Meta-analysis: IV iron in HFrEF with iron deficiency

Jankowska EA, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur H Heart Fail 2016;18:786-95.

Bottom line: In patients with HFrEF who have iron deficiency, IV iron therapy for up to 1 year:

  • has no clear effect on all-cause or CV mortality;

  • reduces the risk of HF hospitalizations (NNT 10), but the effect on all-cause hospitalization remains uncertain;

  • improves quality of life, functional capacity & walking distance, although individual patients may only notice modest effects.

    Context

    • Iron deficiency (as defined below) HF is:
      • Present in half of patients with HF (46% of those without anemia);
      • Associated with higher NYHA class (i.e. worse symptom burden) & higher serum natriuretic peptide concentrations;
      • Associated with higher risk of death, independent from serum hemoglobin.

    Design

    • Search timeframe: 1950 to September 2014
    • Databases searched: PubMed, Embase, Cochrane, Web of Science, FDA.gov, ClinicalTrials.gov
    • Additional measures: Handsearch of published reviews & meta-analyses
    • Eligibility criteria:
      • Published in English
      • Design: Randomized controlled trial (RCT), at least single-blind
      • Population: HF with LVEF 45% or less ("HFrEF")
      • Intervention: IV iron without erythropoiesis-stimulating agents
    • 5 trials identified (including the large trials FAIR-HF & CONFIRM-HF)
    • Risk of bias (Table 2 of article):

    Risk of bias table (Table 2) from Jankowska et al.

    Patients (n=851)

    • Inclusion criteria of 2 largest trials:
      • FAIR-HF: HF with LVEF <45%, NYHA 2-3, anemia (hemoglobin (Hb) 95-135 g/L, iron deficiency (ferritin <100 ug/L, or ferritin 100-299 ug/L with TSAT <20%)
      • CONFIRM-HF: HF with LVEF <45%, NYHA 2-3, Hb <150 g/L, iron deficiency as in FAIR-HF
    • Baseline characteristics in FAIR-HF:
      • Age 67, female 55%
      • Ischemic cardiomyopathy ~80%, prior MI ~58%
      • NYHA 2 (19%) or 3 (81%); 6MWT distance 270 metres
      • LVEF ~33%
      • Hb 119 g/L, MCV 92 um^3, serum ferritin ~60 ug/L, TSAT ~17%
      • eGFR 65 mL/min/1.73 m^2
      • Meds: ACEI/ARB >90%, beta-blocker ~85%, MRA ? (not reported), digoxin ~15%, anticoagulant 14-22%
    • Baseline characteristics in CONFIRM-HF:
      • Age 69, female 45-50%
      • Ischemic cardiomyopathy 83%, prior MI 60%
      • NYHA 2 (~55%) or 3 (~45%); 6MWT distance ~290 metres
      • LVEF ~37%
      • Hb 124 g/L, serum ferritin 57 ug/L, TSAT 18-20%
      • eGFR ~65 mL/min/1.73 m^2
      • Meds: ACEI 77%, ARB 23%, beta-blocker ~90%, MRA ?, digoxin 19-27%, antiplatelet/anticoagulant 95%

    Interventions

    • Intervention: IV iron
      • Ferric carboxymaltose in 2 trials, iron sucrose in 3 trials
      • Dose varied between studies (e.g. mean 1850 mg given over 24 weeks in FAIR-HF, mean 1500 mg given over 1 year in CONFIRM-HF)
    • Control: Matching placebo infusion

    Results @ 4-12 months

    Other studies

    • Another 2016 meta-analysis that included 4/5 RCTs from this analysis (+1 additional not included here-in) found similar results, as well as significant reduction in severe adverse events with IV iron therapy versus placebo (OR 0.50, 0.35-0.75).
    • A 2017 pooled analysis of FAIR-HF, CONFIRM-HF and 2 unpublished trials of ferric carboxymaltose again found similar results on these outcomes. No significant difference was found in all-cause mortality, all-cause hospitalization, or the composite of these 2 outcomes (hazards ratio 0.81, 0.59-1.12).
    • IRONOUT HF, a RCT of 225 patients with HFrEF & iron deficiency found no difference in the primary outcome of VO2max or any secondary outcome (including QoL, 6MWT distance, NT-proBNP) between iron polysaccharide 150 mg BID & placebo over 4 months;
      • Given the minimal change in ferritin (+11, p=0.6) & TSAT (+3%, p=0.003), it remains unknown if other PO iron formulations, such as sulfate or fumarate salts, may be effective in these patients;
      • It also remains unknown whether PO iron could adequately maintain iron stores in patients first repleted with IV iron.

    Ongoing areas of uncertainty:

    • Long-term efficacy & safety of IV iron therapy in HFrEF;
    • Effect of IV iron on mortality in HFrEF;
    • Optimal duration, route & regimen for maintenance of iron stores following repletion with IV iron;
    • Effect of IV iron in HFpEF.