Influence of serum transferrin concentration on diagnostic criteria for iron deficiency in chronic heart failure

Graham, Fraser J; Pellicori, Pierpaolo; Masini, G; Cuthbert, Joe; Clark, Andrew L.; Cleland, John G.F.

doi:10.1002/ehf2.14438

Cited by 11 publications

(5 citation statements)

References 35 publications

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“… 1 , 9 , 22 TSAT depends not only on serum concentrations of iron but also of transferrin, which is inversely related to serum ferritin. 5 As serum ferritin rises, transferrin falls, leading to a higher TSAT for a given serum iron concentration. Conversely, when serum ferritin is low, transferrin will be higher, leading to lower TSAT for a given serum iron concentration.…”

Section: Discussionmentioning

confidence: 99%

“…There is greater consensus for transferrin saturation (TSAT), with values < 20% generally accepted as evidence of iron deficiency. Serum concentrations of iron 2 , 5 or soluble transferrin receptors 6 , 7 might be better markers of iron deficiency, but neither has been measured routinely in substantial randomized trials of i.v. iron.…”

Section: Introductionmentioning

confidence: 99%

“…Ultimately, the therapeutic response to iron supplements is the best guide to the clinical need for treatment with iron. 5 , 11 However, several measures of response might be considered, including increases in haemoglobin, improvements in symptoms and exercise capacity, or reductions in hospitalization for heart failure or mortality. Accordingly, we now explore the relationship between baseline anaemia severity, serum ferritin, and TSAT, and the clinical response to i.v.…”

Section: Introductionmentioning

confidence: 99%

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Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial

Cleland,

Kalra,

Pellicori

et al. 2024

European Heart Journal

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Background and Aims What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? Methods In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. Results The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. Conclusions This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial

Cleland,

Kalra,

Pellicori

et al. 2024

European Heart Journal

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“…46 The correct definition of iron deficiency as ferritin <100 ng/L or ferritin 100-299 ng/L together with transferrin saturation <20% remains a matter of ongoing debate, even though no better recommendation has been reached in HF so far. 47,48…”

Section: Iron Deficiencymentioning

confidence: 99%

Editors' highlight picks from 2023 in ESC heart failure

Bäck,

von Haehling,

Papp

et al. 2024

ESC Heart Failure

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Heart failure is a devastating syndrome affecting an increasingly high number of patients worldwide. Its aetiology and pathogenesis are complex with the involvement of factors ranging from the genetic material through valvular dysfunctions to numerous organs beyond the entire cardiovascular system. Based on continuous efforts of the heart failure scientific community we have witnessed major advances in many related disciplines during the last year. For example, epidemiological aspects—paving the road for improved risk prevention—have been thoroughly analysed for various geographical regions. Additionally, evidence‐based approaches now allow the introduction of novel guideline recommended medical therapies (i.e. sodium‐glucose transporter 2 inhibitors, and iron supplementation) while basic and translational research aim to explore additional molecular targets for future heart failure diagnostics and medications. All above aspects are addressed in this article, where a selection of articles published in the ESC Heart Failure journal in 2023 are highlighted. The editors are confident that the scientific contributions of ESC Heart Failure effectively served a highly relevant area of cardiovascular research last year.

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“…124,135 However, when biomarkers are analysed individually, the serum ferritin level does not predict heart failure outcomes, whereas both serum iron level ≤13 μmol/L and TSAT <20% have prognostic significance. [136][137][138][139] Although changes in serum iron and TSAT are not perfectly correlated, 140 TSAT <20% (but not ferritin) is used to guide iron supplementation in patients receiving ESAs. 141 Patients with high serum ferritin levels (≥300 μg/L), but low serum iron concentrations (≤13 μmol/L), low TSAT (<20%) or anaemia-features commonly seen in functional iron deficiency-are at particularly high risk of adverse outcomes, 136,139,142 but they are not captured by the guideline definition of iron deficiency.…”

Section: Serum Ferritin Levels Provide Misleading Information About I...mentioning

confidence: 99%

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

Packer,

Anker,

Butler

et al. 2024

European J of Heart Fail

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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.

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Influence of serum transferrin concentration on diagnostic criteria for iron deficiency in chronic heart failure

Cited by 11 publications

References 35 publications

Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial

Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial

Editors' highlight picks from 2023 in ESC heart failure

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

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