Criteria for Iron Deficiency in Patients With Heart Failure

Quick Takes

  • Disparate definitions of iron deficiency provide discordant results for prevalence and prognosis.
  • A clear definition of iron deficiency should be developed so that iron replacement therapy is not excluded from those patients who may benefit from this treatment.
  • When defined by current guideline criteria, iron deficiency was not associated with poor outcome; and lower serum ferritin concentrations were associated with a better survival. Transferrin saturation (TSAT) <20% and serum iron ≤13 mmol/L were associated with a higher mortality and this was independent of heart failure phenotype.

Study Questions:

How do different definitions of iron deficiency (ID) affect its prevalence and relationship to prognosis in ambulatory patients with chronic heart failure (HF)?

Methods:

The study cohort was comprised of patients with symptoms and signs of HF and either: 1) a left ventricular ejection fraction (LVEF) ≤40% (HF with reduced EF [HFrEF] or moderate or severe LV systolic dysfunction [LVSD]), or 2) a plasma N-terminal pro–B-type natriuretic peptide ≥125 ng/L. Anemia was defined according to World Health Organization criteria as hemoglobin <12.0 g/dL in women and <13.0 g/dL in men. Serum ferritin, transferring saturation (TSAT), and serum iron were used as biomarkers of ID. Serum concentrations of ferritin and iron were measured and TSAT (%) calculated using the formula: [iron (mmol/L)/(transferrin [g/L] × 25.2) × 100]. Only patients with all these iron biomarkers and hemoglobin values available were included in this analysis. Prevalence, relationship with patients’ characteristics, and outcomes of various ID definitions were evaluated among patients with HF.

Results:

The study cohort was comprised of 4,422 patients with HF (median age, 75 years [range, 68-82 years], 60% men, 32% with reduced LVEF), of whom 46% had TSAT <20%, 48% had serum iron ≤13 mmol/L, 57% had serum ferritin <100 ng/mL; 68% fulfilled current guideline criteria for ID, of whom 35% had a TSAT >20%. The study authors found that irrespective of definition, ID was more common in women and those with more severe symptoms, anemia, or preserved EF. The 5-year mortality was 34.5%. TSAT <20% and serum iron ≤13 mmol/L, but not guideline criteria, were associated with higher 5-year mortality (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.14-1.43; p < 0.001; and HR, 1.37; 95% CI, 1.22-1.54; p < 0.001, respectively). Serum ferritin <100 ng/mL tended to be associated with lower mortality (HR, 0.91; 95% CI, 0.81-1.01; p = 0.09). Mortality was highest for those with a serum ferritin >100 ng/mL with a TSAT <20%.

Conclusions:

The authors concluded that different definitions of ID provide discordant results for prevalence and prognosis. They opined that definitions lacking specificity may attenuate the benefits of intravenous iron observed in trials, while definitions lacking sensitivity may exclude patients who should receive intravenous iron. They suggested that prespecified subgroup analyses of ongoing randomized trials should address this issue.

Perspective:

Although this is a single-center study, it highlights the importance of building a consensus on defining ID, particularly because biomarkers such as serum ferritin are also elevated in inflammatory states and the latter is often associated with ID. A consensus group of nephrologists, hematologists, endocrinologists, infectious disease specialists, and cardiologists should be charged by societies, such as the American Heart Association, American College of Cardiology, European Society of Cardiology, and Heart Failure Society of America, to clearly define ID state so that replacement therapy is administered to those who will benefit from this treatment and also to ensure those who are eligible are not excluded.

Keywords: Anemia, Iron-Deficiency, Biomarkers, Ferritins, Geriatrics, Heart Failure, Hemoglobins, Iron, Natriuretic Peptide, Brain, Phenotype, Secondary Prevention, Stroke Volume, Transferrins, Ventricular Function, Left


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