Usefulness of Oral Ferric Citrate in Patients With

Iron-Deficiency Anemia and Chronic Kidney Disease

With or Without Heart Failure
D1X XPeter A. McCullough, D2X XMD, MPHa*, D3X XKatrin Uhlig, D4X XMD, MSb, D5X XJohn F. Neylan, D6X XMDb,
D7X XPablo E. Pergola, D8X XMDc, and D9X XSteven Fishbane, D10X XMDd

Patients with chronic inflammatory conditions including chronic kidney disease (CKD)
and heart failure (HF) are undertreated with iron-deficiency anemia (IDA). Progressive
inflammation and reduced iron transport associated with CKD and HF may reduce the
efficacy of oral iron therapy. Oral ferric citrate improves anemia markers in CKD, but its
effects in patients with CKD and concomitant HF have not been described. Patients with
CKD not on dialysis and IDA from a phase 2 and 3 trial were treated with ferric citrate
(n = 190) or placebo (n = 188); patients with HF were identified from medical histories.
Hemoglobin response was defined as a
10.0-g/L increase in hemoglobin. Changes in
hemoglobin, transferrin saturation, ferritin, and serum phosphate from baseline to week
12 and the incidence of adverse events potentially related to HF were evaluated. HF was
reported in 22% (n = 81) of patients. The proportion of patients with hemoglobin response
to ferric citrate treatment did not significantly differ in patients with and without HF
(43% vs 49%, respectively; p = 0.47); changes from baseline in hemoglobin, iron parame-
ters, and serum phosphate were similar. Adverse events potentially related to HF were
noted more frequently in patients with HF (ferric citrate, 23%; placebo, 17%) versus
those without HF (ferric citrate, 12%; placebo, 11%). In conclusion, these results indicate
a potential role for ferric citrate in the treatment of IDA in patients with CKD not on dial-
ysis and concomitant HF. © 2018 The Author(s). Published by Elsevier Inc. This is an
open access article under the CC BY-NC-ND license. (http://creativecommons.org/
licenses/by-nc-nd/4.0/) (Am J Cardiol 2018;122:683
688)

Heart failure (HF) and anemia are common comorbid-
ities associated with a poor prognosis in patients with
chronic kidney disease (CKD).1
5 Normal iron absorption
and transport are impaired in CKD and HF due to associ-
ated inflammation, and in the case of CKD, by way of
changes in hepcidin6
10; therefore, both CKD and HF are
independently associated with iron-deficiency anemia
(IDA).5,11 Effective IDA treatment is especially important
for patients with CKD and concomitant HF because hemo-
globin (Hgb) concentrations may decrease further due to
iron restriction and volume overload.5,9,11 In the recent
Oral Iron Repletion Effects on Oxygen Uptake in Heart
Failure (IRONOUT-HF)study, patients with HF (n = 225)
receiving oral iron polysaccharide (100 mg elemental iron/
day) experienced minimal increases in iron stores and exer-
cise/functional capacity compared with placebo
a
Baylor University Medical Center, Baylor Heart and Vascular Hospi-
tal, Baylor Heart and Vascular Institute, Dallas, Texas 75246; bKeryx Bio-
pharmaceuticals, Inc., Boston, Massachusetts; cRenal Associates PA, San
Antonio, Texas; and dHofstra Northwell School of Medicine, Great Neck,
New York. Manuscript received February 21, 2018; revised manuscript
received and accepted April 30, 2018.
This study was presented in part as a poster at the Twenty-First Annual
Scientific Meeting of the Heart Failure Society of America (HFSA) held at
Dallas, TX from September 16, 2017 to September 19, 2017.
See page 687 for disclosure information.
*Corresponding author: Tel.: (214) 820-7997; fax: (214) 820-7553
E-mail address: peteramccullough@gmail.com (P.A. McCullough).
recipients.12 These results suggest that over-the-counter
iron polysaccharide ineffectively treats IDA in patients
with HF, possibly because poor tolerability limits elemental
iron dose delivery. Ferric citrate, an oral phosphate binder
approved in adult patients with CKD on dialysis, delivers
210 mg of elemental ferric iron per gram.13 Ferric citrate
was recently approved as an iron-replacement agent for the
treatment of IDA in adult patients with CKD not on dialy-
sis.13 In 2 randomized clinical trials among patients with
CKD not on dialysis and IDA, ferric citrate increased Hgb
and transferrin saturation (TSAT) and decreased serum
phosphate levels compared with placebo.14,15 The impact
of ferric citrate treatment on patients with CKD, IDA, and
HF has not been previously reported. Here, we present the
results of a hypothesis-generating pooled post hoc analysis
of these 2 trials stratified by HF status.
Methods
The corresponding author had complete access to all the
raw data and takes responsibility for data integrity and the
data analyses. The data that support the findings of this
study are available from the corresponding author upon rea-
sonable request.
Individual patient data were pooled from the randomized
periods of a phase 2 (ClinicalTrials.gov identifier:
NCT01736397) and phase 3 clinical trial (NCT02268994),
both of which evaluated ferric citrate versus placebo in

0002-9149/© 2018 The Author(s). Published by Elsevier Inc. This is an open access article www.ajconline.org
under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
https://doi.org/10.1016/j.amjcard.2018.04.062
684 The American Journal of Cardiology (www.ajconline.org)

Table 1
Baseline characteristics (safety analysis set)
Parameter Patients with heart failure (n = 81) Patients without heart failure (n = 297)
Ferric citrate (n = 40) Placebo (n = 41) Ferric citrate (n = 150) Placebo (n = 147)
Age (years) 65.0 (36
87) 67.5 (34
93) 65.6 (25
86) 64.0 (21
89)
Women 48% 61% 71% 61%
Black/African-American 35% 22% 27% 26%
Chronic kidney disease stage at baseline
3 40% 42% 41% 48%
4 45% 49% 47% 43%
5 15% 10% 12% 10%
eGFR (mL/min/1.73 m2) 23.8 (8
50) 25.2 (10
51) 27.5 (6
66) 27.3 (8
63)
Weight (kg) 99.0 (57.5
152.8) 95.8 (58.3
157.9) 90.8 (46.9
154.7) 89.8 (47.9
167.8)
Diabetes mellitus 78% 66% 67% 71%
Ischemic heart disease 38% 61% 25% 20%
Hemoglobin (g/L) 106 (91
124) 105 (86
125) 104 (85
123) 105 (84
147)
Transferrin saturation (%) 19.8 (11
36) 19.5 (4
43) 21.1 (6
50) 20.5 (7
45)
Ferritin (pmol/L) 224.5 (40.4
705.6) 241.6 (31.5
582.0) 219.1 (6.7
853.9) 198.6 (13.5
797.7)
Phosphorus (mmol/L) 1.4 (1.0
2.8) 1.4 (1.0
2.0) 1.4 (0.9
2.4) 1.4 (0.9
2.2)
Median iPTH (pg/mL) (range) 129.5 (30
453) 108.0 (21
374) 99.5 (6
586) 121.0 (16
551)
Median iFGF23 (pg/mL) (IQR) 227.6 (235.8) 171.4 (108.0) 135.5 (132.3) 138.0 (155.9)
Median cFGF23 (RU/mL) (IQR) 544.6 (531.6) 425.7 (545.3) 344.2 (353.7) 331.0 (378.6)
Data are mean (range) unless otherwise indicated.
cFGF23 = C-terminal fibroblast growth factor 23; eGFR = estimated glomerular filtration rate; iFGF23 = intact fibroblast growth factor 23; iPTH = intact
parathyroid hormone; IQR = interquartile range.

patients with IDA and stage 3 to 5 non
dialysis-depen-
dent CKD (estimated glomerular filtration rate <60 mL/
min/1.73 m2 by the 4-variable Modification of Diet in
Renal Disease Study equation). The design of these trials
has previously been reported (Supplementary Table 1).14,15
Both trials were randomized, double-blind, multicenter
studies with similar patient populations and drug doses;
however, they differed with respect to the randomization
period (12 and 16 weeks for the phase 2 and 3 trials,
respectively) and ferric citrate dose titration (to achieve
target serum phosphate levels of 0.97
1.13 mmol/L in the
phase 2 trial and a target Hgb increase of
10.0 g/L above
baseline in the phase 3 trial). Also, as inclusion criteria for
baseline serum phosphate levels differed in the phase 2
and 3 trials (
1.29 to <1.94 mmol/L and
1.13 mmol/L,
respectively), patients in the phase 2 study had higher
serum phosphate levels at baseline. In the phase 2 trial,
the co-primary end points were changes in TSAT and
serum phosphate from baseline; in the phase 3 trial, the
primary end point was the proportion of patients achieving
a
1.0-g/dL Hgb increase at any time during the random-
ized period.
For the purposes of the pooled post hoc analysis, patients
with baseline HF were identified from diagnoses entered for
their medical history. The safety analysis set comprised all
randomized patients who received
1 dose of study medi-
cation; the intention-to-treat analysis set comprised patients
who received
1 dose of study medication and had
1
baseline and
1 postbaseline laboratory assessment (Sup-
plementary Figure 1).
The primary end point of this analysis was the propor-
tion of Hgb responders, defined as patients who achieved
a
10.0-g/L Hgb increase at any time during the random-
ized periods. Mean changes in Hgb, TSAT, ferritin, and

Figure 1. Maximum change in hemoglobin by HF status (intention-to-treat analysis set). Cumulative frequency of the maximum change from baseline in
hemoglobin by HF status. HF = heart failure.
 Miscellaneous/Ferric Citrate, IDA, and Heart Failure 685

Table 2
Mean change in hemoglobin, iron parameters, and phosphate from baseline to week 12 (intention-to-treat analysis set)
Variable Patients with heart failure Patients without heart failure
Ferric citrate (n = 40) Placebo (n = 41) Ferric citrate (n = 150) Placebo (n = 147)
Hemoglobin (g/L) 4.1 § 7.3
2.1 § 6.4 5.7 § 8.5
1.1 § 8.6
Transferrin saturation (%) 10.9 § 13.7
1.3 § 7.7 12.0 § 15.2
1.4 § 6.4
Ferritin (pmol/L) 201.6 § 172.3
27.4 § 66.5 210.8 § 198.4
7.4 § 86.1
Serum phosphate (mmol/L)
0.17 § 0.26
0.12 § 0.22
0.15 § 0.23
0.05 § 0.21
Data are mean § standard deviation.

phosphate from baseline to week 12 during the randomized
period were also evaluated. The maximum change in Hgb
(i.e., the difference between baseline and the highest Hgb
value during follow-up) was also assessed.
Adverse events (AEs) potentially related to HF were
considered AEs of special interest, which are listed in Sup-
plementary Table 2.
Descriptive analyses of baseline characteristics and AEs
were conducted using the safety analysis set. Analyses of
efficacy with changes in laboratory parameters over time
employed the intention-to-treat analysis set. To assess if the
effect of treatment on Hgb response differed for those with
and without HF, treatment-by-HF interaction was tested in
a logistic regression model with responder status as the out-
come and study, HF status, treatment, and treatment-by-HF
status interaction as predictors. The maximum change in
Hgb was computed for each patient, and the cumulative fre-
quency of the maximum changes was plotted according to
HF status and treatment group.
Both trials were conducted in accordance with the Interna-
tional Conference on Harmonization Good Clinical Practice
guidelines, the Declaration of Helsinki, and applicable local
regulatory requirements and laws. All versions of the study
protocol were reviewed and approved by the Liberty Institu-
tional Review Board (DeLand, Florida and Columbia, Mary-
land) before patient enrollment at each site. Institutional
review board-approved written informed consent was obtained
from each patient before performing any study assessments.
Results
Overall, 190 patients were treated with ferric citrate and
188 with placebo. A total of 81 patients (22%) had HF
reported in their medical history. Baseline characteristics
were relatively similar across studies and treatment groups
(Table 1). Patients in the HF subgroups had a slightly lower
estimated glomerular filtration rate and a higher rate of
ischemic heart disease than those without HF. Mean base-
line intact and c-terminal fibroblast growth factor 23
(FGF23)—risk markers for mortality in CKD—were higher
in patients with HF versus those without HF, respectively
(intact FGF23, 381.5 vs 317.9 pg/mL; c-terminal FGF23,
782.4 vs 519.7 RU/mL).
The mean ferric citrate dose in the pooled patient popu-
lation was 5.0 g/day (delivering 1,050 mg of elemental
iron/day). HF did not modify the treatment effect of ferric
citrate compared with placebo. Among ferric citrate-treated
patients, the frequency of Hgb responders was 43% for
those with HF and 49% for those without HF (p = 0.472 for
treatment-by-HF interaction) (Supplementary Table 3).
Although longer treatment duration resulted in a higher
overall response rate in the 16-week phase 3 study com-
pared with the 12-week phase 2 study, the treatment-by-
interaction terms within each study were not statistically
significant (phase 3 study, p = 0.430; phase 2 study,
p = 0.943) (Supplementary Table 3). In the pooled analysis,
mean changes from baseline to 12 weeks in Hgb, iron
parameters, and serum phosphate were similar among all
patients who received ferric citrate, regardless of HF status
(Table 2).
The maximum change from baseline in Hgb was greater
in the ferric citrate groups than in the placebo groups but
similar among patients with and without HF (Figure 1).
There was no statistically significant difference
(p = 0.5842) in the average time to maximum Hgb change
among ferric citrate-treated patients with HF (60.1 days)

Table 3
Adverse events of special interest in patients in the pooled analysis with and without heart failure
Patients with heart failure Patients without heart failure
Ferric citrate (n = 40) Placebo (n = 41) Ferric citrate (n = 150) Placebo (n = 147)
AE related to a heart failure safety signal* 9 (23%) 7 (17%) 18 (12%) 16 (11%)
AE related to ischemic heart diseasey 1 (3%) 1 (2%) 1 (1%) 3 (2%)
AE related to cerebrovascular disorderz 0 0 0 0
AE related to either a heart failure safety 10 (25%) 7 (17%) 19 (13%) 16 (11%)
signal, ischemic heart disease, or cerebrovascular disorderx
*Includes preferred terms under SMQ codes for cardiac arrhythmias, heart failure, cardiomyopathy, hyponatremia/syndrome of inappropriate antidiuretic
hormone secretion, hypotonic
hyporesponsive episode, and pulmonary hypertension.
AE = adverse event; SMQ = Standardized Medical Dictionary for Regulatory Activities Queries.
y
Includes preferred terms under SMQ codes for ischemic heart disease.
z
Includes preferred terms under SMQ codes for cerebrovascular disorders.
x
Includes preferred terms under all SMQ codes above.
686 The American Journal of Cardiology (www.ajconline.org)
Figure 2. Mean hemoglobin, transferrin saturation, ferritin, and serum
phosphate levels by week and HF status (intention-to-treat analysis set).*
Mean (standard error) changes in (A) hemoglobin, (B) transferrin satura-
tion, (C) ferritin, and (D) serum phosphate levels by week and HF status.
*Data for study weeks 14 and 16 are from patients in the phase 3 study
only. BL = baseline; HF = heart failure.
and without HF (63.4 days). Over the entire randomized
study periods, mean values for Hgb, TSAT, ferritin, and
serum phosphate were similar in ferric citrate-treated
patients with and without HF. They were also similar
among placebo recipients with and without HF (Figure 2).
Ferric citrate-treated patients had higher AE rates than
placebo recipients. Most treatment-emergent AEs were
mild or moderate across all groups. In both the ferric citrate
and placebo groups, the incidence and severity of treat-
ment-emergent AEs were similar among patients with or
without HF. However, ferric citrate-treated patients with
HF showed the highest incidences of drug-related treat-
ment-emergent AEs, serious AEs, and treatment-emergent
AEs resulting in discontinuation (Supplementary Table 4).
Gastrointestinal AEs were the most common treatment-
emergent AEs among ferric citrate-treated patients and
were similar among patients with and without HF (Supple-
mentary Table 5). Hypophosphatemia was reported as an
AE in 1% and 2% of patients who received ferric citrate
and placebo, respectively.
AEs of special interest among patients with HF are
shown in Table 3. The frequency of AEs possibly related to
HF was higher in patients with HF than in those without HF
(Table 3).
Discussion
This pooled post hoc analysis shows that ferric citrate
effectively delivered iron and improved IDA in patients
with CKD both with and without HF. While these results
are consistent with previous studies among patients with
IDA and HF,16,17 they differ from those of the IRONOUT
HF study, in which oral iron polysaccharide showed mini-
mal increases in TSAT and ferritin and no improvement in
exercise capacity versus placebo.12 However, it is difficult
to draw direct parallels between our study and the IRON-
OUT-HF study because of differences in the eligibility cri-
teria used to define IDA among patients with HF alone
(IRONOUT-HF) versus those with HF and CKD (current
pooled analysis).18 In addition, baseline Hgb levels were
higher in IRONOUT-HF (mean 126 g/L) compared with
the current analysis (mean 104 g/L). Yet, increases in iron
parameters with ferric citrate (TSAT, +11% to 12%; ferri-
tin, +200 pmol/L) were notable when compared with iron
polysaccharide (TSAT, +2%; ferritin, +40 pmol/L), which
could be attributable to the greater elemental iron dose with
ferric citrate (1050 mg/day) versus iron polysaccharide
(100 mg/day). The formulation of the ferric citrate
coordi-
nation complex given with food allows for a large amount
of ferric iron to be tolerated and effectively delivered
through the gut, despite the additive inhibitions and iron
restrictions that occur in patients with both HF and CKD;
this distinguishes ferric citrate from other oral iron
preparations.14,18
Intravenous (IV) iron (ferric carboxymaltose) in patients
with HF improves exercise tolerance and quality of life
while reducing the risk of hospitalizations for HF and mor-
tality.19,20 Based on results from the Ferinject Assessment
in Patients With Iron Deficiency and Chronic Heart Failure
and Ferric Carboxymaltose Evaluation on Performance in
Patients With Iron Deficiency in Combination With
Chronic Heart Failure trials,21,22 which defined iron defi-
ciency with the same criteria as the IRONOUT-HF study,
IV iron is now recommended in the American College of
Cardiology/American Heart Association guidelines for the
treatment of patients with New York Heart Association
 Miscellaneous/Ferric Citrate, IDA, and Heart Failure
functional class IIb
III HF with anemia.23,24 Of note, nei-
ther the Ferinject Assessment in Patients With Iron Defi-
ciency and Chronic Heart Failure nor Ferric
Carboxymaltose Evaluation on Performance in Patients
With Iron Deficiency in Combination With Chronic Heart
Failure trials were powered to evaluate the effect of IV iron
on major cardiovascular outcomes in anemic versus nona-
nemic patients.1,24
Despite these recommendations, the percentage of
patients with HF who are evaluated and treated for iron
deficiency remains low in clinical practice.25 This may be a
result of the lack of long-term safety and efficacy data or
the heterogeneity of guidelines for the diagnosis and man-
agement of iron deficiency in patients with HF.26 Practical
barriers to providing IV iron therapy may be another reason
for the low guideline uptake. An oral iron formulation that
is effective in treating IDA in patients with HF would be
attractive given the ease of use and avoidance of parenteral
infusions.
In our analysis, the most common AEs with ferric citrate
were gastrointestinal symptoms; in the phase 3 trial, 26%
of patients experienced gastrointestinal AEs of any grade.
For reference, in a systematic review of oral iron supple-
ments across 111 trials (not including ferric citrate), the
reported incidence of gastrointestinal AEs ranged from 4%
to 43% and was directly related to the daily elemental iron
dose; however, the maximum elemental iron dose in the tri-
als included in this analysis did not exceed 175 mg/day.27
Patients with HF experienced more AEs of special interest
compared with patients without HF, confirming the greater
event risk in patients with HF and concomitant kidney dis-
ease and its attendant comorbidities. Ferric citrate also
resulted in significant decreases in FGF23 in the overall
study population, although it was not analyzed in patients
with concomitant HF.14,15 FGF23, a phosphate-regulating
hormone, is known to be a risk factor for cardiovascular
events in patients with CKD.28
This analysis has limitations. Although the current anal-
ysis used prospectively collected data, it was retrospective
in nature. Patients with HF were identified post hoc based
on spontaneously reported HF diagnoses from their past
medical history, rather than a systematic ascertainment of
HF status; therefore, left ventricular ejection fraction, func-
tional class, and etiology of HF were not available. The 2
studies, while similar in patient populations and treatment
doses, had different primary end points and dose-titration
strategies. Subgroup analysis by race and gender was pre-
cluded by small patient numbers and neither study was
powered for subgroup analysis. Measurement of key (and
potentially informative) biomarkers such as hepcidin-25
was lacking, and outcomes of particular relevance to HF,
such as quality of life and exercise capacity, were not
assessed.
Due to the limitations mentioned previously, this analy-
sis should be considered as hypothesis-generating; an ade-
quately designed and sufficiently powered trial is needed to
confirm if ferric citrate treatment is safe and beneficial in
patients with IDA and HF regarding the outcomes of hospi-
talization for HF and cardiovascular death. The diagnosis
of IDA in patients with HF can be challenging. In a study
of patients hospitalized for HF, bone marrow examinations
687
demonstrated absence of iron stores in patients with normal
ferritin concentrations, suggesting that ferritin may be a
poor measure of IDA in patients with HF.29 Therefore, eli-
gibility criteria for prospective trials may define IDA in the
context of other parameters (i.e., Hgb and TSAT) that may
be more relevant to patients with HF. Anemia- and HF-
related quality of life, exercise capacity, freedom from
transfusion, and the need for rescue therapy with IV iron
should be considered as secondary points of interest.
Our findings suggest a potential role for ferric citrate-
based oral iron treatment of IDA in patients with non
dial-
ysis-dependent CKD and HF. Administration of oral ferric
citrate may not only treat IDA and its symptoms but could
potentially influence HF-specific outcomes in patients with
both conditions.
Acknowledgment
Statistical support was provided by Prometrika, LLC and
funded by Keryx Biopharmaceuticals, Inc. Medical writing
support was provided by Meghan Sullivan, PhD, and Vasu-
pradha Vethantham, PhD, of inScience Communications,
Springer Healthcare (New York, New York), and was
funded by Keryx Biopharmaceuticals, Inc.
Disclosures
Dr. McCullough has served as a consultant for and has
received research support from Keryx Biopharmaceuticals,
Inc. Drs. Uhlig and Neylan are employees of Keryx Bio-
pharmaceuticals, Inc. Dr. Fishbane has served as a consul-
tant for AstraZeneca and Keryx, is on the advisory board
for Keryx, has received research funding from AstraZe-
neca, Corvidia, Fibrogen, and Keryx, and has received hon-
oraria from AstraZeneca and Keryx. Dr. Pergola has served
as a consultant for Akebia, Alnylam, ExThera, Keryx, and
Reata.
Funding
Funding was provided by Keryx Biopharmaceuticals,
Inc. (Boston, Massachusetts).
Supplementary Data
Supplementary data associated with this article can be
found, in the online version, at https://doi.org/10.1016/j.amj
card.2018.04.062.
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