Andrea S. Lukes

Multivariable analysis of DNA ploidy, p53, and HER-2/neu as prognostic factors in endometrial cancer

Background. Several molecular‐genetic alterations in endometrial cancers, including aneuploidy and aberrant expression of p53 and HER‐2/neu, have been associated with poor prognosis. To determine the importance of molecular‐genetic factors relative to more traditional surgical‐pathologic prognostic factors, a multivariable analysis was performed.

Tranexamic Acid Treatment for Heavy Menstrual Bleeding: A Randomized Controlled Trial

OBJECTIVE: To assess the efficacy and safety of an oral formulation of tranexamic acid for the treatment of heavy menstrual bleeding. METHODS: Adult women with heavy menstrual bleeding (mean menstrual blood loss 80 mL or more per cycle) were enrolled in a double-blind, placebo-controlled study. After two pretreatment menstrual cycles, women were randomized to receive tranexamic acid 3.9 g/d or placebo for up to 5 days per menstrual cycle through six cycles. To meet the prespecified three-component primary efficacy end point, mean reduction in menstrual blood loss from baseline with tranexamic acid treatment needed to be 1) significantly greater than placebo, 2) greater than 50 mL, and 3) greater than a predetermined meaningful threshold (36 mL or higher). Health-related quality of life was measured using a validated patient-reported outcome instrument. RESULTS: Women who received tranexamic acid (n=115) met all three primary efficacy end points: first, a significantly greater reduction in menstrual blood loss of −69.6 mL (40.4%) compared with −12.6 mL (8.2%) in the 72 women who received placebo (P<.001); reduction of menstrual blood loss exceeding a prespecified 50 mL; and last, reduction of menstrual blood loss considered meaningful to women. Compared with women receiving placebo, women treated with tranexamic acid experienced significant improvements in limitations in social or leisure and physical activities, work inside and outside the home, and self-perceived menstrual blood loss (P<.01). The majority of adverse events were mild to moderate in severity, and the incidence of gastrointestinal adverse events was comparable with placebo. CONCLUSION: 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. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00386308. LEVEL OF EVIDENCE: I

Multisite management study of menorrhagia with abnormal laboratory haemostasis: A prospective crossover study of intranasal desmopressin and oral tranexamic acid

The optimal management of menorrhagia among women with abnormal laboratory haemostasis is uncertain. In a crossover study, 116 women with menorrhagia [pictorial blood assessment chart (PBAC) score >100], negative gynaecological evaluation and abnormal laboratory haemostasis were randomly assigned to either intranasal desmopressin (IN‐DDAVP) or tranexamic acid (TA) therapy for two menstrual cycles. The subjects then crossed over to the second study drug for two additional cycles. Menstrual blood loss (MBL) was measured by PBAC scores at baseline and after each menstrual cycle. Quality of life (QOL) was assessed with four validated instruments. There was a statistically significant decrease in PBAC scores for both treatments. On average, the estimated decrease in the PBAC from baseline was −64·1 [95% confidence interval (CI) = −88·0, −40·3] for IN‐DDAVP and −105·7 (95% CI = −130·5, −81·0) for TA. The decrease in PBAC score was greater for TA than IN‐DDAVP (a difference of 41·6, P‐value = 0·0002, 95% CI = 19·6, 63·6). The test for treatment‐type effect was significant (P < 0·0001) suggesting a greater reduction in PBAC score with TA. Use of both IN‐DDAVP and TA improved QOL by all four instruments. We conclude that both medications reduced MBL and improved QOL among females with menorrhagia and abnormal laboratory haemostasis, but TA proved more effective.

A Benefit-Risk Review of Systemic Haemostatic Agents Part 2. In Excessive or Heavy Menstrual Bleeding

The first part of this benefit-risk review examined the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in major surgery. The second part of this review examines the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in the treatment of excessive or heavy menstrual bleeding, and provides individual benefit-risk profiles that may assist clinicians in selecting appropriate pharmacological therapy in this setting. Historically, surgery has played a dominant role in treatment; however, pharmacological therapy is increasingly popular, especially in women who wish to retain their fertility. When selecting the appropriate treatment, patient preference should be considered, as well as the benefits and risks associated with each agent. Recommended pharmacological therapies that are effective and generally well tolerated include the levonorgestrel-releasing intrauterine system and the oral agents tranexamic acid, NSAIDs (e.g. mefenamic acid) and combined estrogen/progestogen oral contraceptives. In patients with an underlying bleeding disorder (e.g. von Willebrand disease), an additional option is intranasal desmopressin.

The spectrum of haemostatic characteristics of women with unexplained menorrhagia

Summary.  While an estimated 13% of women with unexplained menorrhagia have von Willebrand disease (VWD), the frequency of other potential bleeding disorders has been uncertain. This study describes the relatively wide range of laboratory characteristics of women with unexplained menorrhagia and presents issues affecting diagnosis in this population. Women with pictorial blood assessment chart (PBAC) score >100 were identified at six U.S. sites and asked to remain drug free for 10 days prior to testing. Blood was collected on one of the first four menstrual cycle days and tested at a central laboratory for procoagulant factors, VWD and fibrinolytic factors. Platelet function testing by PFA‐100® (PFA) and platelet aggregation with ATP release (PAGG/ATPR) were performed locally using standardized methods. Among 232 subjects, a laboratory abnormality was found in 170 (73.3%), including 124 of 182 White (68.1%) and 34 of 37 Black (91.9%) subjects; 6.0% had VWD, 56.0% had abnormal PAGG/ATPR, 4.7% had a non‐VWD coagulation defect (NVCD) and 6.5% had an abnormal PFA only. AGG/ATPR was reduced in 58.9% of subjects, with multiple agonists in 28.6%, a single agonist in 6.1% and ristocetin alone in 24.2%. Frequencies of PAGG/ATPR defects varied by study site and race; frequencies of VWD and NVCD were similar. Laboratory abnormalities of haemostasis, especially platelet function defects, were common among women with unexplained menorrhagia across multiple U.S. sites. To what degree these abnormalities are clinically significant requires further study.

A benefit-risk review of systemic haemostatic agents - Part 1: In major surgery

The first part of this benefit-risk review examined the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in major surgery. The second part of this review examines the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in the treatment of excessive or heavy menstrual bleeding, and provides individual benefit-risk profiles that may assist clinicians in selecting appropriate pharmacological therapy in this setting. Historically, surgery has played a dominant role in treatment; however, pharmacological therapy is increasingly popular, especially in women who wish to retain their fertility. When selecting the appropriate treatment, patient preference should be considered, as well as the benefits and risks associated with each agent. Recommended pharmacological therapies that are effective and generally well tolerated include the levonorgestrel-releasing intrauterine system and the oral agents tranexamic acid, NSAIDs (e.g. mefenamic acid) and combined estrogen/ progestogen oral contraceptives. In patients with an underlying bleeding disorder (e.g. von Willebrand disease), an additional option is intranasal desmopressin.Systemic haemostatic agents play an important role in the management of blood loss during major surgery where significant blood loss is likely and their use has increased in recent times as a consequence of demand for blood products outstripping supply and the risks associated with transfusions. Their main application is as prophylaxis to reduce bleeding in major surgery, including cardiac and orthopaedic surgery and orthotopic liver transplantation. Aprotinin has been the predominant agent used in this setting; of the other antifibrinolytic agents that have been studied, tranexamic acid is the most effective and e-aminocaproic acid may also have a role. Eptacog alfa (recombinant factor VIIa) has also shown promise. Tranexamic acid, e-aminocaproic acid and eptacog alfa are generally well tolerated; however, when considering the methods to reduce or prevent blood loss intra- and postoperatively, the benefits of these agents need to be weighed against the risk of adverse events. Recently, concerns have been raised about the safety of aprotinin after an association between increased renal dysfunction and mortality was shown in retrospective observational studies and an increase in allcause mortality with aprotinin relative to tranexamic acid or e-aminocaproic acid was seen after a pre-planned periodic analysis of the large BART (Blood conservation using Antifibrinolytics in a Randomized Trial) study. The latter finding resulted in the trial being halted, and aprotinin has subsequently been withdrawn from the market pending detailed analysis of efficacy and safety results from the study. Part 1 of this benefit-risk review examines the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in surgery, and provides individual benefit-risk profiles that may assist clinicians in selecting appropriate pharmacological therapy in this setting.

Evaluation of a screening tool for bleeding disorders in a US multisite cohort of women with menorrhagia.

OBJECTIVE The purpose of this study was to determine the usefulness of a simple screening tool for bleeding disorders in a multisite population of women with menorrhagia. STUDY DESIGN Women with menorrhagia between the ages of 18 and 50 years from 6 geographically diverse US centers underwent hemostatic testing for bleeding disorders, complete blood cell count, and ferritin. A questionnaire that contained all elements of the 8-question screening tool was administered. Sensitivity of the screening tool, a screening tool with a pictorial blood assessment chart (PBAC) score of >185, and a screening tool with serum ferritin were calculated for hemostatic disorders. RESULTS Two hundred and seventeen women who were identified with a PBAC score of ≥100 participated in the study. The sensitivity of the screening tool was 89% for hemostatic defects, and sensitivity increased to 93% and 95% with a serum ferritin level of ≤20 ng/mL and a PBAC score of >185, respectively. CONCLUSION This study confirms the usefulness of a short screening tool for the stratification of women with menorrhagia for hemostatic evaluation.

von Willebrand's disease diagnosed after menorrhagia worsened from levonorgestrel intrauterine system.

BACKGROUND: Adult females with menorrhagia may have unrecognized mild von Willebrands disease. Most females with known von Willebrands disease report menorrhagia. CASE: A 38-year-old healthy female desired contraception. She described heavy menses lasting 8 days since menarche. History included uncomplicated vaginal deliveries. Physical examination was normal. The levonorgestrel intrauterine system was placed. Her menorrhagia then worsened to 14 successive days each month. Evaluation revealed mild von Willebrands disease. At 19 months of follow-up, she retained her levonorgestrel intrauterine system and avoided pregnancy. Her menses slowly improved to spotting for 8 days each month. CONCLUSION: Von Willebrands disease is a likely cause of menorrhagia that goes unrecognized as well as a potential cause for “failed” conservative treatment for menorrhagia. Understanding the cause of menorrhagia is an important aspect of evaluating this common symptom.

Hysterectomy versus expanded medical treatment for abnormal uterine bleeding: clinical outcomes in the medicine or surgery trial.

To the Editor: We read with interest the May 2004 article by Dr. Learman et al. This important study evaluates women with excessively heavy menses or menorrhagia who were dissatisfied with previous medroxyprogesterone acetate. Women were randomized to either hysterectomy or expanded medical therapy. Not surprisingly, hysterectomy cured excessively heavy menses. Of the 31 women randomized to hysterectomy, 28 received one, and the majority had improved quality of life at each interval of follow-up. On the other hand, of the 32 women who received medical therapy, approximately one third had undergone hysterectomy at 9 months. One half had undergone hysterectomy at 18 months. This represents significant “failed” medical therapy. If we accept that a hysterectomy cures menorrhagia, then why do women often sometimes fail medical therapy? One potential reason for failed medical therapy not considered in this study is the possibility of an underlying bleeding disorder. The most common inherited bleeding disorder is von Willebrand disease, with an overall prevalence of approximately 1%. Most women with known von Willebrand disease report menorrhagia, and nearly one fifth of these patients have undergone a hysterectomy for control of menorrhagia. There is growing evidence that women with menorrhagia may have an undiagnosed form of von Willebrand disease. In 2 landmark studies evaluating objectively verified menorrhagia, between 13% and 20% of women had von Willebrand disease. The gynecologist must consider the possibility of von Willebrand disease in a woman who complains of excessively heavy menses. Clinicians still only identify the cause of menorrhagia in approximately 50% of the cases. We support continued efforts to understanding why women have menorrhagia. Gynecologists reliably think of causes within the uterus. The problem of menorrhagia provides an opportunity to involve hematologists and consider reasons for bleeding that are outside the uterus. Andrea S. Lukes, MD, MHS Women’s Hemostasis and Thrombosis Clinic, Box 3463, Duke University Medical Center, Durham, NC 27710; e-mail: lukes001@mc.duke.edu

Randomized comparative trial of cervical block protocols for pain management during hysteroscopic removal of polyps and myomas

Purpose To evaluate the efficacy of two cervical block protocols for pain management during hysteroscopic removal of intrauterine polyps and myomas using the MyoSure® device. Patients and methods This was a randomized, comparative treatment trial conducted by five private Obstetrics and Gynecology practices in the USA. Forty premenopausal women aged 18 years and older were randomized to receive either a combination para/intracervical block protocol of 37 cc local anesthetic administered at six injections sites in association with the application of topic 1% lidocaine gel, or an intracervical block protocol of 22 cc local anesthetic administered at three injections sites without topical anesthetic, for pain management during hysteroscopic removal of intrauterine polyps and/or a single type 0 or type 1 submucosal myoma ≤3 cm. The main outcomes were a composite measure of procedure-related pain and pain during the postoperative recovery period, assessed by the Wong-Baker Faces Rating Scale (0= no pain to 10= maximum pain). The lesion characteristics, procedure time, and adverse events were summarized. Results A total of 17 polyps and eight myomas were removed in the para/intracervical block group, with diameters of 1.3±0.5 cm and 1.8±0.8 cm, respectively. In the intracervical block group, 25 polyps with a mean diameter of 1.2±0.7 cm and 7 myomas with a mean diameter of 1.9±0.9 cm were removed. The mean tissue resection time was 1.2±2.0 minutes and 1.2±1.4 minutes for the para/intracervical and intracervical block groups, respectively. The mean composite procedure-related pain score was low for both cervical block protocols, 1.3±1.4 in the para/intracervical block group vs 2.1±1.5 in the intracervical block group. During the postoperative recovery period, the mean pain scores were 0.3±0.7 vs 1.2±1.7 for the para/intracervical and intracervical block groups, respectively. There were no serious adverse events. Conclusion The MyoSure procedure for removal of polyps and myomas was well tolerated, with low pain scores reported for both the para/intracervical and intracervical block protocols.