Cardiovascular effects of hemoglobin response in patients receiving epoetin alfa and oral iron in heart failure with a preserved ejection fraction

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Abstract

Background

Previous data from a recently conducted prospective, single blind randomized clinical trial among community dwelling older patients with heart failure with a preserved ejection fraction (HFPEF) and anemia randomized to treatment with epoetin alfa (erythropoiesis-stimulating agents, ESA) vs. placebo did not demonstrate significant benefits of therapy regarding left ventricular (LV) structure, functional capacity, or quality of life (QOL). However, several patients randomized to the treatment arm were non-responders with a suboptimal increase in hemoglobin. All patients in the trial also received oral ferrous gluconate, which could have contributed to increases in hemoglobin observed in those receiving placebo. Accordingly, we performed an analysis separating patients into responders vs. non-responders in order to determine if measured improvement in anemia would have any effect on clinical endpoints.

Methods

A total of 56 patients (age 77 ± 11 years, 68% female) were recruited who had anemia defined as a hemoglobin of ≤ 12 g/dL (average, 10.4 ± 1 g/dL) with HFPEF defined as having NHANES-CHF (National Health And Nutrition Examination Survey: Congestive Heart Failure) criteria score of ≥ 3 and an ejection fraction of > 40% (average EF = 63% ± 15%). Patients were randomly allocated to receive either ESA and ferrous gluconate or ferrous gluconate only. In this analysis, a responder was defined as a patient with an increase of 1 g/dL in the first 4 weeks of the trial.

Results

Nineteen subjects were classified as responders compared to 33 non-responders. While the average hemoglobin increased significantly at the end of 6 months for responders (1.8 ± 0.3 vs. 0.8 ± 0.2 g/dL, P = 0.004), 50% of the subjects assigned to ESA were non-responders. Left ventricular function including ejection fraction ( P = 0.32) and end diastolic volume ( P = 0.59) was unchanged in responders compared to non-responders. Responders also showed no significant improvements in New York Heart Association (NYHA) class, Six Minute Walk Test (6 MWT) and peak VO ₂. Though QOL improved significantly within each group, there was no difference between the two.

Conclusions

A significant hemoglobin response to anemia treatment with ESA and oral iron does not lead to differences in LV remodeling, functional status, or QOL. Additionally, a significant percent of older adults with HFPEF and anemia do not respond to ESA therapy. Given the results of this small trial, it appears as though using objective improvements in anemia as a marker in older adult subjects with HFPEF does not have significant clinical utility.

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Most cited references 24

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A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.

Marc Pfeffer, Emmanuel A. Burdmann, Chao-Yin Chen … (2009)

Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested. In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.) 2009 Massachusetts Medical Society

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J Beard (2001)

The estimated prevalence of iron deficiency in the world suggests that there should be widespread negative consequences of this nutrient deficiency in both developed and developing countries. In considering the reality of these estimates, the Belmont Conference seeks to reconsider the accepted relationships of iron status to physiological, biochemical and neurological outcomes. This review focuses on the biological processes that we believe are the basis for alterations in the immune system, neural systems, and energy metabolism and exercise. The strength of evidence is considered in each of the domains and the large gaps in knowledge of basic biology or iron-dependent processes are identified. Iron is both an essential nutrient and a potential toxicant to cells; it requires a highly sophisticated and complex set of regulatory approaches to meet the demands of cells as well as prevent excess accumulation. It is hoped that this review of the more basic aspects of the biology of iron will set the stage for subsequent in-depth reviews of the relationship of iron to morbidity, mortality and functioning of iron-deficient individuals and populations.

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Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database.

Clyde Yancy, Margarita Lopatin, Lynne Stevenson … (2006)

Approximately 50% of patients hospitalized for heart failure have preserved systolic function. These patients are more likely to be older, women, and hypertensive. Their duration of hospitalization is similar to that of heart failure patients with systolic dysfunction, but their in-hospital mortality risk is lower. This mortality risk is increased in the setting of renal insufficiency, and the two most important risk predictors are elevated blood urea nitrogen and systolic blood pressure 100,000 hospitalizations from the Acute Decompensated Heart Failure National Registry (ADHERE) database were analyzed. Heart failure with PSF was present in 50.4% of patients with in-hospital assessment of left ventricular function. When compared with patients with systolic dysfunction, patients with PSF were more likely to be older, women, and hypertensive and less likely to have had a prior myocardial infarction or be receiving an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. In-hospital mortality was lower in patients with PSF compared with patients with systolic dysfunction (2.8% vs. 3.9%; adjusted odds ratio [OR]: 0.86; p = 0.005), but duration of intensive care unit stay and total hospital length of stay were similar. Serum creatinine >2 mg/dl was associated with increased in-hospital mortality in both systolic function groups (PSF: 4.8%; systolic dysfunction: 8.4%; p 37 mg/dl (OR: 2.53; 95% confidence interval [CI]: 2.22 to 2.87) and systolic blood pressure < or =125 mm Hg (OR: 2.58; 95% CI: 2.33 to 2.86). Heart failure with PSF is common and is characterized by a unique patient profile. Event rates are worrisome and reflect a need for more effective management strategies.

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Author and article information

Journal

Journal ID (nlm-ta): J Geriatr Cardiol

Journal ID (iso-abbrev): J Geriatr Cardiol

Journal ID (publisher-id): JGC

Title: Journal of Geriatric Cardiology : JGC

Publisher: Science Press

ISSN (Print): 1671-5411

Publication date (Print): June 2014

Volume: 11

Issue: 2

Pages: 100-105

Affiliations

[1 ]Clinical Cardiovascular Research Lab for the Elderly, Allen Hospital of New York Presbyterian Hospital, 5141 Broadway, 3 Field West, Room 037, New York, NY 10032, USA

[2 ]Columbia Mailman School of Public Health, 722 W 168 ^th Street, Rm 630, New York, NY 10032, USA

Author notes

Correspondence to: Mathew S. Maurer, MD, Clinical Cardiovascular Research Lab for the Elderly, Allen Hospital of New York Presbyterian Hospital, 5141 Broadway, 3 Field West, Room 037, New York, NY 10032, USA. E-mail: msm10@ 123456columbia.edu Telephone:+1-212932-4537 Fax:+1-212932-4538

Article

Publisher ID: jgc-11-02-100

DOI: 10.3969/j.issn.1671-5411.2014.02.002

PMC ID: 4076448

PubMed ID: 25009558

SO-VID: 17895267-5eee-43e2-a16d-1d1a52b5e6fa

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License, which allows readers to alter, transform, or build upon the article and then distribute the resulting work under the same or similar license to this one. The work must be attributed back to the original author and commercial use is not permitted without specific permission.

History

Date received : 27 February 2014

Date revision received : 3 May 2014

Date accepted : 10 May 2014

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