RCT Irondose Adults
RCT Irondose Adults
RCT Irondose Adults
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ORIGINAL ARTICLE
Received: 21 August 2019 / Accepted: 24 November 2019 / Published online: 6 December 2019
# Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract
Recent studies in iron-depleted women have challenged the current approach of treating iron-deficiency anemia (IDA) with oral
iron in divided daily doses. Alternate day dosing leads to more fractional absorption of iron. In this randomized controlled trial,
we looked at the efficacy and safety of alternate-day (AD) versus twice-daily (BD) oral iron in all severity of IDA. Total of 62
patients were randomized, 31 patients in BD arm received 60 mg elemental iron twice daily while 31 patients in AD arm received
120 mg iron on alternate days. The primary endpoint of 2 g/dl rise in hemoglobin was met in significantly more patients in the BD
arm at 3 weeks (32.3% vs. 6.5%, p < 0.0001) and 6 weeks (58% vs. 35.5%, p = 0.001). There was a significant rise in the median
hemoglobin at 3 (1.6 vs. 1.1, p = 0.02) and 6 weeks (2.9 vs. 2.0 g/dl, p = 0.03) in the BD arm. However, the median hemoglobin
rise in the AD arm at 6 weeks was not significantly different than the BD arm at 3 weeks. Alternate-day dosing for 6 weeks and
twice-daily dosing for 3 weeks resulted in the provision of the same total amount of iron. There were more reports of nausea in the
BD arm (p = 0.03). In conclusion, the choice of twice-daily or alternate-day oral iron therapy should depend on the severity of
anemia, the rapidity of response desired, and patient preference to either regimen due to adverse events. Trial Registration: CTRI
reg. no. CTRI/2018/07/015106 http://ctri.nic.in/Clinicaltrials/login.php.
Introduction IDA. The standard dosing for oral iron is a single tablet contain-
ing 60 mg of elemental iron to be taken two–three times a day
Oral iron therapy is the mainstay of treatment of IDA. Current [1]. The recent study by Moretti et al. elegantly described what
guidelines recommend daily oral iron in divided doses to treat happens with different oral iron dosing and schedules [2]. The
morning dose augments the diurnal hepcidin increase in the af-
Presented at the 24th Congress of the European Hematology Association, ternoon and thereby decreases the fractional iron absorption from
14 June 2019 the afternoon dose. In addition, the afternoon dose leads to an-
Electronic supplementary material The online version of this article other hepcidin increase for 24 h, decreasing the fractional iron
(https://doi.org/10.1007/s00277-019-03871-z) contains supplementary absorption from the following morning dose. Alternate-day or
material, which is available to authorized users. weekly dosing leads to more fractional absorption of iron. What
is important is that these iron kinetic studies were done in iron-
* Deepesh P. Lad depleted young women and are not necessarily true in all anemic
deepesh.lad12@gmail.com
patients. This study challenged the way we should be treating
1
Department of Internal Medicine, Postgraduate Institute of Medical
IDA and was the basis of our hypothesis single dosing on alter-
Education and Research, Chandigarh 160012, India nate days is better than the standard of care twice-daily dosing of
2
Department of Pediatrics, Postgraduate Institute of Medical
oral iron in the treatment of IDA [3]. There are already pre-
Education and Research, Chandigarh, India existing studies on the prevention and treatment of mild IDA in
3
Department of Hematology, Postgraduate Institute of Medical
school-going children and pregnant women with intermittent
Education and Research, Chandigarh, India dosing schedules of iron. These studies have shown that
58 Ann Hematol (2020) 99:57–63
intermittent dosing schedules are effective in preventing and im- Randomization and masking
proving mild IDA [4, 5]. This was also answered in a mechanis-
tic randomized controlled trial in iron-depleted women and in One study author assessed the patients for study eligibility
women with mild IDA, which showed higher cumulative frac- (DPL). Another author (RK) was involved in patient random-
tional and total iron absorption in the alternate-day group than the ization, study drug administration, and ensuring compliance.
consecutive-day group at the end of treatment [6]. A follow-up The patients were randomized with a 1:1 allocation in blocks
study by the same group showed that iron absorption was greater of three to receive either tablet ferrous sulfate 200 mg per oral
with alternate-day than with consecutive-day dosing in women empty stomach twice-daily (120 mg elemental iron per day)
with mild IDA [7]. (arm BD: standard arm) or tablet ferrous sulfate 400 mg per
In this randomized, controlled, open-label trial, we looked oral empty stomach on alternate days (120 mg elemental iron
at the efficacy and safety of once alternate-day schedule com- on alternate days) (arm AD: experimental arm).
pared to the twice-daily schedule in the treatment of all sever- Randomization was stratified by the severity of anemia (mild,
ity of anemia. moderate, severe as above). The study drug was generic an-
hydrous ferrous sulfate tablets (Jackson Laboratories, India) of
200 mg, each containing 60 mg elemental iron. Compliance
was ensured by weekly phone calls. All the other authors were
Methods involved in assessing adverse events and follow-up investiga-
tions. All adverse events (AE) subjectively reported by the
The institutional review board approved the study. Written patients were recorded as per the CTCAE version 4.0 on
informed consent was obtained from all the participants before follow-up visits and weekly phone calls.
the enrollment. The study was performed in accordance with
the Consolidated Standards of Reporting Trials and the decla- Laboratory parameters
ration of Helsinki. The study was conducted at a single center
(tertiary referral center in North India) from July 2017 to The CBC, along with reticulocyte, RHC, and RBC indices,
December 2018. The study protocol is mentioned in the sup- was performed on baseline samples and after 1 week (at day
plement. The study was registered at the clinical trials registry 8). The samples were run on XN-1000® (Sysmex
of India CTRI Reg. no CTRI/2018/07/015106. Corporation, Kobe, Japan) automated hematology analyzer.
Patients of either gender, age > 15 years, and proven iron- Repeat assessment of hemoglobin was done at 3 and 6 weeks
deficiency anemia were included in the study. Iron-deficiency of therapy. Plasma hepcidin was measured at the end of week
anemia was confirmed by serum ferritin level of < 20 ng/ml. 1 (day 8) using the Human Hepcidin ELISA Kit (Sincere
Patients with borderline anemia (hemoglobin ≥ 11.5 g/dl), very Biotech, China) based on sandwich ELISA principle as per
severe anemia (hemoglobin < 6 g/dl), cardiac failure, pregnan- the manufacturer’s instructions. A standard curve was obtain-
cy, and clinical or laboratory evidence of other causes of anemia ed with an intra-run coefficient of variation of 10%. The
(iron malabsorption, gastrointestinal bleed, megaloblastic ane- ELISA run was read on Tecan ELISA reader, providing both
mia, or anemia of chronic disease) were excluded from the optical density and absolute values for hepcidin. The upper
study. Patients were classified as mild anemia (11–11.4 g/dl), and lower detection limits for the kit were 3.12 to 200 ng/ml,
moderate anemia (8–10.9 g/dl), and severe anemia (6–8 g/dl) as with a sensitivity of 0.6 ng/ml.
per the World Health Organization definition [8]. The primary
objective of the study was to assess the efficacy of alternate-day Statistical analysis
oral iron therapy in comparison to twice-daily oral iron therapy
in subjects with iron-deficiency anemia. The secondary objec- The sample size was estimated based on previously pub-
tive was to assess the adverse events, change in plasma hepcidin lished studies with a difference in the experimental and con-
(PHep), and RBC parameters in both the arms. The primary trol arm means of 0.7 g/dl after 30 doses and a standard
endpoint was the proportion of patients achieving ≥ 2 g/dl he- deviation of 1 g/dl [6] (~ 1 g/dl of hemoglobin after 42
moglobin rise by 3 weeks (day 22) [3, 9] and the quantity of doses), 1:1 allocation, type I error probability of 0.05, and
hemoglobin rise by 3 and 6 weeks in both arms. The secondary a power of 0.95. This was estimated to be a total of 27
endpoints were (1) incidence of adverse events, (2) change in patients in each arm. Assuming a loss to follow-up rate of
plasma hepcidin after 1 week of therapy compared to the base- 15%, the accrual goal was 31 patients per arm. Categorical
line, (3) change in reticulocyte hemoglobin content (RHC) after variables, including the proportion of patients with response
1 week of therapy compared to the baseline, and (4) change in and adverse events, were compared using the chi-square
automated red blood cell indices—mean corpuscular volume test. The Mann-Whitney test was used for the comparison
(MCV) and mean corpuscular hemoglobin (MCH) after 6 of two groups. Significance was set at p < 0.05 for all tests.
weeks of therapy compared to baseline. Prism v7∙0 software was used for statistical analysis.
Ann Hematol (2020) 99:57–63 59
BD twice a day, AD alternate day, Hb hemoglobin, MCV mean corpuscular volume, MCH mean corpuscular
hemoglobin, RHC reticulocyte hemoglobin content, PHep plasma hepcidin
5.2, respectively, p = 0.8 (Fig. 5). There was an increase in arm. The subset analysis of mild anemia showed that the he-
PHep in 13 patients in BD, 11 in AD arm, and a decrease in moglobin rise was not significantly different in both the arms.
nine patients in BD and eight in AD arm (p > 0.1). The RBC
indices MCV and MCH were significantly more in the BD
arm compared to the AD arm at both the 3- and 6-week time
Discussion
points (data not shown).
In this randomized, controlled, open-label trial, we looked
at the efficacy and safety of oral ferrous sulfate once an
Subset analysis
alternate day (400 mg AD) compared to the standard
twice-daily schedule (200 mg BD) in the treatment of all
Stratifying by the severity of anemia, the ΔPHep was more in
severity of anemia. This is the first such trial in all sever-
mild anemia patients (3.4 ± 6.0 ng/ml) as compared to
ity of anemia to the best of our knowledge. We chose the
moderate-severe anemia patients (0.4 ± 5.3 ng/ml), though
simplest form of oral iron tablets (ferrous sulfate 200
this was not significantly different (p = 0.2). On subset anal-
mg—each containing 60 mg elemental iron) since it is
ysis of moderate and severe anemia together, there was sig-
available in our national health programs and is cheap
nificantly more median hemoglobin rise at the end of three
and generic. Plus, there is no data to show the superiority
(1.75 vs. 1.2 g/dl respectively, p = 0.01) and 6 weeks (3.8 vs.
of any other formulation of iron tablets over the age-old
2.1 g/dl respectively, p = 0.02) in the BD compared to the AD
ferrous sulfate formulation [10]. The schedules were so
chosen for the practical ease, compliance, and maintaining
at least one standard of care arm (200 mg BD). The basis
for this trial was the study by Moretti et al. [2] which
challenged the way we should be treating IDA and
questioned whether alternate-day dosing would be better
than daily dosing [3]. This study was done in iron-
depleted young women. Subsequent follow-up studies by
the same group have shown that iron absorption was
greater with alternate-day than with consecutive-day dos-
ing in women with mild IDA [7]. Whereas the median
hemoglobin in this study was 11.3 and 11.6 g/dl and the
primary objective was to compare iron absorption, the
median hemoglobin in our study was 8.9 g/dl in both
Fig. 2 Percentage of patients attaining primary endpoint of ≥ 2 g/dl rise in arms with a clinically relevant primary endpoint to com-
hemoglobin pare change in hemoglobin.
Ann Hematol (2020) 99:57–63 61
the elemental iron delivered in the AD compared to the BD dose given in the current study. Changes in PHep levels in our
arm. This may be important for patients with mild anemia, study can be attributed to increased erythropoiesis in moderate
where the speed of response is less relevant. For patients with and severe anemia after oral iron intake. The production of
moderate anemia, the dosing strategy can be individualized as PHep is inhibited by the expansion of erythropoiesis, iron
per patient preference for faster response or better tolerance. deficiency, and tissue hypoxia [11]. In patients with moderate
to severe IDA, the erythropoiesis is geared for expansion in
the face of available iron and hence suppresses the increase in
Early response and hepcidin kinetics
hepcidin after the availability of oral iron.
Reticulocyte hemoglobin content (RHC) is the measure of
available functional iron over the previous few days for the Response stratified by severity of anemia
new RBCs and one of the earliest means of detecting response
to treatment. Patients in the BD arm had greater rise in RHC On subset analysis, the median rise in hemoglobin levels was
and reticulocytosis than patients in the AD arm, indicating the similar across both the arms in mild anemia. This is as expect-
availability of more iron for erythropoiesis in the BD com- ed from previously published studies [2, 4–6]. This could be
pared to the AD dosing. The PHep kinetics were not signifi- due to less strain for erythropoiesis in mild anemia after the
cantly different from the baseline and between the two arms at availability of oral iron and intact hepcidin axis. This could
the end of 1 week. Though the change in PHep was more in also be because the rise in hemoglobin in mild anemia is only
mild IDA than moderate to severe anemia, this was insignif- of a smaller degree to normalization and hence not statistically
icant probably due to small patient numbers in the mild IDA significant. On the contrary, in moderate-severe anemia, the
subgroup. This is in contrast to the previous study by Stoffel patients in the BD arm had significantly more median hemo-
et al., in which serum PHep were uniformly higher in the daily globin rise than patients in the AD arm at both the time points
arm than alternate day arm throughout the first 14 days [6]. of 3 (1.7 vs. 1.2, respectively, p = 0.01) and 6 weeks (3.8 vs.
This finding was demonstrated only in patients who were iron 2.1, respectively, p = 0.02, respectively). However, this subset
depleted or had mild anemia. Patients in this study were given analysis was not part of the planned primary endpoint analysis
60 mg elemental iron on alternate days, which is half of the and the patient numbers are small to draw any conclusions.
In summary, ours is the first study to the best of our knowl-
edge testing the impact of twice-daily versus alternate-day oral
iron therapy in the treatment of all severity of IDA. If the institutional research committee and with the 1964 Helsinki declaration
and its later amendments or comparable ethical standards.
speed of hemoglobin response is desirable, which is the case
in severe anemia, twice-daily dosing of oral iron is still better
Informed consent Informed consent was obtained from all individual
than alternate-day dosing. If the speed of response is not de- participants included in the study.
sirable, but tolerance is as is the case in mild anemia, alternate-
day iron therapy is better. This could be the preferred choice
specifically in preventive strategies or in iron-depleted pa- References
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Author contributions DPL, PM, SV, and PB conceived and designed the daily split dosing in iron-depleted women: two open-label,
study. All authors were involved in patient recruitment and clinical care of randomised controlled trials. Lancet Haematol. 4(11):e524–ee33
the patients. PB, RD, and NV analyzed the lab data. DPL, RK, PB, and 7. Stoffel NU, Zeder C, Brittenham GM, Moretti D, Zimmermann
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proved the final version. nate day than with consecutive day dosing in iron-deficient anemic
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Funding information This study was funded in part by an intramural
sessment of severity. Vitamin and Mineral Nutrition Information
grant (IM/2018/99) to DPL and RK from the Department of Internal
System. Geneva, World Health Organization, 2011 (WHO/NMH/
Medicine, Postgraduate Institute of Medical Education and Research,
NHD/MNM/11.1) (http://www.who.int/vmnis/indicators/
India. The funder of the study had no role in study design; the collection,
haemoglobin. pdf, accessed May 28, 2019).
analysis, and interpretation of the data; or in the writing of the report. DPL
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and RK had full access to all the data in the study and the final respon-
ciency and overload. In: Hoffman RBEJ, Silberstein LEHS, Weitz
sibility to submit the paper for publication.
J, Anastasi J (eds) Hematology: basic principles and practice, 6th
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Compliance with ethical standards 10. Camaschella C (2015) Iron-deficiency anemia. N Engl J Med.
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Conflict of interest The authors declare that they have no conflict of 11. Ganz T (2011) Hepcidin and iron regulation, 10 years later. Blood.
interest. 117(17):4425–4433
Ethical approval All procedures performed in studies involving human Publisher’s note Springer Nature remains neutral with regard to jurisdic-
participants were in accordance with the ethical standards of the tional claims in published maps and institutional affiliations.