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PubMed1979

New approach to protein-losing gastroenteropathy.

Fibrinolytic activity in the biopsied gastrointestinal mucosa was investigated in patients with protein-losing gastroenteropathy, and the increased activity was observed in patients associated with erosive gastritis, Menetrier's disease, atrophic gastritis, or Crohn's disease. However, patients with intestinal lymphangiectasia showed normal mucosal fibrinolysis. Antifibrinolytic therapy with tranexamic acid revealed significant therapeutic effect in the group with increased mucosal fibrinolysis. It is concluded that tranexamic acid appeared to be successful in blocking the vicious circle of "membrane disorder","increased tissue fibrinolysis", "increased vascular permeability", and "hypoproteinemia" in protein-losing gastroenteropathy.

Antifibrinolytic Agents↗

PubMed2000

The use of technologies to minimize exposure to perioperative allogeneic blood transfusion in elective surgery. A survey of Canadian hospitals.

BACKGROUND: Despite the growing medical and public interest in reducing exposure to allogeneic blood, little is known about the use of alternatives to allogeneic transfusion. This study was conducted to determine the availability of these technologies in Canadian hospitals and was undertaken under the auspices of the International Study of Peri-Operative Transfusion (ISPOT), a 10-country study of the effectiveness of, attitudes toward, and practices related to the use of alternatives to allogeneic transfusion. METHODS: A cross-sectional national mail survey of Canadian hospitals with greater than 50 medical/surgical beds. Chiefs of anesthesia, surgery, and the divisions of cardiac, orthopedic, vascular, and urology were initially mailed a brief postcard asking which of seven technologies were used in their center. This was then followed up with a one-page questionnaire asking how frequently the technologies were used, their thoughts on the appropriateness of the use of the technologies, barriers to their greater use, and reasons for nonuse of the technologies. RESULTS: Response rates to the postcard survey ranged from 70%-98%, depending on the technology and type of surgery, and ranged from 27%-53% for the follow-up questionnaire. All technologies were used most frequently in cardiac surgery. Aprotinin, tranexamic acid, aminocaproic acid, desmopressin, and cell salvage were reported used in over 70% of cardiac surgery centers. Of these, tranexamic acid and cell salvage were the only ones used routinely in some centers. Acute normovolemic hemodilution and erythropoietin were used in 45% and 20% of cardiac centers, respectively. The drugs were used in less than 15% of orthopedic, vascular, and urologic divisions, with the exception of desmopressin in urologic and vascular surgery and aminocaproic acid in urologic surgery. The techniques of cell salvage and acute normovolemic hemodilution were used in 30%-45% of these divisions, with the exception of cell salvage, which was used in less than 15% of urology units. In more than 60% of cases, the technologies were considered to be used "about right," although an important minority felt that they were underused. CONCLUSIONS: In general, alternatives to perioperative allogeneic transfusion were rarely used except in cardiac surgery.

Blood Loss, Surgical↗

PubMed1990

Idarubicin (4-demethoxydaunorubicin) as single agent for remission induction of previously untreated acute promyelocytic leukemia: a pilot study of the Italian cooperative group GIMEMA.

Because of the reported high sensitivity of acute promyelocytic leukemia to daunorubicin, we treated 27 consecutive, newly diagnosed, acute promyelocytic leukemia (APL) patients with the new anthracycline idarubicin (IDA) as induction therapy. IDA dosage ranged from 0.25 to 0.30 mg/kg/day and the drug was administered as single agent during a single induction course of 6 days. A total of 22/27 patients (81%) achieved complete remission, 4 (15%) died during induction and 1 patient was resistant to IDA. Extrahematological toxicity was acceptable. A total of 13/22 patients having achieved CR are still alive and in first CR after a median follow-up of 12 months. As for the treatment of the coagulopathy present in APL: 17/27 (63%) received tranexamic acid (6 g/daily) in continuous infusion for total of 7 d. None of the patients treated with tranexamic acid experienced thromboembolic complications. In conclusion, this multicentric pilot study confirms the antileukemic potency of IDA and the high sensitivity of APL to anthracycline derivatives.

Adolescent↗

PubMed1985

Thrombin-induced alterations in lung fluid balance in awake sheep.

We examined the effect of fibrinolysis depression on thrombin-induced pulmonary microembolism in awake sheep prepared with chronic lung lymph fistulas. Fibrinolysis was depressed by an intravenous infusion (100 mg) of tranexamic acid [trans-4-(Aminomethyl)cyclohexanecarboxylic acid]. Pulmonary microembolism was induced by an intravenous infusion of alpha-thrombin (80 NIH U/kg) in normal (n = 7) and in tranexamic acid-treated (n = 6) sheep. Thrombin immediately increased pulmonary lymph flow (Qlym) in both groups. The increased Qlym was not associated with a change in the lymph-to-plasma protein concentration (L/P) ratio in the control group and with a small decrease in the tranexamic acid-treated group. The increases in Qlym and pulmonary transvascular protein clearance (Qlym X L/P ratio) in the tranexamic acid-treated group were greater and sustained at four- to fivefold above base line for 10 h after the thrombin and remained elevated at twofold above base line even at 24 h. In contrast, Qlym and protein clearance were transiently increased in the control group. The mean pulmonary arterial pressure (Ppa) and pulmonary vascular resistance (PVR) increased after thrombin in tranexamic acid-treated group; the increases in Ppa and PVR in the control group were transient. Protein reflection coefficient as determined by the filtration independent method decreased after thrombin in tranexamic acid-treated sheep (n = 5), indicating an increased vascular permeability to proteins. We conclude that prolongation of microthrombi retention in the pulmonary circulation results in an increased vascular permeability to proteins. Both increased vascular permeability and vascular hydrostatic pressure are important determinants of the increases in Qlym and transvascular protein clearance after thrombin-induced pulmonary microembolism.

Amino Acids↗

PubMed2000

Management of menorrhagia in primary care-impact on referral and hysterectomy: data from the Somerset Morbidity Project.

OBJECTIVE: To investigate the management of menorrhagia in primary care and its impact on referral and hysterectomy rates. DESIGN: Prospective observational study. SETTING: 11 general practices from the Somerset Morbidity Project. SUBJECTS: 885 women consulting their general practitioner with menorrhagia over four years. MAIN OUTCOME MEASURES: Proportions of these women investigated and treated with drugs in primary care, referred to a gynaecologist and undergoing operative procedures. The relation between investigation and prescribing in primary care and referral to and surgery in secondary care. RESULTS: Less than half of women had a vaginal examination (42%, 95% CI 39% to 45%), or a full blood count (39%, 95% CI 36% to 43%). Almost a quarter of women, 23% (95% CI 20% to 26%), received no drugs and 37% (95% CI 34% to 40%) received norethisterone. Over a third, 38% (95% CI 34% to 40%), of women were referred, and once referred 43% (95% CI 38% to 48%) of women were operated on. Women referred to a gynaecologist were significantly more likely to have received tranexamic acid and/or mefenamic acid in primary care (chi(2)=16.4, df=1, p<0.001). There were substantial between practice variations in management, for example in prescribing of tranexamic acid and/or mefenamic acid (range 16% to 72%) and referral to gynaecology (range 24% to 52%). There was a significant association between high referral and high operative rates (Spearman's correlation coefficient=0.86, p=0.001). CONCLUSIONS: Substantial differences in management exist between practices when investigating and prescribing for menorrhagia in primary care. Rates of prescribing of effective medical treatment remain low. The decision to refer a woman impacts markedly on her chances of subsequently being operated on. Effective management in primary care may not reduce referral or hysterectomy rates.

Adult↗

PubMed1994

Cardiac anesthesia risk management. Hemorrhage, coagulation, and transfusion: a risk-benefit analysis.

Transfusion risks include the possibility of ABO/Rh incompatibility, sepsis, febrile reactions, immunosuppression, and viral transmission; incidences and consequences of these complications are reviewed. Predonation of autologous blood generally reduces the need for homologous blood by about 30% to 40%, but relatively few coronary artery bypass surgery (CABG) patients predonate blood. Drug products to decrease blood use include 1-deamino-8-D-arginine vasopressin (DDAVP), tranexamic acid, epsilon-aminocaproic acid, and aprotinin. A recent study suggests that a subgroup of patients with abnormal platelet function may benefit from a platelet therapy such as DDAVP. The prophylactic use of tranexamic acid reduces cardiac surgery postoperative blood loss, as measured by chest-tube output, by about 30%; unfortunately, data demonstrating a reduction in transfusion requirements are not available. Aprotinin use is associated with major reductions in blood transfusion requirements. Aprotinin provides platelet protection during cardiopulmonary bypass. Duration of stay in the intensive care unit was not increased by use of aprotinin, thus alleviating some concerns that aprotinin might promote coronary thrombosis. A recent report cites early graft closure as a major concern with aprotinin therapy, but data from other studies show no significant differences in rates of graft closure between patients receiving and those not receiving aprotinin. Routine use of a thromboelastogram with all cardiopulmonary bypass surgery at the University of Washington Hospital has reduced use of blood products by 30%.

Blood Coagulation Disorders↗

PubMed1995

[A fatal case of hereditary angioedema].

A 27 year old woman suffered from recurrent attacks of laryngeal oedema due to C1-inhibitor deficiency, and was treated with danazol and tranexamic acid. The trachea was intubated with great difficulty, twice on one occasion. Two and a half years later she was admitted to the Intensive Care Unit with dyspnoea and dysphagia. Tranexamic acid, corticosteroids, adrenaline (also inhalated), were administered intravenously, but dyspnoea progressed. During preparation for tracheostomy the patient suffered from sudden airway collapse. Attempts to ventilate by mask, puncture of the cricothyroid membrane and intubation were unsuccessful. A small tube was eventually inserted into the trachea after four minutes. The patient was then severely cyanotic with a pulse of thirty, and had dilated pupils. The next morning convulsions ensued and a CT scan showed cerebral oedema. In spite of treatment with pentothal, mannitol and hyperventilation she died. The authors advocate the use of intravenous infusion of C1-inhibitor concentrate, since traditional treatment is inadequate. Persons with hereditary angio-oedema should have a personal supply of C1-inhibitor at hand.

Adult↗

PubMed2001

Phosphatidylinositol-specific-phospholipase C cleaves urokinase plasminogen activator receptor from the cell surface and leads to inhibition of pemphigus-IgG-induced acantholysis in DJM-1 cells, a squamous cell carcinoma line.

We showed previously that pemphigus IgG enhanced both the activity of urokinase plasminogen activator (uPA) in cultured cells and the expression of its receptor (uPAR) on uPA-binding keratinocytes. In the present study, to clarify whether uPAR and uPA-activated plasmin are actually involved in the blistering process after pemphigus IgG binding to the cell surface, we examined the effects of the following on uPAR expression and on cell-cell detachment in DJM-1 cells, a squamous cell carcinoma line: (i) phosphatidylinositol-specific phospholipase C (PI-PLC) - which releases uPAR from the membrane surface into the culture medium by cleaving the glycosylphosphatidylinositol anchor thus inhibiting uPAR activity, and (ii) uPA inhibitors (tranexamic acid, aprotinin, p-aminobenzonic acid and dexamethasone). Preincubation with PI-PLC decreased dramatically the pemphigus IgG-induced uPAR expression in a dose-dependent manner, and inhibited pemphigus IgG-induced cell-cell detachment at 10 microg/mL. On the other hand, tranexamic acid (15 mM) inhibited pemphigus IgG-induced cell-cell detachment without reduction of uPAR expression, although aprotinin, p-aminobenzonic acid and dexamethasone failed to alter either of these parameters. Although uPAR expression on the pemphigus IgG-bound cell surface and uPA activation may contribute significantly to the pathogenesis of acantholysis in pemphigus, the mechanisms are complicated and should be defined further.

Acantholysis↗

PubMed2006

Pharmacological approaches to reducing blood loss and transfusions in the surgical patient.

PURPOSE: To review the efficacy, effectiveness and safety of hemostatic drugs to reduce surgical blood loss. METHODS: Analysis of randomized controlled trials and meta-analyses exploring the efficacy of desmopressin, aprotinin, lysine analogues and recombinant activated factor VII (rFVIIa) on clinically important endpoints. MAIN FINDINGS: Although potentially useful in surgical patients with mild hemophilia or type I von Willebrand's disease, desmopressin has no proven benefit in patients without previous hemostatic defects. Aprotinin has been studied extensively in cardiopulmonary bypass surgery, with evidence of a blood sparing effect. Additional benefits are suggested. The drug is less consistently effective in liver transplantation and major orthopedic surgery. Although rare, hypersensitivity reactions to aprotinin may occur, especially on re-exposure. Tranexamic acid can reduce blood transfusion in cardiac surgery, liver transplantation and total knee arthroplasty surgery with a satisfactory safety profile. Epsilon aminocaproic acid has not been investigated adequately, despite its widespread use. While rFVIIa may be beneficial in controlling massive coagulopathic bleeding in trauma and surgical patients, there is currently no evidence to support its prophylactic use in elective surgical patients. CONCLUSION: Aprotinin and tranexamic acid are valuable pharmacologic options for reducing surgical bleeding. The expected benefit of these drugs is highly dependent on the actual blood usage for a given procedure at the institutional level. More studies using clinically significant endpoints are necessary to assess the relative efficacy and optimal dosing of these drugs.

Aprotinin↗

PubMed2006

Recombinant activated factor VII combined with desmopressin in preventing bleeding from dental extraction in a patient with Glanzmann's thrombasthenia.

The case of a 41-year-old woman with Glanzmann's thrombasthenia who underwent double dental extraction is presented. In the past, treatments with desmopressin (DDAVP) and tranexamic acid had often unsuccessful efficacy to stop or decrease bleeding. After ineffective DDAVP administration, the removal was performed successfully with recombinant activated factor VII (rFVIIa) infusion. rFVIIa infusion after DDAVP administration could be useful in patients with Glanzmann's thrombasthenia in which DDAVP and tranexamic acid weren't always effective.

Adult↗

PubMed2004

A practical concept for preoperative management of patients with impaired primary hemostasis.

In a prospective study, 254 of 5649 unselected patients scheduled for surgery at our hospital were identified preoperatively as having either acquired (n=182) or inherited (n=72) impaired primary hemostasis (platelet dysfunction including von Willebrand disease). All patients were initially pretreated with desmopressin (DDAVP). Response to DDAVP or subsequent treatment(s) was defined as correction of any one of the abnormal PFA-100 platelet function tests. The non-responders were additionally treated with tranexamic acid or aprotinin; those with von Willebrand disease (vWD) received factor VIII concentrates with von Willebrand factor (vWF). Those still unresponsive to therapy received conjugated estrogens and, as a last attempt, a platelet transfusion. The administration of DDAVP led to a correction of platelet dysfunction in 229 of the 254 patients treated (90.2%). Tranexamic acid was effective in 12 of 16, aprotinin in 3 of 5, and factor VIII concentrates with vWF in all 4 patients with unresponsive to DDAVP. The remaining 6 patients were pretreated with conjugated estrogens, and 2 of these patients were additionally treated with platelet transfusion. The frequency of blood transfusion was lower, but not statistically significant (9.4% vs. 12.2%: p = 0.202) in preoperatively treated patients with impaired hemostasis than in patients without impaired hemostasis. In a retrospective group, the frequency of blood transfusion was statistically significant higher (89.3% vs. 11.3%: p < 0.001) in patients without preoperative correction of impaired hemostasis than in patients without impaired hemostasis. Preoperative correction of impaired primary hemostasis is possible in nearly all patients affected, and results in a reduction of homologous blood transfusions.

Adolescent↗

PubMed1995

Concomitant treatment with factor IX concentrates and antifibrinolytics in hemophilia B.

Concomitant use of the monoclonal antibody-purified factor IX concentrate (Mononine, Armour Pharmaceutical Company, Collegeville, Pa.) and two antifibrinolytic agents, epsilon-aminocaproic acid (EACA; Amicar, Immunex, Seattle, Wash.) or tranexamic acid (AMCA; Cyklokapron, Kabi Pharmacia, Piscataway, N.J.) was examined for safety and efficacy in patients with hemophilia B. In a retrospective review of 19 patients treated with monoclonal antibody-purified factor IX and EACA on 35 occasions, bleeding was successfully controlled and no instances of clinical thrombotic complications were reported; one instance of urticaria resolved without additional treatment. The use of EACA or AMCA in combination with monoclonal antibody-purified factor IX was also examined prospectively in a study of 9 patients. Bleeding was effectively controlled and no thrombotic events were detected clinically with either antifibrinolytic agent. No significant changes in hematocrit or hemoglobin were detected, and there was no evidence of thrombosis as evaluated clinically and by sensitive molecular markers. It was concluded from both the retrospective and prospective data that monoclonal antibody-purified factor IX concentrate in combination with an antifibrinolytic agent does not activate the coagulation cascade and is a safe and effective treatment for prevention and control of oral bleeding in hemophilia B patients.

Aminocaproates↗

PubMed1978

Protease inhibitors reduce the reverse passive Arthus reaction.

Trasylol, ovomucoid, tranexamic acid and soybean inhibitor decrease the vascular permeability as measured by extravasation of 131I-albumin when injected with the antibody at induction of a reverse passive Arthus reaction in the rat skin. Trasylol given systemically also had a suppressive effect, similar to phenylbutazone. When the reaction was induced in the pleural cavity, both Trasylol and tranexamic acid reduced the influx of leucocytes.

Animals↗

PubMed1993

Persistence of plasmin-mediated pro-urokinase activation on the surface of human monocytoid leukemia cells in vitro.

Human leukemia cell lines, unlike those from adherent tumors, have been shown to continuously activate the pro-urokinase (pro-u-PA) they produce. In the present study we found that, in normal cell-culture conditions in 10% FCS the plasminogen activation cascade works continuously on monocytoid leukemia cells, which expressed plasmin activity and active u-PA on their cell surface. This plasmin catalyzed the conversion of the produced pro-u-PA to active 2-chain urokinase (tcu-PA), and was derived from bovine serum plasminogen by the activity of cell-bound tcu-PA. Plasmin generation was abolished and pro-u-PA accumulated in cell cultures that were grown for several days, either in the presence of serum thoroughly depleted of plasminogen, or in the presence of 1 mM tranexamic acid. Plasmin generated on the cell surface was found to be present in 2 enzymatically active fragments, of M(r) 85,000 and M(r) 50,000, which were slowly released into the growth medium. These fragments could activate pro-u-PA in serum-free growth medium. Most of the bound plasmin could be washed off cells with 10 mM tranexamic acid, but complete removal of plasmin from the cell surface required washing of the cells with acid-glycine pH 3.0.

Animals↗

PubMed2002

A survey of practice preferences and attitudes to the New Zealand Guidelines for the Management of Heavy Menstrual Bleeding.

OBJECTIVE: To survey the practice preferences and the attitudes of New Zealand gynaecologists, general practitioners and family planning doctors to Guidelines for the Management of Heavy Menstrual Bleeding. STUDY DESIGN: A postal survey collected information on the following: demographics, practice preferences, knowledge of, usage of and attitudes toward the Guidelines for the Management of Heavy Menstrual Bleeding. The survey was sent to randomly selected practising general practitioners (n = 531), all specialist gynaecologists (n = 194) and all Family Planning Association doctors (n = 69) in New Zealand. Replies were received from 441 (56%). RESULTS: The preferred first choice for the management of heavy menstrual bleeding by general practitioners and family planning doctors was nonsteroidal anti-inflammatory medications (23%). Tranexamic acid was the preferred first choice medication for the management of heavy menstrual bleeding by specialists (57%), and preferred second choice (as well as levonorgestrel intrauterine system) by general practitioners and family planning doctors (34%). Barriers identified by general practitioners and family planning doctors to implementing the guideline included inability to access ultrasound scanning and specialist services, and a lack of subsidy for tranexamic acid and the levonorgestrel intrauterine system. CONCLUSIONS: There has been a change in prescribing patterns since 1995 among specialist and general practitioners and family planning doctors in New Zealand in accordance with the Guidelines for the Management of Heavy Menstrual Bleeding. Further attention to reducing barriers should focus on increasing access to ultrasound scanning, specialist services and subsidising the levonorgestrel intrauterine system.

Adult↗

PubMed1993

Human plasmin induces a receptor-mediated arachidonate release coupled with G proteins in endothelial cells.

Treatment of cultured bovine carotid artery endothelial cells with 10(-7) M plasmin increased arachidonate release coupled with the increase in prostacyclin production. The stimulatory effect of plasmin on arachidonate release could be divided into the early and late phases according to its calcium dependency and pertussis toxin sensitivity. The early phase of plasmin-induced arachidonate release was a calcium-dependent and pertussis toxin-sensitive response, which was observed within 20 min after plasmin treatment. The late phase was a calcium-independent and pertussis toxin-insensitive response, which was induced gradually from 20 to 60 min. Induction of the early phase of plasmin's effect required both the lysine binding and catalytic sites in plasmin molecule because it was inhibited either by the binding antagonist tranexamic acid or by the serine protease inhibitor aprotinin. Guanosine 5'-O-(2-thiotriphosphate) potentiated the effect of plasmin in permeabilized or nonpermeabilized cells, indicating that the early phase effect was mediated by a pertussis toxin-sensitive guanosine 5'-triphosphate (GTP)-binding protein. The late phase of plasmin's effect was due to the catalytic activity because it was inhibited by aprotinin but not by tranexamic acid. Microplasmin structurally having the catalytic sites induced a similar late phase effect. Plasmin did not elicit the metabolism of phosphatidyl polyphosphoinositides. These studies demonstrate that the activation of phospholipase A2, which results in arachidonate release, in the early phase of plasmin's effect is a receptor-mediation via GTP-binding protein that is not coupled through phospholipase C activation.

Animals↗

PubMed2004

Current treatment of dysfunctional uterine bleeding.

OBJECTIVES: We performed a review of the treatment modalities for dysfunctional uterine bleeding. METHODS: Dysfunctional uterine bleeding can be treated medically or surgically. Medical treatment consists of anti-fibrinolytic tranexamic acid, non-steroidal anti-inflammatory drugs, the combined contraception pill, progestogen, danazol, or analogues of gonadotrophin releasing hormone. The levonorgestrel releasing intra uterine device is developed for contraception, but is also effective in the treatment of dysfunctional uterine bleeding. Surgical treatment includes endometrial ablation of the first and second-generation, and hysterectomy. This review contains current available evidence on the effectiveness of these therapies. RESULTS: Antifibrinolytic tranexamic acid is the most effective medical therapy to treat dysfunctional uterine bleeding. In general medical therapy is not as effective as endometrial resection in terms of patient satisfaction and health related quality of life. The levonorgestrel releasing intra uterine device is an effective treatment for dysfunctional uterine bleeding. No difference in quality of life was observed in patients treated with a levonorgestrel releasing intra uterine device as compared to hysterectomy. Ablation techniques of the first generation are effective and safe when used by trained surgeons, but have a learning curve. Ablation techniques of the second generation are effective, but long-term follow-up data are not available. Similarly, there are no large randomised controlled trials comparing the levonorgestrel releasing intra uterine device to first and second-generation ablation techniques. Hysterectomy, the traditional standard of care, has a relatively high complication rate, but it generates a high satisfaction rate and good health related quality of life scores. CONCLUSION: Since none of the treatments for dysfunctional bleeding is superior to one of the others, and since all treatments have their advantages and disadvantages, counselling of patients with dysfunctional bleeding should incorporate medical approach, levonorgestrel releasing IUD, endometrial ablation and hysterectomy.

Catheter Ablation↗

PubMed2001

The effectiveness of the levonorgestrel-releasing intrauterine system in menorrhagia: a systematic review.

OBJECTIVE: To determine whether the levonorgestrel-releasing intrauterine device (LNG-IUS), licensed at present for contraceptive use, may reduce menstrual blood loss with few side effects. If effective, surgery could be avoided with consequent resource savings. METHODS: A systematic review addressing the effectiveness and cost effectiveness of the LNG-IUS for menorrhagia was undertaken. RESULTS: Five controlled trials and five case series were found which measured menstrual blood loss. Nine studies recorded statistically significant average menstrual blood loss reductions with LNG-IUS (range 74%-97%). Another showed reduction in menstrual disturbance score. The LNG-IUS was more effective than tranexamic acid, but slightly less effective than endometrial resection at reducing menstrual blood loss. In one study, 64% of women cancelled surgery at six months, compared with 14% of control group women. In another, 82% were taken off surgical waiting lists at one year. No cost effectiveness studies were found. DISCUSSION: Small studies of moderate quality indicate the LNG-IUS is an effective treatment for menorrhagia. Costs may be less than for tranexamic acid in primary and secondary care. Although its use may reduce surgical waiting lists, cost effectiveness assessment requires longer follow up. CONCLUSION: Effectiveness and cost effectiveness relative to other treatments and the effect on surgical waiting lists can only be established in larger trials measuring patient-centred outcomes in women with menorrhagia.

Adult↗