QT-Interval Prolongation, Torsades de Pointes, and Heart Failure With EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: Systematic Review.

A systematic literature review was conducted to determine the incidence and mortality of QT-interval prolongation (QTp), torsades de pointes (TdP), and heart failure (HF) in patients with non-small cell lung cancer (NSCLC) who received epidermal growth factor receptor (EGFR) TKIs. Of 296 identified publications, 95 met eligibility criteria and were abstracted for QTp/TdP and HF outcomes (QTp/TdP: 83 publications, including 5 case study publications; HF: 79 publications, including 6 case study publications [involving 8 patients]). QTp incidence ranged from 0% to 27.8% in observational studies and from 0% to 11% in clinical trials, with no deaths due to QTp. There were no TdP events or deaths due to TdP. The incidence of HF ranged from 0% to 8%, and HF mortality rates ranged from 0% to 4%. Patients receiving treatment with EGFR TKIs should be monitored for signs of QTp, TdP, and HF per prescribing information. Standardized definitions and methods to improve monitoring of QTp, TdP, and HF-related events are needed in patients with NSCLC.

Predictors of Pancreatitis Among Patients with Inflammatory Bowel Disease Treated with Vedolizumab: Observation from a Large Global Safety Database.

BACKGROUND: Patients with inflammatory bowel diseases (IBDs) are at increased risk of pancreatitis. Data from a global safety database (GSD) were queried to identify risk factors for pancreatitis in vedolizumab-treated patients with IBD. METHODS: Takeda's GSD was retrospectively queried for case reports (CRs) of adverse events (AEs) following vedolizumab treatment, from licensure (May 20, 2014) through March 31, 2021. Unsolicited and solicited CRs of pancreatitis were coded using the Medical Dictionary for Regulatory Activities (MedDRA) High-Level Term "Acute and chronic pancreatitis." To examine factors associated with severe pancreatitis, serious CRs (serious AEs [SAEs]) were compared with SAEs from a comparator group of 600 random non-pancreatitis AEs. Comparisons were performed using t, χ2, and Fisher's exact tests. Logistic regression was performed to adjust for covariates allowing backward selection. RESULTS: In total, 196 patients reported pancreatitis in > 700,000 patient-years of vedolizumab exposure. Pancreatitis was serious in 195 patients (99.5%), and non-pancreatitis AEs were serious in 195 of 600 (32.5%) in the random comparator group. In the pancreatitis group, 17 patients (8.7%) had a known history of pancreatitis versus none in the random comparator group. Younger age, vedolizumab indication of ulcerative colitis, concomitant medications (with a risk for pancreatitis), pancreatitis history, and comorbid conditions (especially ongoing pancreatitis) were associated with development of severe pancreatitis. CONCLUSIONS: These analyses identified factors associated with pancreatitis SAEs in patients with IBD treated with vedolizumab, but do not suggest an increased risk of pancreatitis with vedolizumab. These findings will help inform which patients treated for IBD might have an elevated risk, regardless of treatment.

People with inflammatory bowel diseases (IBDs) are at increased risk for inflammation of the pancreas (pancreatitis). Vedolizumab (VE-doe-LIZ-ue-mab), approved for the treatment of IBD, works by preventing cells that cause inflammation from entering the gut lining. We looked at a worldwide safety database to identify factors that may increase the risk for pancreatitis in people with IBD receiving vedolizumab. Since vedolizumab's approval in 2014, 196 people had pancreatitis in > 700,000 person-years of vedolizumab exposure. Person-years account for the number of people in the study and for duration of treatment. Most (195 of 196) people with pancreatitis had serious cases. In a comparator group of people with random side effects other than pancreatitis, about one in three people had serious side effects. Among the 195 people with serious pancreatitis, 17 had a history of pancreatitis, compared with none in the comparator group. We found several factors that may increase the risk for serious pancreatitis: younger age, treatment for ulcerative colitis, previous pancreatitis, taking other medicines, and having additional medical conditions. The relatively few identified cases of pancreatitis from over 700,000 years of patient exposure does not suggest an increased risk for developing pancreatitis. These findings could be used to identify people treated for IBD who may have an increased risk of developing pancreatitis.

Design of a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of prucalopride in pediatric patients with functional constipation.

Background: A previous phase 3 trial of prucalopride in pediatric patients (6 months-18 years old) with functional constipation (FC) demonstrated no efficacy versus placebo. We designed an additional phase 3 trial to further assess the efficacy, long-term safety and tolerability of prucalopride in children and adolescents. Methods: This multicenter trial (ClinicalTrials.gov identifier: NCT04759833; EudraCT number: 2022-003221-22) comprises a 12-week, randomized, double-blind, placebo-controlled phase, followed by a 36-week, double-blind, safety extension phase. Approximately 240 toilet-trained patients aged 3-17 years will be randomized 1:1:1 to receive low- (0.04 mg/kg) or high-dose (0.08 mg/kg) prucalopride, or placebo once daily. Fifteen non-toilet-trained patients ≥6 months old with FC will be included in an exploratory efficacy and safety analysis. Discussion: The efficacy endpoints used in this study will differ from those used in adults and in the previous pediatric phase 3 trial; they have been adapted to be more suitable for a wider age range of pediatric patients. Both study phases will be longer than in the previous pediatric study, providing a longer time period in which to assess the efficacy and safety of prucalopride. Study participants will be identified using the modified Rome IV criteria for FC, instead of the Rome III criteria, and non-toilet-trained patients will be included, which will broaden the population of pediatric patients assessed. Patients will undergo fecal disimpaction before randomization and undergo standardized continuous behavioral therapy throughout the trial. This pediatric study of prucalopride will aim to demonstrate the efficacy and long-term safety of this treatment.

A Review of the Cardiovascular Safety of Prucalopride in Patients With Chronic Idiopathic Constipation.

Prokinetic agents, specifically 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonists, have been shown to provide relief in chronic idiopathic constipation (CIC). The first-generation 5-HT 4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events. This review summarizes CV safety data for prucalopride, a high-affinity 5-HT 4 agonist approved in the United States in 2018 for adults with CIC. No significant effects of prucalopride on CV safety were observed in animal models or early-phase clinical studies, including a thorough QT study at therapeutic (2 mg) or supratherapeutic (10 mg) doses. Among 1,750 patients with CIC who received prucalopride (2-4 mg) in 5 phase 3 studies, no trends in CV adverse events, electrocardiogram parameters, or blood pressure were documented; ≤1.0%-2.0% of patients had prolonged QT interval corrected for heart rate (HR) using Fridericia formula after placebo or prucalopride treatment, and low HR occurred in ≤6.1% and ≤3.3% of these patients, respectively. In two 24-month observational studies among 2,468 patients, changes in electrocardiogram parameters over time were minor, except at occasional time points when significant changes from baseline were reported for HR or QT interval. In a real-world European CV safety study among 35,087 patients (prucalopride, 5,715; polyethylene glycol 3350 [PEG3350], 29,372), results were consistent for no evidence of increased risk of major adverse CV events among patients treated with prucalopride vs PEG3350 (incidence rate ratio = 0.64; 95% confidence interval 0.36-1.14). Studies to date have not raised concerns regarding the impact of prucalopride treatment on CV parameters.

Treatment characteristics among patients with binge-eating disorder: an electronic health records analysis.

OBJECTIVES: Treatment for adults diagnosed with binge-eating disorder (BED) includes psychotherapy and/or pharmacotherapy and aims to reduce the frequency of binge-eating episodes and disordered eating, improve metabolic-related issues and reduce weight, and address mood symptoms. Data describing real-world treatment patterns are lacking; therefore, this study aims to characterize real-world treatment patterns among patients with BED. METHODS: This retrospective study identified adult patients with BED using natural language processing of clinical notes from the Optum electronic health record database from 2009 to 2015. Treatment patterns were examined during the 12 months preceding the BED recognition date and during a follow-up period after BED recognition (1-3 years for most patients). RESULTS: Among 1042 patients, 384 were categorized as the BED cohort and 658, who met less stringent criteria, were categorized as probable BED. In the BED cohort, mean ± SD age was 45.2 ± 13.4 years and 81.8% were women (probable BED, 45.9 ± 12.8 years, 80.2%). A greater percentage of patients in the BED cohort were prescribed pharmacotherapy (70.6% [probable BED, 66.9%]) than received/discussed psychotherapy (53.1% [probable BED, 39.2%]) at baseline. In the BED cohort, 54.4% of patients were prescribed antidepressants (probable BED, 52.4%), 25.3% stimulants (probable BED, 20.1%), and 34.4% nonspecific psychotherapy (probable BED, 24.6%) at baseline, with no substantive differences observed during follow-up. Low percentages of patients in the BED cohort received/discussed cognitive behavioral therapy at baseline (12.5% [probable BED, 9.0%) or during follow-up (13.0% [probable BED, 8.8%). Among patients with ≥1 psychotherapy visit, the mean ± SD number of visits in the BED cohort was 1.2 ± 5.9 at baseline (probable BED, 1.7 ± 7.3) and 2.2 ± 7.7 during follow-up (probable BED, 2.6 ± 7.7). CONCLUSION: This cohort of patients with BED was treated more frequently with pharmacotherapy than psychotherapy. These data may help inform strategies for reducing differences between real-world treatment patterns and evidence-based recommendations.

The Association of Oral Stimulant Medication Adherence with Work Productivity among Adults with ADHD.

OBJECTIVE: Examine associations between oral psychostimulant pharmacotherapy adherence, work productivity, and related indirect costs among US adults with ADHD. METHODS: Medication adherence (Medication Adherence Reasons Scale [MAR-Scale]), work productivity and activity impairment (Work Productivity and Activity Impairment-General Health questionnaire), and ADHD symptom level (Adult ADHD Self-Report Scale version 1.1 Symptom Checklist) were assessed in this noninterventional online survey of adults who self-reported having an ADHD diagnosis and were currently receiving oral psychostimulant treatment for ≥3 months. RESULTS: Of 602 respondents, 395 had low/medium adherence (LMA: MAR-Scale total score ≥1) and 207 had high adherence (HA: MAR-Scale total score 0). After adjusting for covariates, the LMA group had significantly greater levels of absenteeism, absenteeism-related indirect costs, and total indirect costs (all p < .01) than the HA group. CONCLUSION: In adults with ADHD using oral psychostimulants, lower medication adherence was associated with greater absenteeism and indirect costs.

Efficacy of Prucalopride for Chronic Idiopathic Constipation: An Analysis of Participants With Moderate to Very Severe Abdominal Bloating.

INTRODUCTION: This post hoc analysis evaluated the effect of prucalopride on abdominal bloating in participants with chronic idiopathic constipation (CIC) who had moderate to very severe bloating at baseline. METHODS: Data from 6 phase 3/4 studies of prucalopride in participants with CIC were pooled. Abdominal bloating was assessed weekly using a 5-point scale (0-4). RESULTS: The proportion of bloating responders (≥1-point improvement in abdominal bloating score at week 12) was higher in participants treated with prucalopride (62.1%) vs placebo (49.6%). DISCUSSION: The prucalopride arm had a higher proportion of bloating responders vs placebo in this study population.

Suicidality risk among adults with binge-eating disorder.

OBJECTIVE: To estimate relative suicidality risk associated with binge-eating disorder (BED). METHODS: Retrospective study of patients identified as having BED (N = 1042) and a matched general population cohort (N = 10,420) from the Optum electronic health record database between January 2009 and September 2015. Patients had ≥1 outpatient encounter with a provider who recognized BED during the 12-month baseline preceding entry date. Incidence and relative risk of suicidality were assessed. RESULTS: Incidence per 1000 person-years (95% CI) of suicidal ideation and suicide attempts, respectively, was 31.1 (23.1, 41.0) and 12.7 (7.9, 19.4) in the BED cohort and 5.8 (4.7, 7.1) and 1.4 (0.9, 2.2) in the comparator cohort. Risk of suicidal ideation and suicide attempts was greater in the BED cohort (HR [95% CIs], 6.43 [4.42, 9.37]) than in the comparator cohort (HR [95% CI], 9.47 [4.99, 17.98]) during follow-up. After adjusting for psychiatric comorbidities, associations of suicidal ideation and suicide attempts with BED remained elevated in patients with BED having histories of suicidality. CONCLUSIONS: Findings suggest that history of suicidality may result in an increased risk of suicidal ideation and suicide attempts in patients with BED relative to the general population. Psychiatric comorbidity burden may explain the elevated risk of these conditions in BED.

Disruption of Pharmacotherapy During the Transition from Adolescence to Early Adulthood in Patients with Attention-Deficit/Hyperactivity Disorder: A Claims Database Analysis Across the USA.

BACKGROUND AND OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) treatment rates in adults are low, possibly owing to discontinuation of pediatric care due to various circumstances (including inadequate health insurance coverage, poor disease insight, and patient/family resistance, as well as those who manage their ADHD independent of pharmacologic intervention) during the transition from adolescence to adulthood. To improve the understanding of treatment patterns during this transition, this study characterized pharmacotherapy use in patients with ADHD aged 16-21 years. METHODS: A retrospective claims analysis of the IBM® MarketScan® Commercial Databases, which represent all census regions of the USA, included patients aged 16-21 years with two or more ADHD diagnoses between 1/1/2008 and 12/31/2017 (one or more diagnoses during the year of age 17) who were continuously enrolled from ages 16-21 years and prescribed ADHD medication for ≥ 6 months at age 17 years. Pharmacotherapy use was assessed longitudinally. Comparisons between ages were conducted using Wilcoxon signed-rank tests and McNemar tests. Treatment discontinuation was estimated using Kaplan-Meier analyses. RESULTS: The analysis included 10,292 patients. The overall percentage of patients receiving pharmacotherapy significantly decreased (p < 0.001, regardless of treatment type and presence of co-occurring psychiatric disorders) as patients aged, with a median time to treatment discontinuation of 2.94 years. Among patients using pharmacotherapy at the age of 17 years, more than 30% were no longer using pharmacotherapy at age 21 years. As patients aged, the percentage using long-acting amphetamines or methylphenidates decreased, and the percentage receiving no treatment increased. The percentage of patients with disrupted treatment from age 18 to 21 years ranged from 17.9 to 24.1%. After transitioning to disrupted treatment or no treatment, low percentages of patients returned to pharmacotherapy use (disrupted treatment: 15.7-21.5% per year; no treatment, 2.7-3.8% per year). Across all age groups, statistically significantly greater (p < 0.05) percentages of patients with co-occurring psychiatric disorders used lisdexamfetamine, dextroamphetamine-amphetamine mix short acting, and non-stimulants compared with patients without co-occurring psychiatric disorders. Patients with co-occurring psychiatric disorders remained on ADHD pharmacotherapy longer and switched or augmented their pharmacotherapy more frequently than patients without co-occurring psychiatric comorbidities. CONCLUSIONS: Patients rarely reinitiated treatment after pharmacotherapy was disrupted or discontinued, emphasizing the need for increased focus on the management of ADHD as patients transition from adolescence to adulthood.

Epidemiology of status epilepticus in the United States: A systematic review.

OBJECTIVES: Convulsive status epilepticus (CSE) is a life-threatening neurologic emergency, which is defined by the International League Against Epilepsy (ILAE) as bilateral tonic-clonic seizure activity lasting longer than 5 min, while absence status epilepticus (SE) and focal SE are specified as exceeding 10 min. Epidemiological evidence on SE is currently lacking, and the incidence is not well-known, especially in light of changes in the ILAE criteria for SE. The objectives of this systematic literature review were to describe the epidemiology of SE in the US population and the associated burden of illness. METHODS: A systematic review, including literature and pragmatic searches, was conducted. Literature searches were performed using MEDLINE, Embase, BIOSIS, and Web of Science electronic databases from inception to February 2019. Pragmatic searches of the gray literature were carried out using Google, Google Scholar, conference proceedings, and ClinicalTrials.gov to identify additional sources. Only US-based studies or multinational studies reporting US data of interest were included. RESULTS: In total, 69 sources were identified. The incidence of all SE in patients of all ages in the USA ranged from 18.3 to 41 per 100,000 people per year. Incidence of all-age CSE rose from 3.5 (1979) to 12.5 (2010) per 100,000 people per year. Status epilepticus incidence followed a bimodal (U-shaped) distribution, with the highest estimates in the first years of life (0-4 years) and after 60 years. Mortality associated with SE varied from 21% over 30 days to 31.2% over 10 years. For CSE, two studies reported similar in-hospital mortalities (9.2% and 10.7%). Median healthcare costs related to SE admission were approximately US$14,500 per adult (17-45 years) and US$8000 per child (0-16 years). CONCLUSIONS: There is a lack of recent data on the epidemiology and healthcare burden associated with SE. Reports of SE incidence in the USA are highly variable and predate the 2015 ILAE definition of SE. However, the available data suggest a high burden of illness.

Burden of disease in patients with a history of status epilepticus and their caregivers.

OBJECTIVE: Status epilepticus (SE) is a life-threatening neurological emergency with the potential for wide-ranging impact on patients and caregivers. In this study, the burden of disease in patients with a history of SE and their caregivers was assessed. METHODS: Adult patients as well as caregivers of children, adolescents, and adults who had experienced ≥1 SE event in the past 24 months completed an online survey. Functional, social, emotional, and economic burden in patients and caregivers was assessed. Burden was measured through concept-targeted questionnaires, including the US Centers for Disease Control and Prevention (CDC) Health-Related Quality of Life 4 (HRQoL-4) and the Work Productivity and Activity Impairment (WPAI) instruments. RESULTS: The 198 respondents comprised 49 adult patients, 51 caregivers of children, 47 caregivers of adolescents, and 51 caregivers of adults. Most patients (93.9%) were diagnosed with epilepsy. Patients' daily activities were highly affected, and many respondents reported a substantial long-term physical and mental impact on patients. The mean CDC HRQoL-4 score for unhealthy days per month ranged from 11.1 for caregivers of adults to 16.9 for caregivers of children. WPAI scores demonstrated a substantial impact on the ability of adult patients and all caregivers to work. Among respondents, caregivers of children reported the highest absenteeism from work (20%) and the lowest employment rate (33%). Proportions of caregivers reporting that their daily social life was impacted at least 'some of the time' ranged from 80% to 92%, with nearly half (47%) of caregivers of children responding that their social life was impacted 'all the time'. CONCLUSIONS: Status epilepticus episodes place a high burden on patients and caregivers. Notably, the burden appeared high across a variety of domains. This study highlights that the burden of disease is pronounced and wide-reaching and goes beyond the immediate physical and medical impact of an SE episode.

Chronic Constipation in the United States: Results From a Population-Based Survey Assessing Healthcare Seeking and Use of Pharmacotherapy.

OBJECTIVES: Chronic idiopathic constipation (CIC) is characterized by unsatisfactory defecation and difficult or infrequent stools. CIC affects 9%-20% of adults in the United States, and although prevalent, gaps in knowledge remain regarding CIC healthcare seeking and medication use in the community. We recruited a population-based sample to determine the prevalence and predictors of (i) individuals having discussed their constipation symptoms with a healthcare provider and (ii) the use of constipation therapies. METHODS: We recruited a representative sample of Americans aged 18 years or older who had experienced constipation. Those who met the Rome IV criteria for irritable bowel syndrome and opioid-induced constipation were excluded. The survey included questions on constipation severity, healthcare seeking, and the use of constipation medications. We used multivariable regression methods to adjust for confounders. RESULTS: Overall, 4,702 participants had experienced constipation (24.0% met the Rome IV CIC criteria). Among all respondents with previous constipation, 37.6% discussed their symptoms with a clinician (primary care provider 87.6%, gastroenterologist 26.0%, and urgent care/emergency room physician 7.7%). Age, sex, race/ethnicity, marital status, employment status, having a source of usual care, insurance status, comorbidities, locus of control, and constipation severity were associated with seeking care (P < 0.05). Overall, 47.8% of respondents were taking medication to manage their constipation: over-the-counter medication(s) only, 93.5%; prescription medication(s) only, 1.3%; and both over-the-counter medication(s) and prescription medication(s), 5.2%. DISCUSSION: We found that 3 of 5 Americans with constipation have never discussed their symptoms with a healthcare provider. Furthermore, the use of prescription medications for managing constipation symptoms is low because individuals mainly rely on over-the-counter therapies.

Suicidal ideation and attempts in the United States of America among stimulant-treated, non-stimulant-treated, and untreated patients with a diagnosis of attention-deficit/hyperactivity disorder.

BACKGROUND: Studies of the association between attention-deficit/hyperactivity disorder (ADHD) drug therapy and suicidal ideation and attempts (SIA) have conflicting results. METHODS: Cohorts of patients with ADHD aged 6 years or older with at least one pharmacy claim for a central nervous system (CNS) stimulant or a non-stimulant, or with no claims for ADHD pharmacotherapy, were identified in the US IBM® MarketScan® Research Database from January 2008 to March 2018. Incidence density rates (IDRs) of SIA (i.e., claims for suicide and self-inflicted poisoning, suicide and self-inflicted injuries, or suicidal ideation) were calculated. Cohorts were compared (CNS stimulants vs non-stimulants; CNS stimulants vs no pharmacotherapy) using hazard ratios (HRs) estimated from Cox proportional hazards models. Inverse-probability-of-treatment weighting (IPTW) was used to control for confounding. RESULTS: The study included 797,189 patients (CNS stimulants, 622,536; non-stimulants, 54,615; no pharmacotherapy, 120,038). IDRs of SIA (per 1000 patient-years) were: CNS stimulants, 5.8; non-stimulants, 10.5; and no pharmacotherapy, 10.0. The overall SIA risk was significantly lower with CNS stimulants than with non-stimulants (IPTW-adjusted HR = 0.70, 95% confidence interval = 0.61-0.81, p < 0.001) and no pharmacotherapy (0.62, 0.57-0.67, p < 0.001). LIMITATIONS: SIA assessment was based on diagnostic codes; suicidal ideation may not have been reported; completed suicides were generally not captured; and treatment was not verified. CONCLUSIONS: In this population-based study of patients with ADHD, SIA risk was significantly lower in those receiving CNS stimulants relative to those receiving non-stimulants or no pharmacotherapy, suggesting that CNS stimulants may attenuate SIA risk.

Concomitant Use of Psychotropic Medication With Stimulants for the Treatment of ADHD in Children and Adolescents: A Retrospective Insurance Claims Study in the United States.

Objective: To evaluate annual concomitant psychotropic medication use among stimulant-treated children/adolescents with ADHD. Method: Children/adolescents with ≥1 primary ADHD diagnosis who had received ≥30 days of stimulant medication were identified from insurance claims for each calendar year (2011-2014). Use of 15 psychotropic medications concomitantly with stimulants was evaluated and their prevalence in each year was calculated overall and by medication category for children (6-12 years) and adolescents (13-17 years). Results: Each year 133,354 to 157,303 children and 95,632 to 111,280 adolescents were included. Annual period prevalence of any concomitant psychotropic medication use was 22.9% to 25.0% for children and 25.2% to 28.2% for adolescents. The most common medication categories included selective serotonin reuptake inhibitors (children: 6.8%-7.9%; adolescents: 12.7%-14.9%), atypical antipsychotics (4.2%-5.4%; 5.3%-6.3%), and guanfacine extended release (5.1%-7.0%; 2.3%-3.6%). Conclusion: Around a quarter of children/adolescents with ADHD were prescribed psychotropic medication concomitant to stimulant treatment, although only 2 of the 15 medication classes studied were Food and Drug Administration (FDA)-approved for adjunctive use.

Weight and Height in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Longitudinal Database Study Assessing the Impact of Guanfacine, Stimulants, and No Pharmacotherapy.

Objectives: To assess the impact of long-term pharmacotherapy with guanfacine immediate- or extended-release (GXR), administered alone or as an adjunctive to a stimulant, on weight and height in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: Data were extracted from U.S. Department of Defense medical records for patients 4-17 years of age at index date (initiation of any study medication following a year without ADHD medications, or diagnosis if unmedicated) with weight/height measurements for the analysis period (January 2009-June 2013) and the previous year (baseline). Longitudinal weight and height z-scores were analyzed using multivariable regression in three cohorts: guanfacine (initial period of guanfacine exposure), first-line stimulant monotherapy (initial period of exposure), and unmedicated. Guanfacine cohort subgroups were based on previous/concurrent stimulant exposure. Results: The weight analyses included 47,910 patients (66.8% male) and the height analyses 41,248 (67.2% male). Mean initial exposure in the weight analyses was 237 days (standard deviation [SD] = 258, median = 142) for guanfacine and 257 days (SD = 284, median = 151) for first-line stimulant monotherapy, and was similar in the height analyses. Modeling indicated that guanfacine monotherapy was not associated with clinically meaningful deviations from normal z-score trajectories for weight (first-line, n = 943; nonfirst-line, n = 796) or height (first-line, n = 741; nonfirst-line, n = 644). In patients receiving guanfacine adjunctive to a stimulant, modeled weight (n = 1657) and height (n = 1343) z-scores followed declining trajectories. In this subgroup, mean standardized weight/height had decreased during previous stimulant monotherapy. For first-line stimulant monotherapy, modeled weight (n = 32,999) and height (n = 28,470) z-scores followed declining trajectories during year 1. In the unmedicated cohort, modeled weight (n = 11,515) and height (n = 10,050) z-scores were stable. Conclusions: Guanfacine monotherapy (first-line or nonfirst-line) was not associated with marked deviations from normal growth in this modeling study of children and adolescents with ADHD. In contrast, growth trajectories followed an initially declining course with stimulants, whether given alone or with adjunctive guanfacine.

A case-control comparison of direct healthcare-provider medical costs of chronic idiopathic constipation and irritable bowel syndrome with constipation in a community-based cohort.

OBJECTIVE: Patients with constipation account for 3.1 million US physician visits a year, but care costs for patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) compared to the general public have received little study. The study aim was to describe healthcare utilization and compare medical costs for patients with IBS-C or CIC vs matched controls from a community-based sample. METHODS: A nested case-control sample (IBS-C and CIC cases) and matched controls (1:2) for each case group were selected from Olmsted County, MN, individuals responding to a community-based survey of gastrointestinal symptoms (2008) who received healthcare from a participating Rochester Epidemiology Project (REP) provider. Using REP healthcare utilization data, unadjusted and adjusted standardized costs were compared for the 2- and 10-year periods prior to the survey for 115 IBS-C patients and 230 controls and 365 CIC patients and 730 controls. Two time periods were chosen as these conditions are episodic, but long-term. RESULTS: Outpatient costs for IBS-C ($6,800) and CIC ($6,284) patients over a 2-year period prior to the survey were significantly higher than controls ($4,242 and $5,254, respectively) after adjusting for co-morbidities, age, and sex. IBS-C outpatient costs ($25,448) and emergency room costs ($6,892) were significantly higher than controls ($21,024 and $3,962, respectively) for the 10-year period prior. Unadjusted data analyses of cases compared to controls demonstrated significantly higher imaging costs for IBS-C cases and procedure costs for CIC cases over the 10-year period. LIMITATIONS: Data were collected from a random community sample primarily receiving care from a limited number of providers in that area. CONCLUSIONS: Patients with IBS-C and CIC had significantly higher outpatient costs for the 2-year period compared with controls. IBS-C patients also had higher ER costs than the general population.

Economic burden of irritable bowel syndrome with constipation: a retrospective analysis of health care costs in a commercially insured population.

BACKGROUND: The prevalence of irritable bowel syndrome with constipation (IBS-C) is estimated to be between 4.3% and 5.2% among adults in the United States. Little is known about the health care resource utilization and costs associated with IBS-C. OBJECTIVES: To (a) evaluate the annual total all-cause, gastrointestinal (GI)-related, and IBS-C-related health care costs among IBS-C patients seeking medical care in a commercially insured population and (b) estimate the incremental all-cause health care costs among IBS-C patients relative to matched controls. METHODS: Patients aged ≥ 18 years with continuous medical and pharmacy benefit eligibility in 2010 were identified from the HealthCore Integrated Research Database, which consists of administrative claims from 14 geographically dispersed U.S. health plans representing 45 million lives. IBS-C patients were defined as those with ≥ 1 medical claim with an ICD-9-CM diagnosis code in any position for IBS (ICD-9-CM 564.1x) and either ≥ 2 medical claims for constipation (ICD-9-CM 564.0x) on different service dates or ≥ 1 medical claim for constipation plus ≥ 1 pharmacy claim for a constipation-related prescription on different dates of service during the study period. Controls were defined as patients without any medical claims for IBS, constipation, abdominal pain, or bloating or pharmacy claims for constipation-related prescriptions. Controls were randomly selected and matched with IBS-C patients in a 1:1 ratio based on age (± 4 years), gender, health plan region, and health plan type. Patients with diagnoses or prescriptions suggesting mixed IBS, IBS with diarrhea, chronic diarrhea, or drug-induced constipation were excluded. Total health care costs in 2010 U.S. dollars were defined as the sum of health plan and patient paid costs for prescriptions and medical services, including inpatient visits, emergency room (ER) visits, physician office visits, and other outpatient services. The total cost approach was used to assess total all-cause or disease-specific health care costs for patients with IBS-C, while the incremental cost approach was used to examine the excess all-cause costs of IBS-C by comparing IBS-C patients with matched controls. Generalized linear models with bootstrapping were used to assess the incremental all-cause costs attributable solely to IBS-C after adjusting for demographics, Elixhauser Comorbidity Index (ECI) score, and other general and GI-related comorbidities not included in the ECI score. RESULTS: A total of 7,652 patients (n = 3,826 each in the IBS-C and control cohorts) were included in the analysis. The mean (± SD) age was 48 (± 17) years, and 83.6% were female. The mean annual all-cause health care costs for IBS-C patients were $11,182, with over half (53.7%) of the costs attributable to outpatient services, including physician office visits and other outpatient services (13.1% and 40.6%, respectively). Remaining total all-cause costs were attributable to hospitalizations (21.8%), prescriptions (19.1%), and ER visits (5.4%). GI-related costs ($4,456) comprised 39.8% of total all-cause costs, while IBS-C-related costs ($1,335) accounted for 11.9% and were primarily driven by costs of other outpatient services (50.3%). After adjusting for demographics and comorbidities, the incremental annual all-cause health care costs associated with IBS-C were $3,856 ($8,621 for IBS-C patients vs. $4,765 for controls, P less than 0.01) per patient per year, of which 78.1% of the incremental costs were due to medical services, and 21.9% were due to prescription fills. CONCLUSIONS: IBS-C imposes a substantial economic burden in terms of direct health care costs in a commercially insured population. Compared with matched controls, IBS-C patients incurred significantly higher total annual all-cause health care costs even after controlling for general and GI-related comorbidities. Incremental all-cause costs associated with IBS-C were mainly driven by costs related to more frequent use of medical services as opposed to prescriptions.

Healthcare costs among patients with chronic constipation: a retrospective claims analysis in a commercially insured population.

OBJECTIVE: To evaluate total annual all-cause, gastrointestinal-related, and symptom-related healthcare costs among chronic constipation (CC) patients and estimate incremental all-cause healthcare costs of CC patients relative to matched controls. METHODS: Patients aged ≥18 years with continuous medical and pharmacy benefit eligibility in 2010 were identified from the HealthCore Integrated Research Database. CC patients had ≥2 medical claims for constipation (ICD-9-CM code 564.0x) ≥90 days apart or ≥1 medical claim for constipation plus ≥1 constipation-related pharmacy claim ≥90 days apart, and no medical claims for irritable bowel syndrome (IBS). Sub-groups with and without abdominal symptoms were classified according to the presence/absence of abdominal pain (ICD-9-CM code 789.0x) and bloating (ICD-9-CM code 787.3x). Controls without claims for constipation, abdominal pain, bloating, or IBS or constipation-related prescriptions were randomly selected and matched 1:1 with CC patients on age, gender, health plan region, and plan type. Generalized linear models with bootstrapping evaluated incremental all-cause costs attributable to CC, adjusting for demographics and comorbidities. RESULTS: Overall, 14,854 patients (n = 7427 each in CC and control groups) were identified (mean age = 59 years; 75.4% female). Mean annual all-cause costs for CC patients were $11,991 (2010 USD), with nearly half (44.8%) attributable to outpatient services, including physician office visits and other outpatient services (10.0% and 34.8%, respectively). GI-related costs comprised 33.7% of total all-cause costs. Symptom-related costs accounted for 10.5%, primarily driven by costs of other outpatient services (50.6%). Adjusted incremental all-cause costs associated with CC were $3508 per patient per year ($4446 for CC with abdominal symptoms; $2783 for CC without abdominal symptoms), of which 81.0% were from medical services. Incremental cost estimates may be over- or under-estimated due to classification based on claims. CONCLUSIONS: CC imposes a substantial burden in direct healthcare costs in a commercially insured population, mainly attributable to greater use of medical services.

Eszopiclone treatment for insomnia: effect size comparisons in patients with primary insomnia and insomnia with medical and psychiatric comorbidity.

OBJECTIVE: The purpose of this post hoc analysis was to compare the treatment effect size of eszopiclone 3 mg for insomnia in patients with a diagnosis of primary insomnia and in several of the psychiatric and medical conditions that are most commonly comorbid with insomnia. METHOD: Data were analyzed from 5 large, multicenter, randomized, double-blind, placebo-controlled studies of adult outpatients of at least 1 month duration published between 2006 and 2009. Diary-derived indices of sleep and daytime functioning and the Insomnia Severity Index were compared for patients with primary insomnia (DSM-IV-TR criteria, n = 828) and for those with insomnia comorbid with major depressive disorder (MDD, DSM-IV-TR criteria, n = 545), generalized anxiety disorder (GAD, DSM-IV-TR criteria, n = 595), perimenopause/postmenopause (Stages of Reproductive Aging Workshop criteria, n = 410), and rheumatoid arthritis (American College of Rheumatology criteria, n = 153). Cohen d effect sizes were calculated for each individual study as the between-treatment difference score divided by the pooled standard deviation. RESULTS: Effect sizes ranged from 0.40 to 0.69 (small-medium) as early as week 1 and were maintained at 0.26-0.63 at week 4 for sleep latency, wake time after sleep onset, and total sleep time. Sleep latency and total sleep time effect sizes increased from week 1 to week 4 in the primary insomnia group. At week 4, effect sizes on all 3 parameters and the Insomnia Severity Index tended to be highest for the primary insomnia patients and tended to be lowest for patients with comorbid GAD and MDD. The effect sizes for daytime functioning were small for all insomnia patient groups. CONCLUSIONS: Eszopiclone 3 mg is an effective treatment for insomnia across 5 clinically diverse patient populations; however, magnitude of effect is mediated by underlying comorbidity and their treatments, with largest measures of effect seen in primary insomnia and lowest in MDD and GAD. These consistent results, and the fact that clinical trials were conducted in patients being treated as appropriate for their comorbid clinical conditions, support the results' real-world generalizability and utility to clinical practice.

Thromboembolic cardiovascular risk among arthritis patients using cyclooxygenase-2-selective inhibitor or nonselective cyclooxygenase inhibitor nonsteroidal anti-inflammatory drugs.

Selective cyclooxygenase (COX)-2 inhibitors have been associated with an increased risk of thromboembolic cardiovascular (CV) events. Prior studies have found that rofecoxib has a destabilizing effect on blood pressure; however, whether this translates to an increased risk of thromboembolic CV events is unknown. The objective of this study was to evaluate risk of thromboembolic CV events among hypertensive and nonhypertensive patients treated with rofecoxib or celecoxib, nonselective nonsteroidal anti-inflammatory drugs (ns-NSAIDs), or no NSAIDs (nonusers). This was a retrospective cohort study of 31,743 adult arthritis patients enrolled in a Blue Cross/Blue Shield health insurance plan in the northeastern United States. The main outcome measure was incident acute myocardial infarction and stroke. A clinically significant channeling effect was observed where selective COX-2 inhibitor users had a more severe CV risk profile. Among normotensive patients, the hazard ratio (HR) of CV events for ns-NSAIDs, rofecoxib, or celecoxib versus nonusers was 0.91 (95% confidence interval, 0.68-1.21), 1.05 (0.61-1.80), and 1.19 (0.86-1.66), respectively. Among hypertensive patients, the risk of CV events for ns-NSAIDs users was not significantly different versus nonusers (HR=1.21; 0.88-1.67). However, rofecoxib was associated with a significant 2-fold increase in CV risk versus nonusers of NSAIDs (HR=2.16; 1.51-3.09), whereas celecoxib was not (HR=1.18; 0.89-1.57). These data support the hypothesis that elevated CV risk is not a drug class effect of selective COX-2 inhibitors. That this effect was specific to hypertensive patients indicates that blood pressure destabilization is likely an important contributing mechanism.