Impact of Intravenous Iron in patients with heart failure and Iron Deficiency: an updated Meta-analysis of Randomized controlled trials

Abstract

Background

The actual effects of intravenous iron therapy on hospitalizations, mortality and safety in patients with heart failure and iron deficiency remained controversial. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to elucidate the cardiovascular benefits and safety of intravenous iron therapy.

Methods

We searched PubMed, Embase, and Cochrane Library databases for relevant RCTs of intravenous iron therapy in patients with heart failure and iron deficiency published from inception through April 20, 2024. Our primary endpoints of interest were heart failure hospitalizations, all-cause mortality, cardiovascular hospitalizations, and cardiovascular death. Additional risk of treatment complications included infections, administration site conditions, poisoning and procedural complications. We employed the fragility index and the reverse fragility index to further assess the robustness of our meta-analysis results. Additionally, subgroup analyses were conducted to explore potential clinical benefits.

Results

Eleven trials encompassing a collective cohort of 6511 participants met our predefined eligibility criteria and were included in our meta-analysis. Intravenous iron therapy yielded a 21% relative reduction in heart failure hospitalizations and cardiovascular death (P<0.01), a 24% relative reduction in heart failure hospitalization (P<0.01) and a 28% relative reduction in cardiovascular hospitalizations and cardiovascular death (P<0.01). The corresponding high fragility indexes showed these pooled results to be robust. Our analysis revealed no statistically significant differences in terms of all-cause mortality (P = 0.11). Subgroup analyses revealed more favorable effects of intravenous iron therapy in trials that had a treatment duration of ≥ 24 weeks. The administration of intravenous iron did not have an additional risk of treatment-related complications (P = 0.93).

Conclusions

Intravenous iron therapy in patients with chronic heart failure and iron deficiency significantly reduced rehospitalization for heart failure and cardiovascular death but was not associated with all-cause mortality. Long-term administration of iron supplements holds significant promise as a routine therapeutic approach for heart failure patients with iron deficiency.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12872-024-04368-y.

Introduction

Heart failure (HF) is a chronic and progressive syndrome that severely compromises the quality of life and significantly reduces the life expectancy [1]. Despite great advances in drug and device therapy for HF, the mortality and rehospitalization rates remain alarmingly high [2–4]. Iron deficiency is a highly prevalent comorbidity in patients with HF, causing the aggravation of debilitating symptoms, decreased exercise capacity, elevated rehospitalization rates, and heightened mortality risk [5–9]. However, the routine screening and standard therapy for iron deficiency have not been widely integrated into the current management of patients with HF [2, 5]. Intravenous iron repletion has been shown to improve clinical symptoms, enhance the 6-minute walk distance, and potentially reduce the risk of rehospitalization in patients with HF and iron deficiency [10–13]. Therefore, intravenous iron supplementation is recommended in symptomatic patients with HFrEF and HFmrEF and iron deficiency, to alleviate HF symptoms and improve quality of life in the guidelines of the European Society of Cardiology (2023: 2 A; A) [5, 14, 15]. However, previous studies and meta-analyses on intravenous iron therapy in heart failure patients have produced mixed results, particularly regarding its impact on major clinical outcomes such as all-cause mortality and cardiovascular death. The possible explanations can be attributed to the non-inclusion of the most recent RCT, different types of HF, differences in sample size and study design. The latest HEART-FID trial (Ferric Carboxymaltose in Heart Failure with Iron Deficiency) has revealed the minimal impact of intravenous iron on significant cardiovascular outcomes, such as mortality and HF-related hospitalizations, among ambulatory patients with both HF and iron deficiency [16]. As new RCTs continue to emerge, an updated meta-analysis is crucial to synthesizing the latest evidence and providing clearer guidance for clinical practice. Additionally, a prospective observational study has demonstrated that long-term use of intravenous iron therapy might cause cumulative iron build-up in the heart, even leading to an increased risk of iron-overload cardiomyopathy [17]. To assess the efficacy and safety of intravenous iron therapy in patients with HF and iron deficiency, we conducted a systematic review and meta-analysis that incorporated existing clinical evidence from published RCTs. Moreover, we implemented subgroup analyses and fragility scores to determine the population of benefit, the means of administration, and the reliability of study results.

Methods

Search Strategy and Selection Criteria

The present systematic review and meta-analysis (PROSPERO: CRD42024498844) adhered to the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [18]. We systematically searched the PubMed, Embase, and Cochrane Library databases for relevant RCTs investigating the efficacy of intravenous iron therapy in patients with HF and iron deficiency, covering the period from inception through April 20, 2024, without imposing any language restrictions. We used the following MeSH terms and combined text to guide our search: “heart failure” and “iron compounds” or “ferric carboxymaltose” or “iron deficiency” or “iron therapy” or “iron derivative” or “iron saccharate”. In addition, we manually searched the references of relevant systematic reviews and meta-analyses to ensure inclusion of all eligible studies. We did not impose any restrictions on the number of patients, type of intravenous iron, or duration of treatment in potentially eligible studies.

Study selection and data extraction

We included RCTs that compared intravenous iron therapy to placebo in HF patients with iron deficiency. All eligible studies had to report at least one of the predefined clinical endpoints. The primary endpoint was HF hospitalizations and cardiovascular death. The secondary endpoints included HF hospitalizations, all-cause mortality, and cardiovascular hospitalizations and cardiovascular death. Other clinical endpoints encompassed time to first hospitalization, time to first cardiovascular hospitalization, time to first cardiovascular death, time to first HF hospitalization or cardiovascular death, time to first hospitalization or all-cause mortality, and time to first cardiovascular hospitalization or cardiovascular death. We also assessed the safety of intravenous iron by collecting data on adverse effects. Exclusion criteria comprised retrospective or observational trials, RCTs that utilized oral iron therapy, and RCTs that did not report our predetermined outcomes of interest.

Following the database searches, two independent investigators (HW and YHL) screened the retrieved studies based on their titles and abstracts. The studies that met the inclusion criteria were then evaluated in full-text form. Two investigators (HW and YHL) extracted data and conducted comprehensive analysis, while a third investigator (RZ) acted as an arbitrator in cases of disagreement. The quality of the studies was assessed according to PRISMA recommendations, and the risk of bias was evaluated using the Cochrane Risk of Bias Tool.

Statistical analysis

We evaluated ten categorical variable outcomes to assess the clinical benefits of intravenous iron therapy. Given the heterogeneity of all eligible trials and its potential influences on beneficial effects, we used the Cochran Q test and I² test to evaluate the magnitude of the heterogeneity between trials for each outcome. When P value was less than 0.1 or the value of the I² test was greater than 50%, the evaluation of outcome exhibited significant heterogeneity. In cases where high heterogeneity was observed, the clinical effects were evaluated using a random-effects model based on the Restricted Maximum Likelihood method. Alternatively, if heterogeneity was not significant, a fixed-effects model based on the Mantel–Haenszel method was utilized. Pooled estimates were presented as risk ratios (RRs) with corresponding 95% confidence intervals (CIs). Sensitivity analyses using the leave-one-out method were conducted to identify any specific trial that contributed to greater heterogeneity. The effect sizes of the remaining trials were recalculated to assess the robustness and reliability of the findings.

To further assess the robustness of the meta-analysis results, the online tool The Fragility Index of Meta-analyses (https://clinicalepidemio.fr/fragility_ma/) was employed to exhibit the fragility index for statistically significant findings, and the reverse fragility index for non-significant findings. These indices helped determine the vulnerability or stability of the results and provided additional insights into the reliability of the findings [19, 20]. The fragility index or reverse fragility index was calculated as the minimum number of patients in one or more trials included in the meta-analysis, where a modification to the event status (i.e., changing an event to a non-event or vice versa) would alter the statistical significance of the pooled estimates. By identifying the minimum number of patients required to influence the statistical significance, these indices provided valuable information on the fragility of the results and their susceptibility to change [20]. The fragility index or reverse fragility index < 20 was considered a fragile outcome, and the fragility index or reverse fragility index ≥ 40 was a robust outcome [19, 20]. We combine it with the sample size to calculate the fragility quotient and reversed fragility quotient that can more accurately represent the proportion of events required to alter the effect sizes [19]. For instance, Meta-analysis A has a fragility index of 1 and a sample size of 1,000, whereas Meta-analysis B has a fragility index of 1 and a sample size of 10,000. Although both analyses had the same fragility index, the fragility quotient for Meta-analysis A was 0.001, indicating that it took 10 events per 10,000 patients to change the significance of the results, whereas the fragility quotient for Meta-analysis B was 0.0001, indicating that it only took 1 event per 10,000 patients to change the significance of the results [19]. Therefore, the determination of the fragility quotient can help interpret the robustness of the results.

Furthermore, a funnel plot was constructed to assess potential publication bias for each outcome, but this analysis was conducted only when the number of included studies exceeded 10. Additionally, we conducted three subgroup analyses based on the duration of treatment and number of patients to explore potential clinical benefits associated with these variables. To perform statistical analysis, we utilized RevMan 5.3 and Stata 16.0 software, ensuring accurate and reliable processing of the data in our meta-analysis.

Results

Literature search and study characteristics

The initial literature search yielded a total of 469 relevant articles. After applying our predefined eligibility criteria, 11 trials comprising 6511 participants were deemed suitable for inclusion in the present meta-analysis (Fig. 1). The risk of bias assessment for this meta-analysis is presented in Supplemental Fig. 1. All selected studies demonstrated an overall low risk of bias, with only one study showing potential performance bias. Supplemental Table 1 provides a comprehensive summary of the demographic characteristics, concomitant diseases, and medication combinations in the 11 eligible RCTs. Among all the trials that reported on intravenous iron therapy, only one trial (the PRACTICE-ASIA-HF trial) enrolled patients with acute HF, regardless of their left ventricular ejection fraction (LVEF). In contrast, the rest of the trials focused on individuals with chronic HF. Iron deficiency was generally defined as a serum ferritin level < 100 µg/L, regardless of transferrin saturation (TSAT), or a TSAT < 20% if the ferritin level ranged from 100∼300 µg/L. Among the 11 studies included in our analysis, intravenous administration of ferric carboxymaltose was used in 8 of them. The age of the included patients ranged from 40 to 82 years old, and the duration of follow-up varied from 3 weeks to 2.7 years. Most patients had such comorbidities as coronary heart disease, diabetes, hypertension, and dyslipidemia.

Fig. 1.

Study selection process for this systematic review

Primary and secondary endpoints

Intravenous iron therapy demonstrated significant effects in reducing HF hospitalizations and cardiovascular death (RR 0.82, 95% CI 0.75–0.89; P<0.01; I² = 34.86%), hospitalizations related to HF (RR 0.80, 95% CI 0.71–0.89; P<0.01; I² = 29.38%), cardiovascular hospitalizations and cardiovascular death (RR 0.80, 95% CI 0.66–0.96; P = 0.02; I² = 69.21%), with different degrees of significant between-study heterogeneities (Figs. 2, 3 and 4). The calculations of fragility indexes and fragility quotients similarly showed these results to be fragile (Table 1 and Supplemental Figs. 2–7). Through additional rigorous sensitivity analyses, heterogeneities were significantly minimized, revealing that intravenous iron treatment was associated with a 21% relative reduction in HF hospitalizations and cardiovascular death (RR 0.79, 95% CI 0.74–0.85; P<0.01; I² = 0%), a substantial 24% relative reduction in HF hospitalizations (RR 0.76, 95% CI 0.70–0.83; P <0.01; I² = 2.04%) and a 28% relative reduction in cardiovascular hospitalizations and cardiovascular death (RR 0.72, 95% CI 0.56–0.92; P = 0.01; I² = 35.91%), with low heterogeneities after exclusion from the HEART-FID trial and PRACTICE-ASIA-HF study(Figs. 2, 3 and 4). These pooled results with high fragility indexes and fragility quotients were robust (Table 1 and Supplemental Figs. 8–10).

Fig. 2.

Forest plots of studies evaluating HF hospitalizations and cardiovascular death in patients receiving intravenous iron therapy compared to those who received a placebo

Fig. 3.

Forest plots of studies assessing hospitalizations for HF in patients receiving intravenous iron therapy compared to those who received a placebo

Fig. 4.

Forest plots of studies assessing cardiovascular hospitalizations and cardiovascular death in patients receiving intravenous iron therapy compared to those who received a placebo

Table 1.

The robustness of the meta-analysis findings for clinical primary endpoints

Clinical primary endpoints	I2 value	FI/RFI	FQ/RFQ
HF hospitalizations and CV death	34.86%	33	0.0056
HF hospitalizations and CV death (except HEART-FID)	0	46	0.0165
HF hospitalizations	29.38%	9	0.0015
HF hospitalizations (except HEART-FID and PRACTICE-ASIA-HF)	2.04%	14	0.0049
CV hospitalizations and CV death	69.21%	12	0.0024
CV hospitalizations and CV death (except HEART-FID)	35.91%	11	0.0057
All-cause mortality	0.09%	7	0.0014

Footnote: HF: Heart failure; CV: Cardiovascular; FI: Fragility index; RFI: Reversed fragility index; FQ: Fragility quotient; RFQ: Reversed FQ

In a summary analysis of 8 trials, intravenous iron therapy exhibited a notable trend towards reducing all-cause mortality, with no evidence of heterogeneity among the studies (RR 0.90, CI 0.79–1.02; P = 0.11; I² = 0.09%; Fig. 5). Despite not achieving statistical significance, this summary outcome implied fragility, as demonstrated by the reverse fragility index of 7 and the reverse fragility quotient of 0.0014 (Table 1 and Supplemental Fig. 11).

Fig. 5.

Forest plots of studies assessing all-cause mortality in patients receiving intravenous iron therapy compared to those who received a placebo

Other clinical endpoints

Intravenous iron therapy demonstrated a substantial reduction in time to first HF hospitalizations or cardiovascular death (RR 0.83, 95% CI 0.72–0.97; P = 0.02; I² = 50%), with different degrees of significant between-study heterogeneities. The analyses conducted did not reveal any significant differences in terms of time to first hospitalization, time to first cardiovascular hospitalizations, time to first cardiovascular death, time to first hospitalizations or all-cause mortality, and time to first occurrence of cardiovascular hospitalizations or cardiovascular death. Additional sensitivity analyses revealed that intravenous iron treatment enhanced the beneficial effects related to time to first hospitalization (RR 0.65, 95% CI 0.51–0.84; P = 0.001; I² = 0%) after exclusion from the IRONMAN trial, and time to first HF hospitalizations or cardiovascular death (RR 0.78, 95% CI 0.63–0.95; P = 0.01; I² = 41%) after exclusion from the HEART-FID trial (Supplemental Tables 2 and Supplemental Figs. 12–20).

Subgroup analyses

Intravenous iron therapy demonstrated favorable effects in HF hospitalizations and cardiovascular death (RR 0.82, 95% CI 0.75–0.90; P<0.01), HF hospitalizations (RR 0.79, 95% CI 0.70–0.89; P<0.01), cardiovascular hospitalizations and cardiovascular death (RR 0.82, 95% CI 0.69–0.97; P<0.01) in patients with a duration of treatment ≥ 24 weeks. However, these benefits were not observed in patients treated with intravenous iron for less than 24 weeks (Fig. 6).

Fig. 6.

Forest plots of studies assessing primary endpoints in subgroups categorized based on 24-week treatment durations: (A) the effect of intravenous iron therapy on HF hospitalizations; (B) the effect of intravenous iron therapy on HF hospitalizations and cardiovascular death; (C) the effect of intravenous iron therapy on cardiovascular hospitalizations and cardiovascular death; (D) the effect of intravenous iron therapy on all-cause mortality

Clinical benefits of intravenous iron therapy on HF hospitalizations (RR 0.79, 95% CI 0.70–0.89; P<0.01), cardiovascular hospitalizations and cardiovascular death (RR 0.82, 95% CI 0.69–0.97; P = 0.02) were equally observed when considering that the number of individuals in the study exceeded 200 cases. Likewise, the impact of treatment on HF hospitalizations and cardiovascular death, and all-cause mortality remained consistent regardless of the size of the sample (Fig. 7).

Fig. 7.

Forest plots of studies assessing primary endpoints in subgroups categorized based on a sample size of 200 patients: (A) the effect of intravenous iron therapy on HF hospitalizations; (B) the effect of intravenous iron therapy on HF hospitalizations and cardiovascular death; (C) the effect of intravenous iron therapy on cardiovascular hospitalizations and cardiovascular death; (D) the effect of intravenous iron therapy on all-cause mortality

Safety endpoints

The administration of intravenous iron had minimal impacts on infection (RR 0.89, 95% CI 0.74–1.08; P = 0.26; I² = 0%), general disorders and administration site conditions (RR 1.31, 95% CI 0.94–1.83; P = 0.11; I² = 38%), injury, poisoning and procedural complications (RR 0.97, 95% CI 0.69–1.35; P = 0.85; I² = 0%), with no significant between-study heterogeneity (Supplemental Fig. 21).

Discussion

This systematic review and meta-analysis revealed that intravenous iron therapy effectively reduced rehospitalization related to HF and cardiovascular causes. Furthermore, the intravenous administration of iron exhibited a potential reduction in cardiovascular mortality when evaluated alongside the hospitalization risk as a composite endpoint. The prevailing intravenous iron utilized in current trials for treating HF patients with iron deficiency was ferric carboxymaltose. Despite potential confounding factors arising from variations across studies, subgroup analyses revealed a cardiovascular protective effect, particularly in studies with long-term use in larger sample sizes. In addition, intravenous iron did not increase the incidence of adverse events. These findings thus imply that intravenous iron repletion represents a promising strategy to further mitigate residual risks associated with HF when used in conjunction with other medications for clinical management.

Despite significant advancements in therapeutic approaches for HF that greatly improve its prognosis, recurrent hospitalization and mortality rates remain high [7, 21]. Iron deficiency exerts a negative impact on the prognosis of HF and poses a significant obstacle to achieving cardiovascular benefits through current treatments for HF patients [7, 22]. The 2017 IRONOUT HF trial found that oral iron supplements had no improvement in exercise tolerance or clinical outcomes in patients with HF and iron deficiency [23–25]. In our systematic review and meta-analysis, we excluded any RCTs investigating the use of oral iron therapy because oral iron therapy is not recommended in the guidelines of the European Society of Cardiology (2023) for HF and iron deficiency [15, 23, 25]. In addition, including such studies would introduce unnecessary heterogeneity to our analysis and complicate the interpretation of the results [5, 22]. Both the AFFIRM-AHF trial and the IRONMAN trial demonstrated that intravenous iron derivatives effectively relieved clinical symptoms and reduced HF-related hospitalizations, with no effects on mortality [19, 24, 26]. However, the recent HEART-FID trial, the largest RCT involving patients with both HF and iron deficiency, reported that intravenous iron therapy showed no significant impact on the mortality or rehospitalization rates [10, 16]. Our meta-analysis indicates that intravenous iron therapy was associated with substantial reductions in rates of cardiovascular death and HF hospitalizations (21%), HF hospitalizations (24%), and cardiovascular death and hospitalizations (28%). This finding was inconsistent with a previous recent meta-analysis, which demonstrated no significant association between intravenous iron therapy and cardiovascular death [16]. The reason for this difference may be that this meta-analysis was conducted before the results of the HEART-FID trial were available to the public. In addition, this meta-analysis enrolled a large group of patients with both acute and chronic HF and did not differentiate these heterogeneous patients by sensitivity analyses, which could lead to significant between-study heterogeneity and bias in the results.

Interpreting positive or negative results from P-values alone has certain limitations, and aspects of reproducibility and statistical reliability of studies tend to be over-emphasized. Accordingly, the fragility index was proposed in 2014 as a complementary indicator for interpreting the results of a study. Fragility index is defined as the minimum number of events required to raise the P-value to ≥ 0.05. A larger fragility index value indicates a more robust result; conversely, a smaller fragility index value indicates a more fragile result. The fragility index value and its derived fragility quotient value are complementary reflections of the robustness of statistically significant findings and are not an alternative to the P-value. Our results of the above primary endpoints had high fragility indexes and fragility quotients, but significant heterogeneities among the included studies existed. The inconsistencies observed in our analysis can be attributed to various factors, including differences in sample size, treatment protocols (co-administration of oral medications, dosage, and course of intravenous), severity of iron deficiency, type of HF, patient demographics, and even study designs [16, 19, 24, 26]. Subsequent sensitivity analyses showed a notable reduction in heterogeneities while maintaining consistent clinical outcomes. Notably, this reduction in heterogeneity was mainly achieved by excluding the HEART-FID trial from the analysis. After conducting a comprehensive review and comparison of the HEART-FID trial with other studies, the frequent administration of sacubitril-valsartan in the HEART-FID trial potentially influenced the assessment of the positive rate of clinical events in our meta-analysis [16]. While the HEART-FID trial and AFFIRM-AHF trial used the same type of intravenous iron, it is important to highlight that there were notable differences in the dosage and timing of ferrous carboxymethylene administration between the two trials [16, 26].In the HEART-FID trial, patients with HF had a higher mean transferrin saturation at baseline compared to other studies included in our analysis, which contributed to the observed mild clinical benefit of iron supplementation in this trial [11, 16, 24, 26, 27]. Additionally, the PRACTICE-ASIA-HF study contributed to the large heterogeneity because it recruited patients with acute HF, which was different from the remaining studies. It is worth noting that a significant proportion of the heart failure population included in the HEART-FID trial was recruited during the COVID-19 pandemic. This unique circumstance may potentially impact the reporting of hospitalization rates and mortality outcomes [16, 22]. The included trials used different definitions for key outcomes such as heart failure hospitalization, cardiovascular death, and iron deficiency. These inconsistencies can introduce challenges in comparing and pooling data, potentially affecting the validity of the meta-analysis findings.

Strengths and weaknesses

Iron supplementation is primarily utilized to correct cellular energetic and oxidative metabolism deficiencies related to iron deficiency, rather than serving as a therapeutic manipulation directly targeting the pathogenesis of HF [19, 28]. Correcting iron deficiency state may enhance the efficacy of drugs that aim to reverse myocardial remodeling. One particularly noteworthy finding from our meta-analysis was the potential cardioprotective effect of intravenous iron therapy against cardiovascular death, which was supportive of the IRONMAN trial [24]. Our study’s conclusion was based on the assessment of composite endpoints, which may have been impacted by readmissions. Due to the unavailability of individual patient data from the eligible RCTs, our analysis was unable to directly assess the efficacy of intravenous iron repletion on cardiovascular death [22]. In addition, our data revealed a numerical benefit but did not demonstrate statistical significance in all-cause mortality. The calculations of the fragility index and fragility quotient in the result of all-cause mortality are fragile. These meant that a small change in the number of events could shift this result from non-statistically significant to significant [20]. This fragility raised concerns about the robustness of the conclusions drawn from these data points. The reliance on fragile data might weaken the strength of the clinical recommendations based on this finding. If the result was easily altered by minor changes in data, their applicability in real-world clinical settings became questionable. This fragile result can be interpreted in light of the definition of all-cause mortality, which encompasses a broad range of deaths unrelated to HF. The pooled estimates may be influenced by heterogeneities arising from different definitions of all-cause mortality used in the included studies. Therefore, caution is warranted when interpreting the findings in relation to all-cause mortality in this context. Therefore, whether the benefits of iron treatment for HF in improving mortality outcomes are conclusive remains uncertain. Subgroup analyses suggested that longer-term use in larger sample sizes was associated with more pronounced benefits of intravenous iron therapy. The iron supplement with the best clinical evidence at present was ferric carboxymaltose. While previous studies revealed that iron supplementation could lead to excessive tissue iron deposition and subsequent free radical-induced tissue damage [26, 27, 29], our result confirmed that up to 2.7 years of intravenous iron use did not increase the risk of iron overload cardiomyopathy. However, given the risk of myocardial iron overload, we also favored the need for MR-based monitoring of myocardial iron in HF patients receiving intravenous iron therapy, rather than relying solely on changes in plasma ferritin levels [17]. There was the need for further investigation into the optimal dosing and duration of iron therapy in HF patients.

The limitations still exist. Firstly, the populations included in the eligible trials exhibited heterogeneity in the type of HF, specifically in terms of preserved ejection fraction versus reduced ejection fraction HF [5, 19, 30]. Due to the unavailability of individual participant data, we were unable to conduct a direct comparison of the efficacy of intravenous iron treatment in different categories of HF within our analysis. Secondly, the variation in the dosage and administration protocols of intravenous iron treatment among the included studies may have contributed to significant heterogeneity in our results. Thirdly, six trials included in our analysis had a recruitment size of fewer than 200 individuals with HF [11, 31–35]. Additionally, the recent large-scale trials included in our analysis enrolled a significant number of patients with COVID-19, which poses a challenge in determining whether the pandemic may have influenced our findings [16, 24, 26]. Therefore, it is crucial not to underestimate the significance of sample deviation and the potential for Type I error. In order to obtain more accurate estimates of the efficacy of intravenous iron administration, it is imperative that future RCTs prioritize comprehensive clinical designs and incorporate long-term observation of hospitalizations and mortality outcomes [36].

Conclusion

The results from our analysis reveal that intravenous iron therapy may decrease the risk of rehospitalization for HF and result in a lower likelihood of cardiovascular death, but this treatment may not be applicable to all HF populations. We recommend that clinicians consider incorporating intravenous iron therapy into clinical treatment decisions for patients with chronic HF and iron deficiency, pending further research to confirm these findings.

Authors’ contributions

HW, YL, XG and RZ contributed to the study conception and design, and writing the manuscript. HW, YL, JW, JL, JZ and JS performed data collection and analysis. HW, YL, XG and RZ commented on the research design, data analysis, writing the manuscript, and supervision of the study. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by the National Key Research and Development Program of China (grant numbers 2021YFC2701700 and 2021YFC2701703).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

Not applicable.