|Heavy Menstrual Bleeding Improved With Effective Drug Treatment
September 29, 2010 — A new oral formulation of tranexamic acid may be safe and effective for treatment of heavy menstrual bleeding, according to the results of a phase 3 trial by Andrea S. Lukes, MD, MHSc, from the Carolina Women's Research and Wellness Center in Durham, North Carolina, and colleagues. Findings from this double-blind, randomized, placebo-controlled trial are reported in the October issue of Obstetrics & Gynecology.
"Tranexamic acid has been used in daily practice [for heavy menstrual bleeding] for a long time without any sufficient scientific evidence," Murat Gultekin, MD, gynecologist oncologist at ZTB Maternity Hospital, and deputy director of the Gynecologic Oncology Division, Turkish Ministry of Health, Cancer Control Department, told Medscape Medical News when asked for independent comment. "This article is unique with Level A scientific evidence [for efficacy, and the] new oral formulation is also found to have a good safety and tolerance profile. This study presents good scientific data for a first line, non-hormonal, nonsurgical treatment option for women with cyclic heavy menstrual bleeding."
Study participants were adult women with heavy menstrual bleeding, defined as mean menstrual blood loss of at least 80 mL per cycle. After 2 pretreatment menstrual cycles, women were assigned to receive an oral formulation of tranexamic acid 3.9 g/day (n = 115) or placebo (n = 72) for up to 5 days per menstrual cycle through 6 cycles.
The predefined 3-component efficacy endpoint for tranexamic acid was a mean decrease from baseline in menstrual blood loss that was significantly greater than that seen with placebo, greater than 50 mL, and greater than a predetermined meaningful threshold of 36 mL or higher. A validated patient-reported outcome instrument was used to assess health-related quality of life.
"[This trial] is a placebo controlled, prospective, multicenter, double blind study using a validated patient reported outcome tool, and it includes both intergroup comparisons (treatment group vs. placebo) and also intragroup evaluations (within the treatment arm)," said Dr. Gultekin when asked about the strengths of this study. "Sample size is sufficient for statistical evaluations. [The trial] also evaluates the menstrual bleeding amounts by both objective and subjective methods."
All 3 primary efficacy endpoints were achieved in women who received tranexamic acid. Reduction in menstrual blood loss was significantly greater in this group (–69.6 mL [40.4%] vs –12.6 mL [8.2%]) in the placebo group (P < .001). This reduction of menstrual blood loss with tranexamic acid also exceeded the prespecified endpoint of 50 mL and was considered meaningful to women. Compared with the placebo group, the tranexamic acid group reported significant improvements in limitations in social or leisure and physical activities, work within and outside the home, and self-perceived menstrual blood loss (P < .01).
The rate of gastrointestinal tract adverse events with tranexamic acid was similar to that seen with placebo, and the majority of adverse events was mild to moderate in severity.
When asked about the main limitations of this study, Dr. Gultekin noted short follow-up time and lack of follow-up data after treatment was stopped.
"The clinical situation after cessation of the therapy is challenging since we do not know what occurs when the patients stop medication or if there is any rebound effect possible after cessation of the therapy," Dr. Gultekin said. "Another limitation is the exclusion of patients with anovulatory bleeding; but in contrast, inclusion of the patients with leiomyoma. The authors did not state a rational reason for this."
In addition, Dr. Gultekin pointed out that no detailed data were reported about the size of the myomas in each group, which may cause a patient selection bias among the groups.
"The tranexamic acid group had a higher mean blood loss per month -- the reason for this is not well documented and may be related to the size of the myomas," Dr. Gultekin said. "However, since the treatment arm has higher median blood loss, subjective tools evaluating the patients' satisfaction may also be biased. Iron supplementations should also be standardized in such a prospective trial. Accordingly, hemoglobin and ferritin levels, which are the most objective tools of anemia and treatment effect, are not different between the groups after 6 months."
Safety and Monitoring Data Suggested
Regarding additional research, Dr. Gultekin recommends obtaining long-term safety and monitoring data; comparing tranexamic acid vs nonsteroidal agents; and evaluating the effect of the drug in a homogeneous patient population, such as all patients with anovulatory bleeding or all patients with myoma-related bleeding.
"In this study, a new oral tranexamic acid treatment was well tolerated and significantly improved both menstrual blood loss and health-related quality of life in women with heavy menstrual bleeding," the study authors conclude.
Xanodyne Pharmaceuticals, Inc, and Ferring Pharmaceuticals, Inc, supported this study. Xanodyne employs 2 of the study authors. Some of the other study authors have disclosed various financial relationships with Xanodyne, Ethicon, Merck, Bayer, Luitpold, Hologic, National Improvement for Women's Healthcare, Duramed, the National Institutes of Health, the Centers for Disease Control and Prevention/Association for Prevention Teaching and Research, Smith & Nephew, Trent Foundation, American Medical Systems, Ferring, Interlace Medical, Boehinger Ingelheim, Myriad, Microsulis, AMAG, Daichii, Amgen, BioSante Pharmaceuticals, Wyeth Research, Organon, Warner Chilcott, Wyeth, Perrigo, Ortho-McNeil, Serono, Kabi Pharmacia, Pharmacia & Upjohn, AstraZeneca, Schering, University of California at San Francisco, Pfizer, Astellas Pharmaceuticals, Church & Dwight Co, Orasure Technology, Quatrx Pharmaceuticals, KV Pharmaceutical, Roche Molecular Systems, FemmePharma Global Healthcare, Inc, TriPath Imaging, Meritage, Amylin, and/or Teva Pharmaceuticals.
Dr. Gultekin has disclosed no relevant financial relationships.
Obstet Gynecol. 2010;116:865-875. Abstract
More information on menstrual dysfunction is available online from the Cleveland Clinic.
Heavy menstrual bleeding is the loss of 80 mL or more blood per menstrual cycle, as noted by Hallberg and colleagues in the 1966 issue of Acta Obstetricia et Gynecologica Scandinavica. A treatment of heavy menstrual bleeding is tranexamic acid, a competitive plasminogen inhibitor, which has been associated with adverse gastrointestinal tract effects, according to Wellington and Wagstaff in the 2003 issue of Drugs. A formulation of tranexamic acid that appears to reduce gastrointestinal tract effects has been approved by the US Food and Drug Administration.
This multicenter, double-blind, parallel-group study describes the efficacy and safety of a phase 3 clinical trial of a tranexamic acid treatment of heavy menstrual bleeding.
196 women aged 18 to 49 years with heavy menstrual bleeding were randomly assigned to receive tranexamic acid or placebo for 6 menstrual cycles.
Inclusion criteria were at least 3 consecutive days of heavy menstrual bleeding for at least 4 of the last 6 menstrual periods, at least 60 mL of blood loss during 1 menstrual period with an average of at least 80 mL during 2 pretreatment cycles, normal result on pelvic examination, no significant cervical cytology abnormalities, no significant uterine pathologic features, regular menstrual periods up to 10 days, cycles of 21 to 35 days, and normal color vision.
Exclusion criteria were significant medical conditions, hemoglobin level of less than 8 g/dL, pregnancy or lactation, endometrial abnormalities, cervical carcinoma, anovulatory dysfunctional uterine bleeding, metrorrhagia, menometrorrhagia, polymenorrhea, glaucoma, ocular hypertension, macular degeneration, or retinopathies.
Prohibited medications were anticoagulants, aspirin, dong quai, aminocaproic acid, or hydroxychloroquine.
Permitted medications were cyclooxygenase-2 inhibitors, intermenstrual nonsteroidal anti-inflammatory drugs, acetaminophen, analgesic opioids, iron, and vitamins.
Oral iron was prescribed for a hemoglobin level lower than 11 g/dL and, at the investigator's discretion, for a hemoglobin level between 11 and 12 g/dL.
Of 123 women randomly assigned to receive tranexamic acid 1.3 g up to 3 times daily at least 6 hours apart for up to 5 days per cycle, 115 had posttreatment data.
Of 73 women randomly assigned to placebo, 72 women took at least 1 dose.
148 women completed the study: 94 in the tranexamic acid group and 54 in the placebo group.
Baseline and demographic characteristics were similar for both groups.
Menstrual blood volume was measured with use of the alkaline hematin method on collected sanitary products.
The primary endpoints of tranexamic acid efficacy were whether mean reduction in menstrual blood loss from baseline was greater vs placebo, greater than 50 mL, and greater than predetermined clinically meaningful threshold of at least 36 mL:
The tranexamic acid group vs the placebo group had significant reduction in mean blood loss (–69.6 mL vs –12.6 mL; P < .001).
Reduction of at least 50 mL of blood loss occurred in more cycles of the tranexamic acid group vs the placebo group (56% vs 19%; P < .001).
Reduction of at least 36 mL of blood loss occurred in more cycles in the tranexamic acid group vs the placebo group (69% vs 29%; P < .001).
Blood loss was less than 80 mL in more cycles in the tranexamic acid group vs the placebo group (43% vs 17%; P < .001).
The tranexamic acid group vs the placebo group had improved Menorrhagia Impact Questionnaire scores for limitations in social or leisure, physical activities, and work inside and outside the home.
Mean hemoglobin level did not improve in the tranexamic acid group and had statistically, but not clinically, significant improvement in the placebo group.
Ferritin level did not improve in the tranexamic acid group or placebo group.
Adverse events were mostly of mild to moderate in severity.
The most common adverse events reported in the tranexamic acid group vs the placebo group were menstrual discomfort or cramps (61.5% vs 50%), headache (55.6% vs 50%), and back pain (23.9% vs 19.4%).
7 patients had possible or probable treatment-related ocular adverse events: 2 patients in the tranexamic acid group and 5 in the placebo group.
Gastrointestinal tract adverse events were similar for both groups.
In the tranexamic acid group, 6 patients reported serious adverse events unrelated to treatment: tachycardia, acute bronchitis, hypoglycemia, posttraumatic stress disorder, and urticaria. There was an incidence of deep vein thrombosis in 1 patient in the placebo group.
No deaths occurred.
No significant changes occurred in blood pressure, pulse rate, physical or gynecologic findings, or electrocardiography findings.
In women with heavy menstrual bleeding, tranexamic acid decreases mean menstrual blood loss more than placebo, greater than 50 mL, and more than a clinically greater threshold of at least 36 mL.
In women with heavy menstrual bleeding, tranexamic acid is well tolerated, with the most common adverse events being menstrual discomfort or cramps, headache, and back pain.
According to the study of women with heavy menstrual bleeding, tranexamic acid was effective in the reduction of menstrual blood loss according to which of the following parameters?
Greater than placebo
Greater than 50 mL
Greater than clinically determined threshold
All of the above
None of the above
A woman with heavy menstrual bleeding starts receiving tranexamic acid. Which of the following adverse events is most likely to occur?
Gastrointestinal tract symptoms