Is low-molecular weight iron dextran really the most risky iron?-Unconvincing data from an unconvincing study
Authors: Thomas G. DeLoughery, Michael Auerbach
Journal: American Journal of Hematology (2016)

The use of intravenous iron has expanded over the past few years as accepted indications for its use have increased. It is now recognized that intravenous iron will raise iron stores faster and more reliably in conditions in which oral iron is unlikely to work or poorly tolerated such as chronic kidney disease, inflammatory bowel disease, heavy uterine bleeding, hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu), pregnancy, and those having undergone bariatric surgery. However, the acceptance of this effective therapy by physicians has been hindered by concerns about safety of iron infusions. The use of early formulations, such as ferric hydroxide, was associated with high levels of labile free iron release and an unacceptably high incidence of serious hemodynamically significant infusion reactions. By the early 1950s, products with carbohydrate cores which bound the elemental iron more tightly, such as high-molecular weight iron dextran—ImFeron, (Fisons, Homes Chapel, England) and later DexFerrum, (American Regent, Shirley, New York)—which are no longer available, and iron sucrose, were much better tolerated but still associated with rare anaphylactic reactions. Newer formulations which release labile free iron much more slowly, such as low-molecular weight iron dextran (INFeD, Pfizer, New York, NY), ferumoxytol (Feraheme, AMAG, Waltham, MA), ferric carboxymaltose (InjectoFer, American Regent, Shirley, NY), and iron isomaltoside (Monofer, Europe only, Pharmacosmos, Haelbeck, Denmark) are much better tolerated and provide the added convenience of being able to be administered safely in complete replacement doses over 15–60 min. While there are many factors to consider in the choice of iron products—expense, numbers of infusions, effectiveness—safety is also a key factor. One iron product did stand out in risk—high-molecular weight iron dextran (DexFerrum) which has been shown in several studies to have reaction rates higher than other iron products 1-3. This formulation was removed from market in 2009. The accumulated data show that low-molecular weight iron dextran does not share this higher risk. Studies ranging from dialysis database reviews to a European Medical Agency review have shown no difference in risk with low-molecular weight iron dextran versus other iron products 3-5. Recently, this notion of equivalent risk was challenged by a study from the FDA which purported to show a significantly higher rate of "anaphylaxis" with iron dextran compared to other iron products 6. This study examined 688,183 non-dialysis new users of intravenous iron over 10 years in the outpatient Medicare claims database. The anaphylaxis rate for iron dextran was compared to iron gluconate, iron sucrose, and ferumoxytol. The key finding was that the rate of anaphylaxis for iron dextran had an odds ratio 2.6 times higher reaction rate than all non-dextran irons—68 vs. 23 per 100,000 persons. However, there are several issues with this study that cast doubt on the conclusion that low-molecular weight iron dextran is truly the more dangerous iron product. The most striking, as stated in the manuscript, was the inability to distinguish between high- and low-molecular weight iron dextran, both of which were available during the conduct of the study. Another is that cases of anaphylaxis were derived from an algorithm based on ICD-9 codes. Two of the criteria were having the "other anaphylactic shock" code documented, but the third criteria were a combination of codes for allergies, symptoms, and treatments such as the administration of diphenhydramine and steroids. The algorithm was unable to distinguish between the administrations of diphenhydramine for an infusion reaction or the now proscribed premedication with diphenhydramine as prophylaxis. The article does note the potential for false-positive coding for anaphylaxis for mild allergic reactions, respiratory symptoms, or hives—all common infusion reactions. For this study, there was no chart review of a subset of patients to insure the algorithm was correctly identifying patients with anaphylaxis. In fact, one of the studies the authors cite to support their methods noted in their conclusion: "While the overall PPV [positive predictive value] of 63% was higher than previous publications, it remains low for its use in surveillance" 7. The concerns about over coding are heightened by calculation of death rates, not reported in the article, but able to be derived from data in the supplement (Table 1). The iron dextran death rate was numerically the lowest supporting the idea that many of the "anaphylaxis" reactions were actually infusion symptoms and not anaphylaxis. Another concerning issue is the population studied is not representative of the totality of the patients receiving iron. The average age of the study patients was in the 70s and receiving iron for either chronic renal disease or gastrointestinal/genitourinary bleeding. Thus, younger patients and those receiving iron for pregnancy, heavy uterine bleeding, inflammatory bowel disease, iron deficiency associated with bariatric surgery were underrepresented in this results. Finally, this study did not provide a perspective for reaction rates with other commonly used agents. The reaction rates for intravenous iron is in the same range or lower for commonly used drugs such as penicillin, contrast agents, antiseizure medications, and acetaminophen (0.01–0.1% range) and pales in comparison to widely used monoclonal antibodies such as rituximab and infliximab 2. This is supported by a recent meta-analysis of studies including 10,390 patients which concluded that whereas intravenous iron is associated with minor infusion reactions, there is no increase in serious adverse events observed with its administration 4. Studies have shown that true allergic reactions to iron are rare and the symptoms seen with iron infusions are related to infusion reactions seen with other parenteral agents such as rituximab and intravenous gammaglobulin 8, 9. It is now felt that these reactions are due to activation of complement by the labile free iron leading to symptoms such as flushing, myalagias of the chest or flank, or sensations of fullness in the throat. This has been named complement activation-related pseudoallergy 10. This would explain why therapy aimed at true allergic reactions may not be effective and a sign of true allergies such as a rise in tryptase is not seen in patients reacting to iron. One of us (MA) has measured tryptase levels after more than 200 minor infusion reactions. None were elevated. Indeed many of the reactions seen with iron infusions may be actually side effects of therapies given for or to prevent "anaphylaxis." One prospective study reported that the majority of reactions ostensibly attributed to intravenous iron were actually due to premedication with diphenhydramine 11. This knowledge has led to a protocol that treats iron reactions for the infusion reactions they are instead wrongly treated as allergic reactions (Table 2) 9, 11, 12. This includes treating mild reactions (flushing, itching) with holding the infusion for 15 min and if the patient improves resuming the infusion at a reduced rate diphenhydramine is to be avoided. This algorithm emphasizes reassurance that infusion reactions are rare and resolve spontaneously, will ease anxiety. The totality of the data concerning intravenous iron over the past 15 years shows that all currently available intravenous iron products share the same risks. The major challenge for use of iron is not to continue revisiting a settled issue but to make providers aware of the situations where intravenous iron is the treatment of choice and the appropriate treatment of infusion reactions.