HEART-FID Trial: Ferric Carboxymaltose resulted in modest improvement in hierarchical outcomes but did not reach statistical significance

By Jamie Diamond on

Key Points:

  • Prior data suggest that heart failure with reduced ejection fraction (HFrEF) patients with iron deficiency receiving IV iron supplementation had improvement in exercise capacity and HF hospitalizations, but the long-term safety and efficacy of the treatment is unknown.
  • The HEART-FID trial was a double-blind, placebo-controlled event-driven randomized trial assessing whether there would be improvement in the incidence of death and hospitalization for heart failure or 6-minute walk distance with ferric carboxymaltose therapy compared with placebo in patients with heart failure with a reduced ejection fraction and iron deficiency.
  • Patients receiving IV ferric carboxymaltose (FCM) had slightly fewer all-cause mortality events, HF hospitalizations and modestly longer 6-minute walk duration. However,there was no apparent difference in the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.
  • Overall FCM supplementation is safe and shows potential clinical benefits; further context can be obtained via pooled analysis with other IV FCM trials.

Iron deficiency has a prevalence of nearly 50% among patients with heart failure with reduced ejection fraction (HFrEF) and leads to impaired health-related quality of life, worsening heart failure (HF) symptoms, and adverse outcomes. The mechanism for iron deficiency in HF is not fully understood though thought to be related to reduction in iron intake as well as absorption and mobilization with increased loss as well. Treatment with intravenous (IV) ferric carboxymaltose (FCM) has previously been shown to improve HF patients’ symptoms and functional capacity. Notably, evidence regarding the utility of IV FCM for improving clinical outcomes such as morbidity and mortality is more limited. Information regarding the long-term efficacy and safety of IV iron infusions is also limited. Furthermore, the majority of available data on the subject was obtained in Europe and excluded other geographic HF populations.

The HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency) (NCT03037931) was a multicenter, randomized, double-blind, placebo-controlled trial that sought to assess the efficacy and safety of IV FCM in the treatment of symptomatic patients in HFrEF with iron deficiency over a period of at least 12 months. Over three thousand patients were randomized at 281 study locations in various geographic regions that included North America, Australia, New Zealand, and Europe. Heart failure patients had ejection fraction (EF) ≤40% within 24 months or ≤30% within 36 months of screening and NYHA Class II-IV symptoms on maximally tolerated background therapy for ≥2 weeks before randomization. They had to have documented HF hospitalization within 12 months of enrollment or elevated N-terminal-pro-brain natriuretic peptide within 90 days of randomization. Criteria for iron deficiency were ferritin <100 ng/mL or 100 to 300 ng/mL with a transferrin saturation <20% with hemoglobin >9.0 g/dL and <13.5 g/dL (females) or <15.0 g/dL (males). Importantly, the trial included those patients with and without anemia. Active bleeding or recent blood transfusion was prohibitive for enrollment.

Eligible patients were given an initial 28-day screening period and then randomized in a 1:1 ratio to receive FCM or placebo. They were then given the study drug on day 0 and 7 and followed up with additional study visits at 3 month intervals. Patients were eligible for additional dosing of the drug every 6 months as needed. HEART-FID trial clinical endpoints included a hierarchical composite of death and HF hospitalizations in the first 12 months, and change in 6 minute walk test (6-MWT) distance at 6 months. Notably a significance level of 0.01 was pre-specified for regulatory purposes by the US Food and Drug Administration (FDA).

Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group, and a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12. The mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (Wilcoxon–Mann–Whitney P=0.02; unmatched win ratio, 1.10; 99% confidence interval, 0.99 to 1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients.

Presented at the 2023 European Society of Cardiology Congress on August 26th by Dr. Robert Mentz (Duke Clinical Research Institute, Durham, NC) the HEART-FID trial data showed that administration of FCM resulted in modest improvement for the primary hierarchical endpoint which narrowly missed statistical significance (P=0.019).. When reporting the win ratio in order to translate the endpoint into clinical significance, there were 20% more wins with FCM than placebo for all-cause mortality. When assessing heart failure hospitalizations in those without a death event, there were similar wins in both groups. Change in 6MWT slightly benefited the FCM group. There was a similar percentage of treatment emergent adverse events in each group.

Overall Dr. Mentz states that there was “modest improvement” in the FCM group compared to placebo but importantly IV iron supplementation showed “numerical improvements in mortality.” He goes on to say, “FCM is safe and we build on the prior data showing benefit in quality of life and exercise capacity [with FCM]. Each component of the primary endpoint favors FCM.” He believes that the importance of this study is in providing “another tool in our toolkit in addition to quadruple therapy specifically for HFrEF patients with iron deficiency.” He stated that one significant advantage of FCM is that it does not involve another daily medication and can be administered in clinic in a straightforward way to produce net benefit. Overall, FCM can be used clinically for patients with HFrEF and iron deficiency to help them feel and function better with evidence of a clinical outcome benefit as well. The trial results were simultaneously published in The New England Journal of Medicine.