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Effectiveness of Intravenous Iron Treatment Versus Standard Care in Patients With Heart Failure and Iron Deficiency - IRONMAN
Contribution To Literature:
Highlighted text has been updated as of November 8, 2024.
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 (TSAT) <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 (CI) 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 (MLwHF) 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)
Impact of baseline blood tests of anemia: Overall, 771 (68%) patients were anemic, of whom 348 were considered to have mild anemia and 423 had moderate anemia. For those with moderate anemia at baseline, MLwHF total score at 4 months favored those assigned to IV ferric derisomaltose compared to control (mean difference −7 [95% CI −13 to −2]), but little difference was observed for those with mild anemia (mean difference −3 [95% CI −9 to +3]) or without anemia (mean difference +1 [95% CI −5 to +6]) (p for interaction = 0.14). By 4 months, the increase in hemoglobin was greater in patients with a serum ferritin ≤30 µg/L randomized to ferric derisomaltose (p for interaction = 0.028). There was no difference in the effect of ferric derisomaltose on MLwHF by serum ferritin category (p for interaction = 1.0). For patients with a serum ferritin ≥100 µg/L (and therefore TSAT <20%), walk distance tended to be greater for patients randomized to ferric derisomaltose (mean increase 40 (95% CI −12 to +93), but no effect was observed for other groups. The increase in hemoglobin in response to ferric derisomaltose was greatest for patients with a TSAT <10% (p for interaction < 0.001), with a progressively smaller response for higher values of TSAT. There was little difference in the improvement in MLwHF scores across TSAT categories, overall (p for interaction = 1.0). Although there was no statistical interaction between TSAT/ferritin categories, the largest absolute differences in clinical events were observed in those with a TSAT <20% and a ferritin ≥100 µg/L.
Unplanned hospitalizations: Compared with control, patients randomized to IV ferric derisomaltose had fewer unplanned hospitalizations (RR 0.83, 95% CI 0.71-0.97; p = 0.02), with similar reductions in cardiovascular (RR 0.83, 95% CI 0.69-1.01) and noncardiovascular (RR 0.83, 95% CI 0.67-1.03) hospitalizations, as well as hospitalizations for heart failure (RR 0.78, 95% CI 0.60-1.00), respiratory disease (RR 0.70, 95% CI 0.53-0.97), or infection (RR 0.82, 95% CI 0.66-1.03).
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. An exploratory analysis suggested that either anemia severity and/or a TSAT <20% might identify patients with HF who are most likely to benefit from IV iron; the relationship between serum ferritin and response to IV iron was complex and likely of less clinical value than the other two parameters. Improvements in unplanned hospitalizations were noted with IV ferric derisomaltose, with similar reductions in cardiovascular and noncardiovascular hospitalizations.
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:
Cleland JG, Pellicori P, Graham FJ, et al., on behalf of the IRONMAN Study Group. J Am Coll Cardiol 2024;84:1704-17.
Editorial Comment: Neuen BL, Badve SV, Arnott C. Optimizing Clinical Outcomes Beyond Heart Failure With Intravenous Iron. J Am Coll Cardiol 2024;84:1718-20.
Cleland JG, Kalra PA, Pellicori P, et al., on behalf of the IRONMAN Study Group. Intravenous Iron for Heart Failure, Iron Deficiency Definitions, and Clinical Response: The IRONMAN Trial. Eur Heart J 2024;45:1410-26.
Editorial Comment: van der Meer P, Beverborg NG. Intravenous iron, only for those in need. Eur Heart J 2024;45:1427-9.
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;400:2199-2209.
Presented by Dr. Paul R. Kalra at the American Heart Association Scientific Sessions, Chicago, IL, November 5, 2022.
Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: AHA22, Anemia, Iron-Deficiency, Heart Failure
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