Deficiency in Care: Underutilization of Intravenous Iron for Acute Heart Failure

Heart failure (HF) accounts for over 1 million hospitalizations annually in the US and Europe alone.¹ Nearly half of these patients have concurrent iron deficiency (ID), a known independent contributor to worsened outcomes, but a retrospective review found that less than 15% of patients hospitalized with acute HF were actually treated with intravenous (IV) iron.^2,3

IV iron is recommended by the American Heart Association/American College of Cardiology and the European Society of Cardiology at a Class IIa and Class I level of recommendation, respectively, for symptomatic HF with reduced ejection fraction (HFrEF) with concurrent ID to improve patient functional status and exercise capacity, as well as overall quality of life.^4,5 The international heart failure guidelines define ID as a serum ferritin less than 100 ng/mL or a serum ferritin level of 100 to 299 ng/mL plus transferrin saturation less than 20%. Routine screening for ID is the current guideline recommendation for all patients with HF, irrespective of EF, although treatment of ID is currently recommended only for patients with HFrEF.⁴

Although there is mixed evidence surrounding the use of certain iron formulations, the findings of the phase 4 AFFIRM-AHF (NCT02937454) and FAIR-HF2 (NCT03036462) trials definitively support the use of ferric carboxymaltose (FCM) in patients with HF, primarily during the peridischarge period of admission, to improve overall functional capacity.^2,6 Similarly, in the phase 4 IRONMAN trial (NCT02642562), ferric derisomaltose (FDI) was also found to improve symptoms and lower the risk of hospital admissions in patients with symptomatic HFrEF with iron deficiency.⁷ The details and clinical implications of these landmark trials are discussed in greater depth below.

Understanding the Trial Data: AFFIRM-AHF

AFFIRM-AHF directly compared IV FCM with placebo in patients hospitalized for acute HF with concurrent ID. In this randomized, double-blind, placebo-controlled trial, patients assigned to the treatment group received anywhere from 500 to 2000 mg of FCM, based on weight and baseline hemoglobin level. This study included patients with ID (per the above criteria) with a left ventricular ejection fraction of less than 50% who were clinically stable and ready for discharge.

The primary outcome of this study was a composite of total HF hospitalizations and cardiovascular death, which was found to be nearly 15% lower in the FCM group as compared with placebo, albeit not statistically significant. The secondary outcomes analyzed the composite components in isolation and found a 26% relative risk reduction in total HF hospitalizations in the group treated with FCM: a statistically significant outcome (P = .013). AFFIRM-AHF also found a 33% relative risk reduction in days lost to HF hospitalizations/CV death per 100 patient-years in the FCM group compared with the placebo group (369 days vs 568 days, respectively).⁶

Exploring the Results of FAIR-HF2

Similar results were observed in FAIR-HF2: a randomized, double-blind trial that studied whether the treatment of ID with FCM in patients with chronic, stable HF led to symptomatic improvement. Although FAIR-HF2 included patients at a lower baseline EF level (<45%), these were also ambulatory patients, who are expected to be better controlled and healthier at baseline. Patients received up to 2000 mg IV of FCM (or placebo saline) at their first 2 weekly visits based on hemoglobin (Hgb) concentration and body weight. Then beginning at week 4, fixed 500-mg doses were administered once every 4 months, based on prespecified Hgb and ferritin limits. The primary end points of FAIR-HF2 were New York Heart Association (NYHA) functional class and the results of the self-reported Patient Global Assessment at week 24.

According to the study results, 50% of patients in the FCM group reported much/moderate improvement at week 24, compared with 28% in the placebo group, a statistically significant outcome (P < .001). Additionally, over 99% of patients in the treatment and placebo groups were NYHA functional class II/III at baseline. However, nearly 50% of patients in the FCM group were categorized in the NYHA functional class of I/II at week 24, compared with 30% in the placebo group, which was also determined to be statistically significant (P < .001).²

Strong Outcomes From the IRONMAN Trial

In IRONMAN, patients with new or established HFrEF (EF <45%) with evidence of iron deficiency were randomly assigned 1:1 to receive either FDI or usual care consisting primarily of guideline-directed, optimized HF therapy. Within this group, physicians were allowed to administer oral/IV iron at their own discretion, but IV iron use was very limited in this group, and oral iron usage was both minimal and inconsistent. Iron deficits were calculated for each of the patients assigned to the FDI group at baseline based on weight and hemoglobin level. Treatments were administered as needed at regular 4-month intervals based on prespecified ferritin and transferrin saturation thresholds at the time of visits.

The primary outcome of this trial was a composite of CV death plus recurrent HF hospitalizations, and although FDI demonstrated an 18% relative risk reduction as compared with usual care, this result was not statistically significant. IRONMAN analyzed an extensive list of secondary outcomes, including but not limited to all-cause mortality/hospitalization, quality of life, and walking distance. Although the vast majority of the secondary outcomes favored FDI, none of the results were statistically significant, with the exceptions of the physical domain and overall scores of the quality-of-life questionnaire at the 4-month visit.⁷

Takeaways for Pharmacists

The results of the IRONMAN trial were promising at best, but the inability of the results to reach statistical significance minimizes the clinical extrapolation potential. When discussing AFFIRM-HF and FAIR-HF2, however, with respect to the slight differences in patient populations, dosing protocols, and measured outcomes, a shared feature is the preferential use of FCM over other IV iron formulations. FCM is not the most widely available or utilized iron preparation, particularly in the inpatient setting. It is unlikely that FCM or FDI are included on most inpatient hospital formularies. If admitted patients receive any iron treatment at all, it is typically in the form of iron sucrose or ferric gluconate, per clinician discretion, hospital formulary, and pharmacy stock. This begs the question of why FCM is not an inherent element of an acute heart failure treatment protocol, especially considering the overwhelmingly positive findings of the above literature and subsequent guideline recommendations.

Cost and lack of access are arguably the greatest barriers to regular FCM administration. Accounting for variability based on manufacturer and specific product, the price per mL of FCM can range anywhere from 9-fold to 68-fold the cost of either iron sucrose or ferric gluconate. Unlike its counterparts, both FCM and FDI have the option of single-dose administration, but a full treatment course of either iron sucrose or ferric gluconate (1 g) would still be more cost efficient.^8-11 Additionally, hospitals can benefit greatly from the prevention of readmissions that has been demonstrated by FCM use in the existing literature.⁶ Use of FCM for acute HF would require hospitals to incur a much higher up-front cost per dose per patient, creating a major barrier to its regular inpatient administration (See Table 1^8-11).

Both iron sucrose and ferric gluconate have been studied in the acute HF population. Although these iron formulations demonstrated an improvement in quality of life and an increase in exercise capacity, neither demonstrated the decrease in readmission rates found with FCM.^12,13 Additionally, there is an overarching lack of large-scale, robust evidence for either iron sucrose or ferric gluconate, unlike FCM, which has been rather extensively studied in this population. Unless the cost differential between these agents narrows, it is unlikely that FCM will become a standardized implementation in the treatment of patients hospitalized with acute HF. However, the improvements demonstrated by iron sucrose and ferric gluconate in both exercise capacity and quality of life are sufficient grounds to, at least, standardize the implementation of their use in acute HF hospitalizations based upon their ability to improve patients’ overall functional capacity.¹⁴

Although literature and guidelines review who should be receiving concurrent IV iron supplementation in addition to guideline-directed treatment, several patient populations have been understudied or excluded altogether.¹⁵ See Table 2¹⁵ for guidance regarding these patient populations.

Looking Ahead

Future directives should include efforts to expand the use of FCM where possible, particularly for outpatients, as this remains the agent of choice for this indication based upon the findings of the literature. FDI could also be explored as a potential alternative to FCM, pending research with more conclusive results that could establish a definitive place in therapy. Additionally, accumulating a greater volume of robust data on the benefits and risks of iron sucrose and ferric gluconate in the inpatient population would help objectively characterize the feasibility of their use in place of FCM. Finally, studies exploring and comparing the effects of various iron formulations could help identify agents that could provide comparable quality of life, functional capacity, and readmission outcomes, while addressing the high cost associated with regular FCM use.

Regardless of the type of iron product utilized, pharmacists should work with their institutions and health care systems to develop inpatient and/or outpatient ID protocols for IV iron therapy in patients with HF.¹⁵ A multidisciplinary approach that standardizes ID treatment should include pharmacy, nursing, case management/social work, provider champions, and administrative leaders. ID protocols should establish patient selection criteria, personnel workflow, choice and dosing of iron product(s) for inpatient/outpatient use, and insurance coverage. Providers should also familiarize themselves with the patient assistance programs available for various iron formulations and, moreover, offer these resources to eligible patients. Pharmacists can lead this effort to improve outcomes in patients with HF.

REFERENCES

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2. Anker SD, Friede T, Butler J, et al. Intravenous ferric carboxymaltose in heart failure with iron deficiency: the FAIR-HF2 DZHK05 randomized clinical trial. JAMA. 2025;333(22):1965-1976. doi:10.1001/jama.2025.3833

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7. Kalra PR, Cleland JGF, Petrie MC, 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. Lancet. 2022;400(10369):2199-2209. doi:10.1016/S0140-6736(22)02083-9

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