Antifibrinolytics for heavy menstrual bleeding.
BACKGROUND
Heavy menstrual bleeding (HMB) is an important cause of ill health in women. Medical therapy, with the avoidance of possibly unnecessary surgery, is an attractive treatment option. A wide variety of medications are available to reduce heavy menstrual bleeding but there is considerable variation in practice and uncertainty about the most appropriate therapy. Plasminogen activators are a group of enzymes that cause fibrinolysis (the dissolution of clots). An increase in the levels of plasminogen activators has been found in the endometrium of women with heavy menstrual bleeding compared to those with normal menstrual loss. Plasminogen activator inhibitors (antifibrinolytic agents) have therefore been promoted as a treatment for heavy menstrual bleeding. There has been a reluctance to prescribe tranexamic acid due to possible side effects of the drugs such as an increased risk of thrombogenic disease (deep venous thrombosis). Long term studies in Sweden, however, have shown that the rate of incidence of thrombosis in women treated with tranexamic acid is comparable with the spontaneous frequency of thrombosis in women.


OBJECTIVE
To determine the effectiveness of antifibrinolytics in achieving a reduction in heavy menstrual bleeding.


METHODS
All studies which might describe randomised controlled trials of antifibrinolytic therapy for the treatment of heavy menstrual bleeding were obtained by electronic searches of MEDLINE 1966-1997, EMBASE 1980-1997 and the Cochrane Library. Companies producing antifibrinolytics and experts within the field were contacted for reference lists and information on unpublished trials.


METHODS
Randomised controlled trials in women of reproductive age treated with antifibrinolytic agents versus placebo, no treatment or any other medical (non-surgical) therapy for regular heavy menstrual bleeding within either the primary, family planning or specialist clinic settings. Women with post menopausal bleeding, intermenstrual bleeding, iatrogenic or pathological causes of heavy menstrual bleeding were excluded.


METHODS
Fifteen eligible trials were assessed by three reviewers and eight of these did not meet with the inclusion criteria. Of the seven remaining trials, four of these could be included within the meta-analysis. The remaining three trials had a crossover design and despite contacting the authors and appropriate companies, we were unable to extract the results in a format suitable to include these within the meta-analysis. However the results are included within the text of the review for discussion.


RESULTS
Antifibrinolytic therapy compared to placebo showed a significant reduction in mean blood loss (WMD -94.0 [-151.4, -36.5]) and significant change in mean reduction of blood loss (WMD -110.2 [-146.5, -73.8]). This objective improvement was not mirrored by a patient perceived improvement in monthly menstrual blood loss (RR 2.5 [0.9, 7.3]) in the one study which recorded this outcome (~~ Edlund 1995~~). Antifibrinolytic agents were compared to only three other medical (non-surgical) therapies: mefenamic acid, norethisterone administered in the luteal phase and ethamsylate. In all instances, there was a significant reduction in mean blood loss (WMD -73.0 [-123.4, -22.6], WMD -111.0 [-178.5, -43.5] and (WMD -100 [-143.9, -56.1] respectively) and a strong, although non-significant trend in favour of tranexamic acid in the participants' perception of an improvement in menstrual blood loss. There were no significant differences in the frequency of reported side effects with tranexamic acid when compared to oral luteal phase progestogens (RR 0.4 [0.1, 1.2]) or withdrawal from treatment because of adverse events when compared with NSAIDs and ethamsylate when these treatments were used for heavy menstrual bleeding. Change in the quality of life measures, flooding and leakage and sex life, were significantly improved in the tranexamic acid group when compared to the oral progestagen group. These findings are based in most cases on only one trial.


CONCLUSIONS
Antifibrinolytic therapy causes a greater reduction in objective measurements of heavy menstrual bleeding when compared to placebo or other medical therapies (NSAIDS, oral luteal phase progestagens and ethamsylate). This treatment is not associated with an increase in side effects compared to placebo, NSAIDS, oral luteal phase progestagens or ethamsylate. Flooding and leakage and sex life is significantly improved after tranexamic acid therapy when compared with oral luteal progestogens but no other measures of quality of life were assessed. No study has used resource cost as an outcome. There are no data available within randomised controlled trials which record the frequency of thromboembolic events.
Lethaby
A
A
Department of Obstetrics and Gynaecology, University of Auckland, 2nd Floor, National Women's Hospital, Claude Road, Epsom, Auckland, New Zealand. a.lethaby@auckland.ac.nz
Farquhar
C
C
Cooke
I
I
D000933:Antifibrinolytic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008595:Menorrhagia / Q000188:drug therapy*; D009640:Norethindrone / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D014148:Tranexamic Acid / Q000627:therapeutic use
D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid; D009640:Norethindrone