Randomized Double-Blind Trial of Darbepoetin Alfa in Patients With Symptomatic Heart Failure and Anemia

Wayne State University, Detroit, Mich, USA.
Circulation (Impact Factor: 14.43). 01/2008; 117(4):526-35. DOI: 10.1161/CIRCULATIONAHA.107.698514
Source: PubMed


Substantial evidence suggests that anemia is an independent risk factor for worse outcomes in patients with heart failure (HF). The Study of Anemia in Heart Failure Trial (STAMINA-HeFT) is the largest multicenter, randomized, double-blind, placebo-controlled trial to date evaluating the effect of treating anemia in HF.
Patients (N=319) with symptomatic HF, left ventricular ejection fraction < or = 40%, and hemoglobin > or = 9.0 g/dL and < or = 12.5 g/dL were randomized (double-blind) to placebo (N=157) or darbepoetin alfa (N=162) subcutaneously every 2 weeks for 1 year (target hemoglobin, 14.0+/-1.0 g/dL). The primary end point was change from baseline to week 27 in treadmill exercise time. Secondary end points were change from baseline in New York Heart Association class and quality of life at week 27. An additional prespecified efficacy analysis included the time to death by any cause or first HF-related hospitalization by 1 year. At baseline, the median (interquartile range) hemoglobin was 11.4 (10.9, 12.0) g/dL. At week 27, darbepoetin alfa treatment increased median (interquartile range) hemoglobin by 1.8 (1.1, 2.5) g/dL (placebo, 0.3 [-0.2, 1.0] g/dL; P<0.001). Of the patients treated with darbepoetin alfa, 85% achieved 2 consecutive hemoglobin levels of 14.0+/-1.0 g/dL during the study and experienced a hemoglobin increase of > or = 1.0 g/dL from baseline. By intent-to-treat analysis, darbepoetin alfa treatment did not significantly improve exercise duration, New York Heart Association class, or quality of life score compared with placebo. A nonsignificant trend was observed toward a lower risk of all-cause mortality or first HF hospitalization in darbepoetin alfa-treated patients compared with placebo (hazard ratio, 0.68; 95% CI, 0.43, 1.08; P=0.10). Occurrences of adverse events were similar in both treatment groups.
In this study of patients with symptomatic HF and anemia, treatment with darbepoetin alfa was not associated with significant clinical benefits. Darbepoetin alfa treatment was well tolerated and effectively raised hemoglobin. A trend of lower risk of morbidity and mortality was observed.

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    • "Results are expressed as mean ± SE unless otherwise specified. We defined responders as those who had an increase in hemoglobin ≥ 1 g/dL in the first four weeks of the trial regardless of assigned arm and a non-responder was an individual with an increase in hemoglobin < 1 g/dL in the first four weeks which was a definition used in a published set of guidelines for poor ESA responders.[10] The primary endpoints of the original analysis were change in LVEDV as measured by freehand 3D transthoracic echocardiography and secondary endpoints included changes in stroke volume and EF, sub-maximal exercise tolerance measured via 6MWT, maximal exercise capacity measured by CPET with peak VO2, and QOL as measured by assessing changes in scores from the KCCQ. "
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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 VO2. 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.
    Full-text · Article · Jun 2014 · Journal of Geriatric Cardiology
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    • "Thus, rhEpo administration and anaemia correction might reduce HF hospitalisations, and also improve exercise capacity and quality of life [106]. Thus, rhEpo administration and anaemia correction might reduce HF hospitalisations, and also improve exercise capacity and quality of life [107] [108] [109] [110] [111]. One of the main difficulties related to the concomitant effects of rhEpo therapy in HF treatment is the associated increase in red blood cell mass. "
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    ABSTRACT: Erythropoietin (Epo) has been thought to act exclusively on erythroid progenitor cells. The identification of Epo receptor (EpoR) in non-haematopoietic cells and tissues including neurons, astrocytes, microglia, immune cells, cancer cell lines, endothelial cells, bone marrow stromal cells, as well as cells of myocardium, reproductive system, gastrointestinal tract, kidney, pancreas and skeletal muscle indicates that Epo has pleiotropic actions. Epo shows signals through protein kinases, anti-apoptotic proteins and transcription factors. In light of interest of administering recombinant human erythropoietin (rhEpo) and its analogues for limiting infarct size and left ventricular (LV) remodelling after acute myocardial infarction (AMI) in humans, the foremost studies utilising rhEpo are reviewed. The putative mechanisms involved in Epo-induced cardioprotection are related to the antiapoptotic, anti-inflammatory and angiogenic effects of Epo. Thus, cardioprotective potentials of rhEpo are reviewed in this article by focusing on clinical applicability. An overview of non-haematopoietic Epo analogues, which are a reliable alternative to the classic EpoR agonists and may prevent undesired side effects, is also provided.
    Full-text · Article · Dec 2013 · International journal of cardiology
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    • "The individuals were randomized to receive placebo or darbepoetin alpha, with the objective of keeping hemoglobin at 14 g/dL. The results did not show improvement of the functional capacity among the groups44. "
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    ABSTRACT: Anemia is a prevalent comorbidity and marker of a poorer prognosis in patients with heart failure (HF). Its clinical relevance, as well as its pathophysiology and the clinical management of these patients are important subjects in the specialized literature. In the present review, we describe the current concepts on the pathophysiology of anemia in HF, its diagnostic criteria, and the recommendations for iron supplementation. Also, we make a critical analysis of the major studies showing evidences on the benefits of this supplementation. The four main components of anemia are addressed: chronic disease, dilutional, "renal" and malabsorption. In patients with HF, the diagnostic criteria are the same as those used in the general population: serum ferritin levels lower than 30 mcg/L in patients without kidney diseases and lower than 100 mcg/L or serum ferritin levels between 100-299 mcg/L with transferring saturation lower than 20% in patients with chronic kidney diseases. Finally, the therapeutic possibilities for anemia in this specific patient population are discussed.
    Full-text · Article · Jul 2013 · Arquivos brasileiros de cardiologia
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