kinase-Akt, in adult cardiomyocytes exposed to hypoxic injury . Several reports indicate that administration of recombinant EPO during prolonged ischemia or at the time of reperfusion reduces IS and improves cardiac function in animal models of reperfused MI . All these experimental data suggest that EPO may be a good candidate for an adjunct to reperfusion in MI patients.
However, several recent clinical trials, designed to investigate the safety and efficacy of EPO in patients with MI, have already been published with negative or inconclusive results . In these trials, the timing of the cardioprotective strategy could have missed crucial events that occur in the first few minutes of myocardial reperfusion. Numerous studies performed during the past two decades testing new cardioprotective strategies have already failed to translate promising laboratory research into the clinical setting. Recently, the UCL-Hatter Cardiovascular Institute 6th International Cardioprotection Workshop with the Working Group of Cellular Biology of the Heart of the European Society of Cardiology and the 2010 National Heart Lung and Blood Institute Workshop have published recommendations in order to facilitate the translation of novel cardioprotective strategies . The duration of ischemia, the Thrombolysis In Myocardial Infarction (TIMI) flow grade at admission and after reopening of the culprit coronary artery, the size of the area at risk (AAR), the extent of the collateral circulation and last but not least the optimal timing of the application of the drug are key issues that need to be addressed in IS reduction trials. To protect the myocardium from reperfusion injury, the drug must be active during the first minutes of reperfusion. However, we do not know for how long the exposure to the drug should continue in order to optimize the prevention of myocardial reperfusion injury.
The objective of the present study was to determine whether the early intracoronary administration of darbepoetin-alpha (DA), a long-acting analogue of EPO, at the onset of reperfusion reduces IS in patients with ongoing acute MI.
Methods
Trial
The Intra-Co-EpoMI Trial was a prospective multicentre randomized single-blinded controlled trial. The trial was designed, the data were collected and analysed, and the manuscript was written solely by the authors. DA for the trial was purchased with institutional grant support; the manufacturer had no role in the study. The trial was performed according to the Declaration of Helsinki (revised version of Somerset West, Republic of South Africa, 1996), the European Guidelines of Good Clinical Practice (version 11, July 1990) and French laws. The study protocol was approved by the ethics committee of the institution of the principal investigator (C.P.) acting on behalf of all the institutions involved in this trial. The protocol was accepted on 01 July 2008. All subjects gave written informed consent before inclusion.
Study population
Male and female patients aged > 18 years who presented within 12 hours of onset of chest pain, had ST-segment elevation > 0.1 mV in at least two contiguous leads and for whom the clinical decision was made to treat with PCI were eligible for enrolment. Patients were eligible for the study whether they were undergoing primary PCI or rescue PCI. The culprit coronary artery had to be occluded at the time of admission (TIMI flow grade 0) and had to be adequately reperfused (TIMI 2–3 flow grade) after PCI.
Patients with cardiac arrest, ventricular fibrillation, cardiogenic shock, stent thrombosis or previous MI were not included. Patients with evidence of coronary collaterals (Rentrop grade > 1) supplying the region at risk were excluded from the study. Also excluded were patients with known hypersensitivity to EPO, known polyglobulia, uncontrolled hypertension or thromboembolic disease, contraindication to cardiac magnetic resonance (CMR) imaging, patients already treated with EPO or cyclosporine and women who were pregnant or who were of childbearing age and were not using contraception.
Experimental protocol
After the patients gave informed consent, they were randomly assigned to either the control group or the DA group. Randomization was performed with the use of a computer-generated randomization sequence. Numbered, sealed envelopes that contained the study group assignment were distributed to each catheterization laboratory.
All patients received clopidogrel 600 mg orally, aspirin 500 mg and unfractionated heparin with or without a glycoprotein IIb/IIIa inhibitor intravenously prior to PCI. In the treated group, the patients received an intracoronary bolus injection of DA 150 μg (Amgen © Inc., Thousand Oaks, CA, USA) at the onset of reperfusion (i.e. less than 1 minute after reopening of the culprit coronary artery). The patients in the control group received an equivalent volume of normal saline. The dose of DA was chosen based on experimental data and previous clinical studies . The PCI procedure was then completed according to the physician’s judgment. Postinterventional therapy consisted of clopidogrel 75 mg/day for at least 1 year. Aspirin 75 mg/day was recommended indefinitely. Other cardiac medications were prescribed at the discretion of the treating physician.
The patient and the assessors of data analysis and clinical outcomes were blinded to the treatment allocation.
Endpoints
The primary endpoint was MI size as determined by creatine kinase (CK) release obtained at admission and repeated over the following 3 days, as described previously . Blood samples were taken at admission, every 4 hours after opening of the coronary artery during day 1 and every 6 hours on days 2 and 3. Area under the curve (arbitrary units) of serum CK release (Beckman Kit, expressed in IU/L) was measured in each patient by computerized planimetry (Image J 1.29x) and used as a surrogate marker of infarct size. The principal secondary endpoint was MI size as assessed between 3 and 7 days and at 3 months (± 1 week) postinfarction by the area of hyperenhancement on CMR expressed as a percentage of the left ventricular myocardium .
Other endpoints
Major adverse events that occurred during the initial hospitalization and 3 months after acute MI, including death, heart failure, acute MI, stroke, recurrent ischemia, the need for repeat revascularization, renal or hepatic insufficiency, vascular complications and bleeding, were recorded.
Angiography
Coronary angiography was performed using standard techniques. All images were reanalysed in a core laboratory separately by two senior interventional cardiologists in a blinded fashion to classify TIMI flow before and after PCI.
For each patient, the size of the AAR (i.e. the myocardium supplied by the occluded coronary artery) was assessed by two angiographical scores. The modified version of the angiographical APPROACH score is based on pathological and necropsy studies evaluating the amount of myocardium supplied by different coronary arteries . The angiographical BARI score is based upon an individualized assessment of the length and calibre of coronary arteries for the assessment of the jeopardized myocardium . AAR was expressed as a percentage of the left ventricular myocardium.
CMR imaging
CMR imaging was performed between 3 and 7 days and repeated at 3 months (± 1 week) using a 1.5 T scanner (Avanto-Siemens, Erlangen, Germany) with infusion of 0.5 mL/kg of gadoterate meglumine (Gd-DOTA, Dotarem; Guerbet SA, Paris, France). T2-weighted CMR was performed by encompassing the left ventricle in cardiac short-axis, vertical long-axis and four-chamber directions with a dark-blood T2-weighted short tau inversion recovery fast spin-echo sequence. Imaging variables were repetition time, 2 heartbeats; echo time, 100 ms; turbo factor 33; field of view, 350 mm; slice thickness, 8 mm. Both cine and contrast-enhanced short-axis CMR images were prescribed every 10 mm (slice thickness, 6 mm) from base to apex. In-plane resolution was typically 1.2 × 1.8 mm. Cine CMR was performed using a steady-state free-precession sequence. Contrast CMR images were acquired on average 5–10 minutes after contrast (power injector) using a segmented inversion recovery gradient echo three-dimensional technique, constantly adjusting inversion time to null normal myocardium, and acquisition in phase sensitive inversion recovery of 10 slices on a single breath-hold. Therefore, total acquisition time was between 30 and 40 minutes for all cine and contrast images. All patients were able to tolerate lying flat in the magnet until the examination was completed. The contrast dose was 0.1 mmol/kg.
CMR analysis
All images were evaluated separately by two blinded observers (seniors radiologists) and were analysed on an offline workstation (Argus, Siemens AG, Munich, Germany).
The AAR was quantified on the T2-weighted images by delineation of myocardium with hypersignal intensity from the CMR imaging performed between 3 and 7 days postinfarction, and the IS by delineation of hyperenhancement on the contrast-enhanced CMR performed between 3 and 7 days and at 3 months (± 1 week) postinfarction. The hypoenhanced surface of microvascular obstruction and hypointense T2-weighted signal within the area of increased signal intensity (haemorrhagic infarction) were included in the IS. The transmurality degree of MI was quantified in four different groups (extent of contrast enhancement/normal myocardium: 0–25%; 25–50%; 50–75%; > 75% of transmurality). Areas of hyperintense T2-weighted signal and late gadolinium enhancement on contrast enhancement sequences were reported separately on a 17-segment model of the left ventricle. IS and AAR results were expressed as a percentage of the total segment area. The IS/AAR ratio was calculated as follows: number of segments with IS/number of segments with T2-weighted hypersignal.
Statistical analysis
The number of patients to be included was calculated using the following hypotheses: an infarct size of 40% (reported to the area at risk); a reduction of 15% in the treated group (standard error of mean = 7.5%), with α = 0.05, β = 0.20; and 10% without a complete follow-up or without primary endpoint evaluation. On this basis it was necessary to include 55 patients.
The data processing was performed using SAS software package version 9.1. A general descriptive analysis was done for each variable of the study. The distribution of qualitative variables between groups was compared using the chi-square test. If one of the calculated frequencies in the contingency table did not exceed 5, Fisher’s exact test was performed. Quantitative variables were compared using the Wilcoxon-Mann-Whitney test as the variables were not normally distributed.
The Kendall test was used for the correlations between the areas at risk. The area under the curve was not calculated when there were two successive missing data points. When there was only one missing dose, its value was estimated by linear regression on convex-transformed data.
Results
Characteristics of the population
Between December 2008 and November 2009, 56 patients (10 women, 46 men) 59 ± 13 years of age were randomized in four academic medical centres (Clermont-Ferrand, Nîmes, Marseille and Montpellier): 30 received DA and 26 received placebo ( Fig. 1 ). Five patients were excluded from the study: one because reperfusion had occurred before PCI (TIMI 2 flow grade on the initial coronary angiography) and four because of Rentrop 2 and 3 collateral coronary circulation to the AAR. Table 1 summarizes the main characteristics of the randomized population. Major risk factors, angiographical findings, left ventricular ejection fraction (LVEF) and treatments were similar between the two groups except for hypertension ( P = 0.02).
| Characteristics | EPO group ( n = 27) | Control group ( n = 24) | P |
|---|---|---|---|
| Age (years) | 62.77 ± 12.61 | 55.13 ± 11.84 | 0.03 |
| Men | 20 | 21 | 0.30 |
| BMI (kg/m 2 ) | 26.70 ± 3.95 | 25.96 ± 4.17 | |
| Hypertension | 13 | 4 | 0.02 |
| Tabagism | 15 | 19 | 0.07 |
| Familial history of coronary artery disease | 10 | 8 | 0.78 |
| Diabetes | 6 | 1 | 0.10 |
| Overweight | 14 | 11 | 0.66 |
| Dyslipidaemia | 14 | 9 | 0.30 |
| Heart rate on admission (bpm) | 73.04 ± 12.42 | 68.08 ± 12.91 | 0.20 |
| Angiographical findings | |||
| Ischemia time (minutes) | 233.73 ± 174.49 | 308.57 ± 282.53 | 0.53 |
| Infarct-related artery | |||
| Common trunk | 0/27 | 0/24 | |
| Left descending artery | |||
| Culprit lesion | 10/27 | 7/24 | 0.43 |
| Successful angioplasty | 10/10 | 6/7 | 0.35 |
| Circumflex | |||
| Culprit lesion | 5/27 | 7/24 | 0.08 |
| Successful angioplasty | 5/5 | 7/7 | 0.74 |
| Right coronary artery | |||
| Culprit lesion | 9/27 | 10/24 | 0.97 |
| Successful angioplasty | 8/9 | 10/10 | 0.75 |
| Collaterality (Rentrop ≥ 2) | 0 | 0 | 1.0 |
| LVEF (%) a | 51.54 ± 11.07 | 48.88 ± 10.90 | 0.45 |
| Treatment before PCI | |||
| Aspirin | 19 | 16 | 0.32 |
| Clopidogrel | 15 | 15 | 0.85 |
| Glycoprotein IIb/IIIa inhibitor | 1 | 1 | 1.0 |
| Heparin | 16 | 12 | 0.17 |
| LMWH | 1 | 4 | 0.35 |
| Oral anticoagulant | 0 | 0 | |
| Statin | 1 | 1 | 1.0 |
| Beta-blocker | 1 | 1 | 1.0 |
| ACE inhibitor | 0 | 0 | |
| ARI | 1 | 1 | 1.0 |
| Anti-inflammatory drugs | 0 | 0 | |
| Treatment at time of PCI | |||
| Aspirin | 3 | 8 | 0.08 |
| Clopidogrel | 2 | 2 | 1.0 |
| Glycoprotein IIb/IIIa inhibitor | 10 | 12 | 0.46 |
| Heparin | 3 | 8 | 0.16 |
| LMWH | 0 | 1 | 0.49 |
| Oral anticoagulant | 0 | 0 | |
| Statin | 1 | 1 | 0.49 |
| Beta-blocker | 0 | 1 | 0.49 |
| ACE inhibitor | 1 | 0 | 1.0 |
| ARI | 0 | 1 | 0.44 |
| Anti-inflammatory drugs | 0 | 0 | |
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