Common Misconceptions About Iron Deficiency in Heart Failure and What to Do About It

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Dr. Butler:
Iron deficiency is a common complication of heart failure, and evidence continues to grow regarding its impact on patients’ outcomes.  However, misconception surrounding its diagnosis and treatment persist.  What are some of the misconceptions, and what should we be doing for our patients? 

This is CME on Reach MD, and I am Dr. Javed Butler, Professor and Chairman of the Department of Medicine at University of Mississippi in Jackson, Mississippi.

Dr. van der Meer:
And I’m Dr. Peter van der Meer, Professor in Cardiology at the University Medical Center, Groningen, in the Netherlands.

Dr. Butler:
So Peter, let me start by asking you the first question, which is, why are we even talking about iron deficiency?  There is not this level of comfort with treating iron deficiency, evaluating iron deficiency in patients with heart failure.  And perhaps part of the root of the issue is that people don’t realize the importance.  Can you tell us a little bit about the epidemiology and the prevalence and the relations of iron deficiency with outcomes in our patients?

Dr. van der Meer:
Iron deficiency is fairly common in patients with heart failure, and it depends a bit on the severity and in which condition a patient is, how often we see it.  So, for example, if we look in large populations of patients with heart failure with reduced ejection fraction [HFrEF], we find that about 50% of the patients are iron deficient.  But if we move to a more sick population, for example with patients with acute heart failure or with worsening heart failure, we even see that two-thirds to three-quarters of the patients with heart failure are iron deficient.  So it’s very common.  It is also associated with a poor quality of life and a poor functional capacity.  And in addition, patients with iron deficiency have a much worse prognosis compared to patients who are not iron deficient.

Dr. Butler:
So will you particularly only evaluate iron deficiency in heart failure if somebody is having any symptoms?  What are those symptoms?  Or should this be screened in patients with heart failure? 

Dr. van der Meer:
So we did a large study where we looked at predictors for iron deficiency, but it’s very difficult to predict iron deficiency because it’s so common.  So if half of the population of patients with heart failure – half to three-quarters of the patients are iron deficient, I think it’s fair to say that screening for iron deficiency is indicated.  And that’s also written down in the ESC Guidelines – Heart Failure Guidelines of 2016.  That’s a Class 1C recommendation, to screen for iron deficiency.

Dr. Butler:
Now, there is another misconception, and that is that we all get trained very well to evaluate iron deficiency as a cause of anemia, so we associate iron deficiency with iron deficiency anemia per se, and not necessarily iron deficiency as a disease by itself or a condition by itself.  Is iron deficiency always associated with iron deficiency anemia, or can you get iron deficiency in patients without anemia?  And, does it actually matter if somebody doesn’t have anemia and only has iron deficiency?

Dr. van der Meer:
So if we look at the large, stable, chronic HFrEF population which has been studied in more than 2,000 patients, we see that around two-thirds of the patients had iron deficiency.  And when we divided the group of iron deficient patients into an anemic part and a non-anemic part, it became apparent that only one-third of the iron deficient patients had anemia.  So two-thirds of the patients with iron deficiency were non-anemic.  So hence, it means that only screening for hemoglobin, you would miss two-thirds of the patients with iron deficiency.  So, iron deficiency in itself, without anemia, is commonly seen.  

And if we, for example, look at the intervention trials – so you can always say is it association, or is iron deficiency really causing, for example, a reduction in exercise capacity and quality of life?  So there have been two relatively large outcome trials with intravenous iron where patients with iron deficiency – and there was a group consisting of patients with iron deficiency with anemia and without anemia – were treated with intravenous iron, and the primary endpoint was exercise capacity and quality of life.  And we see that treatment with intravenous iron increased quality of life and increased exercise capacity, and it did not matter if the patients were anemic at baseline or were non-anemic.  So the treatment effect is similar between patients with iron deficiency anemia and iron deficiency alone, without the anemia. 

So as you can see, screening for iron deficiency is important.  In fact, the European Society for Cardiology recommends screening for iron deficiency in all patients with newly diagnosed heart failure, with regular monitoring of patients thereafter, as we discussed.  I think another misconception is that measuring ferritin levels is enough to determine whether or not a patient is iron deficient, since there’s more to this than only ferritin levels.  Dr. Butler, can you walk us through how we should assess iron deficiency in patients with heart failure?

Dr. Butler:
Yeah, Peter, so that’s sort of really interesting question, and it’s really not that complex, as we sometimes feel when we think about several different iron indices.  So let me just break it down physiologically, and it’s very logical.   So you can have iron deficiency because you are not eating enough iron, so depending on what foods you eat, or cachexia or decreased appetite.  You can have decreased absorption because of gut edema.  You can have increased GI losses because of peptic ulcer disease, gastritis, what you have.  So, all of these things lead to absolute iron deficiency.  

But then, even if you don’t have absolute iron deficiency, iron is stored intracellularly.  It is transported out of the cell through a – it’s binding with transferrin.  It is then transported all over the body for it being utilized for ATP generation and hemoglobin production, and for all the reasons the body needs iron per se.  So then you can have a relative iron deficiency.  Even if your intake and absorption and iron stores, as measured by ferritin levels, are normal, you can have relative iron deficiency because in a prurient inflammatory state like heart failure with increased hepcidin level, that mechanism of transporting intracellular iron to the extracellular and binding with trasferrin and transporting it to the rest of the body is defective. 

And then finally, remember that ferritin is an acute-phase reactant, and therefore your ferritin level may go up, even in the presence of iron deficiency.  So if you put all of these things together – if your absolute ferritin levels are less than 100, well, you get your diagnosis.  But even if the ferritin levels are higher, between 100 to 300, then you look at your transferrin saturation, and if the transferrin saturations are less than 20, then you can diagnose iron deficiency as well. 

For those just tuning in, you’re listening to CME on ReachMD.  I am Dr. Javed Butler, and here with me today is Dr. Peter van der Meer.  We are discussing some of the common misconceptions that surround iron deficiency and heart failure. 

Let’s consider some cases.  First, let’s suppose we have a female patient, with Class II heart failure, and her ejection fraction is reduced to 35%.  An iron panel shows that her hemoglobin is 12 g/dL, ferritin 185, and TSAT 19%.  Peter, is this patient anemic, iron deficient, both, or neither?

Dr. van der Meer:
So there are two things to take into consideration.  So first, the question is, is the patient anemic, yes or no.  With a hemoglobin less than 12 g/dL – in Europe we use, in some places, millimoles per liter, so that’s equal to 7.5 mmol/L – that’s actually precisely the threshold the WHO uses for the definition of anemia, less than 12 g/dL.  So I would say she’s borderline anemic.  When we look into the iron parameters, like ferritin of 185 and TSAT of 19%, this patient has relatively high ferritin levels.  But I think we should take into consideration that chronic heart failure is a chronic inflammatory condition, and ferritin is an acute phase protein, which is elevated in inflammatory conditions.  So, her ferritin is between 100 and a 300, and her TSAT is below 20.  So I would consider this patient as borderline anemia with iron deficiency.

Dr. Butler:
So now let’s consider if this patient – with very same parameters: hemoglobin of 12, ferritin of 185 and TSAT of 19 – but if this patient were a man, what would your diagnosis be? 

Dr. van der Meer:
We already diagnosed the iron deficiency, so that stays the same also in male patients, so there are no differences between the definition of iron deficiency between male and female patients.  But the WH criteria for anemia are – have different cutoff values for males versus females.  So for females, it was a 12 g/dL.  For males, it’s 13 grams – 13 g/dL.  So that equals to 8.1 mmol/L.  So clearly, where this female was borderline anemic, a male patient would be considered clearly anemic.

Dr. Butler:
So, Dr. van der Meer, is iron deficiency a risk factor or a risk marker in patients with heart failure?  That’s the key question, because even if iron deficiency is associated with prognosis, that doesn’t mean we should be replacing iron unless and until it improves outcomes.  So, is it a risk factor or a risk marker?

Dr. van der Meer:
Well, that’s an excellent question.  And I think that’s the most important question because we have so many markers which are associated with a poor outcome.  But it’s unclear whether the correction of such a condition indeed leads to a better clinical situation.  The FAIR-HF, which was the first trial which looked at the effects of intravenous iron on patients’ reported outcome, so how were patients feeling, and also a New York Heart Association Class Functional Class.  And in that FAIR-HF trial, it was clearly shown that patients were feeling better if they were treated with intravenous iron.  So that first trial, the FAIR-HF, has been followed up by the CONFIRM trial, which had, as a primary endpoint, the 6-minute walk test.  And also, in that trial, it was clear that patients who were treated with intravenous iron had a better 6-minute walk test after six months of treatment.  So, I think we can clearly say that iron deficiency causes impaired exercise capacity and a lower quality of life. 

The second part is the association of iron deficiency with outcome is currently a little bit less clear.  There has been executed the meta-analysis of this CONFIRM and FAIR-HF trial looking at the endpoint of heart failure hospitalizations.  And in that meta-analysis, treatment with iron showed lower amounts of heart failure hospitalizations.  So, that meta-analysis, pointing to the right direction.  And currently, there are several large, randomized control trials underway answering the question whether intravenous iron indeed improves hard endpoints, like heart failure hospitalizations and cardiovascular mortality.  And one of the first results we are eagerly awaiting is the AFFIRM acute heart failure trial.

Dr. Butler:
So, Peter, let me ask you a question.  I can understand that if you have iron deficiency anemia, you have decreased oxygen-carrying capacity that leads to all the symptoms and functional capacity problem.  But if you don’t have anemia, how does iron deficiency lead to poor outcomes?

Dr. van der Meer:
So you’re right, that if iron deficiency leads to anemia, so there is less hemoglobin, so there – your peak VO2 would go down.  But we should also not forget that iron plays an important role in mitochondrial function.  So several of the mitochondrial complexes or iron sulfur complexes, where iron is needed to eventually get this proton gradient and, subsequently, ATP is being formed.  So we know from skeletal muscle studies in patients with heart failure, we know from some in vitro data from human cardiomyocytes, that iron deficiency indeed leads to a reduced mitochondrial function and less ATP production and, in a cellular model, leading to a lower contractile force of these cardiomyocytes.  So, I think we have two ways, at least from what we understand from it now, is one would be lower hemoglobin levels, but also clearly effects of iron on mitochondrial function. 

Dr. Butler:
So, really excited to know all the research going on in this field, and I’m looking forward to the AFFIRM-AHF results.  For our listeners who are interested in hearing more about how to manage and treat iron deficiency in heart failure, be sure to check out “Beyond Anemia: Understanding the Significance and Treatment of Iron Deficiency,”  with Drs. Ewa Jankowska and Stefan Anker.  Dr. van der Meer, in our last few minutes today, can you share with our audience your one take-home message?

Dr. van der Meer:
So my take-home message would be that iron deficiency is common in patients with heart failure and is observed also in patients who are not anemic.  And Javed, what would be your final take-home message?

Dr. Butler:
My take-home message will be that iron deficiency – we should think not only as a precursor of anemia, but as an entity – a disease entity in itself, very much like, say, diabetes, where patients may or may not have symptoms; you screen for it.  You need to screen for iron deficiency, because the data clearly show that it’s not only a risk marker, but is actually a risk factor, and treatment matters. 

Well, that’s all the time we have today.  I want to thank our audience for listening in and thank you, Dr. Peter van der Meer, for joining me and for sharing all of your valuable thoughts.  It was a real pleasure speaking with you, Peter.

Dr. van der Meer:
Thank you, Javed.  I really enjoyed the discussion.

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