A response by Strauss et al. to “a comment on the comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia”
Authors: William E. Strauss, N. Franklin Adkinson, Iain C. Macdougall, Michael Auerbach, Robert F. Kaper, Glenn M. Chertow, Julie S. Krop
Journal: American Journal of Hematology (2018)

We thank Mundy and Wohlfeil for their interest in our study addressing the comparative rates of hypersensitivity reactions, including anaphylaxis by means of a large double-blind randomized controlled trial comparing ferumoxytol and ferric carboxymaltose (FCM).1 The study robustly demonstrated the statistically significant noninferiority of ferumoxytol versus FCM regarding the primary endpoint: the composite of moderate to severe hypersensitivity reactions (HSRs), including anaphylaxis and moderate to severe hypotension (P < .0001). Mundy and Wohlfeil have raised several questions about the study.2 First, they suggest that the population represented only a “narrow study population” due to three exclusion criteria: patients with a history of allergy to intravenous iron, multiple drug allergies, or hypotension. While the sponsors of comparative trials investigating FCM have previously excluded patients with “prior hypersensitivity to FCM or iron sucrose,” we did feel it was prudent to exclude those who had had such a reaction to any of the currently available IV irons. As noted, we also excluded those who had a history of multiple drug allergies due to data from studies with other IV irons that hypersensitivity reactions may occur more frequently in those cases. Finally, at the request of the FDA, we excluded patients whose baseline SBP was <90 mmHg or DBP <60 mmHg, as further decrease in BP, a potential adverse reaction associated with all IV irons, might place patients at additional risk. Clinically, this also would be considered prudent. We do not believe that many patients were excluded on the basis of these exclusion criteria and, thus, we strongly believe that the population of patients studied in this trial was representative of patients with iron deficiency anemia that a clinician would consider treating with an IV iron. In any case, no matter how selected the population is, or not, it would not affect the comparison between ferumoxytol and FCM due to the randomized design. To the second point, we do agree that the cited confidence interval of 0.4-0.1 as published in the original open access version was incorrect due to a transcription error that assessed a negative sign to represent a dash. The correct legend should be “−0.2 (−0.4, −0.1)” for the treatment difference for mean change in Hgb from baseline to week 5; and 0.3 (0.2, 0.4) for the treatment difference for mean change in Hgb per gram of iron administered. This error was corrected prior to the publication of the print issue May 2018. Given that 50% more iron was administered to those receiving FCM, we leave it to the clinician to decide whether the approximately ¼ g/dL increase in Hgb in either direction is clinically relevant. We agree with Mundy and Wohlfeil that a number of ranges for serum phosphate are reported in the literature. However, we believe that more germane than the “shading” for the figure is that the cut-off point of <2.0 mg/dL (0.6 mmol/L) is defined as “severe hypophosphatemia” according to the Common Terminology Criteria for Adverse Events of the NCI. According to that definition, severe hypophosphatemia occurred in 38.7% of patients exposed to FCM (compared to 0.4% of patients exposed to ferumoxytol). This figure is not dissimilar from those reported in the literature and the FCM Prescribing Information. Our study was not intended to evaluate symptomatic hypophosphatemia; however, given the large size of the study we felt it appropriate to confirm the rate. Given that reports are accumulating that the hypophosphatemia induced by FCM treatment is neither always benign nor transient,3 we believe that increasing the awareness of this common adverse reaction to FCM to clinicians is warranted. Indeed, a publication of a recent study makes a strong clinical recommendation to measure serum phosphate levels in patients using FCM and in certain situations take more drastic action, “such as reducing the dose of FCM or using an IV iron preparation not associated with phosphate wasting… in order to prevent potential FCM-associated morbidity and hospital readmissions”.4 Finally, we are unclear as to what Mundy and Wohlfeil intend by the suggestion that the serious cardiovascular (CV) event analysis by “proportional mortality ratio” was only applied to a subgroup and not the full studied population. Both mortality rate and the rate of serious CV events were measured across the entire study population. However, we agree that the study was neither designed nor expected to uncover CV events broadly. Serious CV events and deaths were included as part of the secondary composite endpoint at the request of the FDA, because CV symptoms could emerge in patients with a hypersensitivity reaction. Of note: none of the six CV events in the ferumoxytol treated cohort were considered related to the study drug by the investigator and only three of the 13 in the FCM cohort were considered related to the study drug. Nothing to report.