What new evidence is available regarding intravenous iron replacement in patients with heart failure?

Introduction
Approximately half of all patients with symptomatic heart failure are impacted by iron deficiency (typically defined in patients with heart failure as a serum ferritin level <100 mcg/L or a serum ferritin level of 100 to 300 mcg/L with transferrin saturation [TSAT] <20%).1 Of note, a substantial proportion of patients with heart failure (25%-42%) develop iron deficiency without accompanying anemia.2 The cutoffs for diagnosis of iron deficiency in heart failure patients are higher than those in patients who do not have heart failure because ferritin levels are elevated in the presence of inflammation and heart failure is a pro-inflammatory disease. In patients with heart failure, iron deficiency ultimately develops due to impairment in the metabolism of iron; insufficient dietary intake of iron, venous congestion and associated reductions in intestinal iron absorption, and overt/occult blood loss.2,3

Iron deficiency is associated with adverse physiological effects including reduced physical capability and exercise capacity, shortness of breath, and fatigue.4 Moreover, the development of iron deficiency in patients with heart failure (regardless of whether anemia is present) is associated with adverse clinical outcomes, including increased duration of hospitalization, decreased health-related quality of life, and increased mortality.2 While oral iron products are commonly used to manage iron deficiency, many of the available oral products are poorly absorbed and associated with adverse gastrointestinal effects.2,4 Additionally, oral formulations of iron have not been found to improve iron stores or exercise capacity in patients with heart failure to date.4,5 More recently, research has been conducted to evaluate the potential impact of intravenous (IV) iron therapy in patients with heart failure; thus, the purpose of this frequently asked question (FAQ) summary is to describe recent research surrounding use of IV iron in patients with heart failure.

Literature summary
A literature search was conducted to identify recent literature summarizing efficacy data for use of IV iron products to treat iron deficiency in patients with heart failure. The search revealed a meta-analysis/meta-regression of 14 randomized controlled trials (RCTs; N=6624) published in March 2024 describing outcomes in patients with heart failure and iron deficiency who were treated with IV iron.6 Primary efficacy outcomes analyzed included cardiovascular (CV) mortality, a composite of CV death and hospitalization for heart failure (HHF), first HHF, and total HHFs. These outcomes were assessed in 10 RCTs and a meta-analysis of 4 RCTs. The majority of included trials used IV ferric carboxymaltose (FCM) as the iron intervention (n=9); other formulations of IV iron used included iron sucrose (n=3 studies; 1 study used iron sucrose in combination with FCM), ferric derisomaltose (n=1 study), and ferric gluconate (n=1 study); all trials compared IV iron to placebo, although some trials referred to the placebo arm as the “standard of care” arm. Most studies included patients with HFrEF and defined iron deficiency as a ferritin <100 ng/mL or a ferritin between 100-300 ng/mL with a TSAT <20%. Among the included trials, follow-up ranged from 12 weeks to 140 weeks. Pooled results for each of the 4 primary outcomes (IV iron compared to placebo) are described below:

  • CV death: odds ratio (OR), 0.867; 95% CI, 0.755 to 0.995; p=0.0427; I2=0%
  • Composite, CV death and HHF: OR, 0.838; 95% CI, 0.751 to 0.935; p=0.0015; I2=45%
  • First HHF: OR, 0.855; 95% CI, 0.744 to 0.983; p=0.0281; I2=60%
  • Total HHF: rate ratio, 0.739; 95% CI, 0.661 to 0.827; p<0.001; I2=76%

The authors also assessed the impact of baseline TSAT on the treatment effect through meta-regression and found that the reduction in HHF events associated with IV iron was only seen when the baseline TSAT was ≤20%.6 Based on these findings, the authors ultimately concluded that use of IV iron reduces CV death and HHF in patients with heart failure and iron deficiency, but the TSAT at baseline may impact effectiveness of therapy on HHF.

These results were largely driven by 3 trials (HEART-FID, IRONMAN, and AFFIRM-AHF) that each included a population of more than 1000 patients with heart failure and iron deficiency.7-9 The characteristics and key results of these trials are further summarized in the Table below.

Table. Summary of major trials evaluating IV iron in patients with heart failure.7-9
CitationStudy design and durationSubjectsInterventionsOutcomes
Mentz 20237

HEART-FID		Prospective R, DB, MC, PC

Duration: minimum 365 days of follow-up per participant		N=3065 adults with heart failure (LVEF ≤40%) and either HHF within ≤12 months or elevated natriuretic peptide, along with the following hematologic parameters: Hgb >9 mg/dL but <13.5 g/dL (women) or <15 g/dL (men); ferritin <100 ng/mL OR 100-300 ng/mL with TSAT <20%

At baseline, mean serum ferritin, ~56.5 ng/mL; mean TSAT, ~23%		FCM (n=1532), maximum dose of 750 mga given IV at a rate of 100 mg/min on day 0, day 7, and every 6 months thereafter based on Hgb and iron levels

Placebo (n=1533)		Primary: Hierarchical composite of death, HHF, or change in 6MWTb
  • Unmatched win ratio (FCM vs. placebo): 1.10 (99% CI, 0.99 to 1.23; p=0.02c)
  • Death: FCM, 8.6%; placebo, 10.3%
  • HHF: FCM, n=297; placebo, n=332
  • Change in 6MWD (mean±SD): FCM, 8±60 m; placebo, 4±59 m

Secondary: Composite of CV death or HHF over follow-up period
  • FCM: 16 events per 100 PYs; Placebo: 17.3 events per 100 PYs (HR, 0.93; 96% CI, 0.81 to 1.06)
Kalra 20228

IRONMAN		Prospective, R, OL, MC, blinded-endpoint

Duration: median duration, 2.7 years; maximum duration, 5.4 years		N=1137 adult patients with heart failure (LVEF ≤45%) and TSAT <20% OR ferritin <100 mcg/L

At baseline, median serum ferritin ~49.5 ng/mL; mean TSAT, 15%		FDI (n=569), dosing based on body weight and hemoglobin up to a maximum of 2000 mg IV. Follow-up visits occurred 4 weeks after initial dosing, then every 4 months thereafter; FDI was administered on these visits if ferritin was <100 mcg/L or ≤400 mcg/L with TSAT <25%

Usual care, based on guidelines at the time of study (n=568)		Primary: Composite of CV death and HHF
  • FDI, 22.4 events per 100 PYs; Placebo, 27.5 events per 100 PYs (rate ratio, 0.82; 95% CI, 0.66 to 1.02; p=0.07)

Secondary:
  • No significant differences found between groups for CV death or HHF assessed individually
Ponikowski 20209

AFFIRM-AHF		Prospective, R, DB, MC, PC

Duration: Patients followed for up to 52 weeks		N=1132 adults hospitalized for acute heart failure (LVEF <50%) treated with IV diuretics and with ferritin <100 ng/mL or 100-299 ng/mL with TSAT <20%

At baseline, mean serum ferritin, ~86 ng/mL; mean TSAT, ~14.7%		FCM (n=558), IV dosing based on weight and Hgb (maximum dose not specified); administered at discharge, week 6, then weeks 12 and 24 if iron deficiency persisted and Hgb was 8-15 g/dL

Placebo (n=550)		Primary: Composite of CV death and HHF
  • FDI, 57.16 events per 100 PYs; Placebo, 72.51 events per 100 PYs (rate ratio, 0.79; 95% CI, 0.62 to 1.01; p=0.059)

Secondary:
  • Total HHF significantly reduced with IV iron compared to placebo: rate ratio, 0.74; 95% CI, 0.58 to 0.94; p=0.13)
  • CV death: no difference found between groups
Abbreviations: 6MWT=6-minute walk test; CI, confidence interval; CV=cardiovascular; DB=double-blinded; FCM=ferric carboxymaltose; FDI=ferric derisomaltose; Hgb=hemoglobin; HHF=hospitalization for heart failure; IV=intravenous; LVEF=left ventricular ejection fraction; MC=multicenter; OL=open-label; PC=placebo-controlled; PY=patient year; R=randomized; SD, standard deviation; TSAT=transferrin saturation.
aDose adjusted to 15 mg/kg (max 750 mg per dose) for patients weighing <50 kg.
bDeath and HHF occurring within 12 months after randomization, change in 6MWD measured from baseline to 6 months.
cTwo-sided alpha set at 0.01; result is not significant.

Discussion
While the results for the primary composite outcomes in HEART-FID, IRONMAN, and AFFIRM-AHF were numerically lower for IV iron compared to placebo/standard of care, none of these reductions were found to be statistically significant.7-9 Most of the results for the individual components of these composite outcomes were also not significant; however, this could have been due to the fact that these trials were not powered to detect differences in individual outcomes. The meta-analysis of 14 RCTs assessing various clinical outcomes in patients with HF and iron deficiency found a modest, but significant reduction in CV death associated with IV iron.6 Results for HHF (both the first instance and all instances) were also significantly lower with IV iron but had significant heterogeneity.

The meta-regression analysis found that patients with a TSAT <20% at baseline had the greatest benefit in terms of HHF.6 This is a known controversy in the management of iron deficiency in patients with heart failure; past research has shown that patients with ferritin 20% do not show evidence of iron deficiency on bone marrow staining, have a reduced response to treatment with iron, and have a lower event rate compared to patients with lower TSATs.10 Patients with chronic heart failure are also more likely to experience isolated reductions in ferritin <100 ng/mL without accompanying reductions in TSAT <20%. This is an important consideration when assessing the results of these clinical trials since the HEART-FID trial enrolled patients with chronic heart failure. At baseline, patients in HEART-FID had mean TSATs of approximately 23%, which were substantially higher than those seen in other trials and could have impacted the outcomes of the trial.

A recent expert consensus decision pathway for treatment of HFrEF from the American College of Cardiology (ACC) summarizes the findings from these and other clinical trials of IV iron, stating that in patients with heart failure, IV iron has been found to improve exercise capacity and quality of life, HHF, and a composite of HHF and CV death.1 However, the largest trial to date (AFFIRM-AHF) did not show an improvement in its composite outcome with IV iron compared to placebo, and additional research is needed. Based on the available literature, the guidelines state that IV iron replacement can be considered to improve symptoms in patients with HFrEF and iron deficiency, regardless if anemia is present (strong association with heart failure outcomes, intermediate clinical trial evidence for modulating comorbidity). A recent scientific statement from the Heart Failure Society of America echoes sentiments from the ACC regarding the need for research to determine the impact of IV iron on mortality in patients with heart failure; the scientific statement also highlights the need for research on the impact of IV iron in heart failure patients with moderately reduced and preserved ejection fractions.

References

  1. Maddox TM, Januzzi JL Jr, Allen LA, et al. 2024 ACC expert consensus decision pathway for treatment of heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2024;83(15):1444-1488. doi: 10.1016/j.jacc.2023.12.024
  2. Beavers CJ, Ambrosy AP, Butler J, et al. Iron deficiency in heart failure: a scientific statement from the Heart Failure Society of America. J Card Fail. 2023;29(7):1059-1077. doi: 10.1016/j.cardfail.2023.03.025
  3. Gale SE, Willeford A, Sandquist K, Watson K. Intravenous iron in patients with iron deficiency and heart failure: a review of modern evidence. Curr Opin Cardiol. 2024;39(3):178-187. doi: 10.1097/HCO.0000000000001121
  4. Singer CE, Vasile CM, Popescu M, et al. Role of iron deficiency in heart failure-clinical and treatment approach: an overview. Diagnostics (Basel). 2023;13(2):304. doi: 10.3390/diagnostics13020304
  5. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA. 2017;317(19):1958-1966. doi:10.1001/jama.2017.5427
  6. Martens P, Augusto SN Jr, Mullens W, Tang WHW. Meta-analysis and metaregression of the treatment effect of intravenous iron in iron-deficient heart failure. JACC Heart Fail. 2024;12(3):525-536. doi:10.1016/j.jchf.2023.11.006
  7. Mentz RJ, Garg J, Rockhold FW, et al. Ferric carboxymaltose in heart failure with iron deficiency. N Engl J Med. 2023;389(11):975-986. doi:10.1056/NEJMoa2304968
  8. 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
  9. Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396(10266):1895-1904. doi:10.1016/S0140-6736(20)32339-4
  10. Augusto SN, Martens P. Heart failure-related iron deficiency anemia pathophysiology and laboratory diagnosis. Curr Heart Fail Rep. 2023;20(5):374-381. doi:10.1007/s11897-023-00623-z

Prepared by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2024

The information presented is current as of April 16, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.