Skip to main content
SpringerLink
Log in

Erythropoiesis Stimulating Agents in Heart Failure Patients with Anemia: A Meta-Analysis

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Background

Anemia is prevalent in patients with heart failure and an independent prognostic sign of poor outcome. The current report is a meta-analysis of published clinical trials assessing the use of erythropoeisis stimulating agents (ESA) in heart failure (HF) patients with anemia.

Methods

Literature and Medline search was performed to identify studies with control groups (case-control, cohort or randomized controlled trials) that examined the effect of ESA therapy in patients with HF and anemia.

Results

Seven prospective controlled trials met inclusion criteria (n = 663 subjects). The ESA studied was darbepoetin in 4 trials and erythropoietin in 3 trials. Mean follow up period ranged from 12 to 27 weeks. Compared to placebo ESA therapy was associated with improvement in six cardiovascular parameters assessed by at least three of the analyzed trials, including increase in hemoglobin levels 2.35(95% confidence interval [Cl], 1.76–2.93, P < 0.00001), increase in exercise duration 0.91(95% Cl, 0.08–1.73, P = 0.03), improvement in New York Heart Association functional class −1.46(95% Cl, −2.32 to −0.60, P = 0.0009), improvement in 6-minute walk test 1.42(95% Cl, 0.31–2.54, P = 0.01), decrease in B-type natriuretic peptide −0.54(95% Cl, −1.03 to −0.06, P = 0.03), and improvement in peak oxygen consumption 0.93(95% Cl, 0.52–1.34, P < 0.00001).

Conclusion

In patients with heart failure and anemia, erythropoiesis stimulating agent therapy appears to have a positive effect on several important cardiovascular parameters, compared to control therapy. Large prospective randomized controlled trials are warranted to comprehensively evaluate the potential effects of erythropoiesis stimulating agents on clinical outcomes in heart failure patients with anemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Anand I, McMurray JJ, Whitmore J, Warren M, Pham A, McCamish MA, et al. Anemia and its relationship to clinical outcome in heart failure. Circulation. 2004;110:149–54.

    Article  PubMed  Google Scholar 

  2. Maggioni AP, Opasich C, Anand I, Barlera S, Carbonieri E, Gonzini L, et al. Anemia in patients with heart failure: prevalence and prognostic role in a controlled trial and in clinical practice. J Card Fail. 2005;11:91–8.

    Article  PubMed  Google Scholar 

  3. Kosiborod M, Curtis JP, Wang Y, Smith GL, Masoudi FA, Foody JM, et al. Anemia and outcomes in patients with heart failure: a study from the National Heart Care Project. Arch Intern Med. 2005;165:2237–44.

    Article  PubMed  Google Scholar 

  4. Go AS, Yang J, Ackerson LM, Lepper K, Robbins S, Massie BM, et al. Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) study. Circulation. 2006;113:2713–23.

    Article  CAS  PubMed  Google Scholar 

  5. Adams KF Jr, Patterson JH, Oren RM, Mehra MR, O’Connor CM, Pina IL, et al. STAMINA-HFP registry investigators. Prospective assessment of concurrence of anemia in patients with heart failure: results from the Study of Anemia in Heart Failure Populations (STAMINA-HFP) registry. Am Heart J. 2009;157:926–32.

    Article  PubMed  Google Scholar 

  6. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure. Circulation. 2003;107:223–5.

    Article  PubMed  Google Scholar 

  7. Silverberg DS, Wexler D, Blum M, Keren G, Sheps D, Leibovitch E, et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000;35:1737–44.

    Article  CAS  PubMed  Google Scholar 

  8. Opasich C, Cazzola M, Scelsi L, De Feo S, Bosimini E, Lagioia R, et al. Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure. Eur Heart J. 2005;26:2232–7.

    Article  CAS  PubMed  Google Scholar 

  9. van der Meer P, Voors AA, Lipsic E, Smilde TD, van Gilst WH, van Veldhuisen DJ. Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure. J Am Coll Cardiol. 2004;44:63–7.

    Article  PubMed  Google Scholar 

  10. van der Meer P, Lok DJ, Januzzi JL, de la Porte PW Bruggink-Andre, Lipzic E, van Wijngaarden J, et al. Adequacy of endogenous erythropoietin levels and mortality in anemic heart failure patients. Eur Heart J. 2008;29:1510–5.

    Article  PubMed  Google Scholar 

  11. Groenveld HF, Januzzi JL, Damman K, van Wijngaarden J, Hillege HL, van Veldhuisen DJ, et al. Anemia and mortality in heart failure patients a systematic review and metaanalysis. J Am Coll Cardiol. 2008;52:818–27.

    Article  PubMed  Google Scholar 

  12. Anand IS. Anemia and chronic heart failure implications and treatment options. J Am Coll Cardiol. 2008;52:501–11.

    Article  PubMed  Google Scholar 

  13. Radford MJ, Arnold JM, Bennett SJ, Cinquegrani MP, Cleland JG, Havranek EP, et al. ACC/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with chronic heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Heart Failure Clinical Data Standards): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Failure Society of America. Circulation. 2005;112:1888–916.

    Article  PubMed  Google Scholar 

  14. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–12.

    Article  CAS  PubMed  Google Scholar 

  15. Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001;20:21–35.

    Article  CAS  PubMed  Google Scholar 

  16. Silverberg DS, Wexler D, Sheps D, Blum M, Keren G, Baruch R, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol. 2001;37:1775–80.

    Article  CAS  PubMed  Google Scholar 

  17. Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation. 2003;107:294–9.

    Article  CAS  PubMed  Google Scholar 

  18. Palazzuoli A, Silverberg DS, Iovine F, et al. Effects of betaerythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome. Am Heart J. 2007;154:645e9–15.

    Article  Google Scholar 

  19. Ponikowski P, Anker SD, Szachniewicz J, et al. Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double blind, placebo-controlled trial. J Am Coll Cardiol. 2007;49:753–62.

    Article  CAS  PubMed  Google Scholar 

  20. van Veldhuisen DJ, Dickstein K, Cohen-Solal A, et al. Randomized, double-blind, placebo controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J. 2007;28:2208–16.

    Article  PubMed  Google Scholar 

  21. Ghali JK, Anand IS, Abraham WT, et al. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 2008;117:526–35.

    Article  CAS  PubMed  Google Scholar 

  22. Parissis JT, Kourea K, Panou F, Farmakis D, Paraskevaidis I, Ikonomidis I, et al. Effects of darbepoetin alpha on right and left ventricular systolic and diastolic function in anemic patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am Heart J. 2008;155:751.e1–7.

    Article  Google Scholar 

  23. Al-Ahmad A, Rand WM, Manjunath G, Konstam MA, Salem DN, Levey AS, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;38:955–62.

    Article  CAS  PubMed  Google Scholar 

  24. O’Meara E, Clayton T, McEntegart MB, McMurray JJ, Lang CC, Roger SD, et al. Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program. Circulation. 2006;113:986–94.

    Article  PubMed  Google Scholar 

  25. Anand IS, Kuskowski MA, Rector TS, Florea VG, Glazer RD, Hester A, et al. Anemia and change in hemoglobin over time related to mortality and morbidity in patients with chronic heart failure: results from Val-HeFT. Circulation. 2005;112:1121–7.

    Article  CAS  PubMed  Google Scholar 

  26. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol. 2002;39:1780–6.

    Article  PubMed  Google Scholar 

  27. Levy WC. Anemia in Heart Failure: Marker or Mediator of Adverse Prognosis? J Am Coll Cardiol. 2008;51:577–8.

    Article  PubMed  Google Scholar 

  28. National Kidney Foundation Kidney Disease Outcomes Quality Initiative. KDOQI clinical practice guideline and clinical practice recommendations for anemia and chronic kidney disease: 2007 update of hemoglobin target. Available at http://www.kidney.org/professionals/KDOQI/. Accessed December 1. 2008.

  29. Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–84.

    Article  PubMed  Google Scholar 

  30. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–98.

    Article  CAS  PubMed  Google Scholar 

  31. Roth D, Smith RD, Schulman G, Steinman TI, Hatch FE, Rudnick MR, et al. Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients. Am J Kidney Dis. 1994;24:777–84.

    CAS  PubMed  Google Scholar 

  32. Kleinman KS, Schweitzer SU, Perdue ST, Bleifer KH, Abels RI. The use of recombinant human erythropoietin in the correction of anemia in predialysis patients and its effect on renal function: a double-blind, placebo-controlled trial. Am J Kidney Dis. 1989;14:486–95.

    CAS  PubMed  Google Scholar 

  33. van Veldhuisen DJ, McMurray JJ, RED-HF Executive Committee. Are erythropoietin stimulating proteins safe and efficacious in heart failure? Why we need an adequately powered randomised outcome trial. Eur J Heart Fail. 2007;9:110–2.

    Article  PubMed  Google Scholar 

  34. Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P, et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci USA. 2003;100:4802–6.

    Article  CAS  PubMed  Google Scholar 

  35. van der Meer P, Lipsic E, Henning RH, Boddeus K, van der Velden J, Voors AA, et al. Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol. 2005;46:125–33.

    Article  PubMed  Google Scholar 

  36. van der Meer P, Lipsic E. Erythropoietin: repair of the failing heart. J Am Coll Cardiol. 2006;48:185–6.

    Article  PubMed  Google Scholar 

  37. Demetri GD. Anaemia and its functional consequences in cancer patients: current challenges in management and prospects for improving therapy. Br J Cancer. 2001;84:31–7.

    Article  CAS  PubMed  Google Scholar 

  38. Bolger AP, Bartlett FR, Penston HS, O’Leary J, Pollock N, Kaprielian R, et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol. 2006;48:1225–7.

    Article  CAS  PubMed  Google Scholar 

  39. Toblli JE, Lombrana A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol. 2007;50:1657–65.

    Article  CAS  PubMed  Google Scholar 

  40. Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Roughton M, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol. 2008;51:103–12.

    Article  CAS  PubMed  Google Scholar 

  41. Van der Meer P, Groenveld H, Januzzi JL, Van Veldhuisen DJ. Erythropoietin treatment in patients with chronic heart failure: a meta-analysis. Heart. 2009 Jan 23. [Epub ahead of print].

  42. Catlin DH, Breidbach A, Elliott S, Glaspy J. Comparison of the isoelectric focusing patterns of darbepoetin alfa, recombinant human erythropoietin, and endogenous erythropoietin from human urine. Clin Chem. 2002;48:2057–9.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, #5534, Los Angeles, CA, 90048, USA

    Faramarz Tehrani, Pavittarpaul Dhesi, Daniel Daneshvar, Anita Phan, Asim Rafique, Robert J. Siegel & Bojan Cercek

Authors
  1. Faramarz Tehrani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pavittarpaul Dhesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel Daneshvar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anita Phan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Asim Rafique
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert J. Siegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bojan Cercek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Faramarz Tehrani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tehrani, F., Dhesi, P., Daneshvar, D. et al. Erythropoiesis Stimulating Agents in Heart Failure Patients with Anemia: A Meta-Analysis. Cardiovasc Drugs Ther 23, 511–518 (2009). https://doi.org/10.1007/s10557-009-6203-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-009-6203-6

Key words

Search

Navigation