Keywords
heavy menstrual bleeding - venous thrombosis - direct oral anticoagulants - rivaroxaban
- apixaban
Introduction
Heavy menstrual bleeding (HMB) is a common complication of anticoagulant therapy in
premenopausal women with venous thromboembolism (VTE). Up to 66% of women will develop
HMB after the start of therapeutic anticoagulation based on an objective measurement
of menstrual blood loss.[1] It impacts quality of life and can lead to premature cessation of anticoagulation.[2] The prevalence of HMB in women treated with oral anticoagulants is significantly
higher than in women who are not anticoagulated.[3] During treatment with anticoagulants, the mean duration of menstrual bleeding can
increase from 5.6 to 6.1 days.[4]
So far, prior to the introduction of the direct oral anticoagulants (DOAC) era, little
has been published on this topic.[3] With the rapidly increasing use of DOAC for treatment of VTE during the last decade,
there is increasing data to suggest that DOAC differ in their menstrual bleeding profiles.[5]
[6]
[7]
[8]
[9]
[10]
[11] These findings come from retrospective or prospective single-center studies and
post hoc analysis of regulatory studies, in which HMB has not been a predefined safety
outcome. In addition, in most of these publications, there is a lack of information
about the use of different contraceptive methods, which can influence HMB. Another
limitation is the various definitions of HMB, which makes comparison between studies
regarding the incidence of HMB difficult.[2]
Therefore, the prospective multicenter noninterventional investigator-initiated HEMBLED
registry (heavy menstrual bleeding in patients treated with DOAC) was performed in eight German outpatient coagulation centers from 2020 to 2024
to analyze HMB in women (18–50 years) treated with DOAC who do not use hormonal contraceptives
or intrauterine devices, because these measures can influence the intensity and duration
of menstrual bleeding.[2]
Methods
The HEMBLED registry was a German prospective, open, multicenter cohort study including
female outpatients of reproductive age who were anticoagulated with therapeutic doses
of either apixaban, rivaroxaban, edoxaban, or dabigatran because of VTE. Patients
were included from 2020 to 2024. The primary aim was to evaluate and compare the incidence
of HMB in women treated with DOAC using a modified pictorial blood assessment chart
(PBAC)-score[2]
[12]: a version translated into German was used for better understanding. In addition,
different numbers of blood drops instead of pictograms were used to better define
the different sizes of tampons and pads and thus also the amount of menstrual blood
loss ([Supplementary Material], available in the online version only). During their first visit, patients were
instructed by the treating physician or a study nurse on how to use the PBAC score.
During the follow-up visit, the completed PBAC score sheets were collected and checked
together with the individual patient for completeness and correct calculation of the
scores per menstrual bleeding.
The study protocol, any amendments, and the subject informed consent received independent
local Ethics Committee approval from all German participating centers before initiation
of the study. Patients were recruited at eight outpatient coagulation centers in Germany
from 2020 to 2024. All patients provided written informed consent.
Patients
We included consecutive menstruating women aged 18 to 50 years with objectively confirmed
symptomatic first or recurrent VTE who fulfilled the following inclusion criteria
and none of the exclusion criteria presenting to one of the participating outpatient
coagulation centers: inclusion criteria were regular menstrual bleeding, treatment
with maintenance therapeutic doses of apixaban (5 mg twice daily), rivaroxaban (20 mg
once daily), dabigatran (150 mg twice daily) or edoxaban (60 mg once daily) for at
least 7 days before inclusion and planned continued therapeutic anticoagulation with
apixaban 5 mg twice daily, rivaroxaban 20 mg once daily,, dabigatran 150 mg twice
daily or edoxaban 60 mg once daily for at least the following next 4 months after
inclusion.
All included patients who had developed VTE while using oral contraceptives had already
stopped hormonal contraception at least 25 days before they were included in the registry.
Key exclusion criteria were patients with antiphospholipid-syndrome, patients with
a past history of hysterectomy or ovarectomy, patients reporting HMB without anticoagulation
in their past history, patients with intake of hormonal contraceptives, hormone replacement
therapy, use of intrauterine devices (IUD, either copper or hormone releasing), contraindications
to treatment with DOAC and treatment with rivaroxaban (10 mg or 15 mg once daily)
or apixaban (2.5 mg twice daily) in reduced dosages.
Study Procedures
Study enrollment was performed during therapeutic treatment with a DOAC, which was
expected to last at least 4 months after inclusion in the registry.
After inclusion, a baseline visit was performed. The bleeding history of the patients
was systematically analyzed by use of a modified International Society of Thrombosis
and Hemostasis (ISTH) Bleeding Assessment Tool (BAT)-Score[2]
[13] with a cut-off for abnormal bleeding ≥ 6 points in women. Four months after inclusion,
a follow up visit (visit 1) was planned ([Fig. 1]). Laboratory samples were taken at the baseline visit and at the follow up visit
(prothrombin time, activated partial thromboplastin time, von Willebrand antigen,
von Willebrand Glycoprotein Ib, factor VIII with DOAC stop, a collagen binding assay,
a blood count, blood group, iron, ferritin, and creatinine, and transaminases only
at baseline; [Fig. 1]). In addition a transvaginal ultrasound was offered free of charge (optional) to
detect possible uterine causes (i.e., uterine fibroids, adenomyosis, endometrial polyps)
of menorrhagia.
Fig. 1 Schedule of assessments.
Patients received three PBAC score Sheets to document the intensity of the menstrual
bleeding of three consecutive menstrual bleeding cycles at home. In addition, they
received three ISTH BAT-Score Sheets to document monthly whether different types of
bleeding, in addition to menstrual bleeding, had occurred in the meantime. Patients
were advised to visit their local gynecologist in case of HMB during follow up and
results of these investigations were additionally documented in the case report form
(CRF). At the follow-up visit, the results of the completed PBAC score sheets and
ISTH BAT-score sheets were collected and added to the CRF.
Outcomes
The primary outcome was the incidence of HMB at least once during the follow-up period.
HMB was defined as a PBAC score > 100 points, which is indicative of a blood loss > 80 mL.[12]
[14]
Main secondary outcome was the prevalence of von Willebrand's disease, further secondary
objectives were to assess the correlation of HMB with von Willebrand's disease, age,
blood group, underlying uterine pathologies, that is, presence of uterine fibroids,
endometrial polyps and/or adenomyosis (only in patients with transvaginal ultrasound),
iron deficiency, hemoglobin level and documentation of use of nonsteroidal anti-inflammatory
drugs (NSAID).
Statistical Analysis
When planning the registry, sample size estimation was based on a binary primary endpoint.
The following primary objective was planned:
Comparison of the frequency of HMB (occurrence at any time point using the PBAC score > 100)
between the different DOAC groups using a two-sided exact Fisher test with a significance
level of α = 5%. If score ratings were missing at some time points (i.e., in patients who only
presented with one or two menstrual bleeding cycles during 4 months of follow-up),
the primary endpoint was defined on the available assessment.
At the time when the registry was planned in 2018, data on HMB during treatment with
DOAC were scarce. At that time, there was only one prospective cohort study available,
which compared the occurrence of HMB in patients treated with apixaban or rivaroxaban.[5] The results of this investigation were used for the original sample size calculation,
which used the assumption of rates of HMB of 25% in the rivaroxaban group and of 9%
in the apixaban group. Data on the occurrence of HMB during treatment with edoxaban
and dabigatran were not available at that time. Therefore, rates were calculated to
be 9% for dabigatran (intake twice daily, similar to apixaban) and 25% for edoxaban
(intake once daily, similar to rivaroxaban). Simulations showed that the power was
at least 80% if 237 patients were included (assuming 101 patients in the apixaban
and 101 patients in the rivaroxaban groups, respectively, and 35 patients in the edoxaban
and dabigatran groups). To account for some missing data or dropouts, it was planned
to prospectively include 250 patients.
Due to the COVID-19 pandemic, the start of the registry was delayed, and the first
patient was included in October 2020 instead of April 2020. In addition, some of the
local ethical committees stopped working for some time, which delayed the initiation
of some of the planned study centers. Besides, many study centers were not able to
include new patients because of the COVID-19 pandemic, even in the following years.
Recruitment of patients slowed down and was therefore expected to remain reduced in
comparison to the initial study plans. For these reasons, it was decided in 2022 to
extend the recruitment time until December 2023 instead of August 2022 and to reduce
the patient number from 250 to 150 patients. The power would have been 61% if the
reduced number of 150 patients were included (assuming approximately 65 patients in
the apixaban and 65 patients in the rivaroxaban groups and approximately 20 patients
in the edoxaban and dabigatran groups). Nevertheless, recruiting time was limited.
As there were strict inclusion and exclusion criteria to ensure a homogeneous population,
finally only 45 women were included in the apixaban group, 19 women in the rivaroxaban
group, and five and four patients in the edoxaban and dabigatran groups, respectively
(total: n = 73 DOAC-treated patients). This was mainly due to the fact that patients were only
included when they did not need or want oral contraceptives or IUDs, despite the fact
that they were informed by the treating physicians that safe contraception was mandatory
during DOAC treatment. Therefore, only a power of 35% for the original primary aim
was reached when comparing the binary primary endpoint. Therefore, before the export
of the final data for statistical analysis, it was decided to change the primary objective
and to use the PBAC score without dichotomization to obtain a larger power. This updated
primary objective was a comparison of the PBAC scores between the different DOAC treatment
groups using a linear mixed effect model with a hierarchical approach: the apixaban
and rivaroxaban groups were compared first, and as a secondary analysis, a comparison
between the apixaban group and either the edoxaban group or the dabigatran group was
performed. A log-transformation was used where appropriate, and a significance level
of α = 5% was applied. In addition, a multivariate linear mixed-effect regression model
of the nondichotomized PBAC scores was used to assess the difference in the primary
endpoint between the DOAC groups with a special focus on comparing the rivaroxaban
and apixaban groups, while accounting for further factors. Because of the small sample
size, the multivariate analysis had to focus on the most important factors. In addition,
the originally planned dichotomized endpoint analysis (PBAC score > 100 points at
least once during follow-up) was evaluated with the exact Fisher test with a significance
level of α = 5%.
As originally planned, further descriptive and explorative analysis was performed
comparing secondary endpoints between the groups with appropriate univariate and multivariate
statistical tests with focus on the exact Fisher test and Mann–Whitney U test. ISTH scores were analyzed with ordinal mixed-effect regression.
Post hoc, we performed a sensitivity analysis of the impact of six patients with a
known change in anticoagulant treatment because of increased menstrual bleeding before
inclusion in the registry and a repeated correlation analysis of the association between
hemoglobin and hemoglobin decrease and PBAC scores.
For categorial variables, absolute and relative frequencies were analyzed. For continuous
variables, the mean and standard deviation or % were given. Pairwise comparisons of
reassessments were performed with the Wilcoxon signed-rank test. All tests were two-sided
and used a significance level of α = 5%.
The statistical analysis was performed with R version 4.4.1 (R Foundation for Statistical
Computing) using the basic packages, doBy, nlme, rmcorr, and lme4.
Results
From October 2020 to April 2024, 73 patients with confirmed symptomatic first or recurrent
VTE and active menstrual cycles, with a mean age of 35 years, were included. At baseline,
45 of 73 patients received apixaban (62%), 19 patients received rivaroxaban (26%),
five patients received edoxaban (7%), and four patients received dabigatran (6%).
Baseline characteristics are summarized in [Table 1].
Table 1
Baseline characteristics of 73 female patients of reproductive age with venous thromboembolism
(VTE)
|
Variable
|
All (n = 73)
|
Apixaban (n = 45)
|
Rivaroxaban (n = 19)
|
Edoxaban (n = 5)
|
Dabigatran (n = 4)
|
|
Age (y)
|
35 ± 9.1
|
34 ± 8.7
|
35 ± 10.6
|
34 ± 10.2
|
40 ± 4.9
|
|
BMI (kg/m2)
|
28.2 ± 7.7
|
27.4 ± 7.1
|
30.3 ± 6.5
|
24.9 ± 6.2
|
32.2 ± 18.0
|
|
ISTH bleeding score
|
1.0 ± 1.2
|
0.9 ± 1.3
|
0.9. ± 0.9
|
1.4 ± 1.3
|
1.3 ± 1.9
|
|
Index VTE[a]
|
|
DVT
|
42 (58%)
|
27 (60%)
|
11 (58%)
|
4 (80%)
|
0 (0%)
|
|
PE
|
22 (30%)
|
13 (29%)
|
6 (32%)
|
2 (40%)
|
1 (25%)
|
|
CVT
|
8 (11%)
|
3 (7%)
|
1 (5%)
|
0 (0%)
|
4 (100%)
|
|
AVT
|
5 (7%)
|
4 (9%)
|
1 (5%)
|
0 (0%)
|
0 (0%)
|
|
ICVT
|
2 (3%)
|
2 (4%)
|
0 (0%)
|
0 (0%)
|
0 (0%)
|
|
ST
|
1 (1%)
|
1 (2%)
|
0 (0%)
|
0 (0%)
|
0 (0%)
|
|
SVT
|
1 (1%)
|
0 (0%)
|
1 (5%)
|
0 (0%)
|
0 (0%)
|
|
MVT
|
1 (1%)
|
1 (2%)
|
0 (0%)
|
0 (0%)
|
0 (0%)
|
|
Hormonal contraception at the time of thrombosis
|
32 (44%)
|
18 (40%)
|
10 (53%)
|
3 (60%)
|
1 (25%)
|
|
Regular menstruation
|
72 (99%)
|
44 (98%)
|
19 (100%)
|
5 (100%)
|
4 (100%)
|
|
Cycle length (d)
|
26 ± 9.5
|
25 ± 11.4
|
27 ± 6.0
|
27 ± 1.7
|
28 ± 1.0
|
|
Family history of bleeding
|
4 (5%)
|
2 (4%)
|
1 (5%)
|
1 (20%)
|
0 (0%)
|
|
Use of NSAIDs
|
10 (14%)
|
5 (11%)
|
4 (21%)
|
0 (0%)
|
1 (25%)
|
Abbreviations: AVT, arm vein thrombosis; BMI, body mass index; CVT, cerebral vein
thrombosis; DVT, deep vein thrombosis; ICVT, inferior caval vein thrombosis; ISTH,
International Society of Thrombosis and Hemostasis; MVT, muscle vein thrombosis; NSAID,
nonsteroidal anti-inflammatory drugs; PE, pulmonary embolism; ST, splanchnic vein
thrombosis; SVT, superficial vein thrombosis; VTE, venous thromboembolism.
Note: Mean ± standard deviation or % are given.
a Multiple index VTEs in a single patient were possible.
The majority of patients presented with deep vein thrombosis (58%), followed by pulmonary
embolism (30%). Overall, 32 patients (44%) had been treated with hormonal contraception
at the time of thrombosis but had already stopped the hormonal contraception at least
25 days (median: 196 days, maximum: 18 years) before inclusion in the registry.
In 18% of the patients (13/73), anticoagulation was changed after the thromboembolic
event but before inclusion in the registry. Nine of the 13 patients were changed from
rivaroxaban to apixaban. Reasons for these changes prior to inclusion were a bleeding
event (n = 6), a single positive lupus anticoagulant measurement (n = 1), nausea (n = 1), and preference for an anticoagulant with twice daily dosing (n = 1). All six patients with a bleeding event during rivaroxaban treatment reported
on enhanced menstrual bleeding, which had been the reason for the switch to apixaban,
but one of these patients changed back to rivaroxaban before study inclusion.
In the four remaining patients, early changes in anticoagulation before inclusion
in the registry were observed: one patient switched from apixaban to rivaroxaban because
of a suspected but not confirmed recurrent thrombosis. Another patient was changed
from apixaban to edoxaban because of nausea and abdominal discomfort. A third patient
was switched from edoxaban to apixaban because of an allergic reaction. The fourth
patient was first treated with enoxaparin because of breastfeeding and was switched
to apixaban after stopping breastfeeding before inclusion in the registry.
After inclusion into the registry, further changes in anticoagulation during the 4-month
study period were documented. Immediately after inclusion, one patient switched from
edoxaban to dabigatran because of the patient's wish, although there were no documented
side effects of edoxaban treatment. One patient was switched by the treating physician
from rivaroxaban to apixaban after 1 month because of menorrhagia, and one patient
stopped the anticoagulation with rivaroxaban because of menorrhagia after 2 months
of follow-up. One further patient stopped edoxaban treatment after the second month
of follow-up because of menorrhagia. In addition, two apixaban-treated patients had
missing data for 1 or 2 months of follow-up.
Eleven percent of the patients had blood group O (8/71; 95% confidence interval [CI]:
5–21%). None of the women had thrombocytopenia, and one patient was diagnosed with
von Willebrand disease type I (1/73, 1.4%).
Incidence of HMB Depending on DOAC Treatment
PBAC scores were evaluated after 1, 2 and 3 months. Overall, 213 monthly assessments
were analyzed in 73 patients. Because of the limited sample size, the primary analysis
focused on all single measurements of the PBAC scores using a linear mixed-effects
model of log-transformed PBAC scores. Overall, PBAC scores in the rivaroxaban group
(mean: 145 points, 95% CI: 103–204 points) were significantly increased by 54% compared
with the apixaban group (mean: 93 points, 95% CI: 73–118 points, p = 0.0193; [Fig. 2]). There were no significant differences in the edoxaban group and the dabigatran
group (p = 0.2192 and p = 0.9384, respectively) compared with the apixaban group. These results were also
confirmed in a sensitivity analysis excluding the six patients who had changed anticoagulation
before study inclusion due to increased menstrual bleeding (the PBAC score in the
rivaroxaban group significantly increased by 47% compared with the apixaban group,
p = 0.0426; no significant results for the edoxaban group and the dabigatran group
compared with the apixaban group, respectively). In addition, the incidence of HMB
(PBAC scores > 100 points at least once during follow-up) was analyzed as was originally
planned. Fifty-three percent of the apixaban group, compared with 79% of the rivaroxaban
group, developed HMB, not reaching statistical significance (p = 0.0913; [Fig. 3]).
Fig. 2 Boxplots of the nondichotomized PBAC score evaluations of the four direct oral anticoagulant
(DOAC) treatment groups. Comparisons were performed using a linear mixed effect regression
model (p-values) which also provides mean values and 95% CIs: apixaban-group mean: 93 points
(95% CI: 73–118), rivaroxaban-group mean: 145 points (95% CI: 103–204), edoxaban-group
mean: 161 points (95% CI: 68–381), dabigatran-group mean: 95 points (95% CI: 44–206).
Mo, month; PBAC, pictorial blood assessment chart.
Fig. 3 Barplots of the percentage of patients with heavy menstrual bleeding (PBAC score > 100
points) at least once during the observation period. The exact Fisher test was used
for comparisons (p-values). PBAC, pictorial blood assessment chart.
Secondary Outcomes with a Potential Influence on HMB
The effects of the intake of NSAIDs on the PBAC scores were analyzed. In a combined
model including the treatment groups and differentiating between patients taking NSAIDs
or not, the intake of NSAIDs did not have a significant influence on the PBAC scores
(p = 0.9548). Similarly, in a univariate model analyzing only the influence of NSAID
on the PBAC scores, again, no significant differences were observed (p = 0.9432). Similar results were received for PBAC scores > 100 points (p = 0.9533).
The potential influence of the blood group (all four groups) on HMB was also investigated.
Neither in a univariate model nor in a model accounting for the different anticoagulants,
an effect of the blood group was observed (p = 0.6663 and p = 0.4949, respectively). A comparison of blood group O with the non-O blood groups
again showed no significant differences (p = 0.5565 in univariate analysis, p = 0.5415 after adjusting for the different anticoagulants).
Even so, the sample size was limited the influence of further parameters on the PBAC
scores was tested. Age, ISTH bleeding score at baseline, iron deficiency (defined
as ferritin < 13 µg/L), hemoglobin, and the presence of uterine myomas and adenomyosis
showed no significant associations with the PBAC scores (p > 0.20 for each evaluation). Hemoglobin levels remained comparable between the baseline
visit and visit 1 after 4 months (Wilcoxon signed rank test p = 0.174). The laboratory results at baseline were missing in two patients, and after
4 months of follow up laboratory results were not available in two additional patients.
With regard to the treatment groups, the mean hemoglobin changed from 13.1 ± 1.2 to
12.8 ± 1.2 g/dL in the apixaban group, from 13.0 ± 0.9 to 13.2 ± 0.9 g/dL in the rivaroxaban
group, from 12.5 ± 1.0 to 12.3 ± 0.6 g/dL in the edoxaban group, and from 13.5 ± 0.9
to 13.6 ± 0.3 g/dL in the dabigatran group. There was no significant difference between
the treatment groups on hemoglobin at baseline and hemoglobin decrease over time (p > 0.20 at baseline and p > 0.20 over time). Repeated measurement correlation between hemoglobin at baseline
or hemoglobin decrease with PBAC Scores was −0.10 and −0.06, respectively (p > 0.20 at baseline and p > 0.20 over time).
Duration of Menstrual Bleeding and Frequency of Intracyclic Bleeding
A comparison of the duration of menstrual bleeding in the DOAC treatment groups was
performed ([Fig. 4]). No significant differences between the groups were observed. The mean bleeding
duration was shortest during treatment with apixaban (5.4 days; 95% CI: 4.9–5.9), followed by rivaroxaban (mean: 6.0 days; 95% CI: 5.2–6.8), edoxaban
(mean: 6.1 days; 95% CI: 4.3–7.9) and dabigatran (mean: 6.6 days; 95% CI: 5.0–8.2).
Fig. 4 Boxplots of the duration of menstrual bleeding during the observation period (days).
Comparisons were performed using a linear mixed effect regression model (p-values) which also provides mean values and 95% CIs: apixaban-group mean: 5.4 days
(95% CI: 4.9–5.9), rivaroxaban-group mean: 6.0 days (95% CI: 5.2–6.8), edoxaban-group
mean: 6.1 days (95% CI: 4.3–7.9), dabigatran-group mean: 6.6 days (95% CI: 5.0–8.2).
Mo, month.
Furthermore, self-reported intracyclic bleedings were assessed, which were more frequently
reported in the apixaban group compared with the other DOAC groups (apixaban group
10/45, 22%; rivaroxaban 0/19, 0%; edoxaban 1/5, 20%; dabigatran 0/4, 0%; p = 0.0962).
Results of the (Optional) Vaginal Ultrasound Examinations
In 18 of 73 patients (25%), vaginal ultrasound examinations were available. Age was
significantly associated with the presence of uterine myomas (p = 0.0049; [Fig. 5]). Overall, 12 myomas in six patients were documented (6/18, 33%). The majority of
myomas were localized intramurally without contact to the endometrium (n = 10), while two were localized intramurally with contact to the endometrium.
Fig. 5 Results of the transvaginal ultrasound in 18 patients. Presence of uterine myomas
(6/18, 33%) in dependence on age. The comparison (p-value) was performed using a Mann–Whitney U test.
Results of the ISTH Bleeding Scores and Additional Bleeding Events during Follow-Up
The ISTH bleeding scores were documented monthly for 4 months ([Fig. 6]). No significant differences between the treatment groups were observed.
Fig. 6 Modified International Society of Thrombosis and Hemostasis (ISTH) bleeding scores
during the observation period (normal values in women without anticoagulants < 6 points).
Comparisons (p-values) were performed using a mixed-effect ordinal regression model. Mo, month.
Additional bleeding events were reported in three patients. In one rivaroxaban -treated
patient, HMB and blood deposits on the stool were reported. She received oral iron
substitution and spontaneous improvement despite unchanged therapeutic anticoagulation
was observed.
In one patient, an asymptomatic minimal intracerebral contusion bleeding occurred
after a car accident during treatment with edoxaban. In the third patient, macrohematuria
without urinary tract infection was observed during treatment with apixaban. She showed
a spontaneous improvement despite continued therapeutic anticoagulation.
Discussion
Already 10 years ago, de Cem et al were the first to report retrospectively that rivaroxaban
treatment increased the duration of menstrual bleeding and patients on rivaroxaban
more frequently reported an unscheduled contact with a physician for abnormal uterine
bleeding than women using vitamin K antagonists (VKA; 41% vs. 25%, p = 0.096). They also reported an increased need for menorrhagia-related medical or
surgical intervention in the rivaroxaban group (25% vs. 7.7%, p = 0.032).[15] This data was confirmed by Ferreira et al in 2016 in a single-center retrospective
study, who published a high incidence of HMB (20%) in women of reproductive age receiving
anticoagulation with rivaroxaban.[16]
In 2017, Myers et al were the first who compare female patients treated with either
rivaroxaban or apixaban. Side effects were monitored prospectively at 1 and 6 months.[5] A total of 139 women aged 55 years or younger were analyzed. Ninety-six were treated
with rivaroxaban and 43 with apixaban. Again, HMB was reported in 25% of the women
during treatment with rivaroxaban. In contrast, only 9.3% of the women taking apixaban
had HMB. Calculated hazard ratio of the likelihood of menorrhagia was 2.688, with
95% confidence limits of 0.989 to 7.273. Although not statistically significant, this
result was consistent with higher rates of menorrhagia during treatment with rivaroxaban
compared with apixaban. These results are in agreement with the findings of the HEMBLED
registry, which is the first cohort study analyzing spontaneous menstrual bleeding
during DOAC-treatment not influenced by hormonal contraceptives or IUDs.
The higher rates of HMB during treatment with rivaroxaban may be due to different
pharmacokinetics with lower peak and higher trough levels when the anticoagulant is
taken twice daily (apixaban) instead of once daily (rivaroxaban). Moldenhauer et al
collected data on peak and trough anti-Xa concentrations in patients treated with
either rivaroxaban (n = 93) or apixaban (n = 51). While they did not observe differences in apixaban peak levels in female patients
compared with male patients, women had significantly higher rivaroxaban peak concentrations
compared with men (308.8 ± 178.1 ng/mL vs. 206.4 ± 80 ng/mL, p = 0.013).[17]
Of note, in post hoc subanalysis of the phase 3 DOAC trials, the incidence of HMB
was estimated to be low, but with a likely low sensitivity to detect HMB caused by
the lack of a standardized prospective assessment of menstrual blood loss when the
trials were performed.[1]
[2]
[18]
[19]
[20] So far, none of the international bleeding definitions used for the analysis of
major bleeding in regulatory studies for anticoagulants includes HMB.
Age, ISTH bleeding score at baseline, iron deficiency, hemoglobin, and the presence
of uterine myomas and adenomyosis showed no significant associations with the PBAC
scores, which might have been due to the low sample size of included patients. This
is in contrast to the results of the BLEED study, which investigated abnormal uterine
bleeding in women taking VKAs or DOAC through a retrospective analysis of prospectively
collected data.[21] 110 women with a median age of 36 years were recruited. PBAC scores significantly
correlated with hemoglobin values at baseline and during therapy, with a significant
difference in hemoglobin values before and during anticoagulant therapy. In the HEMBLED
registry, hemoglobin values before the start of anticoagulation were not available,
and the number of included patients was lower than in the BLEED-study. This may explain
the different findings.
In the BLEED study, 15.5% of women reported uterine fibroids. Women with self-reported
fibroids required more frequent unplanned medical consultations for bleeding during
anticoagulation. In our registry, 33% of patients who received transvaginal ultrasound
presented with uterine myomas. No significant correlation between HMB and myomas was
observed, which may have been due to the lower patient numbers included in the HEMBLED
registry.
The HEMBLED registry is subject to all limitations that are typical for observational
studies, including patient selection bias and nonstandardized treatment decisions
or reporting bias. Moreover, the small number of included patients limits the transferability
of the results to the corresponding patient population. Randomized, controlled, and
prospective studies with higher numbers of patients are therefore needed to verify
our results.
Due to the COVID-19 pandemic, the start of the registry was delayed. Recruitment of
patients slowed down and was therefore expected to remain reduced in comparison to
the initial study plans. For these reasons, it was decided to extend the recruitment
time until December 2023 instead of August 2022 and to reduce the patient number from
250 to 150 patients. Due to very slow recruitment later on and the strict definition
of the end of recruitment time, finally, only 73 DOAC-treated patients could be included
in the analysis. Therefore, only a power of 35% for the original primary aim was reached
when comparing the binary primary endpoint, and it was decided to change the primary
objective and to use the PBAC score without dichotomization to obtain a larger power.
Conclusion
Despite the limitations mentioned above, the lower-than-intended sample size and the
fact that we only analyzed menstruating women in Germany without considering the possible
ethnic differences in bleeding susceptibility, we provide the first prospective assessment
of the risk of spontaneous HMB in DOAC-treated women of childbearing age uninfluenced
by hormonal contraceptive use or IUDs. Rivaroxaban-treated patients experienced significantly
higher PBAC scores and higher numbers of HMB (PBAC scores > 100 points) compared with
apixaban-treated patients.
These findings should be a call to action to increase the awareness of HMB in young
female patients treated with DOAC. Physicians treating young female patients with
DOAC should be trained in taking a careful gynecological history in those patients
before the start of anticoagulation, and routine recording of HMB under DOAC treatment
should be included at every outpatient visit.
In addition, uniform international bleeding definitions to better characterize HMB
should be established by the international societies and should be prospectively included
in future regulatory studies on new oral anticoagulants when major or minor bleeding
is assessed.[2]
What is known about this topic?
-
HMB is a common complication of therapeutic anticoagulation in premenopausal women
with VTE and can occur in up to 70% of women.
-
There is increasing data to suggest that the DOAC used for VTE treatment differ in
their menstrual bleeding profiles.
-
So far, prospective data on the frequency of “spontaneous” HMB in DOAC-treated women
of childbearing age unaltered by oral contraceptives or IUDs have not been analyzed.
What does this paper add?
-
In the prospective HEMBLED registry, spontaneous HMB was more often observed in rivaroxaban-treated
patients (79%) compared with apixaban-treated patients (53%).
-
Pictorial blood assessment scores were significantly higher in rivaroxaban-treated
patients compared with apixaban-treated patients.
