Predictors of response for elagolix with add-back therapy in women with heavy menstrual bleeding associated with uterine fibroids.

BACKGROUND: Uterine fibroids are one of the most common neoplasms found among women globally, with a prevalence of approximately 11 million women in the United States alone. The morbidity of this common disease is significant because it is the leading cause of hysterectomy and causes significant functional impairment for women of reproductive age. Factors including age, body mass index, race, ethnicity, menstrual blood loss, fibroid location, and uterine and fibroid volume influence the incidence of fibroids and severity of symptoms. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that competitively inhibits pituitary gonadotropin-releasing hormone receptor activity and suppresses the release of gonadotropins from the pituitary gland, resulting in dose-dependent suppression of ovarian sex hormones, follicular growth, and ovulation. In Elaris Uterine Fibroids 1 and Uterine Fibroids 2, 2 replicate multicenter, double-blind, randomized, placebo-controlled, phase 3 studies, treatment of premenopausal women with elagolix with hormonal add-back therapy demonstrated reduction in heavy menstrual bleeding associated with uterine fibroids. OBJECTIVE: This analysis aimed to evaluate the safety and efficacy of elagolix (300 mg twice a day) with add-back therapy (1 mg estradiol/0.5 mg norethindrone acetate once a day) in reducing heavy menstrual bleeding associated with uterine fibroids in various subgroups of women over 6 months of treatment. STUDY DESIGN: Data were pooled from Elaris Uterine Fibroid-1 and Uterine Fibroid-2 studies, which evaluated premenopausal women (18-51 years) with heavy menstrual bleeding (>80 mL menstrual blood loss per cycle, alkaline hematin methodology) and ultrasound-confirmed uterine fibroid diagnosis. Subgroups analyzed included age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume (largest fibroid identified by ultrasound). The primary endpoint was the proportion of women with <80 mL menstrual blood loss during the final month and ≥50% menstrual blood loss reduction from baseline to final month. Secondary and other efficacy endpoints included mean change in menstrual blood loss from baseline to final month, amenorrhea, symptom severity, and health-related quality of life. Adverse events and other safety endpoints were monitored. RESULTS: The overall pooled Elaris Uterine Fibroid-1 and Uterine Fibroid-2 population was typical of women with fibroids, with a mean age of 42.4 (standard deviation, 5.4) years and a mean body mass index of 33.6 (standard deviation, 7.3) kg/m2 and 67.6% of participants being black or African American women. A wide range of baseline uterine and fibroid volumes and menstrual blood loss were also represented in the overall pooled study population. In all subgroups, the proportion of responders to the primary endpoint, mean change in menstrual blood loss, amenorrhea, reduction in symptom severity, and improvement in health-related quality of life were clinically meaningfully greater for women who received elagolix with add-back therapy than those who received placebo and consistent with the overall pooled study population for the primary endpoint (72.2% vs 9.3%), mean change in menstrual blood loss (-172.5 mL vs -0.8 mL), amenorrhea (50.4% vs 4.5%), symptom severity (-37.1 vs -9.2), and health-related quality of life score (39.9 vs 8.9). Adverse events by subgroup were consistent with the overall pooled study population. CONCLUSION: Elagolix with hormonal add-back therapy was effective in reducing heavy menstrual bleeding associated with uterine fibroids independent of age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume.

Efficacy and safety of elagolix with add-back therapy in women with uterine fibroids and coexisting adenomyosis.

OBJECTIVE: To determine if coexisting adenomyosis limits the efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy in reducing heavy menstrual bleeding in women with uterine fibroids. DESIGN: Pooled analysis of two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids [UF]-1 and UF-2). SETTING: A total of 153 gynecological clinical care settings in the United States and Canada. PATIENTS: Premenopausal women (18-51 years) with >80 mL of menstrual blood loss (MBL)/cycle and uterine fibroids with and without coexisting adenomyosis diagnosed by ultrasound and/or magnetic resonance imaging at baseline. INTERVENTIONS: Participants were randomized 1:1:2 to placebo, elagolix 300 mg twice daily alone, or elagolix 300 mg twice daily with estradiol 1 mg/norethindrone acetate 0.5 mg once daily. MAIN OUTCOME MEASURES: The primary endpoint was the proportion of women who had <80 mL of MBL during the final month and ≥50% reduction in MBL from baseline to the final month. Adverse events were monitored. RESULTS: Of 786 women treated across the two trials, 16% (126 women) had coexisting adenomyosis. Among this subset, a significantly greater proportion of women who received elagolix with add-back therapy (77.1% [95% confidence interval, 66.2, 88.0]) met both primary endpoint criteria compared with women who received placebo (12.2% [95% confidence interval, 1.0, 23.4]). Adverse events most frequently reported in the elagolix with add-back adenomyosis subset were hot flushes (18.3%), nausea (11.7%), and night sweats (8.3%). CONCLUSIONS: Elagolix with add-back therapy significantly reduced heavy menstrual bleeding in women with uterine fibroids and coexisting adenomyosis, suggesting that elagolix efficacy was not adversely affected by the presence of adenomyosis (Elaris UF-1 and UF-2 Clinical-Trials.gov numbers, NCT02654054 and NCT02691494).

Elagolix Treatment for Up to 12 Months in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas.

OBJECTIVE: To investigate the safety and efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy for up to 12 months in women with heavy menstrual bleeding associated with uterine leiomyomas. METHODS: Elaris UF-EXTEND was a phase 3 extension study that evaluated an additional 6 months (up to 12 months total) of elagolix 300 mg twice daily with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg once daily) in women who completed an initial 6 months of the same treatment in one of two preceding phase 3 studies. The primary endpoint was the percentage of women with both less than 80 mL menstrual blood loss during final month and a 50% or greater reduction in menstrual blood loss from baseline to final month. Safety evaluations included adverse events and bone mineral density changes. The planned sample size of UF-EXTEND was based on estimated rollover and discontinuation rates in the two preceding studies. RESULTS: From September 2016 to March 2019, 433 women were enrolled in UF-EXTEND. Of these women, 218 received up to 12 months of elagolix with add-back therapy; the mean±SD age of this group was 42.4±5.4 years and 67.3% were black. The percentage of women who met the primary endpoint in this elagolix with add-back group was 87.9% (95% CI [83.4-92.3]). The most frequently reported adverse events with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Mean percent decreases in bone mineral density from baseline to extension month 6 were significantly less with elagolix plus add-back therapy than with elagolix alone {between-group difference in lumbar spine: -3.3 (95% CI [-4.1 to -2.5])}. CONCLUSION: Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss in women with uterine leiomyomas, with the addition of add-back therapy attenuating the hypoestrogenic effects of elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with addback therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02925494. FUNDING SOURCE: AbbVie Inc funded this study.

Spontaneous Unilateral Tubal Twin Ectopic Pregnancy.

Background: Unilateral tubal twin pregnancies occur in approximately 1 of every 125,000 spontaneous pregnancies. Because of the paucity of data, little guidance for the appropriate management of a twin tubal ectopic pregnancy is available. Case Report: A 40-year-old female presented to the emergency department (ED) with a 2-day history of vaginal bleeding associated with lower abdominal pain. The patient was hemodynamically stable with signs of an acute abdomen. Pelvic examination elicited clinical findings consistent with potential ectopic pregnancy. Urine pregnancy test in the ED was positive. Serum beta-human chorionic gonadotropin was 23,359 mIU/mL, and transvaginal ultrasound showed findings concerning for a twin ectopic pregnancy. Diagnostic laparoscopy with right salpingostomy was successful, and the patient had an uncomplicated postoperative course. Conclusion: Healthcare providers should have a high index of clinical suspicion for ectopic pregnancies. Unilateral tubal twin ectopic pregnancies, while rare, can be adequately diagnosed with transvaginal ultrasound. Laparoscopic salpingostomy provides conservative and successful treatment of unilateral tubal twin gestation with short recovery time. Medical treatment with methotrexate has not been adequately studied in this clinical scenario, but further exploration of this management modality should be considered.

Using the Flipped Classroom to Bridge the Gap to Generation Y.

BACKGROUND: The flipped classroom is a student-centered approach to learning that increases active learning for the student compared to traditional classroom-based instruction. In the flipped classroom model, students are first exposed to the learning material through didactics outside of the classroom, usually in the form of written material, voice-over lectures, or videos. During the formal teaching time, an instructor facilitates student-driven discussion of the material via case scenarios, allowing for complex problem solving, peer interaction, and a deep understanding of the concepts. A successful flipped classroom should have three goals: (1) allow the students to become critical thinkers, (2) fully engage students and instructors, and (3) stimulate the development of a deep understanding of the material. The flipped classroom model includes teaching and learning methods that can appeal to all four generations in the academic environment. METHODS: During the 2015 academic year, we implemented the flipped classroom in the obstetrics and gynecology clerkship for the Ochsner Clinical School in New Orleans, LA. Voice-over presentations of the lectures that had been given to students in prior years were recorded and made available to the students through an online classroom. Weekly problem-based learning sessions matched to the subjects of the traditional lectures were held, and the faculty who had previously presented the information in the traditional lecture format facilitated the problem-based learning sessions. The knowledge base of students was evaluated at the end of the rotation via a multiple-choice question examination and the Objective Structured Clinical Examination (OSCE) as had been done in previous years. We compared demographic information and examination scores for traditional teaching and flipped classroom groups of students. The traditional teaching group consisted of students from Rotation 2 and Rotation 3 of the 2014 academic year who received traditional classroom-based instruction. The flipped classroom group consisted of students from Rotation 2 and Rotation 3 of the 2015 academic year who received formal didactics via voice-over presentation and had the weekly problem-based learning sessions. RESULTS: When comparing the students taught by traditional methods to those taught in the flipped classroom model, we saw a statistically significant increase in test scores on the multiple-choice question examination in both the obstetrics and gynecology sections in Rotation 2. While the average score for the flipped classroom group increased in Rotation 3 on the obstetrics section of the multiple-choice question examination, the difference was not statistically significant. Unexpectedly, the average score on the gynecology portion of the multiple-choice question examination decreased among the flipped classroom group compared to the traditional teaching group, and this decrease was statistically significant. For both the obstetrics and the gynecology portions of the OSCE, we saw statistically significant increases in the scores for the flipped classroom group in both Rotation 2 and Rotation 3 compared to the traditional teaching group. With the exception of the gynecology portion of the multiple-choice question examination in Rotation 3, we saw improvement in scores after the implementation of the flipped classroom. CONCLUSION: The flipped classroom is a feasible and useful alternative to the traditional classroom. It is a method that embraces Generation Y's need for active learning in a group setting while maintaining a traditional classroom method for introducing the information. Active learning increases student engagement and can lead to improved retention of material as demonstrated on standard examinations.

A Review of Herbal and Pharmaceutical Galactagogues for Breast-Feeding.

BACKGROUND: Therapeutic approaches to addressing insufficient lactation are available but remain poorly understood. Current trends in maternal health, such as increasing rates of obesity, delayed age at childbearing, and high rates of cesarean section, may be associated with physiological challenges for lactation that cannot be managed by counseling alone. Women who have not had success with counseling alone, including adoptive mothers seeking to induce lactation, may use galactagogues (pharmaceutical and herbal compounds used to increase lactation). We present a review of selected studies of galactagogues and data indicating popular demand for such products. METHODS: A systematic search was conducted for published studies on the use of galactagogues for breast-feeding. The following databases were searched: MEDLINE (PubMed), EBSCO (Academic Search Complete), and EMBASE. The search was conducted between July 15, 2015, and August 18, 2015; only English language articles were included, and we imposed no restrictions on publication date. Two authors independently reviewed the studies and extracted data. RESULTS: Blinded, placebo-controlled clinical trials of 2 pharmaceutical galactagogues (domperidone and metoclopramide) and 5 popular herbal galactagogues (shatavari, fenugreek, silymarin, garlic, and malunggay) were identified. All of the studies identified for domperidone showed a significant difference in milk production between the treatment and placebo groups. Of the 6 trials of metoclopramide, only 1 study showed a significant difference in milk production compared to placebo. Results of the clinical trials on herbal galactagogues were mixed. Our review of the evidence for the efficacy of popular pharmaceutical and herbal galactagogues revealed a dearth of high-quality clinical trials and mixed results. CONCLUSION: Health providers face the challenge of prescribing or recommending galactagogues without the benefit of robust evidence. Given the suboptimal rates of exclusive breast-feeding worldwide and the availability and demand for medical and herbal lactation therapies, controlled trials and analyses investigating these medicines are urgently warranted.

Assessment of the quality and content of national and international guidelines on hypertensive disorders of pregnancy using the AGREE II instrument.

OBJECTIVES: High-quality evidence-based clinical practice guidelines can guide diagnosis and treatment to optimise outcomes. The purpose of this study was to evaluate the quality and content of national and international guidelines on hypertensive disorders of pregnancy. DATA SOURCES: The MEDLINE database, the National Guideline Clearinghouse and several international databases were searched for appropriate guidelines from the past 10 years. STUDY APPRAISAL AND SYNTHESIS METHODS: Six guidelines met inclusion and exclusion criteria and were evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. RESULTS: A total of 695 records were identified and screened by two authors. Disorder definitions, classifications, preventive measures and treatment recommendations were evaluated and compared among guidelines. AGREE II results varied widely across domains and categories. Only two guidelines received consistently high ratings across domains and few demonstrated a high level of methodological rigour. Recommendations regarding classification and treatment were similar across guidelines, while assessment of preventive measures varied widely. CONCLUSIONS: Clinical practice guidelines for hypertensive disorders of pregnancy vary significantly in quality and with respect to assessment of preventive measures.