Characterization of serum phosphate levels over time with intravenous ferric carboxymaltose versus placebo as treatment for heart failure with reduced ejection fraction and iron deficiency: An exploratory prospective substudy from HEART‐FID

Abstract Aims Ferric carboxymaltose (FCM) is guideline‐recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well‐established safety profile, the magnitude and clinical significance of FCM‐induced hypophosphataemia in HFrEF remains unclear. This pre‐specified substudy of HEART‐FID evaluated serum phosphate, 1,25‐dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM. Methods and results HEART‐FID was a randomized, double‐blind, placebo‐controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25‐hydroxyvitamin D, 1,25‐dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients ( n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (−0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate‐to‐severe hypophosphataemia. Reductions in 1,25‐dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25‐hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported. Conclusions Transient moderate‐to‐severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25‐dihydroxyvitamin D decrease and PTH increase. Serum levels of 25‐hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM‐related hypophosphataemia to be clinically benign and transient in HFrEF.