Definition of anaemia in heart failure: are the WHO thresholds too low?
M Chimura, P Pellicori, K Docherty, B L Claggett, Akshay S Desai, M Packer, P S Jhund, Jean L Rouleau, John R Teerlink, M Vaduganathan, D J van Veldhuisen, F Zannad, M R Zile, S D Solomon, J McMurrayAbstract
Background
The World Health Organization (WHO) defines anaemia as haemoglobin (Hb) <12 g/dL in women and <13 g/dL in men. These thresholds are widely used in clinical practice and research; however, they are based on the lower fifth percentile of Hb distribution in young healthy populations and were not derived from associations with clinical outcomes. Accordingly, whether these definitions appropriately stratify prognostic risk in heart failure (HF) - a condition defined by reduced tissue oxygen delivery - remains uncertain. We have re-examined the association between Hb concentration and risk of adverse outcomes in men and women with HFrEF and HFpEF (across the full range of Hb).
Purpose
To examine the association between Hb concentration and clinical outcomes in patients with HF and to identify sex-specific Hb values associated with the nadir in risk across HF phenotypes (HFrEF and HFpEF).
Methods
Patient-level data from 5 HFrEF trials and 5 HFpEF trials (EMPHASIS-HF, PARADIGM-HF, DAPA-HF, GALACTIC-HF, CHARM, I-Preserve, PARAGON-HF, TOPCAT-America, FINEARTS-HF) were pooled. Associations between Hb concentration and all-cause death, cardiovascular (CV) death, first HF hospitalization, and the composite of HF hospitalization or CV death were evaluated using Cox proportional hazards models. Non-linear relationships were assessed using restricted cubic spline analyses. Models were stratified by trial and adjusted for age, heart rate, NYHA class III/IV, body mass index, left ventricular ejection fraction (LVEF), serum creatinine, log-transformed NT-proBNP, history of atrial fibrillation, prior myocardial infarction, diabetes, prior stroke, previous HF hospitalization, race, diuretic use, and treatment assignment. Nadir Hb values were identified from spline curves for each outcome.
Results
Among 31826 patients with HFrEF, 7070 (22.2%) were women (age 65.9±11.5 years, LVEF 29.0±6.4%, Hb 12.9±1.5 g/dL) and 24,756 (77.8%) were men (age 64.3±11.2 years, LVEF 28.2±6.4%, Hb 14.0±1.6 g/dL). Among 13,404 patients with HFpEF, 7,453 (55.6%) were women (age 73.0±8.4 years, LVEF 60.3±7.4%, Hb 13.0±1.5 g/dL) and 5,951 (44.4%) were men (age 71.5±9.0 years, LVEF 58.1±6.7%, Hb 13.8±1.8 g/dL). Hb concentration demonstrated a reverse J-shaped or U-shaped association with all outcomes (Figure). In the adjusted model for the overall HF population, the nadir Hb concentration across all outcomes was approximately 14 g/dL in women and 15 g/dL in men. Similar patterns were observed in both HFrEF and HFpEF (Table).
Conclusions
In patients with HF, the Hb concentration associated with the lowest risk of adverse outcomes is approximately 2 g/dL higher than the current WHO anaemia thresholds. Importantly, higher risk was observed even among patients with Hb concentrations up to 2 g/dL above WHO-defined anaemia. These findings suggest that optimal Hb thresholds may warrant reconsideration in patients with HF.Incidence of outcomes by haemoglobin in HFHaemoglobin associated with the lowest risk