Management of Anemia and Iron Deficiency in Heart Failure

Valvular, Myocardial, Pericardial, and Cardiopulmonary Diseases

Opinion statement

Anemia is independently associated with an increased risk of mortality and morbidity in patients with heart failure (HF). The diagnosis of anemia should prompt assessment of the underlying cause(s), first by using routine laboratory measurements (i.e., serum creatinine and estimated glomerular filtration rate [eGFR], serum iron, transferrin saturation, ferritin, vitamin B12, folic acid, and thyroid stimulating hormone). In clinical practice, it remains unclear whether using levels of the soluble transferrin receptor in HF patients to assess iron deficiency is warranted. Further investigation should follow these simple tests when judged appropriate (e.g., if occult gastrointestinal blood losses are suspected). Hemodilution may contribute significantly to anemia in patients with advanced HF and may be suspected when signs of hypervolemia are present. Euvolemia should be the first goal in such cases (as always), followed by optimization of the disease-modifying therapies used in HF (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, or aldosterone antagonists and cardiac resynchronization therapy in selected cases). Erythropoiesis-stimulating agents (ESA) can be used to improve functional capacity in patients with significant chronic kidney disease (CKD), a frequent comorbidity in HF patients. ESA and iron therapy is recommended in patients with moderate-to-severe CKD (eGFR < 60 mL/min/1.73 m2), with a target hemoglobin level of 11.0 g/dL. In a recent randomized, placebo-controlled clinical trial, weekly administration of intravenous iron significantly improved symptoms, New York Heart Association class, quality of life, and exercise capacity in both anemic and non-anemic HF patients. A trend toward fewer hospitalizations was seen in the group treated with intravenous iron. The rates of adverse events were similar in the treatment and the placebo groups. Larger-scale and longer-term studies are needed to establish the safety and efficacy profile of intravenous iron in non-CKD HF patients and in HF patients without anemia. Studies designed to further unravel the pathophysiology of anemia in HF are essential in order to determine 1) novel treatment targets and 2) whether and how the treatment of anemia could improve outcomes.

Notes

Disclosure

Eileen O’Meara’s clinical research on heart failure has been supported by Les Fonds de Recherche en Santé du Québec (FRSQ) and grants from Johnson & Johnson and Pfizer.

Simon de Denus is supported by the Heart and Stroke Foundation of Canada and Les Fonds de la recherche en santé du Québec (FRSQ), and has received grants from AstraZaneca, Pfizer, and Hoffmann LaRoche.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Pfeffer MA, Swedberg K, Granger CB, for the CHARM Investigators and Committees, et al.: Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003, 362:759–766.CrossRefPubMedGoogle Scholar
  2. 2.
    Bardy GH, Lee KL, Mark DB, et al.: Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005, 352:225–237.CrossRefPubMedGoogle Scholar
  3. 3.
    Rosamond W, Flegal K, Friday G, et al.: Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007, 115:e69–171.CrossRefPubMedGoogle Scholar
  4. 4.
    Rose EA, Gelijns AC, Moskowitz AJ, et al.: Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001, 345:1435–1443.CrossRefPubMedGoogle Scholar
  5. 5.
    O’Meara E, Murphy C, McMurray JJV: Anemia and heart failure: a review. Current Heart Fail Rep 2004, 1:176–182.CrossRefGoogle Scholar
  6. 6.
    Komajda M: Prevalence of anemia in patients with chronic heart failure and their clinical characteristics. J Card Fail 2004, 10:S1–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Anand IS: Pathogenesis of anemia in cardiorenal disease. Rev Cardiovasc Med 2005, 6(Suppl 3):S13–21.PubMedGoogle Scholar
  8. 8.
    Tang YD, Katz SD: The prevalence of anemia in chronic heart failure and its impact on clinical outcomes. Heart Fail Rev 2008, 13:387–392.CrossRefPubMedGoogle Scholar
  9. 9.
    O’Meara E, Clayton T, McEntegart MB, et al.: Clinical correlates and consequence 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, 113:986–994.CrossRefPubMedGoogle Scholar
  10. 10.
    Anand IS, Kuskowski MA, Rector TS, 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, 112:1121–1127.CrossRefPubMedGoogle Scholar
  11. 11.
    Anand I, McMurray JJ, Whitmore J, et al.: Anemia and its relationship to clinical outcome in heart failure. Circulation 2004, 110:149–154.CrossRefPubMedGoogle Scholar
  12. 12.
    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, 38:955–962.CrossRefPubMedGoogle Scholar
  13. 13.
    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, 39:1780–1786.CrossRefPubMedGoogle Scholar
  14. 14.
    Nair D, Shlipak MG, Angeja B, et al.: Association of anemia with diastolic dysfunction among patients with coronary artery disease in the Heart and Soul Study. Am J Cardiol 2005, 95:332–336.CrossRefPubMedGoogle Scholar
  15. 15.
    Felker GM, Shaw LK, Stough WG, O’Connor CM: Anemia in patients with heart failure and preserved systolic function. Am Heart J 2006, 151:457–462.CrossRefPubMedGoogle Scholar
  16. 16.
    Berry C, Norrie J, Hogg K, et al.: The prevalence, nature, and importance of hematologic abnormalities in heart failure. Am Heart J 2006, 151:1313–1321.CrossRefPubMedGoogle Scholar
  17. 17.
    Hillege HL, Nitsch D, Pfeffer MA, et al.: Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006, 113:671–678.CrossRefPubMedGoogle Scholar
  18. 18.
    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, 13:1928–1936.CrossRefPubMedGoogle Scholar
  19. 19.
    Szachniewicz J, Petruk-Kowalczyk J, Majda J, et al.: Anaemia is an independent predictor of poor outcome in patients with chronic heart failure. Int J Cardiol 2003, 90:303–308.CrossRefPubMedGoogle Scholar
  20. 20.
    Nordyke RJ, Kim JJ, Goldberg GA, et al.: Impact of anemia on hospitalization time, charges, and mortality in patients with heart failure. Value Health 2004, 7:464–471.CrossRefPubMedGoogle Scholar
  21. 21.
    Beutler E, Waalen J: The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006, 107:1747–1750.CrossRefPubMedGoogle Scholar
  22. 22.
    Hillege HL, Girbes ARJ, de Kam PJ, et al.: Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 2000, 102:203–210.PubMedGoogle Scholar
  23. 23.
    Dries DL, Exner DV, Domanski MJ, et al.: The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol 2000, 35:681–689.CrossRefPubMedGoogle Scholar
  24. 24.
    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, 107:223–225.CrossRefPubMedGoogle Scholar
  25. 25.
    Kazory A, Ross EA: Anemia: the point of convergence or divergence for kidney disease and heart failure? J Am Coll Cardiol 2009, 53:639–647.CrossRefPubMedGoogle Scholar
  26. 26.
    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, 74:468–473.CrossRefPubMedGoogle Scholar
  27. 27.
    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, 26:2232–2237.CrossRefPubMedGoogle Scholar
  28. 28.
    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, 44:63–67.CrossRefPubMedGoogle Scholar
  29. 29.
    Levey AS, Coresh J, Balk E, et al.: National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003, 139:137–147.PubMedGoogle Scholar
  30. 30.
    Silverberg DS, Wexler D, Blum M, Iaina A: The cardio renal anemia syndrome: correcting anemia in patients with resistant congestive heart failure can improve both cardiac and renal function and reduce hospitalizations. Clin Nephrol 2003, 60(Suppl 1):S93–102.PubMedGoogle Scholar
  31. 31.
    Sandhu A, Soman S, Hudson M, Besarab A: Managing anemia in patients with chronic heart failure: what do we know? Vasc Health Risk Manag 2010, 6:237–252.PubMedGoogle Scholar
  32. 32.
    Ronco C, House AA, Haapio M: Cardiorenal and renocardiac syndromes: the need for a comprehensive classification and consensus. Nat Clin Pract Nephrol 2008, 4:310–311.CrossRefPubMedGoogle Scholar
  33. 33.
    Bock JS, Gottlieb SS: Cardiorenal syndrome, new perspectives. Circulation 2010, 121:2592–2600.CrossRefPubMedGoogle Scholar
  34. 34.
    Mrug M, Stopka T, Julian BA, et al.: Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest 1997, 100:2310–2314.CrossRefPubMedGoogle Scholar
  35. 35.
    Nomura S, Sasaki T, Kitano Y, et al.: Effects of ACE inhibitor on renal anemia in predialysis patients. Nephron 1996, 73:336–337.CrossRefPubMedGoogle Scholar
  36. 36.
    Albitar S, Genin R, Fen-Chong M, et al.: High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients. Nephrol Dial Transplant 1998, 13:1206–1210.CrossRefPubMedGoogle Scholar
  37. 37.
    Fyhrquist F, Karppinen K, Honkanen T, et al.: High serum erythropoietin levels are normalized during treatment of congestive heart failure with enalapril. J Intern Med 1989, 226:257–260.PubMedGoogle Scholar
  38. 38.
    Le Meur Y, Lorgeot V, Comte L, et al.: Plasma levels and metabolism of AcSDKP in patients with chronic renal failure: relationship with erythropoietin requirements. Am J Kidney Dis 2001, 38:510–517.CrossRefPubMedGoogle Scholar
  39. 39.
    Anker SD, von Haehling S: Inflammatory mediators in chronic heart failure: an overview. Heart 2004, 90:464–470.CrossRefPubMedGoogle Scholar
  40. 40.
    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, 103:2055–2059.PubMedGoogle Scholar
  41. 41.
    Anand IS, Latini R, Florea VG, et al.: C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation 2005, 112:1428–1434.CrossRefPubMedGoogle Scholar
  42. 42.
    Jelkmann W: Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 1998, 18:555–559.CrossRefPubMedGoogle Scholar
  43. 43.
    Macdougall IC, Cooper AC: Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol Dial Transplant 2002, 17(Suppl 11):39–43.PubMedGoogle Scholar
  44. 44.
    Matsumoto M, Tsujino T, Lee-Kawabata M, et al.: Iron regulatory hormone hepcidin decreases in chronic heart failure patients with anemia. Circ J 2010, 74:301–306.CrossRefPubMedGoogle Scholar
  45. 45.
    Ferrucci L, Semba RD, Guralnik JM, et al.: Proinflammatory state, hepcidin and anemia in older persons. Blood 2010, 115:3810–3816.CrossRefPubMedGoogle Scholar
  46. 46.
    Weiss G, Goonough LT: Anemia of chronic disease. N Engl J Med 2005, 352:1011–1023.CrossRefPubMedGoogle Scholar
  47. 47.
    Nanas JN, Matsouka C, Karageorgopoulos D, et al.: Etiology of anemia in patients with advanced heart failure. J Am Coll Cardiol 2006, 48:2485–2489.CrossRefPubMedGoogle Scholar
  48. 48.
    Androne AS, Katz SD, Lund L, et al.: Hemodilution is common in patients with advanced heart failure. Circulation 2003, 107:226–229.CrossRefPubMedGoogle Scholar
  49. 49.
    Anker SD, Negassa A, Coats AJ, et al.: Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study. Lancet 2003, 361:1077–1083.CrossRefPubMedGoogle Scholar
  50. 50.
    Okonko DO, Anker SD: Anemia in chronic heart failure: pathogenetic mechanisms. J Card Fail 2004, 10(Suppl 1):S5–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Katz SD: Mechanisms and treatment of anemia in chronic heart failure. Congest Heart Fail 2004, 10:243–247.CrossRefPubMedGoogle Scholar
  52. 52.
    Westenbrink BD, Lipsic E, van der Meer P, et al.: Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J 2007, 28:2018–2027.CrossRefPubMedGoogle Scholar
  53. 53.
    Smith KJ, Bleyer AJ, Little WC, Sane DC: The cardiovascular effects of erythropoietin. Cardiovasc Res 2003, 59:538–548.CrossRefPubMedGoogle Scholar
  54. 54.
    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, 361:2019–2032.CrossRefPubMedGoogle Scholar
  55. 55.
    Drüeke TB, Locatelli F, Clyne N, et al.: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006, 355:2071–2084.CrossRefPubMedGoogle Scholar
  56. 56.
    Singh AK, Szczech L, Tang KL: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006, 355:2085–2098.CrossRefPubMedGoogle Scholar
  57. 57.
    van der Meer P, Groenveld HF, Januzzi Jr JL, van Veldhuisen DJ: Erythropoietin treatment in patients with chronic heart failure: a meta-analysis. Heart 2009, 95:1309–1314.CrossRefPubMedGoogle Scholar
  58. 58.
    Desai A, Lewis E, Solomon S, et al.: Impact of erythropoiesis-stimulating agents on morbidity and mortality in patients with heart failure: an updated, post-TREAT meta-analysis. Eur J Heart Fail 2010 Jun 5 [Epub ahead of print].Google Scholar
  59. 59.••
    McMurray JJ, Anand IS, Diaz R, et al.: RED-HF committees investigators: design of the Reduction of Events with Darbepoetin Alfa in Heart Failure (RED-HF): a phase III, anaemia correction, morbidity–mortality trial. Eur J Heart Fail 2009, 11:795–801.CrossRefPubMedGoogle Scholar
  60. 60.•
    Anker SD, Colet JC, Filippatos G, on behalf of the FAIR-HF Committees Investigators, et al.: Rationale and design of Ferinject assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study: a randomized, placebo-controlled study of intravenous iron supplementation in patients with and without anaemia. Eur J Heart Fail 2009, 11:1084–1091. This is an interesting article explaining the role of iron and the potential benefits that could be gained from iron therapy in HF. It also includes a review of the previous trials of intravenous iron therapy in HF patients.CrossRefPubMedGoogle Scholar
  61. 61.
    Davies KJ, Maguire JJ, Brooks GA, et al.: Muscle mitochondrial bioenergetics, oxygen supply, and work capacity during dietary iron deficiency and repletion. Am J Physiol 1982, 242:E418–E427.PubMedGoogle Scholar
  62. 62.
    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, 48:1225–1227.CrossRefPubMedGoogle Scholar
  63. 63.
    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, 50:1657–1665.CrossRefPubMedGoogle Scholar
  64. 64.
    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, 51:103–112.CrossRefPubMedGoogle Scholar
  65. 65.
    Beck-da-Silva L, Luìs Eduardo Rohde L, Pereira-Barretto AC, et al.: Rationale and design of the IRON-HF study: a randomized trial to assess the effects of iron supplementation in heart failure patients with anemia. J Card Fail 2007, 13:14–17.CrossRefPubMedGoogle Scholar
  66. 66.
    Anker SA, Comin-Colet J, Filipatos G, for the FAIR-HF trial Investigators, et al.: Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009, 361:2436–2448.CrossRefPubMedGoogle Scholar
  67. 67.
    National Kidney Foundation Kidney Disease Outcomes Quality Initiative: KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target; 2007. Available at http://www.kidney.org/professionals/KDOQI/. Accessed July 14, 2010.
  68. 68.
    Hunt SA, Abraham WT, Chin MH, et al.: 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009, 119:e391–479.CrossRefPubMedGoogle Scholar
  69. 69.••
    Locatelli F, Aljama P, Canaud B, et al., on behalf of the Anaemia Working Group of European Renal Best Practice (ERBP): Target haemoglobin to aim for with erythropoiesis-stimulating agents: a position statement by ERBP following publication of the Trial to Reduce Cardiovascular Events with Aranesp(R) Therapy (TREAT) Study. Nephrol Dial Transplant 2010 Jun 29 [Epub ahead of print]. This is an important guideline reference (from a different group) for clinicians who prescribe ESAs in patients with CKD. The reference was written after publication of TREAT.Google Scholar
  70. 70.
    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, 37:1775–1780.CrossRefPubMedGoogle Scholar
  71. 71.
    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, 107:294–299.CrossRefPubMedGoogle Scholar
  72. 72.
    Palazzuoli A, Silverberg DS, Calabro A, et al.: Beta-erythropoietin effects on ventricular remodeling, left and right systolic function, pulmonary pressure, and hospitalizations in patients affected with heart failure and anemia. J Cardiovasc Pharmacol 2009, 53:462–467.CrossRefPubMedGoogle Scholar
  73. 73.
    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, 46:155–161.CrossRefPubMedGoogle Scholar
  74. 74.
    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, 49:753–762.CrossRefPubMedGoogle Scholar
  75. 75.
    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, 28:2208–2216.CrossRefPubMedGoogle Scholar
  76. 76.
    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:e751–757.CrossRefGoogle Scholar
  77. 77.
    Parissis JT, Kourea K, Andreadou I, et al.: Effects of Darbepoetin Alfa on plasma mediators of oxidative and nitrosative stress in anemic patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2009, 103:1134–1138.CrossRefPubMedGoogle Scholar
  78. 78.
    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, 117:526–535.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Montreal Heart Institute5000 Belanger StreetMontrealCanada

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