Effect of intravenous iron replacement on recurrent heart failure hospitalizations and cardiovascular mortality in patients with heart failure and iron deficiency: A Bayesian meta‐analysis

Abstract

AimsIron deficiency is common in patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with a poor prognosis. Whether intravenous iron replacement improves recurrent HF hospitalizations and cardiovascular mortality of these patients is uncertain although several trials were conducted. Moreover, none of the trials were powered to assess the effect of intravenous iron in clinically important subgroups. Therefore, we conducted a Bayesian analysis to derive precise estimates of the effect of intravenous iron replacement on recurrent HF hospitalizations and cardiovascular mortality in iron‐deficient HFrEF patients using consistent subgroup definitions across trials.Methods and resultsIndividual participant data were used from the FAIR‐HF (n = 459), CONFIRM‐HF (n = 304) and AFFIRM‐AHF (n = 1108) trials. These data were re‐analysed following as closely as possible the approach taken in the analyses of IRONMAN (n = 1137), for which study level data were used. Definitions of outcomes and subgroups from the FAIR‐HF, CONFIRM‐HF and AFFIRM‐AHF were matched with those used in IRONMAN. The primary endpoint was recurrent HF hospitalizations and cardiovascular mortality. The analysis of recurrent events was based on rate ratios (RR) derived from the Lin‐Wei‐Yang‐Ying model, and the data were pooled using Bayesian random‐effects meta‐analysis. Compared with placebo, intravenous iron significantly reduced the rates of recurrent HF hospitalizations and cardiovascular mortality (RR 0.73, 95% credible interval [CI] 0.48–0.99; between‐trial heterogeneity tau = 0.16). The pooled treatment effects did not provide evidence for any differential effects for subgroups based on sex (ratio of rate ratios [RRR] 1.49 [95% CI 0.95–2.37], age <69.4 vs. ≥69.4 years) (RRR 0.68 [0.40–1.15]), ischaemic versus non‐ischaemic aetiology of HF (RRR 0.73 [0.42–1.33]), transferrin saturation <20% vs. ≥20% (RRR 0.75 [0.40–1.34]), estimated glomerular filtration rate ≤60 versus >60 ml/min/1.73 m2 (RRR 0.97 [0.56–1.68]), haemoglobin <11.8 versus ≥11.8 (RRR 0.95 [0.53–1.60]), ferritin <35 versus ≥35 μg/L (RRR 1.26 [0.72–2.48]) and New York Heart Association class II versus III/IV (RRR 0.91 [0.54–1.56]).ConclusionsTreatment of iron‐deficient HFrEF patients with intravenous iron – namely with ferric carboxymaltose or ferric derisomaltose – results in significant reduction in recurrent HF hospitalizations and cardiovascular mortality. Results were nominally consistent across the subgroups studied, but for several of these subgroups uncertainty remains present.

Ironing out the wrinkles: Unanswered questions in intravenous iron repletion in heart failure

“…In this issue of the Journal, Anker et al 13 conduct a Bayesian meta-analysis, pooling individual patient level data from three IV iron supplementation trials in HFrEF (FAIR-HF, CONFIRM-HF, and AFFIRM-AHF) with study level data from the recently published IRONMAN to assess a composite primary endpoint of recurrent HF hospitalizations and CV death. Using a Bayesian approach, the authors estimate not only the mean effect of IV iron over all four trials, but also the predicted true treatment effect, by incorporating metrics of uncertainty and heterogeneity from the four trial into their analysis.…”

July 2023 at a glance: heart failure with preserved ejection fraction and comorbidities

“…1,31,33 In a Bayesian meta-analysis pooling data from randomized controlled trials performed to date, treatment of iron deficiency with intravenous iron was associated with a significant reduction in recurrent HF hospitalizations and CV mortality. 34…”

Combating therapeutic inertia: Optimizing iron deficiency treatment in heart failure

“…Iron deficiency (ID) is a common condition in patients with heart failure (HF) and has been associated with poor prognosis and impaired quality of life, regardless of the presence of anaemia 1,2 . Intravenous (IV) iron replacement therapy with ferric carboxymaltose has shown improvements in symptoms, functional capacity and overall health status in patients with HF and reduced and mildly reduced ejection fraction 2–4 . However, the implementation of guideline recommendations for testing and treating ID in HF patients remains challenging in real‐world clinical practice.…”