Darbepoetin Alfa for Anemia in HF: No Clinical Benefit, Possible Harm

Summary and Comment |
March 10, 2013

Darbepoetin Alfa for Anemia in HF: No Clinical Benefit, Possible Harm

  1. Frederick A. Masoudi, MD, MSPH, FACC, FAHA

Erythropoiesis stimulation corrects the hemoglobin deficiency but fails to improve mortality or hospitalization rates and may increase thromboembolic risk.

  1. Frederick A. Masoudi, MD, MSPH, FACC, FAHA

In patients with heart failure (HF), anemia is common and associated with worse symptoms and increased mortality. To determine whether therapy to reverse anemia improves outcomes, investigators for the manufacturer-sponsored, international, randomized, double-blind, RED-HF trial studied the effects of darbepoetin alpha, an erythropoiesis-stimulating agent (ESA), on clinical outcomes in 2278 adults (mean age, 72; 41% women) with symptomatic systolic HF and anemia, defined as a hemoglobin level of 9.0–12.0 g/dL. Patients were assigned to receive placebo or darbepoetin alpha injections every 2 weeks until hemoglobin levels reached 13.0, followed by monthly maintenance doses. Those with evidence of iron deficiency received supplemental iron.

The median hemoglobin level was 11.2 in both groups at baseline and increased with treatment to 13.0 in the darbepoetin group and 11.5 in the placebo group; the between-group difference achieved statistical significance at 1 month. At a median follow-up of 28 months, the rate of the primary outcome of death or hospitalization for HF was similar in the darbepoetin and placebo groups (50.7% and 49.5%, respectively; P=0.87), and none of the secondary clinical endpoints differed significantly between the two groups. The darbepoetin group had modestly better quality-of-life scores than the placebo group (absolute difference in change in Kansas City Cardiomyopathy Questionnaire score, 2.2 points — not considered clinically important). However, the rate of thromboembolic events was higher in darbepoetin recipients than in placebo recipients (13.5% vs. 10.0%; P=0.01).

Comment

These findings are disappointing but not entirely surprising, given that trials of erythropoiesis-stimulating agents in chronic kidney disease have revealed no cardiovascular benefits and raised concerns of harm. Patients with systolic heart failure and mild or moderate anemia should not be treated with these agents. Furthermore, the suggestion of harm in this trial should forestall ESA use even in patients who were excluded (e.g., those with HF and more significant anemia or preserved left ventricular systolic function) until we have solid evidence of benefit.

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