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Meta-Analysis and Metaregression of the Treatment Effect of Intravenous Iron in Iron-Deficient Heart Failure
Martens, P., Augusto, S. N., Jr., Mullens, W., Tang, W. H. W.
JACC. Heart failure. 2023
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Editor's Choice
Abstract
BACKGROUND Guidelines recommend that intravenous iron should be considered to improve symptoms of heart failure (HF) and reduce the risk for HF admissions in patients after acute HF. OBJECTIVES This study sought to analyze the effect of intravenous iron on cardiovascular (CV) death and HF admissions in a broad population of HF patients with iron deficiency and the relation with baseline transferrin saturation (TSAT). METHODS A systematic review of all published randomized controlled trials assessing the effect of intravenous iron in patients with iron deficiency and HF between January 1, 2000, and August 26, 2023, was performed. The overall treatment effect was estimated using a fixed effect model for: 1) CV death; 2) CV death and HF admission; 3) first HF admission; and 4) total HF admissions. Metaregression through a mixed effect model was used to explore the impact of baseline TSAT in case of heterogeneity among trial results. RESULTS A total of 14 randomized controlled trials were identified in the systematic review and retained in the meta-analysis. Aggregate-level data were included on 6,624 HF patients, 3,407 of whom were randomized to intravenous iron and 3,217 to placebo. Treatment with intravenous iron resulted in a lower risk for CV death (OR: 0.867 [95% CI: 0.755-0.955]; P = 0.0427), combined CV death and HF admission (OR: 0.838 [95% CI: 0.751-0.936]; P = 0.0015), first HF admission (OR: 0.855 [95% CI: 0.744-0.983]; P = 0.0281), and total HF admissions (rate ratio: 0.739 [95% CI: 0.661-0.827]; P < 0.0001). Significant heterogeneity among trial results was observed for first and total HF admissions. Metaregression suggested that some of the heterogeneity was related to the baseline TSAT of the enrolled population, with trials enrolling patients with lower TSAT exhibiting a large effect size on HF-related events. CONCLUSIONS The totality of data suggests that treatment with intravenous iron reduces both CV death and HF-related events in a broad population with HF. A lower baseline TSAT might be important for the effect on HF-related events.
PICO Summary
Population
Patients with iron deficiency and heart failure (HF), (14 randomised controlled trials, n= 6,624).
Intervention
Intravenous iron (n= 3,407).
Comparison
Placebo (n= 3,217).
Outcome
Treatment with intravenous iron resulted in a lower risk for cardiovascular (CV) death (OR: 0.867; 95% CI [0.755, 0.955]), combined CV death and HF admission (OR: 0.838; 95% CI [0.751, 0.936]), first HF admission (OR: 0.855; 95% CI [0.744, 0.983]), and total HF admissions (rate ratio: 0.739; 95% CI [0.661, 0.827]). Significant heterogeneity among trial results was observed for first and total HF admissions. Meta-regression suggested that some of the heterogeneity was related to the baseline transferrin saturation (TSAT) of the enrolled population, with trials enrolling patients with lower TSAT exhibiting a large effect size on HF-related events.
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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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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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Impact of restrictive red blood cell transfusion strategy on thrombosis-related events: A meta-analysis and systematic review
Maimaitiming M, Zhang C, Xie J, Zheng Z, Luo H, Ooi OC
Vox sanguinis. 2022
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Editor's Choice
Abstract
BACKGROUND AND OBJECTIVES There is an ongoing controversy regarding the risks of restrictive and liberal red blood cell (RBC) transfusion strategies. This meta-analysis assessed whether transfusion at a lower threshold was superior to transfusion at a higher threshold, with regard to thrombosis-related events, that is, whether these outcomes can benefit from a restrictive transfusion strategy is debated. MATERIALS AND METHODS We searched PubMed, Cochrane Central Register of Controlled Trials and Scopus from inception up to 31 July 2021. We included randomized controlled trials (RCTs) in any clinical setting that evaluated the effects of restrictive versus liberal RBC transfusion in adults. We used random-effects models to calculate the risk ratios (RRs) and 95% confidence intervals (CIs) based on pooled data. RESULTS Thirty RCTs involving 17,334 participants were included. The pooled RR for thromboembolic events was 0.65 (95% CI 0.44-0.94; p = 0.020; I(2) = 0.0%, very low-quality evidence), favouring the restrictive strategy. There were no significant differences in cerebrovascular accidents (RR = 0.83; 95% CI 0.64-1.09; p = 0.180; I(2) = 0.0%, very low-quality evidence) or myocardial infarction (RR = 1.05; 95% CI 0.87-1.26; p = 0.620; I(2) = 0.0%, low-quality evidence). Subgroup analyses showed that a restrictive (relative to liberal) strategy reduced (1) thromboembolic events in RCTs conducted in North America and (2) myocardial infarctions in the subgroup of RCTs where the restrictive transfusion threshold was 7 g/dl but not in the 8 g/dl subgroup (with a liberal transfusion threshold of 10 g/dl in both subgroups). CONCLUSIONS A restrictive (relative to liberal) transfusion strategy may be effective in reducing venous thrombosis but not arterial thrombosis.
PICO Summary
Population
Adult patients in any clinical setting (30 studies, n= 17,334).
Intervention
Restrictive red blood cell transfusion.
Comparison
Liberal red blood cell transfusion.
Outcome
The pooled risk ratio (RR) for thromboembolic events was 0.65 (very low-quality evidence), favouring the restrictive strategy. There were no significant differences in cerebrovascular accidents (RR= 0.83, very low-quality evidence) or myocardial infarction (RR= 1.05, low-quality evidence). Subgroup analyses showed that a restrictive (relative to liberal) strategy reduced thromboembolic events in trials conducted in North America, and myocardial infarctions in the subgroup of trials where the restrictive transfusion threshold was 7 g/dl but not in the 8 g/dl subgroup (with a liberal transfusion threshold of 10 g/dl in both subgroups).
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Restrictive vs. Liberal Red Blood Cell Transfusion Strategy in Patients With Acute Myocardial Infarction and Anemia: A Systematic Review and Meta-Analysis
Zhang Y, Xu Z, Huang Y, Ye Q, Xie N, Zeng L, Lian X, Dai Y, Chen J, He P, et al
Frontiers in cardiovascular medicine. 2021;8:736163
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Editor's Choice
Abstract
Objective: Anemia is frequent in patients with acute myocardial infarction (AMI), and the optimal red blood cell transfusion strategy for AMI patients with anemia is still controversial. We aimed to compare the efficacy of restrictive and liberal red cell transfusion strategies in AMI patients with anemia. Methods: We systematically searched PubMed, EMBASE, Web of Science, Cochrane Library, and Clinicaltrials.gov, from their inception until March 2021. Studies designed to compare the efficacy between restrictive and liberal red blood cell transfusion strategies in patients with AMI were included. The primary outcome was all-cause mortality, including overall mortality, in-hospital or follow-up mortality. Risk ratios (RR) with 95% confidence intervals (CI) were presented and pooled by random-effects models. Results: The search yielded a total of 6,630 participants in six studies. A total of 2,008 patients received restrictive red blood cell transfusion while 4,622 patients were given liberal red blood cell transfusion. No difference was found in overall mortality and follow-up mortality between restrictive and liberal transfusion groups (RR = 1.07, 95% CI = 0.82-1.40, P = 0.62; RR = 0.89, 95% CI = 0.56-1.42, P = 0.62). However, restrictive transfusion tended to have a higher risk of in-hospital mortality compared with liberal transfusion (RR = 1.22, 95% CI = 1.00-1.50, P = 0.05). No secondary outcomes, including follow-up reinfarction, stroke, and acute heart failure, differed significantly between the two groups. In addition, subgroup analysis showed no differences in overall mortality between the two groups based on sample size and design. Conclusion: Restrictive and liberal red blood cell transfusion have a similar effect on overall mortality and follow-up mortality in AMI patients with anemia. However, restrictive transfusion tended to have a higher risk of in-hospital mortality compared with liberal transfusion. The findings suggest that transfusion strategy should be further evaluated in future studies.
PICO Summary
Population
Patients with acute myocardial infarction and anaemia (6 studies, n= 6,630).
Intervention
Restrictive red blood cell transfusion strategy (n= 2,008).
Comparison
Liberal red blood cell transfusion strategy (n= 4,622).
Outcome
No difference was found in overall mortality and follow-up mortality between restrictive and liberal transfusion groups (RR= 1.07; 95% CI [0.82, 1.40]; RR= 0.89; 95% CI [0.56, 1.42]). However, restrictive transfusion tended to have a higher risk of in-hospital mortality compared with liberal transfusion (RR= 1.22; 95% CI [1.00, 1.50]). No secondary outcomes, including follow-up reinfarction, stroke, and acute heart failure, differed significantly between the two groups. In addition, subgroup analysis showed no differences in overall mortality between the two groups based on sample size and design.
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Risk-assessment models for VTE and bleeding in hospitalized medical patients: an overview of systematic reviews
Darzi AJ, Repp AB, Spencer FA, Morsi RZ, Charide R, Etxeandia-Ikobaltzeta I, Bauer KA, Burnett AE, Cushman M, Dentali F, et al
Blood advances. 2020;4(19):4929-4944
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Editor's Choice
Abstract
Multiple risk-assessment models (RAMs) for venous thromboembolism (VTE) in hospitalized medical patients have been developed. To inform the 2018 American Society of Hematology (ASH) guidelines on VTE, we conducted an overview of systematic reviews to identify and summarize evidence related to RAMs for VTE and bleeding in medical inpatients. We searched Epistemonikos, the Cochrane Database, Medline, and Embase from 2005 through June 2017 and then updated the search in January 2020 to identify systematic reviews that included RAMs for VTE and bleeding in medical inpatients. We conducted study selection, data abstraction and quality assessment (using the Risk of Bias in Systematic Reviews [ROBIS] tool) independently and in duplicate. We described the characteristics of the reviews and their included studies, and compared the identified RAMs using narrative synthesis. Of 15 348 citations, we included 2 systematic reviews, of which 1 had low risk of bias. The reviews included 19 unique studies reporting on 15 RAMs. Seven of the RAMs were derived using individual patient data in which risk factors were included based on their predictive ability in a regression analysis. The other 8 RAMs were empirically developed using consensus approaches, risk factors identified from a literature review, and clinical expertise. The RAMs that have been externally validated include the Caprini, Geneva, IMPROVE, Kucher, and Padua RAMs. The Padua, Geneva, and Kucher RAMs have been evaluated in impact studies that reported an increase in appropriate VTE prophylaxis rates. Our findings informed the ASH guidelines. They also aim to guide health care practitioners in their decision-making processes regarding appropriate individual prophylactic management.
PICO Summary
Population
Adult patients hospitalized for an acute, critical, or chronic medical illness. (2 systematic reviews).
Intervention
Overview of systematic reviews to identify and describe multiple risk-assessment models (RAMs) and their clinical utility for venous thromboembolism (VTE) and bleeding.
Comparison
Standard care without the use of RAMs or a different RAM from the one used in the intervention.
Outcome
Fifteen unique RAMs for VTE were identified, seven were derived from individual participant data and eight were developed empirically using consensus approaches, risk factors identified from a literature review, and clinical expertise. Five systematic reviews described RAMs that have been externally validated and three systematic reviews described RAMs evaluated in terms of thromboprophylaxis rates or clinical outcomes.
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Efficacy and safety of iron therapy in patients with chronic heart failure and iron deficiency: a systematic review and meta-analysis based on 15 randomised controlled trials
Zhang J, Hu S, Jiang Y, Zhou Y
Postgraduate medical journal. 2020
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Editor's Choice
Abstract
Trials studying iron administration in patients with chronic heart failure (CHF) and iron deficiency (ID) have sprung up these years but the results remain inconsistent. The aim of this meta-analysis was to comprehensively evaluate the efficacy and safety of iron therapy in patients with CHF and ID. A literature search was conducted across PubMed, Embase, Cochrane Library, OVID and Web of Science up to 31 July 2019 to search for randomised controlled trials (RCT) comparing iron therapy with placebo in CHF with ID, regardless of presence of anaemia. Published studies reporting data of any of the following outcomes were included: all-cause death, cardiovascular hospitalisation, adverse events, New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF), N-terminal pro b-type natriuretic peptide, peak oxygen consumption, 6 min walking test (6MWT) distance and quality of life (QoL) parameters. 15 RCTs with a total of 1627 patients (911 in iron therapy and 716 in control) were included. Iron therapy was demonstrated to reduce the risk of cardiovascular hospitalisation (OR 0.35, 95% CI 0.12 to 0.99, p=0.049), but was ineffective in reducing all-cause death (OR 0.59, 95% CI 0.33 to 1.06, p=0.078) or cardiovascular death (OR 0.80, 95% CI 0.39 to 1.63, p=0.540). Iron therapy resulted in a reduction in NYHA class (mean difference (MD) -0.73, 95% CI -0.99 to -0.47, p<0.001), an increase in LVEF (MD +4.35, 95% CI 0.69 to 8.00, p=0.020), 6MWT distance (MD +35.44, 95% CI 11.55 to 59.33, p=0.004) and an improvement in QoL: EQ-5D score (MD +4.07, 95% CI 0.84 to 7.31, p=0.014); Minnesota Living With Heart Failure Questionnaire score (MD -19.47, 95% CI -23.36 to -15.59, p<0.001) and Patients Global Assessment (PGA) scale (MD 0.71, 95% CI 0.32 to 1.10, p<0.001). There was no significant difference in adverse events or serious adverse events between iron treatment group and control group. Iron therapy reduces cardiovascular hospitalisation in patients with CHF with ID, and additionally improves cardiac function, exercise capacity and QoL in patients with CHF with ID and anaemia, without an increase of adverse events.
PICO Summary
Population
Patients with chronic heart failure (CHF) and iron deficiency (ID), (15 studies, n= 1627).
Intervention
Iron therapy (n= 911).
Comparison
Placebo (n= 716).
Outcome
Iron therapy reduced the risk of cardiovascular hospitalisation, but was ineffective in reducing all-cause death or cardiovascular death. There was no significant difference in adverse events or serious adverse events between iron treatment group and control group.
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Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a non-cardiac surgery setting: systematic review and meta-analysis
Docherty AB, O'Donnell R, Brunskill S, Trivella M, Doree C, Holst L, Parker M, Gregersen M, Pinheiro de Almeida J, Walsh TS, et al
Bmj.. 2016;352:i1351.
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Editor's Choice
Abstract
OBJECTIVE To compare patient outcomes of restrictive versus liberal blood transfusion strategies in patients with cardiovascular disease not undergoing cardiac surgery. DESIGN Systematic review and meta-analysis. DATA SOURCES Randomised controlled trials involving a threshold for red blood cell transfusion in hospital. We searched (to 2 November 2015) CENTRAL, Medline, Embase, CINAHL, PubMed, LILACS, NHSBT Transfusion Evidence Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ISRCTN Register, and EU Clinical Trials Register. Authors were contacted for data whenever possible. TRIAL SELECTION Published and unpublished randomised controlled trials comparing a restrictive with liberal transfusion threshold and that included patients with cardiovascular disease. DATA EXTRACTION AND SYNTHESIS Data extraction was completed in duplicate. Risk of bias was assessed using Cochrane methods. Relative risk ratios with 95% confidence intervals were presented in all meta-analyses. Mantel-Haenszel random effects models were used to pool risk ratios. MAIN OUTCOME MEASURES 30 day mortality, and cardiovascular events. RESULTS 41 trials were identified; of these, seven included data on patients with cardiovascular disease. Data from a further four trials enrolling patients with cardiovascular disease were obtained from the authors. In total, 11 trials enrolling patients with cardiovascular disease (n=3033) were included for meta-analysis (restrictive transfusion, n=1514 patients; liberal transfusion, n=1519). The pooled risk ratio for the association between transfusion thresholds and 30 day mortality was 1.15 (95% confidence interval 0.88 to 1.50, P=0.50), with little heterogeneity (I(2)=14%). The risk of acute coronary syndrome in patients managed with restrictive compared with liberal transfusion was increased (nine trials; risk ratio 1.78, 95% confidence interval 1.18 to 2.70, P=0.01, I(2)=0%). CONCLUSIONS The results show that it may not be safe to use a restrictive transfusion threshold of less than 80 g/L in patients with ongoing acute coronary syndrome or chronic cardiovascular disease. Effects on mortality and other outcomes are uncertain. These data support the use of a more liberal transfusion threshold (>80 g/L) for patients with both acute and chronic cardiovascular disease until adequately powered high quality randomised trials have been undertaken in patients with cardiovascular disease. REGISTRATION PROSPERO CRD42014014251.Copyright Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
PICO Summary
Population
Patients with cardiovascular disease not undergoing cardiac surgery (11 randomised controlled trials, n= 3,033).
Intervention
Restrictive transfusion strategy (n= 1,514).
Comparison
Liberal transfusion strategy (n= 1,519).
Outcome
The pooled risk ratio for the association between transfusion thresholds and 30-day mortality was 1.15 (95% confidence interval (CI): 0.88 to 1.50), with little heterogeneity (I2= 14%). The risk of acute coronary syndrome in patients managed with restrictive compared with liberal transfusion was increased (nine trials; risk ratio: 1.78, 95% CI: 1.18 to 2.70, I2= 0%).