IMPORTANCE: Uncertainty remains about the efficacy of intravenous iron in patients with heart failure and iron deficiency.
OBJECTIVE: To assess the efficacy and safety of ferric carboxymaltose in patients with heart failure and iron deficiency.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized clinical trial enrolled 1105 patients with heart failure (defined as having a left ventricular ejection fraction of =45%) and iron deficiency (serum ferritin level <100 ng/mL; or if transferrin saturation was <20%, a serum ferritin level between 100 ng/mL and 299 ng/mL) at 70 clinic sites in 6 European countries from March 2017 to November 2023. The median follow-up was 16.6 months (IQR, 7.9-29.9 months).
INTERVENTION: Administration of ferric carboxymaltose (n = 558) initially given at an intravenous dose of up to 2000 mg that was followed by 500 mg every 4 months (unless stopping criteria were met) vs a saline placebo (n = 547).
MAIN OUTCOMES AND MEASURES: The primary end point events were (1) time to cardiovascular death or first heart failure hospitalization, (2) total heart failure hospitalizations, and (3) time to cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation less than 20%. All end point events were measured through follow-up. The end points would be considered statistically significant if they fulfilled at least 1 of the following conditions: (1) P = .05 for all 3 of the end point comparisons, (2) P = .025 for 2 of the end point comparisons, or (3) P = .0167 for any of the 3 end point comparisons (Hochberg procedure).
RESULTS: Of the 1105 participants (mean age, 70 years [SD, 12 years]; 33% were women), cardiovascular death or first heart failure hospitalization (first primary outcome) occurred in 141 in the ferric carboxymaltose group vs 166 in the placebo group (hazard ratio, 0.79 [95% CI, 0.63-0.99]; P = .04). The second primary outcome (total heart failure hospitalizations) occurred 264 times in the ferric carboxymaltose group vs 320 times in the placebo group (rate ratio, 0.80 [95% CI, 0.60-1.06]; P = .12). The third primary outcome (cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation <20%) occurred in 103 patients in the ferric carboxymaltose group vs 128 patients in the placebo group (hazard ratio, 0.79 [95% CI, 0.61-1.02], P = .07). A similar amount of patients had at least 1 serious adverse event in the ferric carboxymaltose group (269; 48.2%) vs in the placebo group (273; 49.9%) (P = .61).
CONCLUSIONS AND RELEVANCE: In patients with heart failure and iron deficiency, ferric carboxymaltose did not significantly reduce the time to first heart failure hospitalization or cardiovascular death in the overall cohort or in patients with a transferrin saturation less than 20%, or reduce the total number of heart failure hospitalizations vs placebo.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03036462.
| Discipline Area | Score |
|---|---|
| Internal Medicine |  |
| Hematology |  |
| Cardiology |  |
| Family Medicine (FM)/General Practice (GP) | |
| General Internal Medicine-Primary Care(US) | |
together with the simultaneously published meta-analysis of previous and current RCTs (Anker et al Nature Medicine https://doi.org/10.1038/s41591025036711), the findings suggest that treating iron deficiency in patients with HF significantly reduces CV events.
This is not my area of expertise; however, if this study is considered valid, it would change practice at my VA. I just came off the inpatient medical service and the house staff were giving IV iron to all the heart failure patients. I assume this is based on practice they were told to do at the University or by specialists. This trial showing no benefit should temper that.
This study addresses an important and relatively common question about using IV iron in heart failure patients with non-traditional (i.e. other than ferritin <50) definitions of iron deficiency. The question about which patients, if any, clearly benefit from this intervention remains uncertain, although these data will hopefully reduce unnecessary drug exposures and costs moving forward.
This has been a controversial subject for some time (whether there is a benefit to aggressively treating HF patients with IV iron). This trial, taken with prior studies, seems to indicate there is little or no benefit to giving IV iron (using the treatment criteria of ferritin <100 or T sat <20%).
Translated by AI: In patients with heart failure, iron deficiency is associated with worse symptoms and outcomes than those without it. Treatment has not shown benefits in mortality but improves quality of life, kidney function, functional class, exercise capacity, LVEF and hospital readmissions, although evidence in patients with HF and preserved and mildly reduced LVEF is limited. Guidelines provide a class 2a recommendation for the use of intravenous iron to improve functional status and quality of life in patients with heart failure with iron deficiency. The European Society of Cardiology guidelines provide a class 2a recommendation for administering intravenous ferric carboxymaltose to recently hospitalized patients to reduce the risk of readmission. The 2017 guidelines from the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America indicated that outcome trials were needed before a strong recommendation could be provided. The IRONOUT HF trial showed that oral iron therapy did not improve exercise capacity in patients with heart failure with a reduced ejection fraction and iron deficiency, and the guidelines do not recommend the use of oral iron therapy in such patients. In contrast, other trials showed that treatment with intravenous ferric carboxymaltose improved quality of life and functional capacity in patients with heart failure with a reduced ejection fraction and iron deficiency. The AFFIRM-AHF trial compared ferric carboxymaltose with placebo with respect to cardiovascular death and total heart failure hospitalizations in hospitalized patients with acute heart failure, a left ventricular ejection fraction of less than 50%, and iron deficiency. The IRONMAN trial, which evaluated a different formulation of intravenous iron (ferric derisomaltose), showed similar findings to the AFFIRM-AHF trial. Conducting these trials in heart failure and iron deficiency showed that intravenous iron appeared to be associated with a reduction in heart failure hospitalizations without an effect on mortality. The HEART-FID trial evaluated the long-term safety and efficacy of ferric carboxymaltose in patients who had heart failure with a reduced ejection fraction and iron deficiency. Among outpatients, there were no apparent differences between ferric carboxymaltose and placebo with respect to mortality, heart failure hospitalizations, or 6-minute walk distance. // Original Comment: En los pacientes con insuficiencia cardíaca, la deficiencia de hierro se asocia con peores síntomas y resultados que aquellos sin ella. Su tratamiento no se ha demostrado beneficios en mortalidad pero mejora la calidad de vida, funcion renal, clase funcional, capacidad de ejercicio, FEVI y reingresos hospitalarios, aunque la evidencia en pacientes con IC y FEVI conservada y ligeramente reducida es limitada. Las guías proporcionan una recomendación de clase 2a para el uso de hierro intravenoso para mejorar elestado funcional y la calidad de vida en pacientes que tienen insuficiencia cardíaca con deficiencia dehierro. Las guías de la Sociedad Europea de Cardiología proporcionan una recomendación de clase 2a para administrar carboximaltosa férrica intravenosa a pacientes hospitalizados recientemente con el fin de reducir el riesgo de rehospitalización. La guía de 2017 del Colegio Americano de Cardiología, laAsociación Americana del Corazón y la Sociedad de Insuficiencia Cardíaca de América indicó que se necesitaban ensayos de resultado antes de poder proporcionar una recomendación sólida. El ensayo IRONOUT HF mostró que la terapia oral con hierro no mejoró la capacidad de ejercicio en pacientes que tenían insuficiencia cardíaca con una fracción de eyección reducida y deficiencia de hierro, y las guías no recomiendan el uso de la terapia oral con hierro en tales pacientes. Por el contrario, otros ensayos mostraron que el tratamiento con carboximaltosa férrica intravenosa mejoró la calidad de vida y la capacidad funcional en pacientes con insuficienciacardíaca con una fracción de eyección reducida y deficiencia de hierro. El ensayo AFFIRM-AHF comparó la carboximaltosa férrica con placebo con respecto a la muerte cardiovascular y las hospitalizaciones totales por insuficiencia cardíaca en pacientes hospitalizados con insuficiencia cardíaca aguda, una fracción de eyección del ventrículo izquierdo de menos del 50% ydeficiencia de hierro. El ensayo IRONMAN, que evaluó una formulación diferente de hierro intravenoso (derisomaltosa férrica), mostró hallazgos similares a los del ensayo AFFIRM-AHF
La realización de estos ensayos con insuficiencia cardíaca y deficiencia de hierro mostró que el hierro intravenoso parecía estar asociado con una reducción de las hospitalizaciones por insuficiencia cardíaca sin un efecto sobre la mortalidad. En el ensayo HEART-FID evaluó la seguridad y eficacia a largo plazo de la carboximaltosa férrica en pacientes que tenían insuficiencia cardíaca con una fracción de eyección reducida y deficiencia de hierro. Entre los pacientes ambulatorios no hubo diferencias aparentes entre la carboximaltosa férrica y el placebo con respecto a mortalidad, hospitalizaciones por insuficiencia cardíaca o distancia de caminata de 6 minutos.
