Heart failure (HF) is a significant health problem that affects millions of Americans every year. Some estimates have shown that anemia is prevalent in up to 61% of patients with HF, and that this condition could lead to increased morbidity and mortality. However, the potential for improved outcome through anemia correction is not well explored. Some small-scale studies have proposed modalities for correction of anemia such as erythropoiesis-stimulating proteins (ESPs) or iron supplementation. These studies, discussed in this review by da Silva et al, have examined the mechanisms of anemia in HF and how new diagnostic and treatment strategies may be developed.

Anemia in HF patients is thought to be caused by a multitude of factors. In many instances, hemodilution, erythropoietin (EPO) deficit, the use of angiotensin-converting enzyme inhibitors, and EPO resistance may play a combined role in the development of anemia. Most commonly, insufficient iron intake or defects in iron utilization are related to mild to moderate forms of anemia. A recent study reported iron deficiency as the primary cause of anemia in HF patients in up to 73% of the cohort. Because the underlying mechanisms of anemia in HF patients are multifactorial, developing specific treatment strategies is difficult.

Thus, combined strategies involving EPO administration and intravenous (IV) iron therapy have been the most extensively studied. Many studies involving a combination of the two therapies have yielded some promising results. In some cases, patients showed increased left ventricle ejection fraction, decreased use of diuretics, and decreased incidence of hospitalizations. Darbepoetin alfa—an erythropoiesis-stimulating protein—was also shown to increase (hemoglobin) Hb levels in anemic HF patients. However, most studies to date have been restricted to patients with specific cardiorenal syndromes, and it is still unclear whether the benefits observed are due to ESP therapy or iron administration. Larger clinical trials are currently underway, including a study that will focus on the impact of iron supplementation alone in anemic HF patients. The authors contend that by determining the effectiveness of such clinical therapies, clinicians will be able to develop specific treatment strategies.

Beck da Silva L, Rohde LE, Clausell N. Etiology and management of anemia in patients with heart failure: how much iron is missing? Congest Heart Fail. 2008 Jan-Feb;14(1):25-30.

NAAC Expert Commentary:
The prevalence of anemia in the NHANES population survey was 5 %.¹ In HF clinical trials and large HF registries, the prevalence has ranged from 15-61%.^2-4 Low Hb levels are independently associated with increased mortality and hospitalizations for HF in patients with acute or chronic HF.^5-7 The prevalence and increase in poor outcomes is the same in patients with impaired or preserved left ventricular function.

As reported in the review article by Da Silva et al, relative or absolute iron deficiency may play an important role in HF patients as indicated in bone marrow studies by the low levels of iron available for erythropoiesis, despite normal ferritin and iron studies from the peripheral blood.⁸ Erythropoietin levels are normally increased in HF patients, but are still lower than expected for the degree of anemia. Several studies tracking the benefit of ESAs, including darbepoetin alfa, have not shown clear benefit in HF symptoms or outcomes. STAMINA-HeFT is the largest study of darbepoetin alpha in HF patients.⁹ In this multicenter, randomized double-blind placebo controlled study, 319 HF patients were randomized to darbepoetin (n=162) or placebo (n=157) to maintain Hb levels at 14.0±1.0 g/dL. At week 27, despite a significant increase in Hb levels, the primary endpoint of change from baseline (in treadmill exercise time) was not improved; nor was there any improvement in NYHA class or MLHFQ score compared with placebo. The drug was well tolerated and adverse effects were similar in both treatment groups.

A general proinflammatory state might be responsible for an inappropriate EPO production and/or defective iron utilization in HF patients.¹⁰ Da Silva’s review calls patients with a true iron deficiency in HF 'ferropenic' and cites a report of 73% prevalence for such patients from a study where bone marrow aspirates were used to diagnose iron store status in HF patients.¹¹ Intravenous iron may provide iron to the bone marrow and bypass the reticuloendothelial system, where it may be unavailable due to a chronic inflammatory state.^10,12 FERRIC-HF randomized 35 HF patients to 16 weeks of IV iron or no treatment and found that in patients with baseline anemia there was an absolute increase in peak VO2 and an overall improvement in NYHA class and patient global assessment.¹³ The IRON-HF study is a multi-center prospectively designed, randomized, double blind, placebo-controlled clinical trial among HF patients with Hb levels of 9-12 g/dL that has the potential to provide evidence for the benefit of IV iron replacement in this group of patients.

References

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8. Beck da Silva L, Rohde LE, Clausell N. Etiology and management of anemia in patients with heart failure: how much iron is missing? Congest Heart Fail. 2008 Jan-Feb;14(1):25-30.
9. Ghali JK, Anand IS, Abraham WT, Fonarow GC, Greenberg B, Krum H, Massie BM, Wasserman SM, Trotman ML, Sun Y, Knusel B, Armstrong P; 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 Jan 29;117(4):526-35.
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12. Handelman GJ, Levin NW. Iron and anemia in human biology: a review of mechanisms. Heart Fail Rev (2008) 13: 393-404.
13. Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Roughton M, Foldes G, Thum T, Majda J, Banasiak W, Missouris CG, Poole-Wilson PA, Anker SD, Ponikowski P. 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 Jan 15;51(2):103-12.

Last Modified: October 1, 2008