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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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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.
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Impact of ferric carboxymaltose for iron deficiency at discharge after heart failure hospitalisation: A European multinational economic evaluation
McEwan P, Harrison C, Binnie R, Lewis RD, Cohen-Solal A, Lund LH, Ohlsson M, von Haehling S, Comin-Colet J, Pascual-Figal DA, et al
European journal of heart failure. 2023
Abstract
AIMS: Iron deficiency (ID) is comorbid in up to 50% patients with heart failure (HF) and exacerbates disease burden. Ferric carboxymaltose (FCM) reduced HF hospitalisations and improved quality of life when used to treat ID at discharge in patients hospitalised for acute HF with left-ventricular ejection fraction of <50% in the AFFIRM-AHF trial. We quantified the effect of FCM on burden of disease and the wider pharmacoeconomic implications in France, Germany, Poland, Spain and Sweden. METHODS AND RESULTS The per country eligible population was calculated, aligning with the ESC 2021 HF guidelines and the AFFIRM-AHF trial. Changes in burden of disease with FCM versus standard of care (SoC) were represented by disability-adjusted life years (DALYs), hospitalisation episodes and bed days, using AFFIRM-AHF data. A Markov model was adapted to each country to estimate cost-effectiveness and combined with epidemiology data to calculate the impact on healthcare budgets. Between 335 (Sweden) and 13,237 (Germany) DALYs were predicted to be avoided with FCM use annually. Fewer hospitalisations and shorter lengths of stay associated with FCM compared to SoC were projected to result in substantial annual savings in bed days, from 5,215 in Sweden to 205,630 in Germany. In all countries, FCM was predicted to be dominant (cost saving with gains in quality-adjusted life years), resulting in net savings to healthcare budgets within one year. CONCLUSIONS This comprehensive evaluation of FCM therapy highlights the potential benefits that could be realised through implementation of the ESC HF guideline recommendations regarding ID treatment. This article is protected by copyright. All rights reserved.
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Health Status Improvement with Ferric Carboxymaltose in Heart Failure with Reduced Ejection Fraction and Iron Deficiency
Butler J, Khan MS, Friede T, Jankowska EA, Fabien V, Goehring UM, Dorigotti F, Metra M, Piña IL, Coats AJ, et al
European journal of heart failure. 2022
Abstract
AIM: Intravenous ferric carboxymaltose (FCM) has been shown to improve overall quality of life in iron-deficient heart failure with reduced ejection fraction (HFrEF) patients at a trial population level. This FAIR-HF and CONFIRM-HF pooled analysis explored the likelihood of individual improvement or deterioration in Kansas City Cardiomyopathy Questionnaire (KCCQ) domains with FCM vs placebo and evaluated the stability of this response over time. METHODS Changes vs baseline in KCCQ overall summary score (OSS), clinical summary score (CSS) and total symptom score (TSS) were assessed at weeks 12 and 24 in FCM and placebo groups . Mean between-group differences were estimated and individual responder analyses and analyses of response stability were performed. RESULTS Overall, 760 (FCM: 454) patients were studied. At week 12, the mean improvement in KCCQ OSS was 10.6 points with FCM vs 4.8 points with placebo (least-square mean difference [95% confidence interval (CI)]: 4.36 [2.14;6.59] points). A higher proportion of patients on FCM vs placebo experienced a KCCQ OSS improvement of ≥5 (58.3% vs 43.5%; odds ratio [95% CI]: 1.81 [1.30;2.51]), ≥10 (42.4% vs 29.3%; 1.73 [1.23;2.43]) or ≥15 (32.1% vs 22.6%; 1.46 [1.02;2.11]) points. Differences were similar at week 24 and for CSS and TSS domains. Of FCM patients with a ≥5-, ≥10- or ≥15-point improvement in KCCQ OSS at week 12, >75% sustained this improvement at week 24. CONCLUSION Treatment of iron-deficient HFrEF patients with intravenous FCM conveyed clinically relevant improvements in health status at an individual-patient level; benefits were sustained over time in most patients. This article is protected by copyright. All rights reserved.
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Ferric carboxymaltose for the treatment of iron deficiency in heart failure: a multinational cost-effectiveness analysis utilising AFFIRM-AHF
McEwan P, Ponikowski P, Davis JA, Rosano G, Coats AJS, Dorigotti F, O'Sullivan D, Ramirez de Arellano A, Jankowska EA
European journal of heart failure. 2021
Abstract
AIMS: Iron deficiency is common in patients with heart failure (HF). In AFFIRM-AHF, ferric carboxymaltose (FCM) reduced the risk of hospitalisations for HF (HHF) and improved quality of life vs. placebo in iron-deficient patients with a recent episode of acute HF. The objective of this study was to estimate the cost-effectiveness of FCM compared with placebo in iron-deficient patients with left ventricular ejection fraction <50%, stabilised after an episode of acute HF, using data from the AFFIRM-AHF trial from Italian, UK, US and Swiss payer perspectives. METHODS AND RESULTS A lifetime Markov model was built to characterise outcomes in patients according to the AFFIRM-AHF trial. Health states were defined using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Subsequent HHF were incorporated using a negative binomial regression model with cardiovascular and all-cause mortality incorporated via parametric survival analysis. Direct healthcare costs (2020 GBP/USD/EUR/CHF) and utility values were sourced from published literature and AFFIRM-AHF. Modelled outcomes indicated that treatment with FCM was dominant (cost saving with additional health gains) in the UK, USA and Switzerland, and highly cost-effective in Italy [incremental cost-effectiveness ratio (ICER) EUR 1269 per quality-adjusted life-year (QALY)]. Results were driven by reduced costs for HHF events combined with QALY gains of 0.43-0.44, attributable to increased time in higher KCCQ states (representing better functional outcomes). Sensitivity and subgroup analyses demonstrated data robustness, with the ICER remaining dominant or highly cost-effective under a wide range of scenarios, including increasing treatment costs and various patient subgroups, despite a moderate increase in costs for de novo HF and smaller QALY gains for ischaemic aetiology. CONCLUSION Ferric carboxymaltose is estimated to be a highly cost-effective treatment across countries (Italy, UK, USA and Switzerland) representing different healthcare systems.
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The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study
Jankowska EA, Kirwan BA, Kosiborod M, Butler J, Anker SD, McDonagh T, Dorobantu M, Drozdz J, Filippatos G, Keren A, et al
European heart journal. 2021
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Abstract
AIMS: Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population. METHODS AND RESULTS The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5-5.3, P = 0.018) for OSS and 2.8 (0.3-5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3-5.6, P = 0.028) for OSS and 2.9 (0.2-5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM. CONCLUSION In iron-deficient patients with HF and left ventricular ejection fraction ≤50% who had stabilized after an episode of acute HF, treatment with IV FCM, compared with placebo, results in clinically meaningful beneficial effects on HRQoL as early as 4 weeks after treatment initiation, lasting up to Week 24.
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Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial
Ponikowski P, Kirwan BA, Anker SD, McDonagh T, Dorobantu M, Drozdz J, Fabien V, Filippatos G, Göhring UM, Keren A, et al
Lancet (London, England). 2020
Abstract
BACKGROUND Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. METHODS AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 μg/L, or 100-299 μg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed. FINDINGS Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group. INTERPRETATION In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death. FUNDING Vifor Pharma.
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Effect of ferric carboxymaltose on calculated plasma volume status and clinical congestion: a FAIR-HF substudy
Okonko DO, Jouhra F, Abu-Own H, Filippatos G, Colet JC, Suki C, Mori C, Ponikowski P, Anker SD
ESC heart failure. 2019
Abstract
AIMS: Iron deficiency worsens symptoms, quality of life, and exercise capacity in chronic heart failure (CHF) and might do so by promoting fluid retention. We assessed whether iron repletion improved congestion in CHF and appraised the prognostic utility of calculated plasma volume status (PVS), a novel index of congestion, in the FAIR-HF data set. METHODS AND RESULTS In FAIR-HF, 459 iron deficient CHF patients were randomized to intravenous ferric carboxymaltose (FCM) or saline and assessed at 4, 12, and 24 weeks. Using weight and haematocrit, we calculated PVS in 436 patients. At baseline, PVS and weight were -5.5 +/- 7.7% and 76.9 +/- 14.3 kg, with peripheral oedema evident in 35% of subjects. Higher PVS values correlated to other congestion surrogates such as lower serum albumin. At 4 weeks, FCM was associated with greater reductions in weight (0.02) and PVS (P < 0.0001), and a trend for improved peripheral oedema at 24 weeks (0.07). Irrespective of treatment allocation, patients with a decrease in PVS from baseline to week 24 had higher increments in 6 min walking distance (61.4 m vs. 43.5 m, 0.02) and were more likely to improve their NYHA class (33.3% vs. 15.5%, 0.001). A PVS > -4% at baseline predicted worse outcomes even after adjustment for treatment assignment (hazard ratio 1.88, 95% confidence interval 1.01-3.51, 0.046). CONCLUSIONS Intravenous iron therapy with FCM is associated with early reductions in PVS and weight, implying that decongestion might be one mechanism via which iron repletion aids CHF patients. Calculated PVS is of prognostic utility in this cohort.
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Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis
Anker SD, Kirwan BA, van Veldhuisen DJ, Filippatos G, Comin-Colet J, Ruschitzka F, Luscher TF, Arutyunov GP, Motro M, Mori C, et al
European Journal of Heart Failure. 2017;20((1):):125-133
Abstract
AIMS: Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF) and has been suggested to be associated with poor prognosis. Recently completed double-blind randomised controlled trials (RCTs) studying HF patients with ID have shown improvements in functional capacity, symptoms and quality of life when treated with i.v. ferric carboxymaltose (FCM). This individual patient data meta-analysis investigates the effect of FCM vs. placebo on recurrent hospitalisations and mortality in HF patients with ID. METHODS AND RESULTS Individual patient data were extracted from four RCTs comparing FCM with placebo in patients with systolic HF and ID. The main outcome measures were recurrent cardiovascular (CV) hospitalisations and CV mortality. Other outcomes included cause-specific hospitalisations and death. The main analyses of recurrent events were backed up by time-to-first-event analyses. In total, 839 patients, of whom 504 were randomised to FCM, were included. Compared with those taking placebo, patients on FCM had lower rates of recurrent CV hospitalisations and CV mortality [rate ratio 0.59, 95% confidence interval (CI) 0.40-0.88; P = 0.009]. Treatment with FCM also reduced recurrent HF hospitalisations and CV mortality (rate ratio 0.53, 95% CI 0.33-0.86; P = 0.011) and recurrent CV hospitalisations and all-cause mortality (rate ratio 0.60, 95% CI 0.41-0.88; P = 0.009). Time-to-first-event analyses showed similar findings, with somewhat attenuated treatment effects. The administration of i.v. FCM was not associated with an increased risk for adverse events. CONCLUSIONS Treatment with i.v. FCM was associated with a reduction in recurrent CV hospitalisations in systolic HF patients with ID.
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Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency
van Veldhuisen DJ, Ponikowski P, van der Meer P, Metra M, Bohm M, Doletsky A, Voors AA, Macdougall IC, Anker SD, Roubert B, et al
Circulation. 2017;136((15):):1374-1383
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Abstract
Background -Iron deficiency is common in patients with heart failure (HF), and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO2], an objective measure of exercise intolerance in HF, has not been examined. Methods -We studied patients with systolic HF (left ventricular ejection fraction [LVEF] ≤45%) and mild to moderate symptoms despite optimal HF medication, Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary endpoint was the change in peak VO2 from baseline to 24 weeks. Secondary endpoints included effect hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of zero imputed for 24-week peak VO2 Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO2 data. Results -A total of 172 HF patients were studied are received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well-matched; mean age was 64 years, 75% were male, LVEF was 32%, peak VO2 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO2 had decreased in the control group (least square means -1.19+/-0.389 mL/min/kg), but was maintained on FCM (-0.16+/-0.387 mL/min/kg; p=0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO2 at 24 weeks decreased by 0.63+/-0.375 mL/min/kg in the control group, and by 0.16+/-0.373 mL/min/kg in the FCM group; p=0.23 between groups). Patients' global assessment and functional class as assessed by New York Heart Association improved on FCM vs. standard of care. Conclusions -Treatment with intravenous FCM in patients with HF and iron deficiency improve iron stores. Although a favourable effect on peak VO2 was observed on FCM, compared to standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO2 among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study. Clinical Trial Registration -URL: https://clinicaltrials.gov Unique identifier: NCT01394562.