11
Update on erythropoiesis-stimulating agents

https://doi.org/10.1016/j.bpa.2012.11.006Get rights and content

Erythropoiesis-stimulating agents (ESAs) have long been approved for the management of anaemia in a variety of clinical settings. Subsequently, a number of clinical trials were undertaken in which the haemoglobin end points were targeted to be maintained at normal or high-normal ranges, in an attempt to demonstrate improvements in long-term survival. For patients undergoing spine surgery, patients with cancer chemotherapy-induced anaemia and those with chronic kidney disease, adverse outcomes in these clinical trials were found, including death, thrombosis and/or cardiovascular events. Informed choice by patients for risks of ESA therapy as well as for blood transfusion should be part of the consent process for management of anaemia. Despite current regulations restricting ESA use, these agents are an effective treatment of anaemia, particularly for those who would be transfusion dependent without ESA therapy.

Section snippets

Post-approval clinical trials

Subsequent to Food and Drug Administration (FDA) approval for use of ESA to reduce allogeneic blood transfusions, a number of clinical trials were undertaken in an attempt to demonstrate long-term improved patient outcomes with ESA therapy. These trials are summarised in Table 2.12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 In elective spine surgery, blood transfusion and patient outcomes were compared for ESA and placebo-treated cohorts. These patients did not receive

Reimbursement and regulatory considerations

In July 2007, Centers for Medicare and Medicaid Services (CMS) issued a national coverage decision (NCD), restricting reimbursement for ESAs to treat chemotherapy-induced anaemia in cancer patients, only to cases in which Hgb levels prior to initiation of ESA are <10 g dl−1.46 The CMS decision was in the context of a series of revisions by the FDA on the label for ESAs,47, 48 following the clinical trials presented above, which showed increased adverse events and higher mortality in cancer

Risk management

The FDA has required that ESAs must be prescribed under a risk management programme, known as a Risk Evaluation and Mitigation Strategy (REMS), to ensure the safe use of these drugs.75 REMS programmes are in place for over 95 other pharmaceuticals, including therapies used in patients with malignancies. These programmes underscore the reality that the practice of medicine includes the use of FDA-approved medications beyond narrow specifications in the label. For ESAs, targeting and maintaining

Role of ESA therapy in cardiac surgery

An unresolved question is the safety of ESA therapy in cardiac surgery patients and its role in this setting. In a European trial,79 the authors found no differences in mortality, thrombotic events or serious adverse events among their 76 patients, whether treated with ESA or placebo, nor any differences in haemostatic parameters during the 14-day preoperative interval during which increased levels of haematocrit (from 42 ± 3% to 48 ± 3%) were demonstrated.80 In fact, the investigators were

Conclusion

Since its approval more than two decades ago, ESA therapy has expanded both on-label and off-label beyond renal failure into a variety of clinical scenarios. Although allogeneic transfusions have been reduced as a result of ESA use, debated data suggest that this therapy can result in negative outcomes for specified patient populations. As with transfusion therapy, selection of both targeted population and suitable dosing will result in appropriate use of these agents. The cost and outcome

Acknowledgement

Conflict of interest

LTG is a consultant for Amgen.

AS is a consultant for: CSL Behring King of Prussia, PA; HemoCue Madison, NJ; Masimo Corporation Irvine, CA; Vifor Pharma Ltd. Glattbrugg, Switzerland.

AS grant/research: CSL Behring King of Prussia, PA.

AS speaker with honorarium: CSL Behring King of Prussia, PA;

Masimo Corporation Irvine, CA.

Funding source

None.

References (85)

  • S. Swift et al.

    Absence of functional EpoR expression in human tumor cell lines

    Blood

    (2010)
  • A.M. Sinclair et al.

    Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells

    Blood

    (2010)
  • E.S. Xenos et al.

    Association of blood transfusion and venous thromboembolism after colorectal cancer resection

    Thromb Res

    (2012)
  • J.D. Rizzo et al.

    American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer

    Blood

    (2010)
  • B. Leyland-Jones

    Breast cancer trial with erythropoietin terminated unexpectedly

    Lancet Oncol

    (2003)
  • H.J. Alter et al.

    Emerging infectious diseases that threaten the blood supply

    Semin Hematol

    (2007)
  • L.T. Goodnough

    Transfusion triggers

    Surgery

    (2007)
  • O. Sowade et al.

    Avoidance of allogeneic blood transfusions by treatment with epoetin beta (recombinant human erythropoietin) in patients undergoing open-heart surgery

    Blood

    (1997)
  • O. Sowade et al.

    The effect of preoperative recombinant human erythropoietin therapy on platelets and hemostasis in patients undergoing cardiac surgery

    J Lab Clin Med

    (1997)
  • O. Sowade et al.

    Evaluation of oxygen availability with oxygen status algorithm in patients undergoing open heart surgery treated with epoetin beta

    J Lab Clin Med

    (1997)
  • M.N. D'Ambra et al.

    Effect of recombinant human erythropoietin on transfusion risk in coronary bypass patients

    Ann Thorac Surg

    (1997)
  • D.M. Moskowitz et al.

    Predictors of transfusion requirements for cardiac surgical procedures at a blood conservation center

    Ann Thorac Surg

    (2004)
  • J.W. Eschbach et al.

    Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial

    N Engl J Med

    (1987)
  • J.W. Eschbach et al.

    Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial

    Ann Intern Med

    (1989)
  • A. Shander et al.

    Iron overload and toxicity: the hidden risk of multiple blood transfusions

    Vox Sang

    (2009)
  • L.T. Goodnough et al.

    Erythropoietin therapy

    N Engl J Med

    (1997)
  • A. Laupacis et al.

    Erythropoietin to minimize perioperative blood transfusion: a systematic review of randomized trials. The International Study of Peri-operative Transfusion (ISPOT) Investigators

    Transfus Med

    (1998)
  • J. Glaspy et al.

    Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group

    J Clin Oncol

    (1997)
  • J. Vansteenkiste et al.

    Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy

    J Natl Cancer Inst

    (2002)
  • J. Seidenfeld et al.

    Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials

    J Natl Cancer Inst

    (2001)
  • J. Bohlius et al.

    Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients

    J Natl Cancer Inst

    (2006)
  • L.T. Goodnough et al.

    Current status of pharmacologic therapies in patient blood management

    Anesth Analg

    (2013)
  • C.P. Stowell et al.

    An open-label, randomized, parallel-group study of perioperative epoetin alfa versus standard of care for blood conservation in major elective spinal surgery: safety analysis

    Spine

    (2009)
  • A. Besarab et al.

    The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin

    N Engl J Med

    (1998)
  • A.K. Singh et al.

    Correction of anemia with epoetin alfa in chronic kidney disease

    N Engl J Med

    (2006)
  • T.B. Drueke et al.

    Normalization of hemoglobin level in patients with chronic kidney disease and anemia

    N Engl J Med

    (2006)
  • M.A. Pfeffer et al.

    A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease

    N Engl J Med

    (2009)
  • S.D. Solomon et al.

    Erythropoietic response and outcomes in kidney disease and type 2 diabetes

    N Engl J Med

    (2010)
  • E.F. Lewis et al.

    Darbepoetin alfa impact on health status in diabetes patients with kidney disease: a randomized trial

    Clin J Am Soc Nephrol

    (2011)
  • M. Hedenus et al.

    Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study

    Br J Haematol

    (2003)
  • B. Leyland-Jones et al.

    Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study

    J Clin Oncol

    (2005)
  • J. Overgaard et al.

    Randomized study of the importance of novel erythropoiesis stimulating protein (Aranesp) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): the Danish Head and Neck Cancer Group DAHANCA 10

    Eur J Cancer

    (2007)
  • Cited by (9)

    • Patient blood management

      2019, Risk Management in Transfusion Medicine
    • Clinical Utility of Reticulocyte Parameters

      2015, Clinics in Laboratory Medicine
      Citation Excerpt :

      The clinical utility of reticulocyte Hb content has been well established as a reliable marker of FID in hemodialysis patients, exhibiting high specificity and sensitivity in the management of intravenous iron therapy. Although ESA treatment has been approved for anemia in several settings outside CKD, appropriate studies still need to be performed to assess the suitability of CHr and/or percentage of Hypo-He concerning the detection of FID in other disease-related anemias, and in the reduction of ESA doses and duration of treatment.170–174 Reticulocyte Hb improves the monitoring of erythropoietic response to intravenous iron administration in ID anemia.

    • Blood Sparing Techniques

      2018, Essentials of Pediatric Neuroanesthesia
    View all citing articles on Scopus
    View full text