Name of the Study: Efficacy of Ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta-analysis

Reviwer: Dr. Cemalettin Akman

Published Congress: ESC 2023

Link: https://doi.org/10.1093/eurheartj/ehad586

Background:

Iron deficiency (ID) is common in heart failure (HF), with a prevalence of 50–80%. The presence of iron deficiency in HF is associated with reduced exercise capacity, impaired quality of life (QoL), increased hospitalization and rehospitalization rates, and increased mortality. Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency (ID) and heart failure (HF) has been consistently demonstrated, the effects of treatment on clinical events remain the subject of research.

Objective:

Given the size of prior studies and their primary objectives, there has been uncertainty on 8 whether therapy with intravenous iron also reduces the risk of clinical events in HF patients with iron deficiency. The purpose of this meta-analysis is to demonstrate the effects of FCM treatment on hospitalizations and mortality.

Methods:

Patients meeting the following criteria were included in this meta-analysis from studies; (i) adult patients with HF and ID (with the same definition across all three trials: ferritin <100 ng/mL or ferritin 100–300 ng/mL with a transferrin saturation [TSAT] <20%); (ii) used FCM as an active treatment for ID; (iii) were randomized, double-blind, placebo-controlled trials; (iv) had at least 52 weeks of follow-up; and (v) prospectively recorded clinical outcomes: first and recurrent HF and CV hospitalizations, CV death, and all-cause death. Shorter follow-up studies were not included. Three randomized controlled trials met these prespecified criteria: CONFIRM-HF, AFFIRM-AHF, and HEART-FID. In the three FCM trials, 4501 patients were randomized to receive either FCM (n=2251) or placebo (n=2250).

Results:

The primary efficacy endpoints were a composite of total cardiovascular hospitalizations and cardiovascular death, as well as a composite of total HF hospitalizations and cardiovascular death. Key secondary endpoints included individual components of the composite endpoints. Findings from the meta-analysis showed FCM therapy significantly reduced the co-primary composite endpoint of total cardiovascular hospitalizations and cardiovascular death compared with placebo.The co-primary composite endpoint of total HF hospitalizations and cardiovascular deaths decreased but did not reach statistical significance (RR 0.87; 95% CI 0.75 vs 1.01; p=0.076). In other findings, FCM therapy was associated with a 17% relative rate reduction in total cardiovascular hospitalizations and a 16% relative rate reduction in total HF hospitalizations. No effect of FCM administration on mortality was observed. Subgroup analyses found that patients in the lowest transferrin saturation tertile (<15%) experience greater benefit from FCM on the composite endpoint of total cardiovascular hospitalizations or cardiovascular death than those with higher baseline transferrin saturation. Overall, treatment with FCM appeared to be safe and well-tolerated.

Conclusion:

In iron-deficient patients with HF with reduced left ventricular ejection fraction, intravenous FCM was associated with significantly reduced risk of hospital admissions for HF and cardiovascular causes, with no apparent effect on mortality. The findings indicate that intravenous FCM should be considered in iron-deficient patients with HF and reduced or mildly reduced ejection fraction to reduce the risk of hospitalization due to HF and cardiovascular causes.

Interpretations:

The results of this meta-analysis should be evaluated in the context of some limitations. Aggregated data could not be used for susceptibility analyzes for the entire cohort alone, as there was no access to IPD from the IRONMAN trial, and data from the IRONMAN trial could not be used for subgroup analyses. Data from the IRONMAN study could not be used for subgroup analyses. Follow-up was limited to 12 months in the main analyzes because this was the maximum possible follow-up period for the CONFIRM-HF and AFFIRM-AHF trials. The results of this large meta-analysis provide further support that FCM treatment significantly reduces recurrent HF and CV hospitalizations. No new security concerns have emerged in the current analysis. Importantly, our findings support ongoing research to identify patients who would most benefit from intravenous iron therapy, particularly as they relate to criteria used for identification and compliance with initial and repeat iron doses.