Control yourself: ISPE-endorsed guidance in the application of self-controlled study designs in pharmacoepidemiology.

PURPOSE: Consensus is needed on conceptual foundations, terminology and relationships among the various self-controlled "trigger" study designs that control for time-invariant confounding factors and target the association between transient exposures (potential triggers) and abrupt outcomes. The International Society for Pharmacoepidemiology (ISPE) funded a working group of ISPE members to develop guidance material for the application and reporting of self-controlled study designs, similar to Standards of Reporting Observational Epidemiology (STROBE). This first paper focuses on navigation between the types of self-controlled designs to permit a foundational understanding with guiding principles. METHODS: We leveraged a systematic review of applications of these designs, that we term Self-controlled Crossover Observational PharmacoEpidemiologic (SCOPE) studies. Starting from first principles and using case examples, we reviewed outcome-anchored (case-crossover [CCO], case-time control [CTC], case-case-time control [CCTC]) and exposure-anchored (self-controlled case-series [SCCS]) study designs. RESULTS: Key methodological features related to exposure, outcome and time-related concerns were clarified, and a common language and worksheet to facilitate the design of SCOPE studies is introduced. CONCLUSIONS: Consensus on conceptual foundations, terminology and relationships among SCOPE designs will facilitate understanding and critical appraisal of published studies, as well as help in the design, analysis and review of new SCOPE studies. This manuscript is endorsed by ISPE.

Factors affecting the delivery of community pharmacist-led medication reviews: evidence from the MedsCheck annual service in Ontario.

BACKGROUND: Medication reviews have become part of pharmacy practice across developed countries. This study aimed to identify factors affecting the likelihood of eligible Ontario seniors receiving a pharmacy-led medication review called MedsCheck annual (MCA). METHODS: We designed a cohort study using a random sample of pharmacy claims for MCA-eligible Ontario seniors using linked administrative data from April 2012 to March 2013. Guided by a conceptual framework, we constructed a generalized-estimating-equations model to estimate the effect of patient, pharmacy and community factors on the likelihood of receiving MCA. RESULTS: Of the 2,878,958 eligible claim-dates, 65,605 included an MCA. Compared to eligible individuals who did not receive an MCA, recipients were more likely to have a prior MCA (OR = 3.03), receive a new medication on the claim-date (OR = 1.78), be hypertensive (OR = 1.18) or have a recent hospitalization (OR = 1.07). MCA recipients had fewer medications (e.g., OR = 0.44 for ≥12 medications versus 0-4 medications), and were less likely to receive an MCA in a rural (OR = 0.74) or high-volume pharmacy (OR = 0.65). CONCLUSIONS: The most important determinant of receiving an MCA was having had a prior MCA. Overall, MCA recipients were healthier, younger, urban-dwelling, and taking fewer medications than non-recipients. Policies regarding current and future medication review programs may need to evolve to ensure that those at greatest need receive timely and comprehensive medication reviews.

Uptake of the MedsCheck annual medication review service in Ontario community pharmacies between 2007 and 2013.

BACKGROUND: MedsCheck Annual (MCA) is an Ontario government-funded medication review service for individuals taking 3 or more prescription medications for chronic conditions. METHODS: This cohort study analyzed linked administrative claims data from April 1, 2007, to March 31, 2013. Trends in MCA claims and recipient characteristics were examined. RESULTS: A total of 1,498,440 Ontarians (55% seniors, 55% female) received an MCA. One-third (36%) had 2 or more MCAs within 6 years. Service provision increased over time, with a sharper increase from 2010 onward. Almost half of Ontario pharmacies made at least 1 MCA claim in the first month of the program. Hypertension, respiratory disease, diabetes, psychiatric conditions and arthritis were common comorbidities. Recipients older than 65 years were most commonly dispensed an antihypertensive and/or antihyperlipidemic drug in the prior year and received an average of 11 unique prescription medications. Thirty-eight percent of recipients visited an emergency department or were hospitalized in the year prior to their first MCA. DISCUSSION: Over the first 6 years of the program, approximately 1 in 9 Ontarians received an MCA. There was rapid and widespread uptake of the service. Common chronic conditions were well represented among MCA recipients. Older MCA recipients had less emergency department use compared with population-based estimates. CONCLUSIONS: Medication reviews increased over time; however, the number of persons receiving the service more than once was low. Service delivery was generally consistent with program eligibility; however, there are some findings possibly consistent with delivery to less complex patients.

Case-crossover study design in pharmacoepidemiology: systematic review and recommendations.

PURPOSE: The purpose of this study is to systematically identify and review articles that use the case-crossover study design in the area of pharmacoepidemiology. METHODS: A systematic search of MEDLINE® (Ovid Technologies, New York City, NY, USA), EMBASE® (Elsevier Inc., Philadelphia, PA, USA), and Web of Science® (Thomson Reuters, New York City, NY, USA) was completed to identify all English language articles that applied the case-crossover study design in the area of pharmacoepidemiology. The number of reviews, methodological contributions, and empirical pharmacoepidemiologic applications were summarized by publication year. Empirical applications were retrieved, and methodological details (outcome, exposure, exposure windows, sensitivity analysis, statistical reporting) were tabulated and compared to methodological recommendations based on exposure characteristics, exposure windows, and discordant pairs data display. RESULTS: Of 836 unique articles identified, 99 pharmacoepidemiologic studies were eligible: 20 methodological contributions, 9 review papers, and 70 empirical applications. Only three empirical applications in the area of pharmacoepidemiology were published before 2000. Since 2000, the number of empirical pharmacoepidemiologic applications published annually has generally increased over time, to before a high of 15 published in 2011. The design was mainly applied to examine drug safety (96%), and most applications investigated: psychotropic (24%) and analgesic (17%) exposure drug classes; and considered hospitalization (23%) and cardiovascular/cerebrovascular (21%) events. Only 31% of applications displayed sufficient data to enable readers to confirm odds ratios presented. CONCLUSIONS: Use of the case-crossover design in pharmacoepidemiology has increased rapidly in the last decade. As the application of the case-crossover design continues to increase, it is important to develop standards of practice, especially for display of data.

Characteristics of patients vaccinated against influenza in physician offices versus pharmacies and predictors of vaccination location: a cross-sectional study.

BACKGROUND: Little is known about those vaccinated against influenza after pharmacists were added to the Ontario Universal Influenza Immunization Program, in 2012. Our aim was to identify characteristics of patients vaccinated against influenza and predictors of vaccination at a physician's office versus a community pharmacy. METHODS: We conducted a cross-sectional study of Ontario residents who had a record of receipt of an influenza vaccine between October and March in the 2013/14 and 2015/16 influenza seasons in Ontario using health administrative databases. We used Poisson regression models to estimate associations between baseline characteristics and the receipt of influenza vaccination in a community pharmacy. All analyses were stratified by age group (≤ 65 yr or ≥ 66 yr). RESULTS: Overall, we found a 7.9% decrease in vaccinations administered in 2015/16 (2 454 178) compared to 2013/14 (2 677 278). The number of patients vaccinated in community pharmacies increased between the 2 periods (757 729 [28.3%] in 2013/14 v. 859 794 [35.0%] in 2015/16). Living in nonurban areas or higher-income neighbourhoods, not identifying as an immigrant, not having a diagnosis of diabetes or hypertension, and receiving a pharmacist service on the same day as the vaccination were predictors of being vaccinated in a pharmacy, regardless of age group. Among patients aged 66 or more, those who had a hospital admission in the previous year were more likely to be vaccinated in a pharmacy than in a physician's office (adjusted incidence rate ratio [IRR] 1.08, 95% confidence interval [CI] 1.06-1.09), whereas those with higher annual medication costs were more likely to be vaccinated in a physician's office. The location of the previous season's vaccination predicted the current season's place of vaccination (age ≥ 66 yr: physician's office: adjusted IRR 0.56 [95% CI 0.56-0.57], pharmacy: adjusted IRR 2.37 [95% CI 2.35-2.39]; age ≤ 65 yr: physician's office: adjusted IRR 0.57 [95% CI 0.57-0.57], pharmacy: adjusted IRR 2.19 [95% CI 2.18-2.20]). INTERPRETATION: For the 2013/14 and 2015/16 influenza seasons, the influenza vaccine was administered more frequently in physician offices than in community pharmacies, but the proportion of patients vaccinated in community pharmacies increased between the 2 periods. Physicians and pharmacists can encourage patients to take advantage of the availability of influenza vaccines across various settings.

Uptake of Community Pharmacist-Delivered MedsCheck Diabetes Medication Review Service in Ontario between 2010 and 2014.

OBJECTIVES: The objective of the study was to describe the demographic and clinical characteristics of MedsCheck Diabetes (MCD) recipients in Ontario between program launch on September 1, 2010, and March 31, 2014. METHODS: This cohort study leveraged linked administrative claims data. Trends in MCD claims and recipient characteristics were examined. RESULTS: A total of 406,694 Ontarians (45.8% women) received an MCD, representing approximately half of all Ontarians with diabetes. Recipients were more likely to be <66 years of age (54.6%), live in an urban centre (94.6%) and be native to Canada (81.0%). A total of 13,587 MCD follow ups were completed (4.1% of MCD recipients ≥66 years of age and 2.7% of MCD recipients <66 years of age). MCD recipients ≥66 years of age had received a mean of 11 unique prescription medications in the previous year, prior to receiving an MCD, and 12.9% had had high medication costs ($4000+) in the previous year. Metformin was dispensed to 76.4% of recipients, insulin to 20.1% and insulin secretagogues to 36.2%. The most common medication classes used by MCD recipients, other than antihyperglycemics, were antihypertensives (89.5%), antilipid therapies (83.8%), diuretics (52.1%), antibiotics (38.2%) and gastroprotective agents (34.9%). They were also taking high-risk medications, including narcotics (25.4%), anticoagulants (23.3%), nonsteroidal anti-inflammatory drugs (NSAIDs) (21.5%), benzodiazepines (15.5%) and glyburide (15.8%). CONCLUSIONS: Over the first 3.5 years of the program, approximately half of Ontarians with diabetes received an MCD. Follow-up assessments were low (2.7% to 4.1% of the population). Ongoing evaluation of the program is required to ensure that continuity of care is being provided to this population.

Diffusion of Innovations model helps interpret the comparative uptake of two methodological innovations: co-authorship network analysis and recommendations for the integration of novel methods in practice.

OBJECTIVE: The objective of this study was to characterize the diffusion of methodological innovation. STUDY DESIGN AND SETTING: Comparative case study analysis of the diffusion of two methods that summarize confounder information into a single score: disease risk score (DRS) and high-dimensional propensity score (hdPS). We completed systematic searches to identify DRS and hdPS papers in the field of pharmacoepidemiology through to the end of 2013, plotted the number of papers and unique authors over time, and created sociograms and animations to visualize co-authorship networks. First and last author affiliations were used to ascribe institutional contributions to each paper and network. RESULTS: We identified 43 DRS papers by 153 authors since 1981, reflecting slow uptake during initial periods of uncertainty and broader diffusion since 2001 linked to early adopters from Vanderbilt. We identified 44 hdPS papers by 147 authors since 2009, reflecting rapid and integrated diffusion, likely facilitated by opinion leaders, early presentation at conferences, easily accessible statistical code, and improvement in funding. Most contributions (87% DRS, 96% hdPS) were from North America. CONCLUSION: When proposing new methods, authors are encouraged to consider innovation attributes and early evaluation to improve knowledge translation of their innovations for integration into practice, and we provide recommendations for consideration.

Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop.

Hormones such as fibroblast growth factor 21 (FGF21) and glucocorticoids (GCs) play crucial roles in coordinating the adaptive starvation response. Here we examine the interplay between these hormones. It was previously shown that FGF21 induces corticosterone levels in mice by acting on the brain. We now show that this induces the expression of genes required for GC synthesis in the adrenal gland. FGF21 also increases corticosterone secretion from the adrenal in response to ACTH. We further show that the relationship between FGF21 and GCs is bidirectional. GCs induce Fgf21 expression in the liver by acting on the GC receptor (GR). The GR binds in a ligand-dependent manner to a noncanonical GR response element located approximately 4.4 kb upstream of the Fgf21 transcription start site. The GR cooperates with the nuclear fatty acid receptor, peroxisome proliferator-activated receptor-α, to stimulate Fgf21 transcription. GR and peroxisome proliferator-activated receptor-α ligands have additive effects on Fgf21 expression both in vivo and in primary cultures of mouse hepatocytes. We conclude that FGF21 and GCs regulate each other's production in a feed-forward loop and suggest that this provides a mechanism for bypassing negative feedback on the hypothalamic-pituitary-adrenal axis to allow sustained gluconeogenesis during starvation.