Download Ferric Carboxymaltose Prevents Recurrence of

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11:269 –277
Ferric Carboxymaltose Prevents Recurrence of Anemia in Patients With
Inflammatory Bowel Disease
RAYKO EVSTATIEV,* OLGA ALEXEEVA,‡ BERND BOKEMEYER,§ IVAN CHOPEY,储 MARCEL FELDER,¶ MAJA GUDEHUS,¶
TARIQ IQBAL,# IGOR KHALIF,** PHILIPPE MARTEAU,‡‡ JÜRGEN STEIN,§§ CHRISTOPH GASCHE,* and the FERGI Study
Group
*Department of Medicine 3, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical
University of Vienna, Vienna, Austria; ‡Regional Clinical Hospital, Nizhni Novgorod, Russian Federation; §Gastroenterology Practice, Minden, Germany; 储National
University, Uzhgorod, Ukraine; ¶Vifor Pharma, Glattbrugg, Switzerland; #University Hospital, Birmingham, United Kingdom; **State Scientific Center of Coloproctology,
Moscow, Russian Federation; ‡‡Hôpital Lariboisiere, Paris, France; and §§Department of Gastroenterology and Clinical Nutrition, Frankfurt/Main, Germany
BACKGROUND & AIMS:
Iron-deficiency anemia is the most common systemic complication of inflammatory bowel
diseases (IBD). Iron-deficiency anemia recurs frequently and rapidly after iron-replacement
therapy in patients with IBD. We performed a randomized, placebo-controlled trial to
determine if administration of ferric carboxymaltose (FCM) prevents anemia in patients
with IBD and low levels of serum ferritin.
METHODS:
We performed a single-blind, multicenter study of nonanemic patients who had completed
the FERGIcor study. Serum levels of ferritin were assessed every second month, and
patients were given FCM (total iron dose, 1181 ⴞ 662 mg; n ⴝ 105) or placebo (n ⴝ 99) when
levels decreased to less than 100 ␮g/L. The primary end point was time to recurrence of
anemia within 8 months. Secondary end points included changes of quality of life, disease
activity, results from laboratory tests, and adverse events.
RESULTS:
Anemia recurred in 26.7% of subjects given FCM and in 39.4% given placebo. The time to
anemia recurrence was longer in the FCM group (hazard ratio, 0.62; 95% confidence
interval, 0.38 –1.00; P ⴝ .049). Markers of body levels of iron increased or remained at
normal levels in subjects given FCM (ferritin increased by 30.3 ␮g/L, transferrin saturation
increased by 0.6%) but decreased in the group given placebo (ferritin decreased by 36.1
␮g/L, transferrin saturation decreased by 4.0%). Changes in quality of life and disease
activity were comparable between groups. Adverse events were reported in 59.0% of the
FCM group and 50.5% of the placebo group, and serious adverse events were reported in
6.7% and 8.1%, respectively.
CONCLUSIONS:
FCM prevents recurrence of anemia in patients with IBD, compared with placebo. Nevertheless, the high rate of anemia recurrence warrants optimization of the frequency and
requirements for FCM treatment. Clinical Trial number: NCT00810004.
Keywords: Intravenous Iron; Crohn’s Disease; Ulcerative Colitis; Iron Maintenance Treatment.
I
ron deficiency is one of the world’s most common and potentially treatable health problems.1 Even in developed countries,
patients suffering from conditions associated with chronic blood
loss and/or chronic inflammation are at risk of developing irondeficiency anemia,2,3 a leading cause of hospitalization and morbidities such as fatigue in inflammatory bowel disease (IBD).2,4 –7
Iron deficiency can result from chronic blood loss, decreased dietary intake, reduced intestinal absorption, or impaired use of
endogenous iron owing to chronic inflammation.8 Anemia and
iron deficiency affect quality of life (QoL), physical performance,
and cardiac function.9 –13 Improvement of hemoglobin (Hb) levels,
serum ferritin, and transferrin saturation (TSAT) improved QoL
independent of changes in disease activity in IBD.14 –16
Intravenous iron preparations such as iron sucrose and ferric
carboxymaltose (FCM) have proven their efficacy in the correction of IBD-associated anemia.2,7 Intravenous iron is more ef-
fective, better tolerated, and improves the QoL to a greater
extent than oral iron.17 Therefore, international and national
guidelines recommend intravenous iron replacement for the
management of IBD-associated anemia.17,18 However, anemia
recurs frequently and quickly after successful intravenous iron
therapy.19 An analysis of 88 patients from 3 prospective clinical
Abbreviations used in this paper: AE, adverse events; CI, confidence
interval; FAS, full analysis set; FCM, ferric carboxymaltose; Hb, hemoglobin; IBD, inflammatory bowel disease; IBDQ, inflammatory bowel
disease questionnaire; PPS, per-protocol set; QoL, quality of life; SF36, health survey short form; TEAE, treatment emergent adverse
event; TSAT, transferrin saturation; UC, ulcerative colitis.
© 2013 by the AGA Institute
1542-3565/$36.00
http://dx.doi.org/10.1016/j.cgh.2012.10.013
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EVSTATIEV ET AL
trials showed that anemia recurred in more than half of the
patients within 12 months.19 The presented study, which was
entitled Ferinject in gastrointestinal maintenance (FERGImain), evaluated whether FCM can prevent anemia in patients
who had been treated previously for IBD-associated anemia.
Methods
Study Design and Patients
FERGImain (ClinicalTrials.gov NCT00810004) was a
randomized, placebo-controlled, multicenter, single-blinded
trial testing the efficacy of iron treatment with intravenous
FCM in preventing anemia recurrence in IBD patients who were
nonanemic at the end of the FERGIcor study.14 The study was
conducted from February 2009 to October 2010 at 69 hospitals
and clinics in 13 countries in accordance with the Declaration
of Helsinki and Good Clinical Practice guidelines and after
approval of the protocol and its amendments by the respective
Ethics Committees and Competent Authorities.
Eligible patients were older than age 18 years, nonanemic
(Hb ⱖ12 g/dL in women or ⱖ13 g/dL in men), had completed
the FERGIcor study,14 had normal levels of vitamin B12 and
folic acid, and provided informed consent. Baseline serum ferritin levels or TSAT were not relevant for inclusion into the
study. Women of child-bearing potential had to have a negative
urine pregnancy test at screening and use an acceptable method
of birth control during the study until 1 month after the last
dose of the study drug.
Patients with a history of erythropoietin treatment, oral iron,
or blood transfusions within 12 weeks before screening were
excluded. Further exclusion criteria comprised chronic alcohol
abuse, chronic liver disease, increase of transaminase levels
more than 3 times above the upper limit of normal, portal
hypertension with esophageal varices, known hypersensitivity
to the study drug, history of acquired iron overload, myelodysplastic syndrome, pregnancy, lactation, known active infection,
clinically significant overt bleeding, active malignancy, chronic
renal failure, surgery with relevant blood loss (Hb decrease ⬎2
g/dL) within 3 months before screening or planned surgery
within the following 3 months, known infection with human
immunodeficiency virus, hepatitis B or C, significant cardiovascular disease, and body weight less than 35 kg.
Randomization and Treatment
Subjects were randomized 1:1 to receive FCM (500 mg
iron in a maximum of 250 mL 0.9% saline solution; Ferinject,
Vifor Pharma, Glattbrugg, Switzerland) or the same volume of
placebo (0.9% saline solution) over 15 minutes. Randomization
was performed according to a predefined, computer-generated
list as provided via sequentially numbered randomization envelopes (Data Management, Parexel International GmbH, Berlin, Germany). Subjects were stratified according to the treatment group of the preceding FERGIcor study (FCM or iron
sucrose) and were blinded to the study drug by using dark
nontransparent bags and infusion lines. Investigators and study
nurses were aware of the treatment allocation.
Treatment Schedule
The last study visit of the preceding FERGIcor study
served as the screening visit of this study and was followed by
the baseline visit within 2 to 7 days. Follow-up visits were
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 3
performed bimonthly until recurrence of anemia or the end of
the study at month 8 was reached. At each visit blood tests were
performed and disease activity indexes were recorded, which
were calculated without consideration of Hb or hematocrit
levels. QoL was assessed using the health survey short form
(SF-36) questionnaire version 2 and inflammatory bowel disease
questionnaire (IBDQ) at baseline, month 2, and month 8. The
subjects received the study drug (500 mg iron or placebo) at
baseline, month 2, month 4, month 6, or month 8 if serum
ferritin had decreased to less than 100 ␮g/L at the respective
study visit. Study drug administration was performed via an
intravenous drip infusion.
Outcome Measures
The primary end point was the time to recurrence of
anemia as defined by World Health Organization criteria (Hb
level ⬍12 g/dL in women or ⬍13 g/dL in men). Because recurrence rates did not exceed 50%, the usual definition for median
time to recurrence, probabilities of developing anemia (based
on Greenwood’s formula for the standard error of the Kaplan–
Meier estimate) were calculated. Secondary efficacy end points
included the proportion of patients without anemia at months
2, 4, 6, and 8; changes in health-related QoL (SF-36 version 220
and IBDQ score21) from baseline to month 8; change in disease
activity (Crohn’s Disease Activity Index, Colitis Activity Index,
C-reactive protein); and days out of work as a result of IBD or
anemia. Disease activity indexes were calculated without consideration of Hb or hematocrit.
Follow-up and Safety Evaluation
Subjects who presented with anemia at a specific study
visit were considered to have reached the end point. Safety end
points included the nature and frequency of adverse events
(AEs) and changes in laboratory parameters. AEs and concomitant medication were recorded continuously. An AE was considered treatment-emergent (TEAE) if it occurred after the first
study drug administration. The relationship to treatment was
rated as certain, probable, possible, unlikely, or not related. The
intensity was rated as mild, moderate, or severe. Safety stopping
rules for premature discontinuation were Hb level less than 7
g/dL, Hb level greater than 18 g/dL (in men) or greater than 16
g/dL (in women), serum ferritin level greater than 800 ␮g/L,
TSAT greater than 50%, and liver transaminase levels 3 times
more than the upper limit of normal.
Statistical Analysis
The sample size was a consequence of the preceding
FERGIcor study, assuming that approximately 50% of patients
from this study would enroll into FERGImain. Kaplan–Meier
survival curves for time to recurrence of anemia (primary end
point) were compared between groups by log-rank test, providing an estimate of the treatment hazard ratio and the corresponding 95% confidence interval (CI). Continuous secondary
efficacy end points were analyzed by descriptive statistics comprising mean and standard deviation and with analysis of covariance models. Categoric end points were analyzed by logistic
regression. Missing data were treated as missing and only observed cases were used for analysis. Data were analyzed from the
safety set, full analysis set (FAS), and per-protocol set (PPS). The
safety set comprises all randomized patients with a baseline and
at least one postbaseline visit. Patients of the safety set who
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INTRAVENOUS IRON FOR PREVENTION OF ANEMIA
271
Figure 1. Patient flow and disposition.
received at least one dose of study drug comprised the FAS.
Patients who did not receive any treatment (serum ferritin level
remaining ⬎100 ␮g/L throughout the study period) were analyzed separately. The PPS comprised patients without major
protocol deviations. Data are presented as percentages of the
analyzed population, mean (standard deviation), or median
(interquartile range Q1, Q3) unless otherwise indicated.
The authors had full access to the study data, statistical
analysis, and reviewed and approved the final manuscript.
Results
Patient and Treatment Characteristics
Of 262 screened patients, 256 were randomized to FCM
or placebo (Figure 1). A total of 245 patients had at least one
postbaseline visit, 105 received FCM, and 99 received placebo
(FAS). A total of 41 patients (22 randomized to FCM, 19
randomized to placebo) received no treatment during the study
because the serum ferritin trigger of less than 100 ␮g/L had not
Table 1. Patient Demographics and Disease Characteristics (Safety Set)
Demographics
Median age, y (range)
Female, n (%)
Disease history and status
CD, n (%)
Median duration of CD, mo (range)
Mean CDAI (SD) in CD patients
UC, n (%)
Median duration of UC, mo (range)
Mean CAI (SD) in UC patients
Mean Hb, g/dL (SD)
Mean ferritin, ␮g/L (SD)
Mean TSAT, % (SD)
Mean CRP, mg/L (SD)
Prior and concomitant medication
(in ⱖ5% patients)
Aminosalicylates, n (%)
Systemic corticosteroids, n (%)
Thiopurines, n (%)
Anti-TNFs, n (%)
FCM
(n ⫽ 105)
Placebo
(n ⫽ 99)
39.0 (18–73)
62 (59.0)
37.0 (20–78)
58 (58.6)
35 (33.3)
74.1 (5.4–413.8)
77.1 (73.3)
70 (66.7)
41.5 (3.7–301.6)
2.5 (2.2)
13.7 (1.0)
76.1 (65.0)
21.8 (11.4)
7.6 (10.0)
25 (25.3)
58.8 (9.4–280.6)
65.4 (45.9)
74 (74.7)
45.3 (3.4–411.1)
2.1 (2.2)
13.6 (0.9)
74.0 (57.9)
23.4 (9.6)
6.3 (8.6)
45 (42.9)
6 (5.7)
12 (11.4)
9 (8.6)
38 (38.4)
3 (3.0)
12 (12.1)
8 (8.1)
No treatment
(n ⫽ 41)
44.0 (18–74)
27 (65.9)
16 (39.0)
61.5 (3.4–278.7)
84.3 (68.3)
25 (61.0)
64.8 (3.6–324.8)
1.9 (1.6)
13.3 (1.0)
221.0 (106.8)
32.1 (13.7)
7.8 (11.0)
15 (36.6)
2 (4.9)
13 (31.7)
4 (9.8)
Total
(n ⫽ 245)
39.0 (18–78)
147 (60.0)
76 (31.0)
67.4 (3.4–413.8)
74.9 (64.3)
169 (69.0)
46.5 (3.4–411.1)
2.2 (2.2)
13.6 (1.0)
99.5 (89.4)
24.1 (11.6)
7.1 (9.6)
98 (40.0)
11 (4.5)
37 (15.1)
21 (8.6)
P valuea
.155c
.719d
.218d
.996c
.655e
.218d
.771c
.423e
.174e
⬍.001b,e
⬍.001b,e
.575e
.753d
.651d
.003b,d
.910d
CAI, Colitis Activity Index; CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; SD, standard deviation; TNF, tumor necrosis factor.
aP values for statistical tests over all groups (FCM, placebo, no treatment).
bStatistical difference only between the treatment (FCM and placebo) and no treatment groups.
cKruskal–Wallis test.
dFisher exact test.
eStudent t test.
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EVSTATIEV ET AL
been met. The PPS comprised 170 patients: 85 FCM-treated and
85 placebo-treated patients. Patient demographics, medical and
surgical history, as well as prior and concomitant medication
were not significantly different between FCM- and placebotreated patients (Table 1). Differences for serum ferritin, TSAT,
and concomitant treatment with thiopurines were owing to
higher counts in the no-treatment group. In the preceding
FERGIcor study, 138 (53.9%) patients had received FCM and
118 (46.1%) patients had received iron sucrose.
In FERGImain, a smaller proportion of FCM- than placebotreated patients required iron infusions at all visits after baseline. FCM-treated patients received a median of 2 infusions
(range, 1–5 infusions), corresponding to 1000 mg iron (range,
500 –2500 mg iron); placebo-treated patients received 3 saline
infusions (range, 1–5 infusions). The median time to first infusion was 5 days (range, 0 –246 days) for FCM and 4 days (range,
4 –246 days) for placebo, respectively.
Recurrence of Anemia (Primary End Point)
Kaplan–Meier analysis of the probability of becoming
anemic showed significantly lower rates in FCM-treated patients compared with the placebo-treated patients of the FAS
(27.2% vs 40.4%; hazard ratio, 0.62; 95% CI, 0.38 –1.00; Kaplan–
Meier analysis; P ⫽ .049, log-rank test) (Figure 2). The calculated time to development of anemia in 25% of patients was 7.6
months (FCM) vs 4.7 months (placebo). The cumulative Kaplan–Meier probabilities of developing anemia at months 2, 4,
6, and 8 were 10.5%, 16.2%, 21.0%, and 27.2% in the FCM group,
and 15.2%, 23.3%, 32.8%, and 40.4% in the placebo group. The
actual number of patients who developed anemia during the
study period was 28 (27.5%) and 39 (41.5%) among FCM- and
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 3
placebo-treated patients who completed the 8-month period or
became anemic during this period (␹2 test: P ⫽ .038).
Patients who did not receive treatment during the study
(because their serum ferritin level was always greater than 100
␮g/L) were not included in the FAS. In this no-treatment group,
anemia had recurred in 14 (35%) patients by month 8 (1 patient
withdrew without postbaseline Hb assessments). In the PPS, the
estimated hazard ratio for anemia recurrence was similar to the
one calculated for the FAS (hazard ratio, 0.65; 95% CI, 0.38 –
1.09).
Secondary End Points
Serum ferritin level improved and TSAT remained
within the normal range in FCM-treated (⫹30.3 ␮g/L and
⫹0.58%) but not in placebo-treated patients (⫺36.1 ␮g/L and
⫺4.00%) over the 8-month study period (P ⬍ .001 and P ⫽ .022;
Figure 3A and B). In this nonanemic patient population, QoL
scores (SF-36 physical component and IBDQ) showed a positive
mean change from baseline to month 8 in the FCM group
(SF-36, 0.3 ⫾ 0.7; IBDQ, 1.7 ⫾ 3.1), but a decrease in the
placebo group (SF-36, ⫺0.6 ⫾ 0.8; IBDQ, ⫺1.1 ⫾ 3.7); however,
differences between the study groups were not significant (P ⫽
.4 and P ⫽ .5, respectively). In addition, changes in clinical
disease activity and C-reactive protein levels from baseline to
the end of the study period were not different between FCM
and placebo (Crohn’s Disease Activity Index, ⫺3.8 ⫾ 46.6 and
13.3 ⫾ 60.4; P ⫽ .171; Colitis Activity Index, ⫺0.1 ⫾ 2.2 and
0.1 ⫾ 2.1; P ⫽ .319; C-reactive protein, ⫺1.0 ⫾ 9.5 mg/L and
1.2 ⫾ 7.0 mg/L, P ⫽ .456). In addition, a trend was observed
toward fewer FCM- than placebo-treated patients who had lost
1 or more working days because of IBD (6.7% vs 11.1%; P ⫽ .25).
The median percentage of days out of work because of IBD was
comparable between FCM and placebo (7.95 [Q1, Q3; 5.06,
19.18] vs 6.41 [Q1, Q3; 1.26, 15.06]).
Tolerability
TEAEs were reported for 59.0% (FCM) and 50.5% (placebo) of patients and serious AEs for 6.7% and 8.1% (FCM vs
placebo; Table 2). The most common TEAEs were ulcerative
colitis (UC)–specific symptoms and nasopharyngitis (7.8% and
7.3%, respectively). Interestingly, gastrointestinal symptoms and
flares of UC were somewhat less frequent with FCM compared
with placebo (20.0% vs 28.3% [P ⫽ .17] and 6.7% vs 12.1% [P ⫽
.18], respectively). No infusion site reaction was reported and
no death occurred. Three FCM-treated patients had TEAEs
leading to permanent discontinuation of the study drug. All
events were of moderate intensity, 2 events (increased alanine
aminotransferase level and increased aspartate aminotransferase level) were considered possibly related, and 1 event (pancreatitis) was considered not related to the study drug. There was
no treatment-related anaphylactic reaction.
Discussion
Figure 2. Kaplan–Meier plots of anemia-free survival from baseline to
month 8 (FAS patient population) (hazard ratio, 0.62; 95% CI, 0.38 –
1.00; P ⫽ .049). Time to recurrence of anemia in 25% of patients: 7.6
months (FCM), 4.7 months (placebo). Recurrence rate at month 8:
26.7% (FCM), 39.4% (placebo).
Iron deficiency is the main cause of anemia in IBD,
which responds well to iron-replacement therapy. However,
anemia recurs in more than half of iron-treated patients within
a year, indicating a need for iron maintenance therapy.2 FERGImain tested intravenous iron maintenance therapy for the
prevention of anemia recurrence in this setting. In this study,
the serum ferritin concentration was measured every 2 months
March 2013
INTRAVENOUS IRON FOR PREVENTION OF ANEMIA
273
Figure 3. Adjusted mean changes and standard error of iron status parameters (A) serum ferritin and (B) TSAT at months 2, 4, 6, and 8. *P ⬍ .05
vs placebo. ⫹Month 8 or early termination.
and FCM (or placebo) was administered when serum ferritin
level had decreased to less than 100 ␮g/L.17 The results show
that FCM infusions (500 mg iron each) can reduce the rate of
anemia recurrence in IBD. Because separation of the Kaplan–
Meier curves continued to increase until the end of the study
period we may anticipate a further benefit from FCM beyond 8
months.
Iron status (serum ferritin and TSAT) improved or remained
normal over the study period in FCM-treated patients, but
worsened in those on placebo. Thus, ferritin-triggered FCM
treatment effectively prevented iron deficiency and IBD-associated anemia. FCM was well tolerated without new safety findings. AE and serious AE rates were comparable between FCM
and placebo. Importantly, no drug-related anaphylaxis or infusion site reaction occurred in this study. Of note, gastrointestinal symptoms and flares of UC were less frequent in the FCM
group. Among patients randomized to placebo, the recurrence
of anemia, 39.4% at 8 months, was considerably high. This is in
line with a previous retrospective analysis that indicated a 40%
recurrence of anemia after 8 months, 50% after 10 months, and
56% after a year.19 Notably, the patient population in FERGImain displayed a rather low clinical disease activity, reflecting
the inclusion criteria of the preceding FERGIcor study.14 Accordingly, the results of this study suggest that even IBD patients with apparently quiescent disease and replenished iron
stores cannot maintain a positive iron balance and are therefore
at a considerable risk of developing anemia. This observation
not only should warrant close monitoring of iron and anemia
markers, but also is suggestive of subclinical mucosal disease
that may need re-evaluation and treatment escalation.17 The
great risk of anemia recurrence, however, supports the implementation of preventive measures as successfully shown in this
study.
In contrast to the traditional watch-and-wait strategy, FERGImain introduces the novel concept of proactive anemia prevention. Considering that anemia in IBD substantially reduces
QoL, contributes to fatigue,13 and is a common trigger for
hospitalization,5,7 effective anemia prevention may provide a
meaningful alleviation of the overall disease burden. Further
support for preventive ferritin-triggered iron replacement
comes from reports showing that treatment of iron deficiency
even without anemia can improve fatigue, exercise performance,
and muscle function.10,11,22,23 Although the study was not designed and powered to detect a treatment effect on QoL, a
positive trend in terms of improved physical characteristics in
favor of FCM treatment was observed. Cost comparisons also
favor a proactive approach to anemia management. Waiting for
anemia recurrence may be expensive because the average annual
health care payments are more than twice as high for anemic
compared with nonanemic IBD patients (US$19,113 vs
US$7678).24 Therefore, FCM maintenance therapy may be a
cost-effective option for anemic IBD patients. Notably, colitis
symptoms were reported less frequently in FCM-treated patients and there was a trend toward a lower percentage of
patients who lost at least 1 working day as a result of IBD. This
confirms the good tolerability profile of FCM and is in line with
clinical experience and in vitro experiments that have shown a
reduced responsiveness of iron-loaded macrophages to the
TH-1 cytokine interferon-␥, leading to lower production of
tumor necrosis factor-␣ and other proinflammatory stim-
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EVSTATIEV ET AL
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 3
Table 2. Safety Results
n (%)
Any TEAE
Any severe TEAE
Any SAE
TEAE leading to discontinuation
Death
Any related TEAE
Any related severe TEAE
Any related SAE
Related TEAE leading to discontinuation
Most common TEAEs (⬎2% of patients
in the FCM or placebo group)
Worsening of UC
Nasopharyngitis
Abdominal pain
Transaminase increase
Worsening of Crohn’s disease
CRP increase
Headache
Viral respiratory tract infection
Hematochezia
Back pain
Nausea
FCM
(n ⫽ 105)
Placebo
(n ⫽ 99)
No treatment
(n ⫽ 41)
Total
(n ⫽ 245)
62 (56.0)
10 (9.5)
7 (6.7)
3 (2.9)
0
8 (7.6)
0
0
2 (1.9)c
50 (50.5)
4 (4.0)
8 (8.1)
0
0
1 (1.0)
0
0
0
16 (39.0)
0
3 (7.3)
0
0
1 (2.4)
0
0
0
128 (52.2)
14 (5.7)
18 (7.3)
3 (1.2)
0
10 (4.1)
0
0
2 (0.8)
.036b
—
—
.652
7 (6.7)
10 (9.5)
7 (6.7)
9 (8.6)
1 (1.0)
5 (4.8)
4 (3.8)
5 (4.8)
1 (1.0)
4 (3.8)
3 (2.9)
12 (12.1)
7 (7.1)
5 (5.1)
3 (3.0)
3 (3.0)
3 (3.0)
2 (2.0)
1 (1.0)
3 (3.0)
0
0
0
1 (2.4)
0
0
4 (9.8)
0
2 (4.9)
0
0
0
0
19 (7.8)
18 (7.3)
12 (4.9)
12 (4.9)
8 (3.3)
8 (3.3)
8 (3.3)
6 (2.4)
4 (1.6)
4 (1.6)
3 (1.2)
.050d
.375
.277
.061
.029d
.397
.641
.180
.399
.132
.216
P valuea
.086
.059
.946
.297
CRP, C-reactive protein.
aP values for statistical tests over all groups (FCM, placebo, no treatment).
bStatistical difference between the FCM and placebo groups (Fisher exact test).
cPossibly related increase in liver enzymes.
dStatistical difference between the treatment group (FCM and placebo) and the no treatment group.
uli.4,8,25,26 These considerations may translate into an individual
as well as a communal benefit of FCM in prevention of IBDassociated anemia.
Because all patients had been part of a preceding anemia
correction trial (FERGIcor14), the study population was well
defined and reflects the clinical situation of anemic IBD patients who are treated until resolution of anemia. Although the
single-blinded design may be considered a potential shortcoming, the primary end point, a laboratory value, was unlikely to
be affected by the study personnel’s awareness of the treatment.
A bias on the physician’s judgment of disease activity or of
drug-related AEs cannot be excluded; however, a single-blinded
design tends to cause an overestimation of drug-related AEs,
and disease activity was persistently in remission in both treatment arms.
Identification of an appropriate trigger and monitoring frequency for iron replacement in a nonanemic IBD patient population was a challenge when designing this study. The conventional definition of iron deficiency in patients without
inflammation is a serum ferritin level less than 30 ␮g/L.27,28
However, because ferritin is an acute-phase protein, serum levels can increase to greater than 30 ␮g/L in patients with chronic
inflammation despite empty iron stores, and a ferritin level less
than 100 ␮g/L may be more appropriate to define iron deficiency in active IBD.14,16,17,29 Accordingly, anemia recurrence in
IBD patients can occur way before a decrease of ferritin level to
less than 30 ␮g/L.19 Therefore, a higher ferritin cut-off value
was chosen to ensure early recognition of patients at risk of
anemia recurrence. Shortcomings of the selected treatment trigger may be the reason that a smaller than expected prolonga-
tion of anemia-free survival was seen, indicating a potential to
improve the maintenance treatment regimen. In fact, despite
the high ferritin cut-off value, a substantial proportion of
FCM-treated patients (26.7%) experienced recurrence within 8
months. Also, 14 of 40 patients (35%) with postbaseline Hb
assessments who did not receive any treatment became anemic
before their serum ferritin levels decreased to less than 100
␮g/L. This no-treatment group had higher serum ferritin and
TSAT levels at baseline (Table 1) and more patients on concomitant thiopurine treatment. It is likely that the observed
mild Hb decrease in this no-treatment population is rather a
consequence of thiopurines than of iron deficiency itself. In a
prior analysis,19 a decrease in TSAT (⬍16%) occurred before
anemia recurrence, indicating that TSAT might have been a
better treatment trigger. However, concerns about the reliability
of TSAT as a diagnostic marker (particularly when blood is
drawn in a nonfasting state or hemolysis occurs within the test
tube) prompted the recommendation of a serum ferritin level of
less than 100 ␮g/L as the treatment trigger instead.
Reasons for recurrence in iron-treated patients may be the
low FCM dose (500 mg iron compared with the maximum
recommended single dose of 1000 mg or 20 mg/kg body
weight) and the monitoring interval between ferritin assessments. Considering this 2-month monitoring interval and prior
findings on early anemia recurrence,19 triggering treatment at a
higher ferritin level might be appropriate. Further subanalyses
of the patient populations that benefit most from FCM maintenance treatment may allow for optimization of the treatment
schedule and the triggers for treatment. In conclusion, serum
ferritin–triggered iron therapy with FCM is an effective and safe
March 2013
treatment to prevent recurrence of anemia in patients who have
responded to prior intravenous iron-replacement therapy. Optimizations regarding the treatment trigger, FCM dose, and
dosing interval, as well as the identification of high-risk groups
are warranted.
INTRAVENOUS IRON FOR PREVENTION OF ANEMIA
20.
21.
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Reprint requests
Address requests for reprints to: Christoph Gasche, MD, Department
of Medicine 3, Division of Gastroenterology and Hepatology, Medical
University of Vienna, Währinger Gürtel 18-20, 1090 Wien, Austria.
e-mail: [email protected]; fax: (43) (1) 404004735.
Acknowledgments
The authors acknowledge the contribution of all investigators at all
study sites (listed in the Appendix).
Conflicts of interest
These authors disclose the following: Bernd Bokemeyer received consultancy honoraria from Vifor Germany and Pharmacosmos. Marcel
Felder and Maja Gudehus are employees of Vifor Pharma (Switzerland).
Tariq Iqbal and Philippe Marteau have received speakers honoraria from
Vifor International. Jürgen Stein is a consultant for and has received
speakers honoraria from Vifor International. Christoph Gasche has received grant and consultancy honoraria from Vifor Pharmacosmos A/S,
Fresenius Medical Care, and Renapharma Sweden. The remaining authors disclose no conflicts. No conflicts of interests were disclosed to
study participants in the informed consent form.
Funding
Vifor Pharma (Switzerland) sponsored this study and supported the
development of the study design and preparation of the manuscript;
an independent clinical research organization (Parexel International,
Germany) conducted the trial and performed the statistical analysis;
276
EVSTATIEV ET AL
and medical writing support was provided by Walter Fürst, SFL Regulatory Affairs & Scientific Communication, Switzerland, and was
funded by Vifor Pharma, Switzerland. The study sponsors had no role
in interpreting the results or in the decision for submission.
Appendix
The following institutions and local principal investigators participated in this study.
Austria: Christoph Gasche, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University
of Vienna; Friedrich Wewalka, Konventhospital der Barmherzigen Brüder Linz; Thomas Feichtenschlager, Krankenanstalt Rudolfstiftung, 4. Medizinische Abteilung mit Gastroenterologie
und Hepatologie, Wien.
Denmark: Jørn Brynskov, Med. Gastroenterology, Herlev
Hospital, Herlev; Ole Bonderup, Medicinsk Gastroenterologsik
Afdeling, Regions Hospitalet Randers, Randers; Vibeke Andersen, Medicinsk Afd., Regions Hospitalet Viborg, Viborg.
France: Philippe Marteau, Gastro-Enterologie et Hepatologie,
Hopital Lariboisiere, Paris Cedex 10; Jean-Louis Dupas, HepatoGastro-Enterologie, Hopital Nord, Amiens Cedex 1.
Germany: Jürgen Stein, Department of Gastroenterology and
Clinical Nutrition and Crohn Colitis Centre Rhein Main, Klinik
für Viszeral und Ernährungsmedizin Katharina Kasper Kliniken, Frankfurt/Main; Ulrich Boecker, Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Mannheim,
Mannheim; Thomas Ochsenkuehn, Medizinische Klinik und
Poliklinik II, Klinikum der Universität München–Campus
Grosshadern; Bernd Bokemeyer, Gastroenterologische Gemeinschaftspraxis Minden, Minden; Giuliano Ramadori, Universitätsklinikum, Göttingen; Ursula Seidler, Medizinische Hochschule für Hannover, Abteilung für Gastroenterologie; Ulrike
Strauch, Klinik und Poliklinik für Innere Medizin I, Universitätsklinikum Regensburg; Andreas Sturm, Medizinische
Klinik mit Schwerpunkt Hepatologie und Gastroenterologie,
Charité-Campus Virchow Klinikum, Berlin; Stefan Zeuzem,
Universitätsklinikum, Frankfurt/Main; Dietrich Hueppe, Gastroenterologische Gemeinschaftspraxis Herne; Carsten Büning,
Charite Campus Mitte, Berlin; Martin Zeitz, Charite Campus
Benjamin Franklin, Berlin.
Norway: Jorgen Jahnsen, Medisinsk Dagpost, Aker Universitetssykehus HF, Oslo; Roald Torp, Sykehuset Innlandet, Medisinsk Avdeling, Hamar.
Romania: Ioan Sporea, Spitalul Clinic Judetean de Urgenta,
Timişoara; Adrian Goldis, Cabinet Particular Policlinic Algomed SRL, Timişoara; Mihail-Radu Voiosu, Spitalul Clinic
Colentina, Bucharest; Mircea Manuc, Institutul Clinic Fundeni,
Bucharest.
Spain: Xavier Calvet Calvo, Corporación Sanitaria Parc Tauli,
Sabadell; Sam Khorrami, Hospital Universitario Son Dureta,
Palma de Mallorca.
Sweden: Henrik Hjortswang, Endokrin-Och Mag/Tarmmedicinska Mottagningen, Universitetssjukhuset, Linköping;
Per-Ove Stotzer, Medicinal Gastroenterology, Gastrosektionen,
Göteborg; Anders Eriksson, Medicine Clinic, Medicinkliniken
Plan 2, Sahlgrenska Universitetssjukhus/Östra Sjukhuset, Göteborg; Ragnar Befrits, Karolinska Universitetssjukhuset, Stockholm.
Switzerland: Rémy Meier, Medizinische Universitätsklinik
Kantonspital Liestal; Janek Binek, Kantonspital St Gallen.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 3
United Kingdom: Tariq Iqbal, University Hospital, Birmingham, Queen Elizabeth Hospital, Edgbaston; Anthony Barnabus
Hawthorne, University Hospital, Wales, Cardiff; Peter Isaacs,
Blackpool Victoria Hospital, Blackpool; Chris Probert, Bristol
Royal Infirmary, Bristol
Russia: Igor Lvovich Khalif, Federal State Institution
“State scientific centre of coloproctology of Rosmedtechnology,” Moscow; Elena Alexandrovna Belousova, State Institution “Moscow Regional Scientific Research Clinical Institute
named M.F. Vladimirsky,” Moscow; Oleg Nikolaevich Minushkin, State Health Institution of Moscow “City Clinical
Hospital # 51,” Moscow; Andrey Yrievich Baranovskiy, St.
Petersburg State Health Institution “City Clinical Hospital #
31,” St. Petersburg; Vladimir Ilich Simanenkov, St. Petersburg State Health Institution “City Hospital # 26,” St. Petersburg; Vladimir Borisovich Grinevich, Federal State
Institution “442 District Military Clinical Hospital of Leningradsky Military District” of the Ministry of Defense of the
Russian Federation, St. Petersburg; Elena Sergeevna Pasechnik, State Health Institution “Kaluga Regional Hospital,”
Kaluga; Oleg Yrievich Dolgikh, Road Clinical Hospital on
Samara Station “RGD,” Samara; Asfold Ivanovich Parfenov,
State Health Institution of Moscow “Central Scientific Educational Institute Of Gastroenterology,” Moscow; Vladimir
Vitalievich Rafalskiy, Municipal Treatment and Prophylactic
Institution “Clinical Hospital No 1,” Smolensk; Alexey Alexandrovich Nizov, State Health Institution “Ryazan Regional
Clinical Hospital,” Ryazan; Elena Alexandrovna Sishkova,
Federal Health State Institution “Clinical Hospital # 122
named L.G. Socolov FMBA of Russia,” St. Petersburg; Olga
Polikarpovna Alexeeva, State Health Institution “Nizhni Regional Clinical Hospital named N.A. Semashko,” Nizhni
Novgorod; Oleg Lenianovich Solovyev, ZAO “Medical Scientific Production Association Clinic Dvizhenie,” Volgograd;
Andrey Vladislavovich Kulyapin, MU City Clinical Hospital #
21, Ufa; Emiliya Prokhorovna Yakovenko, State Educational
Institution of Higher Professional Education “Russian State
Medical University Roszdrava” based on Federal State Institution “National Medical-Surgical Centre named by N.I. Pirogov Roszdrava,” Moscow; Vladimir Vasilievich Pavlenko,
Stavropol State Medical Academy, Stavropol; Ildar Gazimdzhanovich Salikhov, Department of Gastroenterology, Kazan
State Medical University, Republic Clinical Hospital, Kazan;
Igor Borisovich Khlynov, Municipal Institution “City Clinical Hospital # 40,” Ekaterinburg; Irina Yurievna Pirogova,
Municipal Healthcare Institution “City Clinical Hospital #
8,” Chelyabinsk; Olga Vladimirovna Krivtsova, Open JointStock Company (OAO) “Medical Unit Neftyanik,” Tyumen.
Estonia: Lidia Randvee, MEDICUM, Ltd, Tallinn; Kyllikke
Suurmaa, West Tallinn Central Hospital.
Ukraine: Ivan Chopey, Departmental Clinical Hospital, Department of General Therapy, Uzhgorod National University,
Faculty of Post-Graduate Education, Uzhgorod; Borys Palamar,
Kyiv City Clinical Hospital # 3, Department of Gastroenterology, Kiev; Galyna Popik, Odessa Railway Clinical Hospital,
Department of Therapy # 2, Odessa; Mykola Yabluchanskiy,
State Treatment and Preventive Establishment “Central Clinical
Hospital of Railways of Ukraine,” Department of Gastroenterology, Kharkiv National University named after V.N. Karazin,
March 2013
Kharkiv; Iryna Klyaryts’ka, Department of Gastroenterology,
Simferopol, Crimean State Medical University named after S.I.
Georgievsky, Simferopol; Tetyana D. Zvyagintseva, Kharkiv City
Clinical Hospital # 2, Department of Gastroenterology,
Kharkiv; Natalia V. Kharchenko, Department of Gastroenterology, Kyiv City Clinical Hospital # 8, Kyiv; Galina D. Fadieienko,
State Establishment “Institute of Therapy named after L.T.
INTRAVENOUS IRON FOR PREVENTION OF ANEMIA
277
Mala of Academy of Medical Science of Ukraine,” Kharkiv;
Valeriy ⌱. Vdovichenko, Department of Therapy # 1, Lviv City
Municipal Clinical Emergency Hospital, Lviv National Medical
University named after Danylo Halytskyi, Lviv; Yuriy M.
Stepanov, Dnepropetrovsk State Medical Academy, Dnepropetrovsk; Lyubomyr V. Glushko, Ivano-Frankivsk National Medical University, Ivano-Frankovsk.