From the Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands (P.v.d.M., N.G.B., B.D.W., D.J.v.V.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P., S.D.S.), Amgen, Thousand Oaks, CA (K.O.); Department of Medicine, University of Minnesota Medical School and VA Medical Center, Minneapolis (I.S.A.); BHF Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.V.M.); Department of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden (K.S.); and Department of Medicine, Cleveland Clinic, OH (J.B.Y.).
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Background:A poor response to erythropoiesis-stimulating agents such as darbepoetin alfa has been associated with adverse outcomes in patients with diabetes mellitus, chronic kidney disease, and anemia; whether this is also true in heart failure is unclear.Methods and Results:We performed a post hoc analysis of the RED-HF trial (Reduction of Events by Darbepoetin Alfa in Heart Failure), in which 1008 patients with systolic heart failure and anemia (hemoglobin level, 9.0–12.0 g/dL) were randomized to darbepoetin alfa. We examined the relationship between the hematopoietic response to darbepoetin alfa and the incidence of all-cause death or first heart failure hospitalization during a follow-up of 28 months. For the purposes of the present study, patients in the lowest quartile of hemoglobin change after 4 weeks were considered nonresponders. The median initial hemoglobin change in nonresponders (n=252) was −0.25 g/dL and +1.00 g/dL in the remainder of patients (n=756). Worse renal function, lower sodium levels, and less use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were independently associated with nonresponse. Although a low endogenous erythropoietin level helped to differentiate responders from nonresponders, its predictive value in a multivariable model was poor (C statistic=0.69). Nonresponders had a higher rate of all-cause death or first heart failure hospitalization (hazard ratio, 1.25; 95% confidence interval, 1.02–1.54) and a higher risk of all-cause mortality (hazard ratio, 1.30; 95% confidence interval, 1.04–1.63) than responders.Conclusions:A poor response to darbepoetin alfa was associated with worse outcomes in heart failure patients with anemia. Patients with a poor response were difficult to identify using clinical and biochemical biomarkers.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00358215.