US national trends in bariatric surgery: A decade of study.

BACKGROUND: Since the 1990s, the number of bariatric surgeries has dramatically increased, including the number of bariatric centers in the United States; no recent studies have yet assessed trends of bariatric surgery. This study aims to assess the trends of bariatric surgery and the change in utilization by the type of surgery, from 2006 to 2015, using real-world data. METHODS: A cross-sectional analysis of MarketScan databases of privately insured beneficiaries aged equal to or more than 18 years, to assess the annual incidence rate of bariatric surgery type of surgery from 2006 to 2015. Linear regression analysis was used to assess the significance of bariatric surgery changes over time. RESULTS: A gradual increase in overall bariatric surgery was observed from 43.5 per 100,000 in 2006 to 70.6 per 100,000 in 2009. This increasing trend plateaued from 2010 to 2015. Among all bariatric surgeries performed, the sleeve gastrectomy showed a significant increase from (n = 596) 11% in 2006 to (n = 15,425) 70% in 2015 (P < .001), whereas there was a decrease in Roux-en-Y from (n = 10,129) 45% in 2010 to (n = 5074) 24% in 2015 (P < .001). CONCLUSION: Utilization of bariatric surgery showed a gradual increase in the first 5 years, with steady rates in the last 5 years of the study period. Sleeve gastrectomy and Roux-en-Y remain the most performed bariatric procedures. Laparoscopic surgery continues to dominate bariatric surgery compared with open surgery.

Challenges facing drug utilization research in the Latin American region.

PURPOSE: The International Society of Pharmacoepidemiology (ISPE) in collaboration with the Latin America Drug Utilization Research Group (LatAm DURG), the Medicines Utilization Research in Africa (MURIA) group, and the Uppsala Monitoring Center, is leading an initiative to understand challenges to drug utilization research (DUR) in the Latin American (LatAm) and African regions with the goal of communicating results and proposing solutions to these challenges in four scientific publications. The purpose of this first manuscript is to identify the main challenges associated with DUR in the LatAm region. METHODS: Drug utilization (DU) researchers in the LatAm region voluntarily participated in multiple discussions, contributed with local data and reviewed successive drafts and the final manuscript. Additionally, we carried out a literature review to identify the most relevant publications related to DU studies from the LatAm region. RESULTS: Multiple challenges were identified in the LatAm region for DUR including socioeconomic inequality, access to medical care, complexity of the healthcare system, limited investment in research and development, limited institutional and organization resources, language barriers, limited health education and literacy. Further, there is limited use of local DUR data by decision makers particularly in the identification of emerging health needs coming from social and demographic transitions. CONCLUSIONS: The LatAm region faces challenges to DUR which are inherent in the healthcare and political systems, and potential solutions should target changes to the system.

Metabolic syndrome and metabolically healthy status in adults with overweight or obesity, expressing no desire to lose weight.

AIM: To examine the prevalence of metabolic syndrome (MetS) and metabolically healthy status (MHS) in adults with excess weight, who express no desire to lose weight (DLW). METHODS: We used the National Health and Nutrition Examination Survey (2011-2016) to conduct a cross-sectional analysis of 4509 adults with excess weight. The prevalence of MetS and MHS was estimated by a DLW status. The prevalence ratios (PRs) were estimated, adjusting for demographic characteristics, to compare the prevalence of MetS and MHS between those with and without a DLW. RESULTS: Among adults who were overweight, the crude prevalence of MetS was 28.9% (95% CI 23.7, 34.1) in the no-DLW group and 36.0% (95% CI 31.9, 40.0) in the DLW group (adjusted PR 0.88; 95% CI 0.70, 1.11). Among adults with obesity, the crude prevalence of MetS was 60.0% (95% CI 52.3, 67.6) in the no-DLW group and 63.2% (95% CI 60.0, 66.4) in the DLW group (adjusted PR 1.00; 95% CI 0.88, 1.14). Among adults who were overweight, the prevalence of MHS was 17.5% (95% CI 13.4, 22.2) in the no-DLW group, and 9.5% (95% CI 7.6, 11.6) in the DLW group (adjusted PR 1.27; 95% CI 0.96, 1.69). Nearly all adults with obesity had at least one component of MetS regardless of DSW status. CONCLUSIONS: One in four overweight adults and three in five obese adults without a DLW had MetS in the U.S. A majority of adults who were overweight or obese without a DSW had at least one component of MetS.

Real-world Pattern of Biologic Use in Patients With Inflammatory Bowel Disease: Treatment Persistence, Switching, and Importance of Concurrent Immunosuppressive Therapy.

BACKGROUND AND AIMS: Medication persistence, defined as the time from drug initiation to discontinuation of therapy, has been suggested as a proxy for real-world therapeutic benefit and safety. This study seeks to compare the persistence of biologic drugs among patients with inflammatory bowel disease (IBD). METHODS: Patients with newly diagnosed IBD were included in a retrospective study using Truven MarketScan database. Treatment persistence and switching was compared among biologic medications including infliximab, adalimumab, certolizumab, golimumab, and vedolizumab. Predictors for discontinuation and switching were evaluated using time-dependent proportional hazard regression. RESULTS: In total, 5612 patients with Crohn's disease (CD) and 3533 patients with ulcerative colitis (UC) were included in this analysis. Less than half of the patients continued using their initial biologic treatment after 1 year (48.48% in CD cohort; 44.78% in UC cohort). In the first year, adalimumab had the highest persistence and lowest switching rates for both CD (median survival time: 1.04 years) and UC (median survival time: 0.84 years). In subsequent years, infliximab users were more likely to persist in the use of biologic. Combination therapy with immunomodulators significantly decreased the risk of discontinuation, especially when immunomodulator therapy was started more than 30 days before the biologic (hazard ratio [HR], 0.22; CI, 0.16, 0.32). The major predictors for noncompliance included infection and hospitalization. CONCLUSION: Overall, the persistence profiles of biologics suggest a high rate of dissatisfaction or adverse disease outcomes resulting in discontinuation and switching to a different agent. Early initiation of immunomodulators will substantially increase the persistence of biologic treatment.

Decline in dopamine agonists prescribing and characteristics of drugs prescribed during ambulatory office visits for restless legs syndrome: the National Ambulatory Medical Care Survey 2007-2015.

OBJECTIVE: To examine prescribing of drugs treating or exacerbating restless legs syndrome (RLS) during U.S. physician office visits for RLS for the years 2007-2015; and to assess potential prescribing predictors of these drugs. METHODS: Using the National Ambulatory Medical Care Survey data, we conducted a retrospective cross-sectional study. We calculated weighted percentages of RLS-related office visits associated with RLS treatment drugs (alpha-2-delta ligands, dopamine agonists, and other drugs used for RLS) and exacerbating drugs. Using logistic regression, we examined the adjusted association between potential predictors and prescribing of major RLS treatment (dopamine agonists and alpha-2-delta ligands) and exacerbating drugs. RESULTS: A total of 456 RLS-related office visits were included for analysis, representing approximately 9.9 million visits. The weighted percentages of visits with dopamine agonists (excluding levodopa) decreased from 50% to 22% (RR 0.44; 95% CI 0.26, 0.77). A visit to a neurologist was associated with a 76% increase in prescribing of the major RLS treatment drugs compared with a visit to a family/general or internal medicine physician (RR 1.76; 95% CI 1.29, 2.42). RLS exacerbating drugs were listed in 28% (95% CI 21-36) of RLS-related visits, mostly for antidepressants (83%). Younger age groups (18-44 and 45-64) were predictors of RLS exacerbating drug prescribing, compared with the older age group (RR 2.46; RR 2.00, respectively). CONCLUSION: Prescribing of dopamine agonists during RLS-related visits decreased during 2007-2015, but prescribing of RLS exacerbating drugs remained high. More investigation is necessary concerning whether clinicians assess the appropriateness of RLS exacerbating drugs for RLS patients before newly prescribing or continuing those drugs. Also, future research would need to investigate what factors contribute to the difference in the RLS treatment prescribing patterns between neurologists and family/general or internal medicine physicians.

Association Between Recombinant Human Bone Morphogenetic Proteins and Postoperative Opioid Use in Lumbar Fusion Procedure Patients: A Propensity Score-Matched Analysis.

BACKGROUND: Little is known about the effectiveness of recombinant human bone morphogenetic proteins (rhBMPs) in reducing the demand for opioids after surgery. We investigated the association between rhBMP use and the likelihood of achieving opioid independence and changes in opioid demand in the first postoperative year. METHODS: Using the Multi-Payer Claims Database from 2007 to 2010, patients aged >20 years who had undergone a degenerative disc disease-indicated lumbar fusion procedure and had had ≥1 opioid prescription in the 3 months before surgery were identified. Propensity score matching (1:1) of rhBMP-exposed and rhBMP-unexposed patients was used to mitigate confounding. The outcomes of interest were opioid independence and decreases in opioid doses in morphine equivalent units, assessed at 3-6 and 9-12 months after the procedure. Logistic regression and analysis of covariance models were used. RESULTS: The data from 318 patients were analyzed. Most patients were women (61%) and aged <65 years (68%). Few had achieved opioid independence at 3-6 (n = 71; 22.3%) or 9-12 (n = 115; 36.2%) months postoperatively. During the 3-6-month window, the rhBMP group reduced their opioid use rates (estimated mean difference. -28.4 vs. -19.5; P = 0.69) and achieved opioid independence (21.4% vs. 23.3%; odds ratio, 0.92; 95% confidence interval, 0.54-1.56; P = 0.74) at rates that were statistically comparable to their matched comparators. Similar patterns were observed during the 9-12-month window. CONCLUSION: We found no evidence to suggest that rhBMP use during spinal fusion procedures is associated with either the discontinuation or decrease of opioid analgesic therapy. The continued opioid use after surgery warrants further clinical and research attention.

Comparative risk of lipophilic and hydrophilic statins on incident depression: A retrospective cohort study.

OBJECTIVES: To evaluate the risk of new-onset depression in a cohort of US adult patients initiating lipophilic statin therapy compared to hydrophilic statin therapy. DESIGN: Retrospective cohort study. SETTING: Large US commercial claims database PARTICIPANTS: 1:1 propensity score matched cohort of lipophilic (atorvastatin, lovastatin and simvastatin) and hydrophilic (pravastatin and rosuvastatin) statin initiators between January 2009 to June 2015. OUTCOME: New onset of depression. RESULTS: In a propensity-score matched cohort of 299,298 statin initiators, the crude incidence of depression in the hydrophilic and lipophilic group was 136.6 and 142.8 per 10,000 person-years respectively. Compared to hydrophilic statin use, lipophilic statin use was not associated with a statistically significant increase in the risk of depression, adjusted HR 1.05 (95% CI, 1.00-1.10, p = 0.078) and excess incidence of 6.3 (95% CI, -0.7-13.7) per 10,000 person-years. Findings were consistent across the subgroups of patients with history of psychiatric conditions HR 1.05 (95% CI, 0.94-1.16, p = 0.41), and those initiating statins for primary or secondary prevention, HR 1.03 (95% CI, 0.97-1.10, p = 0.33) and 1.07 (95% CI, 0.99-1.16, p = 0.10) respectively. Within individual lipophilic statins, only simvastatin was associated with a moderate increase in the risk of depression HR 1.09 (95% CI, 1.02-1.16, p = 0.003), followed by lovastatin HR 1.07 (95% CI, 0.93-1.24, p = 0.34) and atorvastatin HR 1.05 (95% CI, 0.97-1.13, p = 0.27). LIMITATIONS: Findings are generalizable to patients with commercial insurance. CONCLUSIONS: Lipophilic statin use was not associated with a significant increase in the risk of incident depression.

Adherence and persistence to ropinirole, pramipexole, and gabapentin in patients with newly diagnosed restless legs syndrome.

STUDY OBJECTIVES: The objective of this study is to assess adherence and persistence of ropinirole, pramipexole, and gabapentin; to investigate factors associated with non-adherence and non-persistence in restless legs syndrome (RLS) patients. METHODS: We used the 2008-2014 Marketscan® Research Databases to conduct a retrospective data analysis. The study included newly diagnosed RLS patients who initiated ropinirole, pramipexole, or gabapentin therapy. During 365 days of follow-up, mean medication possession ratios (MPRs) for adherence and the proportion of adherent users were calculated. The mean persistence (time to discontinuation) and the proportion of persistent users were also assessed during the same follow-up period. Factors associated with non-adherence and non-persistence were analyzed using multivariate logistic regression. RESULTS: This study included 5163 ropinirole, 3380 pramipexole, and 1353 gabapentin users. The mean MPRs for ropinirole, pramipexole, and gabapentin were 0.52, 0.52, and 0.48, respectively. The proportions of adherent users were 33.2%, 34.6%, and 27.4%, respectively. Mean time to treatment discontinuation was 158 days, 158 days, and 145 days, respectively. The proportions of persistent users at 365 days were 25.0%, 25.8%, and 20.6%, respectively. Younger age, higher number of concomitant medications, and gabapentin use (vs. ropinirole or pramipexole use) were positively associated with non-adherence and non-persistence. Additionally, retail pharmacy use (vs. mail order pharmacy use) and use of benzodiazepines were positively associated with non-adherence. CONCLUSION: Adherence and persistence to ropinirole, pramipexole, and gabapentin were low in newly diagnosed RLS patients during 365 days of follow-up. Certain patient characteristics were predictors of non-adherence and non-persistence.

Trends in utilization of warfarin and direct oral anticoagulants in older adult patients with atrial fibrillation.

PURPOSE: Results of a study to determine trends in oral anticoagulant (OAC) use and OAC switching in patients with atrial fibrillation (AF) or atrial flutter are presented. METHODS: Warfarin has been the most prescribed anticoagulant in patients with AF for decades. Since 2010, several direct OACs (DOACs) have gained U.S. marketing approval for stroke prevention in AF or atrial flutter. A cross-sectional longitudinal analysis was conducted using healthcare and prescription claims databases to characterize OAC use and rates of OAC and DOAC switching during the period 2008-14 in cohorts of Medicare beneficiaries 65 years of age or older with AF or atrial flutter. RESULTS: Overall, 66% of patients with AF or atrial flutter were receiving OACs during the study period. The prevalence of warfarin use decreased from 69.8% in 2008 to 42.2% in 2014. This decrease in warfarin use was paralleled by an increase in dabigatran use, which rose from 1.3% in 2010 to 12.1% in 2011 and then declined to 7.6% in 2014. The prevalence of rivaroxaban use increased from 0.13% in 2011 to 13.87% in 2014. Among anticoagulated patients, an average of 6% annually were switched from one OAC to another. CONCLUSION: Overall OAC utilization in patients with AF or atrial flutter remained steady over the study period. Beginning in 2010, a gradual decrease in use of warfarin was paralleled by an increase in use of DOACs.

Stimulant use following the publicity of cardiovascular safety and the introduction of patient medication guides.

PURPOSE: To explore changes in stimulant utilization and pre-treatment electrocardiography (ECG) screening in response to cardiovascular (CV) safety concerns. METHODS: Two source populations were established from Florida Medicaid Fee-for-service beneficiaries between 2001 and 2008: approximately 44 571 newly diagnosed attention deficit/hyperactivity disorder patients and 33 000 new stimulant users. Time-series design and Joinpoint analysis were used to describe monthly trend changes in stimulant initiation, persistence, dosing, and pre-treatment ECG screening. RESULTS: Initial and maintenance daily dose declined 6 mg (95% confidence interval [CI] -14 to -1.9) methylphenidate (MPH) equivalent dose from a steady 27 mg after Canada withdrew Adderall XR in February 2005; the trend rebounded to a daily dose of 23 mg, after the remarketing of Adderall XR and a debate in the US over issuing a boxed warning on stimulant CV safety in early 2006. Monthly initiation increased 3.9% (CI -1.0 to 9.1) after the boxed warning debate to 54 per 100 patients per month (CI 44 to 68), but declined 2.4% (CI -3.6 to -1.2) after requirement of medication guides in February 2007. Monthly ECG screening increased 3.2% (CI 2.3 to 4.2) after Adderall XR withdrawal and further increased 13% (CI 4 to 23) after the American Heart Association recommended pre-treatment ECG screening to 40 per 100 patients per month (CI 17 to 48). CONCLUSIONS: The first signal of stimulant CV safety concerns was followed by varying responses depending on the outcome measure used, suggesting that patients and physicians responded at different times after the publicity of safety concerns. Clinical consequences of the changes are uncertain. Copyright © 2015 John Wiley & Sons, Ltd.

A Comparative Assessment of Observational Medical Outcomes Partnership and Mini-Sentinel Common Data Models and Analytics: Implications for Active Drug Safety Surveillance.

INTRODUCTION: An often key component to coordinating surveillance activities across distributed networks is the design and implementation of a common data model (CDM). The purpose of this study was to evaluate two drug safety surveillance CDMs from an ecosystem perspective to better understand how differences in CDMs and analytic tools affect usability and interpretation of results. METHODS: Humana claims data from 2007 to 2012 were mapped to Observational Medical Outcomes Partnership (OMOP) and Mini-Sentinel CDMs. Data were described and compared at the patient level by source code and mapped concepts. Study cohort construction and effect estimates were also compared using two different analytical methods--one based on a new user design implementing a high-dimensional propensity score (HDPS) algorithm and the other based on univariate self-controlled case series (SCCS) design--across six established positive drug-outcome pairs to learn how differences in CDMs and analytics influence steps in the database analytic process and results. RESULTS: Claims data for approximately 7.7 million Humana health plan members were transformed into the two CDMs. Three health outcome cohorts and two drug cohorts showed differences in cohort size and constituency between Mini-Sentinel and OMOP CDMs, which was a result of multiple factors. Overall, the implementation of the HDPS procedure on Mini-Sentinel CDM detected more known positive associations than that on OMOP CDM. The SCCS method results were comparable on both CDMs. Differences in the implementation of the HDPS procedure between the two CDMs were identified; analytic model and risk period specification had a significant impact on the performance of the HDPS procedure on OMOP CDM. CONCLUSIONS: Differences were observed between OMOP and Mini-Sentinel CDMs. The analysis of both CDMs at the data model level indicated that such conceptual differences had only a slight but not significant impact on identifying known safety associations. Our results show that differences at the ecosystem level of analyses across the CDMs can lead to strikingly different risk estimations, but this can be primarily attributed to the choices of analytic approach and their implementation in the community-developed analytic tools. The opportunities of using CDMs are clear, but our study shows the need for judicious comparison of analyses across the CDMs. Our work emphasizes the need for ongoing efforts to ensure sustainable transparent platforms to maintain and develop CDMs and associated tools for effective safety surveillance.

Application of multicategory exposure marginal structural models to investigate the association between long-acting beta-agonists and prescribing of oral corticosteroids for asthma exacerbations in the Clinical Practice Research Datalink.

OBJECTIVE: To examine the comparative effectiveness of inhaled long-acting beta-agonist (LABA), inhaled corticosteroid (ICS), and ICS/LABA combinations. METHODS: We used a retrospective cohort design of patients older than 12 years with asthma diagnosis in the Clinical Practice Research Datalink to evaluate asthma-related morbidity measured by oral corticosteroid (OCS) initiation within 12 months of initiating LABAs, ICSs, or ICSs/LABAs. Asthma severity 12 months before drug initiation (use of OCSs, asthma-related hospital or emergency department visits, and number of short-acting beta-agonist prescriptions) and during follow-up (short-acting beta-agonist prescriptions and total number of asthma drug classes) was adjusted as a time-varying variable via marginal structural models. RESULTS: A total of 51,103 patients with asthma were followed for 12 months after receiving first prescription for study drugs from 1993 to 2010. About 92% initiated ICSs, 1% initiated LABAs, and 7% initiated ICSs/LABAs. Compared with ICSs, LABAs were associated with a 10% increased risk of asthma exacerbations requiring short courses of OCSs (hazard ratio [HR] 1.10; 95% confidence interval [CI] 1.07-1.18). ICS/LABA initiators were 62% less likely than ICS initiators (HR 0.38; 95% CI 0.12-0.66) and 50% less likely than LABA initiators to receive OCS prescriptions for asthma exacerbations (HR 0.50; 95% CI 0.14-0.78). CONCLUSIONS: In concordance with current asthma management guidelines, inhaled LABAs should not be prescribed as monotherapy to patients with asthma. The findings suggest the presence of time-dependent confounding by asthma severity, which was accounted for by the marginal structural model.

Bridging islands of information to establish an integrated knowledge base of drugs and health outcomes of interest.

The entire drug safety enterprise has a need to search, retrieve, evaluate, and synthesize scientific evidence more efficiently. This discovery and synthesis process would be greatly accelerated through access to a common framework that brings all relevant information sources together within a standardized structure. This presents an opportunity to establish an open-source community effort to develop a global knowledge base, one that brings together and standardizes all available information for all drugs and all health outcomes of interest (HOIs) from all electronic sources pertinent to drug safety. To make this vision a reality, we have established a workgroup within the Observational Health Data Sciences and Informatics (OHDSI, http://ohdsi.org) collaborative. The workgroup's mission is to develop an open-source standardized knowledge base for the effects of medical products and an efficient procedure for maintaining and expanding it. The knowledge base will make it simpler for practitioners to access, retrieve, and synthesize evidence so that they can reach a rigorous and accurate assessment of causal relationships between a given drug and HOI. Development of the knowledge base will proceed with the measureable goal of supporting an efficient and thorough evidence-based assessment of the effects of 1,000 active ingredients across 100 HOIs. This non-trivial task will result in a high-quality and generally applicable drug safety knowledge base. It will also yield a reference standard of drug-HOI pairs that will enable more advanced methodological research that empirically evaluates the performance of drug safety analysis methods.

Pediatric exclusivity: evolving legislation and novel complexities within pediatric therapeutic development.

OBJECTIVE: To review the successes and omissions of the Food and Drug Administration (FDA) pediatric exclusivity incentive. DATA SOURCES: Pediatric drug development receives less attention and funding than drug development targeting adults resulting in fewer appropriately labeled pediatric drugs. Newly introduced legislation aims to correct this deficit using market exclusivity incentives. Under the Food and Drug Administration Modernization Act (FDAMA, 1997), the FDA established the exclusivity principle. This legislation was renewed and amended in 2007 under Food and Drug Administration Amendments Act (FDAAA) allowing drug companies to receive a 6-month patent extension for initiating clinical investigation in pediatric populations. Fostering improved knowledge in pediatric indications and dosing is the motivating force behind this program. STUDY SELECTION AND DATA EXTRACTION: We examined drugs granted exclusivity through FDA published database as well as relevant drug labeling and postmarket safety studies. Our examination shows that studies conducted in support of patent protection are often not designed to meet current pediatric needs. CONCLUSION: Amendments to FDAAA are needed to ensure that studies approved for exclusivity strive to meet the following requirements: relevant pediatric clinical indication ; disease addressed should represent a significant disease burden to the appropriate population; important age ranges should be covered; studies should not be allowed when a safety signal is identified prior to initiation of the study; and trials where endpoints are successfully achieved providing considerable contribution to pediatric dosing knowledge or result in labeling changes may gain an additional incentive.

Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology.

OBJECTIVE: To characterize risk of hypotension requiring admission to hospital in middle aged and older men treated with tamsulosin for benign prostatic hyperplasia. DESIGN: Population based retrospective cohort study (between patient methodology) and self controlled case series (within patient methodology). SETTING: Healthcare claims data from the IMS Lifelink database in the United States. PARTICIPANTS: Men aged 40-85 years with private US healthcare insurance entering the cohort at their first dispensing for tamsulosin or for a 5α reductase inhibitor (5ARI) between January 2001 and June 2011 after a minimum of six months' enrolment. MAIN OUTCOMES MEASURES: Hypotension requiring admission to hospital. Cox proportional hazards models estimated rate ratios at time varying intervals during follow-up: weeks 1-4, 5-8, and 9-12 after tamsulosin initiation; weeks 1-4, 5-8, and 9-12 after restarting tamsulosin (after a four week gap); and maintenance tamsulosin treatment (remaining exposed person time). Covariates included age, calendar year, demographics, antihypertensive use, healthcare use, and a Charlson comorbidity score. A self controlled case series, having implicit control for time invariant covariates, was additionally conducted. RESULTS: Among 383,567 new users of study drugs (tamsulosin 297,596; 5ARI 85,971), 2562 admissions to hospital for severe hypotension were identified. The incidence for hypotension was higher for tamsulosin (42.4 events per 10,000 person years) than for 5ARIs (31.3 events per 10,000 person years) or all accrued person time (29.1 events per 10,000 person years). After tamsulosin initiation, the cohort analysis identified an increased rate of hypotension during weeks 1-4 (rate ratio 2.12 (95% confidence interval 1.29 to 3.04)) and 5-8 (1.51 (1.04 to 2.18)), and no significant increase at weeks 9-12. The rate ratio for hypotension also increased at weeks 1-4 (1.84 (1.46 to 2.33)) and 5-8 (1.85 (1.45 to 2.36)) after restarting tamsulosin, as did maintenance tamsulosin treatment (1.19 (1.07 to 1.32)). The self controlled case series gave similar results as the cohort analysis. CONCLUSIONS: We observed a temporal association between tamsulosin use for benign prostatic hyperplasia and severe hypotension during the first eight weeks after initiating treatment and the first eight weeks after restarting treatment. This association suggests that physicians should focus on improving counseling strategies to warn patients regarding the "first dose phenomenon" with tamsulosin.

Variation in choice of study design: findings from the Epidemiology Design Decision Inventory and Evaluation (EDDIE) survey.

BACKGROUND: Researchers using observational data to understand drug effects must make a number of analytic design choices that suit the characteristics of the data and the subject of the study. Review of the published literature suggests that there is a lack of consistency even when addressing the same research question in the same database. OBJECTIVE: To characterize the degree of similarity or difference in the method and analysis choices made by observational database research experts when presented with research study scenarios. RESEARCH DESIGN: On-line survey using research scenarios on drug-effect studies to capture method selection and analysis choices that follow a dependency branching based on response to key questions. SUBJECTS: Voluntary participants experienced in epidemiological study design solicited for participation through registration on the Observational Medical Outcomes Partnership website, membership in particular professional organizations, or links in relevant newsletters. MEASURES: Description (proportion) of respondents selecting particular methods and making specific analysis choices based on individual drug-outcome scenario pairs. The number of questions/decisions differed based on stem questions of study design, time-at-risk, outcome definition, and comparator. RESULTS: There is little consistency across scenarios, by drug or by outcome of interest, in the decisions made for design and analyses in scenarios using large healthcare databases. The most consistent choice was the cohort study design but variability in the other critical decisions was common. CONCLUSIONS: There is great variation among epidemiologists in the design and analytical choices that they make when implementing analyses in observational healthcare databases. These findings confirm that it will be important to generate empiric evidence to inform these decisions and to promote a better understanding of the impact of standardization on research implementation.

Defining a reference set to support methodological research in drug safety.

BACKGROUND: Methodological research to evaluate the performance of methods requires a benchmark to serve as a referent comparison. In drug safety, the performance of analyses of spontaneous adverse event reporting databases and observational healthcare data, such as administrative claims and electronic health records, has been limited by the lack of such standards. OBJECTIVES: To establish a reference set of test cases that contain both positive and negative controls, which can serve the basis for methodological research in evaluating methods performance in identifying drug safety issues. RESEARCH DESIGN: Systematic literature review and natural language processing of structured product labeling was performed to identify evidence to support the classification of drugs as either positive controls or negative controls for four outcomes: acute liver injury, acute kidney injury, acute myocardial infarction, and upper gastrointestinal bleeding. RESULTS: Three-hundred and ninety-nine test cases comprised of 165 positive controls and 234 negative controls were identified across the four outcomes. The majority of positive controls for acute kidney injury and upper gastrointestinal bleeding were supported by randomized clinical trial evidence, while the majority of positive controls for acute liver injury and acute myocardial infarction were only supported based on published case reports. Literature estimates for the positive controls shows substantial variability that limits the ability to establish a reference set with known effect sizes. CONCLUSIONS: A reference set of test cases can be established to facilitate methodological research in drug safety. Creating a sufficient sample of drug-outcome pairs with binary classification of having no effect (negative controls) or having an increased effect (positive controls) is possible and can enable estimation of predictive accuracy through discrimination. Since the magnitude of the positive effects cannot be reliably obtained and the quality of evidence may vary across outcomes, assumptions are required to use the test cases in real data for purposes of measuring bias, mean squared error, or coverage probability.