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1.
Effect of Intravenous Iron-Carbohydrate Complexes in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: A Meta-analysis of Randomized Controlled Trials
Mototani R, Watanabe A, Kuno T, Briasoulis A
Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese. 2023
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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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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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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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Meta-Analysis of Efficacy and Safety of Intravenous Iron in Patients With Iron Deficiency and Heart Failure With Reduced Ejection Fraction
Hamza, M., Sattar, Y., Manasrah, N., Patel, N. N., Rashdi, A., Khanal, R., Naveed, H., Zafar, M., Khan, A. M., Alharbi, A., et al
The American journal of cardiology. 2023;202:119-130
Abstract
Iron deficiency is an independent risk factor for heart failure (HF) exacerbation. We aim to study the safety and efficacy of intravenous (IV) iron therapy in patients with HF with reduced ejection fraction (HFrEF). A literature search was conducted on MEDLINE (Embase and PubMed) using a systematic search strategy by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) until October 2022. CRAN-R software (The R Foundation for Statistical Computing, Vienna, Austria) was used for statistical analysis. The quality assessment was performed using the Cochrane Risk of Bias and Newcastle-Ottawa Scale. We included 12 studies with a total of 4,376 patients (IV iron n = 1,985 [45.3%]; standard of care [SOC] n = 2,391 [54.6%]). The mean age was 70.37 ± 8.14 years and 71.75 ± 7.01 years in the IV iron and SOC groups, respectively. There was no significant difference in all-cause mortality and cardiovascular mortality (risk ratio [RR] 0.88, 95% confidence interval [CI] 0.74 to 1.04, p <0.15). However, HF readmissions were significantly lower in the IV iron group (RR 0.73, 95% CI 0.56 to 0.96, p = 0.026). Non-HF cardiac readmissions were not significantly different between the IV iron and SOC groups (RR 0.92, 95% CI 0.82 to 1.02, p = 0.12). In terms of safety, there was a similar rate of infection-related adverse events in both arms (RR 0.86, 95% CI 0.74 to 1, p = 0.05). IV iron therapy in patients with HFrEF is safe and shows a significant reduction in HF hospitalizations compared with SOC. There was no difference in the rate of infection-related adverse events. The changing landscape of HFrEF pharmacotherapy in the last decade may warrant a re-demonstration of the benefit of IV iron with current SOC. The cost-effectiveness of IV iron use also needs further study.
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6.
Intravenous iron therapy among patients with heart failure and iron deficiency: An updated meta-analysis of randomized controlled trials
Hamed, M., Elseidy, S. A., Ahmed, A., Thakker, R., Mansoor, H., Khalili, H., Mohsen, A., Mamas, M. A., Banerjee, S., Kumbhani, D. J., et al
Heliyon. 2023;9(6):e17245
Abstract
BACKGROUND Randomized 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. METHODS Electronic 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. RESULTS The 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. CONCLUSION Among 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.
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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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Systematic review and meta-analysis of intravenous iron-carbohydrate complexes in HFrEF patients with iron deficiency
Sindone A, Doehner W, Comin-Colet J
ESC heart failure. 2022
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Editor's Choice
Abstract
Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF). The present meta-analysis evaluates the effect of intravenous (IV) iron-carbohydrate complex supplementation in patients with HF with reduced ejection fraction (HFrEF) and ID/iron deficiency anaemia (IDA). Randomized controlled trials (RCTs) comparing IV iron-carbohydrate complexes with placebo/standard of care in patients with HFrEF with ID/IDA were identified using Embase (from 1957) and PubMed (from 1989) databases through 25 May 2021. Twelve RCTs including 2381 patients were included in this analysis. The majority (90.8%) of patients receiving IV iron-carbohydrate therapy were administered ferric carboxymaltose (FCM); 7.5% received iron sucrose and 1.6% received iron isomaltoside. IV iron-carbohydrate therapy significantly reduced hospitalization for worsening HF [0.53 (0.42-0.65); P < 0.0001] and first hospitalization for worsening HF or death [0.75 (0.59-0.95); P = 0.016], but did not significantly impact all-cause mortality, compared with control. IV iron-carbohydrate therapy significantly improved functional and exercise capacity compared with the control. There was no significant difference in outcome between IV iron-carbohydrate formulations when similar endpoints were measured. No significant difference in adverse events (AE) was observed between the treatment groups. IV iron-carbohydrate therapy resulted in improvements in a range of clinical outcomes and increased functional and exercise capacity, whereas AEs were not significantly different between IV iron-carbohydrate and placebo/standard of care arms. These findings align with the European Society of Cardiology's 2021 HF guidelines, which recommend the consideration of FCM in symptomatic patients with a left ventricular ejection fraction < 45% and ID.
PICO Summary
Population
Patients with heart failure (HF) with reduced ejection fraction (HFrEF) and iron deficiency, (12 randomised controlled trials, n= 2,381).
Intervention
Intravenous (IV) iron-carbohydrate complex supplementation.
Comparison
Placebo or standard of care.
Outcome
The majority (90.8%) of patients receiving IV iron-carbohydrate therapy were administered ferric carboxymaltose; 7.5% received iron sucrose and 1.6% received iron isomaltoside. IV iron-carbohydrate therapy significantly reduced hospitalization for worsening HF [0.53 (0.42-0.65)] and first hospitalization for worsening HF or death [0.75 (0.59-0.95)], but did not significantly impact all-cause mortality, compared with control. IV iron-carbohydrate therapy significantly improved functional and exercise capacity compared with the control. There was no significant difference in outcome between IV iron-carbohydrate formulations when similar endpoints were measured. No significant difference in adverse events (AE) was observed between the treatment groups. IV iron-carbohydrate therapy resulted in improvements in a range of clinical outcomes and increased functional and exercise capacity, whereas AEs were not significantly different between IV iron-carbohydrate and placebo/standard of care arms.
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A Systematic Review, Meta-Analysis, and Indirect Comparison of Blindly Adjudicated Cardiovascular Event Incidence with Ferric Derisomaltose, Ferric Carboxymaltose, and Iron Sucrose
Pollock RF, Kalra PA, Kalra PR, Ahmed FZ
Advances in therapy. 2022
Abstract
INTRODUCTION Intravenous (IV) iron is the preferred treatment for patients with iron deficiency anemia (IDA) who require rapid replenishment of iron stores or in whom oral iron is not tolerated or effective. Data from two large-scale randomized controlled trials (RCTs) have recently been published reporting the incidence of adjudicated cardiovascular events after ferric derisomaltose (FDI) and iron sucrose (IS). The objective was to calculate the relative incidence of cardiovascular events with FDI and IS, and to conduct an indirect comparison with ferric carboxymaltose (FCM) based on previously published studies of cardiovascular risk. METHODS RCTs reporting the incidence of blindly adjudicated cardiovascular events in IDA patients treated with IV iron were identified by systematic literature review (SLR). Pairwise random effects meta-analyses of FDI versus IS, and FCM versus IS were conducted for the pre-specified adjudicated composite cardiovascular endpoint of: death due to any cause, nonfatal myocardial infarction, nonfatal stroke, unstable angina requiring hospitalization, congestive heart failure, arrhythmia, and protocol-defined hypertensive and hypotensive events. Analyses were also conducted for the composite endpoint excluding blood pressure events. Meta-analysis results were combined in an adjusted indirect comparison to provide an indirect estimate of cardiovascular risk with FDI versus FCM. RESULTS The SLR retrieved 694 unique articles, of which four were RCTs reporting the incidence of the composite cardiovascular endpoint; two studies comparing FCM (N = 1529) with IS (N = 1505), and two studies comparing FDI (N = 2008) with IS (N = 1000). The odds ratios of the composite CV endpoint were 0.59 (95% confidence interval: 0.39-0.90) for FDI versus IS, 1.12 (95% CI 0.90-1.40) for FCM versus IS, and the indirect OR for FDI versus FCM was 0.53 (95% CI 0.33-0.85). CONCLUSIONS Pooling data from four large-scale RCTs suggested that FDI was associated with significantly lower incidence of cardiovascular adverse events compared to both FCM and IS.
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Comparative efficacy of intravenous and oral iron supplements for the treatment of iron deficiency in patients with heart failure: A network meta-analysis of randomized controlled trials
Mei Z, Chen J, Luo S, Jin L, Liu Q, Chen Y
Pharmacological research. 2022;182:106345
Abstract
OBJECTIVE We aimed at comparing the efficacy of intravenous and oral iron supplementations for the treatment of iron deficiency (ID) in patients with heart failure (HF). METHODS We searched the PubMed, Cochrane, and Embase databases from inception to January 15, 2022. We included randomized controlled trials enrolling patients with HF who were treated for ID with intravenous iron supplements, oral iron supplements, or placebo. The primary outcomes were all-cause death, cardiovascular mortality, and hospitalization for heart failure. The secondary outcomes were evaluated through the six-minute walking test (6MWT) and the Kansas City Cardiomyopathy Questionnaire (KCCQ). RESULTS The network meta-analysis included sixteen studies. Compared to placebo/control groups, intravenous iron supplements did not decrease all-cause death (0.69, 0.39-1.23) or cardiovascular mortality (0.89, 0.66-1.20). After 12 weeks, a reduced hospitalization for heart failure was associated with the administration of intravenous iron supplementations (0.58, 0.34-0.97). The most significant improvements regarding 6MWT (44.44, 6.10-82.79) and KCCQ (5.96, 3.19-8.73) were observed with intravenous iron supplements. Oral iron supplements reduced hospitalization for heart failure (0.36, 0.14-0.96) and all-cause death (0.34, 0.12-0.95), but did not influence the 6MWT (29.74, -47.36 to 106.83) and KCCQ (0.10, -10.95 to 11.15). CONCLUSIONS Administering intravenous iron supplements for ID in patients with HF improves their exercise capacity and quality of life. In order to reduce hospitalizations for heart failure, the supplementation should be administered for more than 12 weeks. Although oral iron supplements did not improve exercise capacity and quality of life, they could reduce all-cause death and hospitalizations for heart failure.
