Ferric Carboxymaltose Among Patients with Heart Failure and Iron Deficiency: An Updated Meta-Analysis of Randomized Controlled Trials.

Hospitalizations for New Heart Failure Among Subjects With Diabetes Mellitus in the RENAAL and LIFE Studies

Relation of Baseline Systolic Blood Pressure and Long-Term Outcomes in Ambulatory Patients With Chronic Mild to Moderate Heart Failure

BackgroundRandomized clinical trials (RCTs) evaluating the role of intravenous (IV) iron administration in patients with heart failure (HF) and iron deficiency (ID) have yielded inconsistent results. MethodsElectronic search of MEDLINE, EMBASE and OVID databases was performed until November 2022 for RCTs that evaluated the role of IV iron administration in patients with HF and ID. The main study outcomes were the composite of HF hospitalization or cardiovascular mortality, and individual outcome of HF hospitalization. Summary estimates were evaluated using random effects model. ResultsThe final analysis included 12 RCTs with 3,492 patients (1,831 patients in the IV iron group and 1,661 patients in the control group). The mean follow-up was 8.3 months. IV iron was associated with a lower incidence in the composite of HF hospitalization or cardiovascular mortality (31.9% vs. 45.3%; relative risk [RR] 0.72; 95% confidence interval [CI] 0.59–0.88) and individual outcome of HF hospitalization (28.4% vs. 42.2; RR 0.69; 95% CI 0.57–0.85). There was no significant difference between both groups in cardiovascular mortality (RR 0.88; 95% CI 0.75–1.04) and all-cause mortality (RR 0.95; 95% CI 0.83–1.09). IV iron was associated with lower New York Heart Association class and higher left ventricular ejection fraction (LVEF). Meta-regression analyses showed no effect modification for the main outcomes based on age, hemoglobin level, ferritin level or LVEF. ConclusionAmong patients with HF and ID, IV iron administration was associated with reduction in the composite of HF hospitalization or cardiovascular mortality and driven by a reduction in HF hospitalization.

Targeting Iron Deficiency in Heart Failure: Existing Evidence and Future Expectations.

Background: Iron deficiency (ID) is common among patients with heart failure (HF), and it is associated with poor functional outcomes, increased hospitalizations, and higher mortality. This meta-analysis evaluates the efficacy of intravenous ferric carboxymaltose (FCM) in HF patients with ID. Methods: We conducted a literature search of major bibliographic databases up to April 15, 2025, to identify randomized controlled trials (RCTs) comparing FCM with placebo or standard care in HF patients with ID. The primary outcome was a composite of recurrent hospitalizations for heart failure (HHF) or cardiovascular (CV) death assessed at 1-year and complete follow-up. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were estimated using a random-effects model. Results: Eleven RCTs (6,493 patients) were included in the review. FCM significantly reduced the composite of recurrent HHF or CV death at 1-year (RR 0.73, 95% CI 0.62–0.85) and over maximum follow-up (RR 0.80, 95% CI 0.68–0.94) compared to control. Recurrent HHF was significantly reduced with FCM administration (1-year RR 0.69, 95% CI 0.57–0.84; complete follow-up RR 0.75, 95% CI 0.60–0.94). FCM demonstrated a trend toward reduced all-cause (RR: 0.86, 95% CI: 0.74–1.00) and CV mortality at 1-year (RR: 0.86, 95% CI: 0.72–1.02), but this effect was attenuated over longer follow-up. FCM significantly improved 6-minute walk test performance (MD 29.19 m, 95% CI 11.95–46.43). The trial sequential analysis confirmed robust evidence for the primary outcome. Conclusion: Intravenous FCM in HF patients is associated with reduced risk of adverse cardiovascular events and improved functional capacity. Further trials are needed to clarify its long-term survival impact.

Iron deficiency (ID) is a common and clinically significant comorbidity in patients with heart failure (HF), contributing to reduced exercise capacity, poor quality of life, and increased hospitalization risk. Although intravenous (IV) iron therapy has demonstrated efficacy in improving functional outcomes, the comparative effectiveness of IV vs. oral (per os, or PO) iron supplementation remains uncertain. We conducted a systematic review and network meta-analysis (NMA) of 13 randomized controlled trials (RCTs) evaluating IV iron (ferric carboxymaltose, ferric derisomaltose, iron sucrose), PO iron (ferrous sulfate, ferrous fumarate, polysaccharide, sucrosomial, ferric polymaltose), and placebo in HF patients with ID, analyzed as route-specific class effects. Outcomes analyzed included six-minute walk distance (6MWD), ferritin, transferrin saturation (TSAT), HF hospitalization, all-cause mortality, and cardiovascular (CV) mortality.We used a Hartung-Knapp random-effects framework with Sidik-Jonkman variance, assessed heterogeneity and inconsistency using I2, τ2, design-by-treatment interaction, and node-splitting. Risk of bias was assessed independently by two reviewers using Risk of Bias 2 (RoB 2), and certainty of evidence for all outcomes was graded using GRADE adapted for NMA. Because most contrasts included fewer than 10 RCTs, formal tests for publication bias were not feasible, and potential small-study effects were considered qualitatively in the GRADE assessments. Trials that reported outcomes only as medians and interquartile ranges (IQRs), or baseline values without follow-up data, were excluded from quantitative pooling and described narratively.IV iron significantly improved 6MWD compared to placebo (mean difference (MD) +26.0 m; 95% confidence interval (CI): 18.1 to 33.9), increased ferritin (MD +237.2 μg/L), and reduced the risk of HF hospitalization (risk ratio (RR) 0.79; 95% CI: 0.66 to 0.93), with moderate to high certainty. PO iron showed a comparable, but not statistically significant, mean improvement in 6MWD (MD +35.1 m; 95% CI: -5.2 to +75.4), with wider CIs and inconsistent ferritin and TSAT gains. Neither IV nor PO iron was associated with a significant reduction in all-cause or CV mortality, although a trend toward benefit was observed with IV therapy. Numerical SUCRA values favored IV iron for HF hospitalization (77.9 vs. 57.6 for PO, 14.5 for placebo), ferritin (100.0 vs. 50.0 vs. 0.0), and TSAT (74.0 vs. 75.8 vs. 0.2), while PO iron ranked slightly higher for 6MWD (76.3 vs. 73.7 vs. 0.0). Included PO formulations encompassed both traditional preparations (ferrous sulfate/fumarate, polysaccharide) and newer agents such as sucrosomial iron and ferric polymaltose. Adverse events were comparable across groups: IV iron was not associated with excess mortality or serious adverse events, and PO iron was primarily limited by gastrointestinal intolerance. Sensitivity analyses restricting outcomes to trials with 3-12 months of follow-up showed consistent results, while longer studies mainly influenced event counts rather than the direction of effect. Our findings support the use of IV iron as the preferred strategy to improve symptoms and reduce hospitalizations in HF patients with ID, whereas PO iron may be considered when IV therapy is inaccessible. Further large-scale trials are needed to clarify long-term mortality impact and the role of newer PO formulations.

Clinical outcomes of intravenous iron therapy in patients with heart failure and iron deficiency: Meta-analysis and trial sequential analysis of randomized clinical trials

Sodium-glucose co-transporter 2 inhibitors: strength of evidence for a cardio-renal-metabolic therapy.

The European Society of Cardiology (ESC) provided a focused update to the 2021 Guideline for the Management of Heart Failure, now providing a 1A recommendation for intravenous iron in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency (ID). However, the findings from randomized controlled trials (RCT) are mixed. This systematic review of RCTs aims to provide an update and synthesize the evidence addressing the association of intravenous iron with patient-based outcomes in patients with HFrEF and ID. Any RCT evaluating the effect of intravenous iron in patients with HFrEF and ID was eligible for inclusion. A complete search of the EMBASE and PubMed databases was conducted from inception until 15 September 2023. The primary outcome was the composite of the quality of life (QoL) questionnaires, while the secondary outcomes included first heart failure (HF) hospitalizations and all-cause mortality. Data extraction was performed independently by two reviewers. Data were pooled using a random-effects model. Of the 1035 references, 15 RCTs enrolling 6649 patients were included in this study. Intravenous iron was associated with significant improvement in the composite of QoL (standardized mean difference -1.36, 95% confidence interval [CI] -2.24 to -0.48; p=0.002), a significant reduction in first HF hospitalizations (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.02), and with no change in all-cause mortality (HR 0.90, 95% CI 0.79-1.03; p=0.12). The certainty of the evidence ranged from moderate to very low. Intravenous iron is possibly associated with improved QoL and reduced HF hospitalizations, without impacting all-cause mortality. These findings not only support the use of intravenous iron in patients with HFrEF but also emphasize the need for well-designed and executed RCTs with granular outcome reporting and powered sufficiently to address the impact of intravenous iron on mortality in patients with HFrEF and ID. PROSPERO identifier number CRD42023389.

Uncertainty remains about the efficacy of intravenous iron in patients with heart failure and iron deficiency. To assess the efficacy and safety of ferric carboxymaltose in patients with heart failure and iron deficiency. 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). 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). 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). 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). 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. ClinicalTrials.gov Identifier: NCT03036462.

To examine trends in heart failure (HF) hospitalization rates and risk of readmissions following an incident HF hospitalization. During 2000-2014, we identified in the Cardiovascular Disease in Norway Project 142 109 hospitalizations with HF as primary diagnosis. Trends of incident and total (incident and recurrent) HF hospitalization rates were analysed using negative binomial regression models. Changes over time in 30-day and 3-year risk of HF recurrences or cardiovascular disease (CVD)-related readmissions were analysed using Fine and Grey competing risk regression, with death as competing events. Age-standardized rates declined on average 1.9% per year in men and 1.8% per year in women for incident HF hospitalizations (both Ptrend < 0.001) but did not change significantly in either men or women for total HF hospitalizations. In men surviving the incident HF hospitalization, 30-day and 3-year risk of a HF recurrent event increased 1.7% and 1.2% per year, respectively. Similarly, 30-day and 3-year risk of a CVD-related hospitalization increased 1.5% and 1.0% per year, respectively (all Ptrend < 0.001). No statistically significant changes in the risk of HF recurrences or CVD-related readmissions were observed among women. In-hospital mortality for a first and recurrent HF episode declined over time in both men and women. Incident HF hospitalization rates declined in Norway during 2000-2014. An increase in the risk of recurrences in the context of reduced in-hospital mortality following an incident and recurrent HF hospitalization led to flat trends of total HF hospitalization rates.

BackgroundThe effectiveness of oral and intravenous iron supplementation in reducing the risk of mortality and hospitalizations in HF patients with iron deficiency is not well-established.MethodsA thorough literature search was conducted across 2 electronic databases (Medline and Cochrane Central) from inception through March 2021. RCTs assessing the impact of iron supplementation on clinical outcomes in iron deficient HF patients were considered for inclusion. Primary end-points included all-cause mortality and HF hospitalization. Evaluations were reported as odds ratios (ORs) or risk ratios (RRs) with 95% confidence intervals (CI) and analysis was performed using a random effects model. I2 index was used to assess heterogeneity.ResultsFrom the 2599 articles retrieved from initial search, 10 potentially relevant studies (n = 2187 patients) were included in the final analysis. Both oral (OR: 0.93; 95% CI: 0.08–11.30; p = 0.951) and intravenous (OR: 0.97; 95% CI: 0.73–1.29; p = 0.840) iron supplementation did not significantly reduce all-cause mortality. However, intravenous iron supplementation significantly decreased the rates of overall (OR: 0.52; 95% CI: 0.33–0.81; p = 0.004) and HF (OR: 0.42; 95% CI: 0.22–0.80; p = 0.009) hospitalizations. In addition, intravenous ferric carboxymaltose therapy significantly reduced the time to first HF hospitalization or cardiovascular mortality (RR = 0.70; 95% CI = 0.50–1.00; p = 0.048), but had no effect on time to first cardiovascular death (RR: 0.94; 95% CI: 0.70–1.25; p = 0.655).ConclusionOral or intravenous iron supplementation did not reduce mortality in iron deficient HF patients. However, intravenous iron supplementation was associated with a significant decrease in overall and HF hospitalizations.

For a drug to be effective for the treatment of heart failure, physicians must know who should receive it and how it should be started, titrated and maintained. In prescribing the foundational drugs for heart failure and a reduced ejection fraction, physicians rely on the protocol-specified eligibility criteria and guidance about the initiation and continuation of doses that reduced morbidity and mortality. The decision-making process is somewhat different if a drug is administered to achieve a physiological or biochemical effect. Diuretics alleviate fluid retention, and doses are individualized to achieve euvolaemia without worrisome azotaemia or electrolyte imbalances. Potassium supplements and binders are titrated to maintain serum potassium in a desired range. In both examples, the physiological or biochemical marker serves both as a trigger for treatment and as a guide to the titration of therapy. Should the dosing of iron supplementation be guided by biochemical measurements or by regimens that have been shown to improve outcomes? Historically, patients with an absolute iron deficiency (due to poor nutritional intake or gastrointestinal bleeding) were identified by exceptionally low levels of serum ferritin (i.e. <15–25 μg/L).1 However, patients with heart failure are typically iron deficient because of a functional block on the absorption of iron from the duodenum or the release of iron from the reticuloendothelial system, related to inflammation or other cellular stresses that increase both hepcidin and ferritin.2 Consequently, in patients with heart failure, the threshold for serum ferritin in the diagnosis of iron deficiency is increased by 1–2 orders of magnitude on a natural log scale, to <100 μg/L or to <300 μg/L if the transferrin saturation (TSAT) is <20%. However, these shifts do not fully account for the possibility of functional iron deficiency,3 and current ferritin criteria in the identification of iron-deficient patients with heart failure have been questioned.4 Furthermore, the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors distort the ability of conventional iron biomarkers to guide the dosing of iron supplements.2 Therefore, in contrast with diuretics and potassium supplements/binders, the goal of iron therapy is to improve functional capacity and to reduce the risk of cardiovascular death or hospitalization for heart failure, rather than to normalize values for laboratory measurements that have not been clinically validated or may be influenced by coadministration of foundational drugs. As a result, the approach to the correction of iron deficiency should be guided by the design of randomized controlled trials that have shown a benefit of iron supplements on clinically relevant endpoints. Table 1 summarizes the design of the seven completed or ongoing randomized controlled trials of iron supplementation with >100 patients with heart failure.5-11 In six of the seven trials, iron supplementation with ferric carboxymaltose or derisomaltose was initiated during a 1–6 week repletion period, during which patients received as little as 500 mg or as much as 2000 mg of elemental iron, using algorithms that were largely based on haemoglobin and body weight, and not influenced by the severity of iron deficiency. The trials used broadly similar approaches for the initial dosing of iron supplements, but they differed markedly with respect to their recommendations regarding repeated dosing. In four trials, the protocol recommended repeat iron supplementation after the initial repletion period only if patients continued to fulfill the criteria for iron deficiency that had been established at the time of enrolment. If patient had a serum ferritin <100 μg/L or the combination of a TSAT <20% with a serum ferritin <300 μg/L, patients were to receive additional iron supplements (typically, 500 mg of ferric carboxymaltose) at 12, 24 or 36 weeks in the CONFIRM-HF trial,6 at 12 weeks in the EFFECT-HF trial,7 at 12 or 24 weeks in the AFFIRM-AHF trial,8 and every 6 months in the HEART-FID trial.10 The variability in these recommendations was largely related to differences in the trial duration. The total doses of ferric carboxymaltose over the trial duration were 500–3500 mg over 52 weeks in CONFIRM-HF,6 1000–2000 mg over 24 weeks in EFFECT-HF,7 and up to 3000 mg over 52 weeks in AFFIRM-AHF.8 In these three trials, follow-up was truncated at 6 to 12 months, and thus, no guidance about dosing was provided beyond the first year. In striking contrast, three trials recommended repeated dosing with an iron supplement as long as the ferritin levels did not exceed a threshold level that was meaningfully higher than that currently used to identify patients with heart failure who have an iron-deficiency state. FAIR-HF specified repeated iron doses as long as the serum ferritin was not >800 μg/L, if the serum ferritin was not >500–800 μg/L if the TSAT >50%, or if haemoglobin was not >16 g/dl.5 IRONMAN recommended repeat iron dosing unless the serum ferritin was >400 μg/L or the TSAT was ≥25%, but most patients received only one or two doses.9 In FAIR-HF2, patients receive ferric carboxymaltose every 4 months unless the serum ferritin exceeds 800 μg/L or haemoglobin exceeds 16 g/dl.11 Due to its high ferritin threshold and long duration of treatment, it is likely that FAIR-HF2 will deliver the highest cumulative doses of iron of any of the seven trials (Table 1). Are higher doses of iron supplements better than low doses? Both AFFIRM-AHF and IRONMAN reported an effect of iron supplementation on the combined risk of cardiovascular death and heart failure hospitalization, with a p > 0.05 but <0.10. In both trials, the effect was driven by a reduction in heart failure hospitalizations without an effect on cardiovascular death or on ischaemic events. Is the FAIR-HF2 trial likely to yield a more persuasive result than AFFIRM-AHF or IRONMAN due to its greater intensity of iron supplementation? Some might believe that aggressive therapy based on higher ferritin thresholds to allow for repeated dosing with intravenous iron is destined to succeed, based on the results of the PIVOTAL trial.12 This trial randomized patients with anaemia and end-stage kidney disease undergoing maintenance haemodialysis to either a low-dose or high-dose strategy of intravenous iron sucrose, which was given as often as 400 mg monthly. In the low-dose arm, patients received iron supplementation only if serum ferritin levels were < 200 mg/L or if TSAT was <20%, whereas in the high-dose arm, patients continued to receive iron until the serum ferritin was >700 μg/L or the TSAT was ≥40%. Accordingly, after 12 months, patients in the high-dose group had received a median of 2000 mg more iron than the patients in the low-dose group. The mean serum ferritin levels at 1 year were 150–200 μg/L in the low-dose group and 550–600 μg/L in the high-dose group. The primary endpoint for the trial was the composite of death from any cause, non-fatal myocardial infarction or stroke or hospitalization for heart failure. The hazard ratio for the effect of high doses of iron versus low doses of iron on the primary endpoint was 0.85 (95% confidence interval [CI] 0.73–1.00; p = 0.04 for superiority) with a nominally significant effect on all-cause mortality alone (hazard ratio 0.84; 95% CI 0.71–1.00), on fatal and non-fatal myocardial infarction alone (hazard ratio 0.69; 95% CI 0.52–0.93), and on hospitalization for heart failure (hazard ratio 0.66; 95% CI 0.46–0.94). Do these results indicate that intravenous iron should be dosed to a ferritin level higher than used in most heart failure trials to date? The primary goal of the PIVOTAL trial was not to test the efficacy of higher versus lower doses of iron, but to determine if higher iron doses would reduce the requirement of concurrently prescribed erythropoiesis-stimulating agents (ESAs).13 ESAs are known to increase the risk of death and non-fatal myocardial infarction in anaemic patients undergoing dialysis, an effect that is related to the administered dose.14, 15 Interventions that allow for lower dosing with ESAs would be expected to have meaningful clinical benefits independent of any other effects. In fact, in the PIVOTAL trial, the median monthly dose of ESAs was 20–25% lower in patients receiving the high-dose versus the low-dose iron regimen (29 757 IU vs. 38 805 IU per month). The difference in ESA utilization in the treatment arms of the PIVOTAL trial likely explains the observed between-group difference in the occurrence of death and myocardial infarction, since these benefits are not seen when intravenous iron is given to patients with heart failure who are not receiving ESAs. Most patients with heart failure are not poised to benefit from an ESA-sparing effect of high-dose iron therapy. Because of the striking heterogeneity in the dosing regimens used in randomized controlled trials, we do not know how to guide repeat dosing of intravenous iron in patients with heart failure who are deemed to be iron deficient, particularly in those receiving SGLT2 inhibitors.2 A comparison of the results of the HEART-FID trial (using a low ferritin-targeting strategy) and the FAIR-HF2 trial (using a high-ferritin targeting strategy) may provide important insights into this important issue. Conflict of interest: During the past 3 years, M.P. reports personal fees for consulting from Abbvie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, Salamandra.

BackgroundThe recent AFFIRM-AHF trial assessing the effect of intravenous (IV) iron on outcomes in patients hospitalised with worsening heart failure who had iron deficiency (ID) narrowly missed its primary efficacy endpoint of recurrent hospitalisations for heart failure (HHF) or cardiovascular (CV) death. We conducted a meta-analysis to determine whether these results were consistent with previous trials.MethodsWe searched for randomised trials of patients with heart failure investigating the effect of IV iron vs placebo/control groups that reported HHF and CV mortality from 1st January 2000 to 5th December 2020. Seven trials were identified and included in this analysis. A fixed effect model was applied to assess the effects of IV iron on the composite of first HHF or CV mortality and individual components of these.ResultsAltogether, 2,166 patients were included (n = 1168 assigned to IV iron; n = 998 assigned to control). IV iron reduced the composite of HHF or CV mortality substantially [OR 0.73; (95% confidence interval 0.59–0.90); p = 0.003]. Outcomes were consistent for the pooled trials prior to AFFIRM-AHF. Whereas first HHF were reduced substantially [OR 0.67; (0.54–0.85); p = 0.0007], the effect on CV mortality was uncertain but appeared smaller [OR 0.89; (0.66–1.21); p = 0.47].ConclusionAdministration of IV iron to patients with heart failure and ID reduces the risk of the composite outcome of first heart failure hospitalisation or cardiovascular mortality, but this outcome may be driven predominantly by an effect on HHF. At least three more substantial trials of intravenous iron are underway.Graphic abstract

Background and Aims In the AFFIRM-AHF trial, treatment with intravenous (IV) ferric carboxymaltose (FCM) reduced the risk of heart failure (HF) hospitalisations vs placebo in patients with iron deficiency after an episode of acute HF. Of these patients, 41% had a medical history of chronic kidney disease (CKD). This prespecified subanalysis of AFFIRM-AHF data was performed to investigate the effect of renal function on FCM efficacy. Methods In AFFIRM-AHF, patients stabilised following hospitalisation for acute HF with concomitant iron deficiency (defined as ferritin &amp;lt;100 μg/L, or 100–299 μg/L with transferrin saturation &amp;lt;20%) were randomised to receive either IV FCM or placebo before discharge for the index hospitalisation. In this analysis, patients who had received at least one dose of the study drug, and who had at least one post-randomisation data point and a baseline value for estimated glomerular filtration rate (eGFR; calculated using the CKD-EPI formula and baseline creatinine value), were stratified into tertiles according to baseline eGFR. The primary outcome was a composite of total HF hospitalisations and CV death. Secondary outcomes included total HF hospitalisations, CV death, time to first HF hospitalisation or CV death, composite of total CV hospitalisations and CV death, and days lost due to HF hospitalisations or CV death. All outcomes were evaluated up to 52 weeks post-randomisation. Results Of the 1,108 patients included in primary AFFIRM-AHF analyses, 967 (FCM: 487; placebo: 480) had a baseline eGFR value and were included in this analysis. In both groups, 60% of patients had an eGFR &amp;lt;60 mL/min/1.73 m2 following the index acute HF episode. Patients were divided into eGFR tertiles 1, 2 and 3, with corresponding respective baseline eGFR values of &amp;lt;42.96, 42.96 to &amp;lt;64.32, and ≥64.32 mL/min/1.73 m2. At baseline, the mean age, proportion of females, and proportions of patients with ischaemic HF aetiology, a documented history of HF, and a medical history of percutaneous coronary intervention, coronary artery bypass graft and/or cardiac resynchronisation therapy, were highest in eGFR tertile 1 and lowest in eGFR tertile 3. In eGFR tertiles 1, 2 and 3, the number of total HF hospitalisations and CV deaths in the FCM group vs placebo group were, respectively, 115 vs 152, 76 vs 83, and 56 vs 79, with respective annualised rate ratios (95% confidence interval [CI]) of 0.76 (0.50, 1.16), 0.76 (0.48, 1.22) and 0.69 (0.42, 1.12) (Figure). In eGFR tertile 3, the total number of CV hospitalisations and CV deaths was significantly lower in the FCM group vs the placebo group (69 vs 107; rate ratio [95% CI] 0.60 [0.39, 0.93]), with a nominally lower number of total HF hospitalisations with FCM vs placebo (44 vs 66; rate ratio [95% CI] 0.62 [0.38, 1.01]). In the time to first event analysis, FCM significantly reduced HF hospitalisation or CV death vs placebo in eGFR tertile 3 (hazard ratio [95% CI] 0.64 [0.42, 0.98]). In eGFR tertiles 1 and 2, differences between FCM and placebo arms for secondary endpoints did not reach statistical significance. The p-trend for treatment by baseline eGFR subgroup was non-significant for the primary outcome (0.941) and also for the secondary outcomes specified here. Conclusion In patients with iron deficiency who were stabilised after an episode of acute HF, numerically fewer primary and secondary events, endpoints or outcomes were consistently observed with FCM vs placebo across the eGFR tertiles. In addition, no significant interaction between kidney function and FCM efficacy was noted. Given that this analysis was limited by small patient numbers following subgroup stratification, further studies in larger cohorts with CKD may help to clarify the effect of IV FCM in this patient population.