Prescriber Compliance With Liver Monitoring Guidelines for Pazopanib in the Postapproval Setting: Results From a Distributed Research Network.

OBJECTIVES: Pazopanib received US Food and Drug Administration approval in 2009 for advanced renal cell carcinoma. During clinical development, liver chemistry abnormalities and adverse hepatic events were observed, leading to a boxed warning for hepatotoxicity and detailed label prescriber guidelines for liver monitoring. As part of postapproval regulatory commitments, a cohort study was conducted to assess prescriber compliance with liver monitoring guidelines. METHODS: Over a 4-year period, a distributed network approach was used across 3 databases: US Veterans Affairs Healthcare System, a US outpatient oncology community practice database, and the Dutch PHARMO Database Network. Measures of prescriber compliance were designed using the original pazopanib label guidelines for liver monitoring. RESULTS: Results from the VA (n = 288) and oncology databases (n = 283) indicate that prescriber liver chemistry monitoring was less than 100%: 73% to 74% compliance with baseline testing and 37% to 39% compliance with testing every 4 weeks. Compliance was highest near drug initiation and decreased over time. Among patients who should have had weekly testing, the compliance was 56% in both databases. The more serious elevations examined, including combinations of liver enzyme elevations meeting the laboratory definition of Hy's law were infrequent but always led to appropriate discontinuation of pazopanib. Only 4 patients were identified for analysis in the Dutch database; none had recorded baseline testing. CONCLUSIONS: In this population-based study, prescriber compliance was reasonable near pazopanib initiation but low during subsequent weeks of treatment. This study provides information from real-world community practice settings and offers feedback to regulators on the effectiveness of label monitoring guidelines.

Cumulative Burden of Glucocorticoid-related Adverse Events in Patients with Systemic Lupus Erythematosus: Findings from a 12-year Longitudinal Study.

OBJECTIVE: The aim of this population-based study is to examine the adverse events (AE) associated with longitudinal systemic glucocorticoid (GC) use among an ethnic Chinese systemic lupus erythematosus (SLE) cohort. METHODS: Our study subjects were patients with newly diagnosed SLE aged 18 and older who received at least 1 prescription of systemic GC between 2001 and 2012 from Taiwan's National Health Insurance Research Database (NHIRD). The earliest prescription date of systemic GC for each subject was defined as the index date. For each subject, we calculated the average prednisolone-equivalent dose and the medication possession ratio (MPR) of GC use every 90 days for each patient after the index date. Patients with a diagnosis of AE (defined by the International Classification of Diseases-9-Clinical Modification diagnosis code) during the followup were also identified from the NHIRD. Generalized estimating equations adjusted for propensity score were applied to examine the association between longitudinal GC use and risks of prespecified AE (musculoskeletal, gastrointestinal, ophthalmologic, infectious, cardiovascular, neuropsychiatric, metabolic, and dermatologic diseases). RESULTS: We identified 11,288 patients with SLE (mean followup: 6.28 yrs). Higher doses and higher MPR of GC were associated with increased risk of osteonecrosis [adjusted OR (aOR) 2.87-9.09]. Similar results were found regarding the risk of osteoporosis (aOR 1.71-3.67), bacterial infection (aOR 2.12-3.89), Cushingoid syndrome (aOR 6.51-62.03), and sleep disorder (aOR 1.42-3.59). CONCLUSION: To our knowledge, this is the first study to show that the dose and intensity of longitudinal use of GC were both associated with risk of AE among a nationwide Asian SLE cohort.

Occurrence of hepatotoxicity with pazopanib and other anti-VEGF treatments for renal cell carcinoma: an observational study utilizing a distributed database network.

PURPOSE: To quantify the hepatic safety of pazopanib and comparator anti-vascular endothelial growth factor (VEGF) therapies in clinical practice among renal cell carcinoma (RCC) patients. METHODS: A population-based cohort study of new anti-VEGF users was conducted in two US healthcare databases, Department of Veterans Affairs (VA) and an oncology practice network (Altos), and the PHARMO Database Network in The Netherlands. A common protocol was used to collect liver chemistry (LC) data from anti-VEGF initiation through 4 years of follow-up. In the VA population, suspected drug-induced liver injury (DILI) outcomes were investigated via chart review, with adjudication by hepatologists. RESULTS: In Altos and VA, respectively, the total RCC patients were: pazopanib (156, 243), bevacizumab (122, 99), sorafenib (82, 249) and sunitinib (285, 751). PHARMO contained too few patients to be included. Few cases of alanine aminotransferase (ALT) ≥8× the upper limit of normal were seen across the anti-VEGF cohorts; incidence rates (per 100 person-years) ranged from 0 (sunitinib) to 8.2 (pazopanib) in Altos and from 0 (bevacizumab and sorafenib) to 2.1 (pazopanib) among VA patients. No cases of Hy's law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; one case was observed in those treated with sorafenib, and two cases were found among sunitinib users. One case of adjudicated DILI was observed in a sunitinib-treated patient; none were found among patients treated with pazopanib, bevacizumab or sorafenib. CONCLUSIONS: Severe liver injury occurred infrequently during exposure to pazopanib and other anti-VEGF therapies in a population-based setting.

Common prescription medication use and erectile dysfunction: results from the Boston Area Community Health (BACH) survey.

OBJECTIVE: To investigate the association of erectile dysfunction (ED) with commonly used medications including antihypertensive treatment (AHT), psychoactive medication and pain and anti-inflammatory medication. SUBJECTS AND METHODS: The Boston Area Community Health (BACH) survey used a multistage stratified design to recruit a random sample of 2301 men aged 30-79 years. ED was assessed using the five-item International Index of Erectile Function (IIEF-5). Prescription medications, captured using a combination of drug inventory and self-report with a prompt by indication, included in this analysis comprised AHT, psychoactive medication, and pain and anti-inflammatory medication. Logistic regression was used to estimate the odds ratios (ORs) of the association of medication use with ED and to adjust for potential confounders including age, comorbid conditions and sociodemographic and lifestyle factors. RESULTS: Multivariable analyses showed benzodiazepines (adjusted OR = 2.34, 95% confidence interval [CI]: 1.03, 5.31) and tricyclic antidepressants (adjusted OR = 3.35, 95% CI: 1.09, 10.27) were associated with ED, while no association was observed for serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and atypical antipsychotics. The use of AHT, whether in monotherapy or in conjunction with other AHTs, and pain or anti-inflammatory medications were not associated with ED after accounting for confounding factors. CONCLUSIONS: Results of the BACH survey suggest adverse effects of some psychoactive medications (benzodiazepines and tricyclic antidepressants). No evidence of an association of AHT or pain and anti-inflammatory medication with ED was observed.

Non steroidal anti-inflammatory drug use and levels of oestrogens and androgens in men.

OBJECTIVE: Studies suggest that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) may lower oestrogen levels in women. However, no large, population-based studies have assessed NSAID/hormone associations in men. Our objective was to examine the association between use of prescription and over-the-counter NSAIDs, and levels of oestrogens and androgens in men. DESIGN: The Boston Area Community Health Survey, an observational survey with initial data collection in 2002-2005. PATIENTS: A total of 1766 men who provided a blood sample and data on recent analgesic use. MEASUREMENTS: Adjusted geometric mean levels of androgens, oestrogens, SHBG, LH and FSH for each category of NSAID use and the per cent difference in hormone levels for users vs nonusers. RESULTS: There was no significant association between prescription/over-the-counter NSAID use and any hormone examined after adjustment for potential confounders. For example, geometric mean testosterone levels were 13·8, 13·6 and 14·2 nM in nonusers, prescription users and over-the-counter NSAID users, respectively; the corresponding levels for estradiol were 80·3, 70·4 and 79·9 pM. In stratified analyses, however, prescription NSAID use was associated with lower testosterone, estradiol and estrone levels in obese men and lower testosterone and dehydroepiandrosterone sulphate levels in inactive men. CONCLUSIONS: While overall these data do not provide strong support for an association between NSAID use and hormone levels in men, prescription NSAIDs may decrease levels of certain oestrogens and androgens in obese and inactive men.

Risk factors for incident erectile dysfunction among community-dwelling men.

INTRODUCTION: Compared to the prevalence of erectile dysfunction (ED), fewer studies have focused on the incidence of ED and even fewer have focused on nonmedical risk factors. AIM: We examined psychosocial, demographic/socioeconomic, medical/behavioral, and sexual function risk factors at T1 (1987-1989) and development of incident ED at T2 (1995-1997). METHODS: Longitudinal population-based epidemiologic study of 814 community-dwelling men participating in the Massachusetts Male Aging Study. MAIN OUTCOME MEASURE: ED was defined according to a validated, discriminant-analytic formula based on questionnaire responses and categorized as moderate/complete ED vs. none/minimal. Multivariate logistic regression models (odds ratios [ORs] and 95% confidence intervals [CI]) were used to estimate the association of risk factors with ED. RESULTS: Among 814 men free of ED at T1, 22% developed moderate/complete ED at T2 (on average, approximately 8.8 years later). In a multivariate model, sexual function variables captured at baseline were inversely associated with ED (e.g., more or similar level of sexual arousal compared to adolescence vs. less, OR = 0.56, 95% CI: 0.34, 0.92; frequency of sexual thoughts at least two to three times weekly vs. less, OR = 0.55, 95% CI: 0.33, 0.92) after adjustment for age, education, and other risk factors. CONCLUSIONS: Our results indicate that in the context of other risk factors, sexual desire variables at baseline were associated with incident ED. This in turn suggests that indications of reduced function appear earlier than ED itself, and that there may be a time window for intervention before a loss of erectile function.

Erectile dysfunction and mortality.

INTRODUCTION: Erectile dysfunction (ED) and cardiovascular disease (CVD) share pathophysiological mechanisms and often co-occur. Yet it is not known whether ED provides an early warning for increased CVD or other causes of mortality. AIM: We sought to examine the association of ED with all-cause and cause-specific mortality. METHODS: Prospective population-based study of 1,709 men (of 3,258 eligible) aged 40-70 years. ED was measured by self-report. Subjects were followed for a mean of 15 years. Hazard ratios (HR) were calculated using the Cox proportional hazards regression model. MAIN OUTCOME MEASURES: Mortality due to all causes, CVD, malignant neoplasms, and other causes. RESULTS: Of 1,709 men, 1,284 survived to the end of 2004 and had complete ED and age data. Of 403 men who died, 371 had complete data. After adjustment for age, body mass index, alcohol consumption, physical activity, cigarette smoking, self-assessed health, and self-reported heart disease, hypertension, and diabetes, ED was associated with HRs of 1.26 (95% confidence interval [CI] 1.01-1.57) for all-cause mortality, and 1.43 (95% CI 1.00-2.05) for CVD mortality. The HR for CVD mortality associated with ED is of comparable magnitude to HRs of some conventional CVD risk factors. CONCLUSIONS: These findings demonstrate that ED is significantly associated with increased all-cause mortality, primarily through its association with CVD mortality.

Temporal trends in testosterone levels and treatment in older men.

PURPOSE OF REVIEW: Longitudinal studies of testosterone concentrations have yielded sharper estimates of age-related androgen declines than their cross-sectional counterparts. A potential explanation for this phenomenon is a secular (age independent) mechanism acting to accelerate within-individual testosterone decreases with time. This article reviews the evidence in favor of such secular trends and discusses potential causes and implications. RECENT FINDINGS: The magnitude of the proposed secular trend may be as much as 1% per calendar year in excess of per year cross-sectional trends. Current evidence suggests that body composition changes as expressed by BMI can in part account for the trend in testosterone. More speculative recent findings suggest a potential contributory role for environmental endocrine disruptors, but to date no longitudinal studies have examined this question. Symptomatic androgen deficiency as currently defined is associated with diverse downstream morbidity, but may not constitute a robust designation over longer term periods of time. Information concerning treatment patterns in the general population is limited. SUMMARY: Existing evidence, though limited, supports the hypothesis of secular declines in serum testosterone levels in adult men. It is conceivable that these trends may influence the health of the public. Studies confirming and accounting for these trends are needed.

The relationship of common medical conditions and medication use with symptoms of painful bladder syndrome: results from the Boston area community health survey.

PURPOSE: The etiology of painful bladder syndrome is currently unknown. We investigated the relationship between medical factors and symptoms suggestive of painful bladder syndrome in a population based random sample. MATERIALS AND METHODS: Data were collected from the Boston Area Community Health Survey, an epidemiological study conducted from 2002 to 2005 in a racially and ethnically diverse population (30 to 79 years old) from Boston, Massachusetts. The operational definition of painful bladder syndrome was symptom based. Those reporting pain increasing as the bladder fills and/or pain relieved by urination (fairly often/usually/almost always) for 3+ months were considered to have symptoms suggestive of painful bladder syndrome. We used multivariate logistic regression to estimate odds ratios and 95% confidence intervals (adjusted for demographics, anthropometric and other factors) for the association of comorbidities, surgery and medication use with painful bladder syndrome symptoms. RESULTS: The prevalence of painful bladder syndrome symptoms was 1.3% in men and 2.6% in women. In men only depression was associated in a multivariate model (OR 4.96; 95% CI 1.65, 14.92). In women associations were observed for depression (OR 3.35; 95% CI 1.93, 5.81), history of urinary tract infections (OR 2.17; 95% CI 1.49, 4.96), chronic yeast infections (OR 3.11; 95% CI 1.29, 7.51), hysterectomy (OR 2.82; 95% CI 1.20, 6.62), calcium channel blockers (OR 4.59; 95% CI 2.71, 9.72) and cardiac glycosides (OR 10.28; 95% CI 1.46, 72.35), while thyroid medications and statins were inversely associated (OR 0.13; 95% CI 0.03, 0.47 and OR 0.24; 95% CI 0.08, 0.76; respectively). CONCLUSIONS: Gynecologic factors and certain medications may be associated with the painful bladder syndrome in women. Our results for medications suggest potentially modifiable risk factors.

Prevalence and psychosocial correlates of symptoms suggestive of painful bladder syndrome: results from the Boston area community health survey.

PURPOSE: We estimated the prevalence of symptoms suggestive of painful bladder syndrome defined as pain increasing as the bladder fills and/or pain relieved by urination for at least 3 months, and its association with sociodemographics (gender, age, race/ethnicity and socioeconomic status), lifestyle (smoking, alcohol consumption, physical activity) and psychosocial variables (sexual, physical, emotional abuse experienced as a child or as an adult, worry, trouble paying for basics, depression). MATERIALS AND METHODS: The data used come from the Boston Area Community Health Survey, an epidemiological study of 5,506 randomly selected adults 30 to 79 years old of 3 race/ethnic groups (black, Hispanic, white). RESULTS: The overall prevalence of symptoms suggestive of painful bladder syndrome was 2% (1.3% in men and 2.6% in women) with increased prevalence in middle-aged adults and those of lower socioeconomic status. Symptoms suggestive of painful bladder syndrome were more common in those who experienced abuse, in those who were worried about someone close to them and in those who were having trouble paying for basics. This pattern held even after adjusting for depression. CONCLUSIONS: Painful bladder syndrome is associated with a number of lifestyle and psychosocial correlates. This suggests that the treatment of patients with painful bladder syndrome (physical symptoms) may benefit from a multifaceted approach of combining medical, psychological and cognitive treatment.

Cluster analysis and lower urinary tract symptoms in men: findings from the Boston Area Community Health Survey.

OBJECTIVES: To classify lower urinary tract symptoms (LUTS) in a large, representative sample of men in the USA by means of cluster analysis and to investigate risk factors and comorbidities associated with the resulting cluster patterns. SUBJECTS AND METHODS: A combination of hierarchical and non-hierarchical cluster methods was used to assign men with LUTS in the Boston Area Community Health (BACH) study to symptom-based categories or clusters. Of the 2301 men in the BACH study, those reporting one or more of 14 common LUTS (1592 men) were included in the analysis. The prevalence and frequency of symptoms in each cluster was assessed, in addition to the demographic, lifestyle risk factors, comorbidities, quality of life, and interference with activities of daily living associated with each cluster. We used anova methods for assessing cluster effects on continuous variables, and cross-classification and chi-square tests for categorical measures. Internal validity of the cluster solution was tested by means of a split-half replication, and external validity by comparison with previously published data. RESULTS: Five clusters were identified among symptomatic men. About half of the symptomatic men were assigned to Cluster 1, which included individuals with a low prevalence and frequency of urological symptoms and a correspondingly low level of interference with activities of daily living. There were intermediate levels of symptom frequency and prevalence in Clusters 2-4, which were characterized by mixed patterns of voiding, storage and postvoiding symptoms. Cluster 5 consisted of predominantly older men (mean age 58.9 years), with a high prevalence and frequency of urological symptoms with a mean (SD) number of symptoms of 9.9 (2.1), and with elevated levels of comorbid cardiovascular disease (P < 0.001). These men also had higher rates of kidney and bladder infections and previous urological surgery. Men with increased waist circumference and more sedentary lifestyles were over-represented in the more symptomatic clusters. CONCLUSION: Cluster analysis provides an empirically based method for categorizing men with LUTS. These findings provide a new framework for examining aetiological pathways and mechanisms, the potential impact of and consequences for comorbid conditions, and for assessing prognosis and outcomes associated with common urological disorders.

Do urological symptoms cluster among women? Results from the Boston Area Community Health Survey.

OBJECTIVES: To conduct a cluster analysis of urological symptoms among women in the Boston Area Community Health (BACH) Survey, to describe the distribution of urological symptoms within each cluster, and to determine whether comorbidities, demographic characteristics, and lifestyle factors were associated with cluster membership. SUBJECTS AND METHODS: The BACH Survey is a racially and ethnically diverse random sample (3205 women) of community-dwelling residents of Boston, MA, USA, aged 30-79 years. Fourteen urological symptoms measured by participant self-report (using previously validated scales) were included in this analysis. Cluster analyses were conducted using hierarchical and non-hierarchical (k-means) methods. Within clusters, demographic characteristics, risk factors for urological symptoms and the interference of symptoms with daily activities were also assessed. RESULTS: Three-quarters of the sample reported at least one urological symptom; four symptom clusters were identified. Most symptomatic women (54%) were assigned to Cluster 1, which was characterized by storage symptoms (nocturia and urinary frequency) with an accompanying low prevalence of other urological symptoms; a second cluster was distinguished by frequency symptoms. Clusters 3 and 4 were characterized by a high prevalence of urinary incontinence and had increased interference scores and more symptoms overall (including voiding and post-voiding symptoms) than the other two clusters. Cluster 4 (8% of symptomatic women) was characterized by a high prevalence of nearly all urological symptoms and the highest interference score. In this most symptomatic cluster, body size and waist circumference were markedly higher, as was the prevalence of diabetes, hypertension and cardiovascular disease than in the other cluster groups or asymptomatic women. Women in Cluster 4 were more likely to be surgically menopausal, or to have had other forms of urogynaecological surgeries than women in the other clusters. CONCLUSION: Four distinct clusters of urological symptoms were identified among symptomatic women in the BACH Survey, two of which had a high prevalence of urinary incontinence. These cluster patterns provide a novel, empirically-based framework for investigating aetiological mechanisms and management outcomes for common urological symptoms in women.

Do statins affect androgen levels in men? Results from the Boston area community health survey.

BACKGROUND: In 2005, statins were among the most commonly used prescription medications in the United States. Some data suggest statins may affect cancer risk and/or disease severity. Because cholesterol is a required intermediate in sex steroid synthesis, it is possible that statins influence prostate cancer risk through effects on steroid hormone metabolism. We investigated whether levels of circulating androgens and their carrier protein, sex hormone-binding globulin (SHBG), varied by statin exposure among a sample of 1,812 men from a population-based epidemiologic study, the Boston Area Community Health Survey. METHODS: We measured serum total testosterone, free testosterone, dehydroepiandrosterone sulfate, luteinizing hormone, and SHBG. Statin exposure was collected through participant self-report and/or interviewer-recorded information. Multivariate linear models were constructed to account for potential confounding. RESULTS: The prevalence of statin use was 12.4% [95% confidence interval (95% CI), 10.3-14.9]. On average, statin users were older, had larger body mass index and more chronic illnesses, and used more medications. We found no relationship between statin use and free testosterone, dehydroepiandrosterone sulfate, or luteinizing hormone. A significant association between statin use and total testosterone was initially observed but was not robust to covariate control in a multivariate model that included age, body mass index, time since awakening, and history of cardiovascular disease and diabetes (-5.5%; 95% CI, -13.2 to 2.9%). In multivariate models adjusted similarly, SHBG levels among statin users were statistically significantly lower compared with nonusers (-10.6%; 95% CI, -18.8 to -1.6%). CONCLUSION: In this sample, it is unlikely that statins affect circulating androgens and prostate cancer risk through a hormonal mechanism.

Defining urban and rural areas in U.S. epidemiologic studies.

Among epidemiologists, there has been increasing interest in the characteristics of communities that influence health. In the United States, the rural health disparity has been a recent focus of attention and made a priority for improvement. While many standardized definitions of urban and rural exist and are used by social scientists and demographers, they are found in sources unfamiliar to health researchers and have largely not been used in public health studies. This paper briefly reviews some available definitions of urban and rural for American geographic subunits and their respective strengths and weaknesses. For example, some definitions are better suited than others for capturing access to health care services. The authors applied different definitions to breast cancer incidence rates to show how urban/rural rate ratio comparisons would vary by choice of definition and found that dichotomous definitions may fail to capture variability in very rural areas. Further study of the utility of these measures in health studies is warranted.

Urbanization and breast cancer incidence in North Carolina, 1995-1999.

PURPOSE: Breast cancer incidence rates are reported to be higher in urban compared with rural areas in the United States. We investigated the relationship between urbanization and breast cancer in North Carolina (1995-1999), and considered hospital characteristics as an explanation. METHODS: We calculated age-adjusted in situ and invasive female breast cancer incidence rates stratified by race, urbanization (Urban Influence Codes), and the presence of a hospital with a cancer registry and cancer program approval in a county. RESULTS: For white women, incidence rate ratios (IRRs) comparing the most urban with the most rural counties were 1.60 for in situ and 1.18 for invasive cancer. For non-white women, IRRs were 1.27 and 0.99, respectively. IRRs for incidence in registry hospital counties versus those without were all > 1.00 and differences were greater for in situ cancer than invasive. For most strata, urban excesses were attenuated when further stratified by registry hospital status. CONCLUSIONS: For most strata, we observed excess incidence in urban counties, but it appeared to be explained through the urban preponderance of registry hospitals. Counties with these hospitals may have higher incidence because of increased detection. Area hospital characteristics should be considered when evaluating geographic patterns of breast cancer incidence.