Iron deficiency is highly prevalent among heart failure patients and is associated with worse quality of life and a higher risk of hospitalizations and mortality. Early randomized clinical trials (RCTs)1–4 evaluating the efficacy of intravenous iron replacement in heart failure patients with iron deficiency showed promising results in improving objective clinical outcomes, including heart failure hospitalizations and cardiovascular mortality. However, they were not explicitly powered for these outcomes. The 2017 ACC/AHA/HFSA focused guideline update provides a IIb recommendation for intravenous iron repletion in NYHA class II and III heart failure patients and iron deficiency to improve functional status and quality of life.5 Most recently, the results of the AFFIRM-AHF (A Randomized, Double-blind Placebo-Controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient Subjects Admitted for Acute Heart Failure) was presented in the American Heart Association Scientific Sessions and has refueled the interest regarding the utility of intravenous iron therapy in patients with heart failure.4 We aimed to pool results from all randomized controlled trials evaluating the efficacy of intravenous iron in improving cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF).
We performed a comprehensive electronic database search for RCTs comparing the outcomes of intravenous iron therapy to standard of care in patients HFrEF who were diagnosed with iron deficiency. Iron deficiency was defined as (serum ferritin level,100 ng/ml, or between 100 and 300 ng/ml if transferrin saturation <20%). We only included RCTs, which enrolled more than 100 patients to avoid the small studies effect. Two authors extracted and analyzed the data using STATA v15.1 software. The outcomes of interest were all-cause mortality, cardiovascular mortality, and heart failure hospitalization. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model.
We identified 4 RCTs with 2,042 patients, mean duration of follow up (31± 14 weeks) (age 69 ± 3 years; females 51%). Compared with the standard of care, intravenous iron therapy was associated with a significant reduction of heart failure hospitalization (RR 0.69, 95% CI 0.61 to 0.78, p = 0.043; Figure 1). There was no difference between intravenous iron therapy and standard of care in all-cause mortality (RR 0.67, 95% CI 0.36 to 1.23, p = 0.37) and cardiovascular mortality (RR 0.90, 95% CI 0.19 to 1.18, p = 0.40; Figure 1).
Figure 1.
Forest plot summarizing the main findings from the meta-analysis.
The exact mechanism by which intravenous iron supplementation improves functional status and clinical outcomes in heart failure patients is unclear. Several mechanisms have been proposed, including improving oxygen transport and metabolism through increased hemoglobin, especially in cells with high oxygen requirements, like cardiac and skeletal myocytes. Randomized trials examining the role of oral iron on improving clinical endpoints in heart failure patients have failed to show benefit likely due to poor absorption of oral iron in the setting of chronic inflammatory state associated with heart failure.1–4
In conclusion, in patients with HFrEF and iron deficiency, treatment with intravenous iron therapy has reduced the risk of heart failure hospitalization by almost 30% with no difference in all-cause mortality and cardiovascular mortality compared to standard of care.
Footnotes
Disclosures
The authors have no conflicts of interest to report.
References
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