RED-HF

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Swedberg K, et al. "Treatment of anemia with darbepoetin alfa in systolic heart failure". The New England Journal of Medicine. 2013. 368(13):1210-9.
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Clinical Question

Among patients with LV systolic dysfunction and mild-to-moderate anemia, does the use of darbepoetin targeting a hemoglobin >13 g/dL reduce the composite outcome of all-cause mortality or first hospitalization for HF?

Bottom Line

Among patients with LV systolic dysfunction and mild-to-moderate anemia, the use of darbepoetin targeting a hemoglobin >13 g/dL does not reduce the composite outcome of all-cause mortality or first hospitalization for HF.

Major Points

Anemia affects some 25-40% of patients with HF and is associated with reduced survival and poor quality of life.[1] In patients with an unidentified cause of anemia, retrospective data suggested that erythropoiesis-stimulating agents (ESAs) could improve hemoglobin and quality of life, while reducing hospitalization rates. Small, non-blinded, prospective studies suggested a similar improvement with ESAs. Two larger trials, including STAMINA-HeFT,[2](2008) randomized patients to darbepoetin alfa or placebo, and demonstrated a favorable trend in the composite endpoint of all-cause mortality or first HF hospitalization. This prompted the larger phase III RED-HF study.[1]

Published in 2013, the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) study enrolled 2,278 patients with HF and anemia without an unidentified cause. Patients were required to have symptomatic HF with LVEF ≤40%, and hemoglobin 9-12 g/dL. Patients were randomized in a 1:1 ratio to darbepoetin alfa or matching placebo, targeting a hemoglobin >13 g/dL. All patients also receive intravenous or oral iron to maintain transferrin saturation >20%. At a median of 2.3 years, the composite endpoint of all-cause mortality or first hospitalization for HF was similar between groups (50.7% vs. 49.5%). More patients had a stroke in the darbepoetin alfa group (3.7% vs. 2.7%), although this difference did not reach statistical significance.

The trial was criticized for its use of a high target hemoglobin value of 13 g/dL.[3] In fact, TREAT (2009) had demonstrated that a high hemoglobin target (also 13 g/dL) was associated with more strokes, in patients with CKD and anemia receiving darbepoetin alfa. The authors recognize this as a limitation of the study, although they note that severe anemia is uncommon among HF patients.

In the absence of clear guidelines from AHA/ACC, the management of patients with HF and anemia should be individualized. In general, reversible causes of anemia (eg, iron deficiency, vitamin B12/folate deficiency, GI losses) should be identified and corrected. ESAs should not routinely be used in patients with HF and mild-to-moderate anemia without an identifiable cause, given the lack of supporting data. However, if ESAs are used, a target level less than 13 g/dL should probably be chosen.

Guidelines

As of August 2014, no guidelines have been published that reflect the results of this trial. Notably, the 2013 AHA/ACC guidelines on HF state that specific treatment recommendations were not given because of the lack of a definitive evidence base.[1]

Design

  • Multicenter, international, randomized, placebo-controlled trial
  • N=2,278 randomized
    • Darbeopetin alfa (n=1,136)
    • Placebo (n=1,142)
  • Setting: 453 sites in 33 countries
  • Enrollment: 2006-2012
  • Mean follow-up: 2.3 years
  • Analysis: As treated
  • Primary outcome: All-cause mortality or first hospitalization for HF

Population

Inclusion Criteria

  • NHYA class II-IV HF
  • LVEF ≤40% receiving guideline-recommended therapy
  • Hgb 9.0-12.0 g/dL

Exclusion Criteria

  • Transferrin saturation <15%
  • Evidence of bleeding or other correctable cause of anemia
  • Cr >3 mg/dL (265 μmol/L)
  • BP >160/100 mm Hg

Baseline Characteristics

From the darbepoetin group.

  • Demographics: Median age 72 years, female 40%, White 69%
  • Baseline health data: Median BP 120/70 mmHg, median HR 72 BPM, BMI 26 kg/m2
  • HF-specific: Median LVEF 31%, median HF duration 3.8 years, ICM 73%
    • NHYA class:
      • II: 33%
      • III-IV: 67%
  • PMH: HTN 73%, diabetes 46%, AF 33%, stroke 8%, any HF hospitalization in prior 6 months 35%, cancer 8%
  • Baseline medications: ACE or ARB 88%, beta-blocker 85%, diuretic 91%, aldosterone antagonist 44%
  • Labs: Creatinine 1.4 mg/dL, GFR 46 ml/min/1.73 m2, hemoglobin 11.2 g/dL, transferrin saturation 24%

Interventions

  • Randomized 1:1 to darbepoetin alfa or matching placebo, stratified by region, ICD use, CRT use, or use of both
  • Darbeopoetin or matching 0.75 μg/kg, every 2 weeks until hemoglobin >13 g/dL on two consecutive visits, then monthly, not to exceed hemolgobin 14.5 g/dL
  • Iron studies performed every 3 months; iron administered for transferrin saturation <20%

Outcomes

Comparisons are darbepoetin alfa vs. placebo.

Primary Outcome

All-cause mortality or first HF hospitalization
50.7% vs. 49.5% (HR 1.01; 95% CI 0.90-1.13; P=0.87)

Secondary Outcomes

All-cause mortality
41.7% vs. 40.1% (HR 1.04; 95% CI 0.92-1.19; P=0.51)
Stroke
3.7% vs. 2.7% (HR 1.33; 95% CI 0.83-2.12; P=0.23)
Median hemoglobin achieved
13.0 vs. 11.5 g/dL (P<0.001)
Non-study ESA use
3.5% vs. 6.7% (P<0.001)
Iron administration
4.9% vs. 5.6% (P=0.47)
Blood transfusions
10.9% vs. 16.5% (P<0.001)

Subgroup Analysis

There was no difference in treatment effect in a subgroup analysis of age, sex, race, region, baseline values of hemoglobin, GFR, or LVEF, or baseline device therapy.

Adverse Events

Adverse event leading to study drug discontinuation
19.5% vs. 20.1% (P=0.73)
Embolic events
13.5% vs. 10.0% (P=0.01)
Hypertension
7.1% vs. 6.1% (P=0.29)

Criticisms

  • The target hemoglobin value may have been too high. An analysis of high and low hemoglobin targets, as was done in the TREAT trial of anemia and CKD, may have demonstrated a benefit to ESA administration in patients with lower baseline hemoglobin levels. As it stands, the use of darbepoetin to achieve a hemoglobin >13 g/dL may have resulted in excess CV events, potentially counteracting any survival benefit from anemia correction.[3]
  • In fact, RED-HF specifically excluded patients with severe anemia (ie, hemoglobin <9 g/dL), who may have experienced greater benefits with ESAs. The authors address this by stating that severe anemia is rare in HF and presumably less relevant.

Funding

Funding from Amgen.

Further Reading

  1. 1.0 1.1 1.2 Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.
  2. Ghali JK, et al. "Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia." Circulation. 2008;117(4):526-535
  3. 3.0 3.1 Multiple authors. "Correspondence: Darbepoetin Alfa in Systolic Heart Failure." N Engl J Med. 2013; 369:487-489