##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 147 No. 2526 (2017)

Iron substitution in the treatment of chronic heart failure

Cite this as:
Swiss Med Wkly. 2017;147:w14453
Published
23.06.2017

Summary

Iron deficiency is a prevalent and clinically relevant comorbidity in up to 50% of patients with chronic heart failure (CHF). Iron deficiency in CHF patients is associated with impaired quality of life, reduced exercise capacity and increased mortality, irrespective of the presence of anaemia. It is diagnosed by determining circulating ferritin levels and transferrin saturation. Three randomised trials (CONFIRM-HF, FAIR-HF, and EFFECT-HF) of intravenous ferric carboxymaltose in the treatment of iron deficiency in CHF patients with reduced left ventricular ejection fraction demonstrated improvement of symptoms, functional capacity and quality of life. These beneficial effects were independent of the presence of anaemia. In addition, CONFIRM-HF and subsequent meta-analyses indicated that treatment of iron deficiency may reduce the rate of hospitalisations for worsening CHF. Oral iron is available at lower cost than intravenous iron, but its use did not translate into beneficial effects in CHF patients with iron deficiency. Large randomised trials designed to assess long-term clinical outcomes of iron treatment in CHF patients are pending. Current guidelines advise establishing evidence-based pharmacological and device therapy to improve symptoms and prognosis in patients with CHF. In addition, screening for iron deficiency is recommended. Intravenous ferric carboxymaltose should be considered for treating iron deficiency in ambulatory symptomatic patients with reduced left ventricular ejection fraction in order to alleviate heart failure symptoms, and to improve exercise capacity and quality of life.

References

  1. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):1137–46. https://doi.org/10.1136/hrt.2003.025270
  2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al.; Authors/Task Force Members. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200. https://doi.org/10.1093/eurheartj/ehw128
  3. Tavazzi L, Senni M, Metra M, Gorini M, Cacciatore G, Chinaglia A, et al.; IN-HF (Italian Network on Heart Failure) Outcome Investigators. Multicenter prospective observational study on acute and chronic heart failure: one-year follow-up results of IN-HF (Italian Network on Heart Failure) outcome registry. Circ Heart Fail. 2013;6(3):473–81. https://doi.org/10.1161/CIRCHEARTFAILURE.112.000161
  4. Hoekstra T, Jaarsma T, van Veldhuisen DJ, Hillege HL, Sanderman R, Lesman-Leegte I. Quality of life and survival in patients with heart failure. Eur J Heart Fail. 2013;15(1):94–102. https://doi.org/10.1093/eurjhf/hfs148
  5. van Deursen VM, Urso R, Laroche C, Damman K, Dahlström U, Tavazzi L, et al. Co-morbidities in patients with heart failure: an analysis of the European Heart Failure Pilot Survey. Eur J Heart Fail. 2014;16(1):103–11. https://doi.org/10.1002/ejhf.30
  6. Klip IT, Comin-Colet J, Voors AA, Ponikowski P, Enjuanes C, Banasiak W, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013;165(4):575–582.e3. https://doi.org/10.1016/j.ahj.2013.01.017
  7. Okonko DO, Mandal AKJ, 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(12):1241–51. https://doi.org/10.1016/j.jacc.2011.04.040
  8. Kasner M, Aleksandrov AS, Westermann D, Lassner D, Gross M, von Haehling S, et al. Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction. Int J Cardiol. 2013;168(5):4652–7. https://doi.org/10.1016/j.ijcard.2013.07.185
  9. Jankowska EA, Kasztura M, Sokolski M, Bronisz M, Nawrocka S, Oleśkowska-Florek W, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. Eur Heart J. 2014;35(36):2468–76. https://doi.org/10.1093/eurheartj/ehu235
  10. van Veldhuisen DJ, Anker SD, Ponikowski P, Macdougall IC. Anemia and iron deficiency in heart failure: mechanisms and therapeutic approaches. Nat Rev Cardiol. 2011;8(9):485–93. https://doi.org/10.1038/nrcardio.2011.77
  11. Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, et al. Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail. 2011;17(11):899–906. https://doi.org/10.1016/j.cardfail.2011.08.003
  12. Comín-Colet J, Enjuanes C, González G, Torrens A, Cladellas M, Meroño O, et al. Iron deficiency is a key determinant of health-related quality of life in patients with chronic heart failure regardless of anaemia status. Eur J Heart Fail. 2013;15(10):1164–72. https://doi.org/10.1093/eurjhf/hft083
  13. McDonagh T, Macdougall IC. Iron therapy for the treatment of iron deficiency in chronic heart failure: intravenous or oral? Eur J Heart Fail. 2015;17(3):248–62. https://doi.org/10.1002/ejhf.236
  14. Turner LR, Premo DA, Gibbs BJ, Hearthway ML, Motsko M, Sappington A, et al. Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy. BMC Physiol. 2002;2(1):1. https://doi.org/10.1186/1472-6793-2-1
  15. Naito Y, Tsujino T, Matsumoto M, Sakoda T, Ohyanagi M, Masuyama T. Adaptive response of the heart to long-term anemia induced by iron deficiency. Am J Physiol Heart Circ Physiol. 2009;296(3):H585–93. https://doi.org/10.1152/ajpheart.00463.2008
  16. Maeder MT, Khammy O, dos Remedios C, Kaye DM. Myocardial and systemic iron depletion in heart failure implications for anemia accompanying heart failure. J Am Coll Cardiol. 2011;58(5):474–80. https://doi.org/10.1016/j.jacc.2011.01.059
  17. Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J. 2010;31(15):1872–80. https://doi.org/10.1093/eurheartj/ehq158
  18. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341(26):1986–95. https://doi.org/10.1056/NEJM199912233412607
  19. Ganz T, Nemeth E. Iron imports. IV. Hepcidin and regulation of body iron metabolism. Am J Physiol Gastrointest Liver Physiol. 2006;290(2):G199–203. https://doi.org/10.1152/ajpgi.00412.2005
  20. Dunn LL, Suryo Rahmanto Y, Richardson DR. Iron uptake and metabolism in the new millennium. Trends Cell Biol. 2007;17(2):93–100. https://doi.org/10.1016/j.tcb.2006.12.003
  21. Cairo G, Bernuzzi F, Recalcati S. A precious metal: Iron, an essential nutrient for all cells. Genes Nutr. 2006;1(1):25–39. https://doi.org/10.1007/BF02829934
  22. Brunner-La Rocca HP, Crijns HJ. Iron i.v. in heart failure: ready for implementation? Eur Heart J. 2015;36(11):645–7. https://doi.org/10.1093/eurheartj/ehu392
  23. Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr. 2001;131(2S-2, Suppl 2):568S–79S, discussion 580S.
  24. Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J. 2013;34(11):816–29. https://doi.org/10.1093/eurheartj/ehs224
  25. Muñoz M, García-Erce JA, Remacha AF. Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis. J Clin Pathol. 2011;64(4):281–6. https://doi.org/10.1136/jcp.2010.079046
  26. Zhang AS, Enns CA. Molecular mechanisms of normal iron homeostasis. Hematology (Am Soc Hematol Educ Program). 2009;1(1):207–14. https://doi.org/10.1182/asheducation-2009.1.207
  27. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142(1):24–38. https://doi.org/10.1016/j.cell.2010.06.028
  28. Anderson GJ, Frazer DM, McLaren GD. Iron absorption and metabolism. Curr Opin Gastroenterol. 2009;25(2):129–35. https://doi.org/10.1097/MOG.0b013e32831ef1f7
  29. Babitt JL, Lin HY. Molecular mechanisms of hepcidin regulation: implications for the anemia of CKD. Am J Kidney Dis. 2010;55(4):726–41. https://doi.org/10.1053/j.ajkd.2009.12.030
  30. Viatte L, Vaulont S. Hepcidin, the iron watcher. Biochimie. 2009;91(10):1223–8. https://doi.org/10.1016/j.biochi.2009.06.012
  31. Franchini M, Montagnana M, Lippi G. Hepcidin and iron metabolism: from laboratory to clinical implications. Clin Chim Acta. 2010;411(21-22):1565–9. https://doi.org/10.1016/j.cca.2010.07.003
  32. Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol. 2009;122(2-3):78–86. https://doi.org/10.1159/000243791
  33. Handelman GJ, Levin NW. Iron and anemia in human biology: a review of mechanisms. Heart Fail Rev. 2008;13(4):393–404. https://doi.org/10.1007/s10741-008-9086-x
  34. Kemna EH, Tjalsma H, Willems HL, Swinkels DW. Hepcidin: from discovery to differential diagnosis. Haematologica. 2008;93(1):90–7. https://doi.org/10.3324/haematol.11705
  35. Jankowska EA, Malyszko J, Ardehali H, Koc-Zorawska E, Banasiak W, von Haehling S, et al. Iron status in patients with chronic heart failure. Eur Heart J. 2013;34(11):827–34. https://doi.org/10.1093/eurheartj/ehs377
  36. Haddad S, Wang Y, Galy B, Korf-Klingebiel M, Hirsch V, Baru AM, et al. Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Eur Heart J. 2016:ehw333; Epub ahead of print. https://doi.org/10.1093/eurheartj/ehw333
  37. Sica DA. Pharmacotherapy in congestive heart failure: drug absorption in the management of congestive heart failure: loop diuretics. Congest Heart Fail. 2003;9(5):287–92. https://doi.org/10.1111/j.1527-5299.2003.02399.x
  38. Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012;59(11):998–1005. https://doi.org/10.1016/j.jacc.2011.11.040
  39. Okonko DO, Anker SD. Anemia in chronic heart failure: pathogenetic mechanisms. J Card Fail. 2004;10(1, Suppl):S5–9. https://doi.org/10.1016/j.cardfail.2004.01.004
  40. Scharf RE. Management of bleeding in patients using antithrombotic agents: prediction, prevention, protection and problem-oriented intervention. Hamostaseologie. 2009;29(4):388–98.
  41. Mast AE, Blinder MA, Gronowski AM, Chumley C, Scott MG. Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations. Clin Chem. 1998;44(1):45–51.
  42. Nanas JN, Matsouka C, Karageorgopoulos D, Leonti A, Tsolakis E, Drakos SG, et al. Etiology of anemia in patients with advanced heart failure. J Am Coll Cardiol. 2006;48(12):2485–9. https://doi.org/10.1016/j.jacc.2006.08.034
  43. Ebner N, von Haehling S. Iron deficiency in heart failure: a practical guide. Nutrients. 2013;5(9):3730–9. https://doi.org/10.3390/nu5093730
  44. Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol. 2006;1(Suppl 1):S4–8. https://doi.org/10.2215/CJN.01490506
  45. Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood. 2010;116(23):4754–61. https://doi.org/10.1182/blood-2010-05-286260
  46. 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(6):1225–7. https://doi.org/10.1016/j.jacc.2006.07.015
  47. Toblli JE, Lombraña 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(17):1657–65. https://doi.org/10.1016/j.jacc.2007.07.029
  48. 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(2):103–12. https://doi.org/10.1016/j.jacc.2007.09.036
  49. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al.; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436–48. https://doi.org/10.1056/NEJMoa0908355
  50. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al.; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33(14):1787–847. https://doi.org/10.1093/eurheartj/ehs104
  51. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, et al.; CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36(11):657–68. https://doi.org/10.1093/eurheartj/ehu385
  52. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, et al. Rationale and design of the CONFIRM-HF study: a double-blind, randomized, placebo-controlled study to assess the effects of intravenous ferric carboxymaltose on functional capacity in patients with chronic heart failure and iron deficiency. ESC Heart Failure. 2014;1(1):52–8. https://doi.org/10.1002/ehf2.12006
  53. US National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01394562. Accessed January 22, 2017.
  54. American College of Cardiology. Latest in cardiology. Studies Explore Use of Iron Supplements in Treating HF Patients. https://www.acc.org/latest-in-cardiology/articles/2016/11/10/15/58/wed-1145amet-ironout-effect-aha-2016. Accessed January 22, 2017.
  55. Qian C, Wei B, Ding J, Wu H, Wang Y. The Efficacy and Safety of Iron Supplementation in Patients With Heart Failure and Iron Deficiency: A Systematic Review and Meta-analysis. Can J Cardiol. 2016;32(2):151–9. https://doi.org/10.1016/j.cjca.2015.06.009
  56. Jankowska EA, Tkaczyszyn M, Suchocki T, Drozd M, von Haehling S, Doehner W, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail. 2016;18(7):786–95. https://doi.org/10.1002/ejhf.473
  57. Herzzentrum Göttingen. Research. http://www.herzzentrum-goettingen.de/de/content/forschung/1980.html. Accessed January 22, 2017.
  58. Deutsches Zentrum für Herz-Kreislauf-Forschung e.v. https://intern.dzhk.de/Klinische-Studien2.html. Accessed January 22, 2017.
  59. Miller HJ, Hu J, Valentine JK, Gable PS. Efficacy and tolerability of intravenous ferric gluconate in the treatment of iron deficiency anemia in patients without kidney disease. Arch Intern Med. 2007;167(12):1327–8. https://doi.org/10.1001/archinte.167.12.1327
  60. Moe GW, Ezekowitz JA, O’Meara E, Lepage S, Howlett JG, Fremes S, et al.; Canadian Cardiovascular Society. The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications. Can J Cardiol. 2015;31(1):3–16. Erratum in: Can J Cardiol. 2016;32(3):394.https://doi.org/10.1016/j.cjca.2014.10.022
  61. Geisser P, Baer M, Schaub E. Structure/histotoxicity relationship of parenteral iron preparations. Arzneimittelforschung. 1992;42(12):1439–52.
  62. Toblli JE, Cao G, Oliveri L, Angerosa M. Assessment of the extent of oxidative stress induced by intravenous ferumoxytol, ferric carboxymaltose, iron sucrose and iron dextran in a nonclinical model. Arzneimittelforschung. 2011;61(7):399–410. https://doi.org/10.1055/s-0031-1296218
  63. Toblli JE, Cao G, Oliveri L, Angerosa M. Evaluation of toxicity and oxidative stress induced by intravenous iron isomaltoside 1000 in a nonclinical model. Arzneimittelforschung. 2011;61(10):553–65.
  64. Toblli JE, Cao G, Olivieri L, Angerosa M. Comparison of the renal, cardiovascular and hepatic toxicity data of original intravenous iron compounds. Nephrol Dial Transplant. 2010;25(11):3631–40. https://doi.org/10.1093/ndt/gfq260
  65. Garcia-Fernandez N, Echeverria A, Sanchez-Ibarrola A, Páramo JA, Coma-Canella I. Randomized clinical trial on acute effects of i.v. iron sucrose during haemodialysis. Nephrology (Carlton). 2010;15(2):178–83. https://doi.org/10.1111/j.1440-1797.2009.01174.x
  66. Rangel EB, Espósito BP, Carneiro FD, Mallet AC, Matos AC, Andreoli MC, et al. Labile plasma iron generation after intravenous iron is time-dependent and transitory in patients undergoing chronic hemodialysis. Ther Apher Dial. 2010;14(2):186–92. https://doi.org/10.1111/j.1744-9987.2009.00786.x
  67. Sato K, Nohtomi K, Demura H, Takeuchi A, Kobayashi T, Kazama J, et al. Saccharated ferric oxide (SFO)-induced osteomalacia: in vitro inhibition by SFO of bone formation and 1,25-dihydroxy-vitamin D production in renal tubules. Bone. 1997;21(1):57–64. https://doi.org/10.1016/S8756-3282(97)00084-7
  68. Sato K, Shiraki M. Saccharated ferric oxide-induced osteomalacia in Japan: iron-induced osteopathy due to nephropathy. Endocr J. 1998;45(4):431–9. https://doi.org/10.1507/endocrj.45.431
  69. Schouten BJ, Doogue MP, Soule SG, Hunt PJ. Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia. Ann Clin Biochem. 2009;46(2):167–9. https://doi.org/10.1258/acb.2008.008151
  70. Okada M, Imamura K, Fuchigami T, Omae T, Iida M, Nanishi F, et al. [2 cases of nonspecific multiple ulcers of the small intestine associated with osteomalacia caused by long-term intravenous administration of saccharated ferric oxide]. Nippon Naika Gakkai Zasshi. 1982;71(11):1566–72.Article in Japanese. https://doi.org/10.2169/naika.71.1566
  71. Ishida JH, Johansen KL. Iron and infection in hemodialysis patients. Semin Dial. 2014;27(1):26–36. https://doi.org/10.1111/sdi.12168
  72. Filippatos G, Farmakis D, Colet JC, Dickstein K, Lüscher TF, Willenheimer R, et al. Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial. Eur J Heart Fail. 2013;15(11):1267–76. https://doi.org/10.1093/eurjhf/hft099
  73. US National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02188784. Accessed January 22, 2017.
  74. Beck-da-Silva L, Piardi D, Soder S, Rohde LE, Pereira-Barretto AC, de Albuquerque D, et al. IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia. Int J Cardiol. 2013;168(4):3439–42. https://doi.org/10.1016/j.ijcard.2013.04.181
  75. Hofmarcher T, Borg S. Cost-effectiveness analysis of ferric carboxymaltose in iron-deficient patients with chronic heart failure in Sweden. J Med Econ. 2015;18(7):492–501. https://doi.org/10.3111/13696998.2015.1029491
  76. 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(7):1737–44. https://doi.org/10.1016/S0735-1097(00)00613-6
  77. 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(7):1775–80. https://doi.org/10.1016/S0735-1097(01)01248-7
  78. Silverberg DS, Wexler D, Blum M, Tchebiner JZ, Sheps D, Keren G, et al. The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol Dial Transplant. 2003;18(1):141–6. https://doi.org/10.1093/ndt/18.1.141
  79. 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(2):294–9. https://doi.org/10.1161/01.CIR.0000044914.42696.6A
  80. Palazzuoli A, Silverberg D, Iovine F, Capobianco S, Giannotti G, Calabrò A, 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(6):1096.e9–15. https://doi.org/10.1016/j.ahj.2006.08.005
  81. Ponikowski P, Anker SD, Szachniewicz J, Okonko D, Ledwidge M, Zymlinski R, 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(7):753–62. https://doi.org/10.1016/j.jacc.2006.11.024
  82. van Veldhuisen DJ, Dickstein K, Cohen-Solal A, Lok DJ, Wasserman SM, Baker N, 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(18):2208–16. https://doi.org/10.1093/eurheartj/ehm328
  83. Ghali JK, Anand IS, Abraham WT, Fonarow GC, Greenberg B, Krum H, et al.; Study of Anemia in Heart Failure Trial (STAMINA-HeFT) Group. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 2008;117(4):526–35. https://doi.org/10.1161/CIRCULATIONAHA.107.698514
  84. Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, et al.; RED-HF Committees; RED-HF Investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013;368(13):1210–9. https://doi.org/10.1056/NEJMoa1214865
  85. Wienbergen H, Pfister O, Hochadel M, Michel S, Bruder O, Remppis BA, et al.; RAID-HF (Registry Analysis of Iron Deficiency–Heart Failure) REGISTRY Study Group. Usefulness of Iron Deficiency Correction in Management of Patients With Heart Failure [from the Registry Analysis of Iron Deficiency-Heart Failure (RAID-HF) Registry]. Am J Cardiol. 2016;118(12):1875–80. Published online September 15, 2016. https://doi.org/10.1016/j.amjcard.2016.08.081