Retrospective observational analysis of ferric pyrophosphate citrate (triferic®) administered via dialysate. Experience at a single facility over 2 years

Background: Ferric pyrophosphate citrate (FPC, Triferic®) is a unique form of iron therapy that is indicated to maintain iron balance and hemoglobin concentration in adult hemodialysis patients. We conducted an analysis of observational data from an independent dialysis facility that has administered FPC via the central delivery system to all patients in the facility over a 2-year period to determine if FPC would offer pharmacoeconomic benefi ts over the current anemia management protocol that was used at the dialysis facility. Methods: FPC was administered in the dialysate to 61 patients via the central delivery system from fi rst quarter 2017 through fourth quarter 2018.Anonymized data were obtained from the Electronic Medical Record of the dialysis facility. Data were summarized descriptively. The analysis used the last quarter (3 months) of data before initiation of FPC as baseline values. Data were aggregated by quarter and presented as total administered dose, average dose per patient or as average per patient-year exposure. Results: FPC reduced the need for supplemental intravenous iron use by an average of 74% over the 2-year observation period and reduced the amount of erythropoietin-stimulating agents needed to maintain hemoglobin levels within the target range of 10.0 to 11.0 g/dL. Small mean improvements in quality of life were observed, as assessed by the 36-item Kidney Disease Quality of Life Questionnaire (KDQoL-36TM) mental and physical component scores. As compared with US Renal Data System (USRDS) data, all-cause hospitalizations, infection-related hospitalizations, and deaths were reduced by approximately 50% after initiation of FPC. Conclusions: Implementation of FPC as an iron maintenance therapy for all patients in a chronic hemodialysis center may result in improvements in anemia management and patient outcomes and in pharmacoeconomic benefi ts to the dialysis center. Research Article Retrospective observational analysis of ferric pyrophosphate citrate (triferic®) administered via dialysate. Experience at a single facility over 2 years Marc Hoffman1, Richard Delvalle2 and Raymond D Pratt1* 1Rockwell Medical, Inc, Wixom, Michigan, USA 2Center for Renal Replacement, Lincolnwood, Illinois, USA Received: 13 May, 2021 Accepted: 16 June, 2021 Published: 17 June, 2021 *Corresponding author: Raymond D Pratt, MD, Rockwell Medical Inc, 30142 S Wixom Rd, Wixom, MI, 48335, USA, Tel: 248-960-9009; E-mail:


Introduction
Ferric pyrophosphate citrate (FPC, Triferic ® ) is a unique form of iron therapy indicated to maintain iron balance and hemoglobin concentration in adult hemodialysis patients.
FPC is a low-molecular-weight iron salt that is added to the liquid bicarbonate and that is subsequently mixed with acid concentrate and water to produce a dialysate with 110 μg iron/ liter. FPC diffuses across the dialyzer membrane to enter the blood compartment. FPC does not require processing by macrophages; rather, it donates iron directly to transferrin, bypassing the hepcidin block to iron metabolism and avoiding sequestration within reticuloendothelial macrophages [1]. FPC is rapidly cleared from plasma, with a half-life of Citation: Hoffman  Clinical studies have shown that administration of FPC at each hemodialysis can maintain hemoglobin concentrations, reduce the need for intravenous iron, and improve the effi ciency of erythropoiesis, thereby reducing the need for Erythropoiesis-Stimulating Agents (ESAs) [3]. As only small quantities of FPC are transferred from dialysate to blood, body iron stores are not increased [4].
The initial use of FPC that was approved by the US Food and Drug Administration was for the addition of 27.2mg iron to a 2.5-gallon liquid bicarbonate concentrate formulation to be used in conjunction with acid concentrate in a compatible hemodialysis machine. A subsequent New Drug Application was approved for a FPC powder packet for dialysis facilities that use central delivery liquid sodium bicarbonate systems. This approach uses a 272mg iron per packet that is added to 25 gallons of liquid sodium bicarbonate in the central bicarbonate mixing system for mix, transfer and distribution to all hemodialysis machines in the clinic.
We report observational data from an independent dialysis facility that has administered FPC via the central delivery system to all patients in the facility over a 2-year period. The facility initiated a trial of FPC when the powder packets became available to determine if FPC would offer pharmacoeconomic benefi ts over the then current anemia management protocol that was used at the dialysis facility.

Methods
Data from the Electronic Medical Record (EMR) of the dialysis facility was anonymized by an external contract research organization. Institutional approval was obtained for the study procedures from the relevant administrative offi ces in which the study was conducted. Administration of FPC was initiated in the fi rst quarter 2017; data through the fourth quarter 2018 were available. Hospitalizations were provided by the EMR at the dialysis facility and were confi rmed by data from the 2016/2017 US Renal Data System (USRDS) hospitalization fi le that was linked to the facility fi le. Missed treatments were obtained from the EMR.
Anemia was managed using epoetin alfa or darbepoetin alfa (starting at 45μg/kg), which was titrated to maintain the hemoglobin concentration between 10.0 and 11.5g/dL. Because the clinic changed from epoetin alfa to darbepoetin during the observation period, ESA use was calculated as darbepoetin equivalents using the established conversion (epoetin units divided by 300 = darbepoetin equivalents in micrograms).
FPC was administered via dialysate at an iron concentration of 110μg/L fi nal dialysate to all patients via a central bicarbonate delivery system. FPC was added to the central bicarbonate mixing system at a ratio of 1 to 272mg iron powder packet for each 25 gallons of liquid sodium bicarbonate. Supplemental iron gluconate (IV Fe) was administered, when necessary, according to a protocol that was based on serum ferritin and TSAT values ("rescue" iron). All patients who received intravenous iron received single doses of 125mg elemental iron up to a maximum of 500 mg iron per month when criteria for supplementation were met. Patients received IV Fe when the serum ferritin was <200 μg/L and TSAT was <30% or when TSAT fell below 20%.
Data were analyzed by an independent contract research organization. The analysis plan included descriptive statistics (mean, standard deviation, median, minimum, maximum), as well as trends. Comparative statistics were performed using JMP 15.2.1, SAS Institute Inc. The analysis used the last quarter (3 months) of data before initiation of FPC as baseline values. Data were aggregated by quarter and presented as total administered dose or average dose per patiente. The primary analysis included data on ESA and intravenous iron administration. Laboratory data included hemoglobin, serum iron, and ferritin concentrations.
Health-related quality of life was measured using the 36-item Kidney Disease Quality of Life Questionnaire (KDQoL-36™), which was administered to patients on a yearly basis. Results were obtained from the EMR at the dialysis facility.
The pharmacoeconomic impact of Triferic adoption was assessed using Centers for Medicare & Medicaid Services (CMS) 2018 data on actual selling price for darbepoetin and iron gluconate as well as 'bundled' reimbursement for dialysis services. The economic impact of hospitalization was calculated based on weighted national estimates from the Healthcare Cost and Utilization Project (HCUP) National (Nationwide) Inpatient Sample for the cost of an average inpatient day.

Results
The patient profi le of all patients included 61 patients who provided data during the observation period (Error! Reference source not found.). Mean age was 62 years, and mean weight was 78 kg; 51% of patients were men, and 51% of patients had a diagnosis of diabetes mellitus. Primary causes of end-stage kidney disease included diabetes, hypertension, glomerulonephritis, transplant failure, and acute kidney injury. Baseline laboratory values for hemoglobin, serum iron, TSAT, and serum ferritin were within the expected ranges for a chronic hemodialysis population. The number of patients in the analysis ranged from 61 in the fi rst quarter to 57 in the fi nal quarter ( Figure 1).
During the baseline period (months -3 to 0), total iron gluconate administration was 21,750 mg per quarter (105.5 mg iron/patient/month). After initiation of FPC, iron administration decreased by 56.2% (46 mg/patient/month) in the fi rst quarter. Over the next 5 quarters, further reductions in use of iron gluconate were observed, resulting in an average iron requirement of 33.3 mg iron/patient/month (68.4% reduction from baseline). Although some patients required intermittent intravenous iron, the reduction in use was sustained throughout the 2-year observation period.

Discussion
This report is the fi rst report to demonstrate the use of center-wide administration of FPC to all patients. FPC is a  maintenance iron replacement treatment and was expected to reduce the requirement for supplemental intravenous iron therapy. The results that were observed during use of FPC for a 2-year period support those that have previously been reported in clinical studies [3,4]. Because only small quantities of iron are administered with FPC (approximately 6.5 mg/ treatment), iron losses due to blood trapping in the dialysis circuit, phlebotomy, and gastrointestinal losses are replaced to maintain hemoglobin concentration [4]. FPC donates iron directly to transferrin avoiding the hepcidin block to iron metabolism and may improve the effi ciency of erythropoiesis [1]. This has been shown in a double-blind placebo-controlled trial [3] and now in this analysis of a single dialysis facility that has used FPC for over 2 years.