Anemia treatment not beneficial in heart failure


SAN FRANCISCO – Treatment of anemic heart failure patients with the erythropoiesis-stimulating agent darbepoetin alfa failed to produce any clinically meaningful improvements and significantly raised the incidence of ischemic stroke and thrombotic events in a randomized, multicenter trial with more than 2,200 patients.

“Our findings do not support the use of erythropoiesis-stimulating agents to reduced cardiovascular morbidity and mortality in patients with systolic heart failure and mild-to-moderately severe anemia,” Dr. Karl Swedberg said on March 10 at the annual meeting of the American College of Cardiology.

Dr. Karl Swedberg

Patients with heart failure also often have anemia, and results from small studies had suggested that increasing patients’ hemoglobin levels could improve their functional capacity. In addition, results from observational studies had shown worse outcomes in heart failure patients with hemoglobin levels less than 12.0 g/dL, and that a 1.0 g/dL change in hemoglobin level linked with a difference of 15-20 percentage points in all-cause mortality.

But the results of the current study called into question whether anemia plays any primary role in worsened outcomes.

Treatment with darbepoetin had “questionable clinical impact and increased thromboembolic events.” The treatment also significantly linked with an increased rate of ischemic cerebrovascular disorders that was “worrying. Our findings suggest that the hemoglobin level, like other surrogates, is simply a marker of poor prognosis in heart failure rather than a therapeutic target," said Dr. Swedberg, professor of medicine at the University of Gothenburg, Sweden. Simultaneously with his report at the meeting, the findings were also published online (N. Engl. J. Med. 2013; 368: doi:10.1056/NEJMoa1214865).

The Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) trial enrolled 2,278 patients with New York Heart Association class II-IV heart failure and a hemoglobin level of 9.0-12.0 g/dL at 453 sites in 33 countries during June 2006–May 2012. All patients also had a left ventricular ejection fraction of 40% or less. The study excluded patients with iron deficiency (transferrin saturation of less than 15%), evidence or bleeding or other causes of anemia, and patients with a high serum creatinine level or blood pressure above 160/100 mm Hg. The median age of the enrolled patients was 72 years, 65% had class III or IV heart failure, and their median ejection fraction was 31%. Median hemoglobin at entry was 11.2 g/dL.

The 1,136 patients assigned to receive darbepoetin injections began at a dose of 0.75 mcg/kg body weight once every 2 weeks; once they achieved a hemoglobin level of 13.0 g/dL treatment scaled back to once monthly, and treatment was continued to maintain a hemoglobin level of 13.0-14.5 g/dL. The difference in hemoglobin levels between these patients and the 1,142 randomized to the placebo control group became statistically significant after 1 month and remained significant through the study, which had a median follow-up of 28 months. The median monthly darbepoetin dosage was 167 mcg. When patients’ transferrin saturation fell below 20% they received supplemental iron.

The study’s primary endpoint was the combined rate of all-cause death and hospitalization for worsening heart failure. This occurred in 51% of the patients treated with darbepoetin alfa and 50% of those who received placebo, a difference that was not statistically significant. The result was consistent across all subgroups examined, and was not affected by adjustment for baseline differences between the two treatment arms. Total mortality was also similar between the two groups, 42% in the darbepoetin-treated patients and 40% in the controls.

The total number of hospitalizations for heart failure was 572 in the darbepoetin arm and 695 among the placebo patients, a difference that just missed being statistically significant (P = 0.06).

The overall Summary Score of the Kansas City Cardiomyopathy Questionnaire, a measure of quality of life in heart failure patients, was 6.68 in the darbepoetin-treated patients and 4.48 in the placebo patients, an average 2.2 point difference that was statistically significant. But the percent of patients with at least a 5-point increase in their score over baseline – a clinically meaningful increase – was 53% in the darbepoetin group and 48% in the placebo arm, a difference that fell short of statistical significant (P = 0.06).

The rate of study drug discontinuations due to adverse events was similar in the two arms. The rate of any embolic and thrombotic event was 14% in the darbepoetin patients and 10% in the placebo patients, a statistically significant difference. The rate of ischemic cerebrovascular events was 5% in the darbepoetin arm and 3% in the placebo arm, a statistically significant difference, although the overall rate of all cerebrovascular disorders – ischemic or hemorrhagic – was not significantly different between the two treatment groups. Episodes of septic shock were also significantly more frequent in the darbepoetin-treatment patients.


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