Critical re-evaluation of the identification of iron deficiency states and effective iron repletion strategies in patients with chronic heart failure

Abstract

According to current guidelines, iron deficiency is defined by a serum ferritin level <100 ng/ml or a transferrin saturation (TSAT) <20% if the serum ferritin level is 100–299 μg/L. These criteria were developed to encourage the use of intravenous iron as an adjunct to erythropoiesis-stimulating agents in the treatment of renal anaemia. However, in patients with heart failure, these criteria are not supported by any pathophysiological or clinical evidence that they identify an absolute or functional iron deficiency state. A low baseline TSAT—but not serum ferritin level—appears to be a reliable indicator of the effect of intravenous iron to reduce major heart failure events. In randomized controlled trials, intravenous iron decreased the risk of cardiovascular death or total heart failure hospitalization in patients with a TSAT <20% (risk ratio 0.67 [0.49–0.92]) but not in patients with a TSAT ≥20% (risk ratio 0.99 [0.74–1.30]), with the magnitude of the risk reduction being proportional to the severity of hypoferraemia. Patients who were enrolled in clinical trials solely because they had a serum ferritin level <100 μg/L showed no significant benefit on heart failure outcomes, and it is noteworthy that serum ferritin levels of 20–300 μg/L lie entirely within the range of normal values for healthy adults. Current guidelines reflect the eligibility criteria of clinical trials, which inadvertently adopted unvalidated criteria to define iron deficiency. Reliance on these guidelines would lead to the treatment of many patients who are not iron deficient (serum ferritin level <100 μg/L but normal TSAT) and ignores the possibility of iron deficiency in patients with a low TSAT but with serum ferritin level of >300 μg/L. Importantly, analyses of benefit based on trial eligibility-driven guidelines substantially underestimate the magnitude of heart-failure-event risk reduction with intravenous iron in patients who are truly iron deficient. Based on all available data, we recommend a new mechanism-based and trial-tested approach that reflects the totality of evidence more faithfully than the historical process adopted by clinical investigators and by the guidelines. Until additional evidence is forthcoming, an iron deficiency state in patients with heart failure should be defined by a TSAT <20% (as long as the serum ferritin level is <400 μg/L), and furthermore, the use of a serum ferritin level <100 μg/L alone as a diagnostic criterion should be discarded.