Hypophosphatemia after High Dosage Iron Substitution with Ferric Carboxymaltose (FCM) and Iron Isomaltoside (IM) — the Randomised Controlled Home Afers 1 Trial

In iron deficiency anaemia patients, intravenous administration of either ferric carboxymaltose (FCM) or iron isomaltoside (IM) both allow high dosage iron substitution within a single outpatient visit. In contrast, other iron compounds require repetitive, low dosage infusions. Recently, FCM was reported to frequently induce acute, reversible hypophosphatemia. It remains enigmatic whether these hypophosphataemic effects of FCM are substance-specific, or whether they generally occur after high dosage iron substitution. A direct comparison of phosphorus regulation after high dosage iron substitution with either FCM or IM is clinically important, as hypophosphatemia after FCM has anecdotally been associated with osteomalacia and bone fractures.

In the HOMe AFers 1 (HOMburg evaluations on application of Ferrum study 1) trial, we recruited normophosphatemic women with gynaecological bleeding and subsequent iron deficiency anaemia, in whom we assessed the longitudinal biochemical response over 28 days to a single intravenous injection of equivalent doses of randomly-assigned FCM and IM (1000 mg). The primary study hypothesis was that the incidence of hypophosphatemia - defined as plasma phosphorus < 2.0 mg/dl at least out of three post-infusion study time points (day 1, day 8, and week 5) - differs between FCM and IM. HOMe AFers 1 initially planned to recruit 60 women. An interim analysis was pre-specified and scheduled in July 2018, with the option to stop further patient recruitment if the incidence of hypophosphatemia differs significantly at this interim analysis.

At the time point of the interim analysis, 26 patients have been recruited. One patient withdrew her acceptance to participate after day 1, leaving 25 patients for our per protocol interim analysis. Baseline plasma phosphorus did not differ significantly between FMC (3.3 ± 0.4 mg/dl) and IM (3.6 ± 0.6 mg/dl; p = 0.135). Analysis on the primary endpoint demonstrated that significantly more women developed hypophosphatemia < 2.0 mg/dl after FMC infusion (9 out of 12 patients) than after IM infusion (1 out of 13 patient) (p=0.001). Further, the minimum plasma phosphorus during any of the three post-infusion study time points was lower after FMC (1.8 ± 0.3 mg/dl) than after IM (2.7 ± 0.6 mg/dl; p < 0.001). As expected, ferritin and haemoglobin increased in both study groups after iron infusion. No severe adverse events occurred in either group.

In conclusion, while both FCM and IM provide efficient iron substitution in iron deficiency anaemia, FCM induced a substantially higher incidence of hypophosphatemia.