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Intravenous ferric carboxymaltose for iron repletion following acute heart failure in patients with and without diabetes: a subgroup analysis of the randomized AFFIRM-AHF trial
Rosano, G., Ponikowski, P., Vitale, C., Anker, S. D., Butler, J., Fabien, V., Filippatos, G., Kirwan, B. A., Macdougall, I. C., Metra, M., et al
Cardiovascular diabetology. 2023;22(1):215
Abstract
BACKGROUND In AFFIRM-AHF, treatment of iron deficiency with intravenous ferric carboxymaltose (FCM) reduced the risk of heart failure (HF) hospitalization and improved quality of life (QoL) vs placebo in patients stabilized following an acute HF (AHF) episode, with no effect on cardiovascular (CV) death. Diabetes and iron deficiency frequently accompany AHF. This post hoc analysis explored the effects of diabetes on outcomes in AFFIRM-AHF patients. METHODS Patients were stratified by diabetes yes/no at baseline. The effects of FCM vs placebo on primary (total HF hospitalizations and CV death) and secondary (total CV hospitalizations and CV death; CV death; total HF hospitalizations; time to first HF hospitalization or CV death; and days lost due to HF hospitalizations or CV death) endpoints at Week 52 and change vs baseline in disease-specific QoL (12-item Kansas City Cardiomyopathy Questionnaire [KCCQ-12]) at Week 24 were assessed by subgroup. For each endpoint, the interaction between diabetes status and treatment outcome was explored. RESULTS Of 1108 AFFIRM-AHF patients, 475 (FCM: 231; placebo: 244) had diabetes and 633 (FCM: 327; placebo: 306) did not have diabetes. Patients with diabetes were more commonly male (61.5% vs 50.9%), with a higher frequency of ischemic HF etiology (57.9% vs 39.0%), prior HF history (77.7% vs 66.5%), and comorbidities (including previous myocardial infarction [49.3% vs 32.9%] and chronic kidney disease [51.4% vs 32.4%]) than those without diabetes. The annualized event rate/100 patient-years with FCM vs placebo for the primary endpoint was 66.9 vs 80.9 in patients with diabetes (rate ratio [RR]: 0.83, 95% CI 0.58-1.81) and 51.3 vs 66.9 in patients without diabetes (RR: 0.77, 95% CI 0.55-1.07), with no significant interaction between diabetes status and treatment effect (p(interaction) = 0.76). Similar findings were observed for secondary outcomes. Change from baseline in KCCQ-12 overall summary score was numerically greater with FCM vs placebo at almost all time points in both subgroups, with no interaction between diabetes and treatment effect at Week 24. CONCLUSIONS The clinical and QoL benefits observed with intravenous FCM in patients with iron deficiency following stabilization from an AHF episode are independent of diabetes status. Trial registration Clinicaltrials.gov, NCT02937454 (registered 10.18.2016).
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Association Between Hemoglobin Levels and Efficacy of Intravenous Ferric Carboxymaltose in Patients With Acute Heart Failure and Iron Deficiency: An AFFIRM-AHF Subgroup Analysis
Filippatos G, Ponikowski P, Farmakis D, Anker SD, Butler J, Fabien V, Kirwan BA, Macdougall IC, Metra M, Rosano G, et al
Circulation. 2023
Abstract
BACKGROUND Iron deficiency, with or without anemia, is an adverse prognostic factor in heart failure (HF). In AFFIRM-AHF (a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure), intravenous ferric carboxymaltose (FCM), although having no significant effect on the primary end point, reduced the risk of HF hospitalization (hHF) and improved quality of life versus placebo in iron-deficient patients stabilized after an acute HF (AHF) episode. These prespecified AFFIRM-AHF subanalyses explored the association between hemoglobin levels and FCM treatment effects. METHODS AFFIRM-AHF was a multicenter, double-blind, randomized, placebo-controlled trial of FCM in hospitalized AHF patients with iron deficiency. Patients were stratified by baseline hemoglobin level (<12 versus ≥12 g/dL). In each subgroup, the primary composite (total hHF and cardiovascular death) and secondary (total hHF; total cardiovascular hospitalizations and cardiovascular death; time to cardiovascular death, and time to first/days lost due to hHF or cardiovascular death) outcomes were assessed with FCM versus placebo at week 52. Sensitivity analyses using the World Health Organization anemia definition (hemoglobin level <12 g/dL [women] or <13 g/dL [men]) were performed, among others. RESULTS Of 1108 AFFIRM-AHF patients, 1107 were included in these subanalyses: 464 (FCM group, 228; placebo group, 236) had a hemoglobin level <12 g/dL, and 643 (FCM, 329; placebo, 314) had a hemoglobin level ≥12 g/dL. Patients with a hemoglobin level <12 g/dL were older (mean, 73.7 versus 69.1 years), with more frequent previous HF (75.0% versus 68.7%), serum ferritin <100 μg/L (75.4% versus 68.1%), and transferrin saturation <20% (87.9% versus 81.4%). For the primary outcome, annualized event rates per 100 patient-years with FCM versus placebo were 71.1 and 73.6 (rate ratio, 0.97 [95% CI, 0.66-1.41]), respectively, and 48.5 versus 72.9 (RR, 0.67 [95% CI, 0.48-0.93]) in the hemoglobin levels <12 and ≥12 g/dL subgroups, respectively. No significant interactions between hemoglobin subgroup and treatment effect were observed for primary (P(interaction)=0.15) or secondary outcomes. Changes from baseline in hemoglobin, serum ferritin and transferrin saturation were significantly greater with FCM versus placebo in both subgroups between weeks 6 and 52. Findings were similar using the World Health Organization definition for anemia. CONCLUSIONS The effects of intravenous FCM on outcomes in iron-deficient patients stabilized after an AHF episode, including improvements in iron parameters over time, did not differ between patients with hemoglobin levels <12 and ≥12 g/dL. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT02937454.
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Economic evaluation of ferric carboxymaltose compared with placebo in iron-deficient patients with heart failure: a systematic review
Rezapour A, Souresrafil A, Shamsaei M, Barzegar M, Tashakori-Miyanroudi M, Ketabchi E
International journal of clinical pharmacy. 2023
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Editor's Choice
Abstract
BACKGROUND It has been shown that ferric carboxymaltose (FCM) improves symptoms and quality of life in iron-deficient patients with heart failure (HF). AIM: We aimed to systematically review studies conducted on the cost-effectiveness of FCM compared to placebo in iron-deficient patients with HF. METHOD We searched PubMed, EMBASE, Scopus, and Web of Science to find the relevant studies. After removing duplicates, two authors independently evaluated the titles, abstracts, and full texts. We included studies that investigated the full economic evaluations of FCM in HF patients with iron deficiency (cost-effectiveness analysis, cost-utility analysis, and cost-benefit analysis) and used the CHEERS tool to evaluate the quality of the studies. RESULTS Seven studies were included which evaluated the economic analysis of treatments with FCM in iron-deficient patients with HF. The CHEERS scores for most of the studies (n = 6) were 0.77 or higher (very good quality). The lowest incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALY) of FCM ($1801.96) was from Italy, and the highest ICER per QALY of FCM ($25,981.28) South Korea. Results of the studies showed that FCM, compared to placebo, was cost-effective in iron-deficient patients with HF. CONCLUSION FCM is a cost-effective treatment for iron-deficient patients with HF. Considering the fact that all the included studies in the present systematic review took place in high-income countries, we recommend further studies investigating the cost-effectiveness of FCM in low- and middle-income countries.
PICO Summary
Population
Iron-deficient patients with heart failure (HF), (7 studies).
Intervention
Ferric carboxymaltose (FCM).
Comparison
Placebo.
Outcome
The included studies investigated cost-effectiveness analysis, cost-utility analysis, and cost-benefit analysis, and used the CHEERS tool to evaluate the quality of the studies. The CHEERS scores for most of the studies (n = 6) were 0.77 or higher (very good quality). The lowest incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALY) of FCM ($1,801.96) was from Italy, and the highest ICER per QALY of FCM ($25,981.28) South Korea. Results of the studies showed that FCM, compared to placebo, was cost-effective in iron-deficient patients with HF.
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Ferric Carboxymaltose in Iron-Deficient Patients with Hospitalized Heart Failure and Reduced Kidney Function
Macdougall, I. C., Ponikowski, P., Stack, A. G., Wheeler, D. C., Anker, S. D., Butler, J., Filippatos, G., Göhring, U. M., Kirwan, B. A., Kumpeson, V., et al
Clinical journal of the American Society of Nephrology : CJASN. 2023
Abstract
BACKGROUND Reduced kidney function is common among patients with heart failure. In patients with heart failure and/or kidney disease, iron deficiency is an independent predictor of adverse outcomes. In the AFFIRM-AHF trial, acute heart failure patients with iron deficiency treated with intravenous ferric carboxymaltose demonstrated reduced risk of heart failure hospitalization, with improved quality of life. We aimed to further characterize the impact of ferric carboxymaltose among patients with coexisting kidney impairment. METHODS The double-blind, placebo-controlled AFFIRM-AHF trial randomized 1132 stabilized adults with acute heart failure (left ventricular ejection fraction <50%) and iron deficiency. Patients on dialysis were excluded. The primary endpoint was a composite of total heart failure hospitalizations and cardiovascular death during the 52-week follow-up period. Additional endpoints included cardiovascular hospitalizations, total heart failure hospitalizations, and days lost to heart failure hospitalizations or cardiovascular death. For this subgroup analysis, patients were stratified according to baseline estimated glomerular filtration rate (eGFR). RESULTS Overall, 60% of patients had an eGFR <60 ml/min/1.73 m 2 (the lower eGFR subgroup). These patients were significantly older, more likely to be female and to have ischemic heart failure, and had higher baseline serum phosphate levels and higher rates of anemia. For all endpoints, event rates were higher in the lower eGFR group. In the lower eGFR group, the annualized event rates for the primary composite outcome were 68.96 and 86.30 per 100 patient-years in the ferric carboxymaltose and placebo arms, respectively (rate ratio, 0.76; 95% confidence interval, 0.54-1.06). The treatment effect was similar in the higher eGFR subgroup (rate ratio, 0.65; 95% confidence interval, 0.42-1.02; Pinteraction =0.60). A similar pattern was observed for all endpoints ( Pinteraction >0.05). CONCLUSIONS In a cohort of patients with acute heart failure, left ventricular ejection fraction <50%, and iron deficiency, the safety and efficacy of ferric carboxymaltose were consistent across a range of eGFR values.
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Efficacy and safety of intravenous iron repletion in patients with heart failure: a systematic review and meta-analysis
Vukadinović D, Abdin A, Emrich I, Schulze PC, von Haehling S, Böhm M
Clinical research in cardiology : official journal of the German Cardiac Society. 2023;:1-13
Abstract
INTRODUCTION AFFIRM-AHF and IRONMAN demonstrated lower rates of the combined endpoint recurrent heart failure (HF) hospitalizations and cardiovascular death (CVD) using intravenous (IV) ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), respectively in patients with HF and iron deficiency (ID) utilizing prespecified COVID-19 analyses. MATERIAL AND METHODS We meta-analyzed efficacy, between trial heterogeneity and data robustness for the primary endpoint and CVD in AFFIRM-AHF and IRONMAN. As sensitivity analysis, we analyzed data from all eligible exploratory trials investigating FCM/FDI in HF. RESULTS FCM/FDI reduced the primary endpoint (RR = 0.81, 95% CI 0.69-0.95, p = 0.01, I(2) = 0%), with the number needed to treat (NNT) being 7. Power was 73% and findings were robust with fragility index (FI) of 94 and fragility quotient (FQ) of 0.041. Effects of FCM/FDI were neutral concerning CVD (OR = 0.88, 95% CI 0.71-1.09, p = 0.24, I(2) = 0%). Power was 21% while findings were fragile with reverse FI of 14 and reversed FQ of 0.006. The sensitivity analysis from all eligible trials (n = 3258) confirmed positive effects of FCM/FDI on the primary endpoint (RR = 0.77, 95% CI 0.66-0.90, p = 0.0008, I(2) = 0%), with NNT being 6. Power was 91% while findings were robust (FI of 147 and FQ of 0.045). Effect on CVD was neutral (RR = 0.87, 95% CI 0.71-1.07, p = 0.18, I(2) = 0%). Power was 10% while findings were fragile (reverse FI of 7 and reverse FQ of 0.002). Rate of infections (OR = 0.85, 95% CI 0.71-1.02, p = 0.09, I(2) = 0%), vascular disorder (OR = 0.84, 95% CI 0.57-1.25, p = 0.34, I(2) = 0%) and general or injection-site related disorders (OR = 1.39, 95% CI 0.88-1.29, p = 0.16, I(2) = 30%) were comparable between groups. There was no relevant heterogeneity (I(2) > 50%) between the trials for any of the analyzed outcomes. CONCLUSIONS Use of FCM/FDI is safe and reduces the composite of recurrent HF hospitalizations and CVD, while effects on CVD alone are based on available level of data indeterminate. Findings concerning composite outcomes exhibit a high level of robustness without heterogeneity between trials with FCM and FDI.
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Standard of care versus Octreotide in Angiodysplasia-related bleeding (the OCEAN study): A Multicenter Randomized Controlled trial
Goltstein, L. C. M. J., Grooteman, K. V., Bernts, L. H. P., Scheffer, R. C. H., Laheij, R. J. F., Gilissen, L. P. L., Schrauwen, R. W. M., Talstra, N. C., Zuur, A. T., Braat, H., et al
Gastroenterology. 2023
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Editor's Choice
Abstract
BACKGROUND AND AIMS Gastrointestinal angiodysplasias are vascular anomalies that may result in transfusion-dependent anemia despite endoscopic therapy. An individual patient data meta-analysis of cohort studies suggests that octreotide decreases rebleeding rates, but component studies possessed a high risk of bias. We aimed to investigate the efficacy of octreotide in reducing the transfusion requirements of patients with angiodysplasia-related anemia in a clinical trial setting. METHODS The study was designed as a multicenter, open-label, randomized controlled trial. Patients with angiodysplasia bleeding were required to have had at least four red blood cell (RBC) units and/or parental iron infusions in the year preceding randomization. Patients were allocated (1:1) to 40mg octreotide long-acting release intramuscular every 28 days or standard of care, including endoscopic therapy. The treatment duration was one year. The primary outcome was the mean difference in the number of transfusion units (RBC + parental iron) between the octreotide and standard of care groups. Patients who received at least one octreotide injection or followed standard of care for at least one month were included in the intention-to-treat analyses. Analyses of covariance were used to adjust for baseline transfusion requirements and incomplete follow-up. RESULTS We enrolled 62 patients (mean age 72 years, 32 males) from 17 Dutch hospitals in the octreotide (n=31) and standard of care (n=31) groups. Patients required a mean number of 20.3 (SD 15.6) transfusion units and 2.4 (SD 2.0) endoscopic procedures in the year before enrolment. The total number of transfusions was lower with octreotide (11.0; 95% CI, 5.5-16.5) compared to standard of care (21.2; 95% CI, 15.7-26.7). Octreotide reduced the mean number of transfusion units by 10.2 (95% CI, 2.4-18.1; P = .012). Octreotide reduced the annual volume of endoscopic procedures by 0.9 (95% CI, 0.3-1.5). CONCLUSION Octreotide effectively reduces transfusion requirements and the need for endoscopic therapy in patients with angiodysplasia-related anemia. CLINICALTRIALS gov, NCT02384122.
PICO Summary
Population
Patients with refractory anemia due to bleeding gastrointestinal angiodysplasias, enrolled in the OCEAN randomised controlled trial (n= 62).
Intervention
Octreotide (n= 31).
Comparison
Standard of care (n= 31).
Outcome
The treatment duration was one year. The primary outcome was the mean difference in the number of transfusion units (red blood cell + parental iron) between the octreotide and standard of care groups. The total number of transfusions was lower with octreotide (11.0; 95% CI [5.5, 16.5]) compared to standard of care (21.2; 95% CI [15.7, 26.7]). Octreotide reduced the mean number of transfusion units by 10.2; 95% CI [2.4, 18.1]. Octreotide reduced the annual volume of endoscopic procedures by 0.9; 95% CI [0.3, 1.5].
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Efficacy of Ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta-analysis
Ponikowski, P., Mentz, R. J., Hernandez, A. F., Butler, J., Khan, M. S., van Veldhuisen, D. J., Roubert, B., Blackman, N., Friede, T., Jankowska, E. A., et al
European heart journal. 2023
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Editor's Choice
Abstract
BACKGROUND AND AIMS Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency (ID) and heart failure (HF) has been consistently demonstrated, the effects of treatment on clinical events remain the subject of research. This meta-analysis aimed to characterize the effects of FCM therapy on hospitalizations and mortality. METHODS Patient-level data from randomized, placebo-controlled FCM trials including adults with HF and ID with ≥52 weeks follow-up were analysed. The co-primary efficacy endpoints were (1) composite of total/recurrent cardiovascular hospitalizations and cardiovascular death, and (2) composite of total HF hospitalizations and cardiovascular death, through 52 weeks. Key secondary endpoints included individual composite endpoint components. Event rates were analysed using a negative binomial model. Treatment-emergent adverse events were also examined. RESULTS Three FCM trials with a total of 4501 patients were included. FCM was associated with a significantly reduced risk of co-primary endpoint 1 (rate ratio [RR] 0.86; 95% confidence interval [CI] 0.75-0.98; P=0.029; Cochran Q: 0.008), with a trend towards a reduction of co-primary endpoint 2 (RR 0.87; 95% CI 0.75-1.01; P=0.076; Cochran Q: 0.024). Treatment effects appeared to result from reduced hospitalization rates, not improved survival. Treatment appeared to have a good safety profile and was well-tolerated. CONCLUSIONS In iron-deficient patients with HF with reduced left ventricular ejection fraction, intravenous FCM was associated with significantly reduced risk of hospital admissions for HF and cardiovascular causes, with no apparent effect on mortality.
PICO Summary
Population
Adults with heart failure (HF) and iron deficiency enrolled in the ferric carboxymaltose (FCM) trials: CONFIRM-HF, AFFIRM-AHF, and HEART-FID (3 randomised controlled trials, n= 4,501).
Intervention
FCM (n= 2,251).
Comparison
Placebo (n= 2,250).
Outcome
The co-primary efficacy endpoints were (1) composite of total/recurrent cardiovascular hospitalizations and cardiovascular death, and (2) composite of total HF hospitalizations and cardiovascular death, through 52 weeks. FCM was associated with a significantly reduced risk of co-primary endpoint 1 (rate ratio [RR] 0.86; 95% confidence interval (CI) [0.75, 0.98]; Cochran Q: 0.008), with a trend towards a reduction of co-primary endpoint 2 (RR 0.87; 95% CI [0.75, 1.01]; Cochran Q: 0.024).
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Ferric Carboxymaltose in Heart Failure with Iron Deficiency
Mentz, R. J., Garg, J., Rockhold, F. W., Butler, J., De Pasquale, C. G., Ezekowitz, J. A., Lewis, G. D., O'Meara, E., Ponikowski, P., Troughton, R. W., et al
The New England journal of medicine. 2023
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Editor's Choice
Abstract
BACKGROUND Ferric carboxymaltose therapy reduces symptoms and improves quality of life in patients who have heart failure with a reduced ejection fraction and iron deficiency. Additional evidence about the effects of ferric carboxymaltose on clinical events is needed. METHODS In this double-blind, randomized trial, we assigned ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency, in a 1:1 ratio, to receive intravenous ferric carboxymaltose or placebo, in addition to standard therapy for heart failure. Ferric carboxymaltose or placebo was given every 6 months as needed on the basis of iron indexes and hemoglobin levels. The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at 0.01. RESULTS We enrolled 3065 patients, of whom 1532 were randomly assigned to the ferric carboxymaltose group and 1533 to the placebo group. Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (Wilcoxon-Mann-Whitney P = 0.02; unmatched win ratio, 1.10; 99% confidence interval, 0.99 to 1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (413 patients [27.0%] in the ferric carboxymaltose group and 401 [26.2%] in the placebo group). CONCLUSIONS Among ambulatory patients who had heart failure with a reduced ejection fraction and iron deficiency, there was no apparent difference between ferric carboxymaltose and placebo with respect to the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance. (Funded by American Regent, a Daiichi Sankyo Group company; HEART-FID ClinicalTrials.gov number, NCT03037931.).
PICO Summary
Population
Patients with heart failure and iron deficiency (n= 3,065).
Intervention
Intravenous ferric carboxymaltose group (n= 1,532).
Comparison
Placebo (n= 1,533).
Outcome
Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (unmatched win ratio, 1.10; 99% confidence interval [0.99, 1.23]). The number of patients with serious adverse events occurring during the treatment period was similar in the two groups: 413 patients (27.0%) in the ferric carboxymaltose group, and 401 (26.2%) in the placebo group.
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Treating Iron Deficiency (ID) Anemia in Heart Failure (HF) Patients with IV Iron: A Meta-Analysis
Ogugua, F. M., Aguilar, F. A., Gamam, A., Maqsood, M. H., Yoo, T. K., Kasmi, F., AlKowatli, O., Lo, K.
Cureus. 2023;15(7):e41895
Abstract
Findings on the effects of iron on heart failure (HF) hospitalizations and mortality among patients with iron deficiency (ID) and HF remain conflicting across different studies. We performed a meta-analysis of clinical trials assessing the clinical, hematic and cardiovascular benefits of treating ID in HF patients. We completed a systematic search for studies comparing IV iron to placebo in HF patients with ID. The primary outcomes were rates of HF hospitalization and all-cause mortality. Secondary outcomes included change in hematic values, New York Heart Association (NYHA) class and ejection fraction. We applied a random-effects model with planned sensitivity analyses of studies with skewed effect sizes. Nine studies were included with a total of 2,261 patients. Analysis revealed that treatment of HF patients with IV iron replacement significantly reduced the odds of HF hospitalization (odds ratio (OR): 0.44; 95% confidence interval (CI): 0.24 to 0.78; p=0.005, I(2)=67%),) but did not significantly impact all-cause mortality compared to placebo (OR: 0.89; 95%, CI: 0.67 to 1.19; p=0.44, I(2): 0%). Analysis showed that IV iron treatment group had significantly higher serum ferritin, transferrin saturation and hemoglobin (Hb) levels. They also had lower NYHA class -1.90 (95% CI (-2.91 to -0.89); p<0.001, I(2):89%) with higher ejection fraction 0.50 (95% CI (0.09 to 0.90) p=0.016, I(2):86%). Treatment with IV iron in HF patients with ID is associated with a significant reduction of HF hospitalization but no effects on all-cause mortality. There were also significant increases in hematic values and ejection fraction with a reduction in NYHA class.
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Effect of Intravenous Iron Replacement on Recurrent Heart Failure Hospitalizations and Cardiovascular Mortality in Patients with Heart Failure and Iron Deficiency: A Bayesian Meta-Analysis
Anker SD, Shahzeb Khan M, Butler J, von Haehling S, Jankowska EA, Ponikowski P, Friede T
European journal of heart failure. 2023
Abstract
AIMS: Iron deficiency is common in patients with heart failure and reduced ejection fraction (HFrEF) and is associated with a poor prognosis. Whether intravenous iron replacement improves recurrent HF hospitalizations and cardiovascular mortality of these patients is uncertain although several trials were conducted. Moreover, none of the trials were powered to assess the effect of intravenous iron in clinically important subgroups. Therefore, we conducted a Bayesian analysis to derive precise estimates of the effect of intravenous iron replacement on recurrent HF hospitalizations and cardiovascular mortality in iron-deficient HFrEF patients using consistent subgroup definitions across trials. METHODS Individual participant data was used from the FAIR-HF (n=459), CONFIRM-HF (n=304) and AFFIRM-AHF (n=1,108) trials. This data was re-analyzed following as closely as possible the approach taken in the analyses of IRONMAN (n=1,137), for which study level data was used. Definitions of outcomes and subgroups from the FAIR-HF, CONFIRM-HF and AFFIRM-AHF were matched with those used in IRONMAN. The primary endpoint was recurrent HF hospitalizations and cardiovascular mortality. The analysis of recurrent events was based on rate ratios (RR) derived from the Lin-Wei-Yang-Ying model, and the data were pooled using Bayesian random effect meta-analysis. RESULTS Compared with placebo, intravenous iron significantly reduced the rates of recurrent HF hospitalizations and cardiovascular mortality (RR: 0.73, 95% credible interval (CI) [0.48-0.99]; between-trial heterogeneity tau=0.16). The pooled treatment effects did not provide evidence for any differential effects for subgroups based on sex (ratio of rate ratios [RRR]: 1.49 , 95% CI [0.95-2.37], age < vs ≥69.4 years (RRR= 0.68 [0.40-1.15]), ischemic vs non-ischemic etiology of HF (RRR=0.73 [0.42-1.33]), transferrin saturation < vs ≥20% (RRR=0.75 [0.40-1.34]), estimated glomerular filtration rate (≤ vs >60 mL/min/1.73m(2) (RRR=0.97 [0.56-1.68]), haemoglobin < vs ≥ 11.8 (RRR=0.95 [0.53-1.60]), ferritin < vs ≥35 μg/L (RRR=1.26 [0.72-2.48]) and New York Heart Association Class II vs III/IV (RRR=0.91 [0.54-1.56]). CONCLUSIONS Treatment of iron-deficient HFrEF patients with intravenous iron - namely with ferric carboxymaltose or ferric derisomaltose - results in significant reduction in recurrent HF hospitalizations and cardiovascular mortality. Results were nominally consistent across the subgroups studied, but for several of these subgroups uncertainty remains present. This article is protected by copyright. All rights reserved.