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Iron Supplementation Improves Cardiovascular Outcomes in Patients with Heart Failure
Accepted Manuscript Iron supplementation improves cardiovascular outcomes in patients with heart failure
Xiang Zhou, Weiting Xu, Youjia Xu, Zhiyuan Qian PII: DOI: Reference:
S0002-9343(19)30213-X https://doi.org/10.1016/j.amjmed.2019.02.018 AJM 15042
To appear in:
The American Journal of Medicine
Please cite this article as: X. Zhou, W. Xu, Y. Xu, et al., Iron supplementation improves cardiovascular outcomes in patients with heart failure, The American Journal of Medicine, https://doi.org/10.1016/j.amjmed.2019.02.018
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ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Iron supplementation improves cardiovascular outcomes in patients with heart failure
Running title: Iron supplementation in heart failure
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Xiang Zhou, MD, PhDa; Weiting Xu, MDa; Youjia Xu, MDb; Zhiyuan Qian, MDc
Department of Cardiology, The Second Affiliated Hospital of Soochow
b
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University, Suzhou, China
Department of Orthopedics, The Second Affiliated Hospital of Soochow
Department of Neurosurgery, The Second Affiliated Hospital of Soochow
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c
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University, Suzhou, China
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Corresponding author
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University, Suzhou, China
Xiang Zhou
Department of Cardiology
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The Second Affiliated Hospital of Soochow University No. 1055 Sanxiang Road
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Suzhou 215004, China Tel: +86 512 67784079 Fax: +86 512 68284303 E-mail: [email protected]
Article type: Clinical Research Study All authors had access to the data and a role in writing the manuscript. The authors had no conflict of interest. 1
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Abstract Background: Iron deficiency is prevalent in patients with heart failure. This meta-analysis was performed to evaluate the therapeutic effects of iron in patients with systolic heart failure and iron deficiency. Methods: We searched PubMed, Embase, and Cochrane databases through
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March 2018 and included 10 randomised controlled trials involving 1404 heart failure patients who underwent iron or placebo treatment. Odds ratio (OR) and
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weighted mean differences (WMD) were calculated using fixed or random
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effects models.
Results: Our results showed that iron supplementation significantly reduced hospitalization for worsening heart failure (OR: 0.39, 95% CI: 0.19 to 0.80)
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and the combined endpoint of death and heart failure hospitalization (OR: 0.47, 95% CI: 0.32 to 0.69). In addition, iron treatment was found to improve
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New York Heart Association class, 6-min walk distance, left ventricular ejection fraction, and peak oxygen consumption. Iron therapy was also associated with improvements in Patient Global Assessment, Kansas City
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Cardiomyopathy Questionnaire score, European Quality of Life-5 Dimensions
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score, and Minnesota Living with Heart Failure Questionnaire score. Moreover, serum levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and Creactive protein (CRP) were markedly decreased in patients with iron repletion
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compared with placebo treatment (WMD: -332.48 pg/ml, 95% CI: -497.48 to 167.47; WMD: -4.64 mg/L, 95% CI: -6.12 to -3.17, respectively).
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Conclusions: Our meta-analysis suggests that iron therapy can reduce heart failure hospitalization, increase cardiac function, improve quality of life, and decrease serum levels of NT-proBNP and CRP in patients with heart failure.
Keywords: Heart failure; Iron therapy; Meta-analysis
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Introduction Heart failure is a complex clinical syndrome characterized by neuroendocrine system activation, cardiac pathological remodeling, and impaired myocardial contractility. In recent years, the clinical applications of beta blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, and aldosterone antagonists have
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significantly improved the cardiovascular prognosis in patients with heart failure.1 However, heart failure remains a leading cause of cardiovascular
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mortality and morbidity and it brings a heavy economic burden to society.
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Iron deficiency is a prevalent and clinically relevant comorbidity in up to 50% of patients with heart failure and is associated with the severity of the
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disease.2 Iron plays a critical role in oxygen transport, not only through hematopoiesis, but also in the metabolism of myocardial and skeletal muscles.
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Iron deficiency in heart failure patients may contribute to reduced exercise capacity, impaired quality of life, and increased cardiac mortality, irrespective of the presence of anaemia.3-5 Over the past decade, several small
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randomised controlled trials (RCTs) have been performed to evaluate the
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effects of iron therapy in patients with heart failure. These trials investigated cardiac function, exercise capacity, quality of life, heart failure hospitalization, and all-cause mortality. However, the conclusions drawn from these studies
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are not consistent. We therefore carried out a meta-analysis of RCTs to confirm whether iron supplementation is beneficial in patients with systolic
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heart failure and iron deficiency.
Methods
Search strategy and selection criteria We conducted an electronic literature search of PubMed, Embase, and Cochrane databases through March 2018, using the terms “iron deficiency”, “iron therapy”, “iron supplementation”, “iron repletion”, “ferric carboxymaltose”, “heart
failure”,
“cardiac
failure”,
“cardiac 3
dysfunction”,
and
“cardiac
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
insufficiency”. Sensitive filters identified clinical trial or RCT in the Medline and Embase databases. The search was limited to human studies in the English language. RCTs comparing iron repletion with placebo treatment in irondeficient patients with systolic heart failure and reporting at least one of the following outcomes were included in this meta-analysis. The outcomes consisted of all-cause mortality, hospitalization for worsening heart failure, New York Heart Association (NYHA) class, 6-min walk test (6MWT), left
Patient
Global
Assessment
(PGA),
Kansas
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ventricular ejection fraction (LVEF), peak oxygen consumption (pVO2), City
Cardiomyopathy
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Questionnaire (KCCQ), European Quality of Life-5 Dimensions (EQ-5D),
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Minnesota Living with Heart Failure Questionnaire (MLHFQ), N-terminal pro-
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B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP).
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Data extraction and quality assessment
Two reviewers independently evaluated all potentially eligible studies using predefined criteria and collected data from included trials. In case of
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disagreement between the two reviewers, a consensus was achieved by open
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discussion. We contacted the investigators of included studies for missing information. The extracted data include patient characteristics, inclusion criteria, dosage and methods of administration, duration of follow-up, and
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clinical outcomes including all-cause mortality, heart failure hospitalization, NYHA class, 6MWT distance, LVEF, pVO2, PGA, KCCQ score, EQ-5D score,
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MLHFQ score, and serum levels of NT-proBNP and CRP. The quality of included trials was evaluated using the Cochrane Collaboration's tool for assessing risk for bias, which consists of selection bias, performance bias, detection bias, attrition bias, and reporting bias.6
Statistical analysis Dichotomous variables were analyzed using odds ratio (OR) with 95% confidence interval (CI), while continuous data were analyzed using weighted 4
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
mean difference (WMD) and 95% CI. Statistical heterogeneity across the studies was evaluated using the Chi-square-based Q-test. A p-value < 0.10 for the Q-test indicated significant heterogeneity, and a random-effects model was used to calculate the pooled effect. Otherwise, a fixed-effects model was applied. Sensitivity analysis was performed to determine the influence of each individual study on overall estimates. Publication bias was assessed using Begg's funnel plot and Egger's test. All statistical analyses were performed
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using the STATA software 12.0 (Stata Corp., College Station, Texas, USA).
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The pooled effect was considered significant if p < 0.05.
Results
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Study characteristics
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The flow diagram of study selection process is shown in Figure 1. Among the initial 232 RCTs, 27 trials were retrieved for detailed evaluation, and 10 studies meeting the inclusion criteria were finally analyzed.7-16 A total of 1404
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patients with systolic heart failure and iron deficiency were included in this
received placebo.
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meta-analysis. Among them, 785 received iron supplementation and 619
The baseline characteristics of included studies are shown in Table 1. The
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duration of follow-up ranged from 2 to 52 weeks. Iron deficiency was defined as ferritin < 100 ng/ml or 100-300 ng/ml with transferrin saturation < 20%.
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Intravenous iron therapy (ferric carboxymaltose or iron sucrose) was used in 8 studies with the dose varying from 200 to 1000 mg weekly, while oral iron repletion (ferrous sulfate or iron polysaccharide) was applied in 3 studies with the dose varying from 300 to 600 mg daily. Among the included studies, 6 trials reported all-cause mortality,8-11,14,16 5 heart failure hospitalization,7-9,11,16 5 NYHA class,7-9,11,12 5 6MWT,7,9,11,14,15 3 LVEF,7,8,12 3 pVO2,8,14,16 3 PGA,8,9,11 4 KCCQ score,9,11,13,14 2 EQ-5D score,9,11 2 MLHFQ score,7,8 5 NT-proBNP,7,12-14,16 and 3 CRP.7,8,12
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Quality assessment The Cochrane Collaboration's tool for assessing risk of bias was used to evaluate the quality of included RCTs (Table 2). Overall, random sequence generation was observed in 7 studies,7-12,14 and 2 of them had reported allocation concealment.9,11 Eight studies were double blinded
7,9-15
and 2 trials
were open-label.8,16 Blinding of outcome assessment was performed in 7
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studies.7,9-12,14,16 Neither incomplete outcome data nor selective reporting was
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observed in any of the included studies.
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Major adverse events
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Six studies reported all-cause mortality and there was no significant heterogeneity among them. In general, 23 (3.3%) patients in the iron group (n = 695) reached the endpoint compared with 24 (4.6%) patients in the control
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group (n = 522). The pooled analysis suggested that there was no significant difference in all-cause mortality between iron group and placebo group (OR:
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0.76, 95% CI: 0.43 to 1.37) (Figure 2A). In addition, Begg's and Egger's tests
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showed no significant publication bias (p = 1.00 and p = 0.87, respectively) Five studies reported heart failure hospitalization and no significant heterogeneity was found. There were 31 (5.3%) hospitalizations for worsening
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heart failure in the iron group (n = 587) compared with 61 (14.5%) hospitalizations in the control group (n = 422). The pooled results indicated
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that iron repletion markedly reduced hospitalization for heart failure (OR: 0.39, 95% CI: 0.19 to 0.80) (Figure 2B). In addition, Begg's and Egger's tests showed no significant publication bias (p = 0.81 and p = 0.45, respectively) Four studies reported the composite endpoint of death and heart failure hospitalization. Overall, 49 (8.6%) patients in the iron group (n = 567) reached the combined endpoint compared with 78 (19.4%) patients in the control group (n = 402). The pooled analysis revealed that iron therapy was associated with a remarkable decrease in all-cause mortality and heart failure hospitalization (OR: 0.47, 95% CI: 0.32 to 0.69) (Figure 2C). Moreover, 6
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Begg's and Egger's tests showed no significant publication bias (p = 0.73 and p = 0.82, respectively)
Cardiac function and exercise capacity In this meta-analysis, NYHA class, 6MWT distance, LVEF, and pVO2 were
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used to evaluate the effects of iron supplementation on cardiac function and exercise capacity in patients with systolic heart failure and iron deficiency. As
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shown in Figure 3, iron treatment was found to improve cardiac function and increase exercise capacity in patients with heart failure. In addition, there was
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no significant publication bias in these analyses using Begg's funnel plot and
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Egger's test.
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Quality of life
In this meta-analysis, KCCQ score, PGA, EQ-5D score, and MLHFQ score
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were applied to assess the effects of iron repletion on quality of life in heart failure patients with reduced LVEF and iron deficiency. As shown in Figure 4,
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iron therapy was associated with a remarkable improvement in quality of life scores in patients with heart failure. In addition, there was no significant
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publication bias in these analyses using Begg's funnel plot and Egger's test.
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Serum markers
We also determined the effects of iron therapy on serum levels of NT-proBNP and CRP in patients with heart failure. The pooled results suggested that NTproBNP and CRP levels were markedly decreased in patients with iron repletion compared with placebo treatment (WMD: -332.48 pg/ml, 95% CI: 497.48 to -167.47; WMD: -4.64 mg/L, 95% CI: -6.12 to -3.17, respectively) (Figure 5). Moreover, no significant publication bias was found using the Begg's and Egger's tests.
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ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Sensitivity analysis Since significant heterogeneity across studies was observed regarding NYHA class, 6MWT distance, LVEF, pVO2, KCCQ score, and NT-proBNP level, we performed sensitivity analysis to determine the effect of each study on the pooled estimates under the random effects model. Our results showed that removal of any individual study could not significantly reduce the
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heterogeneity.
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Discussion
The present meta-analysis was conducted to determine whether iron therapy
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is beneficial in heart failure patients with iron deficiency. Our results revealed that iron supplementation could reduce heart failure hospitalization, increase
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cardiac function and exercise capacity, improve quality of life, and decrease serum levels of NT-proBNP and CRP. However, iron treatment was not found to significantly reduce all-cause mortality in patients with heart failure.
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Iron deficiency, which is a major risk factor for disability and mortality
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worldwide, has been identified as a common comorbidity in patients with heart failure. Current evidence indicates that the presence of chronic inflammation in heart failure is responsible for impaired iron absorption, recycling, and
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release from body stores.17 Iron deficiency in heart failure can lead to decreased oxygen delivery and aggravation of symptoms such as dyspnea
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and fatigue, and consequently impair exercise tolerance and quality of life.18 Several observational studies investigated the association between iron deficiency and clinical outcomes in patients with heart failure, and showed that iron deficiency was a strong and independent predictor of mortality.2,3,19 In recent years, a number of clinical trials have been conducted to determine the effects of iron therapy on exercise capacity, quality of life, and adverse events in heart failure patients. In the FAIR-HF study, treatment with intravenous ferric carboxymaltose (FCM) in patients with systolic heart failure could significantly improve clinical symptoms, functional capacity, and quality 8
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
of life.9 In the CONFIRM-HF study, FCM treatment over a 1-year period in symptomatic and iron-deficient heart failure patients contributed to sustained improvements in functional capacity, symptoms and quality of life.11 In the EFFECT-HF study, intravenous FCM supplementation in patients with heart failure and iron deficiency had a beneficial effect on pVO2 compared with standard treatment, irrespective of the presence of anemia. 16 In addition to intravenous iron therapy, some other studies investigated the effects of oral
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iron repletion on cardiac performance and exercise capacity in heart failure. In the IRONOUT HF study, high-dose oral iron was not found to significantly
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improve exercise capacity in heart failure patients with reduced LVEF and iron
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deficiency.14 On the contrary, another clinical trial with small sample size indicated that oral iron therapy for 12 weeks improved functional capacity in
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patients with heart failure.15
Based on the results of above studies, we performed a meta-analysis of RCTs
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to confirm whether iron treatment is beneficial in patients with heart failure. Our results suggested that iron supplementation reduced hospitalization for worsening heart failure, but could not decrease all-cause mortality, which
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might result from a relatively small number of reported all-cause deaths. In
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addition, we also evaluated the effects of iron therapy on cardiac function and exercise tolerance, and found that iron repletion was associated with improvements in NYHA class, 6MWT distance, LVEF, and pVO2 in patients
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with heart failure. Furthermore, PGA, KCCQ score, EQ-5D score, and MLHFQ score were applied to assess the effect of iron treatment on quality of life. Our
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results revealed that iron supplementation could improve quality of life and prognosis in patients with heart failure. There are three other meta-analyses that evaluate the therapeutic effects of iron in patients with heart failure.20-22 However, the number of RCTs included in each meta-analysis is no more than 5 and the total number of participants is relatively small, which may reduce the statistical power of the analysis. Moreover, some conclusions drawn from these meta-analyses are not consistent. We therefore conducted an updated meta-analysis which included
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ACCEPTED MANUSCRIPT Iron supplementation in heart failure
10 RCTs comprising a total of 1404 patients to provide more convincing evidence of iron treatment in heart failure. There are several limitations in this meta-analysis. Firstly, the methodological quality of included studies was less than optimal, so the potential risk of bias could not be excluded. Secondly, we did not consider the influences of iron dose, administration method, and cardiac function on therapeutic effects due
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to the incomplete information. Thirdly, the sample size and follow-up duration
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in these trials varied widely, which might affect the statistical power.
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Conclusions
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Our meta-analysis demonstrates that iron supplementation can reduce heart failure hospitalization, increase cardiac function and exercise capacity,
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improve quality of life and prognosis, and decrease serum levels of NT-
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proBNP and CRP in patients with heart failure.
Acknowledgements
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This study was financially supported by the National Natural Science Foundation of China (No. 81770370), Scientific Research Program for Young Talents of China National Nuclear Corporation (No. 51001), and Advantage
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Discipline Group of the Second Affiliated Hospital of Soochow University (No. XKQ2015001). .
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References 1. Raj L, Adhyaru B. An evidence-based review of recent advances in therapy for heart failure with reduced ejection fraction (HFrEF). Postgrad Med J. 2016;92:726-34. 2. Klip IT, Comin-Colet J, Voors AA, Ponikowski P, Enjuanes C, Banasiak W, Lok DJ, Rosentryt P, Torrens A, Polonski L, van Veldhuisen DJ, van der Meer
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P, Jankowska EA. Iron deficiency in chronic heart failure: an international
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pooled analysis. Am Heart J. 2013;165:575-82.e3.
3. Okonko DO, Mandal AK, Missouris CG, Poole-Wilson PA. Disordered iron
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homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. J Am Coll Cardiol. 2011;58:1241-51.
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4. Cohen-Solal A, Damy T, Terbah M, Kerebel S, Baguet JP, Hanon O, Zannad F, Laperche T, Leclercq C, Concas V, Duvillié L, Darné B, Anker S,
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Mebazaa A. High prevalence of iron deficiency in patients with acute decompensated heart failure. Eur J Heart Fail. 2014;16:984-91.
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5. Comín-Colet J, Enjuanes C, González G, Torrens A, Cladellas M, Meroño
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6. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group;
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Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. 7. Toblli JE, Lombraña A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol. 2007;50:1657-65. 8. Okonko DO, Grzeslo A, Witkowski T, Mandal AK, Slater RM, Roughton M, Foldes G, Thum T, Majda J, Banasiak W, Missouris CG, Poole-Wilson PA, Anker SD, Ponikowski P. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart 11
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failure and iron deficiency FERRIC-HF: a randomized, controlled, observerblinded trial. J Am Coll Cardiol. 2008;51:103-12. 9. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Lüscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and
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Albuquerque D, Bocchi E, Vilas-Boas F, Moura LZ, Montera MW, Rassi S,
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Clausell N. IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia. Int J Cardiol. 2013;168:3439-42.
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11. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Beneficial
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12. Toblli JE, Di Gennaro F, Rivas C. Changes in Echocardiographic Parameters in Iron Deficiency Patients with Heart Failure and Chronic Kidney
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Disease Treated with Intravenous Iron. Heart Lung Circ. 2015;24:686-95. 13. Wong C, Ng A, Lau J, Kritharides L, Sindone A. Early responses to intravenous iron therapy in patients with chronic heart failure and iron
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deficiency. Heart Lung Circ. 2016;25:S107 14. Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, Tang WHW, LaRue SJ, Redfield MM, Semigran MJ, Givertz MM, Van Buren P, Whellan D, Anstrom KJ, Shah MR, Desvigne-Nickens P, Butler J, Braunwald E; NHLBI Heart Failure Clinical Research Network. Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA. 2017;317:1958-66. 12
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15. Lita Suryani L, Siswanto BB, Raharjo, SB, Hersunarti N, Soerarso R, Angkasa H. Oral iron therapy improves functional capacity of heart failure patients with iron deficiency anemia. Eur J Heart Fail. 2017;19:245. 16. van Veldhuisen DJ, Ponikowski P, van der Meer P, Metra M, Böhm M, Doletsky A, Voors AA, Macdougall IC, Anker SD, Roubert B, Zakin L, CohenSolal A; EFFECT-HF Investigators. Effect of Ferric Carboxymaltose on
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Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency. Circulation. 2017;136:1374-83.
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17. Cohen-Solal A, Leclercq C, Deray G, Lasocki S, Zambrowski JJ, Mebazaa A, de Groote P, Damy T, Galinier M. Iron deficiency: an emerging therapeutic
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18. Ebner N, Jankowska EA, Ponikowski P, Lainscak M, Elsner S, Sliziuk V,
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Steinbeck L, Kube J, Bekfani T, Scherbakov N, Valentova M, Sandek A, Doehner W, Springer J, Anker SD, von Haehling S. The impact of iron
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19. Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O,
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Ponikowska B, Borodulin-Nadzieja L, Banasiak W, Polonski L, Filippatos G, McMurray JJ, Anker SD, Ponikowski P. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J 2010;31:1872-80.
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20. Avni T, Leibovici L, Gafter-Gvili A. Iron supplementation for the treatment of chronic heart failure and iron deficiency: systematic review and meta-
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analysis. Eur J Heart Fail. 2012;14:423-9. 21. Qian C, Wei B, Ding J, Wu H, Wang Y. The Efficacy and Safety of Iron Supplementation in Patients With Heart Failure and Iron Deficiency: A Systematic Review and Meta-analysis. Can J Cardiol. 2016;32:151-9. 22. Jankowska EA, Tkaczyszyn M, Suchocki T, Drozd M, von Haehling S, Doehner W, Banasiak W, Filippatos G, Anker SD, Ponikowski P. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail. 2016;18:78695. 13
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Figure legends
Figure 1. Flow diagram for inclusion of eligible studies in the meta-analysis.
Figure 2. Forest plots for major adverse events. (A) All-cause mortality; (B)
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Hospitalization for worsening heart failure; (C) Death and heart failure
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hospitalization. OR = odds ratio; CI = confidence interval.
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Figure 3. Forest plots for cardiac function and exercise capacity. (A) New York Heart Association (NYHA) class; (B) 6-min walk test (6MWT); (C) Left ventricular ejection fraction (LVEF); (D) Peak oxygen consumption (pVO2).
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WMD = weighted mean difference; CI = confidence interval.
Figure 4. Forest plots for quality of life. (A) Kansas City Cardiomyopathy Questionnaire (KCCQ); (B) patient global assessment (PGA); (C) European
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Quality of Life 5 Dimensions (EQ-5D); (D) Minnesota Living with Heart Failure
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Questionnaire (MLHFQ). WMD = weighted mean difference; CI = confidence interval.
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Figure 5. Forest plots for serum markers. (A) N-terminal prohormone brain natriuretic peptide (NT-proBNP); (B) C-reactive protein (CRP). WMD =
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weighted mean difference; CI = confidence interval.
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Table 1. Baseline characteristics of the included studies.
Study
Toblli et al.
Patients (Iron/Control )
20 / 20
Mean age (Iron/Control )
Iron dose
Administratio n
76 / 74
Intravenously
weekly
M
D E
(2008)
24 / 11
E C
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64 / 62
C A
IS 200 mg
Intravenously
weekly
15
I R
Ischemic cause (%)
C S U
N A
IS 200 mg
T P
Inclusion criteria
duration
methods
(2007)
Okonko et al.
Follow-up
6 months
18 weeks
LVEF ≤35%, NYHA class II-IV, Hb <12.5 g/dl (men) or <11.5 g/dl (women), ferritin <100 ng/ml, TSAT ≤20%, CrCl ≤90 ml/min
NYHA class II-III, LVEF ≤45%, pVO2/kg ≤18 ml/kg/min, Hb <12.5 or 12.5-14.5 g/dl, ferritin <100 μg/l or 100-300 μg/l with TSAT <20%
Endpoints
62.5
NT-proBNP, CRP, 6MWT, MLHFQ, LVEF, heart failure hospitalization
74.3
NYHA class, LVEF, pVO2, PGA, MLHFQ, CRP, adverse events
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Anker et al.
304 / 155
68 / 67
(2009)
FCM 200 mg
Intravenously
26 weeks
FS 200 mg,
66 / 69
Intravenously
three times a day
150 / 151
T P E
69 / 70
et al. (2015)
A
C C
FCM 500 mg or 1000 mg
U N
A M
or orally
D E
Ponikowski
NYHA class, 6MWT, PGA, EQ5D, KCCQ, adverse events
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IS 200 mg, weekly; 17 / 6
T P
80.2
I R
weekly
Beck-da-Silva et al. (2013)
LVEF ≤40% (NYHA class II) or LVEF ≤45% (NYHA class III), Hb 9.5-13.5 g/dl, ferritin <100 μg/l or 100-299 μg/l with TSAT <20%
Intravenously
weekly
16
3 months
52 weeks
NYHA class II-IV, LVEF <40%, Hb 9-12 g/dl, ferritin <500 μg/l, TSAT <20%
NYHA class II-III, LVEF ≤45%,NTproBNP >400 pg/ml, Hb <15 g/dl, ferritin <100 ng/ml or 100300 ng/ml with TSAT <20%
39.1
83.4
pVO2, NYHA class, adverse events
NYHA class, 6MWT, PGA, KCCQ, EQ-5D, adverse events
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Toblli et al.
30 / 30
75 / 75
(2015)
IS 200 mg
Wong et al.
Intravenously
weekly
16 / 19
NS
FCM 1000 mg one time
(2016)
Lita Suryani
C C
111 / 114
(2017)
T P E
63 / 63
IP 150mg twice daily
C S U
N A
Intravenously
2 weeks
M
Orally
16 weeks
A 27 / 27
NS
NS
T P
68.3
I R
D E
Lewis et al.
6 months
LVEF ≤35%, NYHA class II-IV, Hb <12.5 g/dl (men) or <11.5 g/dl (women), ferritin <100 ng/ml, TSAT ≤20%, CrCl ≤90 ml/min
Orally
12 weeks
Stable heart failure, ferritin <100 μg/l or <300 μg/l with TSAT <20%
LVEF ≤40%, NYHA class II-IV, ferritin 15100 ng/ml or 100-299 ng/ml with TSAT <20%, Hb 9-15 g/dl (men) or 9-13.5 g/dl (women)
LVEF <50%, IDA, eGFR >30 ml/min/ 1.73m2
17
LVEF, NYHA class, NTproBNP, CRP
NS
KCCQ, 6MWT, stroke volume, cardiac index, NT-proBNP
77.8
pVO2, 6MWT, KCCQ, NTproBNP, adverse events
NS
6MWT, NTproBNP, adverse events
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
et al. (2017)
van Veldhuisen et al. (2017)
86 / 86
63 / 64
FCM 500 or 1000 mg weekly
T P
Intravenously
24 weeks
NYHA class II-III, LVEF ≤45%,NTproBNP >400 pg/ml, ferritin <100 ng/ml or 100-300 ng/ml with TSAT <20%
N A
C S U
I R
65.7
pVO2, NYHA class, PGA, NTproBNP, adverse events
CrCl = creatinine clearance; CRP = C-reactive protein; EQ-5D = European Quality of Life 5 Dimensions; FCM = ferric carboxymaltose; FS = ferrous sulfate; Hb = hemoglobin; IDA = iron-deficiency anemia; IP = iron polysaccharide; IS = iron sucrose; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection fraction; MLHFQ = Minnesota Living with Heart Failure Questionnaire; NS = not stated; NT-proBNP = N-terminal prohormone brain natriuretic peptide; NYHA = New York Heart Association; PGA = patient global assessment; pVO2 = peak oxygen consumption; TSAT = transferrin saturation; 6MWT = 6-min walk test.
D E
M
T P E
C C
A
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Table 2. Risk of bias assessment in the included studies.
Study
Random sequence generation
Allocation
(selection bias)
concealment (selection bias)
Toblli et al. (2007)
+
?
Okonko et al. (2008)
+
?
Anker et al. (2009)
+
+
Beck-da-Silva et al. (2013)
+
Ponikowski et al. (2015)
+
Toblli et al. (2015)
+
Wong et al. (2016) Lewis et al. (2017) Lita Suryani et al. (2017)
Blinding of participants
Blinding of outcome
and personnel
assessment
(performance bias)
(detection bias)
(attrition bias)
Selective reporting (reporting bias)
+
+
?
–
+
+
+
+
+
+
?
+
+
?
?
+
+
+
+
+
?
+
+
+
+
?
+
?
?
?
+
?
+
+
+
+
?
?
+
?
?
?
D E
C A
E C
?
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+
C S U
I R
T P
Incomplete outcome data
N A –
M
19
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
van Veldhuisen et al. (2017)
?
–
?
+
+
T P
(+) Low risk of bias; (−) high risk of bias; (?) unclear risk of bias.
I R
C S U
N A
D E
M
T P E
C C
A
20
+
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Clinical Significance
Iron supplementation can reduce heart failure hospitalization but not allcause mortality in patients with heart failure.
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Iron treatment can increase cardiac function and exercise capacity, and
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improve quality of life and prognosis in patients with heart failure.
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Iron repletion can decrease serum levels of N-terminal pro-B-type
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natriuretic peptide and C-reactive protein in patients with heart failure.
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Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Xiang Zhou, Weiting Xu, Youjia Xu, Zhiyuan Qian PII: DOI: Reference:
S0002-9343(19)30213-X https://doi.org/10.1016/j.amjmed.2019.02.018 AJM 15042
To appear in:
The American Journal of Medicine
Please cite this article as: X. Zhou, W. Xu, Y. Xu, et al., Iron supplementation improves cardiovascular outcomes in patients with heart failure, The American Journal of Medicine, https://doi.org/10.1016/j.amjmed.2019.02.018
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Iron supplementation improves cardiovascular outcomes in patients with heart failure
Running title: Iron supplementation in heart failure
a
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Xiang Zhou, MD, PhDa; Weiting Xu, MDa; Youjia Xu, MDb; Zhiyuan Qian, MDc
Department of Cardiology, The Second Affiliated Hospital of Soochow
b
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University, Suzhou, China
Department of Orthopedics, The Second Affiliated Hospital of Soochow
Department of Neurosurgery, The Second Affiliated Hospital of Soochow
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c
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University, Suzhou, China
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Corresponding author
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University, Suzhou, China
Xiang Zhou
Department of Cardiology
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The Second Affiliated Hospital of Soochow University No. 1055 Sanxiang Road
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Suzhou 215004, China Tel: +86 512 67784079 Fax: +86 512 68284303 E-mail: [email protected]
Article type: Clinical Research Study All authors had access to the data and a role in writing the manuscript. The authors had no conflict of interest. 1
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Abstract Background: Iron deficiency is prevalent in patients with heart failure. This meta-analysis was performed to evaluate the therapeutic effects of iron in patients with systolic heart failure and iron deficiency. Methods: We searched PubMed, Embase, and Cochrane databases through
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March 2018 and included 10 randomised controlled trials involving 1404 heart failure patients who underwent iron or placebo treatment. Odds ratio (OR) and
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weighted mean differences (WMD) were calculated using fixed or random
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effects models.
Results: Our results showed that iron supplementation significantly reduced hospitalization for worsening heart failure (OR: 0.39, 95% CI: 0.19 to 0.80)
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and the combined endpoint of death and heart failure hospitalization (OR: 0.47, 95% CI: 0.32 to 0.69). In addition, iron treatment was found to improve
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New York Heart Association class, 6-min walk distance, left ventricular ejection fraction, and peak oxygen consumption. Iron therapy was also associated with improvements in Patient Global Assessment, Kansas City
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Cardiomyopathy Questionnaire score, European Quality of Life-5 Dimensions
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score, and Minnesota Living with Heart Failure Questionnaire score. Moreover, serum levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and Creactive protein (CRP) were markedly decreased in patients with iron repletion
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compared with placebo treatment (WMD: -332.48 pg/ml, 95% CI: -497.48 to 167.47; WMD: -4.64 mg/L, 95% CI: -6.12 to -3.17, respectively).
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Conclusions: Our meta-analysis suggests that iron therapy can reduce heart failure hospitalization, increase cardiac function, improve quality of life, and decrease serum levels of NT-proBNP and CRP in patients with heart failure.
Keywords: Heart failure; Iron therapy; Meta-analysis
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Introduction Heart failure is a complex clinical syndrome characterized by neuroendocrine system activation, cardiac pathological remodeling, and impaired myocardial contractility. In recent years, the clinical applications of beta blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, and aldosterone antagonists have
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significantly improved the cardiovascular prognosis in patients with heart failure.1 However, heart failure remains a leading cause of cardiovascular
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mortality and morbidity and it brings a heavy economic burden to society.
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Iron deficiency is a prevalent and clinically relevant comorbidity in up to 50% of patients with heart failure and is associated with the severity of the
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disease.2 Iron plays a critical role in oxygen transport, not only through hematopoiesis, but also in the metabolism of myocardial and skeletal muscles.
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Iron deficiency in heart failure patients may contribute to reduced exercise capacity, impaired quality of life, and increased cardiac mortality, irrespective of the presence of anaemia.3-5 Over the past decade, several small
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randomised controlled trials (RCTs) have been performed to evaluate the
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effects of iron therapy in patients with heart failure. These trials investigated cardiac function, exercise capacity, quality of life, heart failure hospitalization, and all-cause mortality. However, the conclusions drawn from these studies
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are not consistent. We therefore carried out a meta-analysis of RCTs to confirm whether iron supplementation is beneficial in patients with systolic
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heart failure and iron deficiency.
Methods
Search strategy and selection criteria We conducted an electronic literature search of PubMed, Embase, and Cochrane databases through March 2018, using the terms “iron deficiency”, “iron therapy”, “iron supplementation”, “iron repletion”, “ferric carboxymaltose”, “heart
failure”,
“cardiac
failure”,
“cardiac 3
dysfunction”,
and
“cardiac
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
insufficiency”. Sensitive filters identified clinical trial or RCT in the Medline and Embase databases. The search was limited to human studies in the English language. RCTs comparing iron repletion with placebo treatment in irondeficient patients with systolic heart failure and reporting at least one of the following outcomes were included in this meta-analysis. The outcomes consisted of all-cause mortality, hospitalization for worsening heart failure, New York Heart Association (NYHA) class, 6-min walk test (6MWT), left
Patient
Global
Assessment
(PGA),
Kansas
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ventricular ejection fraction (LVEF), peak oxygen consumption (pVO2), City
Cardiomyopathy
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Questionnaire (KCCQ), European Quality of Life-5 Dimensions (EQ-5D),
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Minnesota Living with Heart Failure Questionnaire (MLHFQ), N-terminal pro-
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B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP).
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Data extraction and quality assessment
Two reviewers independently evaluated all potentially eligible studies using predefined criteria and collected data from included trials. In case of
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disagreement between the two reviewers, a consensus was achieved by open
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discussion. We contacted the investigators of included studies for missing information. The extracted data include patient characteristics, inclusion criteria, dosage and methods of administration, duration of follow-up, and
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clinical outcomes including all-cause mortality, heart failure hospitalization, NYHA class, 6MWT distance, LVEF, pVO2, PGA, KCCQ score, EQ-5D score,
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MLHFQ score, and serum levels of NT-proBNP and CRP. The quality of included trials was evaluated using the Cochrane Collaboration's tool for assessing risk for bias, which consists of selection bias, performance bias, detection bias, attrition bias, and reporting bias.6
Statistical analysis Dichotomous variables were analyzed using odds ratio (OR) with 95% confidence interval (CI), while continuous data were analyzed using weighted 4
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
mean difference (WMD) and 95% CI. Statistical heterogeneity across the studies was evaluated using the Chi-square-based Q-test. A p-value < 0.10 for the Q-test indicated significant heterogeneity, and a random-effects model was used to calculate the pooled effect. Otherwise, a fixed-effects model was applied. Sensitivity analysis was performed to determine the influence of each individual study on overall estimates. Publication bias was assessed using Begg's funnel plot and Egger's test. All statistical analyses were performed
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using the STATA software 12.0 (Stata Corp., College Station, Texas, USA).
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The pooled effect was considered significant if p < 0.05.
Results
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Study characteristics
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The flow diagram of study selection process is shown in Figure 1. Among the initial 232 RCTs, 27 trials were retrieved for detailed evaluation, and 10 studies meeting the inclusion criteria were finally analyzed.7-16 A total of 1404
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patients with systolic heart failure and iron deficiency were included in this
received placebo.
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meta-analysis. Among them, 785 received iron supplementation and 619
The baseline characteristics of included studies are shown in Table 1. The
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duration of follow-up ranged from 2 to 52 weeks. Iron deficiency was defined as ferritin < 100 ng/ml or 100-300 ng/ml with transferrin saturation < 20%.
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Intravenous iron therapy (ferric carboxymaltose or iron sucrose) was used in 8 studies with the dose varying from 200 to 1000 mg weekly, while oral iron repletion (ferrous sulfate or iron polysaccharide) was applied in 3 studies with the dose varying from 300 to 600 mg daily. Among the included studies, 6 trials reported all-cause mortality,8-11,14,16 5 heart failure hospitalization,7-9,11,16 5 NYHA class,7-9,11,12 5 6MWT,7,9,11,14,15 3 LVEF,7,8,12 3 pVO2,8,14,16 3 PGA,8,9,11 4 KCCQ score,9,11,13,14 2 EQ-5D score,9,11 2 MLHFQ score,7,8 5 NT-proBNP,7,12-14,16 and 3 CRP.7,8,12
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Quality assessment The Cochrane Collaboration's tool for assessing risk of bias was used to evaluate the quality of included RCTs (Table 2). Overall, random sequence generation was observed in 7 studies,7-12,14 and 2 of them had reported allocation concealment.9,11 Eight studies were double blinded
7,9-15
and 2 trials
were open-label.8,16 Blinding of outcome assessment was performed in 7
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studies.7,9-12,14,16 Neither incomplete outcome data nor selective reporting was
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observed in any of the included studies.
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Major adverse events
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Six studies reported all-cause mortality and there was no significant heterogeneity among them. In general, 23 (3.3%) patients in the iron group (n = 695) reached the endpoint compared with 24 (4.6%) patients in the control
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group (n = 522). The pooled analysis suggested that there was no significant difference in all-cause mortality between iron group and placebo group (OR:
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0.76, 95% CI: 0.43 to 1.37) (Figure 2A). In addition, Begg's and Egger's tests
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showed no significant publication bias (p = 1.00 and p = 0.87, respectively) Five studies reported heart failure hospitalization and no significant heterogeneity was found. There were 31 (5.3%) hospitalizations for worsening
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heart failure in the iron group (n = 587) compared with 61 (14.5%) hospitalizations in the control group (n = 422). The pooled results indicated
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that iron repletion markedly reduced hospitalization for heart failure (OR: 0.39, 95% CI: 0.19 to 0.80) (Figure 2B). In addition, Begg's and Egger's tests showed no significant publication bias (p = 0.81 and p = 0.45, respectively) Four studies reported the composite endpoint of death and heart failure hospitalization. Overall, 49 (8.6%) patients in the iron group (n = 567) reached the combined endpoint compared with 78 (19.4%) patients in the control group (n = 402). The pooled analysis revealed that iron therapy was associated with a remarkable decrease in all-cause mortality and heart failure hospitalization (OR: 0.47, 95% CI: 0.32 to 0.69) (Figure 2C). Moreover, 6
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Begg's and Egger's tests showed no significant publication bias (p = 0.73 and p = 0.82, respectively)
Cardiac function and exercise capacity In this meta-analysis, NYHA class, 6MWT distance, LVEF, and pVO2 were
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used to evaluate the effects of iron supplementation on cardiac function and exercise capacity in patients with systolic heart failure and iron deficiency. As
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shown in Figure 3, iron treatment was found to improve cardiac function and increase exercise capacity in patients with heart failure. In addition, there was
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no significant publication bias in these analyses using Begg's funnel plot and
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Egger's test.
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Quality of life
In this meta-analysis, KCCQ score, PGA, EQ-5D score, and MLHFQ score
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were applied to assess the effects of iron repletion on quality of life in heart failure patients with reduced LVEF and iron deficiency. As shown in Figure 4,
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iron therapy was associated with a remarkable improvement in quality of life scores in patients with heart failure. In addition, there was no significant
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publication bias in these analyses using Begg's funnel plot and Egger's test.
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Serum markers
We also determined the effects of iron therapy on serum levels of NT-proBNP and CRP in patients with heart failure. The pooled results suggested that NTproBNP and CRP levels were markedly decreased in patients with iron repletion compared with placebo treatment (WMD: -332.48 pg/ml, 95% CI: 497.48 to -167.47; WMD: -4.64 mg/L, 95% CI: -6.12 to -3.17, respectively) (Figure 5). Moreover, no significant publication bias was found using the Begg's and Egger's tests.
7
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Sensitivity analysis Since significant heterogeneity across studies was observed regarding NYHA class, 6MWT distance, LVEF, pVO2, KCCQ score, and NT-proBNP level, we performed sensitivity analysis to determine the effect of each study on the pooled estimates under the random effects model. Our results showed that removal of any individual study could not significantly reduce the
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heterogeneity.
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Discussion
The present meta-analysis was conducted to determine whether iron therapy
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is beneficial in heart failure patients with iron deficiency. Our results revealed that iron supplementation could reduce heart failure hospitalization, increase
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cardiac function and exercise capacity, improve quality of life, and decrease serum levels of NT-proBNP and CRP. However, iron treatment was not found to significantly reduce all-cause mortality in patients with heart failure.
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Iron deficiency, which is a major risk factor for disability and mortality
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worldwide, has been identified as a common comorbidity in patients with heart failure. Current evidence indicates that the presence of chronic inflammation in heart failure is responsible for impaired iron absorption, recycling, and
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release from body stores.17 Iron deficiency in heart failure can lead to decreased oxygen delivery and aggravation of symptoms such as dyspnea
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and fatigue, and consequently impair exercise tolerance and quality of life.18 Several observational studies investigated the association between iron deficiency and clinical outcomes in patients with heart failure, and showed that iron deficiency was a strong and independent predictor of mortality.2,3,19 In recent years, a number of clinical trials have been conducted to determine the effects of iron therapy on exercise capacity, quality of life, and adverse events in heart failure patients. In the FAIR-HF study, treatment with intravenous ferric carboxymaltose (FCM) in patients with systolic heart failure could significantly improve clinical symptoms, functional capacity, and quality 8
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
of life.9 In the CONFIRM-HF study, FCM treatment over a 1-year period in symptomatic and iron-deficient heart failure patients contributed to sustained improvements in functional capacity, symptoms and quality of life.11 In the EFFECT-HF study, intravenous FCM supplementation in patients with heart failure and iron deficiency had a beneficial effect on pVO2 compared with standard treatment, irrespective of the presence of anemia. 16 In addition to intravenous iron therapy, some other studies investigated the effects of oral
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iron repletion on cardiac performance and exercise capacity in heart failure. In the IRONOUT HF study, high-dose oral iron was not found to significantly
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improve exercise capacity in heart failure patients with reduced LVEF and iron
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deficiency.14 On the contrary, another clinical trial with small sample size indicated that oral iron therapy for 12 weeks improved functional capacity in
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patients with heart failure.15
Based on the results of above studies, we performed a meta-analysis of RCTs
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to confirm whether iron treatment is beneficial in patients with heart failure. Our results suggested that iron supplementation reduced hospitalization for worsening heart failure, but could not decrease all-cause mortality, which
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might result from a relatively small number of reported all-cause deaths. In
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addition, we also evaluated the effects of iron therapy on cardiac function and exercise tolerance, and found that iron repletion was associated with improvements in NYHA class, 6MWT distance, LVEF, and pVO2 in patients
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with heart failure. Furthermore, PGA, KCCQ score, EQ-5D score, and MLHFQ score were applied to assess the effect of iron treatment on quality of life. Our
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results revealed that iron supplementation could improve quality of life and prognosis in patients with heart failure. There are three other meta-analyses that evaluate the therapeutic effects of iron in patients with heart failure.20-22 However, the number of RCTs included in each meta-analysis is no more than 5 and the total number of participants is relatively small, which may reduce the statistical power of the analysis. Moreover, some conclusions drawn from these meta-analyses are not consistent. We therefore conducted an updated meta-analysis which included
9
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
10 RCTs comprising a total of 1404 patients to provide more convincing evidence of iron treatment in heart failure. There are several limitations in this meta-analysis. Firstly, the methodological quality of included studies was less than optimal, so the potential risk of bias could not be excluded. Secondly, we did not consider the influences of iron dose, administration method, and cardiac function on therapeutic effects due
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to the incomplete information. Thirdly, the sample size and follow-up duration
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in these trials varied widely, which might affect the statistical power.
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Conclusions
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Our meta-analysis demonstrates that iron supplementation can reduce heart failure hospitalization, increase cardiac function and exercise capacity,
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improve quality of life and prognosis, and decrease serum levels of NT-
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proBNP and CRP in patients with heart failure.
Acknowledgements
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This study was financially supported by the National Natural Science Foundation of China (No. 81770370), Scientific Research Program for Young Talents of China National Nuclear Corporation (No. 51001), and Advantage
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Discipline Group of the Second Affiliated Hospital of Soochow University (No. XKQ2015001). .
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References 1. Raj L, Adhyaru B. An evidence-based review of recent advances in therapy for heart failure with reduced ejection fraction (HFrEF). Postgrad Med J. 2016;92:726-34. 2. Klip IT, Comin-Colet J, Voors AA, Ponikowski P, Enjuanes C, Banasiak W, Lok DJ, Rosentryt P, Torrens A, Polonski L, van Veldhuisen DJ, van der Meer
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P, Jankowska EA. Iron deficiency in chronic heart failure: an international
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3. Okonko DO, Mandal AK, Missouris CG, Poole-Wilson PA. Disordered iron
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homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. J Am Coll Cardiol. 2011;58:1241-51.
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4. Cohen-Solal A, Damy T, Terbah M, Kerebel S, Baguet JP, Hanon O, Zannad F, Laperche T, Leclercq C, Concas V, Duvillié L, Darné B, Anker S,
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failure and iron deficiency FERRIC-HF: a randomized, controlled, observerblinded trial. J Am Coll Cardiol. 2008;51:103-12. 9. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Lüscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and
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11. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Beneficial
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15. Lita Suryani L, Siswanto BB, Raharjo, SB, Hersunarti N, Soerarso R, Angkasa H. Oral iron therapy improves functional capacity of heart failure patients with iron deficiency anemia. Eur J Heart Fail. 2017;19:245. 16. van Veldhuisen DJ, Ponikowski P, van der Meer P, Metra M, Böhm M, Doletsky A, Voors AA, Macdougall IC, Anker SD, Roubert B, Zakin L, CohenSolal A; EFFECT-HF Investigators. Effect of Ferric Carboxymaltose on
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Steinbeck L, Kube J, Bekfani T, Scherbakov N, Valentova M, Sandek A, Doehner W, Springer J, Anker SD, von Haehling S. The impact of iron
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19. Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O,
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Ponikowska B, Borodulin-Nadzieja L, Banasiak W, Polonski L, Filippatos G, McMurray JJ, Anker SD, Ponikowski P. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J 2010;31:1872-80.
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20. Avni T, Leibovici L, Gafter-Gvili A. Iron supplementation for the treatment of chronic heart failure and iron deficiency: systematic review and meta-
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Figure legends
Figure 1. Flow diagram for inclusion of eligible studies in the meta-analysis.
Figure 2. Forest plots for major adverse events. (A) All-cause mortality; (B)
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Hospitalization for worsening heart failure; (C) Death and heart failure
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hospitalization. OR = odds ratio; CI = confidence interval.
SC
Figure 3. Forest plots for cardiac function and exercise capacity. (A) New York Heart Association (NYHA) class; (B) 6-min walk test (6MWT); (C) Left ventricular ejection fraction (LVEF); (D) Peak oxygen consumption (pVO2).
MA
NU
WMD = weighted mean difference; CI = confidence interval.
Figure 4. Forest plots for quality of life. (A) Kansas City Cardiomyopathy Questionnaire (KCCQ); (B) patient global assessment (PGA); (C) European
D
Quality of Life 5 Dimensions (EQ-5D); (D) Minnesota Living with Heart Failure
PT E
Questionnaire (MLHFQ). WMD = weighted mean difference; CI = confidence interval.
CE
Figure 5. Forest plots for serum markers. (A) N-terminal prohormone brain natriuretic peptide (NT-proBNP); (B) C-reactive protein (CRP). WMD =
AC
weighted mean difference; CI = confidence interval.
14
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Table 1. Baseline characteristics of the included studies.
Study
Toblli et al.
Patients (Iron/Control )
20 / 20
Mean age (Iron/Control )
Iron dose
Administratio n
76 / 74
Intravenously
weekly
M
D E
(2008)
24 / 11
E C
PT
64 / 62
C A
IS 200 mg
Intravenously
weekly
15
I R
Ischemic cause (%)
C S U
N A
IS 200 mg
T P
Inclusion criteria
duration
methods
(2007)
Okonko et al.
Follow-up
6 months
18 weeks
LVEF ≤35%, NYHA class II-IV, Hb <12.5 g/dl (men) or <11.5 g/dl (women), ferritin <100 ng/ml, TSAT ≤20%, CrCl ≤90 ml/min
NYHA class II-III, LVEF ≤45%, pVO2/kg ≤18 ml/kg/min, Hb <12.5 or 12.5-14.5 g/dl, ferritin <100 μg/l or 100-300 μg/l with TSAT <20%
Endpoints
62.5
NT-proBNP, CRP, 6MWT, MLHFQ, LVEF, heart failure hospitalization
74.3
NYHA class, LVEF, pVO2, PGA, MLHFQ, CRP, adverse events
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Anker et al.
304 / 155
68 / 67
(2009)
FCM 200 mg
Intravenously
26 weeks
FS 200 mg,
66 / 69
Intravenously
three times a day
150 / 151
T P E
69 / 70
et al. (2015)
A
C C
FCM 500 mg or 1000 mg
U N
A M
or orally
D E
Ponikowski
NYHA class, 6MWT, PGA, EQ5D, KCCQ, adverse events
SC
IS 200 mg, weekly; 17 / 6
T P
80.2
I R
weekly
Beck-da-Silva et al. (2013)
LVEF ≤40% (NYHA class II) or LVEF ≤45% (NYHA class III), Hb 9.5-13.5 g/dl, ferritin <100 μg/l or 100-299 μg/l with TSAT <20%
Intravenously
weekly
16
3 months
52 weeks
NYHA class II-IV, LVEF <40%, Hb 9-12 g/dl, ferritin <500 μg/l, TSAT <20%
NYHA class II-III, LVEF ≤45%,NTproBNP >400 pg/ml, Hb <15 g/dl, ferritin <100 ng/ml or 100300 ng/ml with TSAT <20%
39.1
83.4
pVO2, NYHA class, adverse events
NYHA class, 6MWT, PGA, KCCQ, EQ-5D, adverse events
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Toblli et al.
30 / 30
75 / 75
(2015)
IS 200 mg
Wong et al.
Intravenously
weekly
16 / 19
NS
FCM 1000 mg one time
(2016)
Lita Suryani
C C
111 / 114
(2017)
T P E
63 / 63
IP 150mg twice daily
C S U
N A
Intravenously
2 weeks
M
Orally
16 weeks
A 27 / 27
NS
NS
T P
68.3
I R
D E
Lewis et al.
6 months
LVEF ≤35%, NYHA class II-IV, Hb <12.5 g/dl (men) or <11.5 g/dl (women), ferritin <100 ng/ml, TSAT ≤20%, CrCl ≤90 ml/min
Orally
12 weeks
Stable heart failure, ferritin <100 μg/l or <300 μg/l with TSAT <20%
LVEF ≤40%, NYHA class II-IV, ferritin 15100 ng/ml or 100-299 ng/ml with TSAT <20%, Hb 9-15 g/dl (men) or 9-13.5 g/dl (women)
LVEF <50%, IDA, eGFR >30 ml/min/ 1.73m2
17
LVEF, NYHA class, NTproBNP, CRP
NS
KCCQ, 6MWT, stroke volume, cardiac index, NT-proBNP
77.8
pVO2, 6MWT, KCCQ, NTproBNP, adverse events
NS
6MWT, NTproBNP, adverse events
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
et al. (2017)
van Veldhuisen et al. (2017)
86 / 86
63 / 64
FCM 500 or 1000 mg weekly
T P
Intravenously
24 weeks
NYHA class II-III, LVEF ≤45%,NTproBNP >400 pg/ml, ferritin <100 ng/ml or 100-300 ng/ml with TSAT <20%
N A
C S U
I R
65.7
pVO2, NYHA class, PGA, NTproBNP, adverse events
CrCl = creatinine clearance; CRP = C-reactive protein; EQ-5D = European Quality of Life 5 Dimensions; FCM = ferric carboxymaltose; FS = ferrous sulfate; Hb = hemoglobin; IDA = iron-deficiency anemia; IP = iron polysaccharide; IS = iron sucrose; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection fraction; MLHFQ = Minnesota Living with Heart Failure Questionnaire; NS = not stated; NT-proBNP = N-terminal prohormone brain natriuretic peptide; NYHA = New York Heart Association; PGA = patient global assessment; pVO2 = peak oxygen consumption; TSAT = transferrin saturation; 6MWT = 6-min walk test.
D E
M
T P E
C C
A
18
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Table 2. Risk of bias assessment in the included studies.
Study
Random sequence generation
Allocation
(selection bias)
concealment (selection bias)
Toblli et al. (2007)
+
?
Okonko et al. (2008)
+
?
Anker et al. (2009)
+
+
Beck-da-Silva et al. (2013)
+
Ponikowski et al. (2015)
+
Toblli et al. (2015)
+
Wong et al. (2016) Lewis et al. (2017) Lita Suryani et al. (2017)
Blinding of participants
Blinding of outcome
and personnel
assessment
(performance bias)
(detection bias)
(attrition bias)
Selective reporting (reporting bias)
+
+
?
–
+
+
+
+
+
+
?
+
+
?
?
+
+
+
+
+
?
+
+
+
+
?
+
?
?
?
+
?
+
+
+
+
?
?
+
?
?
?
D E
C A
E C
?
PT
+
C S U
I R
T P
Incomplete outcome data
N A –
M
19
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
van Veldhuisen et al. (2017)
?
–
?
+
+
T P
(+) Low risk of bias; (−) high risk of bias; (?) unclear risk of bias.
I R
C S U
N A
D E
M
T P E
C C
A
20
+
ACCEPTED MANUSCRIPT Iron supplementation in heart failure
Clinical Significance
Iron supplementation can reduce heart failure hospitalization but not allcause mortality in patients with heart failure.
PT
Iron treatment can increase cardiac function and exercise capacity, and
RI
improve quality of life and prognosis in patients with heart failure.
SC
Iron repletion can decrease serum levels of N-terminal pro-B-type
AC
CE
PT E
D
MA
NU
natriuretic peptide and C-reactive protein in patients with heart failure.
21
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5