Anemia is common in patients with heart failure and has been shown to be an independent risk factor for severe symptoms in heart failure patients, such as lower functional status, worse exercise capacity, cognitive impairment, and worse quality of life. Because of the detrimental impact of anemia on these patients, anemia has become an important target for heart failure therapy.

Preliminary studies have demonstrated that erythropoiesis-stimulating agents (ESAs) may improve exercise capacity and cardiac and renal function in heart failure patients. Although the studies were not designed to be conclusive, the evidence from preliminary studies suggests that treatment of anemia may lead to improved outcomes in heart failure patients.

The Study of Anemia in Heart Failure Trial was designed to test the efficacy of using a long-acting ESA, darbepoetin alfa, to treat patients with heart failure in a multicenter (65 centers), double-blind, randomized, placebo-controlled, phase II study. Patients in the treatment arm received darbepoetin alfa subcutaneously every two weeks for a total of 52 weeks. The primary endpoint was the change from baseline to week 27 in treadmill exercise time. Secondary endpoints consisted of the change from baseline to week 27 in (1) New York Heart Association functional classification and (2) health-related quality-of-life, measured by the Minnesota Living with Heart Failure Questionnaire. One-year analysis of all cause mortality was also conducted.

The study cohort consisted of 157 patients receiving placebo and 162 patients receiving darbepoetin alfa. Transient ischemic attacks occurred in four patients in the darbepoetin alfa group compared with one in the placebo group. However, patients not treated with darbepoetin had a higher number and frequency of worsening heart failure episodes compared to the placebo group. In 85% of patients treated with darbepoetin alfa, two consecutive hemoglobin levels of 14.0 +/- 1.0 g/dL were achieved, and patients experienced >1.0 g/dL increase in Hb level from baseline.

Neither the exercise capacity nor quality-of-life improved significantly in patients receiving darbepoetin alfa compared with placebo. However, a nonsignificant trend was observed toward a lower risk of all cause mortality or first heart failure hospitalization in patients treated with darbepoetin (hazard ratio, 0.68; 95% CI, 0.43, 1.08; P=0.10).

Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Ghali JK, Anand IS, Abraham WT, Fonarow GC, Greenberg B, Krum H, Massie BM, Wasserman SM, Trotman ML, Sun Y, Knusel B, Armstrong P; Study of Anemia in Heart Failure Trial (STAMINA-HeFT) Group. Circulation. 2008 Jan 29;117(4):526-35.

NAAC Expert Commentary:
The risk of death in heart failure patients increases roughly 12% for each g/dL decrease in Hb level. Whether anemia is merely a marker or a mediator of the risk is uncertain. STAMINA-HF is the first of several clinical trials designed to test the hypothesis that correction of the anemia in heart failure patients will obviate the risk of death associated with anemia. In this trial, patients who were iron replete (iron saturation ≥15%) received darbepoetin alpha to correct the anemia. Darbepoetin alpha increased the Hb level by approximately 1.5 g/dL. However, the trial failed to show improvements in heart failure signs and symptoms, or exercise performance. Nevertheless, a post hoc analysis did suggest that patients who had an increase in Hb level, regardless of therapy, had a greater increase in exercise duration. The trial also found a strong trend for survival free of hospitalization at 1 year (hazard ratio 0.68, p=0.10). There was a nonsignificant reduction in mortality (44%) and heart failure related hospitalization (26%).

Treatment with ESAs has come under scrutiny because of association with potential increases in mortality in patients with chronic kidney disease and cancer. Treatment to higher versus lower Hb levels in patients with chronic kidney disease has been associated with harm. However, in this study of patients with heart failure, the trend was the opposite, and results even suggested a potential benefit. Importantly, thrombotic events (MI, TIA, CVA, PE, or DVT) were similar with darbepoetin (7%) and placebo (7%).

Treatment of anemia in heart failure is being approached by two different therapies: intravenous iron or ESA. When the results of these clinical trials are available, we will know if anemia should be treated in heart failure patients and the benefit of these two alternative approaches. It is likely that many heart failure patients will require treatment with both ESA and intravenous iron to correct the anemia as is the current standard for chronic kidney disease patients. We await the results of clinical trials in heart failure patients to determine when we should treat anemia, how to treat it, and what target Hb levels are appropriate. In the mean time, each provider will need to decide how best to treat anemia in heart failure patients.

Last Modified: August 14, 2008