Tranexamic Acid for the Treatment of Heavy Menstrual Bleeding
Good morning. This is Team B and today we are presenting the paper Tranexamic Acid for the Treatment of Heavy Menstrual Bleeding. According to the FIGO recommendations that came out in 2011, it was found that certain terms, like men are or uterine bleeding were not being used properly. There is no regular definition for it. So they came up with a new set of terminologies that define what is normal uterine bleeding and what is abnormal uterine bleeding.
According to their recommendations, abnormal uterine bleeding can be classified based on regularity, as irregular menstrual bleeding or amenorrhea; based on frequency, as oligomenorrhea or frequent bleeding; as heavy menstrual bleeding, heavy prolonged menstrual bleeding and light menstrual flow on the basis of heaviness, shortened or prolonged on the basis of duration; post-coital bleeding or instramenstrual bleeding, based on the irregular bleeding patterns. It can also be differentiated based on bleeding outside reproductive each post-menopausal bleeding or precocious puberty. So what is heavy menstrual bleeding? The NICE guidelines define HMB as excessive menstrual blood loss which interferes with the woman's physical, emotional, social, and material quality of life, and which can occur alone or in combination with other symptoms. They also define this quantitatively as a menstrual blood loss of more than 80 ml per cycle. Just a revision of what the normal physiology is in a menstrual cycle. You have your hypothalamus, which releases your GNRH in a cyclical manner causing your pituitary to release LH and FSH.
Finally, the ovaries to release estrogen and progesterone, which gives rise to your normal menstrual cycle. If there is any irregularities in this whole process, either an imbalance in your hormones or a fibroid in your uterus, it can give rise to heavy menstrual bleeding. So the current treatment for heavy menstrual bleeding according to the NICE clinical part can be classified based as pharmaceutical, where you have tranexamic acid, NSAIDS, oral contraceptive, Noresthisterone, Levonorgestrel releasing IUCD.
Then you also have the non hysterectomy surgery, which is the endometrial ablation. Other interventions, such as uterine artery embolization and myomectomy, are based on the etiologies of the heavy menstrual bleeding. Finally, you have hysterectomy, which is definitely a treatment for heavy menstrual bleeding.
Tranexamic acid is one of the most common treatments that are being used for heavy menstrual bleeding. So in today's presentation, we'll be seeing the paper where we see the efficacy of tranexamic acid in the treatment of heavy menstrual leading. So there are papers that have shown that women with heavy menstrual bleeding, there is an increased amount of plasmin and plasminogen. This implies that there's an increased amount of fibrinolysis that's going on. So, the tranexamic acid acts as a competitive inhibitor at the lysine binding site in the plasminogen. I think here, it prevents the interaction between your plasmin and fibrin, thus decreasing your overall fibrinolysis and thus decreasing your heavy menstrual bleeding. So just a few facts on the pharmacokinetics of tranexamic acid.
It's not affected by food. The maximum plasma concentration is achieved two hours post dose. It is minimally bound to plasma protein. It is not metabolized in the body, and the main elimination route is through the kidneys. So this paper identified 11 randomized control trials on the therapeutic efficacy of tranexamic acid in the treatment of heavy menstrual bleeding. The selection criteria was a woman of reproductive age, with regular idiopathic heavy menstrual bleeding.
And this was either measured quantitatively, via the mean blood loss of more than 80 ml, or subjective perception of menorrhagia by the women themselves. The primary outcome measure in all of these studies was menstrual blood loss, which was measured directly by the alkaline hematin method, or indirectly via the pictorial blood assessment chart. And tranexamic acid was compared with placebo and other treatment modalities, such as the NSAIDS, progestins, and Levonorgestrel releasing IUS. So, several studies compare tranexamic acid with placebo. This is a randomized placebo control double blind study in which 187 women from 18 to 49 years old were given either placebo for day one to day five of their menstrual cycle, versus 1.3 grams of tranexamic acid for day one to day five of their menstrual cycle, and the menstrual blood loss was measured the alkaline hematin method. And overall, it was found that tranexamic acid reduced the measured blood loss by 26% to 50%, in comparison to a 2% to 8% in placebo groups. Especially in the trial that was in the previous slide, the menstrual blood loss was decreased by 40% in the tranexamic acid groups versus 8% in the placebo groups, and a measure of blood loss was also declined to less than 80 ml, which is the definition for heavy menstrual bleeding. In 43% of menstrual cycles compared, we have 17% of menstrual cycles in the placebo groups.
So several studies also compared tranexamic acid with NSAIDS, In particular Flurbiprofen and mefenamic acid. So for this trial, there were 15 women. They were given either tranexamic acid, 1.5 grams for day one to day three of their menstrual cycle, compared to other women, who were given Flurbiprofen 100 milligrams BD for day one to day three of their menstrual cycle. And this is another trial in which women were given tranexamic acid 1 grams-- 1 gram, four times a day for day one to day four, and mefenamic acid, 500 milligrams TDS for day one to day four. And overall, the findings was that the menstrual blood loss was significantly more decreased with tranexamic acid then with flurbiprofen or mefenamic acid.
So, in comparison with tranexamic acid and mefenamic acid, the measured blood loss was decreased by 54%, compared to 20%. And in comparison with flurbiprofen, the menstrual blood loss was decreased by 53% versus 24%. We also compare tranexamic acid Ethamsylate. Ethamsylate is a hemostatic drug that works by vessel constriction and promoting platelet adhesion to the release of thromboplastin. So, 400 milligrams of Ethamsylate was compared with one gram of tranexamic acid, and Ethamsylate showed no reduction in menstrual blood loss. Tranexamic acid, on the other hand, reduced the mean blood loss by 97 ml more than with Ethamsylate. We saw 67% of patients taking Ethamsylate did not wish to continue treatment because of the poor efficacy, while 77% of those taking tranexamic acid wished to continue. Otherwise, they have similar side effect.
So, another paper compare the role of tranexamic acid with medroxyprogesterone acetate. And it compared 2 grams of tranexamic acid with cyclical 10 milligrams of medroxyprogesterone acetate for three cycles. And they were found to be comparable in reducing menstrual blood loss. Whatever the correct sponsorship by the entry patients is trance I mean I see that the impatience of the progestin.
After stopping treatment for three months, 66.7% of patients in a tranexamic acid group had recurrence of menorrhagia, but only 50% in the medroxyprogesterone acetate group had recurrence. And more hysterectomies were performed in the medroxyprogesterone group, probably due to patients discontinued treatment, due to the side effects of hormonal therapy like irregular bleeding, nausea, vomiting, blood thinners, etc, and compliance issue with this technical usage. So, the authors concluded that tranexamic acid is equally efficacious in reducing menstrual blood loss, especially for patients who want to conceive and in whom hormonal therapy is not tolerated. So another study compared tranexamic acid with norethisterone in the treatment of ovulatory menorrhagia. So, in this study, they compare one gram of tranexamic acid versus norethisterone on days 19 and 26 for two cycles.
And they found that tranexamic acid reduced menstrual blood loss by 45%, while norethisterone increased menstrual blood loss by 20%. 14 that received tranexamic acid achieved a mean blood loss of less than 80 ml per cycle, which is the definition of heavy menstrual bleeding. But only two patient that received norethisterone achieved this mean menstrual blood loss. So, the others concluded that tranexamic acid is safe and effective in reducing menorrhagia. Norethisterone at this dosage, however, is ineffective in treating ovulatory menorrhagia. One explanation for this is probably because norethisterone is metabolized through estrogen-like [INAUDIBLE], which can result in proliferation of endometrium. On the other hand, medroxyprogesterone which is a progesterone, is a pure progesterone compound.
Also, in this study, the norethisterone dosage is only given on days 19 and 26, which is probably not appropriate for treating heavy menstrual bleeding. So, this paper also compare tranexamic acid with levonorgestrel-releasing IUCD. And it found that reduction in menstrual blood loss is actually greater with levonorgestrel-releasing IUCD compared with tranexamic acid. But IUCD is probably not appropriate for patients that wish to conceive. So, after we compare different treatment modalities, we will move on to determine a dosages that is most available for tranexamic acid. In this paper, the authors compare 1.95 grams vs. 3.9 grams of tranexamic acid, and they measured three primary efficacy endpoints.
So, first need I mentioned about reduction of tranexamic acid is greater than placebo and is statistically significant. And the measure of blood loss is as perceived the meaning for the subjects. And mean measure of blood loss in patients who have higher doses of tranexamic acid, 3.9 grams is greater than the group with only 1.95 gram, probably suggesting a dose response relationship. They also measure a secondary efficacy endpoint, which is the improvement in quality of life. This will be mentioned within the presentation. Otherwise, there no serious study related to even higher dosages of tranexamic acid. The paper also looked at the effect of quality of life in using treatments with tranexamic acid.
So, specifically they looked at two randomized placebo controlled double-blind studies. In these studies, they used a validated disease specific menorrhagia impact questionnaire that were used to assess the effect of tranexamic acid treatment on the quality of life. Overall, the MIQ scores for limitations in social or leisure activities and physical activities, were decreased significantly compared to placebo.
In the first of these two studies, Freeman et al used a sample size of 294 patients and they were administered tranexamic acid for three cycles in two dosage groups. In the first group, they administer 1.95 grams per day for five days, and other group it was 3.9 grams per day for five days. And it was found that the MIQ scores in both groups decreased significantly compared with placebo. In the second study, with a sample size of 187 patients, they use a dosage of 3.9 grams per day for five days over six cycles. And in this study, they found that the mean MIQ scores for limitations in social leisure activities, physical activities, work outside and inside the home, and self-perceived menstrual blood loss decreased significantly compare with placebo. They also looked at a open-label uncontrolled study with a sample size of 829 patients, with dosage about 3 to 6 grams per day for three to four days over three months. The question-- quality of life was assessed with a 5-point scale questionnaire. And overall, 81% of the participants were satisfied or very satisfied with the treatments, and 94% perceived their menstrual blood loss to be decreased or strongly decreased.
In this part of the presentation, I'll be touching on the long term use of tranexamic acid, specifically focusing on the cause of his treatment, tolerability of its use, and also the recommended dosages. So, to evaluate the use of tranexamic acid as a long term treatment modality, the side effect profile has to be evaluated. In a paper by Lukes comparing the use of tranexamic acid versus placebo, there's actually no reported increase in incidence of headache, menstrual cramps, back pain, or nausea in both patient groups. Additionally, in a second paper by Freeman comparing different dosages of tranexamic acid to placebo, there's actually mild reported increase in side effects in 10% of these patients. The side effects were very mild and it was associated with increased incidence of viral URTI, fatigue, MSK pain, arthalgia, myalgia, and nasal congestion. Significantly, there was no reported increased in GI side effects in the use of tranexamic acid relative to placebo. Additionally, there has been no reported thromboembolic events in a 19 year observational population-based study.
So, clearly we can see that tranexamic acid is a generally well tolerated medication with mild side effects. The dosage requirements for the treatment of heavy menstrual bleeding are as follows. In Europe, it is recommended to use 1 gram TDS of tranexamic acid for four days, not exceeding 4 grams per day. And in US, the recommended dosage just quite similar. It is 1.3 grams TDS for five days. As tranexamic acid is renally excreted, dosage reductions are recommended for patients with renal impairment. Contraindications to it's use will include: active thromboembolic disease, history of thromboembolism, intrinsic risk for thrombosis, severe renal failure, and also hypersensitivity reactions.
Currently, there exists a lack of health economic analysis for the use of tranexamic acid in the treatment of heavy menstrual bleeding. In view of that, NICE guidelines has actually developed a model to evaluate the cost effectiveness of this treatment based on quality adjusted life years. So, for a comparison of tranexamic acid relative to placebo, tranexamic acid provided an additional quality adjusted life years, but this definitely came at an additional cost. In comparison to NSAIDs, tranexamic acid of sexually more superior, providing more quality adjusted life years at a lower cost.
And in compared to levonorgestrel-releasing IUS, tranexamic acid was slightly inferior, providing fewer quality adjusted life years at a greater cost. In view of this, our team has also come up with a cost of treatment based on the recommended guidelines in KKH and also the cost which we obtained from KKH pharmacy. So these are the costs.
Tranexamic acid and medroxyprogesterone acetate actually came up slightly higher in the cost rating, involving $288 and $300 per year expected. Mirena, norethisterone, and mefenamic acid was slightly cheaper than. I like to now touch on a critique of this paper. A comparison of the trials in this paper was actually based on measure of blood loss as the sole outcome measure. We felt that this was insufficient as there was no comparison of other outcome measures, such as relief of this menorrhagia or irregular menstrual blood loss. Also, the cost of treatment was only based on financial costs as the sole comparison measure. Our team feels that the cost of treatment should also include the complications, re-treatments, or follow-up time. Additionally, there were no studies which explore the use of tranexamic acid in a combination therapy, such as tranexamic acid with mefenamic acid, or tranexamic acid with progestogens.
So, in summary, menstrual blood loss was significantly more decreased with tranexamic acid then with NSAIDs or oral progestogens. However, the reduction in menstrual blood loss achieved by levonorgestrel-releasing IUCD is actually greater than the tranexamic acid. With regards to quality of life, 81% of users of tranexamic acid report to be satisfied or very satisfied with the results, and 94% perceived that measured blood loss was decreased or strongly decreased. Also, we have just now mentioned that tranexamic acid is a generally well tolerated medication with mild adverse side effects, and it is relatively cost effective. This is the end of our presentation.
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