Duloxetine Exposure During Pregnancy and the Risk of Offspring Being Born Small for Gestational Age or Prematurely: A Nationwide Danish and Swedish Safety Study.

BACKGROUND: Depression or depressive symptoms are common among pregnant women. The use of antidepressants during pregnancy has grown steadily. The risk of offspring being born small for gestational age or prematurely when exposed to duloxetine during pregnancy is not established. OBJECTIVE: We aimed to investigate the association between duloxetine exposure during pregnancy and offspring being born small for gestational age or prematurely. METHODS: We conducted an observational study including live births in Sweden and Denmark (2004-2016). Duloxetine exposure during early (0-140 days) or late (141 to delivery) pregnancy compared with duloxetine-non-exposed, selective serotonin reuptake inhibitor-exposed, venlafaxine-exposed, and duloxetine discontinuers. RESULTS: In total, 2,083,467 pregnancies were identified, where 1589 and 450 were duloxetine exposed in early and late pregnancy, respectively. For small for gestational age, no increased risk was seen for duloxetine across comparators. In the early and late exposure windows, propensity score-matched odds ratios for small for gestational age ranged between 0.64 (95% confidence interval 0.44-0.95) and 1.48 (95% confidence interval 0.85-2.57). For preterm birth, the findings differed across comparators and exposure-time windows, but trended towards an increased risk for duloxetine-exposed when compared with duloxetine-non-exposed, selective serotonin reuptake inhibitor-exposed, and duloxetine discontinuers in both early exposure and late exposure. The odds ratios ranged between 1.17 and 2.04, of which some did not reach statistical significance. No clear association was observed when compared with venlafaxine exposed, 0.91 (95% confidence interval 0.73-1.14) for early exposure and 1.26 (95% confidence interval 0.86-1.86) for late exposure. Most preterm births (79.2%) occurred in weeks 33-36 of gestation. CONCLUSIONS: Duloxetine exposure during pregnancy is unlikely to increase the risk of small for gestational age. Although not consequently statistically significant across comparisons, a trend towards an increased risk of preterm birth was observed for duloxetine exposed. Therefore, an increased risk of preterm birth cannot be excluded, especially for women exposed to duloxetine throughout pregnancy.

Potential Channeling Bias in the Evaluation of Cardiovascular Risk: The Importance of Comparator Selection in Observational Research.

BACKGROUND: Comparator selection is an important consideration in the design of observational research studies that evaluate potential associations between drug therapies and adverse event risks. It can affect the validity of observational study results, and potentially impact data interpretation, regulatory decision making, and patient medication access. OBJECTIVE: The aim of this study was to assess the impact of comparator selection bias using two real-world case studies evaluating an increased rate of acute myocardial infarction (AMI). METHODS: Data from the Truven Health Analytics MarketScan® electronic medical claims database were used to conduct two retrospective observational cohort studies, utilizing a cohort new-user design, comparing AMI risk between testosterone replacement therapy (TRT) and phosphodiesterase-5 inhibitors (PDE5is) in men treated for hypogonadism, and triptans versus other prescribed acute treatments for migraine in adults. All patients were enrolled continuously in a health plan (no enrollment gap > 31 consecutive days) for ≥ 1 year before index. Baseline period was defined as 365 days prior to index. Exposure was defined by prescription and outcome of interest was defined as occurrence of AMI. Using Cox proportional hazard models, primary analysis for the TRT cohort compared AMI risk between propensity score (PS)-matched TRT-treated and untreated patients; secondary analysis evaluated risk between PS-matched TRT-treated and PDE5i-treated patients. For the triptan cohort, primary analysis compared AMI/ischemic stroke risk between PS-matched triptan-treated and opiate-treated patients; secondary analysis evaluated risk between PS-matched triptan-treated and nonsteroidal anti-inflammatory drug (NSAID)-treated patients and PS-matched non-prescription-treated migraine patients and general patients. RESULTS: No significant association between TRT and AMI was observed among TRT-treated (N = 198,528, mean age 52.4 ± 11.4 years) versus PDE5i-treated men (N = 198,528, mean age 52.3 ± 11.5 years) overall (adjusted hazard ratio [aHR] 1.01; 95% CI 0.95-1.07; p = 0.80). Among patients with prior cardiovascular disease (CVD), risk of AMI was significantly increased for TRT-treated versus PDE5i-treated patients (aHR 1.13; 95% CI 1.03-1.25). The triptan study included three comparisons (triptans [N = 436,642] vs prescription NSAIDs [N = 334,152], opiates [N = 55,234], and untreated migraine [N = 1,168,212]), and a positive control (untreated vs general non-migraine patients [N = 11,735,009]). Analyses of MI risk in migraine patients prescribed triptans versus NSAIDs/opiates had mixed results: the point estimate ranged from 0.33 to 0.84 depending on chosen study window. CONCLUSIONS: Cardiovascular outcomes were not worse in hypogonadism patients with TRT versus PDE5i; however, a potential association with AMI was found in patients with prior CVD receiving TRT versus PDE5i. Findings pointed to a pseudo-protective effect of triptans versus untreated migraine patients or those potentially older and less healthy patients exposed to prescription NSAIDs or opiates. Triptan users should not be compared with those using other anti-migraine prescriptions when evaluating cardiovascular outcomes in migraine patients. Presence of high cardiovascular risks may contribute to channeling bias-healthier subjects being selected to receive treatment-highlighting the importance of choosing comparators wisely in observational studies.

Assessing the incidence of osteosarcoma among teriparatide-treated patients using linkage of commercial pharmacy and state cancer registry data, contributing to the removal of boxed warning and other labeling changes.

BACKGROUND: Teriparatide, a recombinant human parathyroid hormone analogue, is associated with increased bone mineral density and a decreased risk of fractures. A dose-dependent increase in the incidence of osteosarcoma was observed in toxicology studies conducted in rats. The primary objective of this study was to estimate the incidence of osteosarcoma over a 10-year period among teriparatide-treated patients versus patients unexposed to teriparatide with osteoporosis and patients in the general population using national pharmacy dispensing data linked with data from participating state cancer registries (SCRs) in the US. METHODS: Patients aged 18 years or older with a dispensed teriparatide prescription formed two different cohorts: Teriparatide-Osteoporosis (Teriparatide-OP) was formed by matching teriparatide patients to unexposed patients with osteoporosis and Teriparatide-General Population (Teriparatide-GP) was formed by matching teriparatide patients to general population patients with a dispensed prescription for a medication other than teriparatide. Matching was performed using select demographics and other variables. Study cohorts were linked to SCR data to ascertain osteosarcoma status. To account for missing outcome data from non-participating SCRs, two analytic approaches were used: the first adjusted the person-time at-risk using a coverage fraction and the second restricted the analyses to patients from states with participating SCRs. RESULTS: There were 18 osteosarcoma cases across four study cohorts: the same three cases in the Teriparatide-OP and Teriparatide-GP cohorts, six cases in the Osteoporosis cohort, and nine cases in the General Population cohort. For the analysis using the coverage fraction the incidence rate ratio (IRR) comparing the Teriparatide-OP and Teriparatide-GP cohorts to the Osteoporosis and General Population cohorts was 1.0 (95% CI: 0.2, 4.5) and 1.3 (95% CI: 0.2, 5.1), respectively. When restricting the analysis to patients from states with participating SCRs, the IRR was 0.6 (95% CI: 0.1, 3.6) and 0.8 (95% CI 0.1, 4.0), respectively. CONCLUSION: The estimates of association between teriparatide and osteosarcoma were imprecise due to the small number of observed osteosarcoma cases. However, the incidence of osteosarcoma observed in each study cohort was within the expected range given background rates for the US general population. The evidence generated by this study, in conjunction with other real-world studies evaluating the risk of osteosarcoma, was used to support changes to the US teriparatide label (including removal of the black box warning regarding potential risk of osteosarcoma) and expand treatment options for patients with osteoporosis.

Exposure to duloxetine during pregnancy and risk of congenital malformations and stillbirth: A nationwide cohort study in Denmark and Sweden.

BACKGROUND: The prevalence of depression and the exposure to antidepressants are high among women of reproductive age and during pregnancy. Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States and Europe in 2004 for the treatment of depression. Fetal safety of duloxetine is not well established. The present study evaluates the association of exposure to duloxetine during pregnancy and the risk of major and minor congenital malformations and the risk of stillbirths. METHODS AND FINDINGS: A population-based observational study was conducted based on data from registers in Sweden and Denmark. All registered births and stillbirths in the medical birth registers between 2004 and 2016 were included. Malformation diagnoses were identified up to 1 year after birth. Logistic regression analyses were used. Potential confounding was addressed through multiple regression, propensity score (PS) matching, and sensitivity analyses. Confounder variables included sociodemographic information (income, education, age, year of birth, and country), comorbidity and comedication, previous psychiatric contacts, and birth-related information (smoking during pregnancy and previous spontaneous abortions and stillbirths). Duloxetine-exposed women were compared with 4 comparators: (1) duloxetine-nonexposed women; (2) selective serotonin reuptake inhibitor (SSRI)-exposed women; (3) venlafaxine-exposed women; and (4) women exposed to duloxetine prior to, but not during, pregnancy. Exposure was defined as redemption of a prescription during the first trimester and throughout pregnancy for the analyses of malformations and stillbirths, respectively. Outcomes were major and minor malformations and stillbirths gathered from the national patient registers. The cohorts consisted of more than 2 million births with 1,512 duloxetine-exposed pregnancies. No increased risk for major malformations, minor malformations, or stillbirth was found across comparison groups in adjusted and PS-matched analyses. Duloxetine-exposed versus duloxetine-nonexposed PS-matched analyses showed odds ratio (OR) 0.98 (95% confidence interval [CI] 0.74 to 1.30, p = 0.909) for major malformations, OR 1.09 (95% CI 0.82 to 1.45, p = 0.570) for minor malformation, and 1.18 (95% CI 0.43 to 3.19, p = 0.749) for stillbirths. For the individual malformation subtypes, some findings were statistically significant but were associated with large statistical uncertainty due to the extremely small number of events. The main limitations for the study were that the indication for duloxetine and a direct measurement of depression severity were not available to include as covariates. CONCLUSIONS: Based on this observational register-based nationwide study with data from Sweden and Denmark, no increased risk of major or minor congenital malformations or stillbirth was associated with exposure to duloxetine during pregnancy.

Duloxetine Exposure During Pregnancy and the Risk of Spontaneous and Elective Abortion: A Danish Nationwide Observational Study.

BACKGROUND: Depression and antidepressant treatment are widespread among women of childbearing age. OBJECTIVE: This study evaluates the association between duloxetine exposure during pregnancy and spontaneous and elective abortions. PATIENTS AND METHODS: The nationwide, observational study based on register data from Denmark included women with a recorded pregnancy in the birth register or an abortion in the patient register between 2004 and 2016. Duloxetine-exposed women were compared with (1) duloxetine non-exposed, (2) selective serotonin reuptake inhibitor (SSRI)-exposed, (3) venlafaxine-exposed, and (4) women discontinuing duloxetine before pregnancy. Exposure status was based on records of redeemed prescriptions. Cox regression with adjustments and propensity score matching was applied. RESULTS: The data from 1,019,957 pregnancies were used, including 1,212 pregnancies exposed to duloxetine. Duloxetine-exposed women had an increased hazard ratio (HR) for spontaneous abortions compared with SSRI-exposed women: propensity score matched HR 1.25 [95% confidence interval (CI), 1.00-1.57]. No increased hazard was observed for duloxetine-exposed women compared with duloxetine non-exposed: 1.08 (95% CI 0.89-1.31); venlafaxine-exposed: 1.08 (95% CI 0.82-1.41); and duloxetine discontinuers: 0.99 (95% CI 0.76-1.30). An increased HR of elective abortions was observed in duloxetine-exposed women compared to duloxetine non-exposed: 1.41 (95% CI 1.25-1.59); SSRI-exposed: 1.32 (95% CI 1.15-1.51); and duloxetine discontinuers: 1.46 (95% CI 1.23-1.75), but not to venlafaxine-exposed women: 1.09 (95% CI 0.93-1.27). CONCLUSION: There was no increased risk of spontaneous or elective abortion associated with exposure to duloxetine. The increase risk observed for women exposed to duloxetine in comparison with SSRI-exposed for spontaneous and in comparison with all groups (except venlafaxine-exposed) for elective abortion suggested confounding.

Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study.

OBJECTIVE: To evaluate the risk of adverse maternal and infant outcomes following in utero exposure to duloxetine. DESIGN: Cohort study nested in the Medicaid Analytic eXtract for 2004-13. SETTING: Publicly insured pregnancies in the United States. PARTICIPANTS: Pregnant women 18 to 55 years of age and their liveborn infants. INTERVENTIONS: Duloxetine exposure during the etiologically relevant time window, compared with no exposure to duloxetine, exposure to selective serotonin reuptake inhibitors, exposure to venlafaxine, and exposure to duloxetine before but not during pregnancy. MAIN OUTCOME MEASURES: Congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage. RESULTS: Cohort sizes ranged from 1.3 to 4.1 million, depending on the outcome. The number of women exposed to duloxetine varied by cohort and exposure contrast and was around 2500-3000 for early pregnancy exposure and 900-950 for late pregnancy exposure. The base risk per 1000 unexposed women was 36.6 (95% confidence interval 36.3 to 36.9) for congenital malformations overall, 13.7 (13.5 to 13.9) for cardiovascular malformations, 107.8 (107.3 to 108.3) for preterm birth, 20.4 (20.1 to 20.6) for small for gestational age infant, 33.6 (33.3 to 33.9) for pre-eclampsia, and 23.3 (23.1 to 23.4) for postpartum hemorrhage. After adjustment for measured potential confounding variables, all baseline characteristics were well balanced for all exposure contrasts. In propensity score adjusted analyses versus unexposed pregnancies, the relative risk was 1.11 (95% confidence interval 0.93 to 1.33) for congenital malformations overall and 1.29 (0.99 to 1.68) for cardiovascular malformations. For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for early exposure and 1.19 (1.04 to 1.37) for late exposure. For small for gestational age infants the relative risks were 1.14 (0.92 to 1.41) and 1.20 (0.83 to 1.72) for early and late pregnancy exposure, respectively, and for pre-eclampsia they were 1.12 (0.96 to 1.31) and 1.04 (0.80 to 1.35). The relative risk for postpartum hemorrhage was 1.53 (1.08 to 2.18). Results from sensitivity analyses were generally consistent with the findings from the main analyses. CONCLUSIONS: On the basis of the evidence available to date, duloxetine is unlikely to be a major teratogen but may be associated with an increased risk of postpartum hemorrhage and a small increased risk of cardiac malformations. While continuing to monitor the safety of duloxetine as data accumulate over time, these potential small increases in risk of relatively uncommon outcomes must be weighed against the benefits of treating depression and pain during pregnancy in a given patient. TRIAL REGISTRATION: EUPAS 15946.

Testosterone Therapy and Risk of Acute Myocardial Infarction in Hypogonadal Men: An Administrative Health Care Claims Study.

BACKGROUND: There are some ongoing debates on the potential link between testosterone therapy (TT) and risk of acute myocardial infarction (MI). AIM: To investigate the association between acute MI and TT use compared with non-use in men having documented hypogonadism (diagnostic International Classification of Diseases, Ninth Revision codes 257.2, 257.8, 257.9, 758.7) in patient claims records. METHODS: This retrospective cohort study used a real-world US-based administrative health care claims database (MarketScan 2004-2013; Truven Health Analytics, Ann Arbor, MI, USA) to compare MI rates between TT-treated men and a cohort of untreated hypogonadal men matched by a calendar time-specific propensity score. Subgroup analyses were performed by route of administration, age, and prior cardiovascular disease (CVD). OUTCOMES: Incidence rates of MI (per 1,000 person-years) and hazard ratio. RESULTS: After 1:1 calendar time-specific propensity score matching, 207,176 TT-treated men and 207,176 untreated hypogonadal men were included in the analysis (mean age = 51.8 years). Incidence rates of MI were 4.20 (95% CI = 3.87-4.52) in the TT-treated cohort and 4.67 (95% CI = 4.43-4.90) in the untreated hypogonadal cohort. Cox regression model showed no significant association between TT use and MI when comparing TT-treated with untreated hypogonadal men overall (hazard ratio = 0.99, 95% CI = 0.89-1.09), by age, or by prior CVD. A significant association was observed when comparing a subgroup of injectable (short- and long-acting combined) TT users with untreated hypogonadal men (hazard ratio = 1.55, 95% CI = 1.24-1.93). CLINICAL IMPLICATION: In this study, there was no association between TT (overall) and risk of acute MI. STRENGTHS AND LIMITATIONS: Strengths included the use of a comprehensive real-world database, sophisticated matching based on calendar blocks of 6 months to decrease potential bias in this observational study, carefully chosen index dates for the untreated cohort to avoid immortal time bias, and implemented sensitivity analysis to further investigate the findings (stratification by administration route, age, and prior CVD). Key limitations included no information about adherence, hypogonadism condition based solely on diagnosis (no information on clinical symptoms or testosterone levels), lack of information on disease severity, inability to capture diagnoses, medical procedures, and medicine dispensing if corresponding billing codes were not generated and findings could contain biases or fail to generalize well to other populations. CONCLUSION: This large, retrospective, real-world observational study showed no significant association between TT use and acute MI when comparing TT-treated with untreated hypogonadal men overall, by age, or by prior CVD; the suggested association between injectable TT and acute MI deserves further investigation. Li H, Mitchell L, Zhang X, et al. Testosterone Therapy and Risk of Acute Myocardial Infarction in Hypogonadal Men: An Administrative Health Care Claims Study. J Sex Med 2017;14:1307-1317.

Intranasal Fluticasone Propionate Observational Cohort Safety Studies: Reviewing Evidence from Databases on Two Continents.

PURPOSE: Our objective was to highlight the importance of database selection in observational research and to determine the incidence of corticosteroid-related events in patients exposed to fluticasone propionate intranasal spray (FPNS) compared with other intranasal steroids (INS). METHODS: After a feasibility study using an electronic medical record database in the UK (1990-2002), a retrospective cohort study was conducted using a large administrative claims database in the USA from 1994 to 2002 comparing the incidence and rate ratios of steroid-related events among intermittent, sub-chronic, and chronic FPNS use and other INS use episodes. RESULTS: Most patients used INS intermittently; power was low to evaluate risk associated with chronic use. Significantly elevated adjusted rate ratios were observed in the US study comparing FPNS with other INS for hypercorticism, sinusitis, abscess, and empyema, as well as a significantly decreased rate ratio for cataracts. The US claims database provided greater granularity on covariates and markers of severity to improve control of confounding for this study and time period, but neither database was able to assess the indication for prescription and the UK study could not address the use of INS without a prescription. CONCLUSIONS: The FPNS results were consistent with the risk profile for INS and did not raise any new safety signals at the time of study conduct, which is consistent with the current safety profile. We were not able to discern the extent of potential off-label use of FPNS or other INS. Differences in the available data and healthcare systems highlight important considerations for database selection in the feasibility phase to assess the precision and limitations prior to formal risk evaluation.

Association between Use of Exogenous Testosterone Therapy and Risk of Venous Thrombotic Events among Exogenous Testosterone Treated and Untreated Men with Hypogonadism.

PURPOSE: Limited information exists about whether exogenous testosterone therapy is associated with a risk of venous thrombotic events. We investigated via cohort and nested case-control analyses whether exogenous testosterone therapy is associated with the risk of venous thrombotic events in men with hypogonadism. MATERIALS AND METHODS: Databases were reviewed to identify men prescribed exogenous testosterone therapy and/or men with a hypogonadism diagnosis. Propensity score 1:1 matching was used to select patients for cohort analysis. Cases (men with venous thrombotic events) were matched 1:4 with controls (men without venous thrombotic events) for the nested case-control analysis. Primary outcome was defined as incident idiopathic venous thrombotic events. Cox regression and conditional logistic regression were used to assess HRs and ORs, respectively. Sensitivity analyses were also performed. RESULTS: A total of 102,650 exogenous testosterone treated and 102,650 untreated patients were included in cohort analysis after matching, and 2,785 cases and 11,119 controls were included in case-control analysis. Cohort analysis revealed a HR of 1.08 for all testosterone treated patients (95% CI 0.91, 1.27, p = 0.378). Case-control analysis resulted in an OR of 1.02 (95% CI 0.92, 1.13, p = 0.702) for current exogenous testosterone therapy exposure and an OR of 0.92 (95% CI 0.82, 1.03, p = 0.145) for past exogenous testosterone therapy exposure. These results remained nonstatistically significant after stratifying by exogenous testosterone therapy administration route and age category. Most sensitivity analyses yielded consistent results. CONCLUSIONS: No significant association was found between exogenous testosterone therapy and incidents of idiopathic or overall venous thrombotic events in men with hypogonadism. However, some discrepant findings exist for the association between injectable formulations and the risk of overall venous thrombotic events.

Diagnoses of gastrointestinal cancers after gastrointestinal bleeding in patients receiving clopidogrel or warfarin.

BACKGROUND AND AIMS: The association between gastrointestinal (GI) bleeding and subsequent detection of GI cancer in patients using antiplatelet/anticoagulant medications is unclear. We investigated the association between the occurrence of GI bleeding and the detection of GI cancer and assessed whether this association differs in patients treated with clopidogrel or warfarin compared to non-treated patients. METHODS: A claims analysis was conducted using the Truven Health MarketScan(®) Research databases. Patients were grouped into the treatment cohort if they received a prescription for clopidogrel or warfarin or into the non-treatment cohort if they did not receive these medications. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for GI cancer diagnosed after GI bleeding. RESULTS: Overall, in the treatment cohort, patients who experienced a GI bleed were 6 times (HR: 5.64, 95% CI, 5.12, 6.21) more likely to be diagnosed with GI cancer compared with those without bleeding. In the non-treatment cohort patients were 13 times (HR: 13.34, 95% CI, 12.21, 14.58) more likely to be diagnosed with GI cancer after GI bleeding. The HRs of GI cancer were higher within 6 months of the first GI bleed and decreased remarkably thereafter. CONCLUSIONS: This study suggests that an episode of GI bleeding increased the rates of detection of GI cancers.

Risk of Mortality (including Sudden Cardiac Death) and Major Cardiovascular Events in Users of Olanzapine and Other Antipsychotics: A Study with the General Practice Research Database.

Objective. Assess risk of cardiac events and mortality among users of olanzapine and other antipsychotics relative to nonusers. Methods. The General Practice Research Database was used to identify cohorts of antipsychotic users and nonusers with psychiatric illness. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Results. 183,392 antipsychotic users (including 20,954 olanzapine users) and 193,920 psychiatric nonusers were identified. There was a significantly higher rate of cardiac mortality (adjusted RR [aRR]: 1.53, CI, 1.12-2.09) in olanzapine users relative to psychiatric nonusers, consistent with findings for both atypical and typical antipsychotics. Relative to psychiatric nonusers, no increased risk of all-cause mortality was observed among olanzapine users (aRR: 1.04, CI, 0.93-1.17), but elevated all-cause mortality risk was observed when compared to all antipsychotic users (aRR: 1.75, CI, 1.64-1.87). There was no increased risk of CHD or VA among olanzapine users relative to psychiatric nonusers, consistent with findings for atypical but not typical antipsychotics. SCD cases were uncommon. Conclusions. Use of antipsychotic agents was associated with increased risk of all-cause and cardiac mortality. Patients treated with olanzapine were found to be at increased risk of cardiac mortality versus psychiatric nonusers.

Risk of mortality (including sudden cardiac death) and major cardiovascular events in atypical and typical antipsychotic users: a study with the general practice research database.

Objective. Antipsychotics have been associated with increased cardiac events including mortality. This study assessed cardiac events including mortality among antipsychotic users relative to nonusers. Methods. The General Practice Research Database (GPRD) was used to identify antipsychotic users, matched general population controls, and psychiatric diseased nonusers. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Sensitivity analyses were conducted for age, dose, duration, antipsychotic type, and psychiatric disease. Results. 183,392 antipsychotic users (115,491 typical and 67,901 atypical), 544,726 general population controls, and 193,920 psychiatric nonusers were identified. Nonusers with schizophrenia, dementia, or bipolar disorder had increased risks of all-cause mortality compared to general population controls, while nonusers with major depression had comparable risks. Relative to psychiatric nonusers, the adjusted relative ratios (aRR) of all-cause mortality in antipsychotic users was 1.75 (95% CI: 1.64-1.87); cardiac mortality 1.72 (95% CI: 1.42-2.07); SCD primary definition 5.76 (95% CI: 2.90-11.45); SCD secondary definition 2.15 (95% CI: 1.64-2.81); CHD 1.16 (95% CI: 0.94-1.44); and VA 1.16 (95% CI: 1.02-1.31). aRRs of the various outcomes were lower for atypical versus typical antipsychotics (all-cause mortality 0.83 (95% CI: 0.80-0.85); cardiac mortality 0.89 (95% CI: 0.82-0.97); and SCD secondary definition 0.76 (95% CI: 0.55-1.04). Conclusions. Antipsychotic users had an increased risk of cardiac mortality, all-cause mortality, and SCD compared to a psychiatric nonuser cohort.

Epidemiology and healthcare utilization of neurogenic bladder patients in a US claims database.

AIMS: To characterize the patient profile, medication utilization, and healthcare encounters of patients with neurogenic bladder dysfunction related to incontinence. METHODS: Medical and pharmacy claims were retrospectively analyzed from April 1, 2002 to March 31, 2007 to characterize neurogenic bladder patients. There were 46,271 patients in the Neurogenic bladder cohort, and 9,315 and 4,168 patients in Multiple Sclerosis (MS) and Spinal Cord Injury (SCI) subcohorts, respectively. Demographic data, concomitant diseases, use of overactive bladder (OAB) oral drug, and healthcare encounters were summarized using descriptive statistics. RESULTS: The mean age of neurogenic bladder patients was 62.5 (standard deviation 19.6) years. A high frequency of lower urinary tract infections (UTIs; 29%-36%), obstructive uropathies (6%-11%), and urinary retention (9%-14%), was observed. Overall, 33,100 (71.5%) patients were taking an OAB oral drug; 10,110 (30.5%) patients discontinued and did not restart. During the one-year follow-up period, 39.0% (8,034) of neurogenic bladder patients had a urology visit, 31.7% (14,679) had a neurology visit, 33.3% (15,415) were hospitalized, and 14.4% (6,646) were in a nursing home (highest rates observed in SCI subcohort). UTI diagnoses comprised over 20% of all hospitalizations one-year post-index. Annually, neurogenic bladder patients averaged 16 office and 0.5 emergency room visits. CONCLUSIONS: This is the largest observational study conducted to address the epidemiology of the neurogenic bladder population, including healthcare utilization. These data suggest that patients with neurogenic bladder may have suboptimal management, indicated by high incidences of urinary tract complications and hospitalizations.

Prevalence of pediatric dyslipidemia: comparison of a population-based claims database to national surveys.

OBJECTIVE: To determine the prevalence of pediatric dyslipidemia in a large US medical insurance claims database and to compare the resulting estimate to the prevalence from the National Health and Nutrition Examination Survey (NHANES). PATIENTS AND METHODS: Children 10-18 years old who had laboratory-defined dyslipidemia were identified from the Integrated Healthcare Information Services (IHCIS) database 2003-2006. For comparison purposes, the corresponding prevalence among the US children of same age was estimated from the NHANES 1999-2004 data. RESULTS: Among the 273 064 children with at least one laboratory lipid value in the IHCIS database, 22.9% (n = 62 451) had laboratory-defined dyslipidemia. This prevalence was the same as the NHANES estimate (23.9%, 95%CI: 21.6-26.3). Elevated triglyceride (TG) was the most common type of dyslipidemia, detected among 13.2% of the IHCIS children and 14.2% of the US children, followed by elevated total cholesterol (TC), 7.7 and 9.6%, respectively. Among IHCIS dyslipidemic children, older teenage boys had higher rates than younger boys for high-density lipoprotein cholesterol (HDL-C) abnormality, but lower rates for elevated TC and low-density lipoprotein cholesterol (LDL-C). These age-related trends were also seen among NHANES dyslipidemic children. CONCLUSIONS: Analyses of a population-based claims database revealed the same prevalence of pediatric dyslipidemia as that among the US children assessed in the NHANES data. Among dyslipidemic children in the claims database, the occurrence of specific dyslipidemias appeared to vary by age and gender, a trend that was also seen among the dyslipidemic children in the US.

Longitudinal study on pediatric dyslipidemia in population-based claims database.

PURPOSE: To examine the rate of lipid testing among children from a large US medical insurance claims database, describe the characteristics of pediatric dyslipidemia, and assess the sensitivity of the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes for identifying dyslipidemic children. METHODS: This retrospective cohort study used the claims data from the Integrated Healthcare Information Services (IHCIS), for the years 2003-2006. Two study cohorts consisted of children with laboratory-defined and diagnosis/treatment-defined dyslipidemia, respectively. They were compared to age- and gender-matched children without dyslipidemia, with respect to co-morbidities during the 6-month prior to and 12-month after the first dyslipidemic laboratory value or diagnosis/treatment. RESULTS: Seven per cent of the children who had laboratory values available in the database had a cholesterol test during the study period. Only 15% of laboratory-defined children (n = 23,475) had a dyslipidemia diagnosis. Cholesterol-modifying medications were rarely prescribed. Substantially more laboratory-defined children than their comparators were obese (8 times), had diabetes mellitus (10 times), or had hypertension (5 times). These co-morbidities were even higher among diagnosis/treatment-defined children. CONCLUSIONS: The rate of lipid testing among children was low. The ICD-9-CM diagnostic codes showed low sensitivity against laboratory definitions. Though only a small proportion of dyslipidemic children were diagnosed or treated with a medication, co-morbidities associated with dyslipidemia were common.

Effectiveness of rosuvastatin compared to other statins for the prevention of cardiovascular events-a cohort study in 395 039 patients from clinical practice.

PURPOSE: This study compared the effectiveness of rosuvastatin (RSV) to other statins prescribed in clinical practice in prevention of cardiovascular (CV) events. METHODS: This longitudinal inception cohort study, using Thomson Healthcare's MarketScan databases, included patients aged > or = 18 starting statin therapy during August 2003-December 2005. Patients were followed until 90 days after index statin monotherapy exposure, start of another lipid-lowering therapy, an event, end of eligibility, or end of study. The primary endpoint was a composite of CV death (in-hospital only), myocardial infarction, unstable angina, coronary revascularization, stroke, and carotid revascularization. Adjusted time-to-event analyses incorporating a propensity score covariate were used, and analyses were stratified by duration of statin exposure. RESULTS: Among 395 039 patients who met inclusion/exclusion criteria, 12% initiated RSV, and 9622 (2.4%) of the total patient population experienced an outcome event. The median duration of statin treatment and follow-up was 100 days and 180 days, respectively. No statistically significant difference in CV event rates between RSV and other statins was observed after adjustment for demographics and medical/prescription history (HR = 0.99, 95%CI = 0.93-1.06). However, with longer exposure time, there was a suggestion of increased benefit with RSV compared to other statins. CONCLUSIONS: The primary analysis showed similar incidence rates of CV-related events between the statin cohorts over a median of 180 days of follow-up.

Risk of further decline in renal function after the use of oral sodium phosphate or polyethylene glycol in patients with a preexisting glomerular filtration rate below 60 ml/min.

OBJECTIVES: The aim of this study was to estimate the risk of further creatinine increase in patients with preexisting renal disease after the use of oral sodium phosphate (OSP) versus polyethylene glycol (PEG), and to study usage patterns of OSP in relation to renal function. METHODS: A cohort study was done using clinical records and electronic patient information from the Henry Ford Health System (HFHS) in patients who had used either OSP or PEG for colonoscopy between February 1999 and April 2006. Among patients with an estimated GFR < 60 ml/min before colonoscopy, we identified cases with an unexplained creatinine increase of > or = 0.5 mg/dl within 14 days after colonoscopy. RESULTS: We identified 7,971 OSP and 1,511 PEG users. Relative use of OSP versus PEG decreased from 88.0% before 2004 to 48.4% in 2006. 70.2% of OSP users had no recorded creatinine determination within 60 days before colonoscopy, and this proportion did not decrease over time. The study population included 317 patients with a baseline GFR < 60 ml/min, and we identified one case with an unexplained creatinine increase > or = 0.5 mg/dl among 191 PEG users (0.5%) versus eight cases among 126 OSP users (6.3%). Unadjusted and adjusted relative risk estimates on comparing OSP with PEG were 12.1 (95% CI, 1.5-95.8) and 12.6 (95% CI, 1.5-106.5), respectively. CONCLUSIONS: In patients with preexisting renal disease, OSP use was associated with an increased risk of aggravated renal dysfunction versus PEG. Creatinine measurement with GFR estimation should be done before OSP administration in order to avoid its use in patients with renal disease.

Is there an association between hypothyroidism and open-angle glaucoma in an elderly population? An epidemiologic study.

PURPOSE: There have been conflicting reports pertaining to the association between hypothyroidism and open-angle glaucoma (OAG). The purpose of this study was to assess the hypothesized association between preexisting hypothyroidism and development of OAG in a population-based setting. DESIGN: Case-control study. PARTICIPANTS: The study population and controls were taken from all patients in a large US managed care database aged >or=60 years with 4 years of continuous eligibility dating from January 1, 2001, through December 31, 2004. METHODS: A total of 4728 newly diagnosed OAG patients were matched with 14 184 controls (3:1 matching) based on age and gender. MAIN OUTCOME MEASURES: Conditional logistic regression was used to assess the relationship between hypothyroidism and OAG while controlling for various risk factors (ischemic heart disease, cerebrovascular disease, hyperlipidemia, hypertension, arterial disease, diabetes, and migraines). RESULTS: Based on a diagnosis of hypothyroidism or use of a thyroid replacement therapy, prior hypothyroidism was found in 815 (17.2%) OAG subjects and in 2498 (17.6%) control subjects. After adjusting for the specified risk factors, patients with OAG were not found to be associated with a prior hypothyroid diagnosis when compared with control subjects (odds ratio, 0.93; 95% confidence interval, 0.85-1.01). CONCLUSIONS: An association between prior hypothyroidism and OAG development was not found. The large proportion of patients receiving thyroid replacement therapy may have negated any OAG-related consequences of hypothyroidism.

Risk of impaired renal function after colonoscopy: a cohort study in patients receiving either oral sodium phosphate or polyethylene glycol.

OBJECTIVES: We aimed to evaluate frequency, predictors, and monitoring of renal dysfunction related to the use of oral sodium phosphates for colonoscopy in clinical practice. METHODS: Cohort study using clinical records and electronic patient information from the Henry Ford Health System, Detroit, MI. We identified patients undergoing colonoscopy using sodium phosphate or polyethylene glycol (PEG), and estimated the risk of renal impairment associated with bowel preparation and other risk factors. RESULTS: Out of 7,897 patients, 6,833 had used sodium phosphate; 1,617 patients had renal dysfunction within 12 months prior to colonoscopy and 3,928 patients had no creatinine measurement within 12 months prior to or 6 months postcolonoscopy. Among the remaining 2,352 patients, 88 had incident renal dysfunction (glomerular filtration rate [GFR]<60 mL/min) after colonoscopy. The relative risk (RR) estimate for renal dysfunction comparing sodium phosphate with PEG was 1.13 (95% CI 0.58-2.23) without adjustment, and 1.14 (95% CI 0.55-2.39) after multivariate adjustment. Significant univariate risk factors were age>or=65 yr, African-American race, low baseline GFR, hypertension, and use of angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin-renin blockers, or thiazide diuretics. CONCLUSIONS: In patients without preexisting renal disease, the risk of renal impairment after colonoscopy appears to be similar between sodium phosphate and PEG users. Sodium phosphate use in patients with preexisting renal disease is not recommended, but common in clinical practice. Sodium phosphate should not be used in patients with preexisting serious renal disease, adequate hydration should be assured in all patients, and renal function should be monitored before and after colonoscopy in those at risk of renal dysfunction.