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Intravenous Iron Therapy in Acute Decompensated Heart Failure

03 Aug 2021 11:39 AM | MSHP Office (Administrator)

By: Ethan Cowell, PharmD Candidate 2022; University of Health Sciences and Pharmacy in St. Louis

Mentor: Joseph Van Tuyl, PharmD, BCCP; Assistant Professor of Pharmacy Practice/Pharmacy Clinical Specialist – Cardiology; University of Health Sciences and Pharmacy in St. Louis/St. Louis University Hospital

Background:
Heart failure (HF) affected 6 million adults in the United States from 2015 to 2018 and costed approximately $30.7 billion dollars in 2012 alone.1  Economic estimates predict the total cost of HF will increase to $69.8 billion by 2030.1  Costs are primarily due to hospitalizations to treat HF and the comorbidities that commonly accompany this disease state. In 2014, the projected mean cost of primary HF hospitalizations was $11 billion (approximately $11,552 per hospitalization).2

HF can be exacerbated by many comorbidities including iron deficiency, which is defined as a serum ferritin <100 mcg/L or serum ferritin 100 to 300 mcg/L with a transferrin saturation (TSAT) <20%.3  Iron deficiency may be prevalent in up to 21% HF patients with anemia, and iron deficiency may be present regardless of the presence of anemia.3, 4 Iron deficiency leads to lower iron-sulfur cluster-based complex activity in the mitochondria of cardiomyocytes, thereby, impairing mitochondrial respiration, ATP production, and contractility.5 HF patients with comorbid iron deficiency, consequently, are at an increased risk for hospitalizations, decreased quality of life, and exercise intolerance.

Iron stores are regulated by serum hepcidin, an acute phase reactant. Inflammation from HF increases the production of hepcidin. Subsequently, hepcidin binds the ferroportin transporter, which is primarily responsible for gastrointestinal iron absorption and causes its lysosomal destruction.    Consequently, HF patients have a decreased ability to absorb oral iron.3 This was observed in the IRONOUT HF trial, in which clinically insignificant improvements in serum iron and TSAT conferred by oral iron supplementation over a 16-week period demonstrated no significant improvement in the change in peak VO2 (difference, 21 mL/min; 95% CI, -34 to 76; P-value, 0.46) or 6-minute walk distance (difference, -13 m; 95% CI, -24 to 23; P-value, 0.19) compared to patients receiving placebo.6


To overcome the limitations of oral iron supplementation, many clinical trials have assessed the efficacy and safety of intravenous iron therapy to correct iron deficiency in HF. Intravenous iron supplementation may improve clinical outcomes in HF by increasing cardiac mitochondrial function.  

Literature Review:
Intravenous iron supplementation routinely improved functional capacity in randomized controlled trials of chronic HF patients. Study participants were generally characterized as New York Heart Association (NYHA) Class II-III with a left ventricular ejection fraction <45%, and all patients met criteria for iron deficiency (serum ferritin <100 mcg/L or 100-300 mcg/L with a TSAT <20%), regardless of concomitant anemia.7-10 In the FAIR-HF trial, intravenous ferric carboxymaltose improved self-reported patient global assessment and NYHA functional classification over 24 weeks of follow-up.7 Those results were replicated in the CONFIRM-HF trial in which intravenous ferric carboxymaltose improved patient’s 6-minute walk test (difference, 33 ± 11 meters; P=0.002), NYHA functional class, and Kansas City Cardiomyopathy Questionnaire scores when compared to placebo.8 Furthermore, the EFFECT-HF trial observed a significant improvement in peak VO with  intravenous ferric carboxymaltose use.9  Thus, the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure states that it might be reasonable to utilize intravenous iron supplementation in NYHA class II and III HF patients to improve quality of life and functional status (Class IIb; Level of Evidence B-R).10  Recommendations for intravenous iron supplementation in acute HF, however, are absent from the guidelines.

In a small prospective study, Reed et al. examined the safety and efficacy of intravenous sodium ferric gluconate 250 mg every 12 hours (total dose calculated by the Ganzoni formula, mean dose = 1,269 mg) in patients with NYHA class III-I HF and iron deficiency.  The study showed that intravenous sodium ferric gluconate increased the hemoglobin by 1.2 g/dL (95% CI, 0.45-1.9; P=0.005), ferritin by 364.2 ng/ml (95% CI, 129.7-598.7; P=0.007), and TSAT by 10.5% (95% CI, 6.5-14.6%; P<0.001).  Additionally, iron deficiency was no longer present in eight of the nine patients that followed up in the study.11  Kaminsky et al. further illustrated that patients with acute HF and anemia who received intravenous iron (mean dose = 1,057 mg) had greater improvement in hemoglobin in comparison to a no iron replacement (P=0.0001).12 The mean difference in hemoglobin from baseline for iron therapy was 0.74 g/dL on day 7 and 2.61 g/dL on day 28, whereas the control group only saw a mean difference of 0.01 g/dL and 0.23 g/dL on days 7 and 28, respectively.12  This study also found no statistical difference between iron therapy and the control group in respect to all-cause 30-day readmission rates (P=0.2787), but lack of statistical power precluded a definitive conclusion.12 In each study, intravenous iron was well-tolerated without significant adverse effects.11, 12

Recently, the AFFIRM-AHF trial assessed the effect of intravenous ferric carboxymaltose on the risk of total HF hospitalizations and cardiovascular death in patients stabilized after acute HF. Patients included were hospitalized with acute HF with a left ventricular ejection fraction <50% and iron deficiency (serum ferritin <100 mcg/L or 100-300 mcg/L with a TSAT <20%).  Ferric carboxymaltose was administered as two repletion doses, up to 1,000 mg prior to discharge and six weeks later, based on patient weight and hemoglobin; subsequent doses were administered at 12 and 24 weeks if iron deficiency persisted upon follow-up. No significant difference in the composite endpoint of total HF hospitalizations and cardiovascular death between the intervention and placebo groups (RR, 0.79; 95% CI, 0.62-1.01; P=0.059). However, a pre-COVID-19 sensitivity analysis was performed and demonstrated a significant decrease in the composite primary outcome (RR, 0.75; 95% CI, 0.59-0.96; P=0.024). Ferric carboxymaltose also decreased in total hospitalizations (RR, 0.74; 95% CI, 0.58-0.94; P=0.013), days lost due to HF hospitalization and cardiovascular death (RR, 0.67; 95% CI, 0.47-0.97; P=0.035), and rate of first hospitalization due to HF or cardiovascular death (HR, 0.80; 95% CI, 0.66-0.98; P=0.030).  Conversely, the trial did not find a significant difference in cardiovascular death between the two groups (HR, 0.96; 95% CI, 0.70-1.32; P=0.81).13 Therefore, the trial provided evidence of reduced HF hospitalizations with the use of ferric carboxymaltose in stabilized acute HF patients.

Recommendations:
Intravenous iron supplementation is efficacious in patients with chronic or acute HF and iron deficiency by decreasing hospitalizations and improving exercise intolerance, NYHA functional classification, and quality of life. No major adverse events were observed by intravenous iron replacement. Patients admitted for acute HF should be screened for iron deficiency, and intravenous iron may be administered to decrease the risk of worsening HF symptoms and readmissions.

References

  1. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020;141(9):e139-e596.
  2.  Jackson SL, Tong X, King RJ, Loustalot F, Hong Y, Ritchey MD. National burden of heart failure events in the United States, 2006 to 2014. Circ Heart Fail. 2018;11(12):e004873.
  3. von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD. Iron deficiency in heart failure: an overview. JACC Heart Fail. 2019;7(1):36-46.
  4. Cohen-Solal A, Damy T, Terbah M, et al. High prevalence of iron deficiency in patients with acute decompensated heart failure. Eur J Heart Fail. 2014;16:984-991.
  5. Hoes MF, Grote Beverborg N, Kijlstra JD, et al. Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. Eur J Heart Fail. 2018;20(5):910-919.
  6. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA. 2017;317(19):1958-1966.
  7. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436-2448.
  8. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, 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;36(11):657-668.
  9. van Veldhuisen DJ, Ponikowski P, van der Meer P, et al. Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency. Circulation. 2017;136(15):1374-1383.
  10. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161.
  11. Reed BN, Blair EA, Thudium EM, et al. Effects of an accelerated intravenous iron regimen in hospitalized patients with advanced heart failure and iron deficiency. Pharmacotherapy. 2015;35(1):64-71.
  12. Kaminsky BM, Pogue KT, Hanigan S, Koelling TM, Dorsch MP. Effects of total dose infusion of iron intravenously in patients with acute heart failure and anemia (hemoglobin < 13 g/dl). Am J Cardiol. 2016;117(12):1942-1946.
  13. 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(10266):1895-1904.

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