James H. Pickar

Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile

OBJECTIVE To evaluate the effects of a tissue-selective estrogen complex (TSEC) composed of bazedoxifene/conjugated estrogens (BZA/CE) on menopausal symptoms, metabolic parameters, and overall safety. DESIGN Multicenter, double-blind, placebo- and active-controlled phase 3 trial (Selective estrogens, Menopause, And Response to Therapy [SMART]-1). SETTING Outpatient clinical. PATIENT(S) Healthy, postmenopausal women (n = 3,397) age 40 to 75 with an intact uterus. INTERVENTION(S) Single tablets of BZA (10, 20, or 40 mg), each with CE (0.625 or 0.45 mg); raloxifene 60 mg; or placebo taken daily for 2 years. MAIN OUTCOME MEASURE(S) Hot flushes, breast pain, vaginal atrophy, metabolic parameters, and adverse events. RESULT(S) BZA (20 mg)/CE (0.625 or 0.45 mg) significantly reduced the frequency and severity of hot flushes and improved measures of vaginal atrophy compared with placebo. At week 12, the daily number of hot flushes decreased by 51.7% to 85.7% with all BZA/CE doses vs. 17.1% for placebo. BZA/CE improved lipid parameters and homocysteine levels, did not significantly change carbohydrate metabolism, and had only minor effects on some coagulation parameters. The incidences of breast pain and adverse events were similar between BZA/CE and placebo. CONCLUSION The TSEC composed of BZA (20 mg)/CE (0.625 or 0.45 mg) is an effective and safe treatment for menopausal symptoms.

Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women

OBJECTIVE To evaluate the efficacy of the tissue-selective estrogen complex, bazedoxifene/conjugated estrogens (BZA/CE), for postmenopausal osteoporosis prevention. DESIGN Multicenter, randomized, double-blind, placebo- and active-controlled, phase 3 trial (Selective estrogen Menopause And Response to Therapy [SMART]-1). SETTING Outpatient clinical study. PATIENT(S) Women (n = 3,397) more than 5 years and 1-5 years postmenopause were enrolled in the Osteoporosis Prevention I and II Substudies, respectively. INTERVENTION(S) Single tablets of BZA (10, 20, or 40 mg) each with CE (0.625 or 0.45 mg), raloxifene (60 mg), or a placebo taken daily for 2 years. MAIN OUTCOME MEASURE(S) The primary outcome for both substudies was change in bone mineral density of the lumbar spine; bone mineral density was also measured at the hip. RESULT(S) In both substudies, bone mineral density increased significantly more with all BZA/CE doses compared with placebo at the lumbar spine and total hip, and for most BZA/CE doses compared with raloxifene at the lumbar spine. Osteocalcin and N-telopeptide significantly decreased with all BZA/CE doses vs. placebo and most BZA/CE doses vs. raloxifene. CONCLUSION(S) BZA/CE combinations decreased bone turnover and bone loss in postmenopausal women at increased risk for osteoporosis.

Menopausal symptoms in older women and the effects of treatment with hormone therapy.

OBJECTIVE In some women, hot flashes and other symptoms attributed to menopause persist for many years after the cessation of menses. The frequency and severity of such symptoms and response to hormone therapy in older women have not been well documented. METHODS We used data from the Heart and Estrogen/Progestin Replacement Study, a blinded, clinical trial among 2763 women with documented coronary disease and a uterus who were randomized to receive either conjugated estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg in one tablet or placebo. Participants were queried at baseline and annually regarding menopausal symptoms. Breast symptoms were self‐reported, and uterine bleeding was recorded on a daily diary. RESULTS Symptoms associated with menopause were relatively common among Heart and Estrogen/Progestin Replacement Study participants, whose average age was 67 years and who averaged 18 years since menopause. At baseline, 16% of women reported frequent hot flashes, 26% vaginal dryness, 10% genital irritation, 55% trouble sleeping, and 53% early awakening. Women assigned to hormone therapy reported less frequent hot flashes, vaginal dryness, and trouble sleeping compared with women assigned to placebo, but more frequent vaginal discharge, genital irritation, uterine bleeding, and breast symptoms. The reporting of breast symptoms among women in the hormone group decreased from 40% at 1 year to 13% by the 4th year. Uterine bleeding was reported by 31% and spotting by an additional 33% of women in the hormone group during the 1st year of treatment; by the 4th year, these proportions had fallen to 11% and 20%, respectively. CONCLUSION Symptoms typically attributed to menopause are common in elderly women. Postmenopausal hormone therapy reduces hot flashes, trouble sleeping, and vaginal dryness, but at standard doses in elderly women is associated with vaginal discharge, genital irritation, uterine bleeding, and breast symptoms.

Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy

OBJECTIVE To evaluate the endometrial safety of a tissue selective estrogen complex (TSEC; pairing of a selective estrogen receptor modulator [SERM] with estrogens) composed of bazedoxifene/conjugated estrogens (BZA/CE) in postmenopausal women. DESIGN Randomized, double-blind, multicenter, placebo- and active-controlled, phase 3 study (Selective estrogen Menopause And Response to Therapy [SMART]-1). SETTING Outpatient clinical. PATIENT(S) Healthy, postmenopausal women (n = 3,397) age 40-75 with an intact uterus. INTERVENTION(S) Single tablets of BZA (10, 20, or 40 mg) combined with CE (0.625 or 0.45 mg); raloxifene (60 mg); or placebo daily for 2 years. MAIN OUTCOME MEASURE(S) Incidence of endometrial hyperplasia at 12 months in the efficacy evaluable population. RESULT(S) Treatment with BZA (20 or 40 mg)/CE (0.625 or 0.45 mg) was associated with low rates (<1%) of endometrial hyperplasia that were not significantly different from those reported with placebo over 24 months. Endometrial thickness with BZA (20 or 40 mg)/CE (0.625 or 0.45 mg) was not significantly different from that with placebo. CONCLUSION(S) When combined with CE (0.625 mg or 0.45 mg), BZA (20 mg) was the lowest effective dose that prevented endometrial hyperplasia over 2 years of study, creating the possibility for a new, progestin-free menopausal therapy.

Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial

Objective: The aim of this study was to assess the safety and efficacy of bazedoxifene (BZA)/conjugated estrogens (CE) treating moderate to severe vasomotor symptoms in the Selective Estrogen Menopause and Response to Therapy 2 trial. Methods: This was an outpatient, multicenter, double-blind, randomized, placebo-controlled, phase 3 study conducted in the United States. Healthy postmenopausal women (N = 332; aged 40-65 y) with moderate to severe hot flushes (≥7/d or 50/wk) were randomized to BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, or placebo once daily for 12 weeks. Changes from baseline in the average daily number of moderate and severe hot flushes and daily severity score were assessed at weeks 4 and 12; adverse events were recorded. Results: BZA/CE significantly reduced the number and severity of hot flushes at weeks 4 and 12 (P < 0.001). At week 12, BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg reduced hot flushes from baseline by 74% (10.3 hot flushes [baseline] vs 2.8 [week 12]) and 80% (10.4 vs 2.4), respectively, compared with 51% (10.5 vs 5.4) for placebo. More participants at week 12 had at least a 75% decrease in hot flushes with BZA 20 mg/CE 0.45 mg (61%) and BZA 20 mg/CE 0.625 mg (73%) versus placebo (27%; P < 0.001). The safety profile was similar between BZA/CE and placebo, and no unexpected safety findings were reported. Conclusions: BZA 20 mg paired with CE 0.45 or 0.625 mg is effective, with short-term safety, for treating vasomotor symptoms in postmenopausal women.

Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women.

OBJECTIVE: To assess the endometrial effects of bazedoxifene acetate in healthy postmenopausal women. METHODS: The endometrial effects of bazedoxifene 2.5, 5.0, 10, 20, 30, and 40 mg/d were evaluated in a 2-part, 6-month, double-blind, randomized, active- and placebo-controlled study among a total of 497 healthy postmenopausal women. Conjugated estrogens (0.625 mg)/medroxyprogesterone acetate (2.5 mg) served as the active control. Patients underwent transvaginal ultrasonography to measure double-wall endometrial thickness and endometrial biopsy at baseline and at 6 months of treatment. The incidence of amenorrhea was assessed from self-reported daily diaries. RESULTS: Bazedoxifene treatment at 2.5–20 mg/d resulted in mean changes from baseline in endometrial thickness that were no different than those seen with placebo treatment. Changes in endometrial thickness for the bazedoxifene 30 and 40 mg groups were significantly smaller than for placebo. The change from baseline in endometrial thickness was significantly and inversely related to dose (P ≤ .001). None of the endometrial biopsy specimens demonstrated endometrial hyperplasia. Subjects in the 2.5–20 mg bazedoxifene groups experienced amenorrhea rates of 57–74%, comparable with the 59% seen in placebo. Over 90% of subjects treated with bazedoxifene 30 or 40 mg/d were amenorrheic at 6 months. CONCLUSION: Bazedoxifene at dosages up to 40 mg/d was well tolerated and did not stimulate the endometrium. The significant decreases in endometrial thickness and decreased uterine bleeding observed with doses of 30 and 40 mg/d as compared with placebo suggest endometrial antagonism, representing a novel characteristic not previously associated with any selective estrogen receptor modulator. LEVEL OF EVIDENCE: I

The Positive Predictive Value of Cervical Smears in Previously Screened Postmenopausal Women: The Heart and Estrogen/progestin Replacement Study (HERS)

In the United States, there is no consensus about screening postmenopausal women for cervical neoplasia. Current recommendations by professional groups range from discontinuing screening at 65 years of age in previously screened women with a history of normal cervical smears (1) to lifelong screening at less frequent, but undefined, intervals (2). Since women spend one third of their lives in the postmenopausal period, the issue of cervical screening has great public health importance. Although the benefits of screening are clear in unscreened women, benefits of frequent repeated screening in postmenopausal women with a history of normal cytologic results in terms of true-positive test results have not been well defined. Recent studies have demonstrated a low incidence of important cervical disease in previously screened women older than 50 years of age (3, 4). Since the likelihood that a positive test result is false positive increases as disease incidence decreases, cervical smears may have a poor positive predictive value in previously screened postmenopausal women. These false-positive smears are related to the risks associated with screening because they lead to needless patient concern, follow-up diagnostic testing, and invasive procedures. Because few previous studies have comprehensively defined these risks, many women have had limited information on which to base an informed decision about screening. Data are conflicting regarding the effect of exogenous hormone therapy on cervical cytologic conditions in postmenopausal women. A report from a National Cancer Institutesponsored workshop advocates therapeutic use of topical estrogen creams in postmenopausal women with atypical squamous cells of undetermined significance (ASCUS) (5) on the basis of supporting evidence suggesting that the treatment may ameliorate atrophy that can be mistaken for cytologic atypia (6). No controlled trials of this intervention have been performed. That oral hormonal replacement therapy may prevent cervical smears interpreted as ASCUS is biologically plausible; a recent observational study, however, reported that women older than 55 years of age with ASCUS were three times more likely to be users of hormone replacement therapy than women of a similar age with normal cervical cytologic characteristics (7). Because the study was observational, causation could not be determined. Since ASCUS is the most common cytologic abnormality in postmenopausal women, occurring in up to 3.5% of all cervical smears and accounting for more than 70% of cytologic abnormalities in women older than 50 years of age (8), any effect of hormone replacement therapy on cytologic abnormalities, regardless of the direction of effect, would be substantial on a population level. The main objective of this study was to determine the predictive value of an abnormal cervical smear in postmenopausal women with recent normal smears. Specifically, we determined the risk for false-positive test results compared with that for true-positive test results. Using data from a randomized, controlled trial of oral estrogen plus progestin, we also determined the independent effect of oral estrogen plus progestin on development of cytologic abnormalities. Methods The Heart and Estrogen/progestin Replacement Study We used cervical smears collected prospectively during the Heart and Estrogen/progestin Replacement Study (HERS). This study was a randomized, double-blind, placebo-controlled trial of oral estrogen plus progestin in postmenopausal women with a uterus and coronary artery disease. Details of the study have been published elsewhere (9). Briefly, screening interviews were performed on 68 561 women, and 2763 women younger than 80 years of age at 20 participating clinical centers were randomly assigned to receive hormones or placebo and were followed for an average of 4.1 years. As part of the study protocol, cervical smears were performed at annual visits to the study gynecologists. All smears were evaluated at the same central pathology laboratory (Empire Pathology Medical Group, Garden Grove, California). Smear results were reported by using the Bethesda system. Participants We identified women who had normal cervical smears at study entry and an abnormal cervical smear at the first or second annual visit. We focused on smears performed only in the first 2 years of the 4-year study to allow at least 2 years for a final diagnosis to be determined. To avoid counting a woman with several abnormal smears more than once, we censored women with abnormal smears at year 1. We defined abnormal as ASCUS, atypical glandular cells of undetermined significance (AGCUS), low-grade squamous intraepithelial lesion, or high-grade squamous intraepithelial lesion. Data Collection We obtained information on the follow-up of abnormalities from two sources: a questionnaire sent to clinical personnel at each study site and data collected as part of the trial protocol. We used two sources for data abstraction because the main study protocol did not provide a standardized way to follow-up, encode, or report outcomes of abnormal smears. The questionnaire requested specific information on all procedures and therapies that were performed within 2 years of the abnormal smear and were a direct result of the smear abnormality. The HERS database included results of all study cervical smears after the abnormal smear and descriptions of diagnostic and therapeutic cervical procedures performed to evaluate abnormal smears. All study participants gave informed consent to have medical records reviewed. Personnel at clinical sites reviewed medical records. In cases in which the participant received follow-up care from a physician not related to the study, attempts were made to obtain information from the outside physician. If participants underwent any additional diagnostic tests, such as colposcopy, endocervical curettage, or endometrial biopsy (for the evaluation of AGCUS), we obtained copies of original test results and pathology reports confirming histologic diagnoses. We determined the date and type of initial procedure performed in evaluation of the abnormal smear and enumerated all procedures secondary to the abnormal smear, including repeated smears. We classified cervical smears as extra if they were performed within 9 months of an abnormal smear and were not performed as part of the annual evaluation. We included endometrial biopsies only if supporting documentation indicated that the smear result was the primary reason for the test. In addition, we enumerated additional procedures and therapies, such as cone biopsies, loop electrosurgical excision procedures, and hysterectomies. We classified the final histologic status of each woman in one of four diagnostic categories: normal (a nondysplastic process, such as atrophy, cervicitis, or inflammation), low-grade histologic condition (human papillomavirus effect or grade I cervical intraepithelial neoplasia), high-grade histologic condition (cervical intraepithelial neoplasia, grades II to III, or vaginal intraepithelial neoplasia, grades II to III), and unknown. For each cytologic abnormality, we considered the final histologic diagnosis to be normal only if participants met the criteria outlined in Table 1. We considered all other participants, including those who did not meet the criteria for a normal diagnosis and those whose results could not be located, to have unknown final histologic diagnoses. We considered high-grade cervical intraepithelial neoplasia (grades II to III) and invasive cervical cancer to be the most important histologic outcomes because identification and treatment of these lesions are the goals of cervical cytologic screening. Table 1. Criteria for Defining Final Status as Normal in 110 Women with Abnormal Cytologic Results at the First or Second Annual Visit Study participants were randomly assigned to receive one tablet of conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo. Randomization was done by using computer-generated random numbers at each clinical center. The placebo pill was identical in appearance to the active medication. Tablet composition and the accuracy of the blinded medication assignment were confirmed by chemical analysis. Cytotechnologists and pathologists at the laboratory evaluating the cervical smears were blinded to the study group assignment. Demographic data, including information on risk factors for cervical neoplasia (for example, current smoking and parity), were collected at two baseline clinic visits. In addition, we distributed a pretested questionnaire that included information about traditional risk factors for cervical neoplasia, such as age at first intercourse, previous screening frequency, previous cervical smear abnormalities, recency of sexual activity, and history of sexually transmitted infections. Seventeen of 20 sites, involving 2417 enrollees, agreed to distribute the questionnaire, and 1603 questionnaires (66.3%) were returned. Questionnaires were designed to be self-administered, although clinical personnel at some sites assisted participants in completing the forms. We collected this information to provide an overview of the risk status of the HERS sample, which allowed us to address the issue of generalizability of the results to other groups of women. Statistical Analysis We determined the incidence rates of cervical smear abnormalities for each year by dividing the number of women with abnormal smears by the number of women screened. We computed incidence rates for the first 2 years of the study by dividing the total number of women with abnormal smears at the end of the second year by the number of person-years of observation. We calculated the positive predictive value of each smear abnormality by dividing the number of women with high-grade cervical histologic conditions (defined as grade II cervical intraepithelial neoplasia

Bazedoxifene/conjugated estrogens and quality of life in postmenopausal women

OBJECTIVE To assess the effects of bazedoxifene/conjugated estrogens (BZA/CE) on sleep parameters and health-related quality of life (HR-QOL). METHODS This was a 12-week, multicenter, double-blind, placebo-controlled phase 3 study. Postmenopausal women with an intact uterus and experiencing >or=7 moderate-to-severe hot flushes daily were randomized to BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, or placebo. In these secondary efficacy analyses, the Medical Outcomes Study (MOS) sleep scale and Menopause-Specific Quality of Life (MENQOL) questionnaires and the Menopause Symptoms Treatment Satisfaction Questionnaire (MS-TSQ) evaluated measures of sleep, menopausal symptoms, and satisfaction with treatment, respectively. RESULTS A total of 318 subjects (mean age, 53.4 years) received >or=1 dose of study drug. At Week 12, BZA 20 mg/CE 0.45 and 0.625 mg showed significant improvements over placebo in the MOS sleep scale for time to fall asleep, sleep adequacy, sleep disturbance, and sleep problems indexes I and II (P<0.001). A reduction in hot flush frequency was significantly associated with improvement in sleep parameters (P<0.05) based on linear regression and responder analyses. Both BZA/CE doses showed significantly greater improvements over placebo in vasomotor function and total MENQOL score (P<0.001). Results of the MS-TSQ showed that subjects treated with BZA/CE versus placebo reported significantly greater overall satisfaction with treatment (P<0.05), as well as greater satisfaction with sleep quality, ability to control hot flushes during the day and night, effect on mood/emotions, and tolerability. CONCLUSION Symptomatic postmenopausal women treated with BZA/CE experienced significant improvements in sleep parameters and overall HR-QOL.

Effect of Estrogen plus Progestin on Risk for Biliary Tract Surgery in Postmenopausal Women with Coronary Artery Disease: The Heart and Estrogen/progestin Replacement Study

Data from the Third National Health and Nutrition Examination Survey (1) indicate that 11% of U.S. women have a history of clinical gallbladder diseasethat is, either previous cholecystectomy or self-reported history of gallstones. Factors associated with gallbladder disease, at least in some studies, include older age, female sex, white ethnicity/race, obesity, rapid weight loss, and, among women, greater parity, use of oral estrogencontaining contraceptives, and postmenopausal estrogen therapy (2). These associations, in general, have been based on observational data and may partly reflect the effects of ascertainment and recall bias, as well as confounding. While some observational studies suggest that estrogens increase the risk for gallbladder disease by as much as twofold to fourfold (3), such an association has not been reported consistently (2, 3). The effect of combined estrogen plus progestin therapy has been less well studied, and no recent clinical trial data exist on the relation of such therapy to the risk for biliary tract surgery among postmenopausal women. To determine whether estrogen plus progestin therapy is associated with the risk for biliary tract surgery among postmenopausal women, we analyzed data from the Heart and Estrogen/progestin Replacement Study (HERS), the first large randomized, double-blind trial of estrogen plus progestin therapy for the secondary prevention of coronary heart disease (4). Gallbladder disease events, including biliary tract surgery, were among several prespecified secondary outcomes of interest. Methods Participants Between 1 February 1993 and 1 October 1994, 2763 postmenopausal women with coronary artery disease were recruited from 20 clinical centers across the United States for participation in HERS, a randomized, double-blind study of the effect of combined, continuous estrogenprogestin therapy (conjugated equine estrogens, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d) on recurrent coronary heart disease events. Baseline data, which were collected at the visits for initial screening and random allocation, included demographic characteristics, medical history, risk factors for coronary heart disease, physical examination, and laboratory data. Women were not eligible to enroll in HERS if they had used any estrogen or female hormones within the previous 3 months, including pills, suppositories, injections, vaginal creams, or transdermal patches. We excluded 510 women from these analyses who reported at enrollment a history of surgical gallbladder removal. We did include, however, 123 women with a self-reported history of gallstones who had not undergone cholecystectomy. After these exclusions, data from 2253 participants were available for analysis. Measurements Baseline data included participant age, years of education, number of pregnancies, ethnicity/race (white, African American, or other), past use of postmenopausal estrogen therapy, history of cigarette smoking, history of alcohol consumption, and diabetes mellitus. Data were also obtained on use of lipid-lowering medications and antihypertensive medications, including thiazide diuretics. Participants who stated that they had smoked at least 100 cigarettes in their life were considered to have a history of smoking. Participants were asked, Has a doctor told you that you had diabetes, sugar diabetes, or high blood sugar? Those who answered yes were classified as having a history of diabetes. Women with a history of gestational diabetes only were classified as not having diabetes mellitus. Participants were weighed without shoes or outdoor clothing on a standard balance-beam scale to the nearest 0.1 kg. Height was measured to the nearest 0.1 cm by using the height rod of a standard beam scale or, where available, a wall-mounted stadiometer. We calculated the body mass index as weight (kg)/height (m2). At baseline, year 1, and the end of the study, serum lipid and lipoprotein levels were obtained from all participants and were measured at the Johns Hopkins Lipoprotein Analytical Laboratory, Baltimore, Maryland, which is certified by the U.S. Centers for Disease Control and Prevention for the measurement of serum lipids and lipoproteins. Ascertainment of End Points Participants were determined to have incident gallbladder disease by physician adjudicators who were blinded to the randomization status [active hormone treatment or placebo]. Symptomatic nonsurgical biliary tract disease was defined as a hospital admission for acute cholecystitis, choledocholithiasis, or gallstone pancreatitis and was established on the basis of 1) reported symptoms in combination with elevated levels on liver function testing and gallstones with dilated biliary ducts on abdominal ultrasonography or 2) nuclear medicine scan diagnostic of acute gallbladder disease. Incident biliary tract surgery, which included cholecystectomy, sphincterotomy, or bile duct exploration, was established by review of operative reports and discharge summaries. All biliary tract surgeries were cholecystectomies with the exception of 12 sphincterotomies and 2 stent insertions. Nonsurgical and surgical gallbladder disease events were considered separate end points and are mutually exclusive. The main HERS results, reported in 1998 (4), were based on the near-final data available at that time. We present the updated and final results for incident biliary tract events (5). Statistical Analysis We used unpaired two-tailed t-tests to compare the age, level of education, number of pregnancies, body mass index, alcohol consumption, serum lipid level, and lipoprotein levels of the women randomly assigned to receive postmenopausal hormone therapy or placebo. Using chi-square tests, we compared the hormone therapy and placebo groups according to ethnicity/race, history of lipid-lowering medication use, prestudy postmenopausal estrogen use, thiazide diuretic use, cigarette smoking, ascorbic acid supplement use, history of gallbladder disease, and diabetes mellitus. The treatment groups were divided fairly equally with respect to baseline variables, except for statin use. To analyze the association between postmenopausal hormone therapy and incident gallbladder disease events, we used unadjusted and statin useadjusted proportional hazards models. All risk estimates were derived solely from proportional hazards models. We also estimated KaplanMeier curves for time to occurrence of biliary tract surgery, according to treatment assignment. The number of participants needed to be treated for a new case of biliary tract surgery to occur was calculated by using the incidence rates per person-year of observation. For predictor variables other than treatment assignment, we calculated the hazard ratio and 95% CI by using proportional hazards regression models to estimate the risk for incident biliary tract surgery. We used simple regression models that controlled only for treatment assignment; we also used multivariable regression models that included variables with a previously reported association with gallbladder disease. Our model-fitting methods relied primarily on biological criteria; we began by including factors previously reported to be associated with gallbladder disease. Although the risk for type I errors is always present when candidate predictors are many relative to the number of outcomes, our model-building process accounted for this possibility when we considered the statistical significance of the resulting multivariable model. Results were confirmed by using stepwise and backwards selection methods. We identified one statistically significant interaction between postmenopausal hormone treatment and smoking. Adjustment for this interaction did not substantially affect the hazard ratios for other variables entered in the multivariable models. We performed these analyses by using SAS software (6). A correlation between outcomes at each clinical center could potentially affect the SEs for the relative hazard estimates. Therefore, to control for such potential clustering by center, we used STATA software (7) to generate robust SEs for the proportional hazards models (8). Because site-specific practice patterns could confound the relation of statin use to biliary tract surgery, we also examined statistical models that included clinical center as a fixed effect. We calculated the number of participants needed to be treated to result in one additional biliary tract surgery by using the reciprocal of the absolute risk increase. However, because the 95% CI for the absolute risk increase included zero, the CI for the number needed to treat for harm (NNTH) included . We use a method described by Altman (9) to present the CI in these circumstances. The CI around the NNTH will therefore range from an NNTH to to a number needed to treat for benefit (NNTB). Role of the Funding Source Wyeth-Ayerst Research funded HERS. The study was designed and carried out by the HERS investigators, including scientists from Wyeth-Ayerst Research. Investigators at the HERS Coordinating Center at the University of California, San Francisco, collected the outcome data, supervised the adjudication of outcome events, and analyzed the data. Results Gallbladder disease was particularly prevalent among this cohort of postmenopausal women with coronary artery disease. Twenty-three percent of women reported a history of cholelithiasis or cholecystectomy at baseline (10). With the exception of statin use, which was more prevalent among women assigned to receive placebo (P = 0.01), the distribution of baseline variables was similar in both treatment groups (Table 1). Approximately 23% of the HERS participants had a history of pre-enrollment hormone use; the type and duration did not differ between the treatment groups. Table 1. Selected Baseline Characteristics of Postmenopausal Women Receiving Hormone Therapy or Placebo in the Heart and Estrogen/progestin Replacement Study (HERS) A tot

A double-blind, randomly assigned, placebo-controlled study of desvenlafaxine efficacy and safety for the treatment of vasomotor symptoms associated with menopause

OBJECTIVE The objective of the study was to assess the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) for menopausal vasomotor symptoms. STUDY DESIGN Postmenopausal women (n = 458) experiencing 50 or more moderate to severe hot flushes per week received desvenlafaxine 100 or 150 mg/d, with titration at therapy initiation, or placebo. Hot flush number and severity were assessed at weeks 4 and 12. Safety data were collected throughout the trial. RESULTS Desvenlafaxine 100 and 150 mg/d significantly reduced the number of hot flushes compared with placebo at weeks 4 and 12 (all P < or = .012), achieving 65.4% and 66.6% reductions from baseline at week 12, respectively (placebo, 50.8%). Hot flush severity and number of nighttime awakenings were significantly reduced at both time points (all P < or = .048). Desvenlafaxine groups reported significantly more adverse events compared with placebo during week 1 only. No difference in discontinuations because of adverse events was observed. CONCLUSION Desvenlafaxine is an effective nonhormonal treatment for menopausal hot flushes. Dose titration improves initial tolerability.