Iron deficiency and heart failure

Iron deficiency (ID) has adverse clinical and prognostic consequences in patients with chronic heart failure (HF) (1,2)

• little is known about the pathophysiology and aetiology of ID in HF, but suggested mechanisms include poor dietary iron intake, drug interactions, (occult) gastrointestinal blood loss due to antiplatelet drugs and anticoagulants, and hepcidin-induced iron entrapment due to chronic low-grade inflammation
• ID seems to be more prevalent in female than in male HF patients, but the factors driving this sex difference are unknown (1,2)
• opposite to the traditional view, deleterious consequences of ID in HF syndrome are irrespective of anaemia and other important confounders (e.g. age, severity of the disease, renal function) (3)

The effects of ID in heart failure were investigated in the BIOSTAT-CHF study (1):

• patients hospitalized for HF or presenting with worsening HF in an outpatient setting were eligible if they had LVEF <= 40% or BNP > 400 ng/L or NT-proBNP >2000 ng/L
• eligible patients had to receive suboptimal evidence-based HF treatment. Physicians were encouraged to uptitrate ACEi, ARB and/or beta-blockers in the 3 months following inclusion. Serum for iron status analysis was available in 2357 of BIOSTAT-CHF patients. Median follow-up was 21 months. ID was defined as transferrin saturation (TSAT) <20%, with TSAT calculated as follows: [72.17 * iron (mg/dL)]/transferrin (mg/dL).

Study results and conclusions (1):

• in a large cohort of patients with worsening HF, female sex, lower estimated protein intake, higher heart rate, presence of peripheral oedema and orthopnoea, history of renal disease, lower hemoglobin, higher CRP, lower serum albumin and antiplatelet use were identified as independent determinants of ID, in a similar way for both sexes
• the data suggest that the aetiology of ID in worsening HF is multifactorial and may involve a combination of reduced iron uptake, impaired iron storage and iron loss
• adverse prognostic consequences of ID are independent of these predictors
• a biomarker profile in which pro-inflammatory markers seem upregulated was found in patients with ID

Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency:

• CONFIRM-HF (3) was a multi-centre, double-blind, placebo-controlled trial that enrolled 304 ambulatory symptomatic HF patients with left ventricular ejection fraction <=45%, elevated natriuretic peptides, and iron deficiency (ferritin <100 ng/mL or 100-300 ng/mL if transferrin saturation <20%)
  • patients were randomized 1:1 to treatment with i.v. iron, as ferric carboxymaltose (FCM, n= 152) or placebo (saline, n = 152) for 52 weeks. The primary end-point was the change in 6-min-walk-test (6MWT) distance from baseline to Week 24
  • treatment with FCM significantly prolonged 6MWT distance at Week 24 (difference FCM vs. placebo: 33 ± 11 m, P = 0.002). The treatment effect of FCM was consistent in all subgroups and was sustained to Week 52 (difference FCM vs. placebo: 36 +/- 11 m, P < 0.001)
  • study authors concluded that treatment of symptomatic, iron-deficient HF patients with FCM over a 1-year period resulted in sustainable improvement in functional capacity, symptoms, and QoL and may be associated with risk reduction of hospitalization for worsening HF
• AFFIRM-AHF (4) was a multicenter, randomized, double-blind, placebo-controlled trial that included patients hospitalized with acute HF, LVEF <50% and iron deficiency between March 21, 2017 and July 30, 2019
  • primary outcome was a composite of total HF hospitalizations and CV death up to 52 weeks after randomization. Secondary outcomes included the composite of total CV hospitalization and CV death, total HF hospitalizations, CV death, total CV hospitalization, time to first HF hospitalization or CV death, and days lost because of HF hospitalization or CV death. Follow-up was 52 weeks
  • primary event was 293 times observed in 558 patients treated with FCM compared to 372 events in 550 patients receiving placebo (RR 0.79, 95% CI: 0.62-1.01, P=0.059). The effect of FCM was consistent across prespecified subgroups and independent of age, anemia, and NT-proBNP levels
  • the study authors concluded that for patients with iron deficiency hospitalized for acute HF who were treated with IV FCM were less frequently hospitalized for HF compared to those receiving placebo. FCM treatment had no effect on CV death
    
    
• IRONMAN study (5)
  • at 2.7 years follow up, RCT found IV ferric derisomaltose administration was not associated with a lower risk of hospital admissions for heart failure and cardiovascular death vs usual care (n=1869, 22.4 vs 27.5 events/100 patient-years; RR 0.82; 95% CI 0.66 to 1.02; p=0.070)

Patients with CKD are at high risk of developing (6)

• the PIVOTAL trial (7) showed that treatment with high-dose IV iron administered proactively, compared to low-dose IV iron administered reactively, decreased the occurrence of first and recurrent HF events in adults receiving hemodialysis

A hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron (7).

Reference:

1. Van der Wal M et al. Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use. Eur Heart J 2019 ehz680, https://doi.org/10.1093/eurheartj/ehz680
2. Van Veldhuisen DJ, Anker SD, Ponikowski P, Macdougall IC. Anemia and iron deficiency in heart failure: mechanisms and therapeutic approaches. Nature Rev Cardiol. 2011;8:485–493
3. Poninkowski P et al.Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency.Eur Heart J. 2015 Mar 14; 36(11): 657–668
4. Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial Lancet 2020;396:1895-1904. doi: 10.1016/S0140-6736(20)32339-4. Epub 2020 Nov
5. Kalra PR et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet November 5th 2022 https://doi.org/10.1016/S0140-6736(22)02083-9
6. Rangaswami J, McCullough PA. Heart failure in end-stage kidney disease: pathophysiology, diagnosis, and therapeutic strategies. Semin Nephrol 2018;38:600-17
7. Jhund PS, Petrie MC, Robertson M et al. Heart Failure Hospitalization in Adults Receiving Hemodialysis and the Effect of Intravenous Iron Therapy JACC Heart Fail. 2021 Jul;9(7):518-527. doi: 10.1016/j.jchf.2021.04.005.
8. Cleland JGF et al. the IRONMAN Study Group, Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial, European Heart Journal, 2024; ehae086, https://doi.org/10.1093/eurheartj/ehae086