Ferric citrate controls phosphorus and delivers iron in patients on dialysis

Abstract

Patients on dialysis require phosphorus binders to prevent hyperphosphatemia and are iron deficient. We studied ferric citrate as a phosphorus binder and iron source. In this sequential, randomized trial, 441 subjects on dialysis were randomized to ferric citrate or active control in a 52-week active control period followed by a 4-week placebo control period, in which subjects on ferric citrate who completed the active control period were rerandomized to ferric citrate or placebo. The primary analysis compared the mean change in phosphorus between ferric citrate and placebo during the placebo control period. A sequential gatekeeping strategy controlled study-wise type 1 error for serum ferritin, transferrin saturation, and intravenous iron and erythropoietin-stimulating agent usage as prespecified secondary outcomes in the active control period. Ferric citrate controlled phosphorus compared with placebo, with a mean treatment difference of -2.2±0.2 mg/dl (mean±SEM) (P<0.001). Active control period phosphorus was similar between ferric citrate and active control, with comparable safety profiles. Subjects on ferric citrate achieved higher mean iron parameters (ferritin=899±488 ng/ml [mean±SD]; transferrin saturation=39%±17%) versus subjects on active control (ferritin=628±367 ng/ml [mean±SD]; transferrin saturation=30%±12%; P<0.001 for both). Subjects on ferric citrate received less intravenous elemental iron (median=12.95 mg/wk ferric citrate; 26.88 mg/wk active control; P<0.001) and less erythropoietin-stimulating agent (median epoetin-equivalent units per week: 5306 units/wk ferric citrate; 6951 units/wk active control; P=0.04). Hemoglobin levels were statistically higher on ferric citrate. Thus, ferric citrate is an efficacious and safe phosphate binder that increases iron stores and reduces intravenous iron and erythropoietin-stimulating agent use while maintaining hemoglobin.

Keywords: anemia; clinical trial; dialysis; phosphate binders.

Figure 1.

Disposition of subjects in the trial. AP, active control period; PP, placebo control period. *Four subjects on calcium acetate stopped calcium acetate and switched to ferric citrate because of persistent hypercalcemia. **Four subjects entered the final 4-week placebo control period who were ineligible, because they did not complete the 52-week active control period on ferric citrate.

Figure 2.

Serum phosphorus levels (milligrams per deciliter) by study time point during the 52-week active control period, with missing values imputed using the last follow-up observation carried forward. Box plots display 5th, 25th, 50th, 75th, and 95th percentiles. Under the repeated measures mixed effects model, the mean difference in serum phosphorus between the ferric citrate and active control groups over weeks 12, 24, 36, 48, and 52 was −0.0127 mg/dl (95% confidence interval, −0.056 to 0.030 mg/dl). AC, active control; FC, ferric citrate.

Figure 3.

Iron parameters by study time point during the 52-week active control period. (A) Serum ferritin and (B) serum TSAT, with missing values imputed using the last follow-up observation carried forward. Box plots display 5th, 25th, 50th, 75th, and 95th percentiles. AC, active control; FC, ferric citrate.