Author + information
- Received December 11, 2015
- Revision received March 17, 2016
- Accepted April 5, 2016
- Published online July 5, 2016.
- Alain Cariou, MDa,b,c,∗ (, )
- Nicolas Deye, MDd,
- Benoît Vivien, MDb,e,
- Olivier Richard, MDf,
- Nicolas Pichon, MDg,
- Angèle Bourg, MDh,
- Loïc Huet, MDi,
- Clément Buleon, MDj,
- Jérôme Frey, MDk,
- Pierre Asfar, MDl,
- Stéphane Legriel, MDm,
- Sophie Narcisse, MDn,
- Armelle Mathonnet, MDo,
- Aurélie Cravoisy, MDp,
- Pierre-François Dequin, MDq,
- Eric Wiel, MDr,
- Keyvan Razazi, MDs,
- Cédric Daubin, MDt,
- Antoine Kimmoun, MDu,
- Lionel Lamhaut, MDc,e,v,
- Jean-Sébastien Marx, MDe,
- Didier Payen de la Garanderie, MDw,
- Patrick Ecollan, MDx,
- Alain Combes, MDy,
- Christian Spaulding, MDb,c,z,
- Florence Barat, PharmDaa,
- Myriam Ben Boutieb, MDbb,
- Joël Coste, MDb,bb,
- Jean-Daniel Chiche, MDa,b,
- Frédéric Pène, MDa,b,
- Jean-Paul Mira, MDa,b,
- Jean-Marc Treluyer, MDb,cc,
- Olivier Hermine, MDb,dd,
- Pierre Carli, MDb,e,
- Epo-ACR-02 Study Group
- aMedical Intensive Care Unit, Cochin Hospital (APHP), Paris, France
- bParis Descartes University, Paris, France
- cINSERM U970 (team 4), Parisian Cardiovascular Research Center, Paris Descartes University, Paris, France
- dMedical Intensive Care Unit, Lariboisière Hospital (APHP) and INSERM U942, Paris, France
- eSAMU 75, Necker Hospital (AP-HP), Paris, France
- fSAMU 78, Centre Hospitalier de Versailles, Versailles, France
- gMedical ICU, CHU Dupuytren, Limoges, France
- hSAMU 87 and CHU Dupuytren, Limoges, France
- iSAMU 94, Henri Mondor Hospital (APHP), Créteil, France
- jCHU de Caen, Pôle Réanimations, Anesthésie, SAMU, Caen, Caen, France
- kSAMU 54, CHU de Nancy, Nancy, France
- lRéanimation Médicale et de Médecine Hyperbare, CHU d’Angers, Angers, France
- mMedical ICU, Centre Hospitalier de Versailles, Versailles, France
- nSAMU 45, Hôpital de La Source, Orléans, France
- oMedical-Surgical Intensive Care Unit, Hôpital de La Source, Centre Hospitalier Regional d'Orléans, Orléans, France
- pMedical ICU, CHU de Nancy, Nancy, France
- qMedical ICU, François Rabelais University, Inserm U1100 and CRICS group, Tours, France
- rEmergency Department and SAMU 59, Lille University Hospital, Lille, France
- sMedical ICU, Hôpital Henri Mondor (APHP), Créteil, France
- tCHU de Caen, Department of Medical Intensive Care, Caen, France
- uService de Réanimation Médicale Brabois, CHU de Nancy, Vandœuvres-les-Nancy, France
- vIntensive Care Unit, Necker University Hospital (APHP), Paris, France
- wSMUR & Surgical Intensive Care, Lariboisière University Hospital (APHP) and Paris 7 University Denis Diderot, Paris, France
- xSMUR Pitié-Salpêtrière (APHP), Paris, France
- yMedical Intensive Care Unit, INSERM, UMRS-1166, Université Pierre et Marie Curie, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière (APHP), Paris, France
- zCardiology Department, Cochin University Hospital (APHP), Paris, France
- aaClinical Trial Unit, Central Pharmacy, APHP, Paris, France
- bbBiostatistics and Epidemiology Unit, Hôtel-Dieu Hospital (APHP, Paris, France
- ccClinical Research Unit, Paris Centre and Paris Descartes University, Paris, France
- ddHematology Department, Necker Hospital (APHP), Imagine institute, INSERM U1123 CNRS erl 8654, Labex des Globules Rouges Grex, Paris, France
- ↵∗Reprint requests and correspondence:
Dr. Alain Cariou, Medical Intensive Care Unit – Cochin Hospital – APHP, 27 rue du Faubourg Saint-Jacques, F-75679 Paris Cedex 1, France.
Background Preliminary data suggested a clinical benefit in treating out-of-hospital cardiac arrest (OHCA) patients with a high dose of erythropoietin (Epo) analogs.
Objectives The authors aimed to evaluate the efficacy of epoetin alfa treatment on the outcome of OHCA patients in a phase 3 trial.
Methods The authors performed a multicenter, single-blind, randomized controlled trial. Patients still comatose after a witnessed OHCA of presumed cardiac origin were eligible. In the intervention group, patients received 5 intravenous injections spaced 12 h apart during the first 48 h (40,000 units each, resulting in a maximal dose of 200,000 total units), started as soon as possible after resuscitation. In the control group, patients received standard care without Epo. The main endpoint was the proportion of patients in each group reaching level 1 on the Cerebral Performance Category (CPC) scale (survival with no or minor neurological sequelae) at day 60. Secondary endpoints included all-cause mortality rate, distribution of patients in CPC levels at different time points, and side effects.
Results In total, 476 patients were included in the primary analysis. Baseline characteristics were similar in the 2 groups. At day 60, 32.4% of patients (76 of 234) in the intervention group reached a CPC 1 level, as compared with 32.1% of patients (78 of 242) in the control group (odds ratio: 1.01; 95% confidence interval: 0.68 to 1.48). The mortality rate and proportion of patients in each CPC level did not differ at any time points. Serious adverse events were more frequent in Epo-treated patients as compared with controls (22.6% vs. 14.9%; p = 0.03), particularly thrombotic complications (12.4% vs. 5.8%; p = 0.01).
Conclusions In patients resuscitated from an OHCA of presumed cardiac cause, early administration of erythropoietin plus standard therapy did not confer a benefit, and was associated with a higher complication rate. (High Dose of Erythropoietin Analogue After Cardiac Arrest [Epo-ACR-02]; NCT00999583)
Cardiac arrest patients frequently have post-anoxic brain damage, even when the initial resuscitation is successful. This brain injury is either transient or definitive, and represents the major cause of death in these patients (1). Of importance, this brain injury continues even after restoration of cerebral perfusion and oxygenation, in a process known as reperfusion injury. In recent years, evidence of further cerebral damage occurring during this reperfusion phase encouraged intense research aiming to limit the worsening of these neurological lesions. To date, despite numerous attempts, no drug has demonstrated its ability to reduce the consequences of cerebral anoxo-ischemia after out-of-hospital cardiac arrest (OHCA) (2–4). Currently, apart from targeted temperature management, no other treatment is recommended to mitigate the consequences of cerebral ischemia-reperfusion due to cardiac arrest.
The main role of erythropoietin (Epo) is to support erythropoiesis, leading to the use of analogs of this hormone for many years to prevent anemia in different pathological conditions. However, the biological activity of Epo is not restricted to regulation of erythropoiesis. The survival and proliferative activities of Epo that are required for red blood cell formation appear to extend to other Epo receptor–expressing tissues, resulting in Epo protective activity associated with stress or ischemia in nonhematopoietic tissue, such as heart and brain (5). Numerous pre-clinical data suggested a tissue protective effect of Epo and analogs in various experimental models, particularly after brain and myocardial damage related to ischemia-reperfusion stress (6,7). Nevertheless, results obtained in humans, in both acute myocardial infarction and stroke, were disappointing (8,9). In the setting of whole-body ischemia due to cardiac arrest, experimental research showed promising results, and a pilot clinical study showed that early treatment with a high dose of an Epo analog was feasible in conjunction with mild hypothermia (10).
We hypothesized that early administration of a high dose of epoetin alfa, an Epo analog, could improve the neurological outcome of post-cardiac arrest patients still comatose after resuscitation in comparison with standard treatment.
The EPO-ACR-02 (High Dose of Erythropoietin Analogue After Cardiac Arrest) trial was a multicenter, phase 3, randomized, single-blind, controlled trial that evaluated the safety and efficacy of a high dose of Epo in patients resuscitated from a cardiac arrest. The study was performed between October 2009 and July 2013 in 20 French hospitals. In all participating centers, an emergency team (with at least 1 emergency physician) performed out-of-hospital resuscitation, and patients were then referred to a corresponding hospital with all of the facilities required to manage post-cardiac arrest patients. The study received ethics committee approval by CPP Ile de France III, Paris-Tarnier Cochin, Paris (France). The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practices, and adhered to French regulatory requirements. When possible, written informed consent was obtained from patient surrogates before study enrollment. According to French law, in the case of impaired decision-making capacity without any surrogate at the time of inclusion, the patient’s written informed consent could be obtained after enrollment.
Eligibility criteria, randomization, and study medication
Patients who achieved a sustainable return of spontaneous circulation (ROSC) were screened for participation in the study. The following patients were eligible: age between 18 and 80 years; witnessed OHCA of presumed cardiac origin; time from cardiac arrest and recovery of circulatory activity <60 min; persistent coma after ROSC (Glasgow Coma Scale <7). Exclusion criteria were: evidence of extracardiac cause of arrest (trauma, sepsis, acute respiratory insufficiency, asphyxia); previous or chronic treatment with Epo or analogs; pregnancy; rapidly fatal underlying disease (expected life duration <6 months); and patient with no medical insurance (according to French legislation).
Eligible patients were included as soon as possible, either in the resuscitation theater by the pre-hospital medical emergency team or by the intensive care unit (ICU) team at the time of hospital admission. After being screened for eligibility, patients were randomly assigned in a 1:1 ratio to the intervention or the control group. Randomization was performed centrally with the use of a computer-generated assignment sequence. Intervention assignments were made in permuted blocks of varying size and were stratified according to site. In the intervention group, patients received a first dose of Epo intravenously as soon as possible after ROSC, followed by 4 injections every 12 h during the first 48 h. Each injection was 40,000 units, resulting in a maximal dose of 200,000 units in total. Each dose of Epo was conditioned in ready-prepared syringes that were stocked and transported at constant temperature (i.e., between 4°C and 8°C). In the control group, patients received standard care without any Epo medication. In the ICU, all patients were treated according to standard resuscitative guidelines, including early coronary reperfusion and targeted temperature management, when indicated (11).
Neurological performance was assessed at each time point, according to the Cerebral Performance Category (CPC) scale commonly used in this setting (12). Briefly, the CPC scale ranges from 1 to 5, with 1 representing good cerebral performance or minor disability, 2 representing moderate disability, 3 representing severe disability, 4 representing coma or vegetative state, and 5 representing brain death. The primary endpoint of the study was the number of patients in each group who reached level 1 of the CPC scale at day 60. The secondary outcome measures were the distribution of patients in each CPC level at day 30 and day 60 among the 2 groups; the all-cause mortality rate at ICU discharge, at hospital discharge, at day 30, and at day 60; and all adverse events were screened until day 60.
Throughout the study, a data safety monitoring board monitored patients' safety at regular intervals. Serious adverse events (SAE) were defined as any events that occurred during follow-up that were possibly related to the trial intervention. Two authors (A. Cariou, N.D.) and data managers, who were blinded to the randomization assignment, reviewed all patient charts of patients with SAE. They confirmed and categorized these SAE by consensus.
The study was single-blinded, but physicians performing neurological follow-up and final outcome measurement, as well as study administrators and statisticians, were unaware of the intervention assignments. CPC was assessed by face-to-face contact with patients still hospitalized, and through phone interviews in discharged patients using a standardized protocol.
All centers were ordered to follow the most recent guidelines regarding initial resuscitation and ICU management (13). When used, therapeutic hypothermia was started immediately at ICU admission (or continued if initiated pre-hospital) using external or internal cooling (at the discretion of the sites) during the first 24 h in order to obtain a target temperature between 32°C and 34°C. Normothermia between 37°C and 37.5°C was then achieved using passive rewarming (0.3°C/h) and maintained during the next 48 h. In patients with a high suspicion of acute coronary syndrome as the cause of OHCA, early coronary angiograms were routinely performed at hospital admission and followed, when indicated, by immediate percutaneous coronary interventions (PCIs) (14).
Assuming that a CPC 1 level would be reached at day 60 in 30% in controls, a sample of 430 patients would be needed to detect an absolute increase of 15% in this proportion of the intervention group, with an alpha risk of 0.05 and 90% power. This hypothesis was generated on the basis of preliminary clinical results observed in pilot studies (10). A sample of 500 patients was chosen to allow for loss to follow-up and inability to obtain consent in a maximum of 70 patients.
According to French law, all analyses were performed in the modified intention-to-treat population, which was defined as all randomly assigned patients, except for those whose informed consent was impossible to obtain, those whose initial consent was withdrawn, and those placed under legal guardianship. Subgroup analysis was performed regarding the primary endpoint for patients with a first shockable rhythm, those treated with early PCI at admission, those with a confirmed cardiac cause of arrest, and those who received the first dose of Epo in the field. Baseline and follow-up characteristics were described as median (interquartile range) for continuous variables and numbers (percentages) for categorical variables. The Wilcoxon signed rank test was used to compare distributions of continuous variables between the intervention group and the control group. For categorical variables, chi-square tests or Fisher exact tests were performed, and odds ratios were estimated with their 95% confidence intervals. Kaplan-Meier curves were compared using a log-rank test. Finally, a logistic regression model was constructed to test the interaction between the presence of a coronary stent and the treatment group in the occurrence of thrombotic complications.
Two hypotheses were tested for patients lost to follow-up: 1) a “high” hypothesis, in which for the primary analysis, a CPC 1 level was attributed to all patients lost to follow-up; and 2) a “low” hypothesis, in which a CPC 5 level was attributed to all patients lost to follow-up.
A total of 501 patients were enrolled between October 2009 and July 2013. Of these, and according to French law, data from 25 patients were not analyzed because the patient’s written informed consent could not be obtained after enrollment or because consent was withdrawn (Figure 1). The modified intention-to-treat population (the primary analysis population) consisted of 476 patients, of whom 234 were randomly assigned to the Epo group and 242 to the control group. The emergency medical team randomized the majority of these patients (62.8%) (before transportation to the hospital), and all other patients were randomized at hospital admission.
The Epo and control groups had similar pre-randomization characteristics (Table 1). Patients were mostly men nearly 60 years of age, resuscitated from a witnessed cardiac arrest with bystanders providing cardiopulmonary resuscitation in 61.8% of cases. A shockable rhythm (ventricular fibrillation or nonperfusing ventricular tachycardia) was the most frequently monitored cardiac electrical activity at first emergency medical services presentation (47.2%).
No significant differences between the treatment groups with respect to ICU management were observed (Table 1). At ICU admission, therapeutic hypothermia was performed or continued in 93.5% of patients, and the obtained temperature was similar in the 2 groups over the first 48 h (Online Figure 1). The cause of the OHCA was considered of cardiac origin in 397 patients (83%), and an early PCI with coronary stenting was performed in 182 patients (38.2%) (Table 1). All patients received mechanical ventilation and were severely ill, as reflected by high mean Simplified Acute Physiology Score II scores (55 in the Epo group and 54 in the control group; p = 0.26).
In the Epo group (n = 234), because 2 patients died from refractory rearrest after randomization, but before any Epo injection, the first dose of Epo was administered to 232 patients (99.1%). The median time (quartile 1 to quartile 3) between ROSC and first Epo injection was 1.43 (0.8 to 2.7) h. Due to the high mortality rate over the first 48 h, the second injection (hour 12) was administered to 197 patients (82.9%), the third (hour 24) to 188 patients (80.3%), the fourth (hour 36) to 181 patients (77.4%), and the fifth (hour 48) to 177 patients (75.6%).
There was no significant difference between the 2 groups with respect to the primary endpoint: at day 60, 32.4% of patients (76 of 234) in the intervention group reached a CPC 1 level, as compared with 32.1% of patients (78 of 242 patients) in the control group (odds ratio: 1.01; 95% confidence interval: 0.68 to 1.48; p = 0.96). At the end of follow-up, the proportion of patients at each level of the CPC scale was similar between the 2 groups (Table 2). This absence of significant difference in outcome was consistent across all subgroups (Table 3).
During the follow-up, there was no significant difference between the 2 groups with respect to the proportion of patients in each level of the CPC scale at all time points. At ICU discharge, 41 patients reached a CPC 1 in the Epo group (17.5%) versus 40 patients (16.5%) in the control group (p = 0.81).
The mortality rate was similar between the 2 groups at all time points, as reflected by the Kaplan-Meier curves (Figure 2). At day 60, the mortality rate was 57.7% versus 56.4% in the Epo and control patients, respectively (p = 0.85). Irreversible brain damage was the main cause of death in both groups (76.9% in the Epo group vs. 78.2% in controls; p = 0.74).
There was no impact of loss to follow-up (only 1 patient, in the Epo group) on results (data not shown), with similar results obtained with the high and low hypotheses.
Serious adverse events
SAE were more frequent in Epo-treated patients as compared with controls. At least 1 SAE was observed in 53 patients (22.6%) in the Epo group versus 36 patients (14.9%) in the control group (p = 0.03) (Table 4). Thrombotic complications occurred in 29 patients (12.4%) in the Epo group versus 14 (5.8%) in the control group (p = 0.01). The most frequent thrombotic events were deep venous thromboses, which were detected in 20 patients in the intervention group versus 12 patients in the control group (0.12). An acute coronary stent thrombosis occurred in 8 patients in the Epo group and 1 patient in the control group (0.02). No interaction was found between study treatment and the presence of a coronary stent in the occurrence of thrombotic complications (p = 0.53).
Despite encouraging preliminary data, the present study establishes that administering a high dose of an Epo analog in addition to standard therapy did not confer a clinical benefit in comatose survivors of OHCA. Furthermore, the Epo treatment was associated with a higher rate of complications in comparison with standard care, particularly thrombotic events (Central Illustration).
Lack of efficacy
Clinical interest in the use of Epo as a neuroprotective agent emanated from a growing body of experimental evidence. Various in vivo and in vitro experimental models have demonstrated Epo-induced neuronal and vascular protection in the nervous system (15,16). Hence, animal models that tested Epo during cerebral hypoxia-ischemia showed a reduction in ischemia-induced learning disability, increased neuronal survival, and development of ischemic tolerance (17,18). Of note, in models of both focal and global cerebral ischemia, Epo reduced cerebral infarction and was able to protect sensitive hippocampal neurons from injury (19–22). It has also been demonstrated that Epo does not require intrathecal administration in order to provide effective neuroprotection. Systemic delivery of recombinant human Epo reduced cerebral infarct volume by about 75% in a rodent model of middle cerebral artery stroke (22). However, this protective effect is questionable because another animal study showed no effect of Epo on survival and cerebral recovery after cardiac arrest, even with pre-treatment (23). In humans, Ehrenreich et al. (9) studied the safety and efficacy of recombinant human Epo for treatment of ischemic stroke. Despite encouraging results obtained in a proof-of-concept trial, the German Multicenter EPO Stroke Trial (a phase 2/3 trial) was a negative study that also raised safety concerns, particularly in patients receiving systemic thrombolysis (24).
In global brain anoxo-ischemic injury provoked by resuscitated cardiac arrest, preliminary clinical results were also encouraging. In a feasibility study, 18 patients who received Epo-alpha were compared with 40 matched controls. At day 28, survival rates did not differ (55% vs. 47.5%; p = 0.17), but the rate of full neurological recovery appeared higher (55% vs. 37.5%) in Epo-treated patients, although this was not significant due to the low number of patients. More recently, Grmec et al. (25) investigated whether intravenous erythropoietin-beta (another analog of erythropoietin) administered within 2 min of physician-led cardiopulmonary resuscitation improves outcomes from OHCA. The investigators observed a higher rate of ROSC, ICU admission, 24-h survival, and hospital survival in Epo-treated patients. Of note, these preliminary clinical results were obtained in small groups of patients, and both studies were single center and nonrandomized. The present randomized controlled trial failed to replicate these observations, demonstrating that Epo administered as soon as possible after ROSC is not associated with any improvement in neurological outcome. This strongly suggests that previous positive results were probably due to the common bias of nonrandomized trials with a low number of patients. Interestingly, our results are consistent with those obtained in other settings, such as acute myocardial infarction (AMI) and traumatic brain injury. In experimental models of AMI, Epo reduces infarct size and improves left ventricular function, effects that were partly attributed to its antiapoptotic and angiogenic properties. These promising cardioprotective effects of Epo observed in animal models have not been reproduced in clinical studies of AMI (26,27). The REVEAL (Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction) study, which was a prospective, randomized, double-blinded, placebo-controlled trial, failed to demonstrate any benefit in this setting (8). In patients with ST-segment elevation myocardial infarction who had successful reperfusion with PCI, a single intravenous bolus of epoetin alfa within 4 h of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Furthermore, subgroup analyses raised concerns about an increase in infarct size among older patients. On the whole, large randomized controlled trials in different settings (stroke, AMI, and cardiac arrest) have failed to demonstrate any clinical benefit of Epo medication. In patients with closed head injury, the efficacy of Epo is still debated. In an initial study, the intravenous administration of Epo (500 U/kg per dose) did not improve neurological outcomes at 6 months (28). However, in a recent multicenter trial, the results of a pre-specified sensitivity analysis that adjusted for covariates suggested that the effect of Epo on mortality remains uncertain in patients with moderate or severe traumatic brain injury (29). Encouraging preliminary results have been also recently obtained in pre-term infants with cerebral insults, but these findings require confirmation by observation of neurodevelopmental outcomes (30).
Regarding the lack of efficacy of Epo in cardiac arrest patients, it is difficult to reconcile conflicting animal and clinical results. Several reasons can be discussed. It is possible that the effects of erythropoietin differ among species, which would explain why tissue protective effects of Epo observed in animals could not be reproduced in humans. The time window may also differ between animal experiments and clinical use. Animal studies indicate that there is a therapeutic window of time, beyond which the tissue protective effects of erythropoietin are attenuated. In most experimental studies, the protective effect was maximal in pre-treated animals, but a persistent benefit was observed for up to 3 h in some models (22). Even if everything was done to inject the first dose of Epo as soon as possible after resuscitation, we cannot exclude the possibility that administration of Epo in our study occurred beyond the putative therapeutic window. The dose that was used can also be debated. The chosen dosage (200,000 U over 48 h) is twice the dose used by Ehrenreich et al. (9) in stroke patients. This dosage, which is among the highest doses tested in clinical trials at the time the study was designed, was chosen in accordance with the doses previously used in animal experiments demonstrating neuroprotective effects of Epo. This was also the dose used in the pilot study, in which pharmacokinetic parameters appear similar to those reported in healthy subjects. We did not assess the availability of Epo in cerebrospinal fluid (CSF) after intravenous infusion because we considered that lumbar punctures could have been deleterious in our patients, most of who were treated with antithrombotic agents. However, the results of the safety study performed by Ehrenreich et al. (6,9) confirmed that intravenous administration of a total of 100,000 U of Epo after a documented stroke led to a 60- to 100-fold increase in CSF Epo levels. It could be assumed that the greater dose of Epo used in our study provided at least similar or higher CSF Epo concentrations.
In addition to the lack of efficacy, we also observed a significant increase in the composite of SAE. The rate of thrombotic events was notably higher in Epo-treated patients, which was also observed in trials that tested the cardioprotective effects of Epo in AMI. In the REVEAL study, there was also a significant increase in the composite of cardiovascular adverse events including stent thrombosis (8). A recent observational study reported a high incidence of stent thrombosis in patients who had a stent implantation performed during the initial course of resuscitation (31). This was thought to be associated with post-resuscitation shock and insufficient antithrombotic treatment before PCI, but the present study suggests that Epo could also increase this risk, as was previously reported in the treatment of cancer-associated anemia (32). The mechanism by which Epo may cause these events is unclear. Although megakaryocytic progenitors express the Epo receptor, Epo does not play a critical role in megakaryopoiesis. However, we cannot rule out that high doses of Epo, in association with other factors, including hypothermia, cytokines, and factors produced during inflammation, may act synergistically to enhance platelet activation and coagulation activation, and promote thrombosis. Although the exact mechanism warrants further investigation, this result is now of particular importance for all future clinical trials that will aim to test Epo analogs.
The main limitation of the study is related to the single-blind design. As a consequence, health care professionals caring for patients at the very early stage (first 48 h) were aware of the intervention assignments. However, physicians performing neurological follow-up and final outcome measurements, as well as study administrators and statisticians, were unaware of the intervention assignments. This limitation probably did not influence the negative result of the study. Additionally, there is a potential high risk for selection bias, as reflected in the flow chart and the patients’ characteristics. This selection process could also explain the relatively low inclusion rate observed during the study. As a consequence, results of the present study cannot be extrapolated to a less selected population. Finally, and as stated previously, we cannot firmly exclude the possibility that earlier administration of Epo may be associated with a clinical benefit.
In comatose patients resuscitated from a cardiac arrest, early administration of Epo compared with standard therapy during the first 48 h did not confer a benefit and was associated with a higher rate of thrombotic complications.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Administering a high dose of erythropoietin analog in addition to standard therapy does not confer clinical benefit in comatose patients resuscitated from cardiac arrest and is associated with a higher rate of complications, particularly thrombotic events.
TRANSLATIONAL OUTLOOK: Further studies are needed to assess the safety and efficacy of erythropoietin-stimulating agents in other specific clinical settings, such as traumatic brain injury and pre-term infancy with cerebral insults.
The authors sincerely thank Nancy Kentish-Barnes (Réanimation Médicale, Hôpital Saint Louis, APHP, Paris, France) for her help in preparing the manuscript. The authors acknowledge the following members: data monitoring: Maryline Delattre, Adèle Bellino, Samia Kribel, Emilie Vincent, Olivia Jaumat, and Anne Gueye (Clinical Research Unit Paris Centre, APHP); Data and Safety Monitoring Board: Antoine Vieillard-Baron (Réanimation Médicale, Hôpital Ambroise Paré–APHP, Boulogne, France); Gilles Chatellier (Unité de Recherche Clinique, Hôpital Européen Georges Pompidou–APHP, Paris, France); and Pierre Boutouyrie (Pharmacologie Clinique, Hôpital Européen Georges Pompidou–APHP, Paris, France).
This work was funded by a research grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique PHRC-AOM P 071217). Dr. Kimmoun has received a grant from Baxter for the Esmosepsis clinical trial (NCT02068287) and fees for a consultancy activity. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Carli and Hermine contributed equally to this work. Previous presentations: Annual Meeting of the European Society of Intensive Care Medicine, Barcelona, Spain, October 2014.
- Abbreviations and Acronyms
- acute myocardial infarction
- Cerebral Performance Category
- cerebrospinal fluid
- intensive care unit
- out-of-hospital cardiac arrest
- percutaneous coronary intervention
- return of spontaneous circulation
- serious adverse event
- Received December 11, 2015.
- Revision received March 17, 2016.
- Accepted April 5, 2016.
- American College of Cardiology Foundation
- Sirén A.L.,
- Fratelli M.,
- Brines M.,
- et al.
- Morrison L.J.,
- Deakin C.D.,
- Morley P.T.,
- et al.,
- Advanced Life Support Chapter Collaborators
- Nolan J.P.,
- Neumar R.W.,
- Adrie C.,
- et al.
- Dumas F.,
- Cariou A.,
- Manzo-Silberman S.,
- et al.
- Junk A.K.,
- Mammis A.,
- Savitz S.I.,
- et al.
- Olsen N.V.
- Celik M.,
- Gökmen N.,
- Erbayraktar S.,
- et al.
- Chong Z.Z.,
- Kang J.Q.,
- Maiese K.
- Brines M.L.,
- Ghezzi P.,
- Keenan S.,
- et al.
- Ehrenreich H.,
- Weissenborn K.,
- Prange H.,
- et al.,
- EPO Stroke Trial Group
- Ott I.,
- Schulz S.,
- Mehilli J.,
- et al.,
- REVIVAL-3 Study Investigators