Use of olmesartan and enteropathy outcomes: a multi-database study.

BACKGROUND: Multiple case reports suggest that olmesartan may be linked to sprue-like enteropathy; however, few epidemiological studies have examined this association and results have been mixed. AIM: To assess whether olmesartan is associated with a higher rate of enteropathy vs other angiotensin II receptor blockers (ARBs). METHODS: We conducted a cohort study among ARB initiators in 5 US claims databases representing different health insurance programmes. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for enteropathy-related outcomes, including coeliac disease, malabsorption, concomitant diagnoses of diarrhoea and weight loss, and non-infectious enteropathy, comparing olmesartan initiators to initiators of other ARBs after propensity score (PS) matching. RESULTS: We identified 1 928 469 eligible patients. The unadjusted incidence rates were 0.82, 1.41, 1.66 and 29.20 per 1000 person-years for coeliac disease, malabsorption, concomitant diagnoses of diarrhoea and weight loss, and non-infectious enteropathy respectively. HRs after PS matching comparing olmesartan to other ARBs were 1.21 (95% CI, 1.05-1.40), 1.00 (95% CI, 0.88-1.13), 1.22 (95% CI, 1.10-1.36) and 1.04 (95% CI, 1.01-1.07) for each outcome. HRs were larger for patients aged 65 years and older (eg for coeliac disease, 1.57 [95% CI, 1.20-2.05]), for patients receiving treatment for more than 1 year (1.62 [95% CI, 1.24-2.12]), and for patients receiving higher cumulative olmesartan doses (1.78 [95% CI, 1.33-2.37]). CONCLUSIONS: This large-scale, multi-database study found a higher rate of enteropathy in olmesartan initiators as compared to initiators of other ARBs, although the absolute incidence rate was low in both groups.

Impact of hospitalization on medication adherence estimation in claims data.

WHAT IS KNOWN AND OBJECTIVE: Pharmacy claims are commonly used to assess medication adherence. It is unclear how different approaches to handling hospitalizations compare to the gold standard of using outpatient and inpatient drug data. This study aimed to compare the impact of different approaches to handling hospitalizations on medication adherence estimation in administrative claims data. METHODS: We identified ß-blocker initiators after myocardial infarction (MI) and statin initiators regardless of hospitalization histories in the population-based, Taiwan database, which includes outpatient and inpatient drug claims data. Adherence to ß-blockers or to statins during a 365-day follow-up period was estimated in outpatient pharmacy claims using the proportion of days covered (PDC) in three ways: ignoring hospitalizations (PDC1); subtracting hospitalized days from the denominator (PDC2); and assuming drug use on all hospitalized days (PDC3). We compared these to an approach that incorporated inpatient drug use (PDC4). We also used a hypothetical example to examine variations across approaches in several scenarios, such as increasing hospitalized days. RESULTS AND DISCUSSION: Mean 365-day PDC was 74% among 1729 post-MI ß-blocker initiators (range: 73.1%-74.9%) and 44% among 69 435 statins initiators (range: 43.5%-44.0%), which varied little across approaches. Differences across approaches increased with increasing number of hospitalized days. For patients hospitalized for >28 days, mean difference across approaches was >15%. PDC3 consistently yielded the highest value and PDC1 the lowest. WHAT IS NEW AND CONCLUSIONS: On average, different approaches to handling hospitalizations lead to similar adherence estimates to the gold standard of incorporating inpatient drug use. When patients have many hospitalization days during follow-up, the choice of approach should be tailored to the specific setting.

Experts' perspectives on the role of medical marijuana in oncology: A semistructured interview study.

BACKGROUND: Expansion of medical marijuana (MM) laws in the United States may offer oncology new therapeutic options. However, the scientific evidence for MM remains in infancy. This study qualitatively explored professional opinion around the role of MM in cancer care. METHODS: Semistructured interviews were administered to a sample of individuals with expertise at the interface of MM and oncology nationally. Key informant criteria included an oncologic clinical or research background and any of the following: publications, research, or lectures on cannabinoids or cancer symptoms; involvement in the development of MM dispensaries or legislation; and early adoption of state MM certification procedures. A gold standard, grounded, inductive approach was used to identify underlying themes. RESULTS: Participants (N = 15) were predominantly male, in their sixth decade, working in academic settings. Themes ranged from strong beliefs in marijuana's medical utility to reservations about this notion, with calls for expansion of the scientific evidence base and more stringent MM production standards. All participants cited nausea as an appropriate indication, and 13 of 15 pain. Over one-third believed MM to have a more attractive risk profile than opioids and benzodiazepines. CONCLUSIONS: Expert opinion was divided between convictions in marijuana's medicinal potential and guardedness in this assertion, with no participant refuting MM's utility outright. Emergent themes included that MM ameliorates cancer-related pain and nausea and is safer than certain conventional medications. Participants called for enhanced purity and production standards, and further research on MM's utility.

Successful Comparison of US Food and Drug Administration Sentinel Analysis Tools to Traditional Approaches in Quantifying a Known Drug-Adverse Event Association.

The US Food and Drug Administration's Sentinel system has developed the capability to conduct active safety surveillance of marketed medical products in a large network of electronic healthcare databases. We assessed the extent to which the newly developed, semiautomated Sentinel Propensity Score Matching (PSM) tool could produce the same results as a customized protocol-driven assessment, which found an adjusted hazard ratio (HR) of 3.04 (95% confidence interval [CI], 2.81-3.27) comparing angioedema in patients initiating angiotensin-converting enzyme (ACE) inhibitors vs. beta-blockers. Using data from 13 Data Partners between 1 January 2008, and 30 September 2013, the PSM tool identified 2,211,215 eligible ACE inhibitor and 1,673,682 eligible beta-blocker initiators. The tool produced an HR of 3.14 (95% CI, 2.86-3.44). This comparison provides initial evidence that Sentinel analytic tools can produce findings similar to those produced by a highly customized protocol-driven assessment.

Severe hypoglycemia in users of sulfonylurea antidiabetic agents and antihyperlipidemics.

Drug-drug interactions causing severe hypoglycemia due to antidiabetic drugs is a major clinical and public health problem. We assessed whether sulfonylurea use with a statin or fibrate was associated with severe hypoglycemia. We conducted cohort studies of users of glyburide, glipizide, and glimepiride plus a statin or fibrate within a Medicaid population. The outcome was a validated, diagnosis-based algorithm for severe hypoglycemia. Among 592,872 persons newly exposed to a sulfonylurea+antihyperlipidemic, the incidence of severe hypoglycemia was 5.8/100 person-years. Adjusted hazard ratios (HRs) for sulfonylurea+statins were consistent with no association. Most overall HRs for sulfonylurea+fibrate were elevated, with sulfonylurea-specific adjusted HRs as large as 1.50 (95% confidence interval (CI): 1.24-1.81) for glyburide+gemfibrozil, 1.37 (95% CI: 1.11-1.69) for glipizide+gemfibrozil, and 1.63 (95% CI: 1.29-2.06) for glimepiride+fenofibrate. Concomitant therapy with a sulfonylurea and fibrate is associated with an often delayed increased rate of severe hypoglycemia.

Pharmacoepidemiologic Methods for Studying the Health Effects of Drug-Drug Interactions.

A drug-drug interaction (DDI) occurs when one or more drugs affect the pharmacokinetics (the body's effect on the drug) and/or pharmacodynamics (the drug's effect on the body) of one or more other drugs. Pharmacoepidemiologic studies are the principal way of studying the health effects of potential DDIs. This article discusses aspects of pharmacoepidemiologic research designs that are particularly salient to the design and interpretation of pharmacoepidemiologic studies of DDIs.

Strategies for postmarketing surveillance of drugs for rare diseases.

Rare diseases are an important part of the public health, affecting 6-8% of the population, and drugs intended for rare diseases comprise the fastest growing subcategory of new drug approvals in the United States. However, clinical study of therapeutics in these populations is limited by the low prevalence of these diseases, and the natural history or pathogenesis of the disease may be poorly described. In addition, commonly used strategies for evaluation of postapproval safety and effectiveness, such as meta-analyses and review of spontaneous adverse event reports, may not be applicable. Alternative methodological approaches, including natural history studies, adaptive clinical trial designs, and epidemiological studies using patient-organized registries, show substantial promise for the study of rare disease therapeutics. Bayesian trials and distributed networks of large electronic databases are the most promising strategies for active and prospective monitoring of clinical interventions for rare diseases.

Risk of death associated with the use of conventional vs. atypical antipsychotic medications: evaluating the use of the Emilia-Romagna Region database for pharmacoepidemiological studies.

WHAT IS KNOWN AND OBJECTIVE: Since 2005, a mounting base of evidence has identified that conventional antipsychotic medications are associated with an increased risk of mortality among elderly patients when compared to atypical antipsychotics. This study sought to explore the feasibility of using the Emilia-Romagna Region (RER) database for comparative safety analyses by replicating and refining risk estimates of this well-known drug safety example through meta-analysis. METHODS: We identified a cohort of 23 681 Italian RER patients (aged ≥65) who initiated treatment with a conventional or atypical antipsychotic between 1 July 2009 and 30 June 2011. We compared 180-day mortality using Cox proportional hazards models adjusted for risk factors for death, use of other medications and measures of health services utilization intensity, all measured before antipsychotic initiation. We conducted a meta-analysis of studies with similar methods against which to compare our results. RESULTS: Among 14 462 and 9219 patients prescribed conventional and atypical antipsychotics, respectively, we observed 2402 (16·6%) and 821 (8·9%) deaths during follow-up. Conventional antipsychotic initiators were older and generally had higher prevalence of outcome risk factors and higher baseline health service use intensity. The crude hazard ratio (HR) was 1·95 [95% confidence interval (CI), 1·80-2·11], which decreased to 1·47 (95% CI, 1·35-1·60) after full adjustment. We identified seven published studies that examined this association using similar methods. The pooled HR from these studies was 1·34 (95% CI, 1·28-1·39). Including our study, the meta-analysis yielded a summary estimate of 1·35 (95% CI, 1·31-1·40) and did not introduce any heterogeneity (I(2)  = 0%; P = 0·455). WHAT IS NEW AND CONCLUSIONS: Our results support the use of the RER database for pharmacoepidemiological studies and provide an up-to-date and pooled estimate of the magnitude of the association between mortality and conventional vs. atypical antipsychotics.

Active safety monitoring of newly marketed medications in a distributed data network: application of a semi-automated monitoring system.

We developed a semi-automated active monitoring system that uses sequential matched-cohort analyses to assess drug safety across a distributed network of longitudinal electronic health-care data. In a retrospective analysis, we show that the system would have identified cerivastatin-induced rhabdomyolysis. In this study, we evaluated whether the system would generate alerts for three drug-outcome pairs: rosuvastatin and rhabdomyolysis (known null association), rosuvastatin and diabetes mellitus, and telithromycin and hepatotoxicity (two examples for which alerting would be questionable). Over >5 years of monitoring, rate differences (RDs) in comparisons of rosuvastatin with atorvastatin were -0.1 cases of rhabdomyolysis per 1,000 person-years (95% confidence interval (CI): -0.4, 0.1) and -2.2 diabetes cases per 1,000 person-years (95% CI: -6.0, 1.6). The RD for hepatotoxicity comparing telithromycin with azithromycin was 0.3 cases per 1,000 person-years (95% CI: -0.5, 1.0). In a setting in which false positivity is a major concern, the system did not generate alerts for the three drug-outcome pairs.

Assessing the comparative effectiveness of newly marketed medications: methodological challenges and implications for drug development.

Comparative-effectiveness research (CER) aims to produce actionable evidence regarding the effectiveness and safety of medical products and interventions as they are used outside of controlled research settings. Although CER evidence regarding medications is particularly needed shortly after market approval, key methodological challenges include (i) potential bias due to channeling of patients to the newly marketed medication because of various patient-, physician-, and system-related factors; (ii) rapid changes in the characteristics of the user population during the early phase of marketing; and (iii) lack of timely data and the often small number of users in the first few months of marketing. We propose a mix of approaches to generate comparative-effectiveness data in the early marketing period, including sequential cohort monitoring with secondary health-care data and propensity score (PS) balancing, as well as extended follow-up of phase III and phase IV trials, indirect comparisons of placebo-controlled trials, and modeling and simulation of virtual trials.

Antidepressants and fracture risk in older adults: a comparative safety analysis.

We examined variations in fracture rates among patients initiated on antidepressant drug treatment as identified from Medicare data in two US states and assessed whether the observed variation could be explained by affinity for serotonin transport receptors. We used Cox proportional hazards models to compare fracture rates of the hip, humerus, pelvis, wrist, and a composite of these, among propensity score-matched cohorts of users of secondary amine tricyclics, tertiary amine tricyclics, selective serotonin reuptake inhibitors (SSRIs), and atypical antidepressants. As compared with secondary amine tricyclics, SSRIs showed the highest association with composite fracture rate (hazard ratio 1.30; 95% confidence interval (CI) 1.12-1.52), followed by atypical antidepressants (hazard ratio 1.12; 95% CI 0.96-1.31) and tertiary amine tricyclics (hazard ratio 1.01; 95% CI 0.87-1.18). The results were robust to sensitivity analyses. Although SSRI use was associated with the highest rate of fractures, variation in fracture risk across specific antidepressant medications did not depend on affinity for serotonin transport receptors.

Refilling and switching of antiepileptic drugs and seizure-related events.

We sought to estimate the risk of seizure-related events associated with refilling prescriptions for antiepileptic drugs (AEDs) and to estimate the effect of switching between brand-name and generic drugs or between two generic versions of the same drug. We conducted a case-crossover study using health-care databases from British Columbia, Canada, among AED users who had an emergency room visit or hospitalization for seizure (index seizure-related event), defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes 345.xx (epilepsy and recurrent seizures) and 780.3x (convulsions), between 1997 and 2005. AED prescription refilling itself was associated with 2.3-fold elevated odds of seizure-related events when the refill occurred within 21 days before the index event (odds ratio (OR) 2.31; 95% confidence interval (CI) 1.56-3.44). The OR was 2.75 (95% CI 0.88-8.64) for refills that involved switching, yielding a refill-adjusted OR for switching of 1.19 (95% CI 0.35-3.99). Refilling the same AED prescription was associated with an elevated risk of seizure-related events whether or not the refill involved switching from a brand-name to a generic product.

Impact of ALLHAT publication on antihypertensive prescribing patterns in Regione Emilia-Romagna, Italy.

BACKGROUND AND OBJECTIVE: Studies from the US and Canada observed changes in antihypertensive prescribing patterns in accordance with Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study findings immediately after the study's publication, but little is known about the impact of ALLHAT in Italy. The objective of this study was to examine antihypertensive prescribing patterns in Regione Emilia-Romagna (RER), Italy, following the publication of the ALLHAT main results. METHODS: We conducted a time series analysis using automated pharmacy data of approximately 4 million RER residents between 1 January 2000 and 31 December 2003. We computed monthly relative percentages of prescriptions for all antihypertensive medications and separately for all new antihypertensives defined as no recorded antihypertensive use in the previous year. A stepwise auto-regressive forecasting model based on data prior to the ALLHAT publication was used to estimate predicted relative percentages for the 12 months following the ALLHAT publication. Observed and predicted values were compared. RESULTS AND DISCUSSION: Use of thiazide-type diuretics showed a general increasing trend over the study period, but the difference between the observed and predicted values reached statistical significance only for new prescriptions in October 2003 (3.71% vs. 2.32%; P = 0.0170). The relative percentage of new angiotensin-converting enzyme inhibitor and angiotensin receptor blocker (ACE/ARB) prescriptions was higher than predicted for the months May to August 2003 (P < 0.05), but no significant differences were observed for total ACE/ARB prescriptions. Modest changes in patterns of prescribing of calcium channel blockers and alpha-blockers were observed. CONCLUSION: We found little evidence that the ALLHAT study had an impact on antihypertensive prescribing patterns in RER in the year following their publication.

Prevalence and predictors of potential drug-drug interactions in Regione Emilia-Romagna, Italy.

BACKGROUND AND OBJECTIVE: Drug-drug interactions (DDIs) are preventable medication errors associated with potentially serious adverse events and death. Several studies have examined the prevalence of potential DDIs among ambulatory patients in various countries. Limited recent data on the prevalence of potential DDIs in Italy are available in the medical literature. The objective of this study was to estimate the prevalence of clinically important potential DDIs among the approximately 4 million residents of Regione Emilia-Romagna (RER), Italy, and to examine possible predictors of potential DDI exposure. METHODS: A retrospective follow-up study of 2004 outpatient prescription data from RER was conducted. A previously published list of clinically important potential DDIs was refined to include only pairs of drugs in which both drugs were reimbursed by the 2004 Italian National Formulary. A potential DDI was defined as the presence of a minimum 5-day overlap in days supply for drugs in an interacting pair. The 1-year period prevalence of each potential DDI was quantified. A logistic regression analysis was conducted to examine patient characteristics as predictors of potential DDIs. RESULTS AND DISCUSSION: The list of clinically important potential DDIs included 12 drug pairs that could be captured using the RER database. These 12 potential DDIs occurred 8894 times in the RER population in 2004. The most commonly identified potentially interacting medication pairs were warfarin and non-steroidal anti-inflammatory drugs (6824 cases), theophylline/aminophylline and ciprofloxacin/fluvoxamine (930), and warfarin and barbiturates (567). Odds of exposure were highest among those aged 65 years or older, males, and those with more chronic conditions. Odds of exposure increased 1.39 times with each addition of a prescription medication. CONCLUSION: A substantial number of clinically important potential DDIs were identified, particularly among warfarin users. Awareness of the most prevalent potential DDIs can help practitioners prevent concomitant use of these dangerous medication combinations.