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Approximately 50% of patients with heart failure and reduced ejection fraction are considered to be iron deficient, and many of these patients show clinical benefits following treatment with iron supplementation. Most of the experience with iron supplements in clinical trials has focused on the evaluation of ferric carboxymaltose (FCM). Treatment with FCM has produce favorable effects on functional capacity and exercise tolerance in patients with heart failure and reduced ejection fraction. A large-scale trial (AFFIRM-AHF) reported that FCM lowered the combined risk of cardiovascular death or hospitalization for heart failure, an effect that was driven primarily by an action to reduce hospitalizations due to heart failure in patients with underlying ischemic heart disease (interaction P < 0.05 for the difference in the effect in ischemic vs nonischemic patients).
AFFIRM-AHF Investigators. Impact of ischaemic aetiology on the efficacy of intravenous ferric carboxymaltose in patients with iron deficiency and acute heart failure: insights from the AFFIRM-AHF trial.
What might account for the apparent lack of benefit of FCM in patients with nonischemic cardiomyopathy? Many subgroup analyses in clinical trials are due to the play of chance and are not replicated in other trials, even when interaction P values are nominally significant. However, it is difficult to glean insights from earlier heart-failure trials with FCM, because they enrolled primarily patients with coronary artery disease. Importantly, in the AFFIRM-AHF trial, patients with nonischemic cardiomyopathy fulfilled current criteria for iron deficiency, and baseline serum ferritin levels were similar in patients with ischemic and nonischemic cardiomyopathy. Although transferrin saturations were slightly lower in patients with coronary artery disease, this small difference cannot explain the apparent lack of effect on outcomes with FCM in nonischemic cardiomyopathy, assuming it is a real finding. It is possible that ischemia acts to potentiate iron-depletion-related suppression of adenosine triphosphate synthesis, but there is no experimental support for this hypothesis.
It is, therefore, noteworthy that treatment with FCM produces a 3- –6-fold increase in circulating levels of fibroblast growth factor 23 (FGF23) (Fig. 1).
In the kidney, FGF23 acts to augment phosphaturia by downregulating expression of sodium-phosphate cotransporters in the proximal tubule and by decreasing circulating concentrations of 1,25-dihydroxyvitamin D. As a result of these actions, FCM produces severe hypophosphatemia in 25%--50% of patients with heart failure, which is typically seen within the first few weeks of treatment and persists for up to 6 weeks. The frequency and severity of hypophosphatemia are enhanced when FCM is given repeatedly, particularly when renal function is preserved. The degree of phosphate depletion can lead to myopathy, osteomalacia and fractures. It is important to note that the effect of increasing FGF23 and producing phosphate depletion is characteristically seen with FCM but not with other intravenous iron formulations.
Hypophosphatemia is common after intravenous ferric carboxymaltose infusion among patients with symptomatic heart failure with reduced ejection fraction.
Importantly, FGF23 exerts effects on the heart in addition to its actions on the kidney. Increases in FGF23 precede and are an independent predictor of left ventricular hypertrophy in patients with chronic kidney disease.
The adverse effects of FGF23 on hypertrophy are causal, because constitutive activation of FGF23 causes hypertrophy, whereas genetic suppression of the receptor for FGF23 prevents the development of hypertrophy in experimental chronic kidney disease.
FGF23 causes pathological hypertrophy in isolated rat cardiomyocytes through FGF receptor-dependent activation of the calcineurin-nuclear factor of activated T cells (calcineurin-NFAT) signaling pathway. Given these observations, it is noteworthy that increases in FGF23 have been reported to mediate the increased heart failure risk in iron-deficient patients with chronic kidney disease,
and they have adverse prognostic significance in patients with established heart failure. Patients with nonischemic cardiomyopathy who have marked increases in FGF23 experience the most striking declines in ejection fraction during follow-up.
The effects of FCM on FGF23 are relevant to the interpretation of the results of ongoing and future trials of intravenous iron supplementation in patients with heart failure. First, it will be important to distinguish trials that are evaluating FCM from those that are testing other intravenous formulations (eg, iron derisomaltose). Second, in the analysis of trials of iron supplementation, it will be critical to separate the effects seen in trials that administered single doses of intravenous iron from the effects seen in trials where patients were given repeated doses. Increases in FGF23 and associated hypophosphatemia typically last about 6 weeks, but FGF23 elevations and phosphate depletion can be profound when FCM is given as an ongoing treatment. Interestingly, large-scale trials with iron supplementation are recommending repeated doses of iron therapy at periodic intervals if patients continue to show continuing evidence of iron deficiency. Additional study is needed to determine whether the between-dose intervals (ie, every 4--6 months) in these trials may be long enough to prevent sustained FGF23 elevations and their potential adverse consequences in the heart and kidney.
Disclosures
The author reports consulting relationships with Abbvie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, and Salamandra.
References
Metra M
Jankowska EA
Pagnesi M
Anker SD
Butler J
Dorigotti F
et al.
AFFIRM-AHF Investigators. Impact of ischaemic aetiology on the efficacy of intravenous ferric carboxymaltose in patients with iron deficiency and acute heart failure: insights from the AFFIRM-AHF trial.
Hypophosphatemia is common after intravenous ferric carboxymaltose infusion among patients with symptomatic heart failure with reduced ejection fraction.
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