Risk for anaphylaxis from IV iron overall ‘very low,’ but varies between formulations

Michael Auerbach, MD, FACP

The problem with these findings is the definition of anaphylaxis. The researchers used surrogates such as the administration of epinephrine as a definition of anaphylaxis, when practitioners often overreact inappropriately with vasopressors for minor infusion reactions.

The largest head-to-head studies of ferumoxytol, ferric carboxymaltose and iron sucrose, consisting of thousands of patients, including double-blind studies, showed zero difference in hypersensitivity reactions. This study’s methodology is seriously flawed.

Also, because this study used Medicare codes, it excluded the vast majority of patients who receive IV iron, including dialysis, heavy uterine bleeding, pregnancy, most inflammatory bowel disease and most gastric bypass patients. It is very disturbing that such an eclectic population was chosen.

Indeed, serious adverse events (SAEs) with IV iron are vanishingly rare. In an analysis of more than 30 million doses suggested, Chertow and colleagues found that when high-molecular-weight iron dextran is avoided, the incidence of SAEs is less than one in every 250,000 administrations — and high-molecular-weight iron dextran is no longer available. Also in that study, low-molecular-weight iron dextran showed no increase in SAEs compared with iron sucrose, contradicting the results of this study.

IV iron is the choice of therapy for all patients who are intolerant of oral formulations, which is 75% of those to whom it is prescribed. Oral iron worsens the symptoms of inflammatory bowel disease and causes an incommodious growth of the wrong bacteria, negatively altering the microbiome. After bariatric surgery, oral iron is poorly absorbed and very toxic. It cannot keep up with the losses of heavy uterine bleeding as well, and it doesn’t get to the developing infant in the second and third trimesters if the mother is deficient. In these conditions, it should not be front-line therapy.

All of these conditions are indications for first-line IV iron. Misrepresenting the relative safety of IV iron using inferential data that contradict every single head-to-head study ever performed fosters clinically imprudent recommendations about an important treatment modality for the most common nutrient deficiency on the planet.

I have given tens of thousands of doses of both ferumoxytol and low-molecular-weight iron dextran and have never, ever hospitalized a patient. I also have seen zero cases of anaphylaxis, although I have seen minor infusion reactions. These reactions could easily be converted to SAEs with imprudent intervention with epinephrine, which is one of the surrogates that this study used for anaphylaxis. I hope I have made clear how inappropriate this population is for a fair assessment of this extremely rare event.

Additionally, the evaluation of ferumoxytol from 2013 to 2018 is a huge misrepresentation. The early use of ferumoxytol allowed a 17 second bolus of 510 mg, which was way too fast. A huge number of infusion reactions occurred. These events often were misinterpreted as anaphylaxis and treated with vasopressors, with subsequent transformation to SAEs, because doctors believe IV iron causes anaphylaxis. This paper perpetuates that folklore. The current paradigm of 510 mg in 15 minutes or 1,020 mg in 30 minutes obviates this issue. Had the authors done their diligence, this incredibly misleading conclusion would have been avoided.

A different study referenced in this study, by Durup and colleagues, examined more than 180 million doses of IV iron and found exactly the opposite conclusion. Curiously, Dave and colleagues referenced this paper but make no note of its conclusion, which is contrary to theirs.

Using surrogates that are not anaphylaxis, such as wheezing, stridor, periorbital edema and shock, will lead to specious results. Iron sucrose was compared head-to-head to both low-molecular-weight iron dextran and ferumoxytol, and no difference was noted. That is the case with every head-to-head study ever done.

The researchers will argue that the incidence is so rare, you have to use iterations like they did. But it is incredibly disturbing that in every head-to-head study, bar none, these conclusions were not observed.

In the history of medicine, there has never been a cross-reactivity with anti-dextran antibodies with an IV iron formulation — only to dextran as a plasma expander. It is confabulation.

This study’s conclusions are inaccurate, harmful and completely inconsistent with the enormous clinical experience my colleagues and I have with 70,000 to 90,000 doses of IV iron administered. Its misrepresentation of risk fuels the folklore of danger with IV iron and will cause harmful clinical decisions.

References:

Chertow GM, et al. Nephrol Dial Transplant. 2004;doi:10.1093/ndt/gfh185.

Durup D, et al. Expert Rev Hematol. 2020;doi:10.1080/17474086.2020.1738215.

Stephen B. Hanauer, MD

This is a pertinent and relevant study for practitioners treating iron deficiency anemia, the key issue being how safely and efficiently iron stores can be restored using IV iron infusions.

Due to the poor absorption of iron from the gut (5% to 30%) and frequent intolerance to oral iron products, parenteral iron often is required. As with oral iron compounds, IV iron is insoluble and requires a “carrier” for administration, such as dextran, carbohydrate-coated iron oxide nanoparticles, sucrose, gluconate, carboxymaltose or derisomaltose.

Historically, intramuscular iron (dextran) has been painful and has caused tattoos and rare sarcomas, so it has been replaced by IV formulations. Although iron dextran can be administered in sufficient doses to replete iron stores with a single infusion of 1.5 g to 2 g, it requires a “test dose” to avoid anaphylaxis attributed to the dextran component.

Subsequent formulations such as ferric gluconate, ferric carboxymaltose, ferumoxytol and ferric derisomaltose (MonoFerric, Pharmacosmos Therapeutics; not studied in the current trial) require lower doses and more infusions to achieve desired quantities of iron to replace depleted stores.

Although relevant and significant, the results are not surprising as iron dextran was significantly more likely to be associated with anaphylactic reactions. In addition, all the investigated agents were associated with less common anaphylactic reactions, although researchers also reported ferumoxytol (less frequently than iron dextran) to be associated with hospitalizations for anaphylaxis.

These findings are consistent with our gastrointestinal/inflammatory bowel disease practice, where we are accustomed to prescribing parenteral iron replacement for patients who do not tolerate oral iron or for whom active inflammation reduces oral iron absorption related to increased hepcidin levels. We have transitioned away from iron dextran, unless administered by a hematologist, and are cognizant of the risk for hypophosphatemia, which is more prevalent with iron carboxymaltose.

Most doctors are aware of the risks of iron dextran and have migrated to alternative parenteral products despite the need for multiple doses to replace depleted iron stores. They should also be aware of uncommon risks for anaphylaxis and the need to administer in settings prepared to treat anaphylactic reactions included in package insert warnings.

The balance between the risks for anaphylaxis and hypophosphatemia and need for repeated dosing needs to be explained to staff and patients. Protocols can be developed to increase the dose of different formulations along with strategies to mitigate anaphylaxis, such as premedications with steroids, diphenhydramine and acetaminophen, to safely and efficiently restore iron stores.