Effects of ferric citrate hydrate in patients with chronic kidney disease and heart failure: subgroup analysis of a long-term, real-world, post-marketing surveillance study

Iron deficiency is widely present in patients with heart failure (HF) and is associated with an increased risk of mortality and poor clinical outcomes regardless of anemia. HF is highly prevalent in patients with chronic kidney disease (CKD). However, existing oral iron preparations have failed to improve iron-related parameters in patients with HF, and intravenous iron preparations are recommended. Ferric citrate hydrate (FC) is an oral iron-based phosphate binder for CKD that is also approved for the treatment of patients with iron-deficiency anemia in Japan. In this subgroup analysis, we evaluated the effect of oral FC on iron-related parameters in CKD patients with and without HF. We examined iron- and phosphate-related parameters and adverse drug reactions in subpopulations of CKD patients with and without HF enrolled in a previously reported 104-week, real-world, post-marketing surveillance study of FC in Japan. Among 2811 enrolled CKD patients, 348 patients had HF and 2352 did not have HF, including 166 and 1401 undergoing hemodialysis (HD), 36 and 173 undergoing peritoneal dialysis (PD), and 146 and 778 non-dialysis-dependent (ND) patients, respectively. The mean changes (95% confidence interval (CI)) in serum ferritin from baseline to week 36 were 90.98 (62.99–118.97) and 81.86 (72.68–91.03) ng/mL in HD, 158.64 (108.91–208.36) and 132.91 (98.59–167.23) ng/mL in PD, and 68.06 (40.40–95.73) and 99.75 (81.10–118.40) ng/mL in ND group, respectively. The mean changes (95% CI) in transferrin saturation (TSAT) (%) from baseline to week 12 in patients with and without HF were 12.79 (9.15–16.44) % and 9.57 (8.46–10.68) % in HD, 9.55 (1.31–17.78) % and 4.96 (1.44–8.48) % in PD, and 5.85 (2.02–9.69) % and 5.21 (3.34–7.09) in ND patients, respectively. Levels of these parameters were well maintained thereafter. Mean serum phosphate levels decreased after FC treatment initiation and were well maintained in all groups. This study demonstrated that oral FC had a tendency to increase serum ferritin and TSAT, and controlled serum phosphate in CKD patients regardless of the presence of HF. Trial registration This surveillance was conducted in accordance with the Good Post-marketing Study Practice of Ministry of Health, Labour, and Welfare in Japan.


Background
Patients with heart failure (HF) often have iron deficiency with or without anemia [1,2]. Previous studies showed a high prevalence of these conditions in patients with acute and chronic HF. Iron deficiency, defined as ferritin < 100 ng/mL or 100-299 ng/mL with transferrin saturation (TSAT) < 20%, was found in 50% of patients with chronic HF [3] and 69-75% of patients with acute HF [4], whereas anemia (defined by the World Health Organization as hemoglobin < 13 g/dL in men and < 12 g/dL in women) was found in 30% of patients with advanced HF [5] and 57-58% of patients with chronic or acute HF [6,7]. Anemia and iron deficiency are associated with mortality and poor outcomes in HF patients with reduced or preserved left ventricular ejection fraction (HFrEF or HFpEF) [3,[5][6][7][8]. The 2021 European Society of Cardiology (ESC) guidelines recommend periodical screening for anemia and iron deficiency, and the use of intravenous iron preparations with ferric carboxymaltose to treat this condition [1]. Intravenous iron was shown to increase iron-related parameters and improve the exercise capacity and quality of life of patients with chronic HF [9,10] and to reduce the risk of re-hospitalization in patients who have recovered from acute HF [11]. However, there is currently no evidence to indicate that oral iron preparations can improve outcomes in patients with HF. In the IRONOUT HF randomized trial, oral iron (iron polysaccharide, 150 mg, twice daily for 16 weeks) failed to increase iron absorption (median changes (95% confidence interval (CI)) of serum ferritin and TSAT after 16 weeks of treatment were 18 (− 8 to 38) ng/mL and 2 (− 3 to 7) %, respectively) or improve the exercise capacity or quality of life of patients with HFrEF and iron deficiency [12]. In another randomized study, the erythropoiesis-stimulating agent (ESA) darbepoetin alfa failed to improve mortality and increased the risks of embolic and thrombotic events in patients with systolic HF and mild-to-moderate anemia [13]. ESC guidelines accordingly do not recommend the use of ESAs to treat anemia in patients with HF, and the Japanese Circulation Society guidelines for the treatment of HF state that there is currently no established evidence on how to treat anemia in patients with acute and chronic HF [14,15].
Ferric citrate hydrate (FC; Riona ® ; Torii Pharmaceutical Co., Ltd., Tokyo, Japan) has been approved in Japan as an oral iron-based phosphate binder that effectively controls serum phosphate concentrations in patients with chronic kidney disease (CKD), including dialysis-and non-dialysis-dependent patients [16][17][18]. Furthermore, FC increased hemoglobin levels in patients with iron-deficiency anemia with or without CKD [19,20] and has been approved to treat iron-deficiency anemia in Japan. Ferric citrate (Auryxia ® ; Akebia Therapeutics, Inc., Cambridge, MA, USA) has the same active ingredient as that of Riona ® although the formulation provides different amounts of elemental iron (Riona ® has approximately 60 mg elemental iron per 250 mg tablet, whereas Auryxia ® has 210 mg elemental iron per 1 g tablet), and it has been approved to treat hyperphosphatemia in patients with dialysis-dependent CKD and iron-deficiency anemia in patients with non-dialysis-dependent CKD in the USA [21,22]. A previous post hoc analysis compared the iron-related parameters of ferric citrate (Auryxia ® ) in non-dialysis-dependent patients with CKD and irondeficiency anemia with or without HF from phase 2 and 3 trials in the USA. They found mean (standard deviation (SD)) increases from baseline to week 12 in serum ferritin of 201.6 (172.3) pmol/L [89.7 (76.7) ng/mL] and TSAT of 10.9 (13.7) % in patients with HF, which were comparable with changes in patients without HF. However, the previous analysis was conducted only in non-dialysis-dependent patients with CKD and iron-deficiency anemia, and the mean ferric citrate (Auryxia ® ) dose was 5000 mg/day (1050 mg iron/day) [23]. The dose of ferric citrate (Auryxia ® ) provided a higher dose of elemental iron than the dose used in the IRONOUT HF randomized trial, oral iron polysaccharide (150 mg, twice daily, 300 mg iron/day) [12].
We previously conducted a 104-week, real-world, post-marketing surveillance study of FC in dialysisand non-dialysis-dependent patients with CKD [24] and showed that FC improved iron-related parameters, with no new safety concerns. In the current study, we analyzed the association of FC on iron-and erythrocyte-related parameters, and CKD-mineral and bone disorder (MBD)-related parameters in CKD patients with and without HF using data from this previous post-marketing surveillance study [24]. The study population was expected to include a large subpopulation of patients with HF, given that CKD and HF frequently coexist [1] and the prevalence of CKD in patients with HF in Japan was reported to be 23% [25].

Study design
This post-marketing surveillance study was conducted in Japan as part of a risk management plan to ensure the long-term safety of a newly approved drug in a real-world setting. Patients were registered centrally from January 30, 2015. Case report forms were collected from participating institutions for up to a maximum of 2 years. Data collection was terminated on April 30, 2020 [24].

Patients
Patients included in the surveillance study have been described in detail in a previous report [24]. Briefly, CKD patients, including patients undergoing hemodialysis (HD group), peritoneal dialysis (PD group), or no dialysis (ND group), were registered within 14 days from the initiation of FC treatment and followed up prospectively. Patients undergoing combined dialysis (HD plus PD) were excluded from the analyses. Among these registered patients, patients diagnosed with comorbid HF by a physician at baseline were defined as patients with HF, and the other patients were defined as patients without HF in the current analyses. All patients whose case report forms were returned at least once after their first visit were analyzed for safety (safety-analysis set) and patients within this set with available effectiveness data were analyzed for effectiveness (effectiveness-analysis set).

FC treatment
FC (250 mg tablet containing approximately 60 mg of elemental ferric iron) was administered orally three times per day immediately after a meal. The starting dose was 500 mg (1500 mg/day) as recommended in the package insert. The dose was adjusted by physicians according to serum phosphate concentrations or clinical status, with a maximum allowed dose of 6000 mg/day. Concomitant medications (e.g., phosphate binders and iron preparations) were allowed [24].

Evaluation of iron-and erythrocyte-related parameters
Iron-and erythrocyte-related parameters, including serum ferritin, serum iron, TSAT, and hemoglobin, were measured as parameters of special interest in the safetyanalysis set at baseline, 4,12,16,24,28,36,52,76, and 104 weeks after the initiation of FC treatment, and at discontinuation of the treatment. The absolute value of each parameter and the difference from baseline were summarized in each group using descriptive statistics. Timecourse changes in serum ferritin, and TSAT were plotted for each group throughout the observation period.

Evaluation of CKD-MBD-related parameters
CKD-MBD-related parameters, including serum phosphate, serum calcium, and intact parathyroid hormone, were measured in the effectiveness-analysis set at baseline, 4,12,16,24,28,36,52,76, and 104 weeks after the initiation of FC treatment, and at treatment discontinuation. Serum calcium was corrected when serum albumin was < 4.0 g/dL using the formula: corrected calcium [mg/dL] = (absolute value of serum calcium [mg/ dL]) + [4 − (serum albumin [g/dL])]. When serum albumin was ≥ 4.0 g/dL, corrected calcium was equal to the absolute serum calcium value. The absolute value of each parameter and the difference from baseline were summarized in each group using descriptive statistics. Timecourse changes in serum phosphate were plotted for each group throughout the observation period.

Adverse drug reactions
Adverse drug reactions were recorded in the safetyanalysis set using preferred terms from MedDRA Ver. 23.0 and were summarized using descriptive statistics. If a patient experienced an event multiple times, it was recorded as one event.

Statistical analysis
Patient characteristics, iron-and erythrocyte-related parameters and adverse drug reactions were analyzed in the safety-analysis set, and CKD-MBD-related parameters were analyzed in the effectiveness-analysis set. On the basis of data from all Japanese pre-approval clinical studies, we planned to enroll 1000 patients in the HD group, 100 in the PD group, and 500 in the ND group in the post-marketing surveillance study to evaluate longterm safety in the entire CKD population [24]. The current study used the same data set. Mean changes from baseline to each time point and the 95% CI were analyzed for serum ferritin and TSAT at 12, 36, 52, and 104 weeks. All statistical analyses were performed using SAS Ver. 9.4 (SAS Institute Inc., Cary, NC, USA).

Patients
In this observational post-marketing surveillance study, 2811 patients with CKD were registered from 573 institutions [24]. Patients whose case report forms were not returned (n = 76) or who underwent combined dialysis (HD and PD) or did not return after the first visit or did not meet registration criteria were excluded. Among the remaining patients, patients with and without comorbid HF were analyzed in this study (safety-analysis set, n = 348 and n = 2352), comprising 166 and 1401 patients in the HD group, 36 and 173 patients in the PD group, and 146 and 778 patients in the ND group, respectively. The effectiveness-analysis set (n = 303 and n = 2041) comprised 146 and 1232 patients in the HD group, 33 and 150 patients in the PD group, and 124 and 659 patients in the ND group, after excluding 45 and 309 patients from the safety-analysis set, respectively (Fig. 1).
Patients with and without comorbid HF characteristics are summarized in Table 1. The mean (standard deviation; SD) age of patients with and without comorbid HF was 68.3 (12.3) and 65.3 (12.7) years in the HD group, 66.4 (13.0) and 62.7 (12.6) years in the PD group, and 68.4 (14.2) and 65.7 (13.5) years in the ND group, respectively. There were more male than female patients in all groups. At baseline, the use of iron preparations (oral or intravenous) in patients with and without comorbid HF was 48/166 patients (28.9%) and 361/1401 patients (25.8%) in the HD group, 3/36 patients (8.3%) and 15/173 patients (8.7%) in the PD group and 12/146 patients (8.2%) and 68/778 patients (8.7%) in the ND group, respectively.
The daily mean (SD) dose of FC during the study in patients with and without comorbid HF was 1054.5 (516.3) mg and 1082.6 (510.7) mg in the HD group, 951.0 (456.6) mg and 976.4 (509.0) mg in the PD group, and 896.9 (524.1) mg and 845.5 (417.3) in the ND group, respectively.

Iron-and erythrocyte-related parameters
Median (interquartile range (IQR): first quartile, third quartile) serum ferritin levels in patients with and   (Table 2), and these also showed an increasing trend until around 12 weeks after treatment initiation and then remained stable in all groups: mean changes (95% CI) in TSAT in patients with and without comorbid HF from baseline to week 12 were 12.79  (Table 2,  Table 3 and Fig. 3). Hemoglobin levels were well controlled in all groups (Table 2).

CKD-MBD-related parameters
Mean (SD) serum phosphate levels in patients with and without comorbid HF at baseline were 6.73 (1.45) mg/dL and 6.56 (1.38) mg/dL in the HD group, 6.62 (1.36) mg/ dL and 6.06 (1.35) mg/dL in the PD group, and 5.33 (1.09) mg/dL and 5.34 (1.03) mg/dL in the ND group (Table 4). Mean serum phosphate levels decreased after FC treatment initiation and were then maintained, and the levels in patients with and without comorbid HF at 104 weeks were 5.09 (1.22) mg/dL and 5.40 (1.31) mg/dL in the HD group, 5.34 (1.95) mg/dL and 5.10 (1.16) mg/dL in the PD group, and 4.70 (1.05) mg/dL and 4.90 (1.19) mg/dL in the ND group, respectively. Mean serum phosphate levels were well controlled throughout the study (Table 4 and Fig. 4).

Discussion
Because existing oral iron preparations have failed to improve iron-related parameters in patients with HF [12] and HF is highly prevalent in patients with CKD [1], this study evaluated the effects of FC in subgroups of CKD patients with and without comorbid HF. Regardless of the presence of comorbid HF, levels of iron-and erythrocyte-related parameters, including serum ferritin, TSAT, and hemoglobin, showed an increasing trend after the initiation of FC treatment and were then maintained during the 104-week study period. Levels of CKD-MBDrelated parameters, including serum phosphate, were also well controlled. The overall time-course changes in these parameters in patients with and without comorbid HF subpopulations were similar. In particular, median changes in serum ferritin from baseline to week 36 in the PD groups were greater than those in the HD and ND In the IRONOUT HF study, oral polysaccharide iron was administered to patients with HF with reduced ejection fraction and iron deficiency for 16 weeks, and the median increases (95% CI) from baseline were 18 (− 8, 38) ng/mL for serum ferritin and 2 (− 3, 7) % for TSAT [12]. The polysaccharide iron administered in the IRO-NOUT HF study (150 mg twice daily; 300 mg iron/day) was comparable to the elemental iron dose administered in our study. However, the increases in the iron-related parameters from baseline to 12 weeks after FC treatment were greater in this study compared with the IRO-NOUT HF study. These data suggest that oral FC might be absorbed in CKD patients regardless of the presence of comorbid HF. A previous post hoc analysis compared the ironrelated parameters of ferric citrate (Auryxia ® ) in non-dialysis-dependent patients with CKD and irondeficiency anemia with or without HF [23]. They found mean (SD) increases from baseline to week 12 in serum ferritin of 201.6 (172.3) pmol/L [89.7 (76.7) ng/mL] and TSAT of 10.9 (13.7) % in patients with HF, which were comparable with changes in patients without HF. Our results in the ND group were in line with this previous report; however, the mean FC (Riona ® ) dose in the ND group of 896.9 mg/day (approximately 215.3 mg iron/ day) was lower compared with the mean ferric citrate (Auryxia ® ) dose of 5000 mg/day (1050 mg iron/day) in the previous study. The difference between studies might be related to the levels of inflammation between CKD patients in the USA and Japan. Compared with the previous study, we evaluated the iron-and erythroid-related parameters based on real-world data in CKD patients with HF in Japan in the ND group as well as the HD and PD groups and obtained data related to long-term (104 weeks) FC (Riona ® ) treatment.

Conclusions
This long-term, real-world, post-marketing surveillance study demonstrated that oral FC administration had a tendency to increase iron-related parameters in CKD patients regardless of the presence of HF.

Funding
This surveillance study was funded by Japan Tobacco Inc. and Torii Pharmaceutical Co., Ltd.

Availability of data and materials
The datasets generated and/or analyzed during the study are available from the corresponding author upon reasonable request.

Declarations Ethics approval and consent to participate
This observational post-marketing surveillance study was conducted in accordance with the Good Post-Marketing Study Practice (GPSP) of the Ministry of Health, Labour, and Welfare in Japan. The data were anonymized and collected within general clinical practice, and the requirement for informed consent was therefore waived.