CardioNerds Cofounder Dr. Amit Goyal, Chair of the CardioNerds Heart Failure Committee Dr. Jenna Skowronski, and Episode FIT Lead Dr. Shazli Khan discuss iron deficiency and its impact on heart failure with Dr. Robert Mentz, Chief of Heart Failure at Duke University and principal investigator of the HEART-FID trial. In this case-based discussion, they cover the diagnostic criteria of iron deficiency in heart failure, epidemiology, and strengths and limitations of different iron formulations.  They also review clinical trials examining the impact of iron deficiency on quality of life, heart failure hospitalizations, and mortality. Importantly, they stress the relevance of iron metabolism in heart failure, irrespective of the presence of anemia. They also discuss the approach to addressing outpatient management of iron in heart failure and future directions of research needed in this domain.

Notes were drafted by Dr. Shazli Khan, and Dr. Daniel Ambinder engineered episode audio.

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• Think about iron deficiency in ALL patients with heart failure and send appropriate diagnostic labs, even if there is no evidence of anemia!
  
• Iron deficiency in heart failure has a specific and distinguished definition, defined as a ferritin level of <100 ng/mL, or a ferritin level between 100-300 ng/mL with a transferrin saturation of <20%.
  
• Data thus far suggests that treatment of iron deficiency in heart failure results in improved quality of life, as well as a probable reduction in heart failure hospitalizations, and that administration of intravenous iron has a favorable safety profile.
  
• Not all formulations of iron are created equal – intravenous iron formulations have been shown to be effective in this population, but oral iron therapy has not.
  
• Management of iron deficiency in the outpatient setting is an evolving area of research, but patients should typically receive surveillance labs and additional treatment with IV iron if indicated.
  

How is iron deficiency in heart failure defined, and how prevalent is iron deficiency in this patient population?

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• Iron deficiency is common in patients with heart failure, with an estimated prevalence of 50-60%.
  
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  • Iron deficiency in heart failure is associated with worse outcomes, including increased hospitalization and mortality and poorer functional status and quality of life.
    
  
  
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  • Iron deficiency in heart failure is defined as a ferritin level of <100 ng/mL or a ferritin level of 100-300 ng/mL plus a transferrin saturation of <20%.
    
  
  
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  • There is an evolving school of thought that suggests transferrin saturation alone may be the best indicator of iron deficiency in heart failure, but more data are needed.
    
  
  
  

Importantly, iron deficiency in heart failure can be seen in patients with both reduced and preserved ejection fraction. Which patients should be screened for iron deficiency?

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• There is a class I indication to send iron studies in all patients with heart failure as a part of the initial diagnostic work-up for the underlying etiology of the cardiomyopathy, as well as to assess for the presence of iron deficiency.
  
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  • The presence of anemia is not required to check iron studies, as many patients with iron deficiency in heart failure may not have concomitant anemia.
    
  
  
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  • That is, all patients with heart failure should be evaluated for iron deficiency, irrespective of the presence of anemia.
    
  
  
  

What are the hypothesized mechanisms of iron deficiency in heart failure, and how does iron deficiency impact patients with heart failure?

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• Mechanisms causing iron deficiency in heart failure are multifactorial, including reduced oral intake, reduced gut absorption, reduced iron availability due to sequestration, and increased loss due to higher rates of bleeding.
  
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  • Nutritional variation is one proposed mechanism, as patients living with heart failure tend to take in less iron in their diet, and the iron consumed tends to be less easily absorbed.
    
  
  
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  • Due to chronic inflammation, there are increased levels of iron sequestration in cells in patients with heart failure, rendering the available iron stores unable to be used.
    
  
  
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  • Patients with chronic heart failure also tend to be on anti-platelet agents and/or anticoagulants (due to often-occurring comorbidities), which may potentially lead to bleeding complications, consequently causing iron deficiency.
    
  
  
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  • Iron deficiency has been associated with decreased exercise tolerance and functional status, worse quality of life, and increased risk of heart failure hospitalizations.
    
  
  
  

What are the key takeaways of the clinical trials done in patients with heart failure and iron deficiency?

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• The FAIR-HF trial published in 2009 demonstrated that treatment with IV ferrous carboxymaltose (FCM) in patients with heart failure led to improved symptoms and quality of life with an acceptable safety profile. These benefits were verified in a follow-up study known as CONFIRM-HF, demonstrating improvement in 6MWT and functional capacity.
  
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  • The AFFIRM-AHF trial investigated IV FCM in patients with iron deficiency and a left ventricular ejection fraction of <50%. It was a neutral trial with no significant improvement in their primary endpoint, a composite of hospitalization and death. The trial did demonstrate the safety of FCM and decreased hospitalizations. Of note, this trial was significantly impacted by the COVID pandemic, which may have affected the results. 
    
  
  
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  • The IRONMAN trial was similar in design to AFFIRM-AHF but used a different iron formulation (iron derisomaltose) and had similar findings.
    
  
  
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  • The HEART-FID trial was a larger study including 3000 patients with HFrEF investigating treatment with IV ferric carboxymaltose every six months if the patients remained iron deficient. The primary endpoint was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. While it was considered a neutral trial with a p=0.019 with a prespecified significance level of 0.01, it demonstrated a trend to improved mortality and six-minute walk.
    
  
  
  

Which patients should we treat with iron, and with what formulation? What do the guidelines recommend?

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• Patients who have chronic heart failure on maximally tolerated guideline-directed medical therapy with iron deficiency are candidates for intravenous iron supplementation with the goal of improving quality of life and reducing heart failure hospitalizations.
  
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  • Intravenous iron has been shown to be effective, but oral iron therapy has shown no benefit in trials.
    
  
  
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  • Per the updated 2023 ESC guidelines, there is a class IA recommendation to provide intravenous iron supplementation in symptomatic patients with heart failure with reduced and mid-range ejection fraction with iron deficiency to both alleviate HF symptoms and improve quality of life.
    
  
  
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  • There is a class IIA recommendation to provide supplementation to reduce heart failure hospitalizations.
    
  
  
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  • Surveillance labs in the outpatient setting, combined with continued treatment for persistent iron deficiency, are likely beneficial in patients with heart failure.
    
  
  
  

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2. Packer M, Anker SD, Butler J, et al. Identification of three mechanistic pathways for iron-deficient heart failure. Eur Heart J. 2024;45(26):2281-2293. doi:10.1093/eurheartj/ehae284. https://academic.oup.com/eurheartj/article/45/26/2281/7668668
   

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• Salah HM, Savarese G, Rosano GMC, et al. Intravenous iron infusion in patients with heart failure: a systematic review and study-level meta-analysis. ESC Heart Fail. 2023;10(2):1473-1480. doi:10.1002/ehf2.14310. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053151/
  

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• 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. doi:10.1016/S0140-6736(20)32339-4. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32339-4/abstract
  

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• Kalra PR, Cleland JGF, Petrie MC, et al; IRONMAN Study Group. 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. 2022;400(10369):2199-2209. doi:10.1016/S0140-6736(22)02083
  https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02083-9/fulltext
  
• Mentz RJ, Garg J, Rockhold FW, et al; HEART-FID Investigators. Ferric Carboxymaltose in Heart Failure with Iron Deficiency. N Engl J Med. 2023;389(11):975-986. doi:10.1056/NEJMoa2304968. https://www.nejm.org/doi/full/10.1056/NEJMoa2304968
  

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• McDonagh TA, Metra M, Adamo M, et al; ESC Scientific Document Group. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;44(37):3627-3639. doi:10.1093/eurheartj/ehad195. Erratum in: Eur Heart J. 2024;45(1):53. doi:10.1093/eurheartj/ehad613. https://academic.oup.com/eurheartj/article/44/37/3627/7246292?login=false
  

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• 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. doi:10.1056/NEJMoa0908355. https://www.nejm.org/doi/full/10.1056/NEJMoa0908355
  

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• 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. doi:10.1093/eurheartj/ehu385. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359359/