Effectiveness of Intravenous Iron Treatment Versus Standard Care in Patients With Heart Failure and Iron Deficiency - IRONMAN

Contribution To Literature:

The IRONMAN trial showed that iron (ferric derisomaltose) infusion is not superior to usual care among patients with HF and iron deficiency.

Description:

The goal of the trial was to evaluate the safety and efficacy of ferric derisomaltose on cardiovascular outcomes among patients with heart failure (HF) and iron deficiency.

Study Design

Patients were randomized in an open-label 1:1 fashion to either ferric derisomaltose (n = 569) or usual care (n = 568). Patients assigned to ferric derisomaltose had their estimated iron deficiency determined on the basis of hemoglobin value and body weight. For patients with bodyweight <50 kg, the dose of intravenous (IV) ferric derisomaltose was 20 mg/kg, irrespective of hemoglobin. If bodyweight was 50 kg to <70 kg, the dose of intravenous ferric derisomaltose was 1000 mg if hemoglobin was ≥10 g/dL, or 20 mg/kg if hemoglobin was <10 g/dL. Patients with a bodyweight of ≥70 kg received IV ferric derisomaltose at 20 mg/kg up to a maximum of 1500 mg if hemoglobin was ≥10 g/dL, or 2000 mg if hemoglobin was <10 g/dL. In the ferric derisomaltose group, investigators gave IV ferric derisomaltose at trial visits if ferritin was <100 μg/L or if ferritin was ≤400 μg/L and transferrin saturation was <25%.

  • Total screened: 1,869
  • Total randomized: 1,137
  • Duration of follow-up: 2.7 years
  • Mean patient age: 73 years
  • Percentage female: 27%

Inclusion criteria:

  • Age ≥18 years with left ventricular ejection fraction (LVEF) ≤45% within the last 2 years
  • New York Heart Association (NYHA) class II–IV
  • Transferrin saturation <20% or ferritin <100 μg/L
  • Increased risk of cardiovascular events, with either current or recent (<6 months) HF hospitalization
  • N-terminal pro-B-type natriuretic peptide (NT-proBNP) (ng/L) >250 if sinus rhythm/>1,000 if atrial fibrillation

Exclusion criteria:

  • Hemoglobin <9.0 g/dL
  • Hemoglobin >13 g/dL in women or >14 g/dL in men
  • Ferritin >400 μg/L
  • Estimated glomerular filtration rate <15 mL/min/1.73 m2
  • Myocardial infarction, stroke, or cardiac procedure in prior 3 months
  • Planned cardiac surgery or revascularization
  • Cardiac transplant or left ventricular assist device (planned or received)
  • Active infection
  • Disease (other than HF) with life expectancy <2 years
  • Contraindication to IV iron

Other salient features/characteristics:

  • NYHA class III/IV: 43%
  • Hospital admission for HF: 58%
  • LVEF: 34%
  • Baseline hemoglobin 12.1 g/dL, transferrin saturation: 15%

Principal Findings:

The primary outcome, cardiovascular death or HF hospitalization, for ferric derisomaltose vs. usual care, was: 22.4 vs. 27.5 events/100 patient-years (p = 0.07).

  • Primary outcome when censored September 2020 due to COVID-19: relative risk 0.76, 95% confidence interval 0.58-1.00 (p = 0.047)

Secondary outcomes for ferric derisomaltose vs. usual care:

  • HF hospitalization: 16.7 vs. 20.9/100 patient-years (p = 0.085)
  • Cardiovascular death: 21% vs. 24% (p = 0.23)
  • EQ-5D at 4 months, least-squares mean: 63.2 vs. 63.0 (p = 0.88)
  • Minnesota Living With Heart Failure questionnaire at 4 months: 36.9 vs. 40.2 (p = 0.05)
  • All-cause mortality: 32% vs. 34% (p = 0.64)
  • Hospitalization due to infection: 11.7% vs. 14.2% (p = 0.16)

Interpretation:

The results of this trial show that iron infusion is not superior to usual care among patients with HF and iron deficiency. No changes in quality of life measures or walk distance were noted either. The trial results were affected by the COVID-19 pandemic; in a sensitivity analysis, the primary endpoint was lower in the iron infusion arm compared with routine care. No major side effects were noted.

Data for iron therapy in HF have been mixed. Oral iron is not adequate to treat iron deficiency anemia in patients with HF. The use of IV iron has a Class IIa recommendation among patients with HF and anemia in the 2022 AHA/ACC/HSA HF guideline. Most trials of IV iron in patients with HF have investigated ferric carboxymaltose. IRONMAN is one of the first large trials evaluating ferric derisomaltose, which can be given as a rapid, high-dose infusion.

References:

Kalra PR, Cleland JG, Petrie MC, et al., on behalf of the IRONMAN Study Group. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomized, open-label, blinded-endpoint trial. Lancet 2022;Nov 5:[Epub ahead of print].

Presented by Dr. Paul R. Kalra at the American Heart Association Scientific Sessions, Chicago, IL, November 5, 2022.

Clinical Topics: Arrhythmias and Clinical EP, COVID-19 Hub, Dyslipidemia, Heart Failure and Cardiomyopathies, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: AHA Annual Scientific Sessions, AHA22, Anemia, Iron-Deficiency, Atrial Fibrillation, COVID-19, Ferric Compounds, Ferritins, Heart Failure, Hemoglobins, Iron, Natriuretic Peptide, Brain, Quality of Life, Stroke Volume, Transferrins, Ventricular Function, Left


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