A comment on the comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia (2018)

The article by Adkinson et al., reported study findings for the comparative safety of ferumoxytol vs ferric carboxymaltose for the treatment of adults with iron deficiency anemia.1 Given the need to exclude patients with a history of allergy to intravenous iron, multiple drug allergies, systolic blood pressure (BP) ≤90 mm Hg, or diastolic BP ≤60 mm Hg, only a subset of adults with iron deficiency anemia were comparatively studied. As listed in the ferumoxytol USP, these exclusion criteria are either a contraindication (history of allergic reaction to any intravenous iron product) or warning and precautions (greater risk of anaphylaxis in patients with multiple drug allergies; may cause clinically significant hypotension).2 Notably, these trial exclusion criteria are not contraindications, warnings, or precautions for prescribed use of ferric carboxymaltose USP.3 Notwithstanding, non-inferiority was achieved in terms of safety, measured as the 5-week composite incidence of (1) moderate-to-severe hypersensitivity reactions (HSRs), including anaphylaxis, and moderate-to-severe hypotension (primary safety end point), and (2) moderate-to-severe HSRs, including anaphylaxis, serious cardiovascular events, and death (secondary safety end points).4 Beyond the acknowledgement of the narrow study population, there are four reported FIRM study findings noteworthy of mention. First, fig. 1A provides a graphic comparison of the secondary efficacy end point displayed as the least squares mean changes in hemoglobin from baseline to the week 5 time point. The fig. 1A legend reports “Treatment difference (95% CI) = −0.2 (0.4-0.1).” Given the entire 95% confidence interval (CI) is below zero, the fig. 1A legend should state “Treatment difference (95% CI) = −0.2 (−0.4 to −0.1).” This error warrants correction of the secondary efficacy end point for hemoglobin treatment effect, and confirms that ferric carboxymaltose had a statistically significant increase in hemoglobin treatment effect compared with ferumoxytol. Second, serum phosphate is graphically displayed via shading in fig. 2A as a normal range of 3.5-4.5 mg/dL, with citation of a textbook chapter from the year 1990.1 More current reference parameters use serum phosphate values with a normal range of 2.5-4.5 mg/dL.5 Notably, this range is twice as wide as the shaded area in fig. 2A of the published article by Adkinson et al.1 Third, while the proportion of the group treated with ferric carboxymaltose who experienced a change from baseline serum phosphate to a laboratory value of less than 2.0 mg/day was 38.7%, the proportion of the same group deemed to have a treatment-emergent adverse event of hypophosphatemia was 1.8% (reported solely in the online Supporting Information Table S1). These two different measures, studied in the registrational trials for ferric carboxymaltose, are reported as similar proportions in the ferric carboxymaltose USP.3 Lastly, the study was designed to focus on acute moderate-to-severe HSRs as primary and secondary safety end points, and the isolated use of proportionate mortality ratio (PMR) in the report of serious cardiovascular events (Section 3.3), but not the full studied population, is potentially misleading as stated. The report of these events should use the denominators for the studied safety population, not the isolated use of PMR, which is a measure that may be more appropriate of mention in the Discussion section, with inclusion of caveats that further inform on this specific measure. Since ferric carboxymaltose was approved for use by the European Medicines Agency in 2007, the product is marketed for use in 70 countries and continues to have a positive benefit-risk balance for the treatment of iron deficiency anemia. As disease awareness of iron deficiency anemia continues to evolve over the next several years, treatment options for iron repletion will be informed by benefit-risk initiatives that minimize life-threatening acute risks of HSR reactions and promote treatment in various patient populations.