IV Iron Replacements Go Head-to-Head for IBD-Related Anemia

Despite comparable effects on hemoglobin and iron stores, one modern IV iron replacement therapy led to a much higher incidence of hypophosphatemia in patients with inflammatory bowel disease (IBD)-related anemia, according to a randomized study from Europe.

In the PHOSPHARE-IBD trial, which involved 97 IBD patients with iron deficiency anemia, incidence of hypophosphatemia was significantly higher for those assigned to receive ferric carboxymaltose (FCM; Injectafer) compared with ferric derisomaltose (FDI; Monoferric), reported Heinz Zoller, MD, of the Medical University of Innsbruck in Austria, and colleagues.

From baseline to 35 days, hypophosphatemia -- evidenced by serum phosphate levels below 2.0 mg/dL -- was recorded at any time in 51% of patients on FCM versus 8.3% of those on FDI (adjusted risk difference -42.8, 95% CI -57.1 to -24.6, P<0.0001), the group wrote in Gut.

Investigators used identical hemoglobin- and weight-based dosing for the two products, to rule out a potential confounding factor in prior trials. The highest incidence of hypophosphatemia occurred within the first 2 weeks of infusion, and remained elevated in the FCM group at 70 days (59.2% vs 12.5%, P<0.0001).

"Despite equal efficacy and no differences in hypersensitivity reactions, the two most frequently prescribed modern IV iron formulations in Europe have a distinct safety profile, in that ferric derisomaltose can be considered the safer drug," Zoller told MedPage Today.

Iron deficiency anemia is a common extraintestinal complication of IBD that can impair physical and cognitive function and increase the risk for hospitalization. As noted, FCM and FDI showed comparable efficacy in correcting iron deficiency anemia, with a nearly identical rise in hemoglobin by 70 days (25.2 vs 24.9 g/L, respectively).

Past observed differences in rates of hypophosphatemia between the two iron replacement products have been in part attributed to the severity or etiology of the iron deficiency, patients' underlying kidney function, and to the different dosing schedules of the IV products. A prior randomized study comparing the two iron replacement therapies, the U.S. PHOSPHARE-IDA trial, also showed higher hypophosphatemia rates with FCM, but the dosing and administration schedules differed based on their respective FDA-approved prescribing information.

"The present trial also shows that, despite recovery from hypophosphatemia, the time course of the cascade of biochemical changes associated with high FGF23 [fibroblast growth factor 23] expression (termed the '6H syndrome') is protracted in FCM-treated patients," wrote Zoller and colleagues.

"In particular, bone-specific [alkaline phosphatase] remained elevated on day 70 in the FCM group relative to the FDI group, implying that there are effects of FCM on bone turnover during the entire trial period and beyond," they continued. "This finding could link hypophosphatemia with osteomalacia, which is an increasingly reported complication of FCM that has been recently included as a specific warning in the FCM Patient Information in Europe."

Zoller told MedPage Today that further research "is focused on understanding why these two drugs differ with respect to induction of FGF23, which is the hormone that elicits the complex response resulting in hypophosphatemia to avoid this side effect in future drug development and understand the biology of this dysregulation."

PHOSPHARE-IBD was a double-blinded randomized trial that enrolled 97 IBD patients -- ulcerative colitis (UC) in 61%, Crohn's disease (CD) in 39% -- with iron deficiency anemia presenting at 20 outpatient hospital clinics in Europe from 2018 to 2020.

For eligibility, patients needed to have serum ferritin levels of 100 ng/mL or lower, hemoglobin levels below 130 g/L, and had to be in need of rapid iron administration or be intolerant/non-responsive to oral iron, among other criteria.

Participants were randomized 1:1 to receive identical hemoglobin- and weight-based dosing of FDI or FCM at baseline and at 35 days. For patients with hemoglobin levels below 100 g/L, a total dose of 1,500 mg was given for those who weighed under 70 kg and a dose of 2,000 mg was given to patients weighing 70 kg or more. Patients with hemoglobin levels of 100 g/L or above received a total dose of 1,500 mg.

"Considering the trial design, it can be concluded that the observed differences in hypophosphatemia rates are caused solely by differences in iron formulations," wrote Zoller and colleagues, "and are not attributable to differences in total iron dose, administration schedule, CD versus UC, or other patient-related factors such as kidney function, severity of inflammation, degree of iron deficiency, or vitamin D deficiency."

The mean age of patients in the study was 42 years, 53% were women, most were white (86%), and their average body mass index was 27.6. Mean hemoglobin levels at baseline were 105 g/L.

Rates of adverse events (AEs) and serious adverse events (AEs) were similar between the products, but most were mild (80-83%). The FCM group experienced more vitamin D deficiency than the FDI group (35% vs 23%) and more instances of nasopharyngitis (20% vs 17%). In the FDI group, headache was more common (19% vs 10%) as was nausea (13% vs 2%). More patients in the FDI group discontinued due to AEs (6% vs 2%).

Although both interventions led to improvements in patient-reported fatigue scores, greater and faster improvements were seen in the FDI group, though this difference lost significance by 70 days.

Limitations to the data included the short follow-up time, which did not allow for clinical consequences to be fully evaluated.

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