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Asthma exacerbations with respiratory failure (AERF) are associated with hospital mortality of 7% to 15%. Extracorporeal membrane oxygenation (ECMO) has been used as salvage therapy for refractory AERF, but controlled studies showing its association with mortality have not been performed.Is treatment with ECMO associated with lower mortality in refractory AERF compared with standard care?This is a retrospective, epidemiologic, observational cohort study using a national, administrative data set from 2010 to 2020 that includes 25% of US hospitalizations. People were included if they were admitted to an ECMO-capable hospital with an asthma exacerbation, and were treated with short-acting bronchodilators, systemic corticosteroids, and invasive ventilation. People were excluded for age 18 years, no ICU stay, nonasthma chronic lung disease, COVID-19, or multiple admissions. The main exposure was ECMO vs No ECMO. The primary outcome was hospital mortality. Key secondary outcomes were ICU length of stay (LOS), hospital LOS, time receiving invasive ventilation, and total hospital costs.The study analyzed 13,714 patients with AERF, including 127 with ECMO and 13,587 with No ECMO. ECMO was associated with reduced mortality in the covariate-adjusted (OR, 0.33; 95% CI, 0.17-0.64; P = .001), propensity score-adjusted (OR, 0.36; 95% CI, 0.16-0.81; P = .01), and propensity score-matched models (OR, 0.48; 95% CI, 0.24-0.98; P = .04) vs No ECMO. Sensitivity analyses showed that mortality reduction related to ECMO ranged from OR 0.34 to 0.61. ECMO was also associated with increased hospital costs in all three models (P .0001 for all) vs No ECMO, but not with decreased ICU LOS, hospital LOS, or time receiving invasive ventilation.ECMO was associated with lower mortality and higher hospital costs, suggesting that it may be an important salvage therapy for refractory AERF following confirmatory clinical trials.

BackgroundPlacebo-controlled clinical trials have led to concern over possible increased risk of suicide-related events in some populations exposed to antidepressants.AimsTo evaluate the risk of suicide attempts by antidepressant drug class and the presence or absence of depression.MethodA 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.ResultsAmong 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.ConclusionsPatients 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).

Recent evidence suggests that half-dose thrombolysis for pulmonary embolism may provide similar efficacy with reduced bleeding risk compared with full-dose therapy, but comparative studies are lacking. We aimed to evaluate the effectiveness and safety of half-dose versus full-dose alteplase for treatment of pulmonary embolism.A retrospective cohort study comparing outcomes in patients receiving half-dose (50 mg) versus full-dose (100 mg) alteplase for pulmonary embolism. We used propensity score matching and sensitivity analyses to address confounding and hospital-level clustering.Data from 420 hospitals obtained from the Premier Healthcare Database between January 2010 and December 2014.Adult critically ill patients with acute pulmonary embolism treated with IV alteplase therapy.None.This study included 3,768 patients: 699 (18.6%) in the half-dose and 3,069 (81.4%) in the full-dose group. At baseline, patients receiving half-dose alteplase required vasopressor therapy (23.3% vs 39.4%; p0.01) and invasive ventilation (14.3% vs 28.5%; p0.01) less often, compared with full dose. After propensity matching (n = 548 per group), half-dose alteplase was associated with increased treatment escalation (53.8% vs 41.4%; p0.01), driven mostly by secondary thrombolysis (25.9% vs 7.3%; p0.01) and catheter thrombus fragmentation (14.2% vs 3.8%; p0.01). Hospital mortality was similar (13% vs 15%; p = 0.3). There was no difference in cerebral hemorrhage (0.5% vs 0.4%; p = 0.67), gastrointestinal bleeding (1.6% vs 1.6%; p = 0.99), acute blood loss anemia (6.9% vs 4.6%; p = 0.11), use of blood products (p0.05 for all), or documented fibrinolytic adverse events (2.6% vs 2.8%; p = 0.82).Compared with full-dose alteplase, half-dose was associated with similar mortality and rates of major bleeding. Treatment escalation occurred more often in half-dose-treated patients. These results question whether half-dose alteplase provides similar efficacy with improved safety, and highlights the need for further study before use of half-dose alteplase therapy can be routinely recommended in patients with pulmonary embolism.

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.

BACKGROUND: Natalizumab disease-modifying therapy for relapsingremitting multiple sclerosis (MS) is efficacious in randomized controlled trials. Few studies have estimated the association between real-world natalizumab persistence behavior and relapse-related outcomes. OBJECTIVES: To (a) examine the impact of using natalizumab consistently (i.e., persistent) on relapse-related outcomes as compared with transitioning to inconsistent natalizumab use (i.e., nonpersistent) and (b) examine the impact of other treatment patterns on relapse-related outcomes for those who initiated natalizumab. METHODS: Using the IMS PharMetrics Plus claims database (years 20062012), we identified MS subjects who initiated natalizumab (no natalizumab claims in year prior) and had at least 2 years of follow-up. Persistence in annual follow-up periods was defined as no 90-day or greater gap in natalizumab therapy. Relapse was an MS-related hospitalization or outpatient visit with intravenous or oral steroid burst claim within 7 days. Analyses compared observations based on changes in natalizumab persistence and natalizumab nonpersistence status from 1 year to the next (e.g., transitioning from persistent to nonpersistent), estimating differences in mean annual relapses and mean annual relapse-related costs. RESULTS: A total of 2,407 natalizumab initiators had at least 2 years of follow-up, yielding 4,770 year-to-year natalizumab treatment patterns where each subject contributed 1, 2, or 3 year-to-year treatment patterns. In the year prior, 3,187 treatment patterns were persistent; 731 (22.9%) of these transitioned to nonpersistence. The remaining 1,583 treatment patterns were nonpersistent in the year prior; 132 (8.3%) of these transitioned to persistence. Persistent to nonpersistent treatment patterns were associated with a mean relapse-rate increase of 0.23 (95% CI = 0.12, 0.35), and a mean increase in relapse-related costs of $1,346 (95% CI = $97, $2,595). Nonpersistent to persistent treatment patterns were associated with a mean relapse-rate decrease of -0.15 (95% CI = -0.32, 0.017) and a mean decrease in relapse-related costs of -$1,369 (95% CI = -$2,761, $23). CONCLUSIONS: Findings suggest that real-world persistent natalizumab users who become nonpersistent have statistically significant increases in annual relapses and relapse-related costs. Those who transition from nonpersistent to persistent have nonsignificant reductions in relapses and their associated costs.

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 patients9 EHRs using diagnostic codes. Increased documentation of suicidal ideation and behaviors in patients9 EHRs may improve their monitoring in the health care system.

The neuromuscular blocking agent cisatracurium may improve mortality for patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Other neuromuscular blocking agents, such as vecuronium, are commonly used and have different mechanisms of action, side effects, cost, and availability in the setting of drug shortages.To determine whether cisatracurium is associated with improved outcomes when compared with vecuronium in patients at risk for and with ARDS.Using a nationally representative database, patients who were admitted to the ICU with a diagnosis of ARDS or an ARDS risk factor, received mechanical ventilation, and were treated with a continuous infusion of neuromuscular blocking agent for at least 2 days within 2 days of hospital admission were included. Patients were stratified into two groups: those who received cisatracurium or vecuronium. Propensity matching was used to balance both patient- and hospital-specific factors. Outcomes included hospital mortality, duration of mechanical ventilation, ICU and hospital duration, and discharge location.Propensity matching successfully balanced all covariates for 3,802 patients (1,901 per group). There was no significant difference in mortality (odds ratio, 0.932; P = 0.40) or hospital days (-0.66 d; P = 0.411) between groups. However, patients treated with cisatracurium had fewer ventilator days (-1.01 d; P = 0.005) and ICU days (-0.98 d; P = 0.028) but were equally likely to be discharged home (odds ratio, 1.19; P = 0.056).When compared with vecuronium, cisatracurium was not associated with a difference in mortality but was associated with improvements in other clinically important outcomes. These data suggest that cisatracurium may be the preferred neuromuscular blocking agent for patients at risk for and with ARDS.

To assess the impact of a discharge diagnosis of critical illness polyneuromyopathy on health-related outcomes in a large cohort of patients requiring ICU admission.Retrospective cohort with propensity score-matched analysis.Analysis of a large multihospital database.Adult ICU patients without preexisting neuromuscular abnormalities and a discharge diagnosis of critical illness polyneuropathy and/or myopathy along with adult ICU propensity-matched control patients.None.Of 3,567 ICU patients with a discharge diagnosis of critical illness polyneuropathy and/or myopathy, we matched 3,436 of these patients to 3,436 ICU patients who did not have a discharge diagnosis of critical illness polyneuropathy and/or myopathy. After propensity matching and adjusting for unbalanced covariates, we used conditional logistic regression and a repeated measures model to compare patient outcomes. Compared to patients without a discharge diagnosis of critical illness polyneuropathy and/or myopathy, patients with a discharge diagnosis of critical illness polyneuropathy and/or myopathy had fewer 28-day hospital-free days (6 [0.1] vs 7.4 [0.1] d; p0.0001), had fewer 28-day ventilator-free days (15.7 [0.2] vs 17.5 [0.2] d; p0.0001), had higher hospitalization charges (313,508 [4,853] vs 256,288 [4,470] dollars; p0.0001), and were less likely to be discharged home (15.3% vs 32.8%; p0.0001) but had lower in-hospital mortality (13.7% vs 18.3%; p0.0001).In a propensity-matched analysis of a large national database, a discharge diagnosis of critical illness polyneuropathy and/or myopathy is strongly associated with deleterious outcomes including fewer hospital-free days, fewer ventilator-free days, higher hospital charges, and reduced discharge home but also an unexpectedly lower in-hospital mortality. This study demonstrates the clinical importance of a discharge diagnosis of critical illness polyneuropathy and/or myopathy and the need for effective preventive interventions.

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.To examine the effectiveness and safety of lower- versus high-dose CS in patients admitted to the ICU with an AECOPD.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.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; P0.01) and ICU (-0.31 d; 95% CI, -0.46 to -0.16; P0.01) 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%; P0.01), and fungal infections (3.3% vs. 4.4%; P0.01).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.

Background Vascular endothelial growth factor inhibitors such as bevacizumab, sorafenib, and sunitinib are utilized in the treatment of multiple cancers. Although these agents are associated with hypertension, there is a lack of evidence describing patterns of antihypertensive use in patients with vascular endothelial growth factor inhibitor-associated hypertension in a non-trial, “real-world” setting. Objective To describe the occurrence and severity of vascular endothelial growth factor inhibitor-associated hypertension, patterns of antihypertensive use and occurrence of cardiovascular complications in a non-trial population, and to describe patterns of initial antihypertensive therapy in patients developing hypertension during treatment with a vascular endothelial growth factor inhibitor. Methods This retrospective cohort study utilized claims data from the Medstat MarketScan Commercial Claims and Encounter database to identify patients with claims for a vascular endothelial growth factor inhibitor and a diagnosis of cancer using International Classification of Diseases, 9th Revision, Clinical Modification codes, Healthcare Common Procedure Coding System J-codes and National Drug Codes. The study period encompassed claims from one year before the patient’s first claim for a vascular endothelial growth factor inhibitor, and continued through one year after the initial vascular endothelial growth factor inhibitor claim. Patients meeting study criteria were classified into cohorts A1, patients with no hypertension throughout the study period; A2, patients without hypertension at baseline who developed hypertension after starting a vascular endothelial growth factor inhibitor; and cohort B, patients with hypertension prior to receiving a vascular endothelial growth factor inhibitor. We utilized medical and pharmacy claims data to describe the presence of hypertension, its severity, and the occurrence of cardiovascular complications throughout the study period. Initial antihypertensive use in cohort A2 was described. Results In all, 2177 patients met study criteria and were categorized into cohorts A1 (n = 708), A2 (n = 333) and B (n = 1136). Approximately 32% of patients without hypertension at baseline had claims suggestive for hypertension during the study period. Life-threatening (Grade 4) hypertension increased throughout the study period for cohorts A1, A2, and B, to 3.4%, 10.2%, and 16.4%, respectively ( p Conclusion Our study provides valuable insight into non-trial patterns of vascular endothelial growth factor inhibitor-associated hypertension occurrence and severity, and is consistent with prior claims analysis. Identification of optimal strategies to manage vascular endothelial growth factor inhibitor-associated hypertension remain to be clarified with the advent of more comprehensive data sets.

This study assessed blood pressure (BP) goal maintenance in patients controlled with olmesartan monotherapy after switching to another angiotensin type II receptor blocker (ARB). Hypertensive patients prescribed olmesartan monotherapy were identified from GE Healthcare's Centricity electronic medical record between 2007 and 2011. After documentation of BP goal (

Background: Depression is a leading cause of morbidity worldwide. The majority of treatment for depression occurs in primary care, but effective care remains elusive. Clinical decision making and comparative studies of real-world antidepressant effectiveness are limited by the absence of clinical measures of severity of illness and suicidality. Methods: The Distributed Ambulatory Research in Therapeutics Network (DARTNet) was engaged to systematically collect data using the 9-item Patient Health Questionnaire (PHQ-9) at the point of care. We used electronic health records (EHRs) and the PHQ-9 to capture, describe, and compare data on both baseline severity of illness and suicidality and response and suicidality after diagnosis for depressed patients in participating DARTNet practices. Results: EHR data were obtained for 81,028 episodes of depression (61,464 patients) from 14 clinical organizations. Over 9 months, data for 4900 PHQ-9s were collected from 2969 patients in DARTNet practices (this included 1892 PHQ-9s for 1019 adults and adolescents who had at least one depression diagnosis). Only 8.3% of episodes identified in our depression cohort had severity of illness information available in the EHR. For these episodes, considerable variation existed in both severity of illness (32.05% with no depression, 26.89% with minimal, 19.54% with mild, 12.04% with moderate, and 9.47% with severe depression) and suicidality (69.43% with a score of 0, 22.58% with a score of 1, 4.97% with a score of 2, and 3.02% with a score of 3 on item 9 of the PHQ-9). Patients with an EHR diagnosis of depression and a PHQ-9 (n = 1019) had similar severity but slightly higher suicidality levels compared with all patients for which PHQ-9 data were available. The PHQ-9 showed higher sensitivity for identifying depression response and emergent (after diagnosis) severity and suicidality; 25% to 30% of subjects had some degree of suicidal thought at some point in time according to the PHQ-9. Conclusions: This study demonstrated the value of adding PHQ-9 data and prescription fulfillment data to EHRs to improve diagnosis and management of depression in primary care and to enable more robust comparative effectiveness research on antidepressants.

Background context Several investigators have identified an explosive increase in spinal injection rates in the Veterans Administration and Medicare populations. Furthermore, utilization of spinal injection procedures appears to vary by geographic location, subspecialty, and practice setting. Medicare claims analysis has shown that a small percentage of physicians perform a disproportionately large number of injections. Although Medicare utilization has been well characterized, the utilization patterns for privately insured individuals are not clearly known. Purpose The primary purpose of this article was to investigate whether relatively few providers are responsible for a disproportionately high percentage of interventional spine procedures in privately insured plans and to quantify any such findings. The secondary purpose was to determine if provider specialty is a relevant variable in any identified patterns of disproportionate utilization. Study design A descriptive analysis of utilization patterns using the Medstat MarketScan database was conducted between 2003 and 2007. The database contains deidentified medical, pharmacy, and enrollment claims representing 12 to 14 million individuals. Patient sample A data set was generated based on the following inclusion criteria: all patients aged between 18 and 99 years receiving at least one spinal interventional procedure between 2003 and 2007: epidural steroid injections, intra-articular facet or medial branch blocks, medial branch radio frequency neurotomy, sacroiliac joint injections, and discography. Our inclusion criteria yielded data on nearly 200,000 patients treated by over 20,000 providers. Outcome measures Not applicable. Methods The number of procedures was tallied for a 12-month period beginning with a patient’s first procedure claim. The total number of procedures per patient and the mean number of procedures per patient were calculated for the study sample. Within each specialty, all spinal procedures were summed for each individual provider within each procedure category and as an overall total. The overall mean number of therapeutic procedures per patient for all physicians within a specialty was calculated. Within each specialty, the total number of procedures performed by each physician was analyzed in percentiles to highlight any disparity between high- and low-using providers. Results The final therapeutic procedure data set contained 196,332 patients who received 875,627 procedures. The principal nine specialties performing these procedures were anesthesiology (49.2% of the total number of procedures in the final data set), physiatry (12.5%), pain management (12.0%), family practice (10.2%), orthopedics (5.5%), radiology (3.0%), neurology (2.8%), internal medicine (2.8%), and neurosurgery (1.9%). The overall mean number of procedures across all categories performed per patient during the 12-month inclusion period was 4.46±6.44. Neurologists and pain management specialists were the only provider groups in which the mean number of procedures per patient exceeded the overall mean. The highest 10% of providers, which encompasses those providers performing a mean greater than or equal to 5.08 procedures per patient per year, perform 36.6% of the total spinal procedures performed. The highest 20% of providers, which encompasses those providers with a mean greater than or equal to 3.75, account for 57.6% of all spinal procedures. The highest 10% of providers perform nine times more procedures per patient compared with the lowest 10% and 4.5 times more procedures than the median. This same pattern of high utilization by disproportionately few providers was observed across all nine specialties. Conclusions These findings demonstrate that relatively few providers are responsible for a disproportionately high percentage of interventional spine procedures. This pattern of marked overutilization by a minority of providers is the dominant characteristic of utilization within all specialties.

Data describing the use of recommended antihypertensive agents in the resistant hypertension population are limited. Treatment recommendations for resistant hypertension include maximizing diuretic therapy by using chlorthalidone and/or adding an aldosterone antagonist. Additional recommendations include combining antihypertensive agents from different drug classes. This retrospective cohort study describes antihypertensive use in patients with resistant hypertension defined as the concurrent use of ≥4 antihypertensive agents. Claims data from the Medstat MarketScan Commercial Claims and Encounter database were used to identify patients with resistant hypertension based on International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes and National Drug Codes between May 1, 2008 and June 30, 2009. Of the 5 442 410 patients with hypertension in the database, 140 126 met study criteria. The most frequently prescribed antihypertensive classes were angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (96.2%), diuretics (93.2%), calcium channel blockers (83.6%), and β-blockers (80.0%). Only 3.0% and 5.9% of patients were on chlorthalidone or an aldosterone antagonist, respectively. A total of 15.6% of patients were treated with angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker. Our findings demonstrate that frequently prescribed antihypertensive agents for the treatment of resistant hypertension included guideline-recommended first-line agents. However, evidence-based and recommended agents, such as chlorthalidone and aldosterone antagonists, were underused. Moreover, minimally efficacious combinations, such as an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker, were prescribed at higher rates than evidence-based and recommended agents.

We examined the use of 23 diagnostic procedures and monitoring tests for users of disease-modifying therapy (DMT) and non-DMT users with multiple sclerosis (MS). The Medstat MarketScan(®) Commercial Claims and Encounters database (2003-2007), which is composed of medical and pharmacy claims for approximately 8 million beneficiaries from 45 US commercial health plans, was used to identify DMT users with an index claim for an MS drug and a 6-month baseline period without MS drugs. Patients were followed for 12 months. Logistic regression models were used to estimate differences in rates and proportion of patients receiving procedures and tests between cohorts. Baseline rates for DMT users (n = 12,455) included MRIs (76.8%), spinal taps (15.7%), neuropsychological testing (4.7%), chemistry panels (61.4%), complete blood cell counts (76.7%) and liver function tests (60.5%). Relative to non-DMT users (n = 25,534), DMT users were more likely to receive an MRI, neuropsychological testing, chemistry panels, complete blood cell counts and liver function tests.

The Distributed Ambulatory Research in Therapeutics Network (DARTNet) is a federated network of electronic health record (EHR) data, designed as a platform for next-generation comparative effectiveness research in real-world settings. DARTNet links information from nonintegrated primary care clinics that use EHRs to deliver ambulatory care to overcome limitations with traditional observational research.Test the ability to conduct a remote, electronic point of care study in DARTNet practices by prompting clinic staff to obtain specific information during a patient encounter.Prospective survey of patients identified through queries of clinical data repositories in federated network organizations. On patient visit, survey is triggered and data are relinked to the EHR, de-identified, and copied for evaluation.Adult patients diagnosed with diabetes mellitus that scheduled a clinic visit for any reason in a 2-week period in DARTNet primary care practices.Survey on hypoglycemic events (past month) and over-the-counter and herbal supplement use.DARTNet facilitated point of care data collection triggered by an electronic prompt for additional information at a patient visit. More than one-third of respondents (33% response rate) reported either mild (45%) or severe hypoglycemic events (5%) in the month before the survey; only 3 of those were also coded using the ICD-9 (a significant difference in detection rates 37% vs. 1%). Nearly one-quarter of patients reported taking an OTC/herbal, 4% specifically for the treatment of symptoms of diabetes.Prospective data collection is feasible in DARTNet and can enable comparative effectiveness and safety research.

This study aims to determine risk factors of opioid overdose among the Colorado Medicaid population. A retrospective nested case-control study was undertaken. Medicaid beneficiaries who had ≥1 medical claim for an emergency department visit or a hospitalization associated with an opioid overdose from July 2009 to June 2014 were defined as cases. Controls were selected using a nearest neighbor matching without replacement. The matched controls were selected on the basis of age, sex, and opioid prescription. One case was matched with three controls. Multivariate conditional logistic regression was used to compare risk factors. A total of 816 cases with 2,448 controls were included. Six factors were associated with opioid overdose: mean morphine dose equivalent (>50 mg/d; odds ratio [OR] = 1.986 [95% confidence interval [CI], 1.509–2.614]), methadone use (switching opioid to methadone vs. no methadone use; OR = 7.230 [95% CI, 2.346–22.286]), drug/alcohol abuse (OR = 3.104 [95% CI, 2.195–4.388]), other psychiatric illness (OR = 1.730 [95% CI, 1.307–2.291]), benzodiazepine use (OR = 2.005 [95% CI, 1.516–2.652]), and the number of pharmacies used by the beneficiary (≥4 pharmacies vs. 1 pharmacy; OR = 1.514 [95% CI, 1.003–2.286]). In conclusion, several factors are associated with opioid overdose. States and communities should ensure the availability of at-home intranasal naloxone for overdose rescue on the basis of the presence of risk factors. Perspective This article presents the risk factors of opioid overdose among the Colorado Medicaid population. On the basis of study findings, Colorado Medicaid is currently working with physicians, hospitals, and other health system stakeholders to continue to develop policies to identify and assist this subset of our population. One such policy will be to provide at-home intranasal naloxone for overdose rescue.

Background:Patients with chronic diseases are particularly affected by prescription copayment increases, as they are faced with the decision to switch to formulary alternatives or pay more to stay on their current medication.Objective:To evaluate the impact of increased copayments as a result of a change in formulary status on the continuation rates of nonformulary medications in multitiered pharmacy benefit plans.Methods:A retrospective cohort study was conducted on patients with chronic diseases who were part of a health plan in the western US. Individuals were selected if they were taking a medication that was being removed from the health plan's formulary and, thus, experienced increases in their copayments for nonformulary medications (n = 1,244). The time periods before and after the increase in copayments were studied. Adjusting for demographics, chronic comorbidities, medication use, Medicare + Choice status, and percentage increase in copayment for nonformulary medications, Cox regressions were used to assess continuation rates for these drugs.Results:A clear relationship between increasing copayment differentials and continuation rates for nonformulary medications in the period after the copayment increases could not be established. In general, those who experienced higher copayment differentials (50–100%, 100–200%, >200%) were more likely to continue their nonformulary medication than were those who experienced copayment increases of 25–50% and >25%.Conclusions:Individuals confronted with increased copayments often switched their drugs to formulary alternatives. However, a clear relationship could not be established between increasing copayments and continuation behavior. Further research is needed to determine whether these switching behaviors result in inappropriate medication behaviors, such as complete discontinuation of drug therapy due to the increased costs.

Context: The US FDA has issued an advisory warning of a possible link between antidepressant treatment for paediatric patients with major depressive disorder (MDD) and an increased risk of suicidal behaviour. A large database of paid health insurance claims for adolescents with MDD provided the opportunity to examine this possible relationship. Objective: To examine the potential empirical link between antidepressant treatment and suicide attempts among adolescents aged 12–18 years using a community sample of managed care enrollees across the US. Design: A retrospective longitudinal cohort using paid insurance claims for all healthcare and prescription fills for adolescents who were newly diagnosed with MDD and had at least 6 months of follow-up data. A multivariate Cox proportional hazards regression analysis was used to test the hypothesis that antidepressant use increased the risk of suicide attempt, adjusting for propensity for allocation to each treatment group and for demographic and clinical characteristics. Setting: Managed care plans including both commercial and Medicaid plans in the east, midwest, south and western regions of the US from January 1997 to March 2003. Participants: All adolescent insurance members aged 12–18 years at first diagnosis of MDD. Main outcome measures: Suicide attempts as indicated by medical utilisation with International Classification of Diseases (9th edition) [ICD-9] or 10th edition (ICD-10) codes in any healthcare setting or by any covered provider. Results: 24 119 adolescents met inclusion criteria (63% female). Crude suicide attempt rates ranged from 0.0-2.3% by index treatment group. Treatment with SSRIs (hazard ratio) [HR] = 1.59; CI 0.89, 2.82), other antidepressants (HR = 1.03; CI 0.43, 2.44), or multiple antidepressants (HR = 1.43; CI 0.70, 2.89) after index MDD diagnosis resulted in no statistically increased risk of suicide attempt. Treatment with antidepressant medication for at least 180 days (6 months) reduced the likelihood of suicide attempt compared with antidepressant treatment for

The effects of chronic administration of MK-801 (NMDA-receptor antagonist) and remacemide (sodium channel blocker) on monkey learning of several brain function tasks was assessed in juveniles (nine months old). Low (LO) and high (HI) doses of both drugs were given orally each day for 18 months. There were no adverse effects of any treatment on tests of short-term memory or motivation. HI doses of both MK-801 and remacemide delayed acquisition of a visual discrimination task (the remacemide effect was much greater). HI doses of remacemide alone severely disrupted learning task acquisition and this effect lasted for several months after dosing. Thus, in monkeys, chronic blockade of NMDA receptors is relatively well tolerated, whereas blockade of sodium channels (perhaps in conjunction with NMDA receptor blockade) has long-term—perhaps permanent—consequences. To further explore the roles of NMDA receptors and sodium channels in these effects, MK-801, phenytoin (sodium channel blocker), or both were administered to rats and the acquisition of tasks similar to those used in the monkey study were assessed. Dosing began at weaning and continued for nine months. Throughout the study, HI MK-801 subjects exhibited impaired performance in all tasks. Some effects of MK-801 were blocked completely by phenytoin. In the rat, blockade of sodium channels was well tolerated but blockade of NMDA receptors had significant and long-term (permanent?) adverse consequences. These data contrast markedly with those obtained for the monkey and suggest, at least for some drug classes, that the rat might not be a good predictor of effects in primates.

Introduction: Real-world comparative studies evaluating traditional with newer antianginal medications in chronic stable angina (CSA) on cardiovascular (CV) outcomes and healthcare utilization are limited. Methods: Medical and pharmacy claims from 2008-2012 were analyzed using a large commercial database. Patients with a CSA diagnosis receiving ranolazine, beta blocker (BB), calcium channel blocker (CCB), or long-acting nitrates (nitrates) were identified and followed for 12 months after a change in antianginal therapy. Patients on traditional antianginal medication: BB, CCB, and nitrates were required to have concurrent sublingual nitroglycerin. Therapy change was defined as adding or switching to another traditional antianginal or ranolazine to identify patients who had failed prior therapy. Four groups were identified (BB, CCB, nitrates, or ranolazine users) and matched for age,gender, baseline Charlson Comorbidity Index (CCI), acute coronary syndrome,hypertension, diabetes, heart failure, hyperlipidemia, diabetes related complications, and cardiovascular healthcare costs. Rates for percutaneous intervention (PCI) and coronary bypass graft (CABG) at 30, 60, 90, 180 and 360 days, as well as, annual number of CV-related outpatient visits, emergency room (ER) visits, and inpatient admissions post therapy change were compared between groups. Results: A total of 8008 patients were identified with 2002 patients in each antianginal matched group. The majority (63-65%) were male with a mean age of 66 years and a CCI of 2.89-3.01. The Table summarizes the annual rate per 1000 for CV outcomes. Compared to other antianginal therapies, ranolazine consistently exhibited lower PCI and CABG rates at all time periods following therapy change. Compared to BB, CCB,and nitrates,ranolazine had a 21% (p=0.004), 4% (p=0.578), and 23% (p Conclusion: Ranolazine improves CV outcomes and lowers healthcare utilization compared to traditional antianginal therapies.

Introduction: Though, deep vein thrombosis (DVT) and pulmonary embolism (PE) impose a major burden on US healthcare system, limited data exists on the economic impact of DVT and PE on younger working population. DVT, which occurs in approximately 1 in every 1,000 adults every year, is estimated to cost between $5-8 billion annually or on average $20,000 per treated patient per year. PE occurs in 0.6 million patients annually and results in 50,000 to 200,000 deaths every year. This study examined the total burden of illness, including the direct and indirect healthcare costs to employers and employees with DVT and PE. Methods: Retrospective analyses from 2007-2010 were performed using two datasets: (1) Integrated Benefits Institute’s Health and Productivity Benchmarking Database was used for short-term disability (STD) and long term disability (LTD) claims, and (2) IMS LifeLink data was used for medical and pharmacy claims. Indirect costs analyses included costs of lost work days from STD and LTD claims and wage replacement costs. Direct costs included annual pharmacy and medical claims for newly diagnosed DVT and/or PE individuals. Total healthcare cost estimates between the two datasets were linked by derived age and gender analytic weights. Results: 5,445 (female=54%) and 6,199 (female=50%) disability claims were filed for DVT and PE, respectively. Employees with DVT lost on average 57 (SEM 4.6) STD and 440 (SEM 30.5) LTD days per disability incident. For employers, estimated lost productivity costs per DVT claim were STD=$7,414±625 and LTD= $58,181±4,332. Total annual DVT healthcare costs per employee including out of pocket costs were $2,449 + 106 with $2,160±102 for annual medical and $290 ±20 for total pharmacy costs. Employees with PE lost on average 56 (SEM 3.0) STD and 364 (SEM 26.1) LTD days per disability incident. For employers, the estimated lost productivity costs per PE claim for STD and LTD were $7,605±402 and $48,751±3,615, respectively. Total annual PE healthcare costs per employee including out of pocket costs were $5,040 + 460 with $4,851±457 for annual medical and $190 ±22 for total pharmacy costs. Hospitalizations accounted for 84% of total annual PE health costs. Conclusion: DVT and PE constitute a heavy economic and lost productivity burden for both employers and their employees. Direct and disability costs to employees are substantial. Productivity losses for employers are also significantly high. Appropriate management of DVT and PE may help improve lost days from work, reduce healthcare resource utilization, improve workforce productivity, and reduce total economic burden.

To explore possible long-term effects of gestational cocaine exposure in a nonhuman primate model, pregnant rhesus monkeys were treated from about 1 month of gestation until term with either 0 (N = 3), 0.3 (N = 3), 1.0 (N = 3), or escalating doses up to 8.5 (N = 3) mg/kg (IM), three times per day, 5 consecutive days per week. Despite these differences in cocaine exposure, the experimental groups did not differ significantly with respect to the postnatal growth of offspring over an 18-month period following birth. Beginning at 6 months of age, the behavior of offspring was monitored using an operant test battery that included five food-reinforced tasks designed to model aspects of learning, color and position discrimination, time estimation, short-term memory and attention, and motivation. Although the acquisition of each operant behavior by offspring progressed significantly during training between 6 and 18 months of age, this acquisition was not differentially affected by gestational cocaine exposure. It was concluded that, in a rhesus monkey model, chronic cocaine exposure during pregnancy had no significant effect on the offsprings' acquisition of operant behaviors.

The effects of phencyclidine (PCP; a noncompetitive NMDA antagonist) were assessed in rhesus monkeys using performance in an operant test battery (OTB) consisting of five food-reinforced tasks thought to engender responses dependent upon aspects of time estimation, short-term memory, motivation, learning, and color and position discrimination. End-points included percent task completed (PTC), response rate or latency, and response accuracy. Testing occurred 15 min after IV injections of PCP (0.00, 0.003, 0.01, 0.03, 0.1, 0.13, 0.18, and 0.3 mg/kg). PCP disrupted performance of all tasks at 0.30 mg/kg. PTC was significantly decreased in the time estimation, motivation, and learning tasks at doses > or = 0.13 mg/kg. PTC for the short-term memory and color and position discrimination tasks was significantly decreased at 0.18 mg/kg and above. Response rate was significantly decreased at 0.13 mg/kg and above in the motivation and learning tasks and at 0.18 mg/kg and above in the time estimation, short-term memory, and color and position discrimination tasks. Response accuracy was significantly decreased in the time estimation, short-term memory, and learning tasks at doses > or = 0.13 mg/kg, while accuracy in the color and position discrimination task was decreased only at 0.30 mg/kg. PCP's effects on OTB performance were generally nonspecific, in that the time estimation, short-term memory, learning, and motivation tasks were all equally sensitive, with the color and position discrimination task being the least sensitive. These results are different than those obtained from earlier studies on the effects of MK-801, a more selective noncompetitive NMDA antagonist.

The chronic toxicity and carcinogenicity of pyrilamine maleate were evaluated in B6C3F1 mice by feeding for up to 2 years to groups of 60 male or female mice at dietary levels of 0,150, 750, or 1,500 ppm (as the free base). Up to 12 mice per sex and dose group were killed after 65 weeks for clinical chemistry, hematology, and histopathologic evaluation of control and high-dose animals. Histopathology was performed on all animals that were dead or moribund or lived until the study was terminated at 2 years. Daily exposures to pyrilamine ranged from ∼16 to 176 mg/kg, compared with maximum human exposure of 3 mg/kg. Regarding longevity, pyrilamine-treated male mice tended to survive longer than controls, whereas no differences among treated and control female mice were noted. Body weights did not differ among treated and control male groups, but final body weight average of treated female mice was 6–10% lower than that for controls. Although no dose-response trends were noted in male mice for histopathologic end points, liver /body and liver/ brain weight ratios were significantly greater in high-dose male mice than in controls. Chronic liver inflammation exhibited a positive dose-response trend in female mice, but there was no evidence for a carcinogenic response to pyrilamine by either sex.

The antihistamine, pyrilamine maleate, was fed for up to 2 years to groups of 57 Fischer 344 (F344) rats of each sex at dietary levels of 0, 300, 1500, or 3000 ppm (free base). Eight or nine of these rats per sex and dose group were killed at 65 weeks to analyze hematology and clinical chemistry in all groups and histopathology of control and high-dose animals. Histopathology also was performed on all dead or moribund rats and on all that survived for 2 years. Average daily exposures were 11 to 150 mg/kg pyrilamine compared to human dosages up to 3 mg/kg. Pyrilamine treatment did not reduce survival. Final body weights were reduced relative to controls (mid-dose males, 93%, females, 82%: high-dose males, 82%, females, 70%). The incidences of inflammation of the nasolacrimal duct (chronic in females; suppurative in males), liver cytoplasmic vacuolization (males), and the combination of animals with either liver basophilic or clear cell foci (males) tended to significantly increase with dose. Adrenal pheochromocytomas, mammary gland fibroadenomas, and neoplasms of the clitoral gland, thyroid c-cell, and pituitary gland all tended to decrease with increasing dose in females. In males only preputial gland neoplasms exhibited a similar negative trend. While two ovarian granulosatheca cell benign tumors occurred in high-dose females, these were thought to be a random occurrence. There was no evidence for the carcinogenicity of pyrilamine in F344 rats in the current study.

The antihistamine triprolidine hydrochloride, was fed at dietary concentrations of 0, 250, 1000, or 2000 ppm (as the free base) to groups of 60 Fischer 344 (F344) rats of each sex for up to 2 years to evaluate its potential carcinogenicity. Up to 12 per sex from each group were killed at 65 weeks, and hematology, clinical chemistry, and histopathology were evaluated. A complete histopathological evaluation was performed on all other animals; survivors were killed at 2 years. Survival was significantly extended in triprolidine-treated males and females, particularly at the high dose. At the close of the study high-dose males and females had gained significantly less body weight than controls. Among rats killed at 65 weeks females in the mid- and high-dose groups weighed significantly less than controls, but weights of control and dosed males were not significantly different. The incidences of numerous lesions tended to decrease with increasing triprolidine dose. In females, clitoral gland adenomas, thyroid c-cell hyperplasia and neoplasia, mammary gland hyperplasia and fibroadenomas, and uterine stromal polyps, and in males, anterior pituitary gland adenomas, preputial gland neoplasia, thyroid c-cell pancreatic islet neoplasia, mononuclear cell leukemia, and the combination of lymphocytic, histiocytic, and undifferentiated cell malignant lymphomas and mononuclear leukemia, all exhibited negative dose trends. Cytoplasmic alterations of the parotid gland and numerous liver lesions tended to be more frequent in treated than in control animals. Liver lesions that exhibited positive dose trends include chronic inflammation and centrilobular fatty change in both sexes, mixed cell foci, and the combination of mixed cell foci and eosinophilic foci in females, and in males, basophilic foci and eosinophilic foci. Triprolidine was not carcinogenic in F344 rats.

Chronic Study of Triprolidine for Oncogenicity in Mice. Greenman, D. L., Sheldon, W., Schieferstein, G., Allen, R., and Allaben, W. T. (1995). Fundam. Appl. Toxicol. 25, 138-145. Triprolidine hydrochloride was fed to groups of 60 B6C3F1 mice per sex at dietary levels of 0, 500, 2000, or 4000 ppm (as the free base) for up to 2 years. Up to 12 mice of each sex and dose group were terminated after 65 weeks for hematology and clinical chemistry. The control and high-dose groups were examined histologically. A complete histopathological examination was performed on the remaining 48 mice from each dose group when removed from study due to moribund condition, early death, or terminal euthanization at 105 weeks. Triprolidine did not significantly alter the survival of either sex. High-dose male and mid- and high-dose female body weights were significantly less than controls at the end of the study. Significant trends toward lower frequency with increasing dose were noted in females for fatty change in the liver and lymphomas (combination of lymphocytic, mixed, and histiocytic lymphomas). Similar negative trends in males were for lymphocytic cellular infiltration in multiple organs and lung alveolar/bronchiolar adenomas or the combination of alveolar/bronchiolar adenomas or carcinomas. Significant trends toward increased frequency with increasing dose were found in female mice for lymphocytic infiltration in multiple organs and cytoplasmic alterations of the acinar cells of the parotid gland. Similar positive trends were found in males for cytoplasmic alterations of the parotid gland and various hepatocellular changes (e.g., hypertrophy and altered foci). While there was a positive dose-response trend for hepatocellular adenomas in males the combination of these and hepatocellular carcinomas eliminated the significant trend, and it was concluded that there was no evidence of a carcinogenic response to triprolidine in B6C3F1 mice. No effects considered to be adverse were observed in either sex at 500 ppm. Body weight depression was noted in females and liver toxicity was indicated in males at 2000 and 4000 ppm.

To examine the association between frequent gouty arthritis and the presence of absolute/relative contraindications to gout therapies, and health-care expenditure associated with frequent gouty arthritis.This retrospective study used administrative claims to identify patients with gouty arthritis between 1 July 2005 and 30 June 2010. Patients with ≥3 yearly gouty arthritis attacks (frequent gout) were matched 1:2 to patients with3 yearly attacks (infrequent gout). Absolute and relative contraindications to gout medications were evaluated based on product labelling. Negative binomial regression and generalized linear models with logarithmic transformation were used for multivariate analysis of overall and gout-related health-care use and cost.Mean patient age was 58 years (n = 15 669) and 77% were men. Compared with patients with infrequent gout, those with frequent gout had higher rates of absolute/relative contraindications to NSAIDs (91.5% vs 78.7%, P 0.0001), corticosteroids (96.4% vs 87.3%, P 0.0001), allopurinol (51.0% vs 41.2%, P 0.0001) and probenecid (13.4% vs 9.4%, P 0.0001). Mean gout-related costs were $889 for frequent gout vs $210 for infrequent gout (P 0.0001) and all-cause direct costs were $10 913 for frequent vs $10 685 for infrequent gout (P = ns). Mean all-cause outpatient visits among patients with comorbidities compared with those without were 25.8 vs 11.8 among frequent and 19.7 vs 9.0 among infrequent (both P 0.001) groups. Gout-related costs were higher among frequent gout patients with comorbidities than those without comorbidities ($886 vs $513, P = 0.03).Patients with frequent gouty arthritis are likely to have absolute and/or relative contraindications to gout medications and higher gout-related treatment costs.

Robert Lee Page II,1,2 Vahram Ghushchyan,1 Richard R Allen,3 Lisa Roper,4 Don Beck,4 Bamrom H Jonathan,4 Feride Frech-Tamas,5 Wing Chan,5 R Brett McQueen,1 Kavita V Nair11School of Pharmacy, Department of Clinical Pharmacy, 2School of Medicine, Department of Family Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 3Peakstat Statistical Services, Evergreen, CO, 4Universal American, Houston, TX, 5Novartis Pharmaceuticals, East Hanover, New Jersey, USABackground: Current guidelines for acute coronary syndrome recommend clopidogrel for an optimal period of 12 months in order to reduce the risk of reinfarction and mortality. Premature clopidogrel discontinuation has been associated with higher rates of rehospitalization, coronary stent thrombosis, and mortality. No data exist regarding the effect of the Medicare Part D coverage gap on medical costs and outcomes in Medicare beneficiaries who discontinue their clopidogrel upon entering the coverage gap.Methods: Beneficiaries with a Medicare Advantage plan in 2009 who had a diagnosis of acute coronary syndrome were taking clopidogrel 75 mg daily, and reached the gap in the same year representing the study sample. From this cohort, those who filled at least two prescriptions for clopidogrel (continued) versus those that did not (discontinued) while in the gap were compared with regard to outcomes related to acute coronary syndrome and expenditure 30 days after the last prescription was filled and during any time while in the gap. Descriptive and multivariate analyses were used to compare these differences.Results: A total of 1365 beneficiaries with acute coronary syndrome met the inclusion criteria, of which 705 beneficiaries entered into the coverage gap, wherein 103 (14.6%) and 602 (85.4%) of beneficiaries discontinued and continued clopidogrel, respectively. Compared with those who continued clopidogrel during the gap, beneficiaries who discontinued clopidogrel showed a higher trend in the number of hospitalizations related to acute coronary syndrome and emergency room visits, albeit not statistically significant. Those who discontinued clopidogrel showed a higher mean adjusted cost per member per month in hospitalizations ($3604) related to acute coronary syndrome and outpatient visits ($1144) related to acute coronary syndrome and total medical costs ($5614), albeit not statistically significant.Conclusion: Medicare beneficiaries who face large out-of-pocket costs for clopidogrel while in the coverage gap and discontinue therapy may experience adverse events related to acute coronary syndrome.Keywords: Medicare, acute coronary syndrome, clopidogrel, health resource utilization

Study Objective To describe the prevalence of prescribing against-label statin-fibrate combination therapy. Design Retrospective cohort study. Data Source Medstat MarketScan Commercial Claims and Encounter database. Patients Adults (aged 18–89 yrs) who were prescribed statin-fibrate combination therapy between January 1, 2003, and June 30, 2009, had pharmacy claims demonstrating two or more concurrently filled prescriptions for a statin and a fibrate, and had continuous insurance enrollment for at least 12 months. Measurements and Main Results Claims data were used to identify patients with dyslipidemia based on International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. National Drug Codes were used to describe concurrent statin-fibrate combination therapy. The primary outcome was recent use of against-label statin-fibrate combination therapy, defined as use during the last 18 months (January 1, 2008–June 30, 2009) of the study period. Patients were stratified according to statin and dosage to identify against-label combination use (e.g., simvastatin > 10 mg/day with gemfibrozil). Within the recent-use period, 131,394 patients were prescribed concurrent statin-fibrate combination therapy; of these patients, 13,420 (10.2%) had against-label therapy. Simvastatin-gemfibrozil accounted for 8978 (66.9%) of all against-label combinations. Of all 9877 simvastatin-gemfibrozil combinations prescribed in the recent-use period (both on-label and against-label use), 8978 (90.9%) were against label. The secondary outcome was prevalence of against-label statin-fibrate combination therapy on an annual basis: 15.5% in 2003, 18.7% in 2004, 9.1% in 2005, 8.3% in 2006, 9.2% in 2007, and 9.8% in 2008. Conclusion Against-label statin-fibrate combination therapy continues to be prescribed despite established United States Food and Drug Administration (FDA) dose restrictions. Nearly every time the simvastatin-gemfibrozil combination was prescribed, it was against label because simvastatin exceeded the maximum dose restriction. Updated simvastatin labeling in June 2011 includes additional maximum dose restrictions and new contraindications, which include gemfibrozil. Different approaches in clinical practice are needed to ensure adherence with the revised FDA labeling.

The acute effects of MK-801, a selective, noncompetitive NMDA receptor antagonist, were assessed using an operant test battery (OTB) of complex food-reinforced tasks that are thought to depend upon relatively specific brain functions such as motivation to work for food (progressive ratio, PR), learning (incremental repeated acquisition, IRA), color and position discrimination (conditioned position responding, CPR), time estimation (temporal response differentiation, TRD), and short-term memory and attention (delayed matching-to-sample, DMTS). Endpoints included response rates (RR), accuracies (ACC), and percent task completed (PTC). MK-801 (0.003-0.075 mg/kg, IV), given 15 min pretesting, produced significant dose-dependent decreases in measures of IRA and TRD performance at dosesor = 0.03 mg/kg. In both tasks, MK-801 produced significant decreases in accuracy at doses lower than those required to affect response rate. MK-801 also produced statistically significant decreases in PR, CPR, and DMTS measures, but only at higher doses (or = 0.056 mg/kg) that caused significant decreases in both response rates and accuracies. These results indicate that, in monkeys, performance of operant tasks designed to model learning and time estimation is more sensitive to the disruptive effects of MK-801 than performance of tasks that model motivation, color, and position discrimination, and short-term memory and attention.

A co-carcinogenicity experiment was conducted with female Sprague-Dawley rats in which the effects of short-term sodium saccharin dosing and initiation with a direct-acting carcinogen were examined in the urinary bladder. All initiated animals were administered 0.5 mg N-methyl-N-nitrosourea (MNU) by instillation into the bladder at 8 wk of age. The animals were also given saccharin at one of four levels in the diet (0, 1.0, 2.5 or 5%) for 4 wk either (1) just before treatment with MNU (4-8 wk of age), (2) centred on treatment with MNU (6-10 wk of age) or (3) after MNU treatment (8-12 wk of age). Additionally, a group of animals was exposed to saccharin through the milk for 3 wk by dosing the mothers, starting on the day of parturition. The animals were held on control diet until interim killing of 20 animals per group at about 590 days of age, removal for morbidity, or terminal killing of the remainder of 60 animals per treatment around 780 days of age. A histopathological examination was made of the urinary tract and the relationship of saccharin dose to bladder tumour prevalence analysed statistically. A consistent increase (with very weak statistical significance) in tumour rate at interim killing, and for the pathology data overall, was shown by the 2.5% dose group given saccharin from 8 to 12 wk of age. Tumour prevalences of 47.6 and 40.7% v. control prevalences of 21.1 and 25.4% were observed for the two time periods (P values < 0.076 and < 0.0853, respectively). All groups given saccharin neonatally showed increased tumour prevalence for both time periods, but none of the differences was statistically significant at the 95% confidence level. No consistent increase in tumour prevalence was seen in the groups given saccharin from 4 to 8 or 6 to 10 wk of age; thus, these data suggest that saccharin does not act as a strong co-carcinogen in the MNU-treated rat bladder.

Kavita V Nair1, Daniel A Belletti3, Joseph J Doyle3, Richard R Allen4, Robert B McQueen1, Joseph J Saseen1, Joseph Vande Griend1, Jay V Patel5, Angela McQueen2, Saira Jan21School of Pharmacy, University of Colorado, Aurora, CO, USA; 2Horizon Blue Cross Blue Shield of New Jersey, Newark, NJ, USA; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 4Peakstat Statistical Services, Evergreen, CO, USA; 5Care Management International, Marlborough, MA, USABackground: Although hypertension is a major risk factor for cardiovascular disease, adherence to hypertensive medications is low. Previous research identifying factors influencing adherence has focused primarily on broad, population-based approaches. Identifying specific barriers for an individual is more useful in designing meaningful targeted interventions. Using customized telephonic outreach, we examined specific patient-reported barriers influencing hypertensive patients' nonadherence to medication in order to identify targeted interventions.Methods: A telephone survey of 8692 nonadherent hypertensive patients was conducted. The patient sample comprised health plan members with at least two prescriptions for antihypertensive medications in 2008. The telephone script was based on the "target" drug associated with greatest nonadherence (medication possession ratio [MPR]

Patients with hypertension whose blood pressure (BP) does not reduce during the nighttime period (non-dippers) are at increased risk of cardiovascular events. Antihypertensive therapies that improve the dip in BP from daytime to nighttime could improve outcomes beyond overall BPlowering. We investigated the efficacy of LCZ696 (Japanese Adopted Name: Sucabitril Valsartan Sodium Hydrate), a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in sub-populations of patients with hypertension classified as dippers ( 10% decrease in mean ambulatory [ma] systolic blood pressure [SBP] at nighttime vs. daytime) and non-dippers (

Previously our laboratory has shown that ketamine exposure (24h of clinically relevant anesthesia) causes significant increases in neuronal cell death in perinatal rhesus monkeys. Sensitivity to this ketamine-induced neurotoxicity was observed on gestational days 120-123 (in utero exposure via maternal anesthesia) and on postnatal days (PNDs) 5-6, but not on PNDs 35-37. In the present study, six monkeys were exposed on PND 5 or 6 to intravenous ketamine anesthesia to maintain a light surgical plane for 24h and six control animals were unexposed. At 7 months of age all animals were weaned and began training to perform a series of cognitive function tasks as part of the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB). The OTB tasks used here included those for assessing aspects of learning, motivation, color discrimination, and short-term memory. Subjects responded for banana-flavored food pellets by pressing response levers and press-plates during daily (M-F) test sessions (50 min) and were assigned training scores based upon their individual performance. As reported earlier (Paule et al., 2009) beginning around 10 months of age, control animals significantly outperformed (had higher training scores than) ketamine-exposed animals for approximately the next 10 months. For animals now over 3 and one-half years of age, the cognitive impairments continue to manifest in the ketamine-exposed group as poorer performance in the OTB learning and color and position discrimination tasks, as deficits in accuracy of task performance, but also in response speed. There are also apparent differences in the motivation of these animals which may be impacting OTB performance. These observations demonstrate that a single 24-h episode of ketamine anesthesia, occurring during a sensitive period of brain development, results in very long-lasting deficits in brain function in primates and provide proof-of-concept that general anesthesia during critical periods of brain development can result in subsequent functional deficits. Supported by NICHD, CDER/FDA and NCTR/FDA.

The objective of this study was to examine the impact of reducing the prescription co-pay for diabetes medications on pharmacy utilization, medication adherence, medical utilization, and expenditures. The co-pay reduction involved placing all diabetic drugs and testing supplies on the lowest co-pay tier for one employer group. The sample comprised members with diabetes who were both continuously enrolled in the 12-month pre period and the 2 years following co-pay reduction. Measured outcomes included diabetic prescription utilization, medication adherence, medical utilization, and expenditures. Generalized estimating equations for repeated measures were used to estimate differences between the pre period and years 1 and 2, while adjusting for age, sex, and comorbidity risk. Diabetic prescription utilization and medication adherence increased by approximately 3.0% in year 1 and dropped in year 2. The increases were primarily in brand name diabetes medications, which increased by approximately 5%, while generic use decreased in both years. Decreases in emergency room visits and hospitalizations were also observed in both years, followed by a decrease in health care expenditures in year 2. Adherent members experienced greater decreases in emergency room visits following the co-pay reduction compared to nonadherent members. After the implementation of a co-pay reduction, a modest increase in adherence and use of diabetes medications was observed. There were some compensatory cost savings for the employer from lower medical expenditures in year 1. In addition to financial strategies, additional strategies to reinforce medication adherence are needed to gain and sustain more meaningful increases in prescription utilization.

This paper discusses the application of repeated measures methods in the statistical analysis of an experiment in behavioral toxicology. The chronic marijuana smoke exposure study conducted at the National Center for Toxicological Research is used for an example of the types of problems that one encounters in analyzing these types of studies. In particular, the standard univariate analysis most frequently used for repeated measures analyses has some very restrictive assumptions on the form of the covariance matrices. These assumptions are not met in the example discussed and are rarely met in many other problems. Other possible models for analyzing repeated measures when these assumptions are not met are presented and discussed. Other problems specific to the chronic marijuana smoke exposure study that may occur in similar type studies are presented. These include pooling the experimental units into groups with comparable baselines, choosing a function of the measures to be analyzed, dealing with a large data set with many observation times and missing data, unequal group sizes and different designs for different subsets of the experimental animals. The standard univariate repeated measures analysis was chosen to analyze the data even though the violations of the covariance assumptions may lead to finding differences that do not exist (Type I or false-positive errors), since the other methods presented also had covariance assumptions that were not met or had low power. Use of Bonferroni-type multiple comparisons on the single degree of freedom contrasts of interest hopefully reduced the chances of these false-positive results.

A strange thing happened on the way to understanding periodic leg movements in sleep (PLMS). The striking PLMS patterns of repetitive, short activations of anterior tibialis on an electromyography often accompanied by brief electroencephalogram (EEG) arousal certainly seemed to be a potent source of sleep disruption. A periodic limb movement disorder characterized by PLMS and sleep-wake complaints is defined to recognize the presumed sleep-disrupting effects of PLMS and is reported to be a common cause of insomnia and daytime sleepiness. Thus, PLMS are more important as markers of disease and its severity than as disrupters of sleep. Periodic limb movement disorder is rare if it exists. Despite the multiple causes for the pathology producing PLMS, these movements remain an important, easily measured marker of the functioning of subcortical dopamine systems. As a motor sign, they provide both an objective basis for confirming suspected diagnoses and an objective marker of the degree of the dysfunction. This is particularly useful for restless legs syndrome.

The effects of chronic administration of MK-801 (NMDA-receptor antagonist) and remacemide (sodium channel blocker) on monkey learning of several brain function tasks was assessed in juveniles (nine months old). Low (LO) and high (HI) doses of both drugs were given orally each day for 18 months. There were no adverse effects of any treatment on tests of short-term memory or motivation. HI doses of both MK-801 and remacemide delayed acquisition of a visual discrimination task (the remacemide effect was much greater). HI doses of remacemide alone severely disrupted learning task acquisition and this effect lasted for several months after dosing. Thus, in monkeys, chronic blockade of NMDA receptors is relatively well tolerated, whereas blockade of sodium channels (perhaps in conjunction with NMDA receptor blockade) has long-term-perhaps permanent-consequences. To further explore the roles of NMDA receptors and sodium channels in these effects, MK-801, phenytoin (sodium channel blocker), or both were administered to rats and the acquisition of tasks similar to those used in the monkey study were assessed. Dosing began at weaning and continued for nine months. Throughout the study, HI MK-801 subjects exhibited impaired performance in all tasks. Some effects of MK-801 were blocked completely by phenytoin. In the rat, blockade of sodium channels was well tolerated but blockade of NMDA receptors had significant and long-term (permanent?) adverse consequences. These data contrast markedly with those obtained for the monkey and suggest, at least for some drug classes, that the rat might not be a good predictor of effects in primates.

IMPORTANCE Histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are commonly used to prevent gastrointestinal tract (GI) hemorrhage in critically ill patients. The stronger acid suppression of PPIs may reduce the rate of bleeding but enhance infectious complications, specifically pneumonia and Clostridium difficile infection (CDI). OBJECTIVE To evaluate the occurrence and risk factors for GI hemorrhage, pneumonia, and CDI in critically ill patients. DESIGN, SETTING, AND PARTICIPANTS A pharmacoepidemiological cohort study was conducted of adult patients requiring mechanical ventilation for 24 hours or more and administered either an H2RA or PPI for 48 hours or more while intubated across 71 hospitals between January 1, 2003, and December 31, 2008. Propensity score-adjusted and propensity-matched multivariate regression models were used to control for confounders. MAIN OUTCOMES AND MEASURES Primary outcomes were secondary diagnoses of International Classification of Diseases, Ninth Revision (ICD-9)-coded GI hemorrhage, pneumonia, and CDI occurring 48 hours or more after initiating invasive ventilation. RESULTS Of 35 312 patients, 13 439 (38.1%) received H2RAs and 21 873 (61.9%) received PPIs. Gastrointestinal hemorrhage (2.1% vs 5.9%; P lt; .001), pneumonia (27% vs 38.6%; P lt; .001), and CDI (2.2% vs 3.8%; P lt; .001) occurred less frequently in the H2RA group. After adjusting for propensity score and covariates, odds ratios of GI hemorrhage (2.24; 95% CI, 1.81-2.76), pneumonia (1.2; 95% CI, 1.03-1.41), and CDI (1.29; 95% CI, 1.04-1.64) were greater with PPIs. Similar results were obtained in the propensity-matched models of 8799 patients in each cohort. CONCLUSIONS AND RELEVANCE Proton pump inhibitors are associated with greater risks of GI hemorrhage, pneumonia, and CDI than H2RAs in mechanically ventilated patients. Numerous other risk factors are apparent. These data warrant confirmation in comparative prospective studies.

Patients with hypertension whose blood pressure (BP) does not reduce during the nighttime period (non-dippers) are at increased risk of cardiovascular events. Antihypertensive therapies that improve the dip in BP from daytime to nighttime could improve outcomes beyond overall BPlowering. We investigated the efficacy of LCZ696 (Japanese Adopted Name: Sucabitril Valsartan Sodium Hydrate), a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in sub-populations of patients with hypertension classified as dippers ( 10% decrease in mean ambulatory [ma] systolic blood pressure [SBP] at nighttime vs. daytime) and non-dippers (