IV iron in HFrEF with iron deficiency
Updated Jan 4, 2021
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 17 at 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 + transferrin saturation (tsat) <20%
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) 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).
2019 Meta-Analysis - Zhou X, et al. Iron supplementation improves cardiovascular outcomes in patients with heart failure. Am J Med 2019;132:955-63.
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
However, there was an important error in this analysis, with a far wider confidence interval after re-analysis
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
AFFIRM-AHF - Ponikowski P, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet 2020;396:1895-904.
Design
RCT at low risk of bias (randomized; allocation concealed; blinding of patients; clinicians & outcome assessors; modified intention-to-treat; <0.5% loss to follow-up before 1st event)
Patients (n=1132)
Included: Adults hospitalized for acute HF, receiving IV furosemide >=40 mg/d with LVEF <=50% & iron deficiency (per definition in context)
Baseline:
Age 71, female 45%
Ischemic cardiomyopathy ~47%, prior MI ~40%
NYHA 1 (1-3%), 2 (45%), 3 (50%), 4 (~3-4%)
LVEF ~33%
Hb ~120 g/L, ferritin ~86 ug/L, TSat ~15%
eGFR <60 (52%)
Meds: ACEI/ARB/ARNI ~75%, beta-blocker 83%, MRA 65%, digoxin ~17%
Intervention: IV iron
Ferric carboxymaltose, initial dose #1 & #2 dosed based on initial hemoglobin & patient weight, & doses #3 & #4 only if persistently iron deficient
Initial IV bolus dose #1 - before discharge
Hb 140-150 g/L at any weight: 500 mg
Hb 80-140 g/L at any weight: 1000 mg
Initial IV bolus dose #2 - at week 6
Hb >=140 g/L: No dose
Wt <70 kg
Hb 100-140 g/L: No dose
Hb 80-99 g/L: 500 mg
Wt >=70 kg
Hb 100-140 g/L: 500 mg
Hb 80-99 g/L: 1000 mg
Mean total dose throughout trial: 1352 mg
Comparator: Matching placebo
Outcomes @ 12 months
Primary outcome (total CV death + HF hospitalizations):
IV iron 57.2 vs placebo 72.5 per 100 patient-years
Rate ratio 0.79 (95% confidence interval [CI] 0.62-1.01)
Note: Rate includes recurrent HF hospitalizations
No difference in CV death: 14% in both groups, hazard ratio (HR) 0.96 (95% CI 0.70-1.32)
First HF hospitalization or CV death:
IV iron 32% vs placebo 38% (number needed to treat 17)
HR 0.80 (95% CI 0.66-0.98)
Note: This is the more traditional & commonest way to report outcomes in HF trials
Serious adverse events: 45% vs 51%
Premature study drug discontinuation: 28% vs 29%
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)
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)