The role of treatment for anemia as a therapeutic target in the management of chronic heart failure: Insights after RED-HF topical collection on heart failure

Current Treatment Options in Cardiovascular Medicine

Volumn 16, Issue 1, 2014, Pages

  Gaggin, Hanna K ^a   Dec, G William ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Anemia; Chronic heart failure; RED HF; Therapeutic target; Treatment

Indexed keywords

ANGIOTENSIN RECEPTOR ANTAGONIST; ENALAPRIL; ERYTHROPOIETIN; INTERLEUKIN 6; IRON; PLACEBO; TUMOR NECROSIS FACTOR ALPHA;

ANEMIA; ARTICLE; HEART FAILURE; HEMODILUTION; HUMAN; HYPERVOLEMIA; IRON DEFICIENCY ANEMIA; IRON THERAPY; PATHOPHYSIOLOGY; PRACTICE GUIDELINE; PREVALENCE; PROGNOSIS; RANDOMIZED CONTROLLED TRIAL (TOPIC);

EID: 84891785521     PISSN: 10928464     EISSN: 15343189     Source Type: Journal    
DOI: 10.1007/s11936-013-0279-9     Document Type: Article

References (71)

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.
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.
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.
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.
5. Androne AS, Katz SD, Lund L, et al. Hemodilution is common in patients with advanced heart failure. Circulation. 2003;107:226-9.
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.
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.
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.
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.
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.
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.
12. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011-23.
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.
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.
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.
16. Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res. 1998;18:555-9.
17. Macdougall IC, Cooper AC. Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol Dial Transplant. 2002;17 Suppl 11:39-43.
18. Divakaran V, Mehta S, Yao D, et al. Hepcidin in anemia of chronic heart failure. Am J Hematol. 2011;86:107-9.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
31. Parsi A, Kleber FX. Anaemia in heart failure: its diagnosis and management. Eur J Heart Fail. 2003;5:3-4.
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.
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.
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.
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.
36. Belonje AM, Voors AA, van der Meer P, et al. Endogenous erythropoietin and outcome in heart failure. Circulation. 2010;121:245-51.
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.
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.
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.
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.
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.
42. Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA. 1998;279:217-21.
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.
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.
45. Schmidt W, Boning D, Braumann KM. Red cell age effects on metabolism and oxygen affinity in humans. Respir Physiol. 1987;68:215-25.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
64. Alleyne M, Horne MK, Miller JL. Individualized treatment for iron-deficiency anemia in adults. Am J Med. 2008;121:943-8.
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.
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.
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.
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.
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.
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.
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.