Safety and Efficacy of Baricitinib in Patients Receiving Conventional Synthetic Disease-Modifying Antirheumatic Drugs or Corticosteroids.

INTRODUCTION: This study assessed if concomitant use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or corticosteroids altered the response or safety outcomes to baricitinib in rheumatoid arthritis (RA) patients. METHODS: Patients with ≥ 6 swollen/tender joints and no prior biologic DMARD were eligible for study inclusion. In RA-BUILD, csDMARD-inadequate responder (IR) patients were randomized to placebo or baricitinib (2 or 4 mg) once daily (QD). In RA-BEAM, methotrexate (MTX)-IR patients were randomized to placebo QD, baricitinib 4-mg QD, or adalimumab 40-mg biweekly. Patients continued background csDMARD (including MTX) therapy. This post hoc analysis of placebo and baricitinib 4-mg patients assessed the number and type of concomitant csDMARDS and concurrent corticosteroid use. RESULTS: From 716 placebo patients, 71, 21, and 6% were taking MTX alone, MTX + ≥ 1 csDMARD, and non-MTX csDMARDs, respectively; from 714 baricitinib patients, the rates were 74, 18, and 6%; 56% of placebo and 55% of baricitinib patients used corticosteroids at baseline (mean dose, 6.0 mg/day for both groups); patients continued use throughout the studies. The odds ratios for achieving American College of Rheumatology response at the 20% improvement level (ACR20) and Clinical Disease Activity Index (CDAI) ≤ 10 at week 12 favored baricitinib for most subgroups; no significant interactions were observed. Rates of adverse events were similar regardless of csDMARD group or corticosteroid use. There were numerically more serious adverse events in placebo patients taking corticosteroids (4.2 vs. 1.6%) and a higher rate of discontinuations in baricitinib patients taking corticosteroids (4.1 vs. 1.2%). CONCLUSIONS: Baricitinib was efficacious regardless of concomitant use of csDMARDs or corticosteroids; the incidence of adverse events was similar across all groups of patients. FUNDING: Eli Lilly and Company and Incyte Corporation.

Response to baricitinib therapy in patients with rheumatoid arthritis with inadequate response to csDMARDs as a function of baseline characteristics.

OBJECTIVE: We analysed the effects of baseline characteristics on the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) from two phase III trials. METHODS: In RA-BEAM (NCT01710358), patients with inadequate response to methotrexate were randomised to placebo, baricitinib 4 mg or adalimumab 40 mg. RA-BUILD (NCT01721057) patients had inadequate response to ≥1 csDMARDs and were randomised to either placebo or once-daily baricitinib (2 or 4 mg). Both study populations were naïve to biologic DMARDs (bDMARDs). Primary end point for both studies was American College of Rheumatology 20% improvement (ACR20) response at week 12. Pooled data from the two trials were analysed post hoc based on select subgroups defined by age, previous csDMARD use, baseline RA disease activity, etc, with assessment of clinical and safety outcomes at week 12 and radiographic outcomes at week 24 for the baricitinib 4 mg and placebo-treated patients. RESULTS: Efficacy was observed with baricitinib 4 mg treatment irrespective of patient demographics and baseline disease characteristics. ORs primarily favoured baricitinib over placebo in the ACR20 response. In other outcomes such as Disease Activity Score for 28 joints based on high-sensitivity C reactive protein levels, Simplified Disease Activity Index score ≤11 and radiographic progression, baricitinib 4 mg showed better responses than placebo regardless of baseline characteristics. Safety events were more common in patients over 65 years, but similar between baricitinib 4 mg and placebo patients. CONCLUSION: Baseline characteristics did not substantially affect clinical response to baricitinib 4 mg in patients with RA with inadequate response to csDMARDs.

A Pilot Study Using a Web Survey to Identify Characteristics That Influence Hypogonadal Men to Initiate Testosterone Replacement Therapy.

Men with hypogonadism (HG) who choose testosterone replacement therapy (TRT) may have distinct characteristics that provide insight as to why they may/may not initiate therapy. The aim of the current study was to identify trends in patient characteristics and attitudes in men diagnosed with HG who initiated TRT (TRT+) compared with men who were diagnosed with HG but did not initiate TRT (TRT-). The market research-based online survey conducted between 2012 and 2013 included patients from a Federated Sample, a commercially available panel of patients with diverse medical conditions. The current analysis was composed of two groups: TRT+ ( n = 155) and TRT- ( n = 157). Patient demographics, clinical characteristics, and attitudes toward HG and TRT were examined as potential predictors of primary adherence in men with HG; cohorts were compared by using Fisher's exact test. Significant associations among sexual orientation, relationship status, educational level, presence of comorbid erectile dysfunction, area of residence, and TRT initiation were present ( p ≤ .05). College-educated, heterosexual, married men with comorbid erectile dysfunction living in suburban and urban areas were more likely to initiate treatment. The most bothersome symptoms reported were lack of energy (90% vs. 81%, p = .075), decreased strength and endurance (86% vs. 76%, p = .077), and deterioration in work performance (52% vs. 31%, p = .004); lack of energy prompted men to seek help. Patients (48%) in the TRT+ group were more knowledgeable regarding HG as compared with TRT- respondents (14%, p < .001), and most men obtained their information from a health care professional (89% vs. 82%, p = .074). The current analysis identified distinct demographic and clinical characteristics and attitudes among TRT users compared with men who were diagnosed with HG yet remained untreated.

Amount of Testosterone on Laundered Clothing After Use of Testosterone Topical 2% Solution by Healthy Male Volunteers.

INTRODUCTION: Testosterone 2% solution (Axiron) applied to armpit(s) is used for replacement therapy in men with a deficiency of endogenous testosterone. AIM: To determine the amount of testosterone on subjects' T-shirts 12 hours after applying testosterone solution, the residual testosterone on subjects' T-shirts after laundering, and the testosterone transferred to unworn textile items during laundering with worn T-shirts. METHODS: Healthy males ≥18 years old applied 2 × 1.5 mL of testosterone 2% solution to both axillae (total testosterone dose: 120 mg) and dressed in cotton long-sleeved T-shirts after a ≥3-minute waiting period. T-shirts were worn 12 hours before being removed and cut into halves, after which a 10 × 10 cm sample of each armpit area was excised for testosterone quantification before or after laundering with samples of unworn textiles. MAIN OUTCOME MEASURES: Testosterone on worn T-shirts before and after laundering, and on unworn textiles laundered with the worn T-shirts. RESULTS: Twelve subjects enrolled and completed, with only minor adverse events. Mean testosterone in unwashed worn T-shirts was 7603 µg, with high between-subject variability (3359 µg to 13,069 µg), representing 13% of the dose to 1 armpit. Mean testosterone in worn, laundered T-shirts was 260 µg (7.55 µg to 1343 µg), representing 3% of the dose to 1 armpit. Mean transferred testosterone to other textiles during laundering ranged from 69 µg on texturized Dacron 56T Double to 10,402 µg on 87/13 nylon/Lycra knit, representing 0.0382% to 5.78% of the dose to 1 armpit. CONCLUSION: Thirteen percent of the testosterone applied to axillae was transferred to T-shirts during wear. Ninety-seven percent of the transferred testosterone was removed from the T-shirts during washing, some of which was then absorbed to various degrees by other textiles. Clinical implications of these findings and biological activity of the remaining/transferred testosterone are unknown.

Utility of a single serum testosterone measurement to determine response to topical testosterone replacement in hypogonadal men.

OBJECTIVE: To evaluate the utility of single serum testosterone measurement in patients receiving transdermal testosterone therapy. RESEARCH DESIGN AND METHODS: Data were from an open-label, 120 day, multi-center titration trial in androgen-deficient men receiving an initial daily dose of 60 mg testosterone (testosterone topical solution 2%) applied to axillae (30 mg/axilla). Average concentration (Cavg) of serum testosterone (TT) was determined on days 15, 60, and 120; doses were adjusted to maintain normal Cavg (300-1050 ng/dL [10.4-36.4 nmol/L]). Accuracy of single serum TT measurements (2, 4, 8, 12, 16, and 20 hours post-dose) was assessed in patients with Cavg TT within and below (<300 ng/dL [<10.4 nmol/L]) the normal range. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov - NCT00702650. MAIN OUTCOME MEASURE: Serum testosterone levels. RESULTS: In patients with normal Cavg (n = 85), 79% to 92% had serum testosterone levels within normal range 2, 4, 8, 12, 16, and 20 hours post-dose; significant effects of time post-dose for single testosterone measurement accuracy (P = 0.01) were observed: testing accuracy peaked 4-8 hours post-dose and tapered ∼16 hours post-dose. In 28/63 instances with low Cavg TT throughout the study a normal 2 hour serum TT level was observed. The average percentage (across all days) of discordant results between Cavg (<300 ng/dL [<10.4 nmol/L]) and single serum TT measurements (300-1050 ng/dL [10.4-36.4 nmol/L]) declined with increasing time from dose application (44% at 2 hours, 38% at 4 hours, 22% at 8 hours, 3% at 16 hours). CONCLUSIONS: Reliance on a single serum testosterone measurement to determine the need for dose adjustment of testosterone topical solution 2% may lead clinicians to change the dose unnecessarily, or alternatively, not increase the dose when necessary. The results reported here are limited to testosterone topical solution 2% and may not be applicable to other topical agents.

Effects of Testosterone Level on Lower Urinary Tract Symptoms.

Lower urinary tract symptoms (LUTS) are common in older men and are frequently associated with benign prostatic hyperplasia (BPH). The relationship between BPH and endogenous total testosterone (TT) levels has been widely studied. The aim of this post hoc analysis was to determine the association between LUTS and endogenous TT levels in a subset of men participating in the 2013 Prostate Cancer Awareness Week, a U.S. community-based prostate cancer screening program. Men completed the International Prostate Symptom Score (I-PSS) questionnaire, prostate size was estimated by a digital rectal examination, and serum TT and prostate-specific antigen levels were measured. Mean TT levels (ng/dl) did not significantly correlate with prostate size category (r = +.03, p = .69): normal, 419.2 (n = 106); enlarged, 394.7 (n = 71); abnormal, 416.4 (n = 7); and abnormal/suspicious, 515.2 (n = 19). Mean TT levels (ng/dl) did not significantly correlate with I-PSS category (r = -.06, p = .40): none, 468.5 (n = 15); mild, 414.0 (n = 138); moderate, 397.4 (n = 66); and severe, 437.9 (n = 7). Mean TT levels (ng/dl) did not significantly correlate with I-PSS quality of life rating (r = -.13, p = .055): delighted, 474.5 (n = 43); pleased, 424.6 (n = 65); mostly satisfied, 361.2 (n = 63); mixed, 448.2 (n = 29); mostly dissatisfied, 337.2 (n = 17); and unhappy, 435.8 (n = 6). Adjustment for prostate size or prostate-specific antigen levels yielded similar findings. In conclusion, endogenous TT levels did not correlate with LUTS or prostate size, and these findings support the saturation theory in which TT is not able to induce further androgen-stimulated prostate tissue growth due to receptor saturation. Any worsening of LUTS following testosterone replacement therapy in hypogonadal men may be related to stimulation of prostatic cells previously deprived of testosterone.

Measurement of testosterone: how important is a morning blood draw?

OBJECTIVE: Since testosterone levels exhibit a circadian variation with peak levels in the morning, evidence-based guidelines recommend measuring morning total testosterone (TT) levels as the initial diagnostic test for androgen deficiency. However, it has been suggested that morning blood draw may not be necessary in older men due to a blunted circadian rhythm. We sought to determine whether it is possible to expand the morning sampling window for measurement of TT. RESEARCH DESIGN AND METHODS: TT levels were measured in a subset of men (mean age of 61 years) participating in the 2013 Prostate Cancer Awareness Week. RESULTS: TT levels measured in blood drawn from 8 to 11 AM (n = 229) differed significantly from those drawn outside this window (n = 442) (411.7 vs 368.3 ng/dl; p = 0.0003). Differences in TT levels were evident across five blood draw time windows (p = < 0.0001) and persisted after adjustment for age and BMI. TT levels in blood drawn from 2 to 5 PM (344.3 ng/dl) and 5 to 8 PM (334.4 ng/dl) differed significantly from that drawn from 8 to 11 AM (p < 0.05), while TT levels from 11 AM to 2 PM (396.5 ng/dl) and 8 PM to 8 AM (373.4 ng/dl) did not (p = 0.90 and 0.73, respectively). CONCLUSION: Based on these findings, it may be possible to expand the blood draw time window for measurement of serum TT. This community-based study was not prospectively design to determine the most appropriate blood draw window for TT measurement. Only a single TT measurement was made without consideration for day-to-day variability, and TT levels were not measured in the same men at different blood draw times.

Use of Hormone Testing for the Diagnosis and Evaluation of Male Hypogonadism and Monitoring of Testosterone Therapy: Application of Hormone Testing Guideline Recommendations in Clinical Practice.

INTRODUCTION: Clinical practice guidelines recommend that testosterone (T) levels be measured on ≥2 occasions to confirm a diagnosis of hypogonadism, gonadotropins be measured to determine whether hypogonadism is primary or secondary, and T levels be measured to monitor the adequacy of T therapy. However, it is not known whether hormone testing as recommended by guidelines is routinely performed in real-world clinical practice. AIM: The aim of this study was to assess the use of hormone testing for the diagnosis and evaluation of hypogonadism and monitoring of T therapy in clinical practice. METHODS: In this retrospective cohort study of the Truven Health Marketscan(®) Commercial and Medicare Supplemental Insurance Databases during 2010-2012, 63,534 men over 18 years old who received T therapy and had continuous medical benefit enrollment for 1 year prior to and 6 months after T therapy initiation were included in this analysis. MAIN OUTCOME MEASURES: Proportion of patients who received ≥2, 1, or no T-level determinations prior to or following T therapy initiation. RESULTS: Seventy-one percent of hypogonadal men had T measured at least once and 40% had ≥ 2 tests, but only 12% of men had luteinizing hormone and/or follicle-stimulating hormone levels measured prior to T therapy initiation. Following T therapy initiation, 46% had ≥1 follow-up T measurements. CONCLUSIONS: Appropriate use of T and gonadotropin levels in clinical practice as recommended by guidelines is suboptimal, increasing the possibility of overdiagnosis of male hypogonadism, underdiagnosis of secondary hypogonadism, and inappropriate T therapy use and management. Further investigation is needed into reasons for nonadherence to guidelines for appropriate hormone testing to inform future quality improvement efforts.

Retrospective Analysis of Dose Titration and Serum Testosterone Level Assessments in Patients Treated With Topical Testosterone.

Patterns of care following topical testosterone agent (TTA) initiation are poorly understood. This study aimed to characterize care following TTA initiation and compare results between patients with and without a serum testosterone (T) assay within 30 days before and including TTA initiation. Adult men (N=4,146) initiating TTAs from January 1, 2011, to March 31, 2012, were identified from a commercially insured database. Patients were included if they initiated at recommended starting dose (RSD) and had ≥12 and ≥6 months of continuous eligibility preinitiation (baseline) and postinitiation (study period), respectively. Patients were stratified by preinitiation T assay. Maintenance dose attainment month was determined using unadjusted generalized estimating equations regression to compare dose relative to RSD month by month. Outcomes included maintenance dose attainment month, time to stopping of index TTA refills or a claim for nonindex testosterone replacement therapy (TRT), and proportion of patients with study period T assay or diagnosis of hypogonadism (HG) or another low testosterone condition, and were compared using chi-square and Wilcoxon rank-sum tests for categorical and continuous variables, respectively. Maintenance dose was attained in Month 4 postinitiation, at 115.2% of RSD. Approximately 46% of patients had a preinitiation T assay; these men were more likely to receive a diagnosis of HG or another low testosterone condition, to have a follow-up T assay, to continue treatment by filling a nonindex TRT, and less likely to stop refilling treatment with their index TTA. Differences in care following TTA initiation suggest that preinitiation T assays (i.e., guideline-based care) may be helpful in ensuring treatment benefits.

Comparability of single measurements of serum testosterone to the 24-hour C(avg) in patients using testosterone 2% solution.

INTRODUCTION: Efficacy of testosterone replacement therapy is determined by the proportion of men with 24-hour average serum testosterone concentration (Cavg ) in the normal range. In clinical practice, monitoring and dose adjustments are based on single testosterone measurements; however, how single measurements reflect Cavg is unclear. AIM: This post-hoc analysis evaluated whether single serum testosterone measurements and Cavg from the same day are both in the normal range in men receiving testosterone replacement therapy. METHODS: In an open-label, multicenter, titration trial, androgen-deficient men (N = 155) were started on 60-mg daily morning dose of testosterone 2% solution (Axiron®, Eli Lilly and Company, Indianapolis, Indiana, USA) applied to axillae (30 mg/axilla). Serum testosterone Cavg was determined on Days 15, 60, and 120. If necessary, dose was adjusted to maintain Cavg in the normal range (300-1,050 ng/dL). This analysis included subjects (n = 105) whose Cavg was within the normal range on Days 15, 60, and 120. MAIN OUTCOME MEASURES: Proportion of men with normal serum testosterone levels at 2, 4, or 8 hours post-dose on Days 15, 60, and 120. RESULTS: Greater than 93% of subjects had testosterone serum levels within the normal range 2, 4, or 8 hours post-dose on at least 1 day. In subjects with blood samples available from Days 15 and 60 or Days 15 and 120, 71.1% to 79.8% had normal levels at 2, 4, or 8 hours post-dose on both days, and in subjects with blood samples available from Days 15, 60, and 120, 63.9% to 68.8% had normal levels at 2, 4, or 8 hours post-application on all 3 days. CONCLUSION: Less than 70% of single testosterone measurements made on 3 separate days were concordant with same-day Cavg for all 3 days. These findings, which are specific for testosterone 2% solution, indicate that single measurements do not always reflect the 24-hour Cavg , and may possibly lead to inappropriate dose adjustments.

Long-term treatment patterns of testosterone replacement medications.

INTRODUCTION: Testosterone replacement therapy (TRT) is prescribed to men diagnosed with hypogonadism to alleviate symptoms, improve quality of life, and improve overall health. However, most men use TRT for only a short duration. AIM: To evaluate the long-term treatment patterns in hypogonadal men using topical TRT or short-lasting TRT injections. METHODS: Using the Truven MarketScan(®) Database, 15,435 men who received their first (index) topical TRT prescription and 517 men who received their short-lasting TRT injection index prescription in 2009 were followed from 12 to 30 months after treatment initiation. Treatment interruption was defined as a medication gap of >30 days. Patients who remained off treatment were classified as having discontinued treatment. Patients who restarted therapy after 30 days were classified as cyclic users. Patients were required to have continuous insurance coverage during 1 year prior to treatment initiation and at least 1 year afterward. MAIN OUTCOME MEASURES: Main outcome measures were length of therapy, discontinuation, and restarts of topical TRT or short-lasting TRT injections. RESULTS: The patient characteristics were similar for patients who received topical TRT or short-lasting TRT injections. Of the patients who discontinued therapy during the follow-up period, the percentages of patients who were still on therapy after 3 months were 52% and 31% for topical TRT and short-lasting TRT users, respectively. For cyclic users, there was an attrition rate of approximately 40% to 50% of patients in each cycle. For both topical TRT and short-lasting TRT injections, the gap between stopping and restarting therapy tended to decrease over time. CONCLUSIONS: In this analysis, high discontinuation rates were observed. The treatment pattern of TRT may be related to the disease state rather than dosing, daily use, or mode of administration.

Medication adherence and treatment patterns for hypogonadal patients treated with topical testosterone therapy: a retrospective medical claims analysis.

INTRODUCTION: There is limited information on adherence to topical testosterone replacement therapy (TRT) among hypogonadal men. AIM: To determine adherence rates among men treated with topical testosterone gels and to examine factors that may influence adherence, including age, presence of a specific diagnosis, and index dose. METHODS: Included were 15,435 hypogonadal men, from the Thomson Reuters MarketScan Database, who had an initial topical testosterone prescription in 2009 and who were followed for 12 months. MAIN OUTCOME MEASURES: Adherence to testosterone was measured by medication possession ratio (MPR), with high adherence defined as ≥0.8. Persistence was defined as the duration of therapy from the index date to the earliest of the following events: end date of the last prescription, date of the first gap of >30 days between prescriptions, or end of the study period (12 months). RESULTS: Adherence to topical TRT was low. By 6 months, only 34.7% of patients had continued on medication; at 12 months, only 15.4%. Adherence rates were numerically similar among men who received AndroGel or Testim topical gels and did not differ among men of different age groups. Approximately 80% of patients initiated at the recommended dose of 50 mg/day. Over time, an increased proportion of men used a higher dose. This change was the result of dose escalation, rather than of greater adherence among men initiating therapy at a high dose. Dose escalation was seen as early as 1 month into therapy. Approximately 50% of men who discontinued treatment resumed therapy; most men used the same medication and dose. CONCLUSIONS: Discontinuation rates are high among hypogonadal men treated with testosterone gels, irrespective of their age, diagnosis, and index dose. Further study, evaluating other measurable factors associated with low adherence among patients receiving topical TRT, may lead to interventions designed to improve adherence with therapy.

Breast cancer incidence in postmenopausal women with osteoporosis or low bone mass using arzoxifene.

The Generations trial, a multicenter, placebo-controlled, double-blind trial, compared arzoxifene 20 mg/day and placebo in 9,354 postmenopausal women with osteoporosis (N=5,252) or low bone mass (N=4,102). Primary outcomes were vertebral fracture in the osteoporotic population and invasive breast cancer in all study participants. Here, we report the detailed breast cancer findings from the trial. Breast cancers were detected by annual mammograms and clinical examination. After 48 months follow-up, breast cancer incidence was compared between treatment groups by estrogen receptor (ER) and progesterone receptor (PR) status and baseline risk factors. Baseline breast cancer risk factors, including age, estimated Gail risk, and bone mineral density, were well balanced between treatment groups. A total of 75 breast cancers occurred 53 in the placebo group and 22 in the arzoxifene group (HR 0.41, 95% CI 0.25-0.68, P<0.001). There were 62 invasive breast cancers, 39 identified as invasive ER-positive (placebo 30, arzoxifene 9; HR 0.30, 95% CI 0.14-0.63, P=0.001) and 30 identified as invasive PR-positive (placebo 23, arzoxifene 7; HR 0.30, 95% CI 0.13-0.71, P=0.003). Breast cancer risk reduction with arzoxifene was similar between Gail risk groups (P interaction=0.31) and between low bone mass and osteoporosis groups (P interaction=0.35). Although generally well tolerated, there was a significant increase in venous thromboembolism, vasomotor symptoms, muscle cramps, and some gynecological events with arzoxifene. These findings demonstrate that in this study arzoxifene reduced the risk of ER-positive breast cancer in this population of postmenopausal women with low bone mass or osteoporosis, an effect similar to that seen with other SERMs.

Skin reactions in a phase 3 study of a testosterone topical solution applied to the axilla in hypogonadal men.

OBJECTIVE: Axiron (testosterone topical solution 2%) is an approved topical testosterone replacement therapy applied to the axilla. The axilla is a novel application site for testosterone replacement therapy, with differences in skin structure and exposure that could impact the type and/or severity of skin reactions observed with testosterone topical solution 2%. We therefore present a detailed description of data from a pivotal clinical trial regarding the incidence, time of onset, duration, and severity of patient-reported skin reactions as well as visual assessments made by investigators and rated using Draize scoring. *Axiron is a trademark of Eli Lilly and Company, Indianapolis, IN, USA. METHODS: Data were analyzed from a multinational, open-label, clinical study in which a 2% testosterone topical solution was applied to the axilla in hypogonadal men. The primary study was for 120 days (N = 155) with a 60-day extension that evaluated skin safety (N = 71). At each visit investigators asked patients about adverse skin reactions (including those occurring between study visits); visually assessed the application site; and graded observed instances of erythema or edema using Draize scoring (rated from 0 to 4). RESULTS: Application-site irritation following study drug application was the most commonly reported event (n = 12 patients) and was generally mild (n = 11; moderate, n = 1) in severity. Application-site irritation did not increase in severity over time and led to only one discontinuation. Erythema was the second most common patient-reported skin reaction (n = 10 patients) and was also generally mild (n = 9; moderate, n = 1). Draize scoring rated all directly observed cases of erythema as grade 1 (very slight, 6 patients) or grade 2 (well-defined, two patients), and identified two instances of erythema not reported by patients. Erythema was typically transient, and in most cases resolved without interruption of therapy. Three cases of edema were reported by patients, and two of these were also identified by visual inspection; all cases of edema occurred in conjunction with erythema. Two cases of acne (facial, shoulders) and one of folliculitis (scalp) were also reported. CONCLUSIONS: Skin reactions were observed in a minority of patients, were mild or at most moderate in severity, and seldom led to discontinuation.

Gynecologic effects of arzoxifene in postmenopausal women with osteoporosis or low bone mass.

OBJECTIVE: The aim of this study was to report the gynecologic safety findings from the Generations trial, a phase 3 study of the selective estrogen receptor modulator (SERM), arzoxifene. METHODS: A predefined objective of the trial was to evaluate the effects of arzoxifene on the genital tract. Gynecologic examinations were performed yearly, and further gynecologic assessment, including endometrial biopsy, was performed in a predefined subset of women and in those who developed vaginal bleeding. RESULTS: Overall, 9,354 women were randomized (4,678 to placebo, 4,676 to arzoxifene 20 mg/d). There were 13 adjudicated cases of endometrial cancer (placebo, 4 cases; arzoxifene, 9 cases: P = 0.165) and 6 cases of endometrial hyperplasia (placebo, 2 cases; arzoxifene, 4 cases). Endometrial thickness, assessed at 24- and 36-month transvaginal ultrasounds in a subset of women, increased slightly in women assigned to arzoxifene compared with baseline and women in placebo. At the last measurement, 3 (1.7%) women assigned to placebo and 21 (10.2%) assigned to arzoxifene had an endometrial thickness greater than 5 mm (P < 0.001 for difference between treatment groups). Endometrial polyps were more common in women treated with arzoxifene (n = 37) than in women treated with placebo (n = 18; P < 0.05). Vulvular and vaginal inflammation, including mycotic infections, and vaginal discharge were reported more frequently in women treated with arzoxifene than in women treated with placebo, as were urinary tract infections. CONCLUSIONS: Gynecologic events were generally more common in women treated with arzoxifene than in women treated with placebo. The gynecologic effects of arzoxifene seem to differ from those of raloxifene, although both SERMs have a benzothiophene structure. Although all SERMs influence cells through the estrogen receptor, they need to be evaluated independently in terms of their effects on various tissues, including the genital tract.

Breast cancer risk assessment: positive predictive value of family history as a predictor of risk.

OBJECTIVE: The aim of this study was to evaluate the practical usefulness of family history as a tool for breast cancer risk assessment. METHODS: Women from the Raloxifene Use for The Heart trial (N = 10,048), which consisted of postmenopausal women with or at high risk for coronary artery disease, were included in this post hoc analysis. The breast cancer risk score at baseline was calculated using the National Cancer Institute's Breast Cancer Risk Assessment tool. The positive predictive value of family history as a predictor of risk was determined for several risk thresholds. RESULTS: Almost all (99.6%) women with a family history of breast cancer are found to be at high risk using the National Cancer Institute's accepted cutoff point of at least 1.66%, and almost 98% of women with a family history of breast cancer belong to the high-risk group when the cutoff point for risk score is 2%. CONCLUSIONS: Family history alone as a high-risk predictor is associated with a high positive predictive value at commonly used cutoff points based on the risk estimates from the traditional Gail model. Although more complex models of breast cancer risk should still be used as the standard for assessment, screening using family history seems to be a first step in beginning the discussion with women.

Estimated risk of invasive breast cancer in postmenopausal women with and without family history of the disease.

OBJECTIVE: To characterize the estimated risk of invasive breast cancer (IBC) in postmenopausal women without a family history of breast cancer (FHBC), baseline risk scores were calculated using the Breast Cancer Risk Assessment tool. We also analyzed the incidence rates of IBC stratified by FHBC. METHODS: For the Continuing Outcomes Relevant to Evista (CORE) study population (n = 3,991; excluding women ≥86 y of age or with a history of ductal carcinoma in situ or lobular carcinoma in situ), the prevalence of risk factors to the overall IBC risk was calculated. To evaluate IBC incidence rates, the placebo arm of the CORE trial (n = 1,275) was pooled with the placebo arm of the Raloxifene Use for the Heart trial (n = 5,047; total of 6,322 women). RESULTS: Common risk factors in the CORE population were age 65 years or older (78.4%) and menarche at 12 years or younger (29.4%). Incidence rates of IBC in the CORE plus Raloxifene Use for the Heart trial placebo populations correlated with IBC risk estimates; incidence rates were higher as risk scores increased. Of those who developed IBC, 65% (60/92) had scores between 1% and 2% and did not have FHBC; nearly half (43%; 40/92) had risk scores below the high-risk cutoff of 1.66%. CONCLUSIONS: A significant portion of women who develop IBC do not have a family history of the disease. FHBC is important in assessing IBC risk; however, other relevant risk factors, together with FHBC and results from a validated tool risk assessment tool, should be jointly considered to develop a complete assessment of women's IBC risk.

Patient characteristics and utilization of breast cancer screening or diagnostic procedures prior to initiation of raloxifene, bisphosphonates and calcitonin.

OBJECTIVE: This study evaluated the characteristics of postmenopausal women who initiated on raloxifene, bisphosphonates, and calcitonin, specifically evaluating the use of breast cancer screening or diagnostic procedures prior to initiation of therapy. RESEARCH DESIGN AND METHODS: Women 50 years and older with at least one claim for raloxifene (RLX), bisphosphonates (BIS), or calcitonin (CT) in 2005 or 2006 and continuous enrollment (with consecutive gaps in enrollment of no more than 1 month) from January 2004 to December 2007 were identified in a large national commercial and Medicare claims database. Treatment-naïve postmenopausal women initiating on raloxifene, bisphosphonates, and calcitonin were compared in terms of breast cancer screening or diagnostic procedures (i.e., mammogram, breast MRI, ultrasound, and biopsy) as well as age, provider specialty, fractures, bone mineral density screening, Chronic Disease Scores, and comorbidities. RESULTS: Treatment-naïve patients initiated on raloxifene were younger than those initiated on bisphosphonates and calcitonin (mean age 63 years [RLX], 66 years [BIS], 72 years [CT]; p < 0.05). Treatment-naïve patients initiated on raloxifene were more likely to have had breast cancer screening or diagnostic procedures in the 12 months prior to therapy initiation than treatment-naïve bisphosphonate or calcitonin patients (RLX 61%, BIS 57%, CT 41%; p < 0.05), and were more likely to have an increased frequency of mammograms in the 12 months after therapy initiation (RLX 18%, BIS 16%, CT 15%; p < 0.05). Calcitonin patients were the most likely to have had a fracture in the pre-period followed by bisphosphonates then raloxifene patients. CONCLUSION: These data suggest that there are differences in the clinical characteristics of postmenopausal women who initiate osteoporosis medications specifically in regards to age, pre-period fractures and breast cancer screening or diagnostic procedure use prior to initiation. Key limitations include general claims database limitations, lack of ability to assess behavior change, and lack of information on therapy initiation rationale.

The effects of raloxifene on mammographic breast density: a review of clinical trials.

OBJECTIVE: Breast density is an independent risk factor for the development of invasive breast cancer (BC). It has been hypothesized that because raloxifene (RLX) has been shown to reduce BC risk, its use will result in reduced breast density. METHODS: This article provides a review of seven clinical studies that examined the effects of RLX on breast density. RESULTS: Overall, RLX did not increase or decrease mammographic breast density. This article provides a review of the various methods used to determine breast density in these RLX studies and offers a potential explanation as to why the studies failed to show an effect on mammographic density. CONCLUSIONS: Presently, no clinical recommendations can be made with regard to RLX and its effects on breast density. To determine the effect of RLX on breast density, larger studies need to be conducted in postmenopausal women with high breast density at baseline who are at high risk for BC, with a standardized method of breast density measurement.