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

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.