Ferric carboxymaltose not better than placebo for ambulatory heart failure patients with iron deficiency-HEART-FID trial.

Iron deficiency is common among patients with heart failure, occurring in 40 to 50% of patients with chronic heart failure and in up to 80% of patients with acute heart failure. Previous randomized, controlled trials have shown that supplementation with intravenous ferric carboxymaltose (FC) improved functional status and exercise capacity and induced cardiac reverse remodeling in patients with heart failure and a reduced ejection fraction.

But contrary to the above results, findings from the recently published HEART-FID trial suggest that among ambulatory patients who had heart failure with a reduced ejection fraction and iron deficiency, there was no apparent difference between FC and placebo with respect to the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance. These perplexing results were recently published in NEJM.

In this double-blind, randomized, controlled trial, 3065 symptomatic ambulatory patients who had heart failure with a reduced ejection fraction (defined as ≤40%) and iron deficiency were assigned, in a 1:1 ratio, to receive ferric carboxymaltose or placebo, in addition to standard therapy for heart failure.

Among the inclusion criteria were hospitalization for heart failure within the previous 12 months or an elevated natriuretic peptide level.

The primary efficacy end point was a hierarchical composite of death at 12 months, hospitalizations for heart failure at 12 months, and the change in the 6-minute walk distance from baseline to 6 months, assessed as the unmatched win ratio.

The authors found that intravenous iron was safe, but the difference from placebo was not significant. The treatment effect of ferric carboxymaltose on the 6-minute walk distance was surprisingly small in the HEART-FID trial, and the lack of a long-term reduction in hospitalizations for heart failure was unexpected, given the results of the AFFIRM-AHF and IRONMAN trials that have been published in recent years.

Why this discrepancy?

Authors Mentz et al. suggest that the lower-risk population in their trial might be one of the explanations for the lower treatment effects in the HEART-FID trial. Furthermore, analyses from previous trials suggested that intravenous iron did not have a treatment effect in patients with a transferrin saturation of more than 20%. In the present trial, the mean (±SD) transferrin saturation was 23.9%±11.2 at baseline and this may suggest the modest effect of IV FC.

Future analyses — preferably a meta-analysis of individual-patient data from all intravenous iron trials — should assess the importance of the transferrin saturation value at baseline. This could help redefine the definition of iron deficiency in patients with heart failure and, we hope, help clinicians determine which patients might benefit from intravenous iron supplementation.

Source: NEJM: DOI: 10.1056/NEJMoa2304968