BARCELONA — Researchers moved a step closer toward proving that correcting the anemia that often occurs in patients with heart failure improves outcomes, with results from three phase II studies that tested two different ways to boost hemoglobin levels.
Reports from two controlled studies that compared darbepoetin alfa with placebo in 475 patients showed that the treatment was safe, that it produced improvements in patients' exercise capacity that were tied to boosts in hemoglobin levels, and that the drug could cut the rate of death or hospitalization for heart failure at a rate that approached statistical significance, Dr. William T. Abraham reported at a joint meeting of the European Society of Cardiology and the World Heart Federation.
And results from the first randomized, observer-blinded test of intravenous iron in 35 patients with heart failure and low iron levels supported the idea that iron repletion is safe and associated with improvement in exercise capacity and heart failure symptoms, Dr. Stefan D. Anker said in a separate report at the meeting.
Anemia is a common complication of heart failure, but just how common depends on how it's defined. In data collected from one recent, large heart failure treatment trial, 30% of women and 16% of men had anemia if it was defined as a serum hemoglobin level of less than 12.5 g/dL. With a more conservative definition of less than 11.5 g/dL, the prevalence was 10% among women and 8% among men, said Dr. Anker, a cardiologist and professor of medicine at Charité University in Berlin.
These hemoglobin levels would not be severe enough to warrant drug interventions if they occurred in otherwise healthy people, in whom the hemoglobin level would have to be less than 10 g/dL to make drug intervention reasonable, Dr. Anker said in an interview. But in the context of heart failure, experts have hypothesized that higher hemoglobin levels might lead to clinically important improvements in exercise capacity and quality of life, and to a significant drop in heart failure hospitalizations. The two most obvious ways to correct anemia are treatment with an erythropoietin agent and treatment with iron supplementation, which could also be used together.
Three phase II studies of darbepoetin alfa, a long-acting erythropoietin, were recently completed, and results from the two largest of these studies were reported at the meeting. All three studies were sponsored by Amgen, which markets darbepoetin (Aranesp). Dr. Abraham has received research support from Amgen.
One trial involved 319 patients with New York Heart Association class II-IV heart failure and a serum hemoglobin level of 9.0–12.5 g/dL; their average baseline hemoglobin level was 11.35 g/dL. Of the 319 patients, 157 were randomized to receive placebo and 162 received darbepoetin alfa at a starting dosage of 0.75 mcg/kg administered subcutaneously every 2 weeks. The dosage was titrated to produce a rise in hemoglobin of 0.5–1.5 g/dL every 3 weeks and then to maintain a hemoglobin level of 13.0–15.0 g/dL. All patients also received supplemental iron, given as an oral dosage of 200 mg/day. The primary end point for this study was the change in exercise capacity from baseline after 6 months of treatment, measured as time spent walking on a treadmill.
The regimen produced an average hemoglobin level of 13.5 g/dL in patients treated with darbepoetin alfa and no change in the patients treated with placebo.
The change in treadmill-exercise time was an average of 46.5 seconds in placebo patients and 57.3 seconds in the darbepoetin alfa-treated patients, a nonsignificant difference, reported Dr. Abraham, professor of medicine and director of the division of cardiovascular medicine at Ohio State University, Columbus.
However, a post hoc analysis of these data showed a promising and statistically significant link between the rise in serum hemoglobin level and improvements in exercise time (see table). More than 80% of patients treated with darbepoetin alfa had a “robust response to treatment,” with a hemoglobin rise of more than 1 g/dL, and these patients had substantial improvements in their exercise time, noted Dr. Abraham.
A prespecified end point for the two largest of the trials was a combined analysis to assess safety and efficacy measured by the incidence of all-cause death or first hospitalization for heart failure after 1 year of treatment. This combined the results from the 319-patient study described above and the results from a study with 165 patients. The second study randomized 55 patients to placebo, 56 to a weight-based dosage of darbepoetin that was the same as was used in the larger study, and 54 patients to a fixed-dosage regimen of the drug that used 50 mcg every 2 weeks. The results showed no difference between the effects of the weight-based and fixed dosages. Data for the combined analysis were available for 209 patients who received placebo and 266 who received darbepoetin alfa. The 1-year incidence of death or hospitalization for heart failure was reduced by 33% in the patients treated with darbepoetin, compared with those who received placebo, a difference that neared statistical significance. Darbepoetin alfa treatment was also associated with trends in improved quality of life and patients' global self-assessment.