To the Editor:Iron deficiency anemia (IDA) is highly prevalent in women. The main
risk factors for IDA include a low intake of iron, poor absorption, and high iron
requirements such as those observed during pregnancy or with menorrhagia.1
Treatment includes controlling the bleeding and replenishing lost iron. Oral iron
remains the front‐line standard primarily because of its convenience and low cost.
However, international guidelines recommend intravenous (IV) iron as the preferred
route when there is intolerance of oral iron, limited absorption, or when there is
a high iron need.2, 3, 4
Iron isomaltoside is one of the newer IV iron formulations able to supply a complete
replacement dose in a short, single visit in most patients.
Herein, we present data from a subpopulation of gynecology patients with IDA from
a previously reported trial.5 The objective was to compare the efficacy and safety
of iron isomaltoside to iron sucrose in gynecology patients (corresponding to 48.5%
of those in the larger trial) with IDA and who were intolerant of, or unresponsive
to oral iron therapy or who would benefit from rapid iron repletion.
Patients were randomized 2:1 to iron isomaltoside (Monofer®, Pharmacosmos A/S, Holbaek,
Denmark) or iron sucrose (Venofer®, Vifor Pharma, Glattbrugg, Switzerland).5
The primary efficacy endpoint was the proportion of patients with a hemoglobin (Hb)
increase of ≥2 g/dL from baseline (ie, dosing) at any time from week 1 to 5. Secondary
efficacy endpoints were time to Hb increase ≥2 g/dL, and change in Hb, s‐ferritin,
transferrin saturation (TSAT), and total quality of life (QoL) score (Short Form 36
[SF‐36] questionnaire). Safety endpoints included the number of patients who experienced
any adverse drug reaction (ADR). The primary endpoint was tested for non‐inferiority.
If the 95% confidence interval (CI) was above 0, this was evidence of superiority
in terms of statistical significance at the 5% level. Remaining endpoints were only
tested for superiority.
Two hundred forty‐eight patients were randomized to either the iron isomaltoside (164)
or iron sucrose group (84). Baseline characteristics were comparable between the treatment
groups. The mean cumulative dose of iron isomaltoside was 1687 (SD: 381) mg and of
iron sucrose 1154 (SD: 368) mg. The difference in cumulative doses is reflective of
the ability to administer a larger dose of iron isomaltoside in a single setting resulting
in fewer administrations and a shorter treatment period to reach the desired iron
dose.
The primary analysis was conducted on both the full analysis set (FAS) (N = 237) and
the per protocol (PP) analysis set (N = 223).
There were more responders in the iron isomaltoside group compared to the iron sucrose
group. A risk difference of 13.9%‐points in the FAS and 14.3%‐points in the PP set
as well as non‐inferiority of iron isomaltoside to iron sucrose was observed.
A predetermined test for superiority was performed, confirming superiority of iron
isomaltoside over iron sucrose (FAS: P = .033; PP: P = .031).
In the FAS, the largest increase in Hb from baseline to any time from week 1 to week
5 (mean [SD]) was 2.83 (1.33) g/dL in the iron isomaltoside group and 2.34 (1.22)
g/dL in the iron sucrose group. Increases in Hb in the PP analysis set were consistent
with superiority of iron isomaltoside over iron sucrose (2.88 [1.30] vs. 2.39 [1.20]
g/dL). For both FAS and PP, the difference between iron isomaltoside and iron sucrose
was statistically significant (P < .001).
Analysis of time to Hb increase ≥2 g/dL showed a statistically significantly shorter
time to Hb increase ≥2 g/dL in the iron isomaltoside group compared with the iron
sucrose group with a hazard ratio (HR) (95% CI) of 1.71 (0.19; 0.89) (P = .0026).
The change from baseline in Hb and TSAT was statistically significantly higher in
the iron isomaltoside compared to the iron sucrose group at each time point (P ≤ .0005
and P ≤ .0001, respectively) (Figure 1), and s‐ferritin was statistically significantly
higher with iron isomaltoside at weeks 1 to 4 (P ≤ .002) (Figure 1).
Figure 1
Change in hemoglobin, s‐ferritin, and transferrin saturation over time by treatment
group, full analysis set. CI: confidence interval
In both treatment groups, the SF‐36 scores in the eight health domains improved from
baseline to weeks 2 and 5. There were no differences between the groups.
The ADR profiles in the treatment groups were similar to the ones observed in the
main trial.5
One (0.6%) in the iron isomaltoside group experienced serious ADRs (serious adverse
reactions [SARs]; dyspnea and pruritic rash) for which the patient was admitted to
the hospital. On the day after receiving iron isomaltoside, the subject experienced
pruritic rash. There was no involvement of mucous membranes or fever. The event had
a duration of 11 days and the patient made full recovery. No SAR was observed in the
iron sucrose group.
In this trial, we evaluated the efficacy and safety of IV iron isomaltoside in comparison
to iron sucrose in gynecological patients with IDA. The women were primarily pre‐menopausal
with a history of menorrhagia but were otherwise healthy.
For the primary endpoint, the proportion reaching a Hb increase from baseline of ≥2
g/dL at any time between week 1 and 5, both non‐inferiority and superiority was confirmed
for iron isomaltoside compared to iron sucrose. Furthermore, a significantly shorter
time to Hb increase ≥2 g/dL was observed with iron isomaltoside. For all biochemical
efficacy parameters (Hb, s‐ferritin, and TSAT) measured, more rapid and/or greater
improvements were found with iron isomaltoside. These findings are in agreement with
results of the main trial.5
QoL improved in both treatment groups during the trial. In a previous trial including
women with postpartum hemorrhage, a single dose of iron isomaltoside led to statistically
significant differences in fatigue and depression scores, as well as in hematological
and iron parameters, all favoring iron isomaltoside when compared with standard medical
care.6
Treatment with iron isomaltoside and iron sucrose was generally well tolerated with
<1% SARs.
In conclusion, iron isomaltoside was more effective than iron sucrose in ensuring
a rapid improvement in Hb and other iron‐related parameters. Larger doses of iron
isomaltoside can be administered within a shorter time to achieve full iron correction.
Iron isomaltoside administration was well tolerated in gynecological patients with
IDA.
CONFLICT OF INTEREST
Lars L. Thomsen is employed by Pharmacosmos A/S, and the investigators/institutions
received a fee per patient. Richard Derman has been a consultant for Pharmacosmos
A/S. Michael Auerbach has received research funding from Pharmacosmos A/S and AMAG
Pharmaceuticals and has consulted for Pharmacosmos A/S, AMAG Pharmaceuticals, and
Luitpold Pharmaceuticals. Maureen M. Achebe served on a scientific advisory board
for AMAG Pharmaceuticals. Eloy Roman and Gioi N. Smith‐Nguyen have no further conflicts
of interest.