Low-Normal Hemoglobin Concentrations and Clinical Outcomes in Heart Failure

BACKGROUND: The World Health Organization (WHO) defines anemia as hemoglobin concentration <12 g/dL in women and <13 g/dL in men. Although widely used clinically, these thresholds were based on distributions in healthy populations rather than on outcomes. Whether these WHO thresholds adequately reflect the relationship between hemoglobin concentration and clinical outcomes in patients with heart failure (HF) is uncertain. OBJECTIVES: We sought to characterize sex-specific associations between hemoglobin concentration and clinical outcomes and to identify the hemoglobin concentrations associated with the lowest observed risk in patients with HF across the spectrum of left ventricular ejection fraction. METHODS: Patient-level data were pooled from 6 trials in heart failure with reduced ejection fraction (HFrEF) and 5 trials in heart failure with preserved ejection fraction (HFpEF) or heart failure with mildly reduced ejection fraction (HFmrEF). Associations among baseline hemoglobin and a first HF hospitalization or cardiovascular death, the components of this composite, and all-cause death were examined using Cox proportional hazards models. Sex-specific hemoglobin concentrations associated with the lowest incidence rates were estimated using Poisson regression with restricted cubic splines. Outcomes were also examined by hemoglobin categories defined relative to WHO anemia thresholds. RESULTS: Overall, 25,003 patients with HFrEF (5,581 women, 19,422 men) and 17,210 with HFpEF/HFmrEF (8,763 women, 8,447 men) were included. In HFrEF, median hemoglobin was 13.0 g/dL (Q1-Q3: 12.1-13.9 g/dL) in women and 14.0 g/dL (Q1-Q3: 12.9-15.1 g/dL) in men; corresponding values in HFpEF/HFmrEF were 13.1 g/dL (Q1-Q3: 12.1-14.0 g/dL) and 14.0 g/dL (Q1-Q3: 12.8-15.0 g/dL), respectively. Across HF phenotypes and outcomes, the lowest risk occurred at hemoglobin concentrations of approximately 14 g/dL in women and 15 g/dL in men, above the WHO anemia thresholds. With hemoglobin ≥2 g/dL above the WHO anemia thresholds as the reference, WHO-defined anemia was associated with the highest adjusted risk. Excess risk was also observed at 0 to <1 g/dL above the thresholds. CONCLUSIONS: In patients with HF, hemoglobin concentrations associated with the lowest risk of death and HF hospitalization were approximately 14 g/dL in women and 15 g/dL in men. Hemoglobin concentrations above WHO anemia thresholds may still carry prognostic information and, in conjunction with other clinical findings, may prompt consideration of potentially reversible contributors such as iron deficiency. (Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM-Added], NCT00634309; Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM-Alternative], NCT00634400; Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM-Preserved], NCT00634712; A Comparison Of Outcomes In Patients In New York Heart Association [NYHA] Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines [EMPHASIS-HF], NCT00232180; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve], NCT00095238; Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT], NCT00094302; This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure [PARADIGM-HF], NCT01035255; Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF], NCT01920711; Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF], NCT03036124; Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF], NCT02929329; Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626).