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.

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.

"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.

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.

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.

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.

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.

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.

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.

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.

Identifying sequential episodes of pharmacotherapy as a method for assessing treatment failure in comparative effectiveness research.

PURPOSE: To describe and implement a novel method of measuring comparative effectiveness using sequential episodes of pharmacotherapy as a proxy for treatment failure. METHODS: Retrospective cohort study using linked deidentified data from the British Columbia Ministry of Health during a government-sponsored smoking cessation reimbursement program.Three study cohorts were created based on first use of varenicline, bupropion, or nicotine replacement therapy (NRT), for adults aged 18 or older, in the period September 30th, 2011 to March 31st, 2013. The study cohorts were analyzed for sequential episodes of pharmacotherapy, defined as re-initiating a smoking cessation pharmacotherapy after an initial episode of treatment and washout period. The statistical analysis used propensity score adjusted log-binomial regression models with one-year and two-year fixed follow-up after a 12-week washout period. A sensitivity analysis excluded the washout period. A secondary analysis investigated predictors of receiving a sequential episode of smoking cessation pharmacotherapy RESULTS: 116,442 participants of the B.C. Smoking Cessation Program were analyzed. Compared to NRT, varenicline users were 13% less likely, and bupropion users were 18% less likely, to re-start smoking cessation therapy within 1-year after an initial course of treatment. CONCLUSIONS: Sequential episodes of pharmacotherapy identified treatment failures to smoking cessation therapy. Based on sequential episodes of pharmacotherapy during a drug benefit policy of smoking cessation medications, varenicline and bupropion were more effective aids to smoking cessation than NRT. The method was also used to identify patient characteristics associated with treatment effectiveness.

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.

Physical Exertion Immediately Prior to Placental Abruption: A Case-Crossover Study.

While there is consistent evidence that episodes of physical exertion are associated with an immediately higher risk of acute ischemic vascular events, the risk of placental abruption immediately following episodes of physical exertion has not been studied. In a multicenter case-crossover study, we interviewed 663 women with placental abruption at 7 Peruvian hospitals between January 2013 and August 2015. We asked women about physical exertion in the hour before symptom onset and compared this with their frequency of physical exertion over the prior week. Compared with times with light or no exertion, the risk of placental abruption was 7.8 (95% confidence interval (CI): 5.5, 11.0) times greater in the hour following moderate or heavy physical exertion. The instantaneous incidence rate ratio of placental abruption within an hour of moderate or heavy physical exertion was lower for women who habitually engaged in moderate or heavy physical activity more than 3 times per week in the year before pregnancy (rate ratio (RR) = 3.0, 95% CI: 1.6, 5.9) compared with more sedentary women (RR = 17.3, 95% CI: 11.3, 26.7; P for homogeneity < 0.001), and the rate ratio was higher among women with preeclampsia/eclampsia (RR = 13.6, 95% CI: 7.0, 26.2) than among women without (RR = 6.7, 95% CI: 4.4, 10.0; P for homogeneity = 0.07).

Risk of myocardial infarction immediately after alcohol consumption.

BACKGROUND: Habitual moderate alcohol consumption is associated with a lower risk of acute myocardial infarction (MI), whereas heavy (binge) drinking is associated with higher cardiovascular risk. However, less is known about the immediate effects of alcohol consumption on the risk of acute MI and whether any association differs by beverage type or usual drinking patterns. METHODS: We conducted a case-crossover analysis of 3869 participants from the Determinants of Myocardial Infarction Onset Study who were interviewed during hospitalization for acute MI in one of the 64 medical centers across the United States in 1989-1996. We compared the observed number of times that each participant consumed wine, beer, or liquor in the hour preceding MI symptom onset with the expected frequency based on each participant's control information, defined as the number of times the participant consumed alcohol in the past year. RESULTS: Among 3869 participants, 2119 (55%) reported alcohol consumption in the past year, including 76 within 1 hour before acute MI onset. The incidence rate of acute MI onset was elevated 1.72-fold (95% confidence interval [CI] = 1.37-2.16) within 1 hour after alcohol consumption. The association was stronger for liquor than for beer or wine. The higher rate was not apparent for daily drinkers. For the 24 hours after consumption, there was a 14% lower rate (relative risk = 0.86 [95% CI = 0.79-0.95]) of MI compared with periods with no alcohol consumption. CONCLUSIONS: Alcohol consumption is associated with an acutely higher risk of MI in the subsequent hour among people who do not typically drink alcohol daily.

DECISION-MAKING ALIGNED WITH RAPID-CYCLE EVALUATION IN HEALTH CARE.

BACKGROUND: Availability of real-time electronic healthcare data provides new opportunities for rapid-cycle evaluation (RCE) of health technologies, including healthcare delivery and payment programs. We aim to align decision-making processes with stages of RCE to optimize the usefulness and impact of rapid results. Rational decisions about program adoption depend on program effect size in relation to externalities, including implementation cost, sustainability, and likelihood of broad adoption. METHODS: Drawing on case studies and experience from drug safety monitoring, we examine how decision makers have used scientific evidence on complex interventions in the past. We clarify how RCE alters the nature of policy decisions; develop the RAPID framework for synchronizing decision-maker activities with stages of RCE; and provide guidelines on evidence thresholds for incremental decision-making. RESULTS: In contrast to traditional evaluations, RCE provides early evidence on effectiveness and facilitates a stepped approach to decision making in expectation of future regularly updated evidence. RCE allows for identification of trends in adjusted effect size. It supports adapting a program in midstream in response to interim findings, or adapting the evaluation strategy to identify true improvements earlier. The 5-step RAPID approach that utilizes the cumulating evidence of program effectiveness over time could increase policy-makers' confidence in expediting decisions. CONCLUSIONS: RCE enables a step-wise approach to HTA decision-making, based on gradually emerging evidence, reducing delays in decision-making processes after traditional one-time evaluations.

"First-wave" bias when conducting active safety monitoring of newly marketed medications with outcome-indexed self-controlled designs.

Large health care databases are used extensively for pharmacoepidemiologic studies. Unique methodological issues arise when applying self-controlled designs (i.e., using within-person comparisons) for active surveillance of newly marketed drugs. We use 3 examples to illustrate bias related to population-level exposure time trends when using outcome-indexed self-controlled (i.e., case-crossover) designs for active surveillance and evaluate the ability of the case-time-control design to adjust for bias from population-level exposure time trends. We mimicked active surveillance by conducting sequential analyses after market entry for 3 medications and outcomes (valdecoxib for myocardial infarction (MI), aripiprazole for MI, and telithromycin for acute liver failure) using Medicaid Analytic eXtracts (from all 50 US states, 2000-2006). The case-crossover exposure odds ratio (EOR) in the months immediately following valdecoxib market entry implausibly suggested a 12-fold higher risk of MI during exposed time relative to unexposed time; among age-, sex-, and time-matched controls, the corresponding EOR of 4.5 indicated strong population-level exposure time trends. Over subsequent monitoring periods, case-crossover EORs rapidly dropped to 1.4. Adjustment for bias from population-level exposure time trends with the case-time-control analysis resulted in more consistent associations between valdecoxib and MI across sequential monitoring periods. Similar results were observed in each example. Strong population-level exposure time trends can bias case-crossover studies conducted among "first-wave" users of newly marketed medications. Suggested strategies can help assess and adjust for population-level exposure time trends.

Risk of acute myocardial infarction after the death of a significant person in one's life: the Determinants of Myocardial Infarction Onset Study.

BACKGROUND: Acute psychological stress is associated with an abrupt increase in the risk of cardiovascular events. Intense grief in the days after the death of a significant person may trigger the onset of acute myocardial infarction (MI), but this relationship has not been systematically studied. METHODS AND RESULTS: We conducted a case-crossover analysis of 1985 participants from the multicenter Determinants of Myocardial Infarction Onset Study interviewed during index hospitalization for an acute MI between 1989 and 1994. We compared the observed number of deaths in the days preceding MI symptom onset with its expected frequency based on each patient's control information, defined as the occurrence of deaths in the period from 1 to 6 months before infarction. Among the 1985 subjects, 270 (13.6%) experienced the loss of a significant person in the prior 6 months, including 19 within 1 day of their MI. The incidence rate of acute MI onset was elevated 21.1-fold (95% confidence interval, 13.1-34.1) within 24 hours of the death of a significant person and declined steadily on each subsequent day. The absolute risk of MI within 1 week of the death of a significant person is 1 excess MI per 1394 exposed individuals at low (5%) 10-year MI risk and 1 per 320 among individuals at high (20%) 10-year risk. CONCLUSIONS: Grief over the death of a significant person was associated with an acutely increased risk of MI in the subsequent days. The impact may be greatest among individuals at high cardiovascular risk.

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.