Iron deficiency affects 50% of heart failure patients, worsening symptoms and outcomes. The AFFIRM-AHF trial found that IV ferric carboxymaltose reduced cardiovascular death and heart failure hospitalisations.
Iron deficiency is present in 50% of the patients with heart failure and it is associated with worse symptoms and outcomes [1]. There have been a few studies analysing the benefit of intravenous (IV) ferric carboxymaltose in heart failure with iron deficiency. In the AFFIRM-AHF [2] trial, administration of IV ferric carboxymaltose reduced the risk of cardiovascular death and total hospitalisations for heart failure in patients hospitalized for acute heart failure. In the IRONMAN trial [3], the administration of IV ferric derisomaltose also showed a similar benefit as seen in the AFFIRM-AHF trial. A meta-analysis of trials of intravenous iron therapy which included patients with heart failure and iron deficiency also showed that intravenous iron appeared to be associated with reduced hospitalisations for heart failure, though there was no significant effect on mortality [4].
An unexplored population – ambulant patients with heart failure
The Ferric Carboxymaltose in Heart Failure With Iron Deficiency (HEART-FID) study aims to determine if ferric carboxymaltose use in ambulant patients with heart failure and iron deficiency will improve composite outcomes of death, hospitalization for heart failure and 6 minute walk distance [5]. Iron deficiency in this study was defined as ferritin < 100 ng/mL or 100 – 300 ng/mL with transferrin saturation of < 20%). Patients had to be either hospitalized for heart failure within the last 12 months or have an elevated natriuretic peptide level.
Ferric carboxymaltose was dosed based on weight (750mg per dose if > 50kg, 15mg/kg per dose if < 50kg,with cumulative dose not exceeding 1500mg) with and it was administered as two separate doses, 7 days apart. Patients had to follow up every 3 months and ferric carboxymaltose or placebo was administered every 6 months based on haemoglobin and iron indexes.
Results
A total of 3065 participants were enrolled in the trial, and they were randomized 1:1 into placebo group and ferric carboxymaltose group. Dose interruptions occurred in a total of 564 patients and the median number of injections during follow up period was 6 for both groups. Majority of the participants had NYHA II and III heart failure (~98%), with an average baseline haemoglobin level of 12.5-12.6 g/dL at baseline. Ferritin levels at baseline were 56 and 57.3 ng/L in the ferric carboxymaltose and placebo group respectively, with an average transferrin saturation of > 20% for both groups.
At 12 months, this were the results for death, hospitalization for heart failure and the mean change in 6 minute walk distance from baseline to 6 month:
Figure 1: Summary of primary outcome results
Figure 2: Kaplan- Meier curve for main secondary outcome of composite cardiovascular death or first hospitalization for heart failure
Death from any cause occurred in 361 (23.6%) in the ferric carboxymaltose group and 376 (24.5%) in the placebo group (HR 0.9, CI 0.78 – 1.05). Serious adverse events occurred in 581 patients (37.9%) in the ferric carboxymaltose group and in 537 patients (35%) in the placebo group, with the 2 most common adverse events being pneumonia and COVID-19.
There were five hypersensitivity events and two angioedema events in the ferric carboxymaltose group
The results from this trial did not show any apparent difference between the ferric carboxymaltose group and placebo group with respect to a hierarchical composite of death, hospitalization for heart failure or change in 6 minute walking distance. This could be due to the patient population being a low risk, ambulant population than patients with acute failure recruited in the AFFIRM-AHF trial and IRONMAN trial which included hospitalized patients. Patients recruited in this trial also had a transferrin saturation of > 20%, which were higher than the previous trials. It may mean that ambulant patients with heart failure with reduced ejection fraction and transferrin saturation of > 20% may not see significant benefits in terms of death, hospitalization due to heart failure and improvement in 6 minute walking distance with ferric carboxymaltose administration.
References:
- Beavers, Craig J., Andrew P. Ambrosy, Javed Butler, Beth T. Davidson, Stormi E. Gale, Ileana L. PIÑA, Ioannis Mastoris, Nosheen Reza, Robert J. Mentz, and Gregory D. Lewis. “Iron Deficiency in Heart Failure: A Scientific Statement from the Heart Failure Society of America.”Journal of Cardiac Failure 29, no. 7 (2023): 1059–77. https://doi.org/10.1016/j.cardfail.2023.03.025.
- Ponikowski, P., Kirwan, B.-A., Anker, S. D., McDonagh, T., Dorobantu, M., Drozdz, J., … Keren, A. (2020).Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. The Lancet, 396(10266), 1895–1904. doi:10.1016/s0140-6736(20)32339-4
- Kalra, Paul R, John G Cleland, Mark C Petrie, Elizabeth A Thomson, Philip A Kalra, Iain B Squire, Fozia Z Ahmed, et al. “Intravenous Ferric Derisomaltose in Patients with Heart Failure and Iron Deficiency in the UK (Ironman): An Investigator-Initiated, Prospective, Randomised, Open-Label, Blinded-Endpoint Trial.”The Lancet 400, no. 10369 (2022): 2199–2209. https://doi.org/10.1016/s0140-6736(22)02083-9.
- Graham, Fraser J., Pierpaolo Pellicori, Paul R. Kalra, Ian Ford, Dario Bruzzese, and John G.F. Cleland. “Intravenous Iron in Patients with Heart Failure and Iron Deficiency: An Updated Meta‐analysis.”European Journal of Heart Failure25, no. 4 (2023): 528–37. https://doi.org/10.1002/ejhf.2810.
- Mentz, Robert J., Jyotsna Garg, Frank W. Rockhold, Javed Butler, Carmine G. De Pasquale, Justin A. Ezekowitz, Gregory D. Lewis, et al. “Ferric Carboxymaltose in Heart Failure with Iron Deficiency.”New England Journal of Medicine389, no. 11 (2023): 975–86. https://doi.org/10.1056/nejmoa2304968.
