Abstract
Aims
There is considerable variability in the effect of intravenous iron on hard cardiovascular (CV)‐related outcomes in patients with heart failure (HF) in randomized controlled trials (RCTs). We use a meta‐analytic approach to analyse data from existing RCTs to derive a more robust estimate of the effect size of intravenous iron infusion on CV‐related outcomes in patients with HF.
Method and results
PubMed/Medline was searched using the following terms: (‘intravenous’ and ‘iron’ and ‘heart failure’) from inception till 6 November 2022 for RCTs comparing intravenous iron infusion with placebo or standard of care in patients with HF and iron deficiency. Outcomes were the composite of CV mortality and first hospitalization for HF; all‐cause mortality; CV mortality; first hospitalization for HF; and total hospitalizations for HF. Random effects risk ratio (RR) with 95% confidence intervals (CIs) were calculated. Ten RCTs with a total of 3438 patients were included. Intravenous iron resulted in a significant reduction in the composite of CV mortality and first hospitalization for HF [RR 0.0.85; 95% CI (0.77, 0.95)], first hospitalization for HF [RR 0.82; 95% CI (0.67, 0.99)], and total hospitalizations for HF [RR 0.74; 95% CI (0.60, 0.91)] but no statistically significant difference in all‐cause mortality [RR 0.95; 95% CI. (0.83, 1.09)] or CV mortality [OR 0.89; 95% CI (0.75, 1.05)].
Conclusions
Intravenous iron infusion in patients with HF reduces the composite risk of first hospitalization for HF and CV mortality as well as the risks of first and recurrent hospitalizations for HF, with no effect on all‐cause mortality or CV mortality alone.
Keywords: Heart failure, Iron deficiency, Iron infusion, Outcomes, Mortality, Hospitalization, Meta‐analysis
Background
Iron deficiency is a common co‐morbidity in patients with heart failure (HF) with an estimated prevalence of 40–60% irrespective of anaemia status and across left ventricular ejection fraction categories. 1 Iron deficiency is associated with suboptimal quality of life, poor functional status, and an increased risk of hospitalizations for HF and mortality. 1 , 2 Clinical trials and meta‐analyses have generally shown that intravenous iron infusion with various iron preparations leads to an early and sustained improvement in signs and symptoms, quality of life, and functional capacity and may decrease cardiovascular (CV)‐related and HF‐related morbidity among patients with HF. 3 Although most prior studies have been adequately powered to convincingly demonstrate the effect of intravenous iron infusion on symptom burden and quality of life measures, there have been considerable variability in its effect on hard CV‐related outcomes, including mortality, across prior studies with most of them not being powered for hard outcomes.
Aims
Herein, we use a meta‐analytic approach to analyse data from existing randomized controlled trials (RCTs), including the recently published IRONMAN trial, 4 to derive a more robust estimate of the effect size of intravenous iron infusion on CV‐related outcomes in patients with HF.
Method
We searched Medline/PubMed from inception till 6 November 2022 using the following terms: (‘intravenous’ and ‘iron’ and ‘heart failure’). We limited the search to RCTs; no other search restrictions were applied. The prespecified selection criteria included (i) RCTs; (ii) studies comparing intravenous iron infusion with placebo or standard of care (control) in patients with concurrent HF and iron deficiency; and (iii) studies reporting prespecified outcomes of interest. The main outcomes of interest were the composite of CV mortality and first hospitalization for HF; all‐cause mortality; CV mortality; first hospitalization for HF; and total hospitalizations for HF.
Two investigators (H.M.S) and (M.F.) independently performed the study search and selection, abstracted the data, and appraised the accuracy of the abstractions and the potential risks of bias of the RCTs using the Version 2 of the Cochrane risk‐of‐bias tool for randomized trials (RoB 2) and assessed the quality of the evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach (GRADEpro GDT). Quality of evidence was classified as high, moderate, low, or very low.
Statistical analyses were conducted using the Review Manager software (version 5.4, The Cochrane Collaboration, 2020). Mantel–Haenszel risk ratios (RRs) and 95% confidence intervals (CIs) were used to summarize outcomes utilizing a random‐effects modelling approach. Heterogeneity was assessed using Cochrane Q statistic, and Higgins and Thompsons' I 2, and was considered to be low if I 2 was less than 25%, moderate if I 2 was between 25 and 75%, and high if I 2 was greater than 75%. Publication bias could not be assessed as the current meta‐analyses with <10 RCTs in each analysis is underpowered to detect such bias.
Results
The initial search yielded 395 studies. After restricting the search to RCTs using the National Center for Biotechnology Information (NCBI) filters, 45 studies were identified, of which only 10 RCTs with a total of 3438 patients with HF met our inclusion criteria and were included in the meta‐analysis (Figure 1 ). 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 Characteristics of the included studies are summarized in Table 1 . In total, 1801 (52.4%) of the included patients were in the intravenous iron infusion arm. Iron sucrose was used in two RCTs (N = 75; 2.2%), 8 , 13 ferric carboxymaltose was used in six RCTs (N = 2192; 63.8%), 5 , 6 , 7 , 10 , 11 , 12 ferric derisomaltose was used in one RCT (N = 1137; 33.1%), 4 and ferric gluconate was used in one RCT (N = 34; 0.9%). 9 Eight RCTs included patients with HFrEF only, 4 , 6 , 7 , 8 , 10 , 11 , 12 , 13 whereas two RCTs included patients with HF regardless of their ejection fraction. 5 , 9 Nine RCTs were deemed to have a low risk of bias, whereas one RCT was deemed to have a high risk of bias (Figure 2 ).
Figure 1.
Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) flow diagram for the included studies.
Table 1.
Baseline characteristics of the included studies
| Study | Toblli et al. | FERRIC‐HF | FAIR‐HF | CONFIRM‐HF | EFFECT‐HF | PRACTICE‐ASIA‐HF | AFFIRM‐AHF | IRON‐CRT | Marcusohn et al. | IRONMAN |
|---|---|---|---|---|---|---|---|---|---|---|
| Year | 2007 | 2008 | 2009 | 2015 | 2017 | 2018 | 2020 | 2021 | 2022 | 2022 |
| Iron preparation | Iron sucrose | Iron sucrose | Ferric carboxymaltose | Ferric carboxymaltose | Ferric carboxymaltose | Ferric carboxymaltose | Ferric carboxymaltose | Ferric carboxymaltose | Ferric gluconate | Ferric derisomaltose |
| Dosing strategy | 200 mg weekly for 5 weeks | Correction phase: weekly infusion unless ferritin was ≥500 ng/mL; maintenance phase: infusion at weeks 4, 8, 12, and 16 | Correction phase: weekly dosing frequency until iron repletion; maintenance phase: every 4 weeks dosing frequency starting at week 8 or week 12 (depending on the required iron‐repletion dose) | Therapy phase: total doses between 500 and 2000 mg; maintenance dosing of 500 mg at weeks 12, 24, and 36 if iron deficiency was still present | Doses at day 0 and week 6 based on screening weight and screening haemoglobin | Single dose of 1000 mg | Repletion doses: one dose was administered before discharge and another dose was administered at week 6; maintenance doses: doses at weeks 12 and 24 when iron deficiency persisted | Dose was determined based on screening weight and screening haemoglobin. Patients who required a dose of more than 1,000 mg received the remaining dose after 1–2 weeks of the initial dose | 3–5 doses of 125 mg during index hospitalization | Initial dose based on screening weight and haemoglobin followed by doses at 4 weeks after random assignment and every 4 months thereafter until trial conclusion based on ferritin levels and transferrin saturation |
| Type of patients (based on left ventricular ejection fraction) | Patients with left ventricular ejection fraction of ≤35% | Patients with left ventricular ejection fraction of ≤45% | Ambulatory patients with left ventricular ejection fraction of ≤40% (for NYHA class II) or ≤45% (for patients in NYHA class III) | Ambulatory patients with left ventricular ejection fraction of ≤45% | Patients with left ventricular ejection fraction of ≤45% | Patients hospitalized for acute heart failure, regardless of ejection fraction | Patients with left ventricular ejection fraction of <50% who were hospitalized for acute heart failure | Patients with left ventricular ejection fraction of <45% who received cardiac resynchronization therapy | Patients hospitalized for acute heart failure, regardless of ejection fraction | Patients with left ventricular ejection fraction of ≤45% |
| Participants (N) | 40 | 35 | 459 | 304 | 172 | 50 | 1132 | 75 | 34 | 1137 |
| Iron group (N) | 20 | 24 | 305 | 150 | 86 | 25 | 567 | 37 | 18 | 569 |
| Control group (N) | 20 | 11 | 154 | 151 | 86 | 25 | 565 | 38 | 16 | 568 |
| Age, years | Iron group: 76; control group: 74 | Iron group: 64; control group: 62 | Iron group: 67.8; control group: 67.4 | Iron group: 68.8; control group 69.5 | Iron group: 63; control group: 64 | Iron group: 61.1; control group: 64 | Iron group: 71.2; control group: 70.9 | Iron group: 72; control group: 73 | Iron group: 70; control group: 74.5 | Iron group: 73.2; control group: 73.5 |
| Women (%) | Not reported | Iron group: 29%; control group: 27% | Iron group: 52.3%; control group: 54.8% | Iron group: 45%; control group: 49% | Iron group: 30%; control group: 20% | Iron group: 25%; control group: 20% | Iron group: 44%; control group: 45% | Iron group: 30%; control group: 34% | Iron group: 33.3%; control group: 31.2% | Iron group: 25%; control group: 28% |
| Race | Not reported | Iron group: 88% White; control group: 91% White | Iron group: 99.7% White; control group: 100% White | Iron group: 99% White; control group: 99% White | Not reported | Iron group: 41/7% Chinese, 12.5% Indian, 41.7% Malay, and 4.2% others; control group: 60% Chinese, 16% Indian, 24% Malay | Iron group: 95% White, 5% Asian, 1% others; control group: 95% White, 4% Asian, 1% others | Not reported | Not reported | Iron group: 91% White, 2% Black, 6% Asian, and 1% others; control group: 92% White, 1% Black, 5% Asian, and 1% others |
| Follow‐up | 26 weeks | 18 weeks | 24 weeks | 52 weeks | 24 weeks | 12 weeks | 52 weeks | 13 weeks | 24 weeks | 2.7 years |
Figure 2.
Panel A: Risk of bias assessment using the Risk of Bias 2.0 tool. Panel B: Funnel plot for publication bias assessment.
Compared with control, intravenous iron infusion in patients with HF resulted in a significant reduction in the composite of CV mortality and first hospitalization for HF (RR 0.85; 95% CI [0.77, 0.95]; I 2 = 0%; GRADE quality level: high), first hospitalization for HF (RR 0.82; 95% CI [0.67, 0.99]; I 2 = 8%; GRADE quality level: high), and total hospitalizations for HF (RR 0.74; 95% CI [0.60, 0.91]; I 2 = 47%; GRADE quality level: moderate due to serious inconsistency), but no statistically significant difference in all‐cause mortality (RR 0.95; 95% CI. [0.83, 1.09]; I 2 = 0%; GRADE quality level: high) or CV mortality (RR 0.89; 95% CI [0.75, 1.05]; I 2 = 0%; GRADE quality level: high; Figure 3 ). The AFFIRM‐AHF study did not report all‐cause mortality in the main publication 11 ; however, we extracted all‐cause mortality from a subsequent pre‐specified analysis of the trial. 14
Figure 3.
Forest plots examining the cardiovascular outcomes of intravenous iron infusion in patients with heart failure. M–H: Mantel–Haenszel; CI, confidence interval; M–H: Mantel–Haenszel.
Given that our meta‐analysis included mostly small studies, which tend to overestimate the effect size in meta‐analyses, we performed a sensitivity analysis by only including the AFFIRM‐AHF and IRONMAN trials, both of which had the greatest weights, with consistent results across all the outcomes of interest.
Conclusions
The current meta‐analysis demonstrates that intravenous iron infusion in patients with HF and iron deficiency (regardless of the presence of anaemia) results in a 15% reduction in the risk of the composite of CV mortality and first hospitalization for HF; this reduction is mostly driven by reduction in the risk of first hospitalization for HF. In addition, intravenous iron infusion results in a 26% reduction in the risk of total hospitalizations for HF.
The results of this meta‐analysis are in agreement with the updated 2022 American guidelines for the management of HF that recommend to include iron studies in the laboratory evaluation of patients diagnosed with HF and to consider intravenous iron replacement in patients with HFrEF and iron deficiency (class of recommendation: 2a) 15 ; they also align with the 2021 European guidelines for the management of HF that recommend periodical screening for iron deficiency in patients with HF (class of recommendation 1) and to consider intravenous iron replacement in (i) symptomatic HF patients with left ventricular ejection fraction (LVEF) of <45% and concurrent iron deficiency and (ii) symptomatic HF patients with LVEF of <50% and concurrent iron deficiency who had a recent hospitalization for HF (class of recommendation 2a for both). 16 Although there was a trend of improvement in all‐cause mortality and CV mortality in the intravenous iron arm, neither reached statistical significance, which might be related to underpower. Further insights into the effect of intravenous iron on these outcomes will be obtained from the ongoing large‐scale HEART‐FID (NCT03037931) and FAIR‐HF2 (NCT03036462) trials. Nonetheless, the significant reduction in the risk of hospitalization for HF with intravenous iron infusion, similar in magnitude to that observed with other guideline‐directed medical therapies, represents an important opportunity to address the uprising trend of hospitalization for HF in the recent years. 17
There are several limitations in the present analysis that should be acknowledged. First, we used published summary data rather than individual patient level data to conduct a study‐level meta‐analysis. As opposed to patient‐level meta‐analysis, study‐level meta‐analysis does not allow for line‐by‐line patient data collection and limits a consistent identification of the intervention and outcomes across the included RCTs. Second, there were slight differences in the definition of iron deficiency among different RCTs, but it was generally defined as a serum ferritin level of <100 μg/L, or a serum ferritin level of 100–300 μg/L if the transferrin saturation is <20%; there were also differences in the percentage of patients with anaemia in each trial. Third, different preparations and dosing strategies of intravenous iron were used in different RCTs. Fourth, included RCTs had variable predefined endpoints and follow‐up durations that ranged from 12 weeks to 2.7 years. Fifth, our meta‐analysis included mostly small studies, which tend to overestimate the effect size in meta‐analyses 18 ; however, the sensitivity analysis by only including the AFFIRM‐AHF and IROMAN trials (the largest trials with greatest weights) yielded consistent results. Finally, the patient population in the included RCTs was largely an HFrEF population, which limits the generalizability of our analysis to the HFpEF population. Dedicated clinical trials are needed to address the effect of intravenous iron infusion in patients with HFpEF. To that end, the ongoing IRONMET‐HFpEF trial (NCT04945707) aims to examine the effect of intravenous ferric derisomaltose on exercise capacity in patients with HFpEF.
In summary, intravenous iron infusion in patients with HFrEF reduces the composite risk of first hospitalization for HF and CV mortality as well as the risks of first and recurrent hospitalizations for HF, with no effect on all‐cause mortality or CV mortality alone. The effect of intravenous iron infusion in patients with HFpEF remains uncertain.
Conflict of interest
MF was supported by the National Heart, Lung, and Blood Institute (NHLBI) (K23HL151744), the American Heart Association (20IPA35310955), Mario Family Award, Duke Chair's Award, Translating Duke Health Award, Bayer, Bodyport, and BTG Specialty Pharmaceuticals. He receives consulting fees from Abbott, AxonTherapies, Bodyguide, Bodyport, Boston Scientific, CVRx, Daxor, Edwards LifeSciences, Feldschuh Foundation, Fire1, Gradient, Inovise Medical, Intershunt, NXT Biomedical, Pharmacosmos, PreHealth, Splendo, Vironix, and Viscardia, Zoll. All other authors report no conflict of interest.
Salah, H. M. , Savarese, G. , Rosano, G. M. C. , Ambrosy, A. P. , Mentz, R. J. , and Fudim, M. (2023) Intravenous iron infusion in patients with heart failure: a systematic review and study‐level meta‐analysis. ESC Heart Failure, 10: 1473–1480. 10.1002/ehf2.14310.
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