Rationale and Design of a Prospective, Multicenter, Observational Study Evaluating Iron Deficiency in Patients Hospitalized for Heart Failure (FERIC-RO)

Open access

Abstract

Introduction: Several landmark studies, which enrolled heart failure (HF) patients who were ambulatory at the time of inclusion, identified iron deficiency (ID) as an important therapeutic target: intravenous iron administration with ferric carboxymaltose (FCM) improves morbidity, exercise capacity, and quality of life in patients with HF and reduced EF (HFrEF). However, there is still limited knowledge about ID prevalence during hospitalization for Worsening Chronic HF (WCHF) and about the relationship between ID during hospitalization and post-discharge outcomes. Although previous studies documented ID as an independent risk factor for poor outcomes in HFrEF, its prognostic significance in HF patients with EF>40% remains unclear.

Method and Results: The FERIC-RO study is a prospective, multicenter, observational study with longitudinal follow up, conducted in 9 Romanian hospitals that will include 200 consecutive patients admitted for worsening HF. A comprehensive description of the Iron metabolism biomarkers will be performed on discharge and 1-month follow up. The primary endpoint is defined as the prevalence of ID on discharge and 1-month post-discharge, and the secondary endpoints include: all-cause re-hospitalization and all-cause-mortality at 1 and 3 months follow up, and quality of life on discharge and 1-month.

Conclusions: FERIC-RO will provide new evidence about the prevalence and the predictors of ID in patients hospitalized for WCHF regardless of LVEF. Furthermore, the study will explore the relationship between in-hospital ID and post-discharge outcomes. The results of FERIC-RO will thus be highly relevant to the management of patients hospitalized for AHF.

1. Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002;347(18):1397-402. DOI: 10.1056/NEJMoa020265

2. Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S, McMurray JJ. The current cost of heart failure to the National Health Service in the UK. Eur J Heart Fail. 2002;4(3):361-71. DOI: 10.1016/S1388-9842(01)00198-2

3. Schaufelberger M, Swedberg K, Koster M, Rosen M, Rosengren A. Decreasing one-year mortality and hospitalization rates for heart failure in Sweden; Data from the Swedish Hospital Discharge Registry 1988 to 2000. Eur Heart J. 2004;25(4):300-7. DOI: 10.1016/j.ehj.2003.12.012

4. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):1137-46. DOI: 10.1136/hrt.2003.025270

5. Tavazzi L, Senni M, Metra M, Gorini M, Cacciatore G, Chinaglia A, et al. 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. DOI: 10.1161/CIRCHEARTFAILURE.112.000161

6. Crespo-Leiro MG, Anker SD, Maggioni AP, Coats AJ, Filippatos G, Ruschitzka F, et al. European Society of Cardiology Heart Failure Long-Term Registry (ESCHF-LT): 1-year follow-up outcomes and differences across regions. Eur J Heart Fail. 2016;18(6):613-25. DOI: 10.1002/ejhf.566

7. Hamo CE, Butler J, Gheoghiade M, Chioncel O. The bumpy road to drug development for acute heart failure. European Heart Journal Supplements. 2016;18(suppl_G, 1 November 2016):G19–G32.

8. O’Connor CM, Miller AB, Blair JE, Konstam MA, Wedge P, Bahit MC, et al. Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program. Am Heart J. 2010;159(5):841-9 e1.

9. Antohi EL, Dobreanu D, Deleanu D, Tatu-Chitoiu G, Macarie C, Chioncel O. Relation between non-cardiac comorbidities and use of evidence based therapies in patients with in-hospital heart failure-data from SONIC-RO study. Eur J Heart Fail Suppl. 2013;12:S354-S80.

10. 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. 2017;38(5):362-72.

11. 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. DOI: 10.1002/ejhf.473

12. Anand IS. Anemia and chronic heart failure implications and treatment options. J Am Coll Cardiol. 2008;52(7):501-11. DOI: 10.1016/j.jacc.2008.04.044

13. Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol. 2006;1 Suppl 1:S4-8. DOI: 10.2215/CJN.01490506

14. Ponikowski P, Voors AA, Anker SD, Bueno H, Cle-land JGF, Coats AJS, et al. 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. DOI: 10.1093/eurheartj/ehw128

15. Kalantar-Zadeh K, Rodriguez RA, Humphreys MH. Association between serum ferritin and measures of inflammation, nutrition and iron in haemodialysis patients. Nephrol Dial Transplant. 2004;19(1):141-9. DOI: 10.1093/ndt/gfg493

16. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823(9):1434-43. DOI: 10.1016/j.bbamcr.2012.01.014

17. Feelders RA, Kuiper-Kramer EP, van Eijk HG. Structure, function and clinical significance of transferrin receptors. Clin Chem Lab Med. 1999;37(1):1-10. DOI: 10.1515/CCLM.1999.001

18. Divakaran V, Mehta S, Yao D, Hassan S, Simpson S, Wiegerinck E, et al. Hepcidin in anemia of chronic heart failure. Am J Hematol. 2011;86(1):107-9. DOI: 10.1002/ajh.21902

19. Cohen-Solal A, Damy T, Terbah M, Kerebel S, Baguet JP, Hanon O, et al. High prevalence of iron deficiency in patients with acute decompensated heart failure. Eur J Heart Fail. 2014;16(9):984-91. DOI: 10.1002/ejhf.139

20. Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ, Granger CB, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116(13):1482-7. DOI: 10.1161/CIRCULATION-AHA.107.696906

21. Jack BW, Chetty VK, Anthony D, Greenwald JL, Sanchez GM, Johnson AE, et al. A reengineered hospital discharge program to decrease rehospitalization: a randomized trial. Ann Intern Med. 2009;150(3):178-87. DOI: 10.7326/0003-4819-150-3-200902030-00007

22. Ross JS, Chen J, Lin Z, Bueno H, Curtis JP, Keenan PS, et al. Recent national trends in readmission rates after heart failure hospitalization. Circ Heart Fail. 2010;3(1):97-103. DOI: 10.1161/CIRCHEARTFAILURE.109.885210

23. Dharmarajan K, Hsieh AF, Lin Z, Bueno H, Ross JS, Horwitz LI, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-63. DOI: 10.1001/jama.2012.216476

24. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6-e245. DOI: 10.1161/CIR.0b013e31828124ad

25. Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1968;405:5-37.

26. Chioncel O, Vinereanu D, Datcu M, Ionescu DD, Capalneanu R, Brukner I, et al. The Romanian Acute Heart Failure Syndromes (RO-AHFS) registry. Am Heart J. 2011;162(1):142-53 e1.

27. Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013;368(13):1210-9. DOI: 10.1056/NEJMoa1214865

28. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436-48. DOI: 10.1056/NEJMoa0908355

29. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiencydagger. Eur Heart J. 2015;36(11):657-68. DOI: 10.1093/eurheartj/ehu385

30. 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(12):1241-51. DOI: 10.1016/j.jacc.2011.04.040

31. Brownlie Tt, Utermohlen V, Hinton PS, Haas JD. Tissue iron deficiency without anemia impairs adaptation in endurance capacity after aerobic training in previously untrained women. Am J Clin Nutr. 2004;79(3):437-43. DOI: 10.1093/ajcn/79.3.437

32. 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. DOI: 10.1093/eurheartj/ehq158

33. 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. DOI: 10.1016/j.cardfail.2011.08.003

34. Parikh A, Natarajan S, Lipsitz SR, Katz SD. Iron deficiency in community-dwelling US adults with self-reported heart failure in the National Health and Nutrition Examination Survey III: prevalence and associations with anemia and inflammation. Circ Heart Fail. 2011;4(5):599-606. DOI: 10.1161/CIRCHEARTFAILURE.111.960906

35. Corti MC, Guralnik JM, Salive ME, Ferrucci L, Pahor M, Wallace RB, et al. Serum iron level, coronary artery disease, and all-cause mortality in older men and women. Am J Cardiol. 1997;79(2):120-7. DOI: 10.1016/S0002-9149(96)00697-2

36. Verdon F, Burnand B, Stubi CL, Bonard C, Graff M, Michaud A, et al. Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial. BMJ. 2003;326(7399):1124. DOI: 10.1136/bmj.326.7399.1124

37. Cook JD. Diagnosis and management of iron-deficiency anaemia. Best Pract Res Clin Haematol. 2005;18(2):319-32. DOI: 10.1016/j.beha.2004.08.022

38. Skikne BS, Punnonen K, Caldron PH, Bennett MT, Rehu M, Gasior GH, et al. Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index. Am J Hematol. 2011;86(11):923-7. DOI: 10.1002/ajh.22108

39. Beguin Y. The soluble transferrin receptor: biological aspects and clinical usefulness as quantitative measure of erythropoiesis. Haematologica. 1992;77(1):1-10.

40. Cotton F, Thiry P, Boeynaems J. Measurement of soluble transferrin receptor by immunoturbidimetry and immunonephelometry. Clin Biochem. 2000;33(4):263-7. DOI: 10.1016/S0009-9120(00)00071-0

41. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276(11):7811-9. DOI: 10.1074/jbc.M008923200

42. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102(3):783-8. DOI: 10.1182/blood-2003-03-0672

43. Diwan A, Tran T, Misra A, Mann DL. Inflammatory mediators and the failing heart: a translational approach. Curr Mol Med. 2003;3(2):161-82. DOI: 10.2174/1566524033361537

44. Konstam MA, Gheorghiade M, Burnett JC, Jr., Grin-feld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297(12):1319-31. DOI: 10.1001/jama.297.12.1319

45. Gheorghiade M, Bohm M, Greene SJ, Fonarow GC, Lewis EF, Zannad F, et al. Effect of aliskiren on postdis-charge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA. 2013;309(11):1125-35. DOI: 10.1001/jama.2013.1954

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information


IMPACT FACTOR 2017: 0.400
5-year IMPACT FACTOR: 0.320



CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2017: 0.144
Source Normalized Impact per Paper (SNIP) 2017: 0.195

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 129 129 34
PDF Downloads 64 64 17