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The Role of Treatment for Anemia as a Therapeutic Target in the Management of Chronic Heart Failure: Insights After RED-HF

  • Heart Failure (W Tang, Section Editor)
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Anemia is common in patients with heart failure (HF) and appears to be closely linked with HF prognosis. A variety of mechanisms have been implicated in the association between anemia and HF, and treatment of anemia as a therapeutic target in HF patients is gaining increased attention. Recently large randomized controlled trials of erythropoietin-stimulating agents (ESA) and intravenous iron supplementation therapy have been completed and shed light on treatment of anemia in HF patients. ESA therapy did not show improvement in clinical outcomes, but intravenous iron supplementation may be of benefit in improving HF symptoms. Anemia has been commonly reported in patients with chronic heart failure (HF) and its prevalence appears to be closely linked with the severity of HF. Furthermore, the presence of anemia in patients with HF has been consistently associated with poor prognosis. Despite an increasing number of studies evaluating the relationship between HF and anemia, the answer to whether anemia is simply a marker or a mediator of poor prognosis in HF patients remains uncertain. One approach to this pivotal question has been to investigate treatment for anemia as a therapeutic target in HF.

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  1. Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood. 2006;107:1747–50.

    Article  CAS  PubMed  Google Scholar 

  2. Felker GM, Adams Jr KF, Gattis WA, O’Connor CM. Anemia as a risk factor and therapeutic target in heart failure. J Am Coll Cardiol. 2004;44:959–66.

    Article  PubMed  Google Scholar 

  3. Silverberg DS, Wexler D, Blum M, 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 

  4. 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 

  5. Androne AS, Katz SD, Lund L, et al. Hemodilution is common in patients with advanced heart failure. Circulation. 2003;107:226–9.

    Article  PubMed  Google Scholar 

  6. Horwich TB, Fonarow GC, Hamilton MA, et al. 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 

  7. Al-Ahmad A, Rand WM, Manjunath G, 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 

  8. Kosiborod M, Smith GL, Radford MJ, et al. The prognostic importance of anemia in patients with heart failure. Am J Med. 2003;114:112–9.

    Article  PubMed  Google Scholar 

  9. Groenveld HF, Januzzi JL, Damman K, et al. Anemia and mortality in heart failure patients a systematic review and meta-analysis. J Am Coll Cardiol. 2008;52:818–27. A meta-analysis of 153,180 patients that established anemia as an independent predictor of HF prognosis. With its large sample size, investigators were able to thoroughly adjust for co-morbidities that could affect HF prognosis.

    Article  PubMed  Google Scholar 

  10. Allen LA, Anstrom KJ, Horton JR, et al. Relationship between anemia and health care costs in heart failure. J Card Fail. 2009;15:843–9.

    Article  PubMed  Google Scholar 

  11. Reed SD, Li Y, Ellis SJ, et al. Associations between hemoglobin level, resource use, and medical costs in patients with heart failure: findings from HF-ACTION. J Card Fail. 2012;18:784–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–23.

    Article  CAS  PubMed  Google Scholar 

  13. Torre-Amione G, Kapadia S, Benedict C, et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol. 1996;27:1201–6.

    Article  CAS  PubMed  Google Scholar 

  14. Deswal A, Petersen NJ, Feldman AM, et al. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation. 2001;103:2055–9.

    Article  CAS  PubMed  Google Scholar 

  15. Anand IS, Latini R, Florea VG, et al. C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation. 2005;112:1428–34.

    Article  CAS  PubMed  Google Scholar 

  16. Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res. 1998;18:555–9.

    Article  CAS  PubMed  Google Scholar 

  17. Macdougall IC, Cooper AC. Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol Dial Transplant. 2002;17 Suppl 11:39–43.

    Article  CAS  PubMed  Google Scholar 

  18. Divakaran V, Mehta S, Yao D, et al. Hepcidin in anemia of chronic heart failure. Am J Hematol. 2011;86:107–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Matsumoto M, Tsujino T, Lee-Kawabata M, et al. Iron regulatory hormone hepcidin decreases in chronic heart failure patients with anemia. Circ J. 2010;74:301–6. Anemia in HF used to be thought of as the same disease as anemia in chronic disease until the difference in hepcidin levels between the two disease processes suggested that they may arise from separate pathogeneses. This was one of the major studies that showed this difference.

    Article  CAS  PubMed  Google Scholar 

  20. Adlbrecht C, Kommata S, Hulsmann M, et al. Chronic heart failure leads to an expanded plasma volume and pseudoanaemia, but does not lead to a reduction in the body’s red cell volume. Eur Heart J. 2008;29:2343–50.

    Article  PubMed  Google Scholar 

  21. Plata R, Cornejo A, Arratia C, et al. Angiotensin-converting-enzyme inhibition therapy in altitude polycythaemia: a prospective randomised trial. Lancet. 2002;359:663–6.

    Article  CAS  PubMed  Google Scholar 

  22. Ishani A, Weinhandl E, Zhao Z, et al. Angiotensin-converting enzyme inhibitor as a risk factor for the development of anemia, and the impact of incident anemia on mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2005;45:391–9.

    Article  CAS  PubMed  Google Scholar 

  23. van der Meer P, Lipsic E, Westenbrink BD, et al. Levels of hematopoiesis inhibitor N-acetyl-seryl-aspartyl-lysyl-proline partially explain the occurrence of anemia in heart failure. Circulation. 2005;112:1743–7.

    Article  PubMed  Google Scholar 

  24. Witte KK, Desilva R, Chattopadhyay S, et al. Are hematinic deficiencies the cause of anemia in chronic heart failure? Am Heart J. 2004;147:924–30.

    Article  PubMed  Google Scholar 

  25. Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J. 2010;31:1872–80.

    Article  CAS  PubMed  Google Scholar 

  26. Okonko DO, Mandal AK, Missouris CG, Poole-Wilson PA. Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. J Am Coll Cardiol. 2011;58:1241–51.

    Article  CAS  PubMed  Google Scholar 

  27. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436–48. The largest randomized controlled trial of IV iron supplementation in HF patients with iron deficiency. The study showed that IV iron improved exercise capacity, but did not evaluate hard clinical outcomes as its primary end point.

    Article  CAS  PubMed  Google Scholar 

  28. Okonko DO, Grzeslo A, Witkowski T, 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. This was a well-designed study, but limited by the small sample size. Investigators showed that IV iron improved exercise capacity and the benefit was more pronounced in anemic patients compared with non-anemic patients.

    Article  CAS  PubMed  Google Scholar 

  29. Nanas JN, Matsouka C, Karageorgopoulos D, et al. Etiology of anemia in patients with advanced heart failure. J Am Coll Cardiol. 2006;48:2485–9.

    Article  PubMed  Google Scholar 

  30. Silagy CA, McNeil JJ, Donnan GA, et al. Adverse effects of low-dose aspirin in a healthy elderly population. Clin Pharmacol Ther. 1993;54:84–9.

    Article  CAS  PubMed  Google Scholar 

  31. Parsi A, Kleber FX. Anaemia in heart failure: its diagnosis and management. Eur J Heart Fail. 2003;5:3–4.

    Article  PubMed  Google Scholar 

  32. Sandek A, Bauditz J, Swidsinski A, et al. Altered intestinal function in patients with chronic heart failure. J Am Coll Cardiol. 2007;50:1561–9.

    Article  CAS  PubMed  Google Scholar 

  33. Volpe M, Tritto C, Testa U, et al. Blood levels of erythropoietin in congestive heart failure and correlation with clinical, hemodynamic, and hormonal profiles. Am J Cardiol. 1994;74:468–73.

    Article  CAS  PubMed  Google Scholar 

  34. Anand IS, Ferrari R, Kalra GS, et al. Edema of cardiac origin. Studies of body water and sodium, renal function, hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Circulation. 1989;80:299–305.

    Article  CAS  PubMed  Google Scholar 

  35. McClellan WM, Flanders WD, Langston RD, et al. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol. 2002;13:1928–36.

    Article  PubMed  Google Scholar 

  36. Belonje AM, Voors AA, van der Meer P, et al. Endogenous erythropoietin and outcome in heart failure. Circulation. 2010;121:245–51.

    Article  CAS  PubMed  Google Scholar 

  37. Opasich C, Cazzola M, Scelsi L, 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 

  38. George J, Patal S, Wexler D, et al. Circulating erythropoietin levels and prognosis in patients with congestive heart failure: comparison with neurohormonal and inflammatory markers. Arch Intern Med. 2005;165:1304–9.

    Article  CAS  PubMed  Google Scholar 

  39. van der Meer P, Voors AA, Lipsic E, et al. 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 

  40. Asaumi Y, Kagaya Y, Takeda M, et al. Protective role of endogenous erythropoietin system in nonhematopoietic cells against pressure overload-induced left ventricular dysfunction in mice. Circulation. 2007;115:2022–32.

    Article  CAS  PubMed  Google Scholar 

  41. Nakano M, Satoh K, Fukumoto Y, et al. Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res. 2007;100:662–9.

    Article  CAS  PubMed  Google Scholar 

  42. Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA. 1998;279:217–21.

    Article  CAS  PubMed  Google Scholar 

  43. Brannon ES, Merrill AJ, Warren JV, Stead EA. The cardiac output in patients with chronic anemia as measured by the technique of right atrial catheterization. J Clin Invest. 1945;24:332–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Oski FA, Marshall BE, Cohen PJ, et al. The role of the left-shifted or right-shifted oxygen-hemoglobin equilibrium curve. Ann Intern Med. 1971;74:44–6.

    Article  CAS  PubMed  Google Scholar 

  45. Schmidt W, Boning D, Braumann KM. Red cell age effects on metabolism and oxygen affinity in humans. Respir Physiol. 1987;68:215–25.

    Article  CAS  PubMed  Google Scholar 

  46. Anand IS, Chandrashekhar Y, Wander GS, Chawla LS. Endothelium-derived relaxing factor is important in mediating the high output state in chronic severe anemia. J Am Coll Cardiol. 1995;25:1402–7.

    Article  CAS  PubMed  Google Scholar 

  47. Anand IS, Chandrashekhar Y, Ferrari R, et al. Pathogenesis of oedema in chronic severe anaemia: studies of body water and sodium, renal function, haemodynamic variables, and plasma hormones. Br Heart J. 1993;70:357–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Datta BN, Silver MD. Cardiomegaly in chronic anemia in ratsman experimental study including ultrastructural, histometric, and stereologic observations. Lab Investig J Tech Methods Pathol. 1975;32:503–14.

    CAS  Google Scholar 

  49. Tang WH, Tong W, Jain A, et al. Evaluation and long-term prognosis of new-onset, transient, and persistent anemia in ambulatory patients with chronic heart failure. J Am Coll Cardiol. 2008;51:569–76.

    Article  PubMed  Google Scholar 

  50. Silverberg DS, Wexler D, Sheps D, 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 

  51. Mancini DM, Katz SD, Lang CC, et al. 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 

  52. Cleland JG, Sullivan JT, Ball S, et al. Once-monthly administration of darbepoetin alfa for the treatment of patients with chronic heart failure and anemia: a pharmacokinetic and pharmacodynamic investigation. J Cardiovasc Pharmacol. 2005;46:155–61.

    Article  CAS  PubMed  Google Scholar 

  53. Palazzuoli A, Silverberg D, Iovine F, et al. Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia. Am Heart J. 2006;152(1096):e9–15.

    PubMed  Google Scholar 

  54. Palazzuoli A, Silverberg DS, Iovine F, et al. Effects of beta-erythropoietin 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(645):e9–15.

    PubMed  Google Scholar 

  55. 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 

  56. 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 

  57. Cosyns B, Velez-Roa S, Droogmans S, et al. Effects of eythropoietin administration on mitral regurgitation and left ventricular remodeling in heart failure patients. Int J Cardiol. 2010;138:306–7.

    Article  PubMed  Google Scholar 

  58. 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 

  59. Kourea K, Parissis JT, Farmakis D, et al. Effects of darbepoetin-alpha on quality of life and emotional stress in anemic patients with chronic heart failure. Eur J Cardiovasc Prev Rehabil. 2008;15:365–9.

    Article  PubMed  Google Scholar 

  60. Parissis JT, Kourea K, Panou F, 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.

    PubMed  Google Scholar 

  61. Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013;368:1210–9. The largest randomized controlled trial of ESA and the only one to be adequately powered to evaluate the role of ESA in HF patients with anemia. This study is also the only study of its kind that used hard clinical outcomes as its primary end point. In this study, ESA was not beneficial in patients with HF and anemia.

    Article  CAS  PubMed  Google Scholar 

  62. Kotecha D, Ngo K, Walters JA, et al. Erythropoietin as a treatment of anemia in heart failure: systematic review of randomized trials. Am Heart J. 2011;161:822–31. e2.

    Article  CAS  PubMed  Google Scholar 

  63. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019–32.

    Article  PubMed  Google Scholar 

  64. Alleyne M, Horne MK, Miller JL. Individualized treatment for iron-deficiency anemia in adults. Am J Med. 2008;121:943–8.

    Article  PubMed Central  PubMed  Google Scholar 

  65. Kruske SG, Ruben AR, Brewster DR. An iron treatment trial in an aboriginal community: improving non-adherence. J Paediatr Child Health. 1999;35:153–8.

    Article  CAS  PubMed  Google Scholar 

  66. Auerbach M, Ballard H. Clinical use of intravenous iron: administration, efficacy, and safety. Hematol Educ Program Am Soc Hematol Am Soc Hematol Educ Program. 2010;2010:338–47.

    Article  Google Scholar 

  67. Bolger AP, Bartlett FR, Penston HS, 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 

  68. Comin-Colet J, Ruiz S, Cladellas M, et al. A pilot evaluation of the long-term effect of combined therapy with intravenous iron sucrose and erythropoietin in elderly patients with advanced chronic heart failure and cardio-renal anemia syndrome: influence on neurohormonal activation and clinical outcomes. J Card Fail. 2009;15:727–35.

    Article  CAS  PubMed  Google Scholar 

  69. Usmanov RI, Zueva EB, Silverberg DS, Shaked M. Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency. J Nephrol. 2008;21:236–42.

    CAS  PubMed  Google Scholar 

  70. 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 

  71. Beck-da-Silva L, Piardi D, Soder S et al. IRON-HF study: A randomized trial to assess the effects of iron in heart failure patients with anemia. Int J Cardiol 2013, In press.

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Dr. Hanna K. Gaggin is supported in part by the Ruth and James Clark Fund for Cardiac Research Innovation.

Dr. G. William Dec declares no potential conflicts of interest relevant to this article.

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  1. Cardiology Division, Massachusetts General Hospital, Yawkey 5B, 55 Fruit Street, Boston, MA, 02114, USA

    Hanna K. Gaggin MD, MPH & G. William Dec MD

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  1. Hanna K. Gaggin MD, MPH
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Correspondence to Hanna K. Gaggin MD, MPH.

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This article is part of the Topical Collection on Heart Failure

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Gaggin, H.K., Dec, G.W. The Role of Treatment for Anemia as a Therapeutic Target in the Management of Chronic Heart Failure: Insights After RED-HF. Curr Treat Options Cardio Med 16, 279 (2014). https://doi.org/10.1007/s11936-013-0279-9

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