Intravenous iron therapy among patients with heart failure and iron deficiency: An updated meta-analysis of randomized controlled trials

Background Randomized clinical trials (RCTs) evaluating the role of intravenous (IV) iron administration in patients with heart failure (HF) and iron deficiency (ID) have yielded inconsistent results. Methods Electronic search of MEDLINE, EMBASE and OVID databases was performed until November 2022 for RCTs that evaluated the role of IV iron administration in patients with HF and ID. The main study outcomes were the composite of HF hospitalization or cardiovascular mortality, and individual outcome of HF hospitalization. Summary estimates were evaluated using random effects model. Results The final analysis included 12 RCTs with 3,492 patients (1,831 patients in the IV iron group and 1,661 patients in the control group). The mean follow-up was 8.3 months. IV iron was associated with a lower incidence in the composite of HF hospitalization or cardiovascular mortality (31.9% vs. 45.3%; relative risk [RR] 0.72; 95% confidence interval [CI] 0.59–0.88) and individual outcome of HF hospitalization (28.4% vs. 42.2; RR 0.69; 95% CI 0.57–0.85). There was no significant difference between both groups in cardiovascular mortality (RR 0.88; 95% CI 0.75–1.04) and all-cause mortality (RR 0.95; 95% CI 0.83–1.09). IV iron was associated with lower New York Heart Association class and higher left ventricular ejection fraction (LVEF). Meta-regression analyses showed no effect modification for the main outcomes based on age, hemoglobin level, ferritin level or LVEF. Conclusion Among patients with HF and ID, IV iron administration was associated with reduction in the composite of HF hospitalization or cardiovascular mortality and driven by a reduction in HF hospitalization.


Introduction
Iron deficiency (ID) is a common co-morbidity among patients with heart failure (HF) [1,2]. It is reported that ID is prevalent up to 30-50% of stable chronic HF patients and up to 50-80% among those with acute HF [1]. The association between HF and ID is hypothesized to be related to the decrease in iron absorption, depletion of iron stores and reduced availability of the recycled iron from the reticuloendothelial system among patients with HF [3,4]. With the known important role of iron in oxygen storage, oxygen transport and aerobic metabolism in skeletal muscles, ID may contribute to fatigue, dyspnea, and the exercise intolerance in HF patients [1,3,5]. Irrespective of anemia, ID is suggested to increase mortality and worsen prognosis in HF patients; hence iron therapy has been studied as a potential treatment for HF [5]. Intravenous (IV) iron may be the preferred treatment for iron deficiency in only certain medical conditions due to its possible allergic/anaphylactic side effects [6][7][8]. Although multiple studies have studied the effect of IV iron on improving the clinical outcomes of HF and reducing the risk of HF hospitalization, these studies have yielded inconsistent results [3,7,. In the recent IRONMAN (Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency) trial, IV iron among patients with HF and ID did not reduce the risk of HF hospitalization or cardiovascular mortality compared with usual care [18]. Thus, we sought to conduct a meta-analysis of the available randomized controlled trials (RCTs) to evaluate the efficacy of IV iron administration on patients with HF and ID.

Data sources and search strategy
A comprehensive electronic database search of MEDLINE, Cochrane, and OVID was performed through November 2022, using the search terms "iron deficiency" OR "intravenous iron" OR "iron therapy" AND "heart failure" for RCTs that evaluated the efficacy of IV iron administration in improving clinical outcomes in patients with HF and ID. Further screening of the bibliographies of the retrieved articles, earlier meta-analyses, and ClinicalTrials.gov to identify any other pertinent studies. This systematic review and meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [31] (Supplemental Table 1). The protocol for this meta-analysis and systematic review was prospectively registered at PROSPERO (ID 388733).

Selection criteria
This study included RCTs that evaluated the role of IV iron administration compared with control in patients with HF and ID. Included studies enrolled patients with ID regardless of the presence of anemia. Only English-language studies with full results published until November 2022 were included. Studies which did not report clinical outcomes were excluded.

Data extraction
The following data were independently extracted from the included studies by two investigators (SAE and MH): study design, baseline characteristics and clinical outcomes. Disagreements between investigators were resolved by consensus.

Outcomes
The main study outcomes were the composite of HF hospitalization or cardiovascular mortality and the individual outcome of HF hospitalization. Other outcomes included cardiovascular mortality, all-cause mortality, improvement of left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) class and 6-min walk (6 MW) test. Clinical outcomes were reported using an intention-to-treat basis at the longest reported follow-up period.

Assessment of the quality of the included studies
The quality of the included trials and risk of bias was assessed using the Cochrane bias risk assessment tool, which comprises 7 criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias [32]. Then studies were classified into high risk, low risk or unclear risk of bias (Supplemental Table 2).

Statistical analysis
Random effects model utilizing Mantel-Haenszel method was used to pool data and generate estimates of the treatment effect. I 2 statistic was used to assess the heterogeneity among the included trials. I 2 statistic values of <25%, 25% to 50%, and >50% were considered to be a low, moderate, and a high degree of heterogeneity, respectively [32]. A subgroup analysis for acute versus chronic HF was performed. The following sensitivity analyses were conducted: including studies that used IV ferric carboxymaltose (FCM) (i.e., the most frequently used IV iron formulation), excluding studies with higher risk of bias, including only studies with >100 sample size at each group, and including only studies with follow-up >3 months. Also, stepwise sensitivity analyses were conducted by excluding one study at a time to evaluate the study with highest contribution to heterogeneity in the main study outcomes. Meta-regression analyses were conducted to evaluate the effect modification of main outcomes based on age, sex, hemoglobin level, ferritin level and LVEF. We reported the outcomes as risk ratios (RR) for categorical variables and mean differences (MD) for continuous variables. P-values <0.05 were considered statistically significant. Funnel plot was used to assess publications bias [33]. RevMan 5.4 software (Cochrane Collaboration, Oxford, UK) was used to conduct all the statistical analyses.

Discussion
In this meta-analysis of 12 RCTs including 3,492 patients [3,7,[9][10][11][12][13][14][15][16][17][18], we evaluated the efficacy of IV iron administration in patients with HF and concomitant ID. The main findings of this study are: 1) patients with HF and ID who received IV iron had lower incidence of the composite of HF hospitalization or cardiovascular mortality driven by a lower incidence of HF hospitalizations; 2) this benefit was observed in both acute and chronic HF, 3) meta-regression suggested no effect modification based on age, sex, hemoglobin level, ferritin level or LVEF; 4) there was no difference in all-cause and cardiovascular mortality in patients with HF and ID who received IV iron; 5) IV iron administration in patients with HF and ID demonstrated improvement in hemoglobin and ferritin levels, higher EF and lower NYHA class compared with control.
Treatment of ID among patients with HF has been evaluated previously via high dose oral iron, however, studies showed no significant clinical benefits, and this was attributed to poor absorption of oral iron formulations in patients with HF [34]. The role of IV iron administration in patients with HF and ID has been explored in multiple randomized studies and prior meta-analyses [3,7,. The results of these studies suggested beneficial impact for IV iron on improving the symptoms and functionality of patients with HF. However, these studies showed inconsistencies regarding the impact of IV iron on reducing hard clinical outcomes including HF hospitalizations, cardiovascular or all-cause mortality. Prior meta-analyses demonstrated a potential reduction in cardiovascular hospitalizations or HF hospitalizations with IV iron [19][20][21][22][23][24][25][26][27]29]. In addition, Mei et al. compared both oral and IV iron in patients with ID and HF. It showed that both IV and oral iron reduced all-cause death and HF hospitalization, but only IV iron improved the exercise capacity and quality of life [28]. A recent meta-analysis by Salah et al. demonstrated that IV iron in patients with HFrEF reduced the composite risk of first hospitalization for HF or CV mortality in addition to a reduced risks of first hospitalization and recurrent HF hospitalizations, but showed no effect on CV morality or all-cause mortality [30]. The IRONMAN trial is the most recent and largest RCT that evaluated the role of IV iron among patients with HF. IRONMAN RCT study of 1,137 patients showed no statistically significant difference in the primary endpoint of HF hospitalization or all-cause mortality between the IV iron and control groups during a median follow-up of 2.7 years [18].
In the current meta-analysis, we included the totality of available randomized data, including the IRONMAN trial. Our analysis demonstrated the beneficial impact of IV iron in reducing the composite of HF hospitalization or cardiovascular mortality and individual outcome of HF hospitalization. While our analysis suggested a numerical reduction in cardiovascular mortality with IV iron, there was no statistically significant difference in cardiovascular or all-cause mortality among both groups. Importantly, we have conducted subgroup and several exploratory analyses which demonstrated consistent beneficial impact of IV iron irrespective of the clinical presentation (i.e., acute versus chronic HF), and without heterogeneity of treatment effect across age, sex, hemoglobin level,

Fig. 2.
Forrest plot for composite of heart failure hospitalization or cardiovascular mortality, heart failure hospitalization, cardiovascular mortality, and all-cause mortality among the IV iron versus control groups. ferritin level or LVEF. These findings suggest that the clinical benefits with IV iron could be still attained through initiation of IV iron during inpatient or outpatient settings, and across a broad spectrum of patients with HF at various severities of ID. Our study results are discordant with those of the IRONMAN trial. This might be related to the limitations and restrictions in the IRONMAN trial that was conducted during the COVID-19 pandemic, which affected obtaining blood tests to assess for iron deficiency and the need for redosing with IV iron therapy [18].
Despite the advances in current guideline-directed medical therapies for HF, recurrent HF hospitalizations remains to be a major burden on the healthcare system, that is associated with high morbidity and mortality. Our study results confirm the viable role for IV iron in the current armamentarium for treating patients with HF. However, our updated analysis still failed to demonstrate a significant survival benefit with IV iron among patients with HF, despite including the largest and most recent RCTs. It is plausible that our study is still underpowered to detect survival benefits, and larger RCTs are still warranted to interrogate the possible survival benefit with IV iron.
Several mechanisms are proposed to be the etiology of ID in patients with HF. Hepcidin plays an important role in the regulation of ferroportin which has a major role in iron uptake. Heart failure, a known state of inflammation, results in an increase of hepcidin. This in turn results in down regulation of ferroportin and as a result causes less iron absorption [35]. Furthermore, gut wall edema and resultant decreased absorption play an important role [36]. By contrast, ID has been proposed to be a risk factor for worsening HF [37]. Iron is a metal cofactor in the production of mitochondrial enzymes which is essential in energy production and cellular metabolism in the myocardium [37][38][39]. Moreover, iron has a role in oxygen delivery, storage (in the form of myoglobin) and oxidative metabolism in the cardiac muscle [40]. As a result, ID can cause abnormal cellular metabolism and mitochondrial dysfunction which may predispose to worsening HF [41,42]. IV iron administration can improve oxygen metabolism and transport, in addition to increase oxygen carrying capacity through increase in hemoglobin especially in cells with high oxygen demands [26]. Previous studies demonstrated that IV iron in patients with HFrEF could replenish the intra-myocardial iron content which could help improve left ventricular function [43,44]. It was previously recommended that all patients with HF undergo screening for iron deficiency with baseline labs including complete blood count, ferritin, and transferrin saturation [45].
This meta-analysis encompasses the totality of available randomized trials regarding the efficacy of IV iron administration in patients with HF and ID. Our results demonstrated that the use of IV iron in patients with HF and ID regardless of anemia decreases the composite of HF hospitalization or cardiovascular mortality, and the individual risk of recurrent HF hospitalization. Nevertheless, this study had several limitations. First, there were variabilities among the included studies in the IV iron formulas, which may impact the treatment effect. There were also variabilities in the LVEF of included patients. To mitigate these variabilities, we have conducted exploratory analyses by including studies using consistent IV iron formula (i.e, FCM), and found similar results. Also, a meta-regression analysis showed no effect modification of the primary outcome based on LVEF. Second, despite including the totality of randomized data, our analysis might have been underpowered for some of the secondary outcomes, such as all-cause mortality and cardiovascular mortality. Third, there were moderate degree of heterogeneity in the main study outcomes, so we conducted stepwise sensitivity analyses to evaluate the source of heterogeneity by excluding one study at a time, then we excluded the study with the highest contribution to heterogeneity. Fourth, most of the included studies had very low sample size and limited follow-up. We have conducted sensitivity analyses including only studies with >100 sample size at each group, and including studies with follow-up >3 months, both showed similar results on the primary outcome. Fifth, our study included non-blinded and single center studies, so we have conducted a sensitivity analysis excluding studies with higher risk of bias that have showed similar results. Finally, there was lack of patient level data, so we could not ascertain which group drives the most benefit from IV iron therapy.

Conclusions
In this meta-analysis of RCTs, IV iron administration among patients with HF and ID was associated with a lower incidence of the composite of HF hospitalization or cardiovascular mortality, an effect that was driven by a reduction in the incidence of HF hospitalizations. The beneficial outcomes with IV iron were observed across a broad spectrum of patients with HF, regardless of the clinical setting (i.e., inpatient versus outpatient), age, sex, LVEF, hemoglobin level or ferritin level. There was no significant difference in the incidence of all-cause mortality or cardiovascular mortality among both study groups. Further efforts may be considered towards widespread testing and treatment of ID in patients with HF.

Data availability statement
Data will be made available on request.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.