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Background Several Canadian provinces have introduced reimbursement policies mandating substitution of innovator biologics with lower-cost biosimilars. We estimated the number of patients affected and cost implications if such policy changes were to be implemented in Ontario, Canada. Methods We conducted a cross-sectional time series analysis of Ontarians dispensed publicly funded biologics indicated for inflammatory diseases (rheumatic conditions, inflammatory bowel disease: infliximab, etanercept, adalimumab) between January 2018 and December 2019, and forecasted trends to Dec. 31, 2020. The primary source of data was pharmacy claims data for all biologics reimbursed by the public drug program. We modelled the number of patients affected and government expenditures (in nominal Canadian dollars) of several biosimilar policy options, including mandatory nonmedical biosimilar substitution, substitution in new users, introduction of a biosimilar for adalimumab, and price negotiations. In a secondary analysis, we included insulin glargine. Results In 2018, 14 089 individuals were prescribed a publicly funded biologic for inflammatory diseases. A mandatory nonmedical biosimilar substitution would potentially have affected 7209 patients and saved $238.6 million from 2018 to 2020. A new-user substitution would have affected 757 patients and saved $34.2 million. If an adalimumab biosimilar were to become available, 12 928 patients would be affected by a mandatory nonmedical substitution and the 3-year savings would increase to $645.9 million (all biosimilars priced at 25% of innovator biologics). Finally, an expanded nonmedical substitution policy including insulin glargine would affect 115 895 patients and save $288.7 million (not including adalimumab). Interpretation Policies designed to curb rising costs of biologics can have substantially different effects on patients and government expenditures. Such analyses warrant careful consideration of the balance between cost savings and effects on patients.

Background Older Canadians frequently migrate to warmer destinations for the winter season (snowbirds). Our aim was to examine the prevalence of migration to warmer destinations among Ontarians, and to compare the characteristics and use of health care services of snowbirds to those of older Ontarians who did not migrate for the winter. Methods We conducted a population-based analysis using health administrative databases from Ontario. We compiled 10 seasonal cohorts (2009/10 to 2018/19) of adults aged 65 or more who filled a travel supply of medications under the Ontario Drug Benefits program (snowbirds) between September and January (snowbird season). We calculated the seasonal prevalence of snowbirds per 100 Ontarians aged 65 or more. We matched each snowbird in the 2018/19 season to 2 nonsnowbirds on age and sex, and compared their characteristics and patterns of use of government-funded health care services. Results Over the 10-year period, 53 431 to 70 863 Ontarians aged 65 or more were identified as snowbirds (seasonal prevalence 2.6%-3.3%). Compared to nonsnowbirds, snowbirds were more likely to be recent migrants, live in higher-income neighbourhoods, have fewer comorbidities and make more visits to primary care physicians. From January to March 2019, snowbirds accessed government-funded health care services for a median of 0 days (interquartile range [IQR] 0-1 d), compared to 4 days (IQR 2-8 d) among nonsnowbirds. Interpretation About 3% of older Ontarians migrate to warmer destinations for the winter each season. Since few access health care services in Ontario from January to March, researchers are encouraged to consider the snowbird population and the impact of their absence on evaluations that assume continuous observation.

Background Trends in off-label postpartum use of domperidone and the impact of safety advisories on its use remain unknown. Our objectives were to describe postpartum use of domperidone in Canada, to evaluate the impact of Health Canada advisories on prescribing patterns, and to describe the association between domperidone use and a composite end point of sudden cardiac death or ventricular tachycardia (VT) among postpartum patients. Methods We conducted a multidatabase cohort study involving pregnant patients with live births between 2004 and 2017 using administrative health databases from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba and Ontario). We excluded patients with less than 1 year of prepregnancy database history and with approved indications for domperidone. We assessed domperidone use in the 6 months postpartum and the impact of the 2012 and 2015 Health Canada advisories on prescribing via interrupted time series analysis. We estimated crude rates of VT and sudden cardiac death. Results We included 1 190 987 live births. Mean maternal age was 28.6 (standard error 0.6) years. Domperidone use increased over time, from 7% in 2003-2005 to 12% in 2009-2011, when it plateaued. The 2012 advisory was followed by a drop in use and a reduction in slope, and the 2015 advisory had a more modest impact. Crude analysis suggests that domperidone may be associated with increased VT or sudden cardiac death (0.74 v. 0.37 per 10 000 person-years; difference per 10 000 person-years: 0.37, 95% confidence interval -0.67 to 1.41). Interpretation Postpartum domperidone use increased between 2004 and 2017, with prescribing attenuated after Health Canada advisories and a very low absolute rate of VT or sudden cardiac death. These findings suggest that Health Canada advisories affected prescribing; any potential increase in VT or sudden cardiac death with use of domperidone is small and could not be confirmed in this large study STUDY REGISTRATION: ClinicalTrials.gov, no. NCT04024865.

Background Oral anticoagulants are commonly used high-risk medications, but little is known about their safety in transition from hospital to home. Our objective was to measure the rates of hemorrhage and thromboembolic events among older adults receiving oral anticoagulant treatment early after hospital discharge compared to later. Methods We conducted a retrospective population-based cohort study among Ontario residents aged 66 years or more who started, continued or resumed oral anticoagulant therapy at hospital discharge between September 2010 and March 2015. We calculated the rates of hemorrhage and thromboembolic events requiring hospital admission or an emergency department visit over a 1-year follow-up period, stratified by the first 30 days after discharge and the remainder of the year. We used multivariable regression models, adjusting for covariates, to estimate the effect of sex, prevalent versus incident use, and switching anticoagulants on events. Results A total of 123 139 patients (68 408 women [55.6%]; mean age 78.2 yr) were included. About one-quarter (32 563 [26.4%]) had a Charlson Comorbidity Index score of 2 or higher. The rates of hemorrhage and thromboembolic events per 100 person-years were highest during the first 30 days after hospital discharge (25.8, 95% CI 24.8-26.8 and 19.3, 95% CI 18.4-20.2, respectively), falling to 15.7 (95% CI 15.3-16.1) and 6.9 (95% CI 6.6-7.1), respectively, during the subsequent 11 months. Multivariable analysis showed that patients whose anticoagulant was switched in hospital and men had more hemorrhages and thromboembolic events in follow-up. Interpretation The first few weeks following hospital discharge represent a very high-risk period for adverse events related to oral anticoagulant treatment among older adults. The results support an intervention trial addressing anticoagulation management in the early postdischarge period.

Background Health interventions and policies for high-cost health care users (HCUs) who are older adults need to be informed by a better understanding of their multimorbidity and medication use. This study aims to determine the financial contribution of medications to HCU expenditures and explore whether potentially inappropriate prescribing is associated with incident HCU development. Methods This is a protocol for a retrospective population-based matched cohort analysis of incident older adult HCUs (those with the highest 5% of costs and 66 years of age or older) in Ontario during fiscal year 2013. We will obtain person-level data for the index year and year before HCU status from health administrative databases and match each HCU to 3 non-HCUs based on age, sex and geographic location. Average annual medication costs (per patient) and the ratio of medication to total health care costs (at population level) will be examined over the HCU transition period and compared with non-HCUs. We will explore potential quality improvement areas for prescribing by analyzing chronic conditions and the use of medications with a strong evidence base for either clinical benefit or risk of harms outweighing benefits in older adults with these diagnoses. The relation between these medication classes and incident HCU status will be explored using logistic regression. Interpretation Using a matched cohort design and focusing on incident rather than prevalent HCUs, this protocol will explore our hypotheses that medications and the quality of their prescribing may be important triggers of HCU status and facilitate the identification of potential preventive clinical interventions or policies. Dissemination of results will occur via publications in peer-reviewed journals, presentations at conferences and academic settings, and knowledge translation activities with relevant health system and patient stakeholder groups. Study registration Clinicaltrials.gov, no. NCT02815930.

BACKGROUND: In pandemics, local hospitals need to anticipate a surge in health care needs. We examined the modelled surge because of the coronavirus disease 2019 (COVID-19) pandemic that was used to inform the early hospital-level response against cases as they transpired. METHODS: To estimate hospital-level surge in March and April 2020, we simulated a range of scenarios of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread in the Greater Toronto Area (GTA), Canada, using the best available data at the time. We applied outputs to hospital-specific data to estimate surge over 6 weeks at 2 hospitals (St. Michael’s Hospital and St. Joseph’s Health Centre). We examined multiple scenarios, wherein the default (R(0) = 2.4) resembled the early trajectory (to Mar. 25, 2020), and compared the default model projections with observed COVID-19 admissions in each hospital from Mar. 25 to May 6, 2020. RESULTS: For the hospitals to remain below non-ICU bed capacity, the default pessimistic scenario required a reduction in non-COVID-19 inpatient care by 38% and 28%, respectively, with St. Michael’s Hospital requiring 40 new ICU beds and St. Joseph’s Health Centre reducing its ICU beds for non-COVID-19 care by 6%. The absolute difference between default-projected and observed census of inpatients with COVID-19 at each hospital was less than 20 from Mar. 25 to Apr. 11; projected and observed cases diverged widely thereafter. Uncertainty in local epidemiological features was more influential than uncertainty in clinical severity. INTERPRETATION: Scenario-based analyses were reliable in estimating short-term cases, but would require frequent re-analyses. Distribution of the city’s surge was expected to vary across hospitals, and community-level strategies were key to mitigating each hospital’s surge.

Background Unplanned visits to the emergency department after total joint arthroplasty are far more common than unplanned readmissions. Our objectives were to characterize the prevalence of presentation to an emergency department for any reason after total joint arthroplasty and to identify risk factors for such visits. Methods Using health administrative databases, we conducted a population-based retrospective cohort study of adults (19-89 yr of age) who received their first primary elective total hip arthroplasty (THA) or total knee arthroplasty (TKA) procedure for arthritis between April 2011 and March 2016 in Ontario. We made univariate comparisons between patients who presented to the emergency department within 30 days of surgery and those who did not in. We determined differences in use of health care services between groups by comparing the change in use in the year before and after surgery between patients who presented to the emergency department and those who did not. We developed logistic regression models for the occurrence of an emergency department visit using backward variable elimination. Results We identified 42 273 total hip recipients and 70 725 total knee recipients, of whom 5640 (13.3%) and 11 224 (15.9%), respectively, presented to the emergency department within 30 days of surgery. Fewer than 1% of these patients required admission, and nearly half (45%) went to a different institution from where they had their surgery. Among both THA and TKA recipients, patients who presented to the emergency department had a net increase in their median annual health care costs (THA: $501, TKA: $682), compared to a net decrease for the cohort as a whole. Factors associated with increased risk of an emergency visit included increased patient age, male sex, rural residence and various comorbidities. Predictive regression models showed poor discriminative ability for both THA (C-statistic 0.57) and TKA (C-statistic 0.58) recipients. Interpretation One in 7 patients presented to the emergency department within 30 days of THA or TKA. Some may conceivably have been managed remotely, and very few required readmission. There is a crucial need for strategies to minimize these events.

Background Direct oral anticoagulants (DOACs) have widely replaced warfarin for stroke prevention in nonvalvular atrial fibrillation. Our objective was to compare the safety and effectiveness of DOACs (dabigatran, rivaroxaban, apixaban) versus warfarin for stroke prevention in nonvalvular atrial fibrillation in the Canadian setting. Methods We conducted a population-based observational multicentre cohort study with propensity score matching and subsequent meta-analysis. We used health care databases from 7 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec and Nova Scotia). Patients with nonvalvular atrial fibrillation who initiated anticoagulation therapy in 2009-2017 were matched to an equal number who initiated warfarin. The primary outcome was the pooled hazard ratio (HR) for ischemic stroke or systemic embolization. Secondary outcomes included pooled HRs for major bleeding; a composite outcome of stroke, systemic embolization, major bleeding and all-cause mortality; and myocardial infarction. We modelled HRs using proportional hazard Cox regression with inverse probability of censoring weights, and estimated pooled HRs with random-effect meta-analyses. Results We included 128 273 patients who initiated anticoagulation with a DOAC (40 503 dabigatran, 49 498 rivaroxaban and 38 272 apixaban) and 128 273 patients who initiated anticoagulation with warfarin. The pooled HR for ischemic stroke or systemic embolization comparing DOACs to warfarin was 1.02 (95% confidence interval [CI] 0.87 to 1.19). Direct oral anticoagulants were associated with lower rates of major bleeding (pooled HR 0.81, 95% CI 0.69 to 0.97), the composite outcome (pooled HR 0.81, 95% CI 0.74 to 0.89) and all-cause mortality (pooled HR 0.81, 95% CI 0.78 to 0.85). Interpretation In this real-world study, DOACs were associated with similar risks of ischemic stroke or systemic embolization, and lower risks of bleeding and total mortality compared to warfarin. These findings support the use of DOACs for anticoagulation in nonvalvular atrial fibrillation. Trial registration ClinicalTrials.gov, no. NCT03596502.

Background Most health care spending is concentrated within a small group of high-cost health care users. To inform health policies, we examined the characteristics of index hospital admissions and their predictors among incident older high-cost users compared to older non-high-cost users in Ontario. Methods Using Ontario administrative data, we identified incident high-cost users aged 66 years or more and matched them 1:3 on age, gender and Local Health Integration Network with non-high-cost users aged 66 years or more. We defined high-cost users as patients within the top 5% most costly high-cost users during fiscal year 2013/14 but not during 2012/13. An index hospital admission, the main outcome, was defined as the first unplanned hospital admission during 2013/14, with no hospital admissions in the preceding 12 months. Descriptively, we analyzed the attributes of index hospital admissions, including costs. We identified predictors of index hospital admissions using stratified logistic regression. Results Over half (95 375/175 847 [54.2%]) of all high-cost users had an unplanned index hospital admission, compared to 8838/527 541 (1.7%) of non-high-cost users. High-cost users had a poorer health status, longer acute length of stay (mean 7.5 d v. 2.9 d) and more frequent designation as alternate level of care before discharge (20.8% v. 1.7%) than did non-high-cost users. Ten diagnosis codes accounted for roughly one-third of the index hospital admission costs in both cohorts. Although many predictors were similar between the cohorts, a lower risk of an index hospital admission was associated with residence in long-term care, attachment to a primary care provider and recent consultation by a geriatrician among high-cost users. Interpretation The high prevalence of index hospital admissions and the corresponding costs are a distinctive feature of incident older high-cost users. Improved access to specialist outpatient care, home-based social care and long-term care when required are worth further investigation.

BACKGROUND: Since 2010, tamper-resistant long-acting oxycodone has been available in both the United States and Canada; however, generic non-tamper-resistant brands of the drug have only been introduced in Canada. We aimed to determine whether the introduction of generic non-tamper-resistant oxycodone in Canada led to increased sales from Canadian pharmacies near the Canada-US border. METHODS: We conducted a retrospective analysis of trends in dispensing of long-acting oxycodone from Canadian community pharmacies in geographic areas contiguous with the Canada-US border between Feb. 1, 2012, and Jan. 31, 2014. We reported the monthly dispensing rates of long-acting oxycodone by province and within each region near the Canada-US border. RESULTS: During the study period, 8 507 882 long-acting oxycodone tablets were dispensed by Canadian pharmacies in regions near Canada-US border crossings. After the introduction of generic non-tamper-resistant formulations in December 2012, the dispensing rate declined in the border regions of Ontario, British Columbia and Quebec, and rose slightly in Manitoba (4.4%) and New Brunswick (3.6%). Dispensing rates rose by 45.5% in Alberta and 92.3% in Saskatchewan; however, only 3341 of the tablets dispensed were a generic non-tamper-resistant formulation. An examination of the dispensing patterns in 50 border areas after the marketing of non-tamper-resistant brands in Canada showed no patterns suggestive of trafficking. INTERPRETATION: We found no large increases in the dispensing rates of generic non-tamper-resistant long-acting oxycodone in Canadian pharmacies near Canada-US border crossings such as were seen after the withdrawal of OxyContin in the United States in 2010. Despite our findings, Canadian clinicians and pharmacists should remain cautious in their prescribing and dispensing of non-tamper-resistant formulations of oxycodone because of their high potential for misuse and abuse.

Background In February 2012, a reformulated tamper-deterrent form of long-acting oxycodone, OxyNeo, was introduced in Canada. We investigated the impact of the introduction of OxyNeo on patterns of opioid prescribing. Methods We conducted population-based, cross-sectional analyses of opioid dispensing in Canada between 2008 and 2016. We estimated monthly community pharmacy dispensing of oral formulations of codeine, morphine, hydromorphone and oxycodone, and a transdermal formulation of fentanyl, and converted quantities to milligrams of morphine equivalents (MMEs) per 1000 population. We used time series analysis to evaluate the effect of the introduction of OxyNeo on these trends. Results National dispensing of long-acting opioids fell by 14.9% between February 2012 and April 2016, from 36 098 MMEs to 30 716 MMEs per 1000 population (p 0.05 in all provinces). Interpretation The findings suggest that the introduction of a tamper-deterrent formulation of long-acting oxycodone in Canada, against a background of changing public drug benefits, was associated with sustained changes in selection of long-acting opioids but only small changes in the quantity of long-acting opioids dispensed. This illustrates the limited effect a tamper-deterrent formulation and associated coverage policy can have when other, non-tamper-deterrent alternatives are readily available.

Background Recently, several new atypical antipsychotic agents have been introduced in Ontario, and regulatory warnings have been issued regarding use of atypical antipsychotics in older adults. We sought to establish the impact of newer atypical antipsychotics on prescribing rates and costs. Methods We performed a population-based cross-sectional study of Ontario adults aged 65 years or more using atypical antipsychotics from Jan. 1, 2007, to Mar. 31, 2013. These people have universal access to publicly funded drugs through the Ontario Health Insurance Plan and the Ontario Drug Benefit. We conducted time-series analysis to assess the impact of the introduction of new atypical antipsychotics on rates of use of atypical antipsychotics and associated expenditures. Results Rates of atypical antipsychotic use increased following the introduction of new agents in 2009, from 27.6 users per 1000 older adults in the third quarter of 2009 to 29.1 users per 1000 older adults at the end of the study period (p = 0.04). Although prescribing rates for the newer atypical agents (paliperidone, ziprasidone and aripiprazole) remained low relative to their older counterparts (risperidone, olanzapine and quetiapine), rates of aripiprazole use rose to 1.0 user per 1000 older adults by the end of the study period. The proportion of prescriptions that were for brand-name agents fell from 57.5% in the second quarter of 2007 to 6.1% in the second quarter of 2009, and then rose to 11.7% by the end of the study period. By the first quarter of 2013, newer atypical antipsychotic agents were used by 4.4% of atypical antipsychotic users but accounted for 14.1% ($1.2 million of $8.5 million) of atypical antipsychotic expenditures. Interpretation Although the overall prevalence of use of new atypical antipsychotic agents remains low, their introduction has led to increased prescribing of this class of drugs in older adults. Given the potential cost implications, further study of these trends would be prudent.

Background The Wait Time Alliance recently established wait time benchmarks for rheumatology consultations in Canada. Our aim was to quantify wait times to primary and rheumatology care for patients with rheumatic diseases. Methods We identified patients from primary care practices in the Electronic Medical Record Administrative data Linked Database who had referrals to Ontario rheumatologists over the period 2000-2013. To assess the full care pathway, we identified dates of symptom onset, presentation in primary care and referral from electronic medical records. Dates of rheumatologist consultations were obtained by linking with physician service claims. We determined the duration of each phase of the care pathway (symptom onset to primary care encounter, primary care encounter to referral, and referral to rheumatologist consultation) and compared them with established benchmarks. Results Among 2430 referrals from 168 family physicians, 2015 patients (82.9%) were seen by 146 rheumatologists within 1 year of referral. Of the 2430 referrals, 2417 (99.5%) occurred between 2005 and 2013. The main reasons for referral were osteoarthritis (32.4%) and systemic inflammatory rheumatic diseases (30.6%). Wait times varied by diagnosis and geographic region. Overall, the median wait time from referral to rheumatologist consultation was 74 (interquartile range 27-101) days; it was 66 (interquartile range 18-84) days for systemic inflammatory rheumatic diseases. Wait time benchmarks were not achieved, even for the most urgent types of referral. For systemic inflammatory rheumatic diseases, most of the delays occurred before referral. Interpretation Rheumatology wait times exceeded established benchmarks. Targeted efforts are needed to promote more timely access to both primary and rheumatology care. Routine linkage of electronic medical records with administrative data may help fill important gaps in knowledge about waits to primary and specialty care.

BACKGROUND In early 2009, 2 observational studies and a US Food and Drug Administration (FDA) advisory addressed the drug interaction between proton pump inhibitors (PPIs) and clopidogrel. One study suggested that pantoprazole could be used safely in this setting, whereas the other study and the FDA advisory did not distinguish among PPIs. We examined trends in PPI prescribing among clopidogrel recipients in the period following these events. METHODS We conducted a population-based time series analysis of Ontario residents aged 66 years or older for whom clopidogrel was prescribed between Apr. 1, 1999, and Sept. 30, 2013. We determined the proportion of clopidogrel recipients dispensed a PPI during each quarter and the proportions who received pantoprazole or other PPIs. The outcome of interest was change in the use of pantoprazole. RESULTS In the final quarter of 2008, pantoprazole represented 23.7% of all PPI prescriptions dispensed to patients receiving clopidogrel. Following the publications and FDA advisory in early 2009, pantoprazole use increased substantially. By the end of 2009, this medication accounted for 52.5% of all PPI prescriptions issued to patients receiving clopidogrel; by the end of the study period, it accounted for 71.0% of all PPI prescriptions dispensed to such patients (p < 0. 001). We also observed a modest drop in overall PPI use among clopidogrel recipients beginning in early 2009. INTERPRETATION In 2009, the prescribing of PPIs with clopidogrel changed substantially in Ontario, with pantoprazole rapidly becoming the most commonly prescribed agent in its class. However, a modest decline in overall PPI use also occurred that may reflect suboptimal translation of emerging drug safety information to clinical practice.

BACKGROUND Orally administered bisphosphonate drugs (i.e., alendronate, etidronate, risedronate) can reduce the risk of vertebral fracture. However, only alendronate and risedronate have proven efficacy in reducing the risk of hip fracture. We sought to examine the comparative effectiveness of orally administered bisphosphonate drugs in reducing hip fractures among older adults. METHODS We identified new users of orally administered bisphosphonate drugs in British Columbia and Ontario between 2001 and 2008. We used province- and sex-specific propensity score-matching strategies to maximize comparability between exposure groups. We used Cox proportional hazards models to compare time-to-hip fracture within 1 year of treatment between exposures by sex in each province. Our secondary analyses considered hip fracture rates within 2 and 3 years' follow-up. We used alendronate as the reference for all comparisons and pooled provincial estimates using random effects variance-weighted meta-analysis. RESULTS We identified 321 755 patients who were eligible for inclusion in the study. We found little difference in fracture rates between men (pooled hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74-1.14) or women (pooled HR 1.15, 95% CI 0.73-1.56) taking risedronate and those taking alendronate. We similarly identified little difference in fracture rates between women taking etidronate and those taking alendronate (pooled HR 1.00, 95% CI 0.82-1.18). However, we identified lower rates of hip fracture among men taking etidronate relative to alendronate (pooled HR 0.77, 95% CI 0.60-0.94). Results extended to 2 and 3 years' follow-up were similar. However, with 3 years' follow-up, rates of hip fracture were lower among women in British Columbia who had taken alendronate. INTERPRETATION We identified little overall difference between alendronate and risedronate in reducing the risk of hip fracture in men or women. Our finding that etidronate is associated with lower fracture risk among men is likely due to selection bias. The long-term comparative effects of orally administered bisphosphonate drugs warrant further study.