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Evolving the Standard of Care: Rethinking the Treatment Paradigm for Iron Deficiency Anemia

  • Authors: Carlo Brugnara, MD
  • CME / ABIM MOC Released: 1/7/2021
  • Valid for credit through: 1/7/2022, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for hematologists, nephrologists, gastroenterologists, and clinicians who care for patients with iron deficiency anemia (IDA).

The goal of this activity is to provide clinicians with the most up-to-date information concerning the treatment of IDA.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Safety data for different iron formulations
  • Have greater competence related to
    • Developing tailored strategies for the treatment of IDA
    • Timely management of adverse events (AEs) related to intravenous (IV) iron
  • Demonstrate greater confidence in their ability to
    • Develop collaborative care models to provide evidence-based care for patients with IDA


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  • Carlo Brugnara, MD

    Professor of Pathology
    Harvard Medical School
    Medical Director of the Hematology Laboratory
    Department of Laboratory Medicine
    Boston Children's Hospital
    Boston, Massachusetts


    Disclosure: Carlo Brugnara, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Sysmex America Inc.


  • George Boutsalis, PhD

    Senior Medical Education Director, Medscape, LLC 


    Disclosure: George Boutsalis, PhD, has disclosed no relevant financial relationships.

CME, CE Reviewer/Nurse Planner

  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Disclosure: Stephanie Corder, ND, RN, CHCP, has disclosed no relevant financial relationships.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.

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Evolving the Standard of Care: Rethinking the Treatment Paradigm for Iron Deficiency Anemia

Authors: Carlo Brugnara, MDFaculty and Disclosures

CME / ABIM MOC Released: 1/7/2021

Valid for credit through: 1/7/2022, 11:59 PM EST




Carlo Brugnara (00:06):

I'm Carlo Brugnara and I'm happy to provide a summary of a Medscape live event that took place at the ASH 2020 meeting. And this was a title involving the standard of care, and rethinking the treatment paradigm for iron deficiency anemia. A key issue on iron metabolism is understanding the particular metabolism of iron in man, and the iron cycle. This slide highlights the defining characteristic of iron metabolism that is the recycling of iron, and the contribution of iron absorption to make up the daily losses of iron. But, as you see, most of the iron is being recycled. With this in mind, iron deficiency is a condition in which this recycling mechanism gets disturbed to the point that the iron acquired through the diet is unable to sustain the requirement of metabolism and erythropoiesis.

Carlo Brugnara (01:37):

There are several symptoms of iron deficiency that are worth considering and I outline in this slide. There's some very frequent ones. There's obviously fatigue, paleness, dyspnea, and headache, and some frequent ones that are restless leg syndrome, glossitis, dry and rough skin, dry and damaged hair, and then some rare ones. All together, these symptoms may be accompanied by signs of iron deficiency, as shown in this slide, that include pallor due to the anemia, decreased population of the tongue, and some mucosal changes, like hair losses, and some nail bed defects, as again outlined in this slide here. Now, what are the defining laboratory features of iron deficiency?

Carlo Brugnara (02:42):

For absolute iron deficiency, certainly the biochemical parameters have been studied for a long time and ferritin, along with the biochemical parameter, is informative if this value is below the cutoff. We will describe in the next slide what is the appropriate cutoff. This is accompanied by low serum iron, and decreased transferrin saturation, increased transferrin, and possibly add markers that are not measured routinely, but serum transferrin receptor, EPO and hepcidin. The hematological changes are classic to an iron deficient data proteases, and so they have a reduction with MCV, in MCH, and in MCHC. Increase of the [inaudible 00:03:41], increase of hypochromic red cells, and reduction in the reticulocyte hemoglobin count and measure as CHr or RET-HE, as well as increased zinc protoporphyrin.

Carlo Brugnara (03:53):

The reticulocyte count is usually reduced for the degree of anemia and iron deficiency compared with other types of anemia. I mentioned the serum ferritin cutoffs, the cutoff by the WHO is 15, but papers have been publishing showing that increasing the cutoff to 30 may increase the sensitivity to diagnose iron deficiency and still maintain excellent specificity. In the presence of inflammation, this cutoff varies and can be 100%, but also can be 300%... I'm sorry, 300 nanograms in congestive heart failure, and 500 nanograms in chronic kidney disease. At times, the decision point for this cutoff, accompanied by also decision point from transferrin saturation, so that for a 500 cutoff in chronic kidney disease, and it is less than 30% that will still prompt possibly iron therapy decisions.

Carlo Brugnara (05:14):

Again, the cutoff of ferritin is very much dependent on the clinical situation, as shown here in this slide. For repeated blood donors, the cutoff of 30 nanograms per ML of ferritin has been used as a prompt to lengthen the donation interval to more than 56 days, and so reduce the number of times that the donor was unable to donate due to the low hemoglobin. I mentioned the inflammation because anemia of inflammation is certainly a very common feature that the physician has to deal with. This slide outlines the pathophysiology of the anemia of inflammation, that there's both iron restriction, of the suppression of [inaudible 00:06:17] due to a variety of cytokines, and also of strong red cell survival. It is seen in a variety of conditions that include autoimmune disease infections, but also malignancies as well as chronic kidney and pulmonary disease, as well as obesity.

Carlo Brugnara (06:38):

What are the laboratory features of the anemia chronic disease? The ferratin can be normal or much more often is elevated. The serum iron may be normal or low, and transferrin may be low, and transferrin separation might be reduced. The reticulocyte count is reduced and there are inappropriately high serum and urinary hepcidin values, as well as changes in red cell and what they call [inaudible 00:07:09]. Inflammatory markers may be elevated, but there is no consensus about what is the most improper inflammatory marker, but CRP or IL-6 might be elevated. I have mentioned hepcidin, and again, this is a central regulator of iron metabolism. We have seen how it can be activated in conditions in which the iron stores are repleted, or in consequence of red cell transfusion, or in a variety of inflammatory diseases. It can be reduced in conditions in which there is an expanded [inaudible 00:07:56] or anemia.

Carlo Brugnara (07:58):

Overall, hepcidin measurements are diagnostic for iron refractory, iron deficiency, anemia, the IRIDA, that is a genetic form of iron deficiency. They're also helpful in the anemia chronic disease because they can show elevated values. And that is mostly driven by the inflammation. And one area that has shown promise is the prediction of responsiveness to oral iron therapy, as shown in this slide by work that was published in blood a few years ago. Low hepcidin value is associated with increased iron incorporation, when you look at patient that had been treated with oral iron due to iron deficiency anemia. And while elevated hepcidin levels are associated with low incorporation of iron, and low response to oral iron therapy. So some conclusions for the section are we have to be careful about how we define normal hemoglobin values.

Carlo Brugnara (09:18):

We have to be careful about that there's no magic biomarker. And so we had to address the methodological and biochemical parameters cap off to the particular condition of the patient. The pathophysiology of [inaudible 00:09:36] is certainly complex and multifactorial when dealing with chronic disease. And hepcidin is a promising marker for both IRIDA, and for predicting the response to iron replacement therapy. And these are some suggested readings. For the treatment side, it's clear what are the indication for oral iron and for IV iron therapy. And they're outlined here in this slide. It's certainly, for IV iron therapy, intolerance or unresponsiveness to oral iron, and also conditions that require rapid replacement, or after bariatric surgery or condition in which we know the oral iron absorption is poor. There are several approved formulation of iron, this slide outlines the ones that are approved for total iron replacement, as well as the appropriate dosing.

Carlo Brugnara (10:36):

And so in both iron dextran as well as ferumoxytol, ferric carboxymaltose, and iron isomaltoside, are approved for a dose that can provide a total iron replacement, and the references for some of these are outlined below in this slide. What are the adverse events for iron supplementation? For oral iron, pretty clear that there is a high frequency of constipation, less often is diarrhea, but also nausea, cramping, and problem with stools. Intravenous iron, there are infusion reactions that are usually mild in trends, and severe hypersensitivity is a rare event. In the oral iron therapy, there have been some new findings that are associated with the timing of oral iron administration and the associated changes in hepcidin. So studies have shown that a single oral dose of iron induces a rise in hepcidin. And as you know, hepcidin is a negative regulator by metabolism. So this increased hepcidin turns off the absorption of oral iron. So the concept has emerged that the next oral iron administration should be timed when this peak in hepcidin subsides.

Carlo Brugnara (12:24):

And so studies have actually shown the alternate dosing of iron is much more efficient in promoting iron absorption than the daily dose, and the advantage of this alternate dosing is not only to have more iron absorption, but also to reduce the side effect associated with oral iron administration, especially with the GI. So I think the field is moving toward a shifting from daily to alternate daily oral iron supplementation. What about the IV iron safety? Multiple trials had been performed, and this work in the Mayo clinic proceeding, look at pool data from more than 10,000 patients, treat them with IV iron, comparing them with oral iron, a placebo, or no iron. And overall, there was no increase in the risk of severe adverse event with IV iron compared to control. And also there was no difference in either efficacy or toxicity among the formulation that there was studied in this retrospective study.

Carlo Brugnara (13:50):

However, the highest quality of evidence come from randomized clinical trial that are designed to compare and to assess the incidence of a severe hypersensitivity reaction. And when these are becoming now pre-specified primary or secondary end points. So these studies have more power than retrospective studies in answering the question about the incidents of severe hypersensitivity reaction. Iron sucrose has consistently shown to have a low risk of hypersensitivity. And from a regulatory authority perspective has been considered the benchmark for comparing a different iron formulation. Again, when one looks at hypersensitivity reaction. So I'm going to briefly outline some clinical trials that have tried to answer this question in a randomized clinical fashion. This study, it's actually two trial, was powered to look at the incidents of serious and severe hypersensitivity reaction for iron isomaltoside compared with iron sucrose.

Carlo Brugnara (15:18):

And then this trial showed actually that there was no significant difference in the frequency of patient with serious or severe hypersensitivity reaction between the two groups. So this was a study showing, that basically the two formulations were equivalent. When you look at severe sensitivity reaction, this study, the first study again, was a randomized multicenter double-blind trial, comparing ferric carboxymaltose for the treatment of iron deficiency and was designed to formally investigate the rates of hypersensitivity reaction. This study took place in over 129 sites in the U.S., and Europe, and Canada and included adults with iron deficiency, or virus etiology, were mostly GI disorder, as well as chronic kidney disease and also women with abdominal uterine bleeding, and the study compare, ferric carboxymaltose with ferumoxytol in a one-to-one fashion and allow the administration of two doses of these IV iron preparations.

Carlo Brugnara (16:43):

So they had the slightly different total dose, but both were total iron replacement. And the primary endpoint for these two compounds were the moderate or severe hypersensitivity reactions, and the study basically showed that there were no statistically significant difference for any of these endpoints. And as well as that the main change of hemoglobin from baseline to week five was similar for the two preparations. And so basically this study shows no difference in these severe hypersensitivity reactions, this third, a large trial, again, composed of two identical design, an open label trial compare a single infusion of a hundred milligram of one iron preparation, versus two infusion of ferric carboxymaltose. And again, the studies show no differences in the hypersensitivity reactions between these two compounds.

Carlo Brugnara (18:09):

So overall we can say that the risk difference, and the risk of adding a severe hypersensitivity reaction, is not different between all these preparations. And so they're equally safe and equally likely to have, or not have, a severe hypersensitivity reaction. Also, worth mentioning is pregnancy, because I think pregnancy is becoming now an area which IV iron is becoming more accepted and more investigated. And so the more studies showing or examining the benefit of IV iron replacement in pregnancy, the last area that I'd like to address is the one of hypophosphatemia. And this is based on the fact of the description of severe hypophosphatemia in a patient being treated with the ferric carboxymaltose, and has been highlighted in the updated label from the AMA for this practice.

Carlo Brugnara (19:32):

I'd like to briefly review the studies and the evidence that brought about this change in labeling. And this is based on the central role that FGF23 has in the regulation of phosphate metabolism. And as shown in this slide, FGF 23 is a very powerful stimulator of phosphaturia, at the same time that it inhibits phosphate production. And the unique feature of FGF23 is it's cleavage, after it is being postulationally modified, and the two different postulation modification of this hormone, either glycosylation or phosphorylation. But the key is that the hormone can be cleaved, and be divided into an N-terminal fragment and a C-terminal fragment. And based on the assays that are used to detect this compound, this form, intact FGF assay will pick the intact molecule. While a C-terminal FGF23 assay will pick up both intact molecule, it will also pick up the cleavage site.

Carlo Brugnara (21:12):

So studies have shown that after an administration of iron, there's a substantial reduction in the C-terminal FGF23 assay data. But if we look at the intact FGF23, the iron dextran and ferric carboxymaltose gave very different results. And as you see here with ferric carboxymaltose, we have a substantial increase in the intact FGF23. So these two compounds have two totally different behaviors when we look at the total molecule. While they seem similar when you look at the C22 terminal, and this translates into quite different physiological responses because the intact terminal is associated with obviously the development of hypophosphatemia. And as you see here in the two groups, the behavior for phosphatemia is quite different for dextran and for ferric carboxymaltose, and as well as in the behavior for a 25, 125 vitamin D, calcium, and peptide hormone.

Carlo Brugnara (22:53):

So the third trial is a trial that compare ferumoxytol versus ferric carboxymaltose. Specifically looking at some of these endpoints for phosphate metabolism. As shown in the other trial, the ferric carboxymaltose was associated with a very significant change in the FGF intact, while again, the C-terminal value were the similar for the two groups. And there was a very substantial portion of patients who develop a hypophosphatemia with the ferric carboxymaltose at both one week, and two weeks, and also five weeks. And this was present both in patient who had chronic kidney disease, and much more so in patient who did not have chronic kidney disease. And so the effect was more pronounced with normal kidney function, but was present in patients with chronic kidney disease. These other trials were two identical design trial, again, randomized to either iron isomaltoside or ferric carboxymaltose, and the primary endpoint was incidence of hypophosphatemia.

Carlo Brugnara (24:36):

The hypophosphatemia was much more prevalent with the use of ferric carboxymaltose compared with the other iron form, as shown in this slide. And as well as the changes in intact FGF value, in serum phosphate, and in urinary fractional excretion of phosphate, they were all substantially different in the ferric carboxymaltose versus the iron. And as you see here, the inactive 25, they are dosing Vitamin D, in the third panel was substantially higher in the patient taking ferric carboxymaltose, as well as the intact peptide hormone, and the alkaline phosphatase value, and the ionized calcium. So what's the bottom line from all these studies? Ferric carboxymaltose does replete iron store, but induces high rate of hypophosphatemia.

Carlo Brugnara (25:50):

And this IV iron induced hypophosphatemia is an under-reported and underappreciated side effect. The mechanism involved acute increases in intact FGF 23, and the effect is magnified in patients with normal kidney function. But is present even in patients with chronic kidney disease. So more studies are needed to precisely define the mechanism that this distribution and duration of hypophosphatemia and what are the potential consequences of this hypophosphatemia in either a patient with heart failure or with, or without chronic kidney disease. And we still don't know, and we should study what is the long-term effect of single or multiple episodes of hypophosphatemia on muscle health. And this is the end of my summary. Thank you so much for listening.

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