EDITORIAL COMMENT
Anemia and Heart FailureA New Pathway?*
Gary S. Francis, MD, FACC2,* and
Anne Kanderian, MD
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.
* Reprint requests and correspondence: Dr. Gary S. Francis, 9500 Euclid Avenue, F15 Cleveland, Ohio 44195. (Email: francig{at}ccf.org).
Anemia is common among patients with heart failure, probably occurring in approximately 20% of patients, depending on the definition of terms and severity of patient illness. Some anemia is likely dilutional (1), but most is probably true anemia due to chronic disease or iron deficiency (2). The degree of anemia in patients with heart failure after acute myocardial infarction is associated with a poor prognosis (3), and anemia in patients with chronic heart failure from any cause has repeatedly been demonstrated to predict a poor outcome (2). A consensus has seemingly emerged in the heart failure community that correction of a reduced hemoglobin (Hb) level is an attractive therapeutic target deserving of further study. Of interest, erythropoietin (EPO) levels are moderately elevated in patients with heart failure, more so in very severe heart failure (4). This finding has not discouraged pharmaceutical companies from testing the concept of using EPO and its analogues as possible treatment for heart failure. This is clearly a case where treatment precedes understanding of pathophysiology, a common occurrence throughout history.
The mechanism of the anemia in patients with heart failure and its role in the pathophysiology of heart failure has been elusive. In some cases, the red blood cell mass is normal despite a low Hb level. Perhaps only 30% or fewer cases are due to iron deficiency (2). However, using acute phase reactants like serum transferrin might under-diagnose iron deficiency anemia in patients with heart failure. The prevalence of iron deficiency anemia might in fact be greater when using transferrin saturation levels or bone marrow aspiration (5). Irrespective of the cause of low Hb, current data suggest that EPO and its analogs when given over several months might improve cardiac and renal function as well as exercise tolerance in patients with anemia and heart failure (6–9). Some of these studies combined use of EPO with intravenous iron (8,9). Controversy has arisen over whether chronic EPO therapy is safe (10), because thrombotic complications and hypertension have been reported in patients with end-stage renal disease when this strategy is employed (11–13). A recent editorial called for a halt to the TREAT (Trial to Reduce Cardiovascular Events with Aranesp [darbepoietin alpha] Therapy) study. This siren was in part based on a recent meta-analysis that casts doubt on the role of targeting Hb concentrations when using EPO in anemic patients with chronic kidney disease (14). Despite such concerns, a trial of darbepoietin alpha in patients with anemia and heart failure (RED-HF [Reduction of Events with Darbepoietin in Heart Failure]) has now been launched, and until more data are forthcoming, we simply won’t know about the long-term safety of this strategy in patients with heart failure. Uncertainty about target Hb levels remains challenging, but cold, hard facts are what we need. The trials of darbepoietin alpha should continue as long as their Data and Safety Monitoring Boards deem them safe to continue. Nevertheless, there is a certain uncomfortableness about driving the Hb level too high with EPO or darbepoietin in patients with chronic kidney disease or heart failure.
These uncertainties about whether and how to use EPO-like hormones to treat the anemia of heart failure aside, there are now 2 small published studies that report the use of intravenous iron alone as a treatment strategy (15,16). For many years, parenteral iron was considered dangerous, but with the emergence of iron saccharate (also known as iron sucrose complex) there are far fewer serious adverse effects than with the older high-molecular-weight dextran preparations (16). Nevertheless, acute myalgias (chest and back tightness) can occur. Bolger et al. (16) treated 16 anemic patients with heart failure with 1 g of iron sucrose by bolus intravenous injections over a 12-day treatment phase in an outpatient setting. Mean follow-up was 92 ± 6 days. Hemoglobin improved, symptoms were reduced, and exercise capacity was improved. There were no adverse effects. Now we have a second small study. With a more traditional randomized, placebo-controlled study design, Toblli et al. (15) studied 40 patients with heart failure and randomly allocated treatment to isotonic saline or iron sucrose complex 200 mg weekly infused over 60 min. Blinding was done by putting a black cover around the intravenous (IV) bag, so it is likely the research nurse was unblinded. Patients were treated for 5 weeks with IV iron and followed for 5 months. The treatment group improved in virtually all measured parameters, including the N-terminal part of the pro-B-type natriuretic peptide (NT-proBNP), New York Heart Association functional class, Minnesota Living with Heart Failure Quality of Life Score, less diuretic requirement, less need for hospital stay, improved 6-min walk test, lower C-reactive protein, reduced creatinine clearance, and improved left ventricular ejection fraction. One seldom sees such remarkably consistent improvement in all measurements in small studies such as this, but the results coupled with the observations of Bolger et al. (16) do suggest that further studies in this field might be fruitful.
The dramatic reduction in NT-proBNP is surprising with IV iron, because few therapies have previously demonstrated such long-term improvement in natriuretic peptides. The tight correlations between NT-proBNP and Hb are also surprising. Most correlations seen in interventional heart failure studies are far less striking. However, anemia is associated with elevated plasma B-type natriuretic peptide with or without heart failure (17,18), and it is possible that simply correcting the Hb leads directly to reduced NT-proBNP, whereas simultaneous improvement in the heart failure condition might further drive down the plasma natriuretic peptide levels.
These 2 clinical studies using IV iron to treat heart failure are important, because they raise the possibility that an alternative strategy different than that of using EPO analogs to treat patients with heart failure and anemia might work. Giving IV iron sucrose complex might prove to be more efficacious, safer, and less costly than employing long-term darbepoietin alpha. It is too early to tell. It should be kept in mind that EPOs might have additional, non-hematological effects. Antiapoptotic, mitogenic, and angiogenic activities can occur (19). Some of the non-hematologic "unintended effects" might be favorable, and some might not. We simply do not know.
We look forward to additional studies with IV iron. Only larger, more robust clinical trials with IV iron will allow confidence to emerge. We also need the large trials using EPO analogs to continue, because we will learn from these experiences. Nevertheless, small observational clinical studies done by single centers with novel strategies still play an important role in the ever-changing picture of therapy for chronic disease. These small studies seed the open mind to new ideas, allowing the construction of creative hypotheses to be eventually tested in a more expansive and scientifically sound manner. We now have 2 such studies. We look forward to further replication. (20).
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Footnotes
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* Editorials published in the Journal of American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
2 Dr. Francis is a consultant to Amgen.
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References
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1. Androne AS, Katz SD, Lund L, et al. Hemodilution is common in patients with advanced heart failure Circulation 2003;107:226-229.[Abstract/Free Full Text]2. Tang YD, SD Katz. Anemia in chronic heart failure: Prevalence, etiology, clinical correlates, and treatment options Circulation 2006;113:2454-2461.[Free Full Text] 3. Valeur N, Nielsen OW, McMurray JJ, Torp-Pedersen C, Køber L, TRACE Study Group Anaemia is an independent predictor of mortality in patients with left ventricular systolic dysfunction following acute myocardial infarction Eur J Heart Fail 2006;8:577-584.[Abstract/Free Full Text] 4. George J, Patal S, Wexler D, Abashidze A, et al. Circulating erythropoietin levels and prognosis in patients with congestive heart failure: comparison with neurohormonal and inflammatory markers Arch Intern Med 2005;165:1304-1309.[Abstract/Free Full Text] 5. 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.[Abstract/Free Full Text] 6. 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;107:294-299.[Abstract/Free Full Text] 7. 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.[Abstract/Free Full Text] 8. 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;35:1737-1744.[Abstract/Free Full Text] 9. 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.[Abstract/Free Full Text] 10. Mitka M. FDA sounds alert on anemia drugs JAMA 2007;297:1868-1869.[Free Full Text] 11. 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.[CrossRef][Medline] 12. Singh AK, Szczech L, Tang KL, et al. CHOIR Investigators Correction of anemia with epoetin alfa in chronic kidney disease N Engl J Med 2006;355:2085-2098.[CrossRef][Medline] 13. Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis Lancet 2007;369:381-388.[CrossRef][Web of Science][Medline] 14. Strippoli GF, Tognoni G, Navaneethan SD, Nicolucci A, Craig JC. Haemoglobin targets: we were wrong, time to move on Lancet 2007;369:346-350.[CrossRef][Web of Science][Medline] 15. 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;50:1657–65.[Abstract/Free Full Text] 16. 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.[Abstract/Free Full Text] 17. Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous iron for anaemia Lancet 2007;369:1502-1504.[CrossRef][Web of Science][Medline] 18. Tsuji H, Nishino N, Kimura Y, et al. Haemoglobin level influences plasma brain natriuretic peptide concentration Acta Cardiol 2004;59:527-531.[CrossRef][Web of Science][Medline] 19. Wold Knudsen C, Vik-Mo H, Omland T. Blood haemoglobin is an independent predictor of B-type natriuretic peptide (BNP) Clin Sci 2005;109:69-74(Lond).[CrossRef][Web of Science][Medline] 20. Smith KJ, Bleyer AJ, Little WC, Sane DC. The cardiovascular effects of erythropoietin Cardiovasc Res 2003;59:538-548.[Abstract/Free Full Text]
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Intravenous Iron Reduces NT-Pro-Brain Natriuretic Peptide in Anemic Patients With Chronic Heart Failure and Renal Insufficiency
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J. Am. Coll. Cardiol. 2007 50: 1657-1665.
[Abstract]
[Full Text]
[PDF]
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