IV iron in HFrEF with iron deficiency

Zhou X, et al. Iron supplementation improves cardiovascular outcomes in patients with heart failure. Am J Med 2019 [epub].

Bottom line: In patients with HFrEF who have iron deficiency, IV iron therapy:

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

  • reduces the risk of HF hospitalizations (NNT 10 at 6-12 months);

  • improves quality of life (~4-point improvement on 100-point scale), functional capacity, & walking distance.

  • Current evidence does not suggest that oral iron supplementation offers any benefit.

Context

  • In patients with heart failure with reduced ejection fraction (HFrEF), iron deficiency is defined as having a serum ferritin <100 ug/L OR ferritin 100-300 ug/L pls transferrin saturation (tsat) <20%

  • In HFrEF, iron deficiency is:

    • Present in 2/3 of patients with anemia & 1/2 of patients without anemia;

    • Associated with higher NYHA class (i.e. worse symptom burden), higher serum NT-proBNP, & higher risk of death (independent of hemoglobin concentration).

  • In the IRONOUT HF trial, oral iron supplementation (using Feramax 150 mg BID x4 months) in patients with HFrEF + iron deficiency did not improve quality of life or exercise capacity;

    • Importantly, 4-months of oral supplementation only modestly improved tsat (+3%) & non-significantly increased ferritin (+11 ug/L, 95% confidence interval [CI] -0.3 to +23), suggesting that this does not efficiently replace iron stores;

    • It remains unknown if other PO iron formulations, such as sulfate or fumarate salts, may be effective in these patients;

    • Also unknown whether PO iron could adequately maintain iron stores in patients first treated with IV iron.

  • 3 prior meta-analyses (Can J Cardiol 2016, Eur J Heart Fail 2016, Eur J Heart Fail 2018) all demonstrated a reduction in HF hospitalizations with intravenous iron (number needed to treat [NNT] over 6-12 months of 10-12); however, these studies were limited by restrictive eligibility criteria that included only 4-5 of the ~10 randomized controlled trials (RCTs).

Design

  • Search timeframe: Database inception to March 2018

  • Databases searched: PubMed, Embase, CENTRAL

  • Additional measures: None

  • Eligibility criteria:

    • Published in English

    • Design: Randomized controlled trial (RCT), at least single-blind

    • Population: “systolic” HF (i.e. HFrEF)

    • Intervention: Iron supplementation

  • 10 trials identified (including the 2 largest trials, FAIR-HF & CONFIRM-HF)

  • Risk of bias: Variable, 2 largest IV iron trials (FAIR-HF & CONFIRM-HF) rated as being at overall low risk of bias

Patients (n=1404)

  • Inclusion criteria of FAIR-HF & CONFIRM-HF, the 2 largest trials:

    • HF with LVEF ≤45%

    • NYHA 2-3

    • Hb 95-135 g/L in FAIR-HF, <150 g/L in CONFIRM-HF

    • Iron deficiency (ferritin <100 ug/L or 100-300 ug/L plus tsat <20%)

  • Baseline characteristics in FAIR-HF:

    • Age 67, female 55%

    • Ischemic cardiomyopathy ~80%, prior MI ~58%

    • NYHA 2 (19%) or 3 (81%); 6-minute walk test (6MWT) distance 270 m

    • LVEF ~33%

    • Hb 119 g/L, MCV 92 um^3, ferritin ~60 ug/L, tsat ~17%

    • eGFR 65 mL/min/1.73 m^2

    • Meds: ACEI/ARB >90%, beta-blocker ~85%, MRA ?, digoxin ~15%

  • 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, 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%

Interventions

  • Intervention: Iron

    • IV iron in 8 studies, with variable doses

      • e.g. mean 1850 mg given over 24 weeks in FAIR-HF, mean 1500 mg given over 1 year in CONFIRM-HF

    • PO iron in 3 studies, 200-600 mg/d

  • Control: Matching placebo infusion

Results @ ~6-12 months (range 2 weeks to 1 year)

  • Mortality (6 trials): Iron 3.3% vs control 4.6%; odds ratio (OR) 0.76, 95% CI 0.43-1.37

  • HF hospitalizations: (5 trials, all IV iron): 5.3% vs 14.5%; OR 0.39, 95% CI 0.19-0.80 (NNT 11)

  • Quality of life (4 trials; measured with Kansas City Cardiomyopathy Questionnaire [KCCQ]): 4.1 points better with iron than control

    • KCCQ range 0-100; 5-point change considered minimally clinically important difference (MCID)

    • Note: Mean improvement over placebo of 4.4 (CONFIRM-HF), 6.6 (FAIR-HF), & 7.6 in 3 trials of IV iron vs placebo; mean improvement 0.1 in 1 trial of PO iron vs placebo (the aforementioned neutral IRONOUT HF trial)

    • Other QoL scales: EQ-5D (2 trials; 4 points better with IV iron), MLHFQ (2 trials; 19 points better with IV iron)

  • NYHA functional class (5 trials): -0.7 (better) with IV iron vs control

  • 6MWT (5 trials): Distance 33 m farther with IV iron vs control

  • LVEF (3 trials): 3.8% higher with IV iron vs control

Ongoing areas of uncertainty:

  • What is the long-term efficacy & safety of IV iron therapy for HFrEF? Does IV iron therapy reduce the risk of death in patients with HFrEF? (ongoing trials: FAIR-HF2, HEART-FID, IRONMAN)

  • Can IV iron therapy reduce the risk of recurrent HF hospitalizations among patients admitted for acute HF? (ongoing trial: AFFIRM-AHF)

  • Would a different PO iron formulation be effective for iron replacement in patients with HFrEF? (ongoing trial: NCT03344523)

  • What is the optimal duration, route & maintenance regimen for iron therapy following IV iron replacement?

  • Is IV iron beneficial in patients with HF with LVEF >45%? (ongoing trials to assess this: FAIR-HFpEF)