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Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis

Bita Mesgarpour| Benedikt H. Heidinger| Michael Schwameis| Calvin Kienbacher| Cathal Walsh| Susanne Schmitz| Harald Herkner
Systematic Review
Volume 39, Issue 11 / November , 2013

Pages 1896 - 1908

Abstract

Purpose

Erythropoiesis stimulating agents (ESAs) are used to treat anemia in critically ill patients. This indication is off-label, because it is not licensed by regulatory authorities. Recently ESAs were suspected to harm critically ill patients. Our objective was to assess the safety of ESAs in off-label indications in critically ill patients.

Methods

Eleven databases were searched up to April 2012. We considered randomized controlled trials (RCTs) and controlled observational studies in any language that compared off-label ESAs treatment with other effective interventions, placebo or no treatment in critically ill patients. Two authors independently screened and evaluated retrieved records, extracted data and assessed risk of bias and quality of reporting.

Results

We used frequentist and Bayesian models to combine studies, and performed sensitivity and subgroup analyses. From 12,888 citations, we included 48 studies (34 RCTs; 14 observational), involving 944,856 participants. Harm reporting was of medium to low quality. There was no statistically significant increased risk of adverse events in general, serious adverse events, the most frequently reported adverse events, and death in critically ill patients treated with ESAs. These results were robust against risk of bias and analysis methods. There is evidence that ESAs increase the risk of clinically relevant thrombotic vascular events, and there is some less certain evidence that ESAs might increase the risk for venous thromboembolism.

Conclusions

In critically ill patients, administration of ESAs is associated with a significant increase in clinically relevant thrombotic vascular events but not with other frequently reported adverse events and death.

Keywords

References

  1. Rodriguez RM, Corwin HL, Gettinger A, Corwin MJ, Gubler D, Pearl RG (2001) Nutritional deficiencies and blunted erythropoietin response as causes of the anemia of critical illness. J Crit Care 16:36–41
    • View reference on PubMed
    • View reference on publisher's website
  2. Corwin HL (2006) The role of erythropoietin therapy in the critically ill. Transfus Med Rev 20:27–33
    • View reference on PubMed
    • View reference on publisher's website
  3. Marik PE, Corwin HL (2008) Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med 36:2667–2674
    • View reference on PubMed
    • View reference on publisher's website
  4. Zarychanski R, Turgeon AF, McIntyre L, Fergusson DA (2007) Erythropoietin-receptor agonists in critically ill patients: a meta-analysis of randomized controlled trials. CMAJ 177:725–734
    • View reference on PubMed
  5. Maiese K, Li F, Chong ZZ (2005) New avenues of exploration for erythropoietin. JAMA 293:90–95
    • View reference on PubMed
    • View reference on publisher's website
  6. Fishbane S (2010) The role of erythropoiesis-stimulating agents in the treatment of anemia. Am J Manag Care 16 (Suppl Issues): S67–S73
  7. Brophy GM, Sheehan V, Shapiro MJ, Lottenberg L, Scarlata D, Audhya P (2008) A US multicenter, retrospective, observational study of erythropoiesis-stimulating agent utilization in anemic, critically ill patients admitted to the intensive care unit. Clin Ther 30:2324–2334
    • View reference on PubMed
    • View reference on publisher's website
  8. Vekeman F, Lefebvre P, Mody SH, Raut M, McKenzie RS, Watson S et al (2006) Dosing and transfusion patterns of erythropoietic stimulating therapies in critically ill patients. Crit Care Med 34:A128
    • View reference on publisher's website
  9. Vekeman F, McKenzie RS, Lefebvre P, Watson SH, Mody SH, Piech CT et al (2007) Dose and cost comparison of erythropoietic agents in the inpatient hospital setting. Am J Health Syst Pharm 64:1943–1949
    • View reference on PubMed
    • View reference on publisher's website
  10. Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J et al (2009) Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 373:1532–1542
    • View reference on PubMed
    • View reference on publisher's website
  11. Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al. (2009) Erythropoietin or darbepoetin for patients with cancer–meta-analysis based on individual patient data. Cochrane Database Syst Rev, CD007303
  12. Phrommintikul A, Haas SJ, Elsik M, Krum H (2007) Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 369:381–388
    • View reference on PubMed
    • View reference on publisher's website
  13. Tonelli M, Hemmelgarn B, Reiman T, Manns B, Reaume MN, Lloyd A et al (2009) Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis. CMAJ 180:E62–E71
    • View reference on PubMed
  14. Palmer SC, Navaneethan SD, Craig JC, Johnson DW, Tonelli M, Garg AX et al (2010) Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med 153:23–33
    • View reference on PubMed
    • View reference on publisher's website
  15. Food and Drug Administration (FDA) (2010) Information on erythropoiesis-stimulating agents (ESA) epoetin alfa (marketed as Procrit, Epogen) darbepoetin alfa (marketed as Aranesp). Safety Announcement from February 16, 2010 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM109375. Accessed July 25, 2012
  16. Mesgarpour B, Heidinger B, Schwameis M, Kienbacher K, Müller M, Herkner H (2012) Safety of off-label erythropoiesis stimulating agents (ESAs) in critically ill patients: a systematic review and meta-analysis. Pharmacoepidemiol Drug Saf 21(Supplement s3):113
  17. Review Manager (RevMan) [Computer program] (2011) Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration
  18. Higgins JPT, Green S (2011) cochrane handbook for systematic reviews of interventions version 5.1.0. The cochrane collaboration. http://www.cochrane-handbook.org
  19. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M et al (2009) The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed July 25, 2012
  20. Santaguida PL, Raina P (2008) The Development of the McHarm Quality Assessment Scale for adverse events: Delphi Consensus on important criteria for evaluating harms. http://hiru.mcmaster.ca/epc/mcharm.pdf. Accessed July 25, 2012
  21. Schwarzer G (2012) Meta: Meta-Analysis with R. R package version 2-1-1. http://CRANR-projectorg/package=meta Accessed July 25, 2012
  22. Rucker G, Schwarzer G, Carpenter J (2008) Arcsine test for publication bias in meta-analyses with binary outcomes. Stat Med 27:746–763
    • View reference on PubMed
    • View reference on publisher's website
  23. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
    • View reference on PubMed
    • View reference on publisher's website
  24. Prevost TC, Abrams KR, Jones DR (2000) Hierarchical models in generalized synthesis of evidence: an example based on studies of breast cancer screening. Stat Med 19:3359–3376
    • View reference on PubMed
    • View reference on publisher's website
  25. Schmitz S, Adams R, Walsh C (2013) Incorporating data from various trial designs into a mixed treatment comparison model. Stat Med 32:2935–2949
    • View reference on PubMed
    • View reference on publisher's website
  26. Sutton AJ, Higgins JP (2008) Recent developments in meta-analysis. Stat Med 27:625–650
    • View reference on PubMed
    • View reference on publisher's website
  27. Higgins J (2012) Convincing evidence from controlled and uncontrolled studies on the lipid-lowering effect of a statin [editorial]. Cochrane Database Syst Rev 12: ED000049. http://www.thecochranelibrary.com/details/editorial/3992221/Convincing-evidence-from-controlled-and-uncontrolled-studies-on-the-lipid-loweri.html. Accessed January 15, 2013
  28. Andreotti F, Agati L, Conti E, Santucci E, Rio T, Tarantino F et al (2009) Update on phase II studies of erythropoietin in acute myocardial infarction. Rationale and design of exogenous erythropoietin in acute myocardial infarction: new outlook and dose association study (EPAMINONDAS). J Thromb Thrombolysis 28:489–495
    • View reference on PubMed
    • View reference on publisher's website
  29. Binbrek AS, Rao NS, Al Khaja N, Assaqqaf J, Sobel BE (2009) Erythropoietin to augment myocardial salvage induced by coronary thrombolysis in patients with ST segment elevation acute myocardial infarction. Am J Cardiol 104:1035–1040
    • View reference on PubMed
    • View reference on publisher's website
  30. Chen B, Xiao ZJ (2008) Clinical efficacy of recombinant human erythropoietin on sepsis with anemia. Chin J Emerg Med 17:510–512
  31. Ferrario M, Arbustini E, Massa M, Rosti V, Marziliano N, Raineri C et al (2011) High-dose erythropoietin in patients with acute myocardial infarction: a pilot, randomised, placebo-controlled study. Int J Cardiol 147:124–131
    • View reference on PubMed
    • View reference on publisher's website
  32. Lakic N, Surlan K, Jerin A, Meglic B, Curk N, Bunc M (2010) Importance of erythropoietin in brain protection after cardiac surgery: a pilot study. Heart Surg Forum 13:E185–E189
    • View reference on PubMed
    • View reference on publisher's website
  33. Liem A, van de Woestijne AP, Bruijns E, Roeters van Lennep HW, de Boo JA, van Halteren HK et al (2009) Effect of EPO administration on myocardial infarct size in patients with non-STE acute coronary syndromes; results from a pilot study. Int J Cardiol 131:285–287
    • View reference on PubMed
    • View reference on publisher's website
  34. Lipsic E, van der Meer P, Voors AA, Westenbrink BD, van den Heuvel AF, de Boer HC et al (2006) 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 20:135–141
    • View reference on PubMed
    • View reference on publisher's website
  35. Mocini D, Muso P, Guendouz E, De Marco L, Mele L, Cini R et al (2008) Endogenous erythropoietin and a single bolus of 40,000 IU of epoetin alpha do not protect the heart from ischaemia-reperfusion injury during extracorporeal circulation for cardiac surgery. Perfusion 23:187–192
    • View reference on PubMed
    • View reference on publisher's website
  36. Springborg JB, Moller C, Gideon P, Jorgensen OS, Juhler M, Olsen NV (2007) Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: a double blind randomised clinical trial. Acta Neurochir 149:1089–1101
    • View reference on PubMed
    • View reference on publisher's website
  37. Stein A, Mohr F, Laux M, Thieme S, Lorenz B, Cetindis M et al (2012) Erythropoietin-induced progenitor cell mobilisation in patients with acute ST-segment-elevation myocardial infarction and restenosis. Thromb Haemost 107:769–774
    • View reference on PubMed
    • View reference on publisher's website
  38. Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN et al (2009) Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg 111:171–180
    • View reference on PubMed
    • View reference on publisher's website
  39. Yip HK, Tsai TH, Lin HS, Chen SF, Sun CK, Leu S et al (2011) Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke. Crit Care 15:R40
    • View reference on PubMed
    • View reference on publisher's website
  40. Kang HJ, Yoon EJ, Lee EJ, Kim MK, Seo JW, Park KW et al (2012) Co-treatment with darbepoetin and granulocyte-colony stimulating factor is efficient to recruit pro-angiogenic cell populations in patients with acute myocardial infarction. Cell Transplant 21:1055–1061
    • View reference on PubMed
    • View reference on publisher's website
  41. Ludman AJ, Yellon DM, Hasleton J, Ariti C, Babu GG, Boston-Griffiths E et al (2011) Effect of erythropoietin as an adjunct to primary percutaneous coronary intervention: a randomised controlled clinical trial. Heart 97:1560–1565
    • View reference on PubMed
    • View reference on publisher's website
  42. Ahmed YA, El Beih EAS, El Moneim AA, El Oteify MA, Ashmawe MM, Thabet N et al (2001) Effect of blood transfusion versus erythropoietin injection on peripheral erythropoietin response in burnt patients. Assiut Med J 25:97–110
  43. El Atroush H, Effat H, El Ghawaby H, Samer N, Mechail S, El Sherif A et al (2005) Efficacy of recombinant human erythropoietin in critically ill anaemic septic patients. Med J Cairo Univ 37:85–95
  44. Ahmed YA, Eloteify MA, Ashmawe MM, El Beih EA, Elmonem AA, Thabet N et al (2000) Effect of blood transfusion versus erythropoietin injection on peripheral erythropoietic response in burnt patients. Vox Sang 79:P164
  45. Effat HS (2010) Efficacy of recombinant human erythropoietin in critically ill anaemic septic patients. Intensive Care Med 36:S406
  46. Alibai E, Zand F, Rahimi A (2010) Erythropoietin plus methylprednisolone or methylprednisolone in the treatment of acute spinal cord injury: a preliminary report [Abstract]. Crit Care Med 38:A209
    • View reference on publisher's website
  47. Brophy GM, Harpe S, Pyles M (2007) Critically ill patients with multiple comorbidities are more likely to receive an erythropoiesis stimulating agent in clinical practice [Abstract]. Crit Care Med 35:A119
    • View reference on publisher's website
  48. Gerasimov LV, Samorukov VY, Moroz VV, Ivanova GP (2012) Use of epoetin alfa in trauma patients. General Reanimatol 5:11–18 (Russian)
  49. Kashkouli MB, Pakdel F, Sanjari MS, Haghighi A, Nojomi M, Homaee MH et al (2011) Erythropoietin: a novel treatment for traumatic optic neuropathy - A pilot study. Graefes Arch Clin Exp Ophthalmol 249:731–736
    • View reference on PubMed
    • View reference on publisher's website
  50. Gerasimov LV, Moroz VV, Samorukov VJ, Bobrinskaya IG, Ivanova GP (2011) Use of epoetin alfa in trauma patients. Transfus Altern Transfus Med 12(1):33
  51. Gabriel A, Kozek S, Chiari A, Fitzgerald R, Grabner C, Geissler K et al (1998) High-dose recombinant human erythropoietin stimulates reticulocyte production in patients with multiple organ dysfunction syndrome. J Trauma 44:361–367
    • View reference on PubMed
    • View reference on publisher's website
  52. Georgopoulos D, Matamis D, Routsi C, Michalopoulos A, Maggina N, Dimopoulos G et al (2005) Recombinant human erythropoietin therapy in critically ill patients: a dose-response study [ISRCTN48523317]. Crit Care 9:R508–R515
    • View reference on PubMed
    • View reference on publisher's website
  53. Kateros K, Sakellariou VI, Sofianos IP, Papagelopoulos PJ (2010) Epoetin alfa reduces blood transfusion requirements in patients with intertrochanteric fracture. J Crit Care 25:348–353
    • View reference on PubMed
    • View reference on publisher's website
  54. Prunier F, Biere L, Gilard M, Boschat J, Mouquet F, Bauchart JJ et al (2012) Single high-dose erythropoietin administration immediately after reperfusion in patients with ST-segment elevation myocardial infarction: results of the erythropoietin in myocardial infarction trial. Am Heart J 163:200–207
    • View reference on PubMed
    • View reference on publisher's website
  55. Suh JW, Chung WY, Kim YS, Kim KI, Jeon EJ, Cho YS et al (2011) The effect of intravenous administration of erythropoietin on the infarct size in primary percutaneous coronary intervention. Int J Cardiol 149:216–220
    • View reference on PubMed
    • View reference on publisher's website
  56. Taniguchi N, Nakamura T, Sawada T, Matsubara K, Furukawa K, Hadase M et al (2010) Erythropoietin prevention trial of coronary restenosis and cardiac remodeling after ST-elevated acute myocardial infarction (EPOC-AMI): a pilot, randomized, placebo-controlled study. Circ J 74:2365–2371
    • View reference on PubMed
    • View reference on publisher's website
  57. van Iperen CE, Gaillard CA, Kraaijenhagen RJ, Braam BG, Marx JJ, van de Wiel A (2000) Response of erythropoiesis and iron metabolism to recombinant human erythropoietin in intensive care unit patients. Crit Care Med 28:2773–2778
    • View reference on PubMed
    • View reference on publisher's website
  58. Voors AA, Belonje AM, Zijlstra F, Hillege HL, Anker SD, Slart RH et al (2010) A single dose of erythropoietin in ST-elevation myocardial infarction. Eur Heart J 31:2593–2600
    • View reference on PubMed
    • View reference on publisher's website
  59. Chicella MF, Jansen P, Falkos S, Krueger KP (2003) Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin administration to reduce red blood cell transfusions in anemic pediatric intensive care patients. Pharmacotherapy 23:407–408
  60. Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S et al (2007) Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 357:965–976
    • View reference on PubMed
    • View reference on publisher's website
  61. Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Shapiro MJ et al (2002) Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 288:2827–2835
    • View reference on PubMed
    • View reference on publisher's website
  62. Corwin HL, Gettinger A, Rodriguez RM, Pearl RG, Gubler KD, Enny C et al (1999) Efficacy of recombinant human erythropoietin in the critically ill patient: a randomized, double-blind, placebo-controlled trial. Crit Care Med 27:2346–2350
    • View reference on PubMed
    • View reference on publisher's website
  63. Endre ZH, Walker RJ, Pickering JW, Shaw GM, Frampton CM, Henderson SJ et al (2010) Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial). Kidney Int 77:1020–1030
    • View reference on PubMed
    • View reference on publisher's website
  64. Silver M, Corwin MJ, Bazan A, Gettinger A, Enny C, Corwin HL (2006) Efficacy of recombinant human erythropoietin in critically ill patients admitted to a long-term acute care facility: a randomized, double-blind, placebo-controlled trial. Crit Care Med 34:2310–2316
    • View reference on PubMed
    • View reference on publisher's website
  65. Vincent JL, Spapen HD, Creteur J, Piagnerelli M, Hubloue I, Diltoer M et al (2006) Pharmacokinetics and pharmacodynamics of once-weekly subcutaneous epoetin alfa in critically ill patients: results of a randomized, double-blind, placebo-controlled trial. Crit Care Med 34:1661–1667
    • View reference on PubMed
    • View reference on publisher's website
  66. Najjar SS, Rao SV, Melloni C, Raman SV, Povsic TJ, Melton L et al (2011) Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial. JAMA 305:1863–1872
    • View reference on PubMed
    • View reference on publisher's website
  67. Ott I, Schulz S, Mehilli J, Fichtner S, Hadamitzky M, Hoppe K et al (2010) Erythropoietin in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomized, double-blind trial. Circ Cardiovasc Interv 3:408–413
    • View reference on PubMed
    • View reference on publisher's website
  68. Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K et al (2009) Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 40:e647–e656
    • View reference on PubMed
    • View reference on publisher's website
  69. Luchette FA, Pasquale MD, Fabian TC, Langholff WK, Wolfson M (2012) A randomized, double-blind, placebo-controlled study to assess the effect of recombinant human erythropoietin on functional outcomes in anemic, critically ill, trauma subjects: the long term trauma outcomes study. Am J Surg 203:508–516
    • View reference on PubMed
    • View reference on publisher's website
  70. Mattich J, Krupp S, Chiolero R, Pannatier A (1993) Erythropoietin therapy in burns: a pilot study. Eur J Plast Surg 16:298–302
    • View reference on publisher's website
  71. Still JM Jr, Belcher K, Law EJ, Thompson W, Jordan M, Lewis M et al (1995) A double-blinded prospective evaluation of recombinant human erythropoietin in acutely burned patients. J Trauma 38:233–236
    • View reference on PubMed
    • View reference on publisher's website
  72. Bush SE, Hampp C, Lottenberg L, LeClaire A (2008) Erythropoiesis-stimulating agent exposure and incidence of venous thromboembolism in high-risk trauma patients receiving enoxaparin [Abstract]. Crit Care Med 36:A51
  73. Kane-Gill SL, Castelli EE, Kirisci L, Rice TL, Fink MP (2007) Effectiveness study of rHuEPO in the ICU [Abstract]. Crit Care Shock 10:53–62
  74. Luh VW, Barlev A, Kern J (2005) Effectiveness of epoetin alfa in reducing the number of blood transfusions in critically ill SICU patients [Abstract]. Value Health 8:281
    • View reference on publisher's website
  75. Shuman C, Jefferson C, Ruppelt S, Erowele G (2009) Efficacy of darbepoetin alfa in reducing red blood cell transfusions in critically ill patients: a retrospective analysis [Abstract]. Crit Care Med 37:A409
  76. Wittbrodt E, Rodriguez F, Medendorp J III, Sherman M (2005) Comparison of selected utilization variables in critically ill patients with anemia who received weekly recombinant human crythropoietin (rHuEPO) or no rHuEPO [Abstract]. Pharmacotherapy 25:1441
    • View reference on publisher's website
  77. Ginger M, Toevs C, Carol G, Capella J, Philp A, Putnam AT et al (2008) Does epoetin alfa decrease mortality in the critically ill trauma population? [Abstract]. Crit Care Med 36:A52
    • View reference on publisher's website
  78. Hecht KA, Fan J, Lee TB, Decerbo MC, Kuhls DA (2007) Risk of venous thromboembolisms in trauma patients receiving erythropoiesis stimulating agents [Abstract]. Crit Care Med 35:A64
    • View reference on publisher's website
  79. Talving P, Lustenberger T, Kobayashi L, Inaba K, Barmparas G, Schnuriger B et al (2010) Erythropoiesis stimulating agent administration improves survival after severe traumatic brain injury: a matched case control study. Ann Surg 251:1–4
    • View reference on PubMed
    • View reference on publisher's website
  80. Cariou A, Claessens YE, Pene F, Marx JS, Spaulding C, Hababou C et al (2008) Early high-dose erythropoietin therapy and hypothermia after out-of-hospital cardiac arrest: a matched control study [Abstract]. Resuscitation 76:397–404
    • View reference on PubMed
    • View reference on publisher's website
  81. Grmec S, Strnad M, Kupnik D, Sinkovic A, Gazmuri RJ (2009) Erythropoietin facilitates the return of spontaneous circulation and survival in victims of out-of-hospital cardiac arrest. Resuscitation 80:631–637
    • View reference on PubMed
    • View reference on publisher's website
  82. Lundy JB, Hetz K, Chung KK, Renz EM, White CE, King BT et al (2010) Outcomes with the use of recombinant human erythropoietin in critically ill burn patients. Am Surg 76:951–956
    • View reference on PubMed
  83. Warn DE, Thompson SG, Spiegelhalter DJ (2002) Bayesian random effects meta-analysis of trials with binary outcomes: methods for the absolute risk difference and relative risk scales. Stat Med 21:1601–1623
    • View reference on PubMed
    • View reference on publisher's website
  84. Napolitano LM, Fabian TC, Kelly KM, Bailey JA, Block EF, Langholff W et al (2008) Improved survival of critically ill trauma patients treated with recombinant human erythropoietin. J Trauma 65:285–297 (discussion 297–289)
    • View reference on PubMed
    • View reference on publisher's website
  85. Cody J, Daly C, Campbell M, Donaldson C, Khan I, Rabindranath K, et al. (2005) Recombinant human erythropoietin for chronic renal failure anaemia in pre-dialysis patients. Cochrane Database Syst Rev, CD003266
  86. Ngo K, Kotecha D, Walters JA, Manzano L, Palazzuoli A, van Veldhuisen DJ, et al. (2010) Erythropoiesis-stimulating agents for anaemia in chronic heart failure patients. Cochrane Database Syst Rev, CD007613
  87. Ribatti D (2012) Angiogenic effects of erythropoietin. Int Rev Cell Mol Biol 299:199–234
    • View reference on PubMed
    • View reference on publisher's website
  88. Chui BK, Pannu N, Hazel M, Dong J, Tonelli M, Klarenbach SW (2012) Economic analysis of epoetin alfa in critically ill trauma patients. J Trauma Acute Care Surg 73:195–201
    • View reference on PubMed
    • View reference on publisher's website
  89. Jelkmann W (2012) Biosimilar recombinant human erythropoietins (“epoetins”) and future erythropoiesis-stimulating treatments. Expert Opin Biol Ther 12:581–592
    • View reference on PubMed
    • View reference on publisher's website
  90. Misra A (2010) Are biosimilars really generics? Expert Opin Biol Ther 10:489–494
    • View reference on PubMed
    • View reference on publisher's website
  91. Golder S, Loke YK (2008) Is there evidence for biased reporting of published adverse effects data in pharmaceutical industry-funded studies? Br J Clin Pharmacol 66:767–773
    • View reference on PubMed
    • View reference on publisher's website
  92. Kesselheim AS, Wang B, Studdert DM, Avorn J (2012) Conflict of interest reporting by authors involved in promotion of off-label drug use: an analysis of journal disclosures. PLoS Med 9:e1001280
    • View reference on PubMed
    • View reference on publisher's website

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