Comparative Analysis of Instrumental Variables on the Assignment of Buprenorphine/Naloxone or Methadone for the Treatment of Opioid Use Disorder.

BACKGROUND: Instrumental variable (IV) analysis provides an alternative set of identification assumptions in the presence of uncontrolled confounding when attempting to estimate causal effects. Our objective was to evaluate the suitability of measures of prescriber preference and calendar time as potential IVs to evaluate the comparative effectiveness of buprenorphine/naloxone versus methadone for treatment of opioid use disorder (OUD). METHODS: Using linked population-level health administrative data, we constructed five IVs: prescribing preference at the individual, facility, and region levels (continuous and categorical variables), calendar time, and a binary prescriber's preference IV in analyzing the treatment assignment-treatment discontinuation association using both incident-user and prevalent-new-user designs. Using published guidelines, we assessed and compared each IV according to the four assumptions for IVs, employing both empirical assessment and content expertise. We evaluated the robustness of results using sensitivity analyses. RESULTS: The study sample included 35,904 incident users (43.3% on buprenorphine/naloxone) initiated on opioid agonist treatment by 1585 prescribers during the study period. While all candidate IVs were strong (A1) according to conventional criteria, by expert opinion, we found no evidence against assumptions of exclusion (A2), independence (A3), monotonicity (A4a), and homogeneity (A4b) for prescribing preference-based IV. Some criteria were violated for the calendar time-based IV. We determined that preference in provider-level prescribing, measured on a continuous scale, was the most suitable IV for comparative effectiveness of buprenorphine/naloxone and methadone for the treatment of OUD. CONCLUSIONS: Our results suggest that prescriber's preference measures are suitable IVs in comparative effectiveness studies of treatment for OUD.

Evaluation of audit and feedback to family physicians on prescribing of opioid analgesics to opioid-naïve patients: A pragmatic randomized delay trial.

BACKGROUND: Exposure to opioid analgesics have historically raised concern for a risk of developing opioid use disorder. Prescriber audit-and-feedback interventions may reduce opioid prescribing, but some studies have shown detrimental effects for current users. We examined the effectiveness of an audit and feedback intervention, named Portrait, to reduce initiation of opioid analgesics among opioid-naïve patients experiencing pain. METHODS: REDONNA was a single-blinded, two-arm (Early vs Delayed mailing) randomized trial of a portrait for eligible family physicians (FPs) in British Columbia (BC), Canada. The primary outcome was the change in the number of initiations of opioid analgesic prescriptions written by FPs for acute/chronic pain management. We compared outcomes for a 6-month window before vs. after each mailed intervention, using differences in percent differences (DPD) with 95% confidence intervals (CI) and odds ratios (OR) from logistic regressions adjusted for clustering of patients by FP. RESULTS: In the Early (n = 2260) and Delayed (n = 2156) groups, opioid initiations per month were the same in the Before (2.10 Early; 2.06 Delayed) and After (1.94 Early; 1.95 Delayed) windows. The DPD was -2.1% (CI: -4.4% to 0.3%), and ORs were: 0.98 (CI: 0.96 to 1.01) for any opioid, 0.97 (CI: 0.94 to 1.01) for codeine (62% of initiations), and 1.0 (CI: 0.97 to 1.07) for tramadol (25% of initiations). There were no differences in mean quantity of tablets, mean milligrams of morphine equivalents (MME), or mean number of days. CONCLUSION: Portrait had no impact on FPs' rates of prescribing opioid analgesics to opioid-naïve patients experiencing pain. TRIAL REGISTRATION: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).

A cluster randomized trial assessing the impact of personalized prescribing feedback on antibiotic prescribing for uncomplicated acute cystitis to family physicians.

OBJECTIVE: To evaluate the impact of personalized prescribing portraits on antibiotic prescribing for treating uncomplicated acute cystitis (UAC) by Family Physicians (FPs). DESIGN: Cluster randomized control trial. SETTING: The intervention was conducted in the primary care setting in the province of BC between December 2010 and February 2012. PARTICIPANTS: We randomized 4 833 FPs by geographic location into an Early intervention arm (n = 2 417) and a Delayed control arm (n = 2 416). INTERVENTION: The Education for Quality Improvement in Patient Care (EQIP) program mailed to each FP in BC, a 'portrait' of their individual prescribing of antibiotics to women with UAC, plus therapeutic recommendations and a chart of trends in antibiotic resistance. MAIN OUTCOME MEASURES: Antibiotic prescribing preference to treat UAC. RESULTS: Implementing exclusion criteria before and after a data system change in the Ministry of Health caused the arms to be unequal in size-intervention arm (1 026 FPs, 17 637 UAC cases); control arm (1 352 FPs, 25 566 UAC cases)-but they were well balanced by age, sex and prior rates of prescribing antibiotics for UAC. In the early intervention group probability of prescribing nitrofurantoin increased from 28% in 2010 to 38% in 2011, a difference of 9.9% (95% confidence interval [CI], 9.1% to 10.7. Ciprofloxacin decreased by 6.2% (95% CI: 5.6% to 6.9%) and TMP-SMX by 3.7% (95% CI: 3.1% to 4.2%). Among 295 FPs who completed reflective surveys, 52% said they were surprized by the E. coli resistance statistics and 57% said they planned to change their treatment of UAC. CONCLUSION: The EQIP intervention demonstrated that feedback of personal data to FPs on their prescribing, plus population data on antibiotic resistance, with a simple therapeutic recommendation, can significantly improve prescribing of antibiotics. Trial registration: ISRCTN 16938907.

Comparative effectiveness of urine drug screening strategies alongside opioid agonist treatment in British Columbia, Canada: a population-based observational study protocol.

INTRODUCTION: Urine drug tests (UDTs) are commonly used for monitoring opioid agonist treatment (OAT) responses, supporting the clinical decision for take-home doses and monitoring potential diversion. However, there is limited evidence supporting the utility of mandatory UDTs-particularly the impact of UDT frequency on OAT retention. Real-world evidence can inform patient-centred approaches to OAT and improve current strategies to address the ongoing opioid public health emergency. Our objective is to determine the safety and comparative effectiveness of alternative UDT monitoring strategies as observed in clinical practice among OAT clients in British Columbia, Canada from 2010 to 2020. METHODS AND ANALYSIS: We propose a population-level retrospective cohort study of all individuals 18 years of age or older who initiated OAT from 1 January 2010 to 17 March 2020. The study will draw on eight linked health administrative databases from British Columbia. Our primary outcomes include OAT discontinuation and all-cause mortality. To determine the effectiveness of the intervention, we will emulate a 'per-protocol' target trial using a clone censoring approach to compare fixed and dynamic UDT monitoring strategies. A range of sensitivity analyses will be executed to determine the robustness of our results. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals electronically and in print.

"I'm almost opioid-a-phobic": family medicine residents' perceptions of enhancing opioid analgesic and agonist treatment training in a Canadian setting.

PURPOSE: As deaths from the illicit drug poisoning crisis continue to rise in Canada, increasing the number of healthcare professionals qualified to effectively prescribe opioids could be beneficial. The willingness of family medicine residents to undertake structured training in prescribing opioids for Opioid Agonist Treatment (OAT) and pain management have not been well described. MATERIALS AND METHODS: Family medicine residents (n = 20) in British Columbia, Canada, were asked about their experience with and willingness to enrol in OAT training. Informed by the Consolidated Framework for Implementation Research, data were analysed thematically using NVivo software. RESULTS: Four themes were identified: (1) challenges to training implementation, (2) feelings and attitudes on prescribing practices, (3) helpful learning spaces and places of substance use training, and (4) recommendations for implementing training. Preparedness, exposure, and supportive learning environments for substance use education increased willingness to pursue OAT accreditation, while ineffective learning experiences, mixed feelings about opioid prescribing, and lack of protected time were the most common reasons for unwillingness. CONCLUSIONS: Protected time and a range of clinical experiences appear to facilitate residents' willingness to complete OAT and opioid training. Implementation strategies to enhance the uptake of OAT accreditation in family medicine residency must be prioritised.

Up-to-date on cancer screening among Ontario patients seen by walk-in clinic physicians: A retrospective cohort study.

Walk-in clinics are typically viewed as high-volume locations for managing acute issues but also may serve as a location for primary care, including cancer screening, for patients without a family physician. In this population-based cohort study, we compared breast, cervical and colorectal cancer screening up-to-date status for people living in the Canadian province of Ontario who were formally enrolled to a family physician versus those not enrolled but who had at least one encounter with a walk-in clinic physician in the previous year. Using provincial administrative databases, we created two mutually exclusive groups: i) those who were formally enrolled to a family physician, ii) those who were not enrolled but had at least one visit with a walk-in clinic physician from April 1, 2019 to March 31, 2020. We compared up to date status for three cancer screenings as of April 1, 2020 among screen-eligible people. We found that people who were not enrolled and had seen a walk-in clinic physician in the previous year consistently were less likely to be up to date on cancer screening than Ontarians who were formally enrolled with a family physician (46.1% vs. 67.4% for breast, 45.8% vs. 67.4% for cervical, 49.5% vs. 73.1% for colorectal). They were also more likely to be foreign-born and to live in structurally marginalized neighbourhoods. New methods are needed to enable screening for people who are reliant on walk-in clinics and to address the urgent need in Ontario for more primary care providers who deliver comprehensive, longitudinal care.

Walk-in clinic patient characteristics and utilization patterns in Ontario, Canada: a cross-sectional study.

BACKGROUND: Walk-in clinics are common in North America and are designed to provide acute episodic care without an appointment. We sought to describe a sample of walk-in clinic patients in Ontario, Canada, which is a setting with high levels of primary care attachment. METHODS: We performed a cross-sectional study using health administrative data from 2019. We compared the sociodemographic characteristics and health care utilization patterns of patients attending 1 of 72 walk-in clinics with those of the general Ontario population. We examined the subset of patients who were enrolled with a family physician and compared walk-in clinic visits to family physician visits. RESULTS: Our study found that 562 781 patients made 1 148 151 visits to the included walk-in clinics. Most (70%) patients who attended a walk-in clinic had an enrolling family physician. Walk-in clinic patients were younger (mean age 36 yr v. 41 yr, standardized mean difference [SMD] 0.24), yet had greater health care utilization (moderate and high use group 74% v. 65%, SMD 0.20) than the general Ontario population. Among enrolled Ontarians, walk-in patients had more comorbidities (moderate and high count 50% v. 45%, SMD 0.10), lived farther from their enrolling physician (median 8 km v. 6 km, SMD 0.21) and saw their enrolling physician less in the previous year (any visit 67% v. 80%, SMD 0.30). Walk-in encounters happened more often after hours (16% v. 9%, SMD 0.20) and on weekends (18% v. 5%, SMD 0.45). Walk-in clinics were more often within 3 km of patients' homes than enrolling physicians' offices (0 to < 3 km: 32% v. 22%, SMD 0.21). INTERPRETATION: Our findings suggest that proximity of walk-in clinics and after-hours access may be contributing to walk-in clinic use among patients enrolled with a family physician. These findings have implications for policy development to improve the integration of walk-in clinics and longitudinal primary care.

Trends in opioid dispensing after common abdominal and orthopedic surgery procedures in British Columbia: a retrospective cohort analysis.

PURPOSE: Postdischarge opioid prescriptions are reportedly much higher in Canada than in other countries. To assess potentially contributing factors, we examined trends after abdominal and orthopedic surgeries in British Columbia (BC). METHODS: Using the BC Ministry of Health's databases on physician billings, hospital discharge abstracts, and medication dispensations in community pharmacies for the period 2003-2016, we assembled a cohort of 263,056 patients who received laparoscopic appendectomy (LA, 11%), laparoscopic cholecystectomy (LC, 30%), open inguinal or femoral hernia repair (IHR, 20%), total hip arthroplasty (THA, 18%), or total knee arthroplasty (TKA, 22%). Adjusting for covariates using generalized linear modeling, we measured trends in percentages of patients dispensed opioids postdischarge (opioid rate) within 30 days after surgery, by surgery type, opioid type, prior use, surgeon, and trends in morphine milligram equivalents of first dispensations (MME) with 95% confidence intervals (CI). RESULTS: Opioid dispensation rates rose steadily. Mean annual increases were 1.7% in LA; 1.3% in LC; 0.8% in IHR; 0.9% in THA; and 0.8% in TKA. By 2016, rates were 69% in LA; 76% in LC; 81% in IHR; 88% in THA; and 94% in TKA. Codeine dispensations fell 2.4% (abdominal) and 3.1% (orthopedic) per year while tramadol dispensations increased 3.6% (abdominal) and 1.7% (orthopedic). Hydromorphone dispensations increased 2.9% per year (orthopedic); oxycodone was level at 22% between 2007 and 2014, but then fell. The mean MME rose 8 mg⋅yr-1 (95% CI, 7 to 9) (abdominal) and 61 mg⋅yr-1 (95% CI, 58 to 64) (orthopedic). Variation in rates was greater among abdominal than orthopedic surgeons. CONCLUSION: Rising opioid dispensation rates, together with shifts to prescribing higher MME opioids, doubled MME per patient in first dispensations postdischarge after abdominal or orthopedic surgery from 2003 to 2016 in BC.

RéSUMé: OBJECTIF: Les ordonnances d'opioïdes après le congé seraient beaucoup plus élevées au Canada que dans d'autres pays. Afin d'évaluer les facteurs contributifs potentiels, nous avons examiné les tendances après les chirurgies abdominales et orthopédiques en Colombie-Britannique (C.-B.). MéTHODE: En utilisant les bases de données du ministère de la Santé de la Colombie-Britannique de facturation des médecins, les résumés des congés d'hôpital et les délivrances de médicaments dans les pharmacies communautaires pour la période 2003-2016, nous avons regroupé une cohorte de 263 056 patients ayant bénéficié d'une appendicectomie par laparoscopie (AL, 11 %), d'une cholécystectomie par laparoscopie (CL, 30 %), d'une réparation ouverte de hernie inguinale ou fémorale (RHI, 20 %), d'une arthroplastie totale de la hanche (ATH, 18 %) ou d'une arthroplastie totale du genou (ATG, 22 %). En tenant compte des covariables à l'aide d'une modélisation linéaire généralisée, nous avons mesuré les tendances dans les pourcentages de patients ayant reçu des opioïdes après leur congé (taux de délivrance d'opioïdes) dans les 30 jours suivant leur chirurgie, par type de chirurgie, type d'opioïde, utilisation antérieure, chirurgien et tendances des équivalents de morphine en milligrammes (EMM) des premières délivrances avec des intervalles de confiance (IC) à 95 %. RéSULTATS: Les taux de délivrance d'opioïdes ont augmenté de manière constante. Les augmentations annuelles moyennes étaient de 1,7 % pour les AL, 1,3 % pour les CL, 0,8 % pour les RHI, 0,9 % pour les ATH, et 0,8 % pour les ATG. En 2016, les taux étaient de 69 % pour les AL, 76 % pour les CL, 81 % pour les RHI, 88 % pour les ATH, et 94 % pour les ATG. Les dispenses de codéine ont chuté de 2,4 % (chirurgie abdominale) et de 3,1 % (chirurgie orthopédique) par année, tandis que les délivrances de tramadol ont augmenté de 3,6 % (chirurgie abdominale) et de 1,7 % (chirurgie orthopédique). Les délivrances d'hydromorphone ont augmenté de 2,9 % par année (orthopédie); l'oxycodone était à 22 % entre 2007 et 2014, mais a ensuite diminué. Les EMM moyens ont augmenté de 8 mg·an-1 (IC 95 %, 7 à 9) (chirurgie abdominale) et de 61 mg·an-1 (IC 95 %, 58 à 64) (chirurgie orthopédique). La variation des taux était plus importante parmi les chirurgiens abdominaux que chez les chirurgiens orthopédistes. CONCLUSION: L'augmentation des taux de délivrance d'opioïdes, ainsi que le passage à une prescription d'opioïdes plus élevés en EMM, ont doublé les EMM par patient dans les premières délivrances après leur congé après une chirurgie abdominale ou orthopédique de 2003 à 2016 en Colombie-Britannique.

Opioid dispensing after Cesarean delivery in British Columbia: a historical cohort analysis from 2004 to 2019.

PURPOSE: To describe postdischarge opioid dispensing after Cesarean delivery (CD) in 49 hospitals in British Columbia (BC) and assess opportunities for opioid stewardship. METHODS: Using the BC Ministry of Health's Hospital Discharge Abstract Database, we linked 135,725 CDs performed in 2004-2016 and 30,919 CDs performed in 2017-2019 (length of stay ≤ four days) by deidentified Personal Health Numbers to data on medications dispensed from all BC community pharmacies (PharmaNet). We excluded patients with cancer and those to whom opioids have been dispensed in the year before. We measured trends in annual percentages of patients dispensed opioids within seven days (opioid rate), with 95% confidence intervals (CIs), stratified by hospital and opioid type, adjusted for length of stay, and for autocorrelation within hospital using generalized linear modeling. RESULTS: The opioid dispensation rate dropped from 31% (95% CI, 30 to 33) in 2004 to 16% (95% CI, 15 to 17) in 2016, where it remained through 2019. Five hospitals showed steep reductions from over 40% to under 10% within two to three years, but in most hospitals the opioid dispensation rate decreased slowly-11 had little reduction and three showed increases. Codeine dispensing dropped from 31% in 2004-2008 by 4% per year, while tramadol and hydromorphone dispensing rose. After 2015, rates were stable (hydromorphone, 8%; tramadol, 6%; codeine, 3%; and oxycodone, 0.5%). CONCLUSION: After Health Canada's 2008 warning against codeine use by breastfeeding mothers, post-CD opioid dispensing declined disjointedly across BC hospitals. Rates did not decrease further after the opioid overdose epidemic was declared a public health emergency in BC in 2016. The present study highlights opportunities for quality improvement and opioid stewardship through monitoring using administrative databases.

RéSUMé: OBJECTIF: Décrire la délivrance d'opioïdes après le congé après un accouchement par césarienne dans 49 hôpitaux de la Colombie-Britannique (C.-B.) et évaluer les occasions de régulation des opioïdes. MéTHODE: À l'aide de la base de données sur les congés des patients du ministère de la Santé de la Colombie-Britannique, nous avons relié 135 725 accouchements par césarienne réalisés en 2004-2016 et 30 919 accouchements par césarienne réalisés en 2017-2019 (durée de séjour ≤ quatre jours) en utilisant les numéros de carte santé personnels dépersonnalisés aux données sur les médicaments délivrés par toutes les pharmacies communautaires de la Colombie-Britannique (PharmaNet). Nous avons exclu les patientes atteintes de cancer et celles à qui des opioïdes avaient été délivrés l'année précédente. À l'aide d'une modélisation linéaire généralisée, nous avons mesuré les tendances en pourcentages annuels de patientes ayant reçu des opioïdes dans les sept jours (taux d'opioïdes), avec des intervalles de confiance (IC) à 95 %, stratifiés par hôpital et par type d'opioïdes, ajustés en fonction de la durée de séjour et des autocorrélations entre des taux de chaque hôpital. RéSULTATS: Le taux de délivrance d'opioïdes est passé de 31 % (IC 95 %, 30 à 33) en 2004 à 16 % (IC 95 %, 15 à 17) en 2016, où il est resté jusqu'en 2019. Cinq hôpitaux ont montré des réductions importantes, passant de plus de 40 % à moins de 10 % en deux à trois ans, mais dans la plupart des hôpitaux, le taux de délivrance d'opioïdes a diminué lentement ­ 11 ont affiché une faible réduction et trois ont montré des augmentations. La délivrance de codéine a diminué de 4 % par année, à partir de 31 % en 2004-2008, tandis que la délivrance de tramadol et d'hydromorphone a augmenté. Après 2015, les taux étaient stables (hydromorphone, 8 %; tramadol, 6 %; codéine, 3 %; et oxycodone, 0,5 %). CONCLUSION: Suite à la mise en garde de Santé Canada en 2008 contre la consommation de codéine par les mères qui allaitent, la délivrance d'opioïdes post-césarienne a diminué de façon inconstante dans les hôpitaux de Colombie-Britannique. Les taux n'ont pas diminué davantage après que l'épidémie de surdose d'opioïdes a été déclarée urgence de santé publique en Colombie-Britannique en 2016. La présente étude met en évidence les possibilités d'amélioration de la qualité et de régulation des opioïdes en procédant à une surveillance via les bases de données administratives.

Development and pilot evaluation of an educational session to support sparing opioid prescriptions to opioid naïve patients in a Canadian primary care setting.

BACKGROUND: Prescribing rates of some analgesics decreased during the public health crisis. Yet, up to a quarter of opioid-naïve persons prescribed opioids for noncancer pain develop prescription opioid use disorder. We, therefore, sought to evaluate a pilot educational session to support primary care-based sparing of opioid analgesics for noncancer pain among opioid-naïve patients in British Columbia (BC). METHODS: Therapeutics Initiative in BC has launched an audit and feedback intervention. Individual prescribing portraits were mailed to opioid prescribers, followed by academic detailing webinars. The webinars' learning outcomes included defining the terms opioid naïve and opioid sparing, and educating attendees on the (lack of) evidence for opioid analgesics to treat noncancer pain. The primary outcome was change in knowledge measured by four multiple-choice questions at the outset and conclusion of the webinar. RESULTS: Two hundred participants attended four webinars; 124 (62%) responded to the knowledge questions. Community-based primary care professionals (80/65%) from mostly urban settings (77/62%) self-identified as family physicians (46/37%), residents (22/18%), nurse practitioners (24/19%), and others (32/26%). Twelve participants (10%) recalled receiving the individualized portraits. While the correct identification of opioid naïve definitions increased by 23%, the correct identification of opioid sparing declined by 7%. Knowledge of the gaps in high-quality evidence supporting opioid analgesics and risk tools increased by 26% and 35%, respectively. CONCLUSION: The educational session outlined in this pilot yielded mixed results but appeared acceptable to learners and may need further refinement to become a feasible way to train professionals to help tackle the current toxic drugs crisis.

Predicting postoperative surgical site infection with administrative data: a random forests algorithm.

BACKGROUND: Since primary data collection can be time-consuming and expensive, surgical site infections (SSIs) could ideally be monitored using routinely collected administrative data. We derived and internally validated efficient algorithms to identify SSIs within 30 days after surgery with health administrative data, using Machine Learning algorithms. METHODS: All patients enrolled in the National Surgical Quality Improvement Program from the Ottawa Hospital were linked to administrative datasets in Ontario, Canada. Machine Learning approaches, including a Random Forests algorithm and the high-performance logistic regression, were used to derive parsimonious models to predict SSI status. Finally, a risk score methodology was used to transform the final models into the risk score system. The SSI risk models were validated in the validation datasets. RESULTS: Of 14,351 patients, 795 (5.5%) had an SSI. First, separate predictive models were built for three distinct administrative datasets. The final model, including hospitalization diagnostic, physician diagnostic and procedure codes, demonstrated excellent discrimination (C statistics, 0.91, 95% CI, 0.90-0.92) and calibration (Hosmer-Lemeshow χ2 statistics, 4.531, p = 0.402). CONCLUSION: We demonstrated that health administrative data can be effectively used to identify SSIs. Machine learning algorithms have shown a high degree of accuracy in predicting postoperative SSIs and can integrate and utilize a large amount of administrative data. External validation of this model is required before it can be routinely used to identify SSIs.

The Use of Active Comparators in Self-Controlled Designs.

For self-controlled studies of medication-related effects, time-varying confounding by indication can occur if the indication varies over time. We describe how active comparators might mitigate such bias, using an empirical example. Approaches to using active comparators are described for case-crossover design, case-time-control design, self-controlled case-series, and sequence symmetry analyses. In the empirical example, we used Danish data from 1996-2018 to study the association between penicillin and venous thromboembolism (VTE), using roxithromycin, a macrolide antibiotic, as comparator. Upper respiratory infection is a transient risk factor for VTE, thus representing time-dependent confounding by indication. Odds ratios for case-crossover analysis were 3.35 (95% confidence interval: 3.23, 3.49) for penicillin and 3.56 (95% confidence interval: 3.30, 3.83) for roxithromycin. We used a Wald-based method or an interaction term to estimate the odds ratio for penicillin with roxithromycin as comparator. These 2 estimates were 0.94 (95% confidence interval: 0.87, 1.03) and 1.03 (95% confidence interval: 0.95, 1.13). Results were similar for the case-time-control analysis, but both the self-controlled case-series and sequence symmetry analysis suggested a weak protective effect of penicillin, seemingly explained by VTE affecting future exposure exclusively for penicillin. The strong association of antibiotics with VTE suggests presence of confounding by indication. Such confounding can be mitigated by using an active comparator.

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.

Comparative Safety of Smoking Cessation Pharmacotherapies During a Government-Sponsored Reimbursement Program.

INTRODUCTION: The British Columbia Ministry of Health launched a Smoking Cessation Program on September 30, 2011, providing financial coverage for smoking cessation pharmacotherapies. Although pharmacotherapies have been shown to have a moderate short-term benefit as a quitting aid, substantial cardiovascular and neuropsychiatric safety concerns have been identified in adverse-reporting databases, leading to prescription label warnings by Health Canada and the U.S. Food and Drug Administration. However, recent studies indicate these warnings may be without merit. This study examined the comparative safety of medications commonly used to aid smoking cessation. AIMS AND METHODS: Population-based retrospective cohort study using B.C. administrative data to assess the relative safety between varenicline, bupropion, and nicotine replacement therapies (NRTs). The primary outcome was a composite of cardiovascular hospitalizations. Secondary outcomes included mortality, a composite of neuropsychiatric hospitalizations, and individual components of the primary outcome. Statistical analysis used propensity score-adjusted log-binomial regression models. A sensitivity analysis excluded patients with a history of cardiovascular disease. RESULTS: The study included 116 442 participants. Compared with NRT, varenicline was associated with a 10% 1-year relative risk decrease of cardiovascular hospitalization (adjusted risk ratio [RR] = 0.90, 95% confidence interval (CI): 0.82 to 1.00), a 20% 1-year relative risk decrease of neuropsychiatric hospitalization (RR: 0.80, CI: 0.7 to 0.89), and a 19% 1-year relative risk decrease of mortality (RR: 0.81, CI: 0.71 to 0.93). We found no significant association between NRT and bupropion for cardiovascular hospitalizations, neuropsychiatric hospitalizations, or mortality. CONCLUSIONS: Compared with NRT, varenicline is associated with fewer serious adverse events and bupropion the same number of serious adverse events. IMPLICATIONS: This study addresses the need for comparative safety evidence in a real-world setting of varenicline and bupropion against an active comparator. Compared with NRT, varenicline was associated with a decreased risk of mortality, serious cardiovascular events, and neuropsychiatric events during the treatment, or shortly after the treatment, in the general population of adults seeking pharmacotherapy to aid smoking cessation. These results provide support for the removal of the varenicline boxed warning for neuropsychiatric events and add substantively to the cardiovascular safety findings of previous observational studies and randomized clinical trials.

Long-term Health Outcomes and Health System Costs Associated With Surgical Site Infections: A Retrospective Cohort Study.

OBJECTIVES: To examine the association between surgical site infections (SSIs) and hospital readmissions and all-cause mortality, and to estimate the attributable health care costs of SSIs 1 year following surgery. BACKGROUND: SSIs are a common postoperative complication; the long-term impact of SSI on health outcomes and costs has not been formally evaluated. METHODS: This retrospective cohort study included all adult patients who underwent surgery at the 1202-bed teaching hospital in Ottawa, Ontario, Canada, and were included in the National Surgical Quality Improvement Program database between 2010 and 2015. The study exposure was postoperative SSI. The study outcomes included hospital readmission, all-cause mortality, and health care costs at 1 year (primary) and at 30 days and 90 days (secondary) following surgery. RESULTS: We identified 14,351 patients, including 795 patients with SSIs. Our multivariable analyses that accounted for competing risks demonstrated that at 1-year following the index date, superficial and deep/organ space SSIs were significantly associated with an increase in hospital readmission [hazard ratio (HR) = 1.63, 95% confidence interval (95% CI) 1.39-1.92 and HR = 3.49, (95% CI 2.76-4.17, respectively) and all-cause mortality (HR = 1.35, 95% CI 1.10-1.98 and HR = 2.21, 95% CI 1.44-2.78, respectively]. At 1 year after surgery, patients with superficial and deep/organ space SSIs incurred higher health care costs C$20,648 (95% CI) C$16,980- C$24,112and C$53,075 (95% CI) C$44,628- C$60,936), than non-SSI patients. CONCLUSION: SSIs, especially deep/organ space SSI, contribute to adverse health outcomes and health care costs across the entire year after surgery. Our findings highlight the importance of effective prevention/monitoring strategies targeting both short- and long-term consequences of SSI.

Do proton pump inhibitors increase mortality? A systematic review and in-depth analysis of the evidence.

Proton pump inhibitors (PPIs) were primarily approved for short-term use (2 to 8 weeks). However, PPI use continues to expand. Widely believed to be safe, we reviewed emerging evidence on increased mortality with PPI long-term use. Our 2016 systematic PPI drug class review found that mortality was not reported as an outcome in randomized controlled trials (RCTs) that directly compared different PPIs. We sought more recent and comprehensive data on PPI harm outcomes from research syntheses as a follow-on. A search was conducted from January 2014 to January 2020. We searched MEDLINE, EMBASE, and Cochrane Central for evidence from systematic reviews (SRs) and primary studies reporting all-cause mortality in adults treated with a PPI for any indication (duration >12 weeks) compared to patients without PPI treatment (no use, placebo, or H2RA use). Two independent investigators assessed study eligibility, synthesized evidence, and assessed the quality of the included studies. Data on all-cause mortality were sought, analyzed, critically examined, and interpreted herein. From 1304 articles, one SR was identified that reported on all-cause mortality. The SRs pooled three observational studies with data to 1 year: odds ratio, 95% confidence interval (CI) 1.53-1.84. A RCT, the COMPASS (Cardiovascular Outcomes for People Using Anticoagulant Strategies) RCT with data to 3 years: hazard ratio (HR) 1.03, 95% CI 0.92-1.15. The US Veterans Affairs cohort study using a large national dataset with data to 10 years found a HR of 1.17, 95% CI (1.10-1.24) and (NNH) of 22. The most common causes of death were from cardiovascular and chronic kidney diseases, with an excess death of 15 and 4 per 1000 patients, respectively, over the 10-year period. Harms arising from real-world medication use are best evaluated using a pharmacovigilance "convergence of proof" approach using data from a variety of sources and various study designs. Given that most PPI indications for use recommended a treatment duration of less than 12 weeks, it seems clear that PPIs were significantly overused in older patients. The median exposure time to PPI ranged from 1 to 4.6 years. Signals of serious harms including increased mortality with long-term PPI use are reported in observational studies. The COMPASS trial findings are not inconsistent with contemporaneous findings from observational studies. The COMPASS RCT was unlikely to detect an increase in mortality given the trial was not powered to detect this outcome. The potential increase in mortality in older patients associated with prolonged PPI exposure needs to be conveyed to health professionals. Clinicians and patients may be able to reverse the relentless expansion of long-term PPI exposure by reviewing indications and considering potential harms as well as benefits.

Comparative effectiveness of buprenorphine-naloxone versus methadone for treatment of opioid use disorder: a population-based observational study protocol in British Columbia, Canada.

INTRODUCTION: Despite a recent meta-analysis including 31 randomised controlled trials comparing methadone and buprenorphine for the treatment of opioid use disorder, important knowledge gaps remain regarding the long-term effectiveness of different treatment modalities across individuals, including rigorously collected data on retention rates and other treatment outcomes. Evidence from real-world data represents a valuable opportunity to improve personalised treatment and patient-centred guidelines for vulnerable populations and inform strategies to reduce opioid-related mortality. Our objective is to determine the comparative effectiveness of methadone versus buprenorphine/naloxone, both overall and within key populations, in a setting where both medications are simultaneously available in office-based practices and specialised clinics. METHODS AND ANALYSIS: We propose a retrospective cohort study of all adults living in British Columbia receiving opioid agonist treatment (OAT) with methadone or buprenorphine/naloxone between 1 January 2008 and 30 September 2018. The study will draw on seven linked population-level administrative databases. The primary outcomes include retention in OAT and all-cause mortality. We will determine the effectiveness of buprenorphine/naloxone vs methadone using intention-to-treat and per-protocol analyses-the former emulating flexible-dose trials and the latter focusing on the comparison of the two medication regimens offered at the optimal dose. Sensitivity analyses will be used to assess the robustness of results to heterogeneity in the patient population and threats to internal validity. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been approved and classified as a quality improvement initiative exempt from ethical review (Providence Health Care Research Institute and the Simon Fraser University Office of Research Ethics). Dissemination is planned via conferences and publications, and through direct engagement and collaboration with entities that issue clinical guidelines, such as professional medical societies and public health organisations.

Bias in case-crossover studies of medications due to persistent use: A simulation study.

PURPOSE: The case-crossover design is increasingly used to evaluate the effects of chronic medications; however, as traditionally implemented in pharmacoepidemiology, with referent period preceding the outcome, it may lead to bias in the presence of persistent exposures. We aimed to evaluate the extent and magnitude of bias in case-crossover analyses of chronic and persistent exposures, using simulations. METHODS: We simulated cohorts with either 30-day, 180-day, or 2-year exposure duration; and with varying degrees of persistence (10%, 30%, 50%, 70%, or 90% of patients not stopping exposure). We evaluated all scenarios under the null and the scenario with 30% persistence under varying exposure effects (odds ratios of 0.25 to 4.0). Cohorts were analyzed using conditional logistic regression that compared the odds of exposure on the outcome day to the odds of exposure on a referent day 30 days prior to the outcome. We further implemented the case-time-control design to evaluate its ability to adjust for bias from persistence. RESULTS: Case-crossover analyses produced unbiased estimates across all scenarios without persistent users, regardless of exposure duration. In scenarios where some patients persisted on treatment, case-crossover analyses resulted in upward bias, which increased with increasing proportion of persistent users, but did not vary substantially in relation to the magnitude of the true effect. Case-time-control analyses removed bias in all scenarios. CONCLUSIONS: Investigators should be aware of bias due to treatment persistence in unidirectional case-crossover analyses of chronic medications, which can be remedied with a control group of similarly persistent noncases.