Paul C. Hébert, MD MHSc* and Matthew Stanbrook, MD PhD
*Rédacteur en chef, JAMC; Rédacteur adjoint, Sciences, JAMC Avec l'équipe de rédaction de l'éditorial (Barbara Sibbald BJ, Sharon Straus MD MSc, Noni MacDonald MD MSc et Amir Attaran LLB PhD)
Ce numéro du JAMC présente une critique systématique (page 725) portant sur l'utilisation, chez les patients aux soins intensifs, de l'érythropoïétine, médicament dont on fait la promotion générale sans qu'il y ait d'indication approuvée dans cette population de patients1. Hormone glycoprotéïque recombinante complexe, l'érythropoïétine est approuvée pour le traitement de l'anémie chez les patients en dialyse, qui ont subi une intervention chirurgicale majeure ou qui sont traités pour un cancer. La critique systématique met en évidence la constatation selon laquelle lorsque l'on utilise ce traitement, qui coûte environ 400 $ la dose, sans suivre les indications de l'étiquette chez des patients aux soins intensifs, il économisera en moyenne moins d'une unité de sang, n'améliorera pas les résultats cliniques et pourrait causer davantage de complications thrombotiques.
Il faudrait féliciter Johnson & Johnson et sa filiale Janssen-Ortho d'avoir investi dans plusieurs études cliniques d'envergure afin d'avoir une idée de l'utilisation de l'érythropoïétine chez les patients aux soins intensifs. Grâce à cet investissement, les médecins et les patients ou leurs proches peuvent maintenant faire des choix éclairés. Les félicitations s'arrêtent toutefois là. Aux États-Unis, les fabricants d'érythropoïétine préconisent agressivement le médicament dans des annonces directes aux consommateurs et en offrant des incitatifs financiers aux médecins. On craint que ces activités n'aient encouragé l'utilisation généralisée non conforme à l'étiquetage et provoqué des effets indésirables pour des patients, ce qui a incité le congrès américain à enquêter2.
Ce n'est pas le seul exemple. Médicament antiépileptique, la gabapentine a été vendue illégalement contre la douleur chronique, et son fabricant, Warner–Lambert, a été condamné au criminel et a dû payer des dommages-intérêts au civil3. Le facteur VII activé, agent de coagulation indiqué pour les patients hémophiles, qui constituent donc un marché très limité, a généré une fortune pour Novo Nordisk comme thérapie contre l'hémorragie massive, même si les données indiquent qu'il pourrait accroître le risque de mort4. Indiquée contre la schizophrénie, la rispéridone est souvent utilisée de façon non conforme à l'étiquetage quelque 66 % du temps5, principalement contre les troubles du comportement dans les cas de démence. C'est depuis peu seulement qu'on dispose de suffisamment de données probantes pour découvrir le risque accru de mortalité que pose la rispéridone dans ce contexte.
Les utilisations non conformes à l'étiquetage découlent habituellement d'hypothèses testées en laboratoire ou de premières observations cliniques ou anecdotiques. Il est clair qu'il ne faudrait pas enrayer les innovations des soins qui découlent de ces observations, car c'est là un moyen de réaliser des progrès en médecine. De plus, l'utilisation non conforme à l'étiquetage constitue souvent un prolongement logique de l'utilisation approuvée, ce qui se produit lorsque des données biologiques appuient l'efficacité d'un médicament (p. ex., utilisation d'antibiotiques guidée par la sensibilité in-vitro), lorsqu'on étend l'utilisation à une maladie semblable sur le plan physiologique (p. ex., salbutamol pour traiter la bronchopneumopathie chronique obstructive) ou lorsqu'une maladie afflige des sous-groupes non approuvés (p. ex., enfants).
Les médecins n'ont pas nécessairement de difficulté à faire preuve de jugement indépendant dans de telles situations. Le problème se pose lorsque les fabricants ont recours au marketing pour inciter les médecins à utiliser ces médicaments de façon non conforme à l'étiquetage. En théorie, les sociétés pharmaceutiques ne sont pas autorisées à promouvoir l'utilisation de médicaments non approuvés par les organismes de réglementation. En pratique, la promotion agressive des médicaments se fait sentir dans l'augmentation des utilisations non conformes à l'étiquetage, conséquence qui n'est peut-être pas non intentionnelle.
L'utilisation non conforme à l'étiquetage crée ainsi une échappatoire qui permet aux fabricants de médicaments de contourner la surveillance exercée par les organismes de réglementation qui ont pour mandat de protéger le public. Ces utilisations sont d'une rentabilité exceptionnelle pour les sociétés pharmaceutiques. Une étude a constaté que 21 % des ordonnances de médicaments d'usage courant sont prescrites pour des utilisations non conforme à l'étiquetage, dont 73 % ne reposent pas sur des données scientifiques solides5.
Comment contrôler les utilisations non conformes à l'étiquetage? Tout d'abord, il faut distinguer les utilisations raisonnables sur le plan clinique de celles qui sont douteuses. Deuxièmement, chaque fois que l'on prescrit un médicament, que l'utilisation en soit indiquée ou non sur l'étiquette, les médecins doivent informer leurs patients des risques pertinents et des connaissances qui manquent. Troisièmement, la diffusion d'information au sujet des utilisations non conformes à l'étiquetage, qu'elle se fasse en ligne, sur papier ou en personne, doit être transparente et conforme à l'éthique. Les journaux médicaux, comme le JAMC, ont un rôle clé à jouer en indiquant quand les auteurs qui ont des conflits avec l'industrie discutent d'utilisations non conformes à l'étiquetage. Quatrièmement, il faut exercer des pressions sur les sociétés pharmaceutiques pour qu'elles vérifient la pertinence de l'utilisation non conforme à l'étiquetage au moyen d'essais cliniques rigoureux comme ceux que l'on a réalisés dans le cas de l'érythropoïétine. Enfin, il faut créer des moyens de repérer les tendances émergentes des utilisations non conformes à l'étiquetage qui feront partie intégrante de la surveillance postcommercialisation.
Il peut être approprié de prescrire des utilisations non conformes à l'étiquetage lorsque les médecins consciencieux, qui comprennent parfaitement les données probantes pertinentes disponibles, s'appuient aussi sur leur expérience clinique pour déterminer avec leurs patients qu'il s'agit là du meilleur choix médical. L'utilisation non conforme à l'étiquetage cesse d'être appropriée lorsque les fabricants de médicaments manipulent le pouvoir de prescrire des médecins afin de contourner des exigences réglementaires onéreuses et coûteuses et de grossir leur part du marché. Les médecins sont tenus d'être vigilants face à ce phénomène et d'éviter d'être des outils essentiels de l'expansion sans assise scientifique des indications dans l'établissement d'ordonnances.
RÉFÉRENCES
Zarychanski R, Turgeon AF, McIntyre L, et al. Erythropoietin-receptor agonists in critically ill patients: a meta-analysis of randomized controlled trials. JAMC 2007;177(7):725-34
Mitka M. FDA sounds alert on anemia drugs. JAMA 2007;297:1868-9
Henney JE. Safeguarding patient welfare: Who's in charge? Ann Intern Med 2006;145:305-7
O'Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295:293-8
Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med 2006;166:1021-6
Senin, 01 Oktober 2007
Erythropoietin use in critically ill patients: forest and trees
Howard L. Corwin, MD
Howard L. Corwin is with the Department of Critical Care Medicine, Dartmouth–Hitchcock Medical Center, Lebanon, NH
Correspondence to: Dr. Howard L. Corwin, Department of Critical Care Medicine, Dartmouth–Hitchcock Medical Center, Lebanon NH 03756; Howard.L.Corwin@hitchcock.org
In this issue, Zarychanski and colleagues present a meta-analysis of randomized controlled trials that evaluates the use of erythropoietin in critically ill patients.1 The primary purpose of this commentary is not to critique their analysis but, rather, to present an overview of the potential role of erythropoietin in critically ill patients. My perspective, and potential bias, is of someone who has had a major involvement in 4 of the included studies, which enrolled more than 90% of the patients included in the meta-analysis by Zarychanski and colleagues.
Anemia is very common among patients who are critically ill. Almost 95% of patients admitted to an intensive care unit have a hemoglobin concentration that is below normal by day 3 of admission.2 Anemia typically persists throughout their stays in the intensive care unit, and as a consequence these patients receive a large number of red blood cell transfusions.3,4 The anemia associated with critical illness is fundamentally similar to the anemia of chronic inflammatory disease.5 A major feature of anemia in critical illness is the failure of circulating erythropoietin concentrations to increase appropriately in response to a reduction in the patient's hemoglobin concentration. These observations have suggested that administering pharmacological doses of erythropoietin will increase the hemoglobin concentration in critically ill patients through stimulation of erythropoiesis and thus decrease their need for allogeneic red blood cell transfusions. A corollary to this is the hope that by avoiding the potentially negative effects of blood transfusions clinical outcomes would improve.
The above rationale for erythropoietin therapy led to a small randomized pilot study with 160 critically ill patients, which showed a reduction in red blood cell transfusions among patients in the erythropoietin treatment group.6 A much larger randomized controlled trial (n = 1302) later confirmed these findings.7 A post-hoc analysis of this latter trial suggested differences in mortality in subgroups (trauma patients, medicine nontrauma patients and surgery nontrauma patients) with erythropoietin treatment. These studies led to a third randomized trial (n = 1460) in which the primary outcome was again transfusion reduction. However, because of the previously observed subgroup differences, the three subgroups were prospectively identified and randomization was stratified on these groups. This study confirmed a mortality benefit among trauma patients receiving erythropoietin.8 Surprisingly, although there was an increase in hemoglobin concentrations, there was no transfusion reduction found in the erythropoietin group. This suggests that the mortality benefit was independent of transfusion effect. Importantly, there was a significant increase in thrombotic events observed in the erythropoietin treatment group that had not been observed in the earlier studies.
Meta-analysis is clearly a useful technique for combining results from multiple primary studies. However, in this case, was a meta-analysis necessary? There have now been 2 large randomized controlled trials that were similarly designed.7,8 These 2 studies enrolled almost 85% of the patients in the meta-analysis by Zarychanski and colleagues.7,8 Combining these 2 studies with others that used different erythropoietin dosing strategies, different patient populations and different clinical situations does not add to the understanding of the role of erythropoietin in critically ill patients. For example, the study by Silver and colleagues9 included only long-term acute care patients (after transfer from an intensive care unit) who received a much longer duration of erythropoietin therapy (up to 12 doses compared with 3 or 4 doses in the other 2 studies); the study by Still and colleagues10 included only burn patients, who were excluded in our randomized controlled trials6–8; our pilot study6 used an erythropoietin dosing strategy that resulted in patients receiving a dose double that used in our more recent studies; and erythropoietin dosing strategies were quite varied in the other studies included in the meta-analysis. In the studies for which sample size was calculated,6–9 sample size was based on transfusion reduction outcomes, not on clinical outcomes. Including all of these additional underpowered studies in a single analysis does not clarify the role of erythropoietin in patients who are critically ill. This issue is particularly important because the timing and the dose, as well as the population studied, may affect the risk–benefit ratio for erythropoietin therapy. The questions of efficacy and safety can be more clearly answered by a close examination of the 2 large randomized controlled trials that had a similar design.7,8
The meta-analysis by Zarychanski and colleagues suggests an overall reduction in the proportion of patients who received transfusions in the erythropoietin group. However, given current transfusion practices, there appears to be no reduction in red blood cell transfusions with erythropoietin treatment. The reduction in the proportion of patients transfused and the total number of units transfused that was observed in the earlier randomized controlled trial7 was not observed in the most recent trial.8 The difference in the results between these studies is probably because of significant changes in transfusion practice over the intervening years. Zarychanski and colleagues suggest that some of the studies were consistent with either a restrictive (hemoglobin concentration 80 g/L) or a liberal (hemoglobin concentration 90 g/L) transfusion strategy. In this context, the use of the word "strategy" implies that there was a prospective plan to transfuse patients according to specific criteria, which was clearly not the case. Regardless, it is clear that transfusion practice in general has changed. There was a significant increase in hemoglobin concentration observed with erythropoietin therapy, which demonstrates that erythropoietin had the expected hematopoietic effect, despite the absence of transfusion reduction.
Erythropoietin appears to decrease mortality among trauma patients admitted to the intensive care unit for more than 48 hours. This was suggested in a post-hoc analysis in our prior study7 and was confirmed in a prospective analysis in our most recent study.8 Questions often arise as to whether subgroup differences are in fact real. Guidelines have been suggested to help interpret subgroup analyses.10 These guidelines suggest asking the following questions: Are the comparisons made within studies? Were the subgroups prospectively identified? Was the number of hypotheses tested small? Is the magnitude of the effect large? Is the effect statistically significant? Is the effect consistent across studies? And is the effect biologically plausible? In our most recent study,8 our analysis of trauma patients is consistent with what would be considered an appropriate subgroup analysis, including biologic plausibility. Taken together, our 2 studies, which included a total of 2762 critically ill patients and 1433 trauma patients, provide strong evidence in support of a mortality benefit for erythropoietin use in trauma patients.7,8 On the other hand, mortality was not significantly decreased among either medicine nontrauma patients or surgery nontrauma patients who received erythropoietin. Whether some subgroups within the medicine or surgery nontrauma population may benefit from erythropoietin therapy requires further study.
The absence of a reduction in transfusions among patients who received erythropoietin suggests that the observed mortality benefit is a result of nonhematopoietic actions of erythropoietin. Erythropoietin and its receptor are expressed by multiple tissues in response to stress and mediate local stress responses.11 Erythropoietin is a cytokine with antiapoptotic activity, and it has been demonstrated in preclinical and small clinical studies to protect cells from hypoxemia and ischemia. These nonhematopoetic, cell-protection activities could be responsible for the observed improvement in outcomes among critically ill patients. Further studies will be necessary to establish the mechanisms responsible for erythropoietin's effects. However, in some respects, there is a greater understanding of the nonhematopoietic actions of erythropoietin than there is of the mechanisms that underlie the adverse effects attributed to red blood cell transfusions.
Are there adverse events associated with erythropoietin therapy? Among critically ill patients, erythropoietin use appears to be associated with increased thrombotic events. This is consistent with the results of recent trials involving noncritically ill patients with either cancer or chronic renal failure. In these studies, erythropoietin, when used to achieve higher target hemoglobin concentrations (i.e., > 120 g/L), was shown to increase the risk of thrombotic complications and death.12–15 A post-hoc analysis performed as part of our most recent trial suggested that this risk can be mitigated by the use of prophylactic anticoagulation therapy.8 In this study, there was greater awareness of the potential for thrombotic complications, which in part may have led to the differences observed in thrombotic events between the study groups compared with what was reported in the earlier studies. However, as Zarychanski and colleagues point out, more systematic surveillance is necessary in future trials.
What is the role of erythropoietin in patients who are critically ill? To answer this question, Zarychanski and colleagues attempt to create a forest from the trees of the individual trials. However, most of this forest is made up of 2 giant redwoods. The data needed to begin to answer the question are available in the 2 large randomized controlled trials.7,8 Certainly, the need for an additional trial in a trauma population, as suggested by Zarychanski and colleagues, is important. However, whether erythropoietin should be used in trauma patients before a confirmatory trial is performed and whether investigators have enough equipoise to randomly allocate trauma patients in a third confirmatory trial are important questions. Given the strength of the findings from the subgroup analyses in the 2 randomized controlled trials,7,8 at this time erythropoietin should be considered for trauma patients who are admitted to an intensive care unit for more than 48 hours and who meet other study criteria (Box 1). On the other hand, the available data do not support the use of erythropoietin in medicine or surgery nontrauma patients admitted to an intensive care unit, unless they have an approved indication for erythropoietin use. Treating these nontrauma patients with erythropoietin would expose them to potential risks with no identifiable benefits in the form of a reduction in transfusions (assuming conservative practice) or mortality. Prophylactic heparin should also be considered if erythropoietin is given. Future studies should focus on understanding how the nonhematopoietic activities of erythropoietin are beneficial for critically ill patients. A better understanding of these mechanisms may help to identify other populations that could benefit from this therapy as well as identify the optimal timing and dose of erythropoietin therapy.
Howard L. Corwin is with the Department of Critical Care Medicine, Dartmouth–Hitchcock Medical Center, Lebanon, NH
Correspondence to: Dr. Howard L. Corwin, Department of Critical Care Medicine, Dartmouth–Hitchcock Medical Center, Lebanon NH 03756; Howard.L.Corwin@hitchcock.org
In this issue, Zarychanski and colleagues present a meta-analysis of randomized controlled trials that evaluates the use of erythropoietin in critically ill patients.1 The primary purpose of this commentary is not to critique their analysis but, rather, to present an overview of the potential role of erythropoietin in critically ill patients. My perspective, and potential bias, is of someone who has had a major involvement in 4 of the included studies, which enrolled more than 90% of the patients included in the meta-analysis by Zarychanski and colleagues.
Anemia is very common among patients who are critically ill. Almost 95% of patients admitted to an intensive care unit have a hemoglobin concentration that is below normal by day 3 of admission.2 Anemia typically persists throughout their stays in the intensive care unit, and as a consequence these patients receive a large number of red blood cell transfusions.3,4 The anemia associated with critical illness is fundamentally similar to the anemia of chronic inflammatory disease.5 A major feature of anemia in critical illness is the failure of circulating erythropoietin concentrations to increase appropriately in response to a reduction in the patient's hemoglobin concentration. These observations have suggested that administering pharmacological doses of erythropoietin will increase the hemoglobin concentration in critically ill patients through stimulation of erythropoiesis and thus decrease their need for allogeneic red blood cell transfusions. A corollary to this is the hope that by avoiding the potentially negative effects of blood transfusions clinical outcomes would improve.
The above rationale for erythropoietin therapy led to a small randomized pilot study with 160 critically ill patients, which showed a reduction in red blood cell transfusions among patients in the erythropoietin treatment group.6 A much larger randomized controlled trial (n = 1302) later confirmed these findings.7 A post-hoc analysis of this latter trial suggested differences in mortality in subgroups (trauma patients, medicine nontrauma patients and surgery nontrauma patients) with erythropoietin treatment. These studies led to a third randomized trial (n = 1460) in which the primary outcome was again transfusion reduction. However, because of the previously observed subgroup differences, the three subgroups were prospectively identified and randomization was stratified on these groups. This study confirmed a mortality benefit among trauma patients receiving erythropoietin.8 Surprisingly, although there was an increase in hemoglobin concentrations, there was no transfusion reduction found in the erythropoietin group. This suggests that the mortality benefit was independent of transfusion effect. Importantly, there was a significant increase in thrombotic events observed in the erythropoietin treatment group that had not been observed in the earlier studies.
Meta-analysis is clearly a useful technique for combining results from multiple primary studies. However, in this case, was a meta-analysis necessary? There have now been 2 large randomized controlled trials that were similarly designed.7,8 These 2 studies enrolled almost 85% of the patients in the meta-analysis by Zarychanski and colleagues.7,8 Combining these 2 studies with others that used different erythropoietin dosing strategies, different patient populations and different clinical situations does not add to the understanding of the role of erythropoietin in critically ill patients. For example, the study by Silver and colleagues9 included only long-term acute care patients (after transfer from an intensive care unit) who received a much longer duration of erythropoietin therapy (up to 12 doses compared with 3 or 4 doses in the other 2 studies); the study by Still and colleagues10 included only burn patients, who were excluded in our randomized controlled trials6–8; our pilot study6 used an erythropoietin dosing strategy that resulted in patients receiving a dose double that used in our more recent studies; and erythropoietin dosing strategies were quite varied in the other studies included in the meta-analysis. In the studies for which sample size was calculated,6–9 sample size was based on transfusion reduction outcomes, not on clinical outcomes. Including all of these additional underpowered studies in a single analysis does not clarify the role of erythropoietin in patients who are critically ill. This issue is particularly important because the timing and the dose, as well as the population studied, may affect the risk–benefit ratio for erythropoietin therapy. The questions of efficacy and safety can be more clearly answered by a close examination of the 2 large randomized controlled trials that had a similar design.7,8
The meta-analysis by Zarychanski and colleagues suggests an overall reduction in the proportion of patients who received transfusions in the erythropoietin group. However, given current transfusion practices, there appears to be no reduction in red blood cell transfusions with erythropoietin treatment. The reduction in the proportion of patients transfused and the total number of units transfused that was observed in the earlier randomized controlled trial7 was not observed in the most recent trial.8 The difference in the results between these studies is probably because of significant changes in transfusion practice over the intervening years. Zarychanski and colleagues suggest that some of the studies were consistent with either a restrictive (hemoglobin concentration 80 g/L) or a liberal (hemoglobin concentration 90 g/L) transfusion strategy. In this context, the use of the word "strategy" implies that there was a prospective plan to transfuse patients according to specific criteria, which was clearly not the case. Regardless, it is clear that transfusion practice in general has changed. There was a significant increase in hemoglobin concentration observed with erythropoietin therapy, which demonstrates that erythropoietin had the expected hematopoietic effect, despite the absence of transfusion reduction.
Erythropoietin appears to decrease mortality among trauma patients admitted to the intensive care unit for more than 48 hours. This was suggested in a post-hoc analysis in our prior study7 and was confirmed in a prospective analysis in our most recent study.8 Questions often arise as to whether subgroup differences are in fact real. Guidelines have been suggested to help interpret subgroup analyses.10 These guidelines suggest asking the following questions: Are the comparisons made within studies? Were the subgroups prospectively identified? Was the number of hypotheses tested small? Is the magnitude of the effect large? Is the effect statistically significant? Is the effect consistent across studies? And is the effect biologically plausible? In our most recent study,8 our analysis of trauma patients is consistent with what would be considered an appropriate subgroup analysis, including biologic plausibility. Taken together, our 2 studies, which included a total of 2762 critically ill patients and 1433 trauma patients, provide strong evidence in support of a mortality benefit for erythropoietin use in trauma patients.7,8 On the other hand, mortality was not significantly decreased among either medicine nontrauma patients or surgery nontrauma patients who received erythropoietin. Whether some subgroups within the medicine or surgery nontrauma population may benefit from erythropoietin therapy requires further study.
The absence of a reduction in transfusions among patients who received erythropoietin suggests that the observed mortality benefit is a result of nonhematopoietic actions of erythropoietin. Erythropoietin and its receptor are expressed by multiple tissues in response to stress and mediate local stress responses.11 Erythropoietin is a cytokine with antiapoptotic activity, and it has been demonstrated in preclinical and small clinical studies to protect cells from hypoxemia and ischemia. These nonhematopoetic, cell-protection activities could be responsible for the observed improvement in outcomes among critically ill patients. Further studies will be necessary to establish the mechanisms responsible for erythropoietin's effects. However, in some respects, there is a greater understanding of the nonhematopoietic actions of erythropoietin than there is of the mechanisms that underlie the adverse effects attributed to red blood cell transfusions.
Are there adverse events associated with erythropoietin therapy? Among critically ill patients, erythropoietin use appears to be associated with increased thrombotic events. This is consistent with the results of recent trials involving noncritically ill patients with either cancer or chronic renal failure. In these studies, erythropoietin, when used to achieve higher target hemoglobin concentrations (i.e., > 120 g/L), was shown to increase the risk of thrombotic complications and death.12–15 A post-hoc analysis performed as part of our most recent trial suggested that this risk can be mitigated by the use of prophylactic anticoagulation therapy.8 In this study, there was greater awareness of the potential for thrombotic complications, which in part may have led to the differences observed in thrombotic events between the study groups compared with what was reported in the earlier studies. However, as Zarychanski and colleagues point out, more systematic surveillance is necessary in future trials.
What is the role of erythropoietin in patients who are critically ill? To answer this question, Zarychanski and colleagues attempt to create a forest from the trees of the individual trials. However, most of this forest is made up of 2 giant redwoods. The data needed to begin to answer the question are available in the 2 large randomized controlled trials.7,8 Certainly, the need for an additional trial in a trauma population, as suggested by Zarychanski and colleagues, is important. However, whether erythropoietin should be used in trauma patients before a confirmatory trial is performed and whether investigators have enough equipoise to randomly allocate trauma patients in a third confirmatory trial are important questions. Given the strength of the findings from the subgroup analyses in the 2 randomized controlled trials,7,8 at this time erythropoietin should be considered for trauma patients who are admitted to an intensive care unit for more than 48 hours and who meet other study criteria (Box 1). On the other hand, the available data do not support the use of erythropoietin in medicine or surgery nontrauma patients admitted to an intensive care unit, unless they have an approved indication for erythropoietin use. Treating these nontrauma patients with erythropoietin would expose them to potential risks with no identifiable benefits in the form of a reduction in transfusions (assuming conservative practice) or mortality. Prophylactic heparin should also be considered if erythropoietin is given. Future studies should focus on understanding how the nonhematopoietic activities of erythropoietin are beneficial for critically ill patients. A better understanding of these mechanisms may help to identify other populations that could benefit from this therapy as well as identify the optimal timing and dose of erythropoietin therapy.
Erythropoietin-receptor agonists in critically ill patients: a meta-analysis of randomized controlled trials
Ryan Zarychanski, MD, Alexis F. Turgeon, MD MSc, Lauralyn McIntyre, MD MHSc and Dean A. Fergusson, MHA PhD
From the Department of Epidemiology and Community Medicine (Zarychanski, McInytre, Fergusson), University of Ottawa; the Ottawa Health Research Institute (Zarychanski, McIntyre, Fergusson), The Ottawa Hospital, Ottawa, Ont.; and the Centre Hospitalier Affilié Universitaire de Québec Research Center, the Department of Anesthesia and the Division of Critical Care Medicine (Turgeon), Laval University, Québec City, Que.
Correspondence to: Dr. Ryan Zarychanski, Ottawa Health Research Institute, 501 Smyth Rd., Ottawa ON K1H 8L6; ryan@zarychanski.com
Introduction: Anemia and the need for red blood cell transfusions are common among patients admitted to intensive care units. Erythropoietin has been used to decrease the need for transfusions; however, its ability to improve clinical outcomes is unknown. We evaluated the effect of erythropoietin-receptor agonists on clinically important outcomes, including mortality, length of stay in hospital or intensive care unit, ventilator use, transfusion requirements and major adverse events.
Methods: To identify relevant studies, we searched electronic databases covering 1950 to 2007 (MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the Scopus database). We also searched conference proceedings and grey literature sources. We selected all randomized controlled trials involving critically ill patients that compared an erythropoietin-receptor agonist with a placebo or no intervention. No language restrictions were considered. Data were extracted using a standardized extraction template. We used a fixed effects model to calculate all summary measures of treatment effects.
Results: Of 673 identified records, 9 studies that investigated erythropoietin alpha met the eligibility criteria and were included in our analysis. Erythropoietin, compared with placebo or no intervention, had no statistically significant effect on overall mortality (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.71–1.05, I2 = 0%). The treatment and control groups did not differ in the length of stay in hospital or intensive care unit, or in the duration of mechanical ventilation, in the 3 studies that reported these outcomes. Erythropoietin, compared with placebo, significantly reduced the odds of a patient receiving at least 1 transfusion (OR 0.73, 95% CI 0.64–0.84, I2 = 54.7%). The mean number of units of blood transfused per patient was decreased by 0.41 units in the erythropoietin group (95% CI 0.10–0.74, I2 = 79.2%). Most of the included studies were performed before the widespread adoption of a restrictive transfusion strategy. Only 1 study provided detailed reports of adverse events, and none of the studies systematically evaluated all patients for venous thromboembolism.
Interpretation: At this time, we do not recommend the routine use of erythropoietin-receptor agonists in critically ill patients. The reduction in red blood cell transfusions per patient was very small, and there is insufficient evidence to determine whether this intervention results in clinically important benefits with acceptable risks.
From the Department of Epidemiology and Community Medicine (Zarychanski, McInytre, Fergusson), University of Ottawa; the Ottawa Health Research Institute (Zarychanski, McIntyre, Fergusson), The Ottawa Hospital, Ottawa, Ont.; and the Centre Hospitalier Affilié Universitaire de Québec Research Center, the Department of Anesthesia and the Division of Critical Care Medicine (Turgeon), Laval University, Québec City, Que.
Correspondence to: Dr. Ryan Zarychanski, Ottawa Health Research Institute, 501 Smyth Rd., Ottawa ON K1H 8L6; ryan@zarychanski.com
Introduction: Anemia and the need for red blood cell transfusions are common among patients admitted to intensive care units. Erythropoietin has been used to decrease the need for transfusions; however, its ability to improve clinical outcomes is unknown. We evaluated the effect of erythropoietin-receptor agonists on clinically important outcomes, including mortality, length of stay in hospital or intensive care unit, ventilator use, transfusion requirements and major adverse events.
Methods: To identify relevant studies, we searched electronic databases covering 1950 to 2007 (MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the Scopus database). We also searched conference proceedings and grey literature sources. We selected all randomized controlled trials involving critically ill patients that compared an erythropoietin-receptor agonist with a placebo or no intervention. No language restrictions were considered. Data were extracted using a standardized extraction template. We used a fixed effects model to calculate all summary measures of treatment effects.
Results: Of 673 identified records, 9 studies that investigated erythropoietin alpha met the eligibility criteria and were included in our analysis. Erythropoietin, compared with placebo or no intervention, had no statistically significant effect on overall mortality (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.71–1.05, I2 = 0%). The treatment and control groups did not differ in the length of stay in hospital or intensive care unit, or in the duration of mechanical ventilation, in the 3 studies that reported these outcomes. Erythropoietin, compared with placebo, significantly reduced the odds of a patient receiving at least 1 transfusion (OR 0.73, 95% CI 0.64–0.84, I2 = 54.7%). The mean number of units of blood transfused per patient was decreased by 0.41 units in the erythropoietin group (95% CI 0.10–0.74, I2 = 79.2%). Most of the included studies were performed before the widespread adoption of a restrictive transfusion strategy. Only 1 study provided detailed reports of adverse events, and none of the studies systematically evaluated all patients for venous thromboembolism.
Interpretation: At this time, we do not recommend the routine use of erythropoietin-receptor agonists in critically ill patients. The reduction in red blood cell transfusions per patient was very small, and there is insufficient evidence to determine whether this intervention results in clinically important benefits with acceptable risks.
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