Role of Intravenous Iron in Spotlight At ESC Congress 2023

A pair of studies and focused guideline update from the European Society of Cardiology (ESC) Congress 2023 are highlighting the role of intravenous iron in patients with iron deficiency and heart failure with reduced ejection fraction (HFrEF).

Results of the HEART-FID trial and a meta-analysis, which were presented the day after new guidance included a recommendation for intravenous iron supplementation, offered new insight into the optimal role of intravenous iron, with the HEART-FID detailing the safety and tolerability while the meta-analysis concluded use of intravenous iron could help reduce hospitalizations and cardiovascular death.^1,2,3

HEART-FID¹

Robert J. Mentz, MD
Credit: Duke University School of Medicine

A double-blind, placebo-controlled, event-driven trial, HEART-FID was designed to assess the effects of intravenous ferric carboxymaltose compared to placebo in people with heart failure and iron deficiency, with the trial’s primary endpoint a hierarchical composite of12-month rate of death, hospitalization for worsening heart failure, and the 6-month change in 6-minute walk test distance included as primary outcomes of interest. Billed as the largest study to assess the long-term safety and efficacy of intravenous ferric carboxymaltose in HFrEF and iron deficiency, the trial also included a composite top secondary endpoint of time to first cardiovascular death or heart failure hospitalization.¹

For inclusion patients needed to have an ejection fraction of 40% or less and iron deficiency. Investigators defined iron deficiency as a ferritin level less than 100 ng/mL or 100-300 ng/mL and a TSAT less than 20%.¹

In total, 3065 underwent randomization in the study, with 1532 randomized to ferric carboxymaltose and 1533 randomized to placebo therapy. For those randomized to ferric carboxymaltose, those weighing less than 50 kg received 2 doses of 15 mg/kg separated by 7 days and those weighing 50 kg or more received 2 doses of 750 mg separated by 7 days. Per trial protocol, visits occurred every 3 months and dosing occurred every 6 months as needed.¹

Upon analysis, investigators found the unmatched win ratio for the primary outcome favored the ferric carboxymaltose group did not meet the prespecified significance level (Win Ratio, 1.10; 99% Confidence interval [CI], 0.99-1.23; P = .019). However, investigators pointed out a there was a trend toward benefit for each of the individual outcomes of the composite. At 12 months, 131 (8.6%) and 158 (10.3%) patients died in the FCM and placebo groups, respectively, and there were 297 and 332 heart failure hospitalizations, respectively. At 6 months, the mean change in 6-minute walk distance was 8±60 meters with ferric carboxymaltose and 4±59 meters in the placebo group.¹

Analysis of the top secondary endpoint suggested fewer events in the ferric carboxymaltose group than the placebo group (16.0 vs. 17.3 events per 100 patient-years; Hazard Ratio [HR], 0.93; 96% CI, 0.81-1.06). Additionally, results appeared to favor ferric carboxymaltose relative to placebo for cardiovascular alone (HR, 0.86; 96%, 0.72-1.03).¹

“The HEART-FID trial confirmed the safety of intravenous FCM in patients with HFrEF and despite suggesting potential outcome benefits did not meet its primary efficacy endpoint,” said principal investigator Robert Mentz, MD, chief of the Heart Failure Section at Duke University School of Medicine.⁴

Iron Supplementation Meta-Analysis²

Piotr Ponikowski, MD, PhD
Credit: Wroclaw Medical University

During the same session Mentz presented HEART-FID, Piotr Ponikowski, MD, PhD, director of the Institute of Heart Diseases at the Wroclaw Medical University, presented what he described as the largest and most up-to-date analysis of the effect of ferric carboxymaltose in iron-deficient heart failure patients with reduced or mildly reduced ejection fraction (HFmrEF). Pooling data from adult patients with heart failure and iron deficiency with at least 52 weeks of follow up from the CONFIRM-HF, AFFIRM-AHF and HEART-FID trials, investigators obtained information related to a cohort of 4501 patients for inclusion, with 2251 and 2250 randomized to ferric carboxymaltose and placebo, respectively.²

Investigators designed the meta-analysis with a pair of coprimary composite endpoints, which were both assessed through 52 weeks. The first composite endpoint included total cardiovascular hospitalizations and cardiovascular death and the second included total heart failure hospitalizations and cardiovascular death.²

Upon analysis, results indicated use of ferric carboxymaltose was associated with a significant reduction in the coprimary composite endpoint of total cardiovascular hospitalizations and cardiovascular death compared with placebo, (Rate Ratio [RR], 0.86; 95% CI, 0.75-0.98; P = .029). Additionally, investigators observed a trend toward reduction of the coprimary composite endpoint of total heart failure hospitalizations and cardiovascular death but noted it failed to reach statistical significance (RR 0.87; 95% CI, 0.75-1.01; P = .076).²

Further analysis suggested used of ferric carboxymaltose was associated a reduced rate of total cardiovascular hospitalizations (RR, 0.83; 95% CI, 0.73-0.96; P = .009) and total heart failure hospitalizations (RR, 0.84; 95% CI, 0.71-0.98; P = .025). Investigators pointed out there was no effect observed on mortality in the meta-analysis.²

“[Ferric carboxymaltose] was associated with a reduction in the composite endpoint of total cardiovascular hospitalizations and cardiovascular death compared with placebo, and with significantly reduced risks of hospitalization due to heart failure or cardiovascular causes, with no effect on survival,” Ponikowski said.⁵ “The findings indicate that intravenous [ferric carboxymaltose] should be considered in iron-deficient patients with heart failure and reduced or mildly reduced ejection fraction to reduce the risk of hospitalization due to heart failure and cardiovascular causes.”

Guideline Recommendations on Iron Supplementation

On the opening day of ESC Congress 2023, the ESC released a focused updated to their 2021 heart failure guidelines to reflect new data from more than half a dozen trials published since the release of those guidelines. Among these were new recommendations for comorbidities in heart failure, including iron deficiency.

Of note, the task force leading the creation of the focus update incorporated data published through March 2023 and, therefore, does not reflect data from HEART-FID or the meta-analysis.

New Iron Supplementation Recommendations:³

• Intravenous iron supplementation is recommended in symptomatic patients with HFrEF and HFmrEF, and iron deficiency, to alleviate heart failure symptoms and improve quality of life. (Class I, Level A)
• Intravenous iron supplementation with ferric carboxymaltose or ferrite derisomaltose should be considered in symptomatic patients with HFrEF and HFmrEF, and iron deficiency, to reduce the risk of heart failure hospitalization. (Class IIa, Level A)

References:

1. Mentz RJ, Garg J, Rockhold W. Ferric Carboxymaltose in Heart Failure with Iron Deficiency. The New England Journal of Medicine. Published online August 26, 2023. doi:10.1056/NEJMoa2304968
2. Ponikowski P. Impact of ferric carboxymaltose (FCM) on heart failure–related clinical outcomes in patients with heart failure and iron deficiency. Trial presented at: European Society of Cardiology (ESC) Congress 2023. Amsterdam, The Netherlands. August 25 - 28, 2023.
3. McDonagh TA, Metra M, Adamo M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [published online ahead of print, 2023 Aug 25]. Eur Heart J. 2023;ehad195. doi:10.1093/eurheartj/ehad195
4. European Society of Cardiology. Trial of ferric carboxymaltose in heart failure does not meet primary endpoint. ESC Congress Home 2023. August 26, 2023. Accessed August 26, 2023. https://www.escardio.org/The-ESC/Press-Office/Press-releases/Trial-of-ferric-carboxymaltose-in-heart-failure-does-not-meet-primary-endpoint.
5. European Society of Cardiology. Iron therapy linked with reduced hospitalisation in iron-deficient heart failure patients. ESC Congress Home 2023. August 26, 2023. Accessed August 26, 2023. https://www.escardio.org/The-ESC/Press-Office/Press-releases/Iron-therapy-linked-with-reduced-hospitalisation-in-iron-deficient-heart-failure-patients.