Comparison between antifibrinolytic and antiprostaglandin treatment in the reduction of increased menstrual blood loss in women with intrauterine contraceptive devices. Control of IUD-induced bleeding by three non-steroidal anti-inflammatory drugs. Prophylactic tranexamic acid decreases bleeding after cardiac operations. Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid. Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. The Writing Group for the Estradiol Clotting Factors Study. An objective evaluation of flurbiprofen and tranexamic acid in the treatment of idiopathic menorrhagia. Randomized trial of 2 hormonal and 2 prostaglandin-inhibiting agents in women with a complaint of menorrhagia. Effects of low and high dose oral contraceptives on blood coagulation and thrombogenesis induced by vascular subendothelium exposed to flowing human blood. Efficacy of mefenamic acid in patients with a complaint of menorrhagia.
The effects of a fibrinolysis inhibitor (tranexamic acid, TA) and prostaglandin synthesis inhibitor (diclofenac sodium, DS) were compared in the reduction of excessive menstrual blood loss in 19 women with an intrauterine contraceptive device (IUCD). These women (mean blood loss before treatment to 135.1 +/- 18.9 SE ml, range 70-294 ml) were treated in random order with TA (1.5 g three times daily for 5 days starting on the first day of menstruation for two periods), and with DS (50 mg three times on the first day followed by 25 mg three times daily for 4 days, for two periods), or with placebo (one period) in a double-blind trial. The placebo treatment did not change menstrual blood loss (128.3 +/- 15.6 ml). The TA treatment decreased blood loss to 59.4 +/- 7.7 ml (P less than 0.001) and the DS treatment to 102.1 +/- 13.6 ml (P less than 0.01). Neither treatment abolished pelvic discomfort during menstruation or shortened its duration. Various side-effects were noted by 12 women during 19 TA treatments and by five women during six DS treatments. Thus, while TA is generally far more effective, DS gave pronounced decreases in menstrual bleeding in some women and had less frequent side-effects. Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) reduced excessive IUD-induced bleeding. The effect of 3 different oral NSAIDs, namely indomethacin, Alclofenac, and flufenamic acid, on menstrual blood loss (MBL) and pain among women fitted with copper IUDs was studied and compared with a placebo on a randomized single blind basis. Each drug was given to 6 subjects (18 cases) over 2 consescutive cycles and was either preceded or followed by placebo for 2 more cycles. 1/2 of the cases on each drug started placebo medication in the 1st 2 months while the other 1/2 started by the drug. The oral treatment was begun on the 1st day of menstrual bleeding or spotting. Estimation of the daily MBL was done by the alkaline hematin method with mechanical extraction of sanitary pads. The 3 drugs tested in this study induced a significant reduction in MBL: maximum reduction by flufenamic acid medication, less with Alclofenac, and least with indomethacin medication. However, these reductions were not statistically different, and marked improvement in IUD-induced pain was observed under the effect of the 3 drugs. Thirty-eight patients undergoing a cardiac operation randomly received either tranexamic acid, a potent inhibitor of plasminogen, or placebo in an effort to determine whether prophylactic antifibrinolytic therapy reduces chest tube drainage. Twelve-hour blood loss was 750 +/- 314 (standard deviation) ml in the placebo group and 496 +/- 228 ml in the drug group (p = 0.0057). Fibrin split products were present more frequently in patients in the placebo group (17 of 20 compared with four of 18 in the drug group; p = 0.0002). Tranexamic acid markedly decreased plasminogen availability (112 +/- 104 units in the placebo group versus 36 +/- 18 units in the drug group, p = 0.0058). Plasma fibrinogen concentrations were similar in the placebo and drug groups. Patients in the placebo group received more fresh-frozen plasma and more mediastinal shed blood than those in the drug group. No coagulation-related complication occurred in the group receiving tranexamic acid. We conclude that prophylactic tranexamic acid can be administered safely to inhibit fibrinolysis during cardiac operations, decrease postoperative bleeding, and possibly decrease the frequency of blood product transfusion. To compare the efficacy and acceptability of ethamsylate, mefenamic acid, and tranexamic acid for treating menorrhagia.
                Randomised controlled trial.
                A university department of obstetrics and gynaecology.
                76 women with dysfunctional uterine bleeding.
                Treatment for five days from day 1 of menses during three consecutive menstrual periods. 27 patients were randomised to take ethamsylate 500 mg six hourly, 23 patients to take mefenamic acid 500 mg eight hourly, and 26 patients to take tranexamic acid 1 g six hourly.
                Menstrual loss measured by the alkaline haematin method in three control menstrual periods and three menstrual periods during treatment; duration of bleeding; patient's estimation of blood loss; sanitary towel usage; the occurrence of dysmenorrhoea; and unwanted events.
                Ethamsylate did not reduce mean menstrual blood loss whereas mefenamic acid reduced blood loss by 20% (mean blood loss 186 ml before treatment, 148 ml during treatment) and tranexamic acid reduced blood loss by 54% (mean blood loss 164 ml before treatment, 75 ml during treatment). Sanitary towel usage was significantly reduced in patients treated with mefenamic acid and tranexamic acid.
                Tranexamic acid given during menstruation is a safe and highly effective treatment for excessive bleeding. Patients with dysfunctional uterine bleeding should be offered medical treatment with tranexamic acid before a decision is made about surgery. After menopause the haemostatic balance shifts towards a latent hypercoagulable state. To evaluate the effects of two regimens of transdermal estradiol (E2) combined with progestin on the balance between procoagulant factors and inhibitors, 255 women in physiological menopause for 1-5 years were randomly allocated to 1 year of treatment with cyclic transdermal E2 (50 micrograms/day for 21 days) plus medroxyprogesterone acetate (MPA) (10 mg/day from days 10 to 21), continuous transdermal E2 (50 micrograms/day for 28 days) plus MPA (10 mg/day from days 14 to 25), or placebo. Fibrinogen, factor VII (FVII), factor VIII:C (FVIII:C), antithrombin III (ATIII), protein C, protein S, heparin cofactor II (HCII) and plasminogen activator inhibitor (PAI-1) levels were measured at baseline and after 6 and 12 cycles. 167 women who took the treatment for at least 6 cycles were evaluable. The continuous treatment group had significantly lower final values of fibrinogen, FVII, ATIII, protein S and HCII than the placebo group; the cyclic treatment reduced fibrinogen in comparison with placebo but the difference was not significant. In conclusion, both regimens produce a clinically relevant decrease of fibrinogen levels; the continuous regimen affects also the levels of FVII and inhibitors suggesting that the haemostatic balance is shifted to a more physiological state. The effect of flurbiprofen (100 mg x 2 for 5 days) was compared with tranexamic acid (1.5 g x 3 for 3 days, 1 g x 2 days 4 and 5) in the treatment of 15 women with idiopathic menorrhagia. The mean blood loss during two medication-free periods was 295 +/- 52 ml. A significant (p less than 0.01) reduction in menstrual blood loss was recorded during treatment with both flurbiprofen and tranexamic acid. The menstrual blood loss was significantly (p less than 0.01) lower during treatment with tranexamic acid (155 +/- 33 ml) than with flurbiprofen (223 +/- 44 ml). Various side effects were recorded by 7 of 15 women during treatment with tranexamic acid and by 4 women of 15 during treatment with flurbiprofen. Many women with menorrhagia suffer simultaneously from dysmenorrhea. Thus although tranexamic acid was generally more effective in reducing menstrual blood loss, flurbiprofen provides an important therapeutic alternative to antifibrinolytic agents, especially in patients with concomitant dysmenorrhea. A series of 45 ovulatory women with a complaint of menorrhagia were randomized into 3 treatment groups, before receiving therapy with mefenamic acid in 2 cycles and 1 of 3 other agents in 2 cycles: naproxen (group 1; n = 14), a low dose monophasic combined oral contraceptive (group 2; n = 12) or low dose danazol (group 3; n = 12). Menstrual blood loss was measured in 2-4 control cycles and during therapy. Mefenamic acid reduced measured blood loss by 20%; 38%; and 39% in groups 1-3 respectively. Naproxen reduced blood loss by 12%; the oral contraceptive by 43%; and danazol by 49%. There was no statistically significant difference in blood loss reduction (mean of 2 cycles) between any of the treatments, although women on danazol experienced a dramatic and highly significant further reduction in blood loss after the first treatment cycle (p less than 0.003). These were all effective therapies in a majority of women, but some 'non-responders' were seen in each group. The 'non-responders' had a significantly lower pretreatment blood loss than responders. Several women in group 1 showed anomalous responses to prostaglandin inhibitors with consistent and substantial exacerbation of menorrhagia during therapy. A number of reasonable therapies exist for the medical treatment of menorrhagia, but because none is suitable for everyone management needs to be individualized for each patient. We investigated the effect of oral contraceptives with low and high estrogen concentration on blood coagulation and thrombogenesis, induced by vascular subendothelium of rabbit aorta exposed to flowing human blood. Twenty healthy women intending to take oral contraceptives were studied [1] before drug ingestion (control), and subsequently during the intake of oral contraceptives with [2] low estrogen content (20 micrograms ethinyl estradiol and 150 micrograms desogestrel per day) and [3] high estrogen content (50 micrograms ethinyl estradiol and 125 micrograms desogestrel per day). All experiments were performed between day 17 and 21 of the menstrual cycle and drug effects were studied during the third tablet cycle. Deposition of fibrin, platelets and platelet thrombi on vascular subendothelium was tested at a defined blood flow and wall shear rate (10 ml/min, 650 s-1) and was quantified by morphometrical techniques. Treatment with the low and high dose contraceptive increased the plasma levels of ethinyl estradiol (728 +/- 139 and 1438 +/- 212 vs. 0 fmol/l [low and high dose vs. control], means +/- SEM, P less than 0.001) and fibrinogen (2.3 +/- 0.1 and 2.6 +/- 0.1 vs. 2.0 +/- 0.1 g/l, P less than 0.05); and decreased antithrombin III activity (95 +/- 3 and 92 +/- 3 vs. 101 +/- 3 %, P less than 0.05). Fibrin deposition on vascular subendothelium was enhanced by the high dose contraceptive only (47 +/- 4 vs. 35 +/- 4 % coverage of the subendothelial surface with fibrin, high dose vs. control, P less than 0.05). The subendothelial deposition of platelets and platelet thrombi was not changed by contraceptive treatment. These results indicate that treatment with high dose contraceptives leads to an increase of fibrin-subendothelial interactions, whereas low dose contraceptives do not significantly alter the blood-subendothelium interactions. observed in this ex vivo model of thrombogenesis. Sixty-nine patients with a convincing history of menorrhagia completed a 4-cycle double-blind randomized placebo-controlled crossover trial of mefenamic acid taken during menstruation. Only 30 of these patients demonstrated objective menorrhagia with a measured menstrual loss greater than 80 ml during the placebo cycles, but the remainder reported passing clots and/or using 2 pads at a time. Fourteen of these women (20%) had a loss of less than 35 ml while taking placebos. This raises serious questions about the establishment of menorrhagia based on history alone. Overall, there was a mean reduction of 28.1% in menstrual blood loss between placebo and mefenamic acid cycles (P less than .001). The greatest reduction recorded was 80%, and most of the large percentage reductions were seen in patients with high loss during placebo cycles. Significant reductions in blood loss (P less than .001) were seen in patients with ovulatory dysfunctional uterine bleeding and menorrhagia that developed after tubal interruption. There was also an indication based on small sample sizes that mefenamic acid reduced blood loss in women with anovulatory dysfunctional uterine bleeding, fibroids, intrauterine devices, and von Willebrand disease. No reduction was seen during the mefenamic acid cycle in the group with a loss of less than 35 ml during the placebo cycle. There was a significant shortening of duration of bleeding (P less than .003). Fifteen patients (21.7%) experienced no objective reduction in blood loss.
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.