Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00904709 |
| Other study ID # |
CDHA-RS/2009-341 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
October 19, 2009 |
| Est. completion date |
March 1, 2014 |
Study information
| Verified date |
July 2018 |
| Source |
Nova Scotia Health Authority |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Many women have heavy periods and this can be associated with low blood, tiredness and
inability to carry out normal activities. Approximately 10-30% of these women will have an
underlying bleeding disorder. There is a drug called tranexamic acid which is commonly used
and is effective in reducing menstrual flow. However, up to 1/3 of women have side effects
and they are more common at higher doses. In the medical literature, there are different
dosing schedules and there is one commonly recommended in Canada. Women with underlying
bleeding disorders may require higher doses of this medication compared to those who do not.
In this study, the investigators want to find the lowest effective dose of tranexamic acid
for girls and women with heavy periods who have bleeding disorders and the investigators
think this will be lower then the usual recommended dose. If the investigators' results
support this, it may contribute to changing how the investigators presently prescribe this
medication and may provide a better option for women with heavy periods in particular those
with bleeding disorders. The investigators have just started a Women with Bleeding Disorders
Clinic and hope that this project will lead to better care for the patients and more research
in the future.
Description:
Menorrhagia, or heavy menstrual bleeding, represents an important health issue for
premenopausal women and is a common cause for primary care consultations. Approximately
10-15% of women have heavy periods. This may be associated with iron deficiency anemia,
fatigue, and time lost from school, work and regular activities. Up to 50% of women with
menorrhagia who have an underlying bleeding disorder have functional limitations and
reduction of quality of life during their menstrual period.
The literature reports that 10-30% of women with menorrhagia have an underlying bleeding
disorder. The American Society of Hematology highlighted this as a major public health issue
in 2006, and there have been ongoing efforts to address this problem. The prevalence of a
bleeding disorder in the normal population is 1 in 100; von Willebrand Disease (VWD) being
the most common. Studies have shown between 57% and 93% of women with bleeding disorders have
menorrhagia. Therefore, women, who present with menorrhagia, should be considered for
investigation of a bleeding disorder.
Obtaining an accurate history of menorrhagia from women is often difficult for several
reasons. Women may be reluctant to initiate discussion about their heavy periods. Also, women
with underlying hereditary bleeding disorders may have heavy periods but since they are the
same as other affected women in their families they consider their menses "normal." Not
infrequently,a mild bleeding disorder may go undiagnosed until adulthood.
Menorrhagia is objectively defined as menstrual blood loss of > 80mls. It is well known that
assessment of menstrual blood loss by history alone is unreliable and inaccurate. The
alkaline hematin method provides an objective and accurate technique for the measurement of
menstrual blood loss and is considered the gold standard. However this method is
time-consuming, not readily available for clinical use and impractical, as it requires women
to collect all of their sanitary products for an entire menstrual cycle. The pictorial blood
assessment chart (PBAC) is a simple, non-laboratory method that provides a semi-quantitative
assessment of menstrual flow. Using this method, the patient records the number and degree of
saturation of pads and/or tampons used for up to 8 days of their menstrual cycle on a
pictorial chart and a corresponding score is calculated. In their original report, Higham et
al defined menorrhagia as a PBAC score of > 100 with a sensitivity of 86% and a specificity
of 81 %. Janssen et al later reported that a cut-off score of 185 provides high positive and
negative predictive values for 'true' menorrhagia as opposed to the score of > 100 that was
not validated by Reid et al, in a more recent publication. In both the Higham and the Janssen
studies the confidence intervals of the estimates of sensitivity were not reported, therefore
it is difficult to select either one as being definitively better to use as a cut-off score.
In our study we have decided to use a cut-off PBAC score of 100 as a more conservative
approach that will allow the inclusion of more patients with heavy menstrual flow.
There are a number of treatment options for women with menorrhagia including hormone therapy
(combined oral estrogen/progesterone, progesterone alone), tranexamic acid (and other
antifibrinolytic agents), danazol, non steroidal anti-inflammatory drugs (NSAIDs),
progesterone releasing intrauterine devices, and, finally, the surgical options of
endometrial ablation and hysterectomy. An additional therapy, for women with certain bleeding
disorders (VWD, platelet dysfunction and Hemophilia A carriers) is desmopressin (DDAVP)
(intranasal or subcutaneous). Tranexamic acid is a first line therapy for women with
menorrhagia who do not require contraception and who prefer non-hormonal therapy. It is
considered standard therapy around the world and in most countries (e.g. Canada), it is
available by prescription only, but interestingly in Sweden it is obtained
'over-the-counter.'
Antifibrinolytic therapy has been used for almost forty years for menorrhagia - the first
publication was in 1965. It has previously been described that fibrinolysis is increased in
the menstrual fluid and endometrium in women with heavy menstrual flow. Tranexamic acid,
which is a fibrinolytic inhibitor, competitively blocks the activation of plasminogen to
plasmin and thereby reducing fibrinolysis. Tranexamic acid reduces menstrual blood loss by up
to 50% and it has been shown to be at least as equally as effective as oral contraceptives,
NSAIDs, and intranasal desmopressin. There is no consensus as to the minimal effective dose,
the dose scheduling and the optimal duration of therapy. In the published literature, the
effective dose is variable and ranges from 1000 mg/day to 6000 mg/day. The recommended dose
by the Compendium of Pharmaceuticals and Specialties (CPS), 2009, published by the Canadian
Pharmacists Association, is 3000 mg/day to 6000 mg/day. The current recommended dose as per
the Clinical Practice Guidelines for the Management of Abnormal Uterine Bleeding by the
Society of Obstetricians and Gynecologists of Canada and the Canadian Hemophilia Society
document on the Management of Women with Bleeding Disorders is 1000 mg orally four times a
day. Interestingly, in China, it is recommended to give 2000 mg/day. The recommended duration
of therapy is also variable; the CPS states the medication should be started "when the flow
is copious" and taken for "several days." Most clinical trials have used a 4-5 day duration
of therapy. It is given in different schedules, most commonly 3 to 4 times per day. A recent
study compared two doses of tranexamic acid, 2000 mg/day vs. 1000 mg/day, both doses given on
a twice-a-day schedule, with an additional placebo arm, assessing the effect on prevention of
menorrhagia in women with intrauterine devices (IUDs). The women randomized to the tranexamic
acid arms had significantly less menstrual flow compared with the placebo group and there was
no significant difference in efficacy between the two doses of tranexamic acid. Women with
underlying bleeding disorders may need higher doses than women without bleeding disorders;
however, this is uncertain. This medication is not without toxicity and up to one-third of
women experience side effects that are dose dependant. The most common adverse effects are
nausea, vomiting, diarrhea and, less common, are headaches, dizziness and allergic reaction.
Tranexamic acid is expensive; the retail price is $1.34/500-mg capsule. For example a dose of
4000 mg/day for 5 days would cost a patient $64.34/month including the dispensing fee. Common
reasons for discontinuing the medication include side effects, cost and the inconvenience
associated with multiple dosing. Many patients will adjust their dose - finding a balance of
efficacy, minimal toxicity, cost, and frequency of dosing. It is our experience that some
patients find this balance with a minimal dose of 500 mg taken twice daily. In this study we
propose to investigate whether the minimal effective and tolerated dose of tranexamic acid,
based on the PBAC score, quality of life factors, and tolerability of side effects is less
than the current Canadian recommended dose of 1000 mg orally four times a day.
Study Objectives:
- Primary Objective
- To determine if the minimal effective and tolerated dose of tranexamic acid for
girls and women with menorrhagia who have bleeding disorders is lower than the
current dose of 1000 mg orally, four times a day, as recommended by the Clinical
Practice Guidelines for the Management of Abnormal Uterine Bleeding by the Society
of Obstetricians and Gynecologists of Canada and the Canadian Hemophilia Society
document on the Management of Women with Bleeding Disorders.
- Secondary Objectives
- To determine an accurate estimate of the proportion of women who present to our
clinics with menorrhagia who have an underlying bleeding disorder. Based on the
literature this is expected to be 10%-30%.
- To determine the effect of body mass index (BMI), age, dose-related side effects,
concurrent medications and quality of life factors on the optimal dose of
tranexamic acid.
Study hypotheses:
- Primary hypothesis
- The minimal effective and tolerated dose of tranexamic acid required by women with
menorrhagia who have bleeding disorders is lower than the current Canadian
recommendation of 1000 mg orally, four times daily (4000 mg/day).
- Secondary hypotheses
- The true proportion of women with menorrhagia who have bleeding disorders is
under-reported.
- Women with menorrhagia without bleeding disorders require a lower dose of
tranexamic acid than women with menorrhagia with bleeding disorders.
- In addition to the presence of a bleeding disorder, there are likely other factors
including age, BMI, tolerance of side effects, subjective assessment of bleeding,
quality of life issues and compliance that impact on the dosing of tranexamic acid
in women with menorrhagia.
- A decision tool can be developed to aid in dosing women with menorrhagia based on
risk factors such as the presence of a bleeding disorder, age and BMI.
