Reduction of Events by Darbepoetin Alfa in Heart Failure - RED-HF

Description:

Patients with systolic heart failure and anemia have worse symptoms, functional capacity, and outcomes than those without anemia. Studies on the role of erythropoietin-stimulating agents (ESAs) have been mixed and small for the most part. The current trial sought to investigate the safety and efficacy of darbepoetin alpha in patients with symptomatic systolic heart failure and anemia.

Hypothesis:

Darbepoetin alpha would be superior to placebo in reducing mortality and rehospitalizations in patients with symptomatic systolic heart failure and anemia.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Hgb 9-12 g/dl
  • Left ventricular ejection fraction ≤40%
  • New York Heart Association (NYHA) class II-IV
  • On guideline-recommended CHF therapy

    Number of screened applicants: 5,788
    Number of enrollees: 2,278
    Duration of follow-up: 1 year
    Mean patient age: 71.5 years
    Percentage female: 42%
    Ejection fraction: 31%
    NYHA class: II (35%), III/IV (65%)

Exclusions:

  • Transferrin saturation <15%
  • Bleeding or other correctable causes of anemia
  • Serum creatinine >3 mg/dl
  • Blood pressure >160/100 mm Hg

Primary Endpoints:

  • Time to death from any cause or first hospital admission for worsening heart failure, whichever occurs first

Secondary Endpoints:

  • Time to death from any cause
  • Time to cardiovascular death or first hospital admission for worsening heart failure, whichever occurs first
  • Change from baseline to month 6 in KCCQ overall summary score
  • Change from baseline to month 6 in KCCQ symptom frequency score

Drug/Procedures Used:

Patients were randomized in a 1:1 fashion to receive either darbepoetin alpha (target hemoglobin [Hgb] 13.0-14.5 g/dl) or placebo. Darbepoetin alpha was administered at a dose of 0.75 mcg/kg every 2 weeks until target Hgb was reached on two consecutive visits.

Concomitant Medications:

Beta-blockers (85%), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (89%), and diuretics (91%)

Principal Findings:

A total of 2,278 patients were randomized at 453 sites in 33 countries, 1,136 to darbepoetin alpha and 1,142 to placebo. Baseline characteristics were fairly similar between the two arms. The median ejection fraction was 31%, and 73% had ischemic cardiomyopathy. Median baseline glomerular filtration rate was 45.7 mg/dl, Hgb 11.2 g/dl, and transferring saturation 24%. Oral iron was utilized by 73% of patients during the study.

Darbepoetin alpha significantly improved Hgb over the study period compared with placebo (13.0 vs. 11.5 g/dl). This effect was apparent as early as 1 month. The primary outcome of death/hospitalization for congestive heart failure (CHF) was similar between the two arms (50.7% vs. 49.5%, hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.90-1.13, p = 0.87). Individual endpoints including all-cause mortality (41.7% vs. 40.1%, p = 0.51) and first hospitalization for worsening CHF (27.6% vs. 27.2%, p = 0.92) were similar. Other outcomes including myocardial infarction (5.6% vs. 6.5%, p = 0.32), stroke (3.7% vs. 2.7%, p = 0.23), deep vein thrombosis (0.9% vs. 0.9%, p = 0.98), and pulmonary embolism (0.5% vs. 0.2%, p = 0.13) were all similar between the two arms.

Any embolic or thrombotic event was higher in the darbepoetin alpha arm (13.5% vs. 10%, p = 0.009). Symptomatic improvement seemed to be higher in the darbepoetin arm: least squares mean change from baseline to month 6 in the overall Kansas City Cardiomyopathy Questionnaire (KCCQ) score was higher (6.68 points vs. 4.48 points, p = 0.005).

Interpretation:

The results of the RED-HF trial indicate that routine use of darbepoetin alpha, an ESA, in symptomatic CHF patients with anemia is not associated with superior clinical outcomes as compared with placebo. As has been noted with ESAs in various patient populations, thrombotic events including stroke were higher in the darbepoetin alpha arm.

This is the largest trial on this topic with ESAs. Several smaller trials had suggested a possible benefit with ESA use in this patient population. Since low Hgb is associated with poor outcomes, but increasing Hgb via ESAs is not beneficial, it appears that low Hgb (anemia) is a marker of adverse outcomes in this patient population, and probably not itself on the causal pathway.

References:

Swedberg K, Young JB, Anand IS, et al., on behalf of the RED-HF Committees and Investigators. Treatment of anemia with darbepoetin alpha in systolic heart failure. N Engl J Med 2013;Mar 10:[Epub ahead of print].

Presented by Dr. Karl Swedberg at ACC.13, San Francisco, March 10, 2013.

Clinical Topics: Heart Failure and Cardiomyopathies, Vascular Medicine, Acute Heart Failure, Chronic Heart Failure

Keywords: Iron, Myocardial Infarction, Follow-Up Studies, Pulmonary Embolism, Heart Failure, Systolic, Least-Squares Analysis, Erythropoietin, Hemoglobins, Cardiomyopathies, Stroke Volume, Glomerular Filtration Rate, Venous Thrombosis, Questionnaires, Confidence Intervals


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