Article Identification

• Title: “Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure”
• Citation: Swedberg K, Young JB, Anand IS, et al. N Engl J Med. 2013;368(13):1210-1219.
• PubMed ID: 23473338
• DOI: 10.1056/NEJMoa1214865

Quick Reference Summary

• In this randomized, double-blind trial (RED-HF) of 2278 patients with systolic heart failure (HF) and mild-to-moderate anemia, darbepoetin alfa (aiming for target hemoglobin of 13 g/dL) did not reduce the rate of death or first HF hospitalization compared with placebo (50.7% vs 49.5%, HR=1.01 [95% CI, 0.90–1.13], p=0.87).
• Although hemoglobin levels rose significantly in the darbepoetin alfa group and modest improvements in HF-related quality-of-life scores were noted, there was no significant clinical outcome benefit and there was a higher incidence of thromboembolic events (13.5% vs 10.0%, p=0.01).

Core Clinical Question

Does correcting mild-to-moderate anemia (hemoglobin 9.0–12.0 g/dL) with darbepoetin alfa in patients with systolic heart failure lead to improved clinical outcomes (death or HF hospitalization) compared with placebo?

Background

• Disease or Condition Overview:
  • Anemia in systolic HF is common and is associated with poorer functional capacity, higher rates of hospitalization, and increased mortality.
  • Causes include decreased erythropoietin production, resistance to erythropoietin, iron deficiency, chronic inflammation, and renal impairment.
• Prior Data on the Topic:
  • Small pilot studies suggested that raising hemoglobin with erythropoiesis-stimulating agents (ESAs) might improve exercise capacity and reduce hospitalizations in HF with anemia.
  • However, larger trials (especially in chronic kidney disease populations) showed neutral effects or even harm (e.g., stroke, thrombotic events) with more aggressive hemoglobin targets.
• Current Standard of Care:
  • Optimal guideline-directed medical therapy for systolic HF includes RAAS inhibitors, beta-blockers, diuretics, and other disease-directed agents.
  • Routine use of ESAs solely for mild-to-moderate anemia in HF is not recommended by major guidelines because previous data have not demonstrated a definitive mortality or morbidity benefit.
• Knowledge Gaps Addressed by Study:
  • Whether systematically targeting a hemoglobin of 13 g/dL in systolic HF patients would improve clinical outcomes.
  • Whether benefits, if present, outweigh known risks such as increased thromboembolic events.
• Study Rationale: Observational data suggested a strong association between anemia in HF and worse outcomes, prompting investigation of a therapeutic approach to elevate hemoglobin to potentially improve survival and reduce hospitalizations.

Methods Summary

• Study Design: Multicenter, randomized, double-blind, placebo-controlled trial (RED-HF).
• Setting and Time Period: 453 sites in 33 countries; enrollment from June 2006 to May 2012 with a median follow-up of 28 months.
• Population Characteristics:
  • 2278 patients, all with systolic HF (LVEF ≤40%), NYHA class II–IV, and mild-to-moderate anemia (hemoglobin 9.0–12.0 g/dL).
  • Median age: 72 years; 41% female; median ejection fraction ~31%.
• Inclusion/Exclusion Criteria:
  • Inclusion: Left ventricular EF ≤40%, NYHA II–IV, hemoglobin 9.0–12.0 g/dL, on guideline-recommended HF therapy.
  • Exclusion: Severe iron deficiency (transferrin saturation <15%), recent significant hemorrhage, CKD with creatinine >3 mg/dL, uncontrolled hypertension (>160/100 mm Hg).
• Intervention Details: Darbepoetin alfa (starting 0.75 μg/kg every 2 weeks) with dose adjustments aiming for hemoglobin of 13.0 g/dL.
• Control/Comparison Group: Placebo injections mirroring darbepoetin alfa schedule and dose increments to maintain blinding.
• Primary and Secondary Outcomes:
  • Primary: Composite of death from any cause or first HF hospitalization.
  • Secondary: Death from any cause; composite of cardiovascular death or first HF hospitalization; patient-reported quality of life (KCCQ).
• Statistical Analysis Approach: Stratified log-rank tests for time-to-event analyses; Cox proportional-hazards estimates for hazard ratios and 95% CIs. Target event accrual: ~1150 primary events to detect a 20% difference with 80% power.
• Sample Size Calculation: Planned ~2600 patients to capture 1150 events; enrollment concluded at 2278 patients when event target was reached.
• Ethics and Funding: Approved by institutional review boards at each site. Funded by Amgen (manufacturer of darbepoetin alfa).

Detailed Results

• Participant Flow and Demographics:
  • 1136 patients randomized to darbepoetin alfa; 1142 to placebo.
  • Median age 72 years, ~65% NYHA class III–IV, median estimated GFR ~46 mL/min/1.73 m².
• Primary Outcome Results:
  • Death or first HF hospitalization: 50.7% (darbepoetin alfa) vs 49.5% (placebo), HR=1.01 (95% CI, 0.90–1.13), p=0.87. (No significant difference)
• Secondary Outcomes:
  • All-cause death: 41.7% (darbepoetin alfa) vs 40.1% (placebo), p=0.51.
  • Cardiovascular death or first HF hospitalization: similar rates in both groups.
  • Quality-of-life KCCQ scores improved slightly more in the darbepoetin alfa group (+2.20 points, 95% CI 0.65–3.75, p=0.005), but magnitude did not translate into robust clinical outcome gains.
• Subgroup Analyses: No significant treatment effect difference by age, sex, region, or renal function.
• Adverse Events/Safety Data:
  • Thromboembolic events: 13.5% vs 10.0% (p=0.01) in the darbepoetin alfa vs placebo groups.
  • Stroke: 3.7% vs 2.7% (p=0.23).
  • Similar cancer-related adverse events between groups.

Results Table (Key Outcomes)

*KCCQ = Kansas City Cardiomyopathy Questionnaire. Change score indicates improvement from baseline; +5 points considered clinically meaningful but overall population effect was modest.

Authors' Conclusions

• Primary Conclusions: Correcting mild-to-moderate anemia in systolic HF up to a hemoglobin target of 13 g/dL with darbepoetin alfa failed to improve survival or reduce HF hospitalizations.
• Authors’ Interpretation of Results:
  • Anemia appears to be predominantly a marker of poor prognosis rather than a therapeutic target in this population.
  • Risk of thromboembolic events was higher with darbepoetin alfa, suggesting a net neutral or potentially harmful effect.
• Clinical Implications Stated by Authors:
  • Routine use of darbepoetin alfa for mild-to-moderate anemia in systolic HF is not supported.
  • Further research should focus on alternative methods of managing anemia (e.g., strategies addressing iron deficiency).
• Future Research Recommendations:
  • Investigations into underlying mechanisms of anemia in HF (e.g., iron metabolism, inflammatory pathways).
  • Evaluation of targeted subpopulations where ESA therapy might be beneficial (e.g., severe anemia, specific phenotypes).

Literature Context

• A. Previous Studies and Meta-Analyses:
  • TREAT: In diabetic chronic kidney disease, darbepoetin alfa was associated with increased stroke risk and no cardiovascular benefit, mirroring RED-HF’s finding of neutral outcomes and elevated thromboembolic risk.
  • Other CKD Studies: Showed ESAs did not improve cardiovascular outcomes and could raise atherothrombotic event risk.
• B. Contrasting Methodological Quality:
  • RED-HF vs. TREAT: Both were large, randomized, placebo-controlled trials. Both demonstrated neutral mortality benefit and increased thromboembolic complications with ESA use.
• C. Comparisons with Guidelines:
  • Guidelines recommend against using ESAs solely to correct mild-to-moderate anemia in HF, referencing lack of mortality benefit and possible harm.
• D. This Trial’s Contribution:
  • Confirms no benefit from targeting a hemoglobin level of 13 g/dL in systolic HF with mild-to-moderate anemia.
  • Reinforces the need to explore alternative anemia treatments (e.g., intravenous iron for iron deficiency).

Critical Analysis

Strengths

• Large sample size (n=2278) with adequate power to detect clinically meaningful differences.
• Randomized, double-blind, placebo-controlled design to minimize selection, performance, and detection biases.
• Comprehensive outcome measures, including mortality, hospitalizations, and patient-reported quality-of-life.

Limitations

• Excluded patients with severe anemia (hemoglobin <9.0 g/dL), so results may not apply to this subgroup.
• Median follow-up of ~28 months may not capture very long-term effects of ESA therapy.
• High use of supplemental iron might limit the generalizability to settings where intensive iron replacement is not standard.
• Elevated thromboembolic events were secondary outcomes, so caution is needed in interpreting these as definitive.

Clinical Application

• Findings strongly suggest that routine use of darbepoetin alfa to raise hemoglobin to ~13 g/dL in patients with systolic HF and mild-to-moderate anemia does not improve outcomes and carries added risk of thromboembolic events.
• Current practice should continue to emphasize guideline-directed HF therapies, identify and treat iron deficiency where indicated, and avoid ESAs for anemia correction in HF absent other clear indications (e.g., end-stage renal disease).

How To Use This Info In Practice

Clinicians should refrain from prescribing darbepoetin alfa solely for mild-to-moderate anemia correction in systolic HF, as robust evidence—including RED-HF—does not support any survival or hospitalization benefit and indicates a potential for harm.