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Daniel A Hoffman,1 Charles DeBattista,2 Rob J Valuck,3 Dan V Iosifescu41Neuro-Therapy Clinic, Inc, Denver, CO, USA; 2Stanford University School of Medicine, Palo Alto, CA, USA; 3University of Colorado, SKAGES School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA; 4Mood and Anxiety Disorders Program, Mount Sinai School of Medicine, New York, NY, USAAbstract: We previously reported on an objective new tool that uses quantitative electroencephalography (QEEG) normative- and referenced-electroencephalography sampling databases (currently called Psychiatric EEG Evaluation Registry [PEER]), which may assist physicians in determining medication selection for optimal efficacy to overcome trial-and-error prescribing. The PEER test compares drug-free QEEG features for individual patients to a database of patients with similar EEG patterns and known outcomes after pharmacological interventions. Based on specific EEG data elements and historical outcomes, the PEER Report may also serve as a marker of future severe adverse events (eg, agitation, hostility, aggressiveness, suicidality, homicidality, mania, hypomania) with specific medications. We used a retrospective chart review to investigate the clinical utility of such a registry in a naturalistic environment.Results: This chart review demonstrated significant improvement on the global assessment scales Clinical Global Impression – Improvement and Quality of Life Enjoyment and Satisfaction – Short Form as well as time to maximum medical improvement and decreased suicidality occurrences. The review also showed that 54.5% of previous medications causing a severe adverse event would have been raised as a caution had the PEER Report been available at the time the drug was prescribed. Finally, due to the significant amount of off-label prescribing of psychotropic medications, additional, objective, evidence-based data aided the prescriber toward better choices.Conclusion: The PEER Report may be useful, particularly in treatment-resistant patients, in helping to guide medication selection. Based on the preliminary data obtained from this chart review, additional studies are warranted to establish the safety and efficacy of adding PEER data when making medication decisions.Keywords: PEER, referenced-EEG, QEEG, adverse events, medication selection, off label

Glen T Schumock1, Robert D Gibbons2, Todd A Lee1,3,4,6, Min J Joo4, Robert J Valuck5, Leslie T Stayner61Center for Pharmacoeconomic Research, and Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA; 2Center for Health Statistics, and Departments of Medicine and Health Studies, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA; 3Center for Management of Complex Chronic Care, Hines VA Hospital, Hines, IL, USA; 4Section of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; 5Department of Clinical Pharmacy, School of Pharmacy, University of Colorado, Aurora, CO, USA; 6Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USABackground: The US Food and Drug Administration has issued warnings about a potential link between leukotriene receptor-modifying agents (LTMA) and suicide. These warnings are based on case reports and there is controversy about the association. While spontaneous reporting of suicide-related events attributed to LTMA has risen dramatically, these data may be biased by the warnings. The objective of this study was to explore the relationship between LTMA and suicide deaths using event data preceding the Food and Drug Administration warnings.Methods: We conducted a mixed-effects Poisson regression analysis of the association between LTMA prescriptions dispensed and suicide deaths at the county level. Counts of suicide deaths in each US county, stratified by race, age group, gender, and year were obtained from the National Center for Health Statistics for the period January 1, 1999 to December 31, 2006. Counts of LTMA prescriptions dispensed in each US county were obtained from IMS Health Incorporated. The model estimated the overall suicide rate conditional on LTMA use, adjusted for age, gender, race, year, and antidepressant utilization. We also assessed the intracounty and intercounty associations.Results: There were 249,872 suicides in the US between 1999 and 2006, and the annual suicide rate ranged from 11.17 to 11.92 per 100,000 population. There were 118.63, 11.68, and 0.12 million prescriptions dispensed for montelukast, zafirlukast, and zileuton, respectively, between 1999 and 2006. The mean rate of LTMA prescriptions dispensed by county was 42.91 (95% confidence interval [CI] 42.78–43.04), 4.82 (95% CI 4.81–4.84), and 0.05 (95% CI 0.05–0.05) per 1000 for montelukast, zafirlukast, and zileuton, respectively. We found a negative within-county association between the rate of total LTMA prescriptions dispensed and the suicide rate by county (P = 0.0296). This association was primarily driven by montelukast.Conclusion: Our results, while subject to certain limitations, provide preliminary evidence that the association between LTMA and suicide could be different (ie, reduced risk) than that which might be anticipated based on previous warnings. Patient-level research is needed to understand more clearly the association between LTMA and suicide.Keywords: suicide, leukotriene-modifying agents, montelukast, drug safety

The US FDA has issued safety alerts and required manufacturers of leukotriene-modifying agents (LTMAs), including montelukast, zafirlukast and zileuton, to include suicide and neuropsychiatric events as a precaution in the drug label. This paper reviews the existing evidence on the potential association between the LTMAs and suicidal behaviour. We conducted a literature search of MEDLINE, EMBASE and International Pharmaceutical Abstracts from 1995 to 2010 (inclusive) to identify pertinent studies and reports. We also examined data obtained from the FDA adverse event reporting system. To date, there are no well conducted, comparative, observational studies of this association, and the safety alerts are based primarily on case reports. While the FDA safety alerts apply to all three LTMAs, montelukast (known by its trade name Singulair®) is by far the most widely used of these drugs and most of the reports to date regarding suicide pertain to montelukast. From 1998 to 2009 there were 838 suicide-related adverse events associated with leukotrienes reported to the FDA, of which all but five involved montelukast. Nearly all cases were reported in 2008 and 2009 (96.1%) after the FDA warnings. LTMAs are approved for use in asthma and allergic rhinitis, and are effective drugs. Both of these diseases are also associated with suicide, making confirmation of the association more difficult. Given the lack of good evidence, we recommend that a large observational cohort or case-control study be conducted to quantify the association between LTMAs and suicide. Until then, when prescribing LTMAs, clinicians should consider the potential for suicide and monitor patients who may be at elevated risk carefully for suicidal ideation or psychiatric symptoms associated with suicidal behaviour. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To characterize healthcare costs associated with antipsychotic polypharmacy and to investigate predictors of high-cost patients. METHODS: A retrospective cohort study using Medicaid claims data from California, Nebraska, Oregon, Utah, and Wyoming evaluated 55 383 fee-for-service patients with antipsychotic prescriptions between 1998 and 2002. Polypharmacy was defined as initiating multiple antipsychotic drugs or concomitant antipsychotic therapy (>or=60 days). Healthcare costs (drug and non-drug) were summed for 365 days following index antipsychotic claim. Adjusted mean costs were compared to antipsychotic monotherapy. Logistic regression was performed to identify predictors of high-cost patients (top quintile) with regard to patient age, gender, race/ethnicity, mental disorders, hospitalization, index antipsychotic, concomitant psychotropic drugs, and polypharmacy. RESULTS: The average annual prevalence of antipsychotic polypharmacy was 6%. 70-80% of total healthcare expenditures for polypharmacy patients were drug-related. Polypharmacy was associated with significantly higher drug expenditures ($1716-2079) in the year following drug initiation than monotherapy even after adjusting for case mix and index antipsychotic (p < 0.05). Differences in non-drug expenditures versus monotherapy were smaller and varied by state ranging from a $77 increase in California (p < 0.001) to a $211 savings in Utah (p = 0.02). In California, polypharmacy alone (OR = 2.69; 95% CI: 2.30-3.16) or in combination with concomitant psychotropics (OR = 6.26; 95% CI: 5.51-7.11) was associated with greater likelihood of being a high-cost patient than monotherapy. CONCLUSIONS: Cost savings from limiting antipsychotic polypharmacy could be significant. Caution must be taken in ensuring reductions in polypharmacy do not lead to unintended consequences or shift care to more costly alternatives. Study limitations, including the known shortcomings of claims data and differences across state Medicaid programs, should be considered when interpreting the results of this or any multi-state study. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In October 2003, the U.S. Food and Drug Administration (FDA) issued a public health advisory about the risk of suicidality in pediatric patients taking selective serotonin reuptake inhibitors (SSRIs) for depression. This study used data from a large national pediatric cohort to examine patterns of diagnosis of depression, prescription of antidepressants, prescription of pharmacological alternatives to antidepressants, and use of psychosocial care before and after the FDA advisory was issued. METHOD: A large pediatric cohort with newly diagnosed episodes of depression was created from a national integrated claims database of managed care plans from October 1998 to September 2005 (N=65,349). Time-series models were used to compare diagnosing and prescribing trends during the 2 years after the FDA advisory and the expected trends based on data from the 5-year period preceding the advisory. RESULTS: From 1999 to 2004, pediatric diagnoses of depression increased from 3 to 5 per 1,000. After the FDA advisory was issued, the national rate decreased to 1999 levels, a significant deviation from the historical trend. Pediatricians and nonpediatrician primary care physicians accounted for the largest reductions in new diagnoses. Among patients with depression, the proportion receiving no antidepressant increased to three times the rate predicted by the preadvisory trend, and SSRI prescription fills were 58% lower than predicted by the trend. There was no evidence of a significant increase in use of treatment alternatives (psychotherapy, atypical antipsychotics, and anxiolytics). CONCLUSIONS: The FDA advisory was associated with significant reductions in aggregate rates of diagnosis and treatment of pediatric depression. [ABSTRACT FROM AUTHOR]

BACKGROUND: Few studies have examined the effectiveness of statins in a managed care setting. OBJECTIVE: The aim of this study was to identify demographic, clinical, and pharmacotherapy-related factors associated with response to drug therapy for hyperlipidemia among members of a managed care organization. METHODS: Claims data from a large US managed care organization from July 1, 1998, through June 30, 2000, were analyzed for adult members with continuous enrollment, >or=1 prescription drug claim, >or=2 sets of fasting low-density lipoprotein cholesterol (LDL-C) laboratory results, and no lipid-lowering prescription claims at any time or=41%). Multiple regression and logistic regression models were developed to identify significant predictors of percentage change in LDL-C from baseline and of >or=10% reduction in LDL-C. RESULTS: A total of 6247 members met the inclusion criteria. The mean (SD) age was 59.6 (12.4) years (range, 21-93 years), and 3003 individuals (48.1%) were women. Furthermore, 337 members (5.4%) received high-efficacy statins, 2633 (42.1%) received moderate-efficacy statins, 934 (15.0%) received low-efficacy statins, and 86 (1.4%) received low-efficacy lipid-lowering drugs from other therapeutic classes during the study period. Compliance with therapy was high (range, 85%-92%), and upward titration of therapy was found in only 160 members (2.6%). Multiple regression analysis indicated that receiving statin therapy compared with other lipid-lowering therapy was a significant predictor of percentage reduction in LDL-C (P < 0.001). Logistic regression analysis indicated that compared with high-efficacy statin regimens, low-efficacy statin regimens (odds ratio [OR] = 0.619; 95% CI, 0.436-0.877) and low-efficacy regimens from other therapeutic classes (OR = 0.171; 95% CI, 0.099-0.295) were less effective in lowering LDL-C by >or=10%. Similar results were observed for subanalyses of subjects with diabetes mellitus or coronary heart disease (CHD); individuals who received more efficacious statin regimens were more likely to reach the National Cholesterol Education Program Adult Treatment Panel II LDL-C goal of

OBJECTIVES:: This study was conducted to estimate the prevalence of antipsychotic polypharmacy among fee-for service state Medicaid beneficiaries initiating antipsychotic drug therapy and to investigate psychiatric and demographic predictors of such polypharmacy. METHODS:: This was a retrospective cohort study employing Medicaid claims data from California, Nebraska, Oregon, Utah, and Wyoming for patients who filled >1 antipsychotic prescription between 1998 and 2003 and who were continuously eligible for benefits from 180 days before to 1 year after the index antipsychotic claim. Antipsychotic Polypharmacy was defined as initiation of multiple antipsychotic medications or at least 60 consecutive days of concomitant antipsychotic medication overlapping the index antipsychotic prescription at any time during the 365 days after the index drug claim. Primary and secondary diagnosis codes (International Classification of Diseases, Ninth Revision, Clinical Modification) were used to identify patients with mental disorders and mental health-related hospitalizations. Multivariate logistic regression, with adjustment for sex, age, race/ethnicity, state, mental health diagnoses, hospitalization, year, and type of index antipsychotic, was performed to identify predictors of polypharmacy. A multivariate Cox proportional hazards model was used to compare the cumulative incidence of polypharmacy by index antipsychotic drug. RESULTS:: The study cohort consisted of 55,481 individuals with >/=1 prescription claim for an antipsychotic drug. The mean prevalence of long-term antipsychotic polypharmacy in the year after initiating antipsychotic medication was 6.4%. Approximately half of those with polypharmacy were started on multiple antipsychotic drugs and half were started on monotherapy but received >/=2 antipsychotic drugs concomitantly in the year after drug initiation. Among the stronger predictors of polypharmacy were a diagnosis of schizophrenia (odds ratio [OR] = 2.95; 95% Cl, 2.43-3.58), recent mental health hospitalization (OR = 1.17; 95% Cl, 1.02-1.33), and the number of mental health diagnoses (OR = 1.07 per diagnosis; 95% CI, 1.06-1.08). Polypharmacy was more likely among male than female patients (OR = 1.26; 95% Cl, 114-1.39) and among those between the ages of 18 and 24 years. The cumulative incidence of polypharmacy was greater among patients initiating clozapine compared with those initiating other antipsychotics (P < 0.001). CONCLUSIONS:: In these fee-for-service Medicaid beneficiaries from 5 states, the prevalence of chronic antipsychotic polypharmacy was low in the year after the initiation of therapy. Polypharmacy was more common in patients with indicators of more severe mental illness. [ABSTRACT FROM AUTHOR]

Importance: Children with severe neurological impairment (SNI) often take multiple medications to treat problematic symptoms. However, for children who cannot self-report symptoms, no system exists to assess multiple symptoms and their association with medication use., Objectives: To assess the prevalence of 28 distinct symptoms, test whether higher global symptom scores (GSS) were associated with use of more medications, and assess the associations between specific symptoms and medications., Design, Setting, and Participants: This cross-sectional study was conducted between April 1, 2019, and December 31, 2019, using structured parent-reported symptom data paired with clinical and pharmacy data, at a single-center, large, hospital-based special health care needs clinic. Participants included children aged 1 to 18 years with SNI and 5 or more prescribed medications. Data analysis was performed from April to June 2020., Exposure: During routine clinical visits, parent-reported symptoms were collected using the validated 28-symptom Memorial Symptom Assessment Scale (MSAS) and merged with clinical and pharmacy data., Main Outcomes and Measures: Symptom prevalence, counts, and GSS (scored 0-100, with 100 being the worst) were calculated, and the association of GSS with medications was examined. To evaluate associations between symptom-medication pairs, the proportion of patients with a symptom who used a medication class or specific medication was calculated., Results: Of 100 patients, 55.0% were boys, the median (interquartile range [IQR]) age was 9 (5-12) years, 62.0% had 3 or more complex chronic conditions, 76.0% took 10 or more medications, and none were able to complete the MSAS themselves. Parents reported a median (IQR) of 7 (4-10) concurrent active symptoms. The median (IQR) GSS was 12.1 (5.4-20.8) (range, 0.0-41.2) and the GSS was 9.8 points (95% CI, 5.5-14.1 points) higher for those with worse recent health than usual. Irritability (65.0%), insomnia (55.0%), and pain (54.0%) were the most prevalent symptoms. Each 10-point GSS increase was associated with 12% (95% CI, 4%-19%) higher medication counts, adjusted for age and complex chronic condition count. Among the 54.0% of children with reported pain, 61.0% were prescribed an analgesic., Conclusions and Relevance: These findings suggest that children with SNI reportedly experience substantial symptom burdens and that higher symptom scores are associated with increased medication use. Paired symptom-medication data may help clinicians identify targets for personalized symptom management, including underrecognized or undertreated symptoms.

Background: Opioids are utilized for pain management during and after mechanical ventilation in the intensive care unit (ICU)., Objective: The purpose of this study was to determine the percentage of potentially unnecessary opioid prescriptions on discharge in previously opioid-naïve patients., Methods: This retrospective cohort study included mechanically ventilated, opioid-naïve ICU patients who received opioids. The primary outcome of this study was the discrepancy between the amounts of opioids prescribed at discharge versus those likely required based on actual 24-hour prehospital discharge opioid requirements., Results: A total of 71 patients were included. Of these, 63.3% (n = 45) of discharge prescriptions were in alignment with 24-hour predischarge requirements, and 36.7% (n = 26) of discharge prescriptions were in excess of calculated predischarge requirements. At discharge, 57.7% (n = 41) of patients received a nonopioid analgesic. Multivariable linear regression revealed that cardiothoracic ICU admission was associated with an increased risk of inappropriate discharge opioid prescribing, whereas a shorter duration of inpatient oral opioid therapy decreased risk of inappropriate discharge prescribing., Conclusion and Relevance: Opioid prescribing for previously mechanically ventilated patients warrants improvement as a part of the discharge planning process. Application of these data may aid in the reduction of opioid overprescribing at discharge after an ICU stay.

Objective: To measure the association between selective serotonin reuptake inhibitor (SSRI) use and out-of-hospital ventricular arrhythmia among the pediatric and young adult population., Study Design: Case-control study using US claims data from 2007 to 2018. Cases were subjects with at least 1 event between ages 2 and 24 years. Controls (matched 10:1 on index date, age, sex, and continuous enrollment) had no events during study period. Independent association between current SSRI use (prescription fill with continuous exposure ending on, or after, the index date) and incident out-of-hospital ventricular arrhythmia (hospitalization or emergency room encounter with primary diagnostic code for ventricular arrhythmia) was estimated using multivariable conditional logistic regression. Separate analyses were performed for pediatric (2-17 years of age) vs young adult (18-24 years of age) subjects and between citalopram/escitalopram vs other SSRIs., Results: During the study period, 237 eligible cases were identified with 2370 matched controls. Cases were more likely to have government insurance and have a mental health, cardiac, or other complex chronic condition. Thirteen cases (5%) and 15 controls (<1%) had current SSRI exposure. After adjustment for mental health and chronic conditions, there was an increased odds of current SSRI use among cases compared with controls (OR 5.11, 95% CI 1.22-21.37). No difference was observed between pediatric and young adult ages, nor between citalopram/escitalopram and other SSRIs., Conclusions: These findings demonstrate increased odds of out-of-hospital ventricular arrhythmia associated with SSRI use in the pediatric and young adult population, suggesting a need for heightened awareness and ongoing monitoring of this potential adverse effect., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Identify administrative claims-based algorithms for capturing out-of-hospital ventricular arrhythmias (VA) and cardiac arrests (CA) due to cardiac causes in the pediatric population with high positive-predictive value (PPV)., Methods: Within a single pediatric center, a retrospective cohort of patients hospitalized or seen in the emergency room for VA or CA were identified from the electronic health records. Eligible encounters were blindly reviewed and linked to administrative data, including ICD-9/ICD-10 codes. Test characteristics, including PPV, for different diagnostic and procedure codes were generated using a 50% training sample. The gold standard was definite or suspected out-of-hospital VA or CA due to cardiac cause verified based on clinical criteria. Algorithms with the highest PPV were then applied to a 50% validation sample to validate performance., Results: From 2004-2017, 598 encounters met eligibility criteria. 174 (29%) had an outcome of interest, with remainder being an inpatient event or CA due to other cause. Within the training sample (n = 263), VA codes in primary position had a PPV 94% (95%CI 81%-99%) with low sensitivity (44%, 95%CI 33%-56%). CA codes in any position or VA codes in nonprimary positions had low PPV (18%-19%, 31% respectively). Applying the top three performing algorithms to the validation sample (n = 252) yielded similar PPV values., Conclusions: Contrary to adults, algorithms including a CA code do not perform well for identifying out-of-hospital VA and CA due to cardiac cause in the pediatric populations. Researchers should be aware of the potential implications for future pediatric drug safety studies for these outcomes., (© 2020 John Wiley & Sons Ltd.)

Objective: To evaluate the impact of 3-tier (copayment) pharmacy benefit structures on medication utilization behavior., Methods: A pretest-posttest quasi-experimental design was employed. Chronic disease sufferers (N=8,132) from a health plan were classified into the following groups: (a) 2-tier copayment moving to a 3-tier structure, ("converting" group), (b) 2-tier staying in a 2-tier structure and, (c) 3-tier staying in a 3-tier structure. The latter 2 were "comparison" groups. Two 7-month time periods were determined: the "preperiod" (June through December 2000) and the "postperiod" (January through July 2001) for a change in pharmacy benefit structure. Pharmacy claims data were used for data collection. Statistical analyses included bivariate tests to evaluate predifferences and postdifferences across study groups. Maximum likelihood estimates from a repeated measures model were used to examine changes in formulary compliance and generic use rates. Discontinuation of nonformulary medications was evaluated using logistic regression., Results: Controlling for demographics, number of comorbidities, disease state, and pharmacy benefit structure, the formulary compliance rate increased by 5.6% for the converting group. No significant increases were seen for the comparison groups. Generic use rates increased by 6 to 8 absolute percentage points for all groups (3.3% to 4.9 % adjusted rates). Converting group members were 1.76 times more likely to discontinue their nonformulary medication than those in the 2-tier comparison group and 1.49 times more likely than those in the 3-tier comparison group., Conclusions: These findings suggest that shifting individuals from a 2-tier to a 3-tier drug benefit copayment structure resulted in changes in medication utilization. Decision makers need to balance these changes with the potential dissatisfaction that members may express in paying higher copayments., Disclosures: Funding for this research was provided by Merck and Company through the Academic Medicine and Managed Care Forum and was obtained by authors Kavita V. Nair, Robert J. Valuck, Pamela Wolfe, Julie M. Ganther, and Marianne M. McCollum. Nair served as principal author of the study. Study concept and design was contributed by Nair, Valuck, Wolfe, Ganther, McCollum, and author Sonya J. Lewis. Analysis and interpretation of data and drafting of the manuscript were primarily the work of Nair and Wolfe, and all authors contributed to the critical revision of the manuscript. Statistical expertise was contributed by Wolfe. Administrative, technical, and/or material support was provided by Mark Enders.

Objective: Whether physical access to psychotropic medication via prescription (ie, prescribed access) is associated with use of psychotropic medication as a means of subsequent suicide attempt remains unclear. In a population of suicide attempters, we investigated whether prescribed access to any psychotropic medication increased the likelihood of using any psychotropic drug in a suicide attempt and whether prescribed access to a specific psychotropic drug type increased the likelihood of using that specific psychotropic drug type in an attempt., Methods: Case-control study design was used. We identified individuals receiving care for a suicide attempt (fatal or nonfatal) in emergency department and inpatient settings from a US insurance claims dataset (2006-2013) using relevant ICD-9-CM codes. Cases used a psychotropic drug in their suicide attempt, while controls used another method. Exposed individuals filled a psychotropic drug prescription within 90 days prior to the attempt. Multivariable logistic regression estimated odds ratios., Results: A population of 27,876 (cases = 10,158, controls = 17,718) was included. Anxiolytics were used most in attempts (n = 6,037, 59.4%), followed by antidepressants (n = 3,573, 35.2%), antipsychotics or mood stabilizers (n = 1,168, 11.5%), and stimulants (n = 368, 3.6%). Thirteen percent (n = 1,316) used more than 1 type of psychotropic drug in the attempt. Across all psychotropic drug groups evaluated, individuals using psychotropic medication in a suicide attempt were significantly more likely to have had prescribed access (adjusted odds ratio [aOR] = 1.7; 95% CI, 1.6-1.9), with the highest drug type-specific odds ratios for antipsychotics or mood stabilizers (aOR = 6.5; 95% CI, 5.4-7.7) and stimulants (aOR = 7.6; 95% CI, 5.5-10.5)., Conclusions: Individuals at high risk for suicide with prescribed access to any psychotropic medication should be targeted for means safety interventions., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Background: Anticholinergic (AC) adverse drug events (ADEs) are caused by inhibition of muscarinic receptors as a result of designated or off-target drug-receptor interactions. In practice, AC toxicity is assessed primarily based on clinician experience. The goal of this study was to evaluate a novel concept of integrating big pharmacological and healthcare data to assess clinical AC toxicity risks., Methods: AC toxicity scores (ATSs) were computed using drug-receptor inhibitions identified through pharmacological data screening. A longitudinal retrospective cohort study using medical claims data was performed to quantify AC clinical risks. ATS was compared with two previously reported toxicity measures. A quantitative structure-activity relationship (QSAR) model was established for rapid assessment and prediction of AC clinical risks., Results: A total of 25 common medications, and 575,228 exposed and unexposed patients were analyzed. Our data indicated that ATS is more consistent with the trend of AC outcomes than other toxicity methods. Incorporating drug pharmacokinetic parameters to ATS yielded a QSAR model with excellent correlation to AC incident rate ( R 2 = 0.83) and predictive performance (cross validation Q 2 = 0.64). Good correlation and predictive performance ( R 2 = 0.68/ Q 2 = 0.29) were also obtained for an M2 receptor-specific QSAR model and tachycardia, an M2 receptor-specific ADE., Conclusions: Albeit using a small medication sample size, our pilot data demonstrated the potential and feasibility of a new computational AC toxicity scoring approach driven by underlying pharmacology and big data analytics. Follow-up work is under way to further develop the ATS scoring approach and clinical toxicity predictive model using a large number of medications and clinical parameters., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Fiks has received an independent research grant from Pfizer unrelated to the current study; the other authors have indicated they have no potential conflicts of interest to disclose.

Objective: Hospital-acquired pressure ulcers (HAPUs) have a mortality rate of 11.6%, are costly to treat, and result in Medicare reimbursement penalties. Medicare codes HAPUs according to Agency for Healthcare Research and Quality Patient-Safety Indicator 3 (PSI-03), but they are sometimes inappropriately coded. The objective is to use electronic health records to predict pressure ulcers and to identify coding issues leading to penalties., Materials and Methods: We evaluated all hospitalized patient electronic medical records at an academic medical center data repository between 2011 and 2014. These data contained patient encounter level demographic variables, diagnoses, prescription drugs, and provider orders. HAPUs were defined by PSI-03: stages III, IV, or unstageable pressure ulcers not present on admission as a secondary diagnosis, excluding cases of paralysis. Random forests reduced data dimensionality. Multilevel logistic regression of patient encounters evaluated associations between covariates and HAPU incidence., Results: The approach produced a sample population of 21 153 patients with 1549 PSI-03 cases. The greatest odds ratio (OR) of HAPU incidence was among patients diagnosed with spinal cord injury (ICD-9 907.2: OR = 14.3; P  < .001), and 71% of spinal cord injuries were not properly coded for paralysis, leading to a PSI-03 flag. Other high ORs included bed confinement (ICD-9 V49.84: OR = 3.1, P  < .001) and provider-ordered pre-albumin lab (OR = 2.5, P  < .001)., Discussion: This analysis identifies spinal cord injuries as high risk for HAPUs and as being often inappropriately coded without paralysis, leading to PSI-03 flags. The resulting statistical model can be tested to predict HAPUs during hospitalization., Conclusion: Inappropriate coding of conditions leads to poor hospital performance measures and Medicare reimbursement penalties., (© The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: In 2008, the Centers for Medicare and Medicaid Services (CMS) established nonpayment policies resulting from costliness of hospital-acquired pressure ulcers (HAPUs) to hospitals. This prompted hospitals to adopt quality improvement (QI) interventions that increase use of evidence-based practices (EBPs) for HAPU prevention., Objective: To evaluate the longitudinal impact of CMS policy and QI adoption on HAPU rates., Materials and Methods: We characterized longitudinal adoption of 25 QI interventions that support EBPs through hospital leadership, staff, information technology, and performance and improvement. Quarterly counts of HAPU incidence and inpatient characteristics were collected from 55 University HealthSystem Consortium hospitals between 2007 and 2012. Mixed-effects regression models tested the longitudinal association of CMS policy, HAPU coding, and QI on HAPU rates. The models assumed level-2 random intercepts and random effects for CMS policy and EBP implementation to account for between-hospital variability in HAPU incidence., Results: Controlling for all 25 QI interventions, specific updates to EBPs for HAPU prevention had a significant, though modest reduction on HAPU rates (-1.86 cases/quarter; P=0.002) and the effect of CMS nonpayment policy on HAPU prevention was much greater (-11.32 cases/quarter; P<0.001)., Conclusions: HAPU rates were significantly lower after changes in CMS reimbursement. Reductions are associated with hospital-wide implementation of EBPs for HAPU prevention. Given that administrative data were used, it remains unknown whether these improvements were due to changes in coding or improved quality of care.

Objective: To estimate the US commercially insured multiple sclerosis (MS) annual prevalence from 2008 to 2012., Methods: The study was a retrospective analysis using PharMetrics Plus, a nationwide claims database for over 42 million covered US representative lives. Annual point prevalence required insurance eligibility during an entire year. Our primary annual MS identification algorithm required 2 inpatient claims coded ICD-9 340 or 3 outpatient claims coded ICD-9 340 or 1 MS-indicated disease-modifying therapy claim. Age-adjusted annual prevalence estimates were extrapolated to the US population using US Census data., Results: The 2012 MS prevalence was 149.2 per 100,000 individuals (95% confidence interval 147.6-150.9). Prevalence was consistent over 2008-2012. Female participants were 3.13 times more likely to have MS. The highest prevalence was in participants aged 45-49 years (303.5 per 100,000 individuals [295.6-311.5]). The East Census region recorded the highest prevalence (192.1 [188.2-196.0]); the West Census region recorded the lowest prevalence (110.7 [105.5-116.0]). The US annual 2012 MS extrapolated population was 403,630 (387,445-419,833)., Conclusions: MS prevalence rates from a representative commercially insured database were higher than or consistent with prior US estimates. For further accuracy improvement of US prevalence estimates, results should be confirmed after validation of MS identification algorithms, and should be expanded to other US populations, including the government-insured and the uninsured., (© 2016 American Academy of Neurology.)

Background: Placebo-controlled clinical trials have led to concern over possible increased risk of suicide-related events in some populations exposed to antidepressants., Aims: To evaluate the risk of suicide attempts by antidepressant drug class and the presence or absence of depression., Method: A retrospective propensity-matched new-user cohort study was used to compare participants with incident depression classified by antidepressant treatment with each other and with the general population., Results: Among the treated group, the suicide attempt rate peaked in the month prior to diagnosis then decreased steadily over the next 6 months. Among the pharmacologically untreated group, the highest rate was seen in the second month after diagnosis. Cohorts with depression had significantly higher suicide attempt risk than the general population, but the treated group did not differ significantly from the untreated group., Conclusions: Patients on antidepressants did not have significantly higher risk compared with untreated patients. No significant differences were observed for patients treated with individual serotonin-noradrenaline reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) or by class (SSRI v. SNRI cohorts)., (© The Royal College of Psychiatrists 2016.)

Objective: In 2008, the U.S. Centers for Medicare and Medicaid Services enacted a nonpayment policy for stage III and IV hospital-acquired pressure ulcers (HAPUs), which incentivized hospitals to improve prevention efforts. In response, hospitals looked for ways to support implementation of evidence-based practices for HAPU prevention, such as adoption of quality improvement (QI) interventions. The objective of this study was to quantify adoption patterns of QI interventions for supporting evidence-based practices for HAPU prevention., Methods: This study surveyed wound care specialists working at hospitals within the University HealthSystem Consortium. A questionnaire was used to retrospectively describe QI adoption patterns according to 25 HAPU-specific QI interventions into four domains: leadership, staff, information technology (IT), and performance and improvement. Respondents indicated QI interventions implemented between 2007 and 2012 to the nearest quarter and year. Descriptive statistics defined patterns of QI adoption. A t-test and statistical process control chart established statistically significant increase in adoption following nonpayment policy enactment in October 2008. Increase are described in terms of scope (number of QI domains employed) and scale (number of QI interventions within domains)., Results: Fifty-three of the 55 hospitals surveyed reported implementing QI interventions for HAPU prevention. Leadership interventions were most frequent, increasing in scope from 40% to 63% between 2008 and 2012; "annual programs to promote pressure ulcer prevention" showed the greatest increase in scale. Staff interventions increased in scope from 32% to 53%; "frequent consult driven huddles" showed the greatest increase in scale. IT interventions increased in scope from 31% to 55%. Performance and improvement interventions increased in scope from 18% to 40%, with "new skin care products . . ." increasing the most., Linking Evidence to Action: Academic medical centers increased adoption of QI interventions following changes in nonpayment policy. These QI interventions supported adherence to implementation of pressure ulcer prevention protocols. Changes in payment policies for prevention are effective in QI efforts., (© 2015 Sigma Theta Tau International.)

Background and Objectives: Outpatient pediatric polypharmacy is poorly characterized. Identification of at-risk populations has clinical implications for pharmacy case management programs. We described the degree of exposure to polypharmacy using parameters of depth (concurrent medication count) and duration, reported commonly dispensed medications and exposure to three example potential drug-drug interactions by different depths of polypharmacy, and determined patient characteristics associated with exposure to increased degrees (a function of depth and duration) of polypharmacy., Methods: Retrospective cohort study of Colorado fee-for-service Medicaid patients aged <18 years with 12 months of continuous enrollment. We calculated depth of polypharmacy using daily concurrent medication counts and duration of polypharmacy using days exposed to a certain depth. Multinomial logistic regression was used to assess patient characteristics associated with different degrees of polypharmacy., Results: Of 242 230 patients, 35% percent were exposed to any depth of polypharmacy, most commonly to anti-infective medications. Patients with higher depth polypharmacy were exposed to less common medications (psychotropic drugs, anticonvulsants, cardiovascular agents, and opioids) and to higher rates of exposure to potential drug-drug interactions. Of 47 972 patients exposed to ≥3 concurrent medications, 50% were exposed for <15 days, 25% for 15-38 days, 15% for 39-111 days, and 10% for 112-327 days. High-degree polypharmacy was associated with increasing age, male gender, and presence of a complex chronic condition., Conclusions: Outpatient pediatric polypharmacy occurs to a substantial degree for a small but vulnerable population of children, who may be candidates for pharmacy case management. We must determine whether increased exposure to high-degree polypharmacy causes harm., (Copyright © 2015 John Wiley & Sons, Ltd.)

Purpose: Recent data show a decrease in hospital-acquired pressure ulcers (PUs) throughout US hospitals; these changes may be associated with increased success in implementing evidence-based practices for PU prevention. The purpose of this study was to identify wound care nurse perceptions of the primary factors that influenced the overall reduction of PUs., Design: Cross-sectional descriptive survey., Subjects and Setting: Surveys were sent to wound care nurses at 98 University HealthSystem Consortium (UHC) hospitals. The UHC consists of more than 120 academic medical centers and affiliated facilities across the United States. Responses solicited from this survey represented a geographically diverse set of hospitals from less than 200 beds to more than 1000 beds., Instrument: The survey questionnaire used a framework of 7 internal and 5 external influential factors for implementing evidence-based practices for PU prevention. Internal influential factors queried included availability of nurse specialists, high nursing job turnover, high PU rates, and prevention campaigns. External influential factors included data sharing, Medicare nonpayment policy, and applications for Magnet recognition., Methods: Hospital-acquired PU prevention experts at UHC hospitals were contacted through the Wound, Ostomy and Continence Nurses Society membership directory to complete the questionnaire. Consenting participants were e-mailed a disclosure and online questionnaire; they were also sent monthly reminders until they either responded to the survey or declined participation., Results: Fifty-five respondents (59% response rate) indicated several internal factors that influenced evidence-based practice: hospital prevention campaigns; the availability of nursing specialists; and the level of preventive knowledge among hospital staff. External influential factors included financial concerns; application for Magnet recognition; data sharing among peer institutions; and regulatory issues., Conclusions: These findings suggest that the Centers for Medicare & Medicaid Services nonpayment policy influenced a large majority of hospital's changes in practice. The availability of nursing specialists for wound consult influenced hospitals internally. These factors are informative of the impact policy has on changes in hospital prioritization of adopting evidence-based practices for PU prevention.

Background: Prevention of pressure ulcers, one of the hospital-acquired conditions (HACs) targeted by the 2008 nonpayment policy of the Centers for Medicare & Medicaid Services (CMS), is a critical issue. This study was conducted to determine the comparative effectiveness of quality improvement (QI) interventions associated with reduced hospital-acquired pressure ulcer (HAPU) rates., Methods: In an quasi-experimental design, interrupted time series analyses were conducted to determine the correlation between HAPU incidence rates and adoption of QI interventions. Among University HealthSystem Consortium hospitals, 55 academic medical centers were surveyed from September 2007 through February 2012 for adoption patterns of QI interventions for pressure ulcer prevention, and hospital-level data for 5,208 pressure ulcer cases were analyzed. Between- and within-hospital reduction significance was tested with t-tests post-CMS policy intervention., Results: Fifty-three (96%) of the 55 hospitals used QI interventions for pressure ulcer prevention. The effect size analysis identified five effective interventions that each reduced pressure ulcer rates by greater than 1 case per 1,000 patient discharges per quarter: leadership initiatives, visual tools, pressure ulcer staging, skin care, and patient nutrition. The greatest reductions in rates occurred earlier in the adoption process (p<.05)., Conclusions: Five QI interventions had clinically meaningful associations with reduced stage III and IV HAPU incidence rates in 55 academic medical centers. These QI interventions can be used in support of an evidence-based prevention protocol for pressure ulcers. Hospitals can not only use these findings from this study as part of a QI bundle for preventing HAPUs.

Background: In 2007, the Centers for Medicare & Medicaid Services (CMS) announced its intention to no longer reimburse hospitals for costs associated with hospital-acquired pressure ulcers (HAPUs) and a list of other hospital-acquired conditions (HACs), which was followed by enactment of the nonpayment policy in October 2008. This study was conducted to define changes in HAPU incidence and variance since 2008., Methods: In a retrospective observational study, HAPU cases were identified at 210 University HealthSystem Consortium (UHC) academic medical centers in the United States. HAPU incidence rates were calculated as a ratio of HAPU cases to the total number of UHC inpatients between the first quarter of 2008 and the second quarter of 2012. HAPU cases were defined by multiple criteria: not present on admission (POA); coded for stage III or IV pressure ulcers; and a length of stay greater than four days., Results: Among the UHC hospitals between 2008 and June 2012, 10,386 HAPU cases were identified among 4.08 million inpatients. The HAPU incidence rate decreased significantly from 11.8 cases per 1,000 inpatients in 2008 to 0.8 cases per 1,000 in 2012 (p < .001; 95% confidence interval: 8.39-8.56). Among HAPU cases were trends of more elderly patients, greater case-mix index, and more surgical cases. The analysis of covariance model identified CMS non-payment policy as a significant covariate of changing trends in HAPU incidence rates., Conclusions: HAPU incidence rates decreased significantly among 210 UHC AMCs after the enactment of the CMS nonpayment policy. The hospitals appeared to be reacting efficiently to economic policy incentives by improving prevention efforts.

Objectives: To characterize off-label prescribing among US pediatric intensive care units (PICUs), determine characteristics associated with off-label use, and identify medications in highest need for additional study., Methods: Medications prescribed for ≥1% PICU patients (age < 18 years) in 2010 were identified from 39 children's hospitals. Use in a patient younger than the Food and Drug Administration (FDA)-approved age for any indication was considered off-label. Hierarchical multivariable modeling was used to identify characteristics associated with off-label use, accounting for center effects. Highest-impact drugs were defined by: 1) high off-label use (off-label use in at least 5% of the PICU cohort), 2) high risk medication, and 3) high priority status by the FDA or Best Pharmaceuticals for Children Act (BPCA)., Results: A total of 66,896 patients received ≥1 medication of interest (n = 162) during their PICU stay. A median of 3 (interquartile range, 2-6) unique drugs per patient were used off-label. Those who received ≥1 drug off-label (85% of the cohort) had longer median PICU (2 days vs 1 day) and hospital (6 days vs 3 days) lengths of stay and higher mortality (3.6% vs 0.7%), p < 0.001. Factors independently associated with off-label drug use included: age 1 to 5 years, chronic conditions, acute organ failures, mechanical ventilation, arterial or venous catheters, dialysis, and blood products. Half of prescribed medications (n = 84) had been used off-label: 26 with significant off-label use, 30 high-risk medications, and 47 with high FDA/BPCA priority. The highest impact medications identified were: dexmedetomidine, dopamine, hydromorphone, ketamine, lorazepam, methadone, milrinone, and oxycodone., Conclusions: Most PICU patients are exposed to off-label medication use, with uncertain evidence. Future medication research in this population should focus on medications with high impact potential.

Purpose: In the 2004, FDA placed a black box warning on antidepressants for risk of suicidal thoughts and behavior in children and adolescents. The purpose of this paper is to examine the risk of suicide attempt and self-inflicted injury in depressed children ages 5-17 treated with antidepressants in two large observational datasets taking account time-varying confounding., Methods: We analyzed two large US medical claims databases (MarketScan and LifeLink) containing 221,028 youth (ages 5-17) with new episodes of depression, with and without antidepressant treatment during the period of 2004-2009. Subjects were followed for up to 180 days. Marginal structural models were used to adjust for time-dependent confounding., Results: For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses. Marginal structural models revealed that the majority of the association is produced by dynamic confounding in the treatment selection process; estimated odds ratios were close to 1.0 consistent with the unadjusted and simple covariate adjusted association being a product of chance alone., Conclusions: Our analysis suggests antidepressant treatment selection is a product of both static and dynamic patient characteristics. Lack of adjustment for treatment selection based on dynamic patient characteristics can lead to the appearance of an association between antidepressant treatment and suicide attempts and self-inflicted injury among youths in unadjusted and simple covariate adjusted analyses. Marginal structural models can be used to adjust for static and dynamic treatment selection processes such as that likely encountered in observational studies of associations between antidepressant treatment selection, suicide and related behaviors in youth., (Copyright © 2014 John Wiley & Sons, Ltd.)

Introduction: Patients at risk for suicide often come into contact with primary care providers, many of whom use electronic health records (EHRs) for charting. It is not known, however, how often suicide ideation or attempts are documented in EHRs., Methods: We used retrospective analyses of de-identified EHR data from a distributed health network of primary care organizations to estimate the frequency of using diagnostic codes to record suicidal ideation and attempts. Data came from 3 sources: a clinician notes field processed using natural language processing; a suicidal ideation item on a patient-reported depression severity instrument (9-item Patient Health Questionnaire [PHQ-9]); and diagnostic codes from the EHR., Results: Only 3% of patients with an indication of suicidal ideation in the notes field had a corresponding International Classification of Diseases, 9th Revision (ICD-9), code (κ = 0.036). Agreement between an indication of suicidal ideation from item 9 of the PHQ-9 and an ICD-9 code was slightly higher (κ = 0.068). Suicide attempt indicated in the notes field was more likely to be recorded using an ICD-9 code (19%; κ = 0.18)., Conclusions: Few cases of suicidal ideation and attempt were documented in patients' EHRs using diagnostic codes. Increased documentation of suicidal ideation and behaviors in patients' EHRs may improve their monitoring in the health care system., (© Copyright 2015 by the American Board of Family Medicine.)

Purpose: To enhance the learner's competence with knowledge about a framework of quality improvement (QI) interventions to implement evidence-based practices for pressure ulcer (PrU) prevention., Target Audience: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care., Objectives: After participating in this educational activity, the participant should be better able to:1. Summarize the process of creating and initiating the best-practice framework of QI for PrU prevention.2. Identify the domains and QI interventions for the best-practice framework of QI for PrU prevention. Pressure ulcer (PrU) prevention is a priority issue in US hospitals. The National Pressure Ulcer Advisory Panel endorses an evidence-based practice (EBP) protocol to help prevent PrUs. Effective implementation of EBPs requires systematic change of existing care units. Quality improvement interventions offer a mechanism of change to existing structures in order to effectively implement EBPs for PrU prevention. The best-practice framework developed by Nelson et al is a useful model of quality improvement interventions that targets process improvement in 4 domains: leadership, staff, information and information technology, and performance and improvement. At 2 academic medical centers, the best-practice framework was shown to physicians, nurses, and health services researchers. Their insight was used to modify the best-practice framework as a reference tool for quality improvement interventions in PrU prevention. The revised framework includes 25 elements across 4 domains. Many of these elements support EBPs for PrU prevention, such as updates in PrU staging and risk assessment. The best-practice framework offers a reference point to initiating a bundle of quality improvement interventions in support of EBPs. Hospitals and clinicians tasked with quality improvement efforts can use this framework to problem-solve PrU prevention and other critical issues.

Rationale: Studies evaluating corticosteroid (CS) dosing for patients hospitalized with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) have largely excluded patients admitted directly to the intensive care unit (ICU), and none have evaluated the effect of CS dosing regimens on mortality., Objectives: To examine the effectiveness and safety of lower- versus high-dose CS in patients admitted to the ICU with an AECOPD., Methods: This pharmacoepidemiologic cohort study evaluated ICU patients with AECOPD admitted to one of 473 hospitals and treated with CS within the first 2 days between January 1, 2003 and December 31, 2008. Patients were grouped into lower-dose (methylprednisolone, ≤240 mg/d) or high-dose (methylprednisolone, >240 mg/d) groups based on CS dosage on hospital Day 1 or 2. The primary outcome was hospital mortality., Measurements and Main Results: A total of 17,239 patients were included; 6,156 (36%) were in the lower-dose and 11,083 (64%) in the high-dose CS group. After propensity score matching and adjustment for unbalanced covariates, lower-dose CS was not associated with a significant reduction in mortality (odds ratio, 0.85; 95% confidence interval [CI], 0.71-1.01; P = 0.06), but it was associated with reduced hospital (-0.44 d; 95% CI, -0.67 to -0.21; P < 0.01) and ICU (-0.31 d; 95% CI, -0.46 to -0.16; P < 0.01) length-of-stay, hospital costs (-$2,559; 95% CI, -$4,508 to -$609; P = 0.01), length of invasive ventilation (-0.29 d; 95% CI, -0.52 to -0.06; P = 0.01), need for insulin therapy (22.7% vs. 25.1%; P < 0.01), and fungal infections (3.3% vs. 4.4%; P < 0.01)., Conclusions: Two-thirds of patients admitted to the ICU with an AECOPD are treated with high doses of CS that are associated with worse outcomes and more frequent adverse effects. Lower dosage strategies should be encouraged for patients admitted to the ICU and the optimum dose should be determined through clinical trials.

Purpose: This study aims to perform a comparative safety study assessing the risk of ventricular arrhythmia, cardiac arrest, or sudden death among pediatric selective serotonin reuptake inhibitor (SSRI) users., Methods: Using US claims data from 1997 to 2009, new pediatric (age < 18 years) users of SSRI monotherapy were identified. Adverse cardiac outcomes occurring within 12 months of SSRI initiation were identified using a previously validated International Classification of Disease, ninth edition algorithm. Cox proportional hazard analysis was used to estimate the risk for each SSRI, using fluoxetine as the referent group, adjusting for the propensity to receive an individual SSRI, demographics, and exposure covariates., Results: Over the study period, 113,714 subjects met the inclusion criteria and contributed 40,639 person-years of SSRI exposure time. Sertraline (33%) and fluoxetine (29%) were the most commonly prescribed SSRIs. Forty events occurred within 12 months of SSRI initiation. The crude incidence rate was highest for escitalopram (19.5/10,000 person-years) and lowest for fluoxetine (4.2/10,000 person-years). The median time to event ranged from 45 to 86 days. The adjusted risk of adverse event, relative to fluoxetine, was highest for citalopram Hazard Ratio (HR) = 3.53, 95% confidence interval [CI] = 1.09–11.46) and escitalopram (HR = 3.30, 95%CI = 1.08–10.14) and lowest for paroxetine (HR = 1.34, 95%CI = 0.30–5.99) and sertraline (HR = 2.14, 95%CI = 0.75–6.16)., Conclusions: The incidence of adverse cardiac events among pediatric SSRI users was low. However, the risk of an adverse outcome was higher for citalopram and escitalopram users as compared with fluoxetine users. Future studies should focus on confirming these findings and identifying modifying risk factors to optimize medication selection for this population.