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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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Clinical outcomes of intravenous Iron therapy in patients with heart failure and Iron deficiency: Meta-analysis and trial sequential analysis of randomized clinical trials
Bhatia, K., Sabharwal, B., Gupta, K., Lopez, P. D., Kaur, A., Bhatia, H. K., Gandhi, K. D., Niroula, S., Correa, A., Birati, E. Y., et al
Journal of cardiology. 2023
Abstract
BACKGROUND Iron deficiency in patients with heart failure (HF) is underdiagnosed and undertreated. The role of intravenous (IV) iron is well-established to improve quality of life measures. Emerging evidence also supports its role in preventing cardiovascular events in patients with HF. METHODOLOGY We conducted a literature search of multiple electronic databases. Randomized controlled trials that compared IV iron to usual care among patients with HF and reported cardiovascular (CV) outcomes were included. Primary outcome was the composite of first heart failure hospitalization (HFH) or CV death. Secondary outcomes included HFH (first or recurrent), CV death, all-cause mortality, hospitalization for any cause, gastrointestinal (GI) side effects, or any infection. We performed trial sequential and cumulative meta-analyses to evaluate the effect of IV iron on the primary endpoint, and on HFH. RESULTS Nine trials enrolling 3337 patients were included. Adding IV iron to usual care significantly reduced the risk of first HFH or CV death [risk ratio (RR) 0.84; 95 % confidence interval (CI) 0.75-0.93; I(2) = 0 %; number needed to treat (NNT) 18], which was primarily driven by a reduction in the risk of HFH of 25 %. IV iron also reduced the risk of the composite of hospitalization for any cause or death (RR 0.92; 95 % CI 0.85-0.99; I(2) = 0 %; NNT 19). There was no significant difference in the risk of CV death, all-cause mortality, adverse GI events, or any infection among patients receiving IV iron compared to usual care. The observed benefits of IV iron were directionally consistent across trials and crossed both the statistical and trial sequential boundaries of benefit. CONCLUSION In patients with HF and iron deficiency, the addition of IV iron to usual care reduces the risk of HFH without affecting the risk of CV or all-cause mortality.
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3.
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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Full text
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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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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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Full text
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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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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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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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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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Effects of Intravenous Iron Replacement Therapy on Cardiovascular Outcomes in Patients with Heart Failure: A Systematic Review and Meta-Analysis
Reinhold, J., Burra, V., Corballis, N., Tsampasian, V., Matthews, G., Papadopoulou, C., Vassiliou, V. S.
Journal of Cardiovascular Development and Disease. 2023;10(3)
Abstract
(1) Background: Iron deficiency (ID) is an important adverse prognostic marker in patients with heart failure (HF); however, it is unclear whether intravenous iron replacement reduces cardiovascular mortality in this patient group. Here, we estimate the effect of intravenous iron replacement therapy on hard clinical outcomes following the publication of IRONMAN, the largest trial in this field. (2) Methods: In this systematic review and meta-analysis, prospectively registered with PROSPERO and reported according to PRISMA guidelines, we searched PubMed and Embase for randomized controlled trials investigating intravenous iron replacement in patients with HF and co-existing ID. The primary outcome was cardiovascular mortality and secondary outcomes were all-cause mortality, hospitalizations for HF and a combination of the primary outcome and hospitalizations for HF. (3) Results: A total of 1671 items were identified and after removal of duplicates we screened titles and abstracts of 1202 records. Some 31 studies were identified for full-text review and 12 studies were included in the final review. The odds ratio (OR) for cardiovascular death using a random effects model was 0.85 (95% CI 0.69 to 1.04) and for all-cause mortality it was 0.83 (95% CI 0.59 to 1.15). There was a significant reduction in hospitalizations for HF (OR 0.49, 95% CI 0.35 to 0.69) and the combination of hospitalizations for HF and cardiovascular death (OR 0.65, 95% CI 0.5 to 0.85). (4) Conclusions: This review supports the use of IV iron replacement reducing hospitalization rates for HF, however more research is required to determine the effect on cardiovascular mortality and to identify the patient population most likely to benefit.
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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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10.
Comparison of revascularization and conservative treatment for hemorrhagic moyamoya disease in East Asian Countries: a single-center case series and a systematic review with meta-analysis
Zhang, X. H., He, J. H., Zhang, X. S., Zhang, J., Wang, C. J., Dong, Y. P., Tao, W.
Frontiers in neurology. 2023;14:1169440
Abstract
OBJECTIVE The optimal treatment approach for hemorrhagic moyamoya disease (HMMD) remains a topic of debate, particularly regarding the comparative efficacy of revascularization versus conservative treatment. Our study, which included a single-center case series and a systematic review with meta-analysis, aimed to determine whether surgical revascularization is associated with a significant reduction in postoperative rebleeding, ischemic events, and mortality compared to conservative treatment among East Asian HMMD patients. METHODS We conducted a systematic literature review by searching PubMed, Google Scholar, Wanfang Med Online (WMO), and the China National Knowledge Infrastructure (CNKI). The outcomes of surgical revascularization and conservative treatment, including rebleeding, ischemic events and mortality, were compared. The authors' institutional series of 24 patients were also included and reviewed in the analysis. RESULTS A total of 19 East Asian studies involving 1,571 patients as well as our institution's retrospective study of 24 patients were included in the study. In the adult patients-only studies, those who underwent revascularization had significantly lower rates of rebleeding, ischemic events, and mortality compared to those who received conservative treatment (13.1% (46/352) vs. 32.4% (82/253), P < 0.00001; 4.0% (5/124) vs. 14.9% (18/121), P = 0.007; and 3.3% (5/153) vs. 12.6% (12/95), P = 0.01, respectively). In the adult/pediatric patients' studies, similar statistical results of rebleeding, ischemic events, and mortality have been obtained (70/588 (11.9%) vs. 103/402 (25.6%), P = 0.003 or <0.0001 in a random or fixed-effects model, respectively; 14/296 (4.7%) vs. 26/183 (14.2%), P = 0.001; and 4.6% (15/328) vs. 18.7% (23/123), P = 0.0001, respectively). CONCLUSION The current single-center case series and systematic review with meta-analysis of studies demonstrated that surgical revascularization, including direct, indirect, and a combination of both, significantly reduces rebleeding, ischemic events, and mortality in HMMD patients in the East Asia region. More well-designed studies are warranted to further confirm these findings.
