Iron Deficiency in Heart Failure: A Scientific Statement from the Heart Failure Society of America

Beavers, Craig J.; Ambrosy, Andrew P.; Butler, Javed; Davidson, Beth Towery; Gale, Stormi E; Piña, Ileana L.; Mastoris, Ioannis; Reza, Nosheen; Mentz, Robert J; Lewis, Gregory D.

doi:10.1016/j.cardfail.2023.03.025

Cited by 25 publications

(12 citation statements)

References 129 publications

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“…The use of IV iron plays an essential role in managing HF and is supported by consistent data which demonstrated benefit in those with iron deficiency (Table 2) [7,8,9 ▪ ,38,39 ▪ ,48–50,51 ▪ ]. Early trial data revealed an association between IV iron administration and improved peak Vo 2 [38,49,50] Evidence suggests there is a correlation between improved peak Vo2 and a lower risk of death or hospitalization in individuals with HF [52–54]. Improvement in left ventricular ejection fraction following IV iron administration has also been reported [48].…”

Section: Clinical Evidencementioning

confidence: 86%

Intravenous iron in patients with iron deficiency and heart failure: a review of modern evidence

Gale,

Willeford,

Sandquist

et al. 2024

Current Opinion in Cardiology

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Purpose of review Iron deficiency is common in patients with heart failure, affecting up to half of ambulatory patients and an even greater percentage of patients admitted for acute decompensation. Iron deficiency in this population is also associated with poor outcomes, including worse quality of life in addition to increased hospitalizations for heart failure and mortality. Evidence suggests that patients with iron deficiency in heart failure may benefit from repletion with IV iron. Recent findings In this review, we outline the etiology and pathophysiology of iron deficiency in heart failure as well as various iron formulations available. We discuss evidence for intravenous iron repletion with a particular focus on recent studies that have evaluated its effects on hospitalizations and mortality. Finally, we discuss areas of uncertainty and future study and provide practical guidance for iron repletion. Summary In summary, there is overwhelming evidence that intravenous iron repletion in patients with iron deficiency in heart failure is both beneficial and safe. However, further evidence is needed to better identify which patients would most benefit from iron repletion as well as the ideal repletion strategy.

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Section: Clinical Evidencementioning

confidence: 86%

Intravenous iron in patients with iron deficiency and heart failure: a review of modern evidence

Gale,

Willeford,

Sandquist

et al. 2024

Current Opinion in Cardiology

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“…Many studies provide evidence of how iron deficiency may contribute to worse HF outcomes. 3,4 The reduction in oxygen carrying capacity related to anaemia taxes a failing heart. But the causal link can be explained at a more generalized level as iron is an essential cofactor for multiple enzymatic functions across organ systems, for example, soluble guanylate cyclase activity.…”

Section: Is There Biologic Plausibility Causally Linking Iron Deficie...mentioning

confidence: 99%

“…In prior trials, the magnitude of improvement in 6MWD with iron replacement in HF was greater than what is typically observed with drug therapy for HF. 3 Notably, none of the trials to date have compared oral versus intravenous iron and it has been challenging to identify specific subgroups who respond to oral iron. 5 Also, clear data are not available demonstrating that intravenous iron increases peak oxygen consumption.…”

Section: Is Iron Replacement Associated With Improved Functional Status?mentioning

confidence: 99%

“…TSAT <20%). 3 Abnormal iron indices may also be a marker of HF exacerbation rather than a cause or mediator. The dose of ferric carboxymaltose and dosing scheduling also differed from prior trials (up to 1500 mg every 6 months in HEART-FID vs. up to 1000 mg at baseline followed by weeks 6, 12, and 24 in AFFIRM-AHF)-the repletion strategy varied.…”

Section: What Did the Heart-fid Trial Show And How To Interpret The R...mentioning

confidence: 99%

“…2 This result contrasted with previous studies that showed improvement in functional capacity and health status, and in exploratory analyses, risk reduction for HF hospitalization, with iron replacement in HF with iron deficiency. 3 Considering the purpose and nature of HEART-FID, it is important to contextualize these results to understand the role of iron therapy in patients with HF.…”

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Iron replacement therapy in heart failure: Contextualizing the results of the HEART‐FID trial

Butler,

Mentz,

Hernandez

2024

European J of Heart Fail

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HEART-FID was the largest randomized trial of intravenous iron replacement therapy in patients with heart failure (HF) and iron deficiency. 1 This trial showed a modest benefit with intravenous iron replacement therapy on the hierarchical composite endpoint of all-cause mortality, HF hospitalization risk, or 6-min walk distance (6MWD) that did not achieve the pre-specified significance level. 2 This result contrasted with previous studies that showed improvement in functional capacity and health status, and in exploratory analyses, risk reduction for HF hospitalization, with iron replacement in HF with iron deficiency. 3 Considering the purpose and nature of HEART-FID, it is important to contextualize these results to understand the role of iron therapy in patients with HF.

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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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Iron Deficiency in Heart Failure: A Scientific Statement from the Heart Failure Society of America

Cited by 25 publications

References 129 publications

Intravenous iron in patients with iron deficiency and heart failure: a review of modern evidence

Intravenous iron in patients with iron deficiency and heart failure: a review of modern evidence

Iron replacement therapy in heart failure: Contextualizing the results of the HEART‐FID trial

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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