Hydrochlorothiazide use and risk of keratinocyte carcinoma and melanoma: A multisite population-based cohort study.

BACKGROUND: The association between hydrochlorothiazide (HCTZ) and skin cancer remains controversial. OBJECTIVE: To determine whether HCTZ is associated with an increased risk of skin cancer compared with angiotensin-converting enzyme inhibitors and calcium channel blockers. METHODS: Two new-user, active comparator cohorts were assembled using 6 Canadian databases. Site-specific hazard ratios (HRs) with 95% CIs were estimated using standardized morbidity ratio weighted Cox proportional hazard models and pooled using random-effects meta-analysis. RESULTS: HCTZ was not associated with an overall increased risk of keratinocyte carcinoma compared with angiotensin-converting enzyme inhibitors or calcium channel blockers, although increased risks were observed with longer durations (≥10 years; HR: 1.12; 95% CI: 1.03-1.21) and higher cumulative doses (≥100,000 mg; HR: 1.49; 95% CI: 1.27-1.76). For melanoma, there was no association with angiotensin-converting enzyme inhibitors, but a 32% increased risk with calcium channel blockers (crude incidence rates: 64.2 vs 58.4 per 100,000 person-years; HR: 1.32; 95% CI: 1.19-1.46; estimated number needed to harm at 5 years of follow-up: 1627 patients), with increased risks with longer durations and cumulative doses. LIMITATIONS: Residual confounding due to the observational design. CONCLUSIONS: Increased risks of keratinocyte carcinoma and melanoma were observed with longer durations of use and higher cumulative doses of HCTZ.

Effectiveness and safety among direct oral anticoagulants in nonvalvular atrial fibrillation: A multi-database cohort study with meta-analysis.

AIMS: There are conflicting signals in the literature about comparative safety and effectiveness of direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF). METHODS: We conducted multicentre matched cohort studies with secondary meta-analysis to assess safety and effectiveness of dabigatran, rivaroxaban and apixaban across 9 administrative healthcare databases. We included adults with NVAF initiating anticoagulation therapy (dabigatran, rivaroxaban or apixaban), and constructed 3 cohorts to compare DOACs pairwise. The primary outcome was pooled hazard ratio (pHR) of ischaemic stroke or systemic thromboembolism. Secondary outcomes included pHR of major bleeding, and a composite of stroke, major bleeding, or all-cause mortality. We used proportional hazard Cox regressions models, and pooled estimates were obtained with random effect meta-analyses. RESULTS: The cohorts included 73 414 new users of dabigatran, 92 881 of rivaroxaban, and 61 284 of apixaban. After matching, the pHRs (95% confidence intervals) comparing rivaroxaban initiation to dabigatran were: 1.11 (0.93, 1.32) for ischaemic stroke or systemic thromboembolism, 1.26 (1.09, 1.46) for major bleeding, and 1.17 (1.05, 1.30) for the composite endpoint. For apixaban vs dabigatran, they were: 0.91 (0.74, 1.12) for ischaemic stroke or systemic thromboembolism, 0.89 (0.75, 1.05) for major bleeding, and 0.94 (0.78 to 1.14) for the composite endpoint. For apixaban vs rivaroxaban, they were: 0.85 (0.74, 0.99) for ischaemic stroke or systemic thromboembolism, 0.61 (0.53, 0.70) for major bleeding, and 0.82 (0.76, 0.88) for the composite endpoint. CONCLUSION: We found that apixaban use is associated with lower risks of stroke and bleeding compared with rivaroxaban, and similar risks compared with dabigatran.

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.

A rapid monitoring plan following a shift in coverage from brand name to biosimilar drugs for rheumatoid arthritis in British Columbia.

PURPOSE: To describe a rapid monitoring plan to assess the impacts of a shift in drug coverage for biosimilar drugs in British Columbia following the introduction of a new policy on 27 May 2019. The Biosimilars Initiative requires users of originator infliximab or etanercept to switch to biosimilar versions of those drugs to maintain coverage. We propose a signal-detection method to provide near-real-time information to policymakers on the impacts of the policy change. METHODS: The exposure will be the Biosimilars Initiative, a policy affecting patients using originator infliximab (Remicade) and etanercept (Enbrel) for approved rheumatologic or dermatologic indications. Two policy cohorts and six historical control cohorts of patients using originator infliximab or etanercept will be assembled using linked and de-identified data from the British Columbia Ministry of Health. Patients will be identified during the 6-month period before the policy anniversary. Outcomes will include medication refills and switching, hospital admissions, emergency department visits, and physician visits. Summary outcome measures, such as cumulative incidence or average quantity as applicable, will be examined daily and reported monthly for 1 year. Outcomes in the policy cohorts will be compared with historical controls using likelihood ratios. RESULTS: The results of this rapid monitoring plan will be based on analyses involving approximately 9000 patients: four infliximab cohorts of approximately 430 patients and four etanercept cohorts of approximately 1800 patients. CONCLUSIONS: Rapid monitoring results will inform ongoing policy decisions related to the Biosimilars Initiative, in terms of impacts on both patient health and health services utilization.

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.

Policy-induced selection bias in pharmacoepidemiology: The example of coverage for Alzheimer's medications in British Columbia.

PURPOSES: To assess the impact of a government-sponsored reimbursement policy for cholinesterase inhibitors (ChEIs) on trends in physician visits with a diagnosis of Alzheimer's disease (AD). METHODS: Longitudinal population-based study using interrupted time series methods. British Columbia outpatient claims data for individuals aged 65 and older were used to compute monthly AD visit rates and examine the impact of the ChEI reimbursement policy on the coding of AD. We examined trends in the number of patients with AD visits, the number of AD visits per patient, and visits with "competing" diagnoses (mental, neurological, and cerebrovascular disorders and accidental falls). Finally, we described demographic and clinical features of diagnosed patients. RESULTS: We analyzed 1.9 million AD visits. Faster growth in recorded AD visits was observed after the policy was implemented, from monthly growth of 7.5 visits per 100 000 person-months before the policy (95% confidence interval [CI], 6.1-8.9) to monthly growth of 16.5 per 100 000 person-months after the policy (95% CI, 14.8-18.3). After the implementation of the policy, we observed increased growth in the number of patients with recorded AD visits and the number of AD visits per patient, as well as a shift in diagnoses away from mental diseases and accidental falls to AD (diagnosis substitution). CONCLUSIONS: British Columbia's reimbursement policy for ChEIs was associated with a significant acceleration in Alzheimer's visits. Evaluations of health services utilization and clinical outcomes following drug policy changes need to consider policy-induced influences on the reliability of the data used in the analysis.

Cholinesterase Inhibitor Utilization: The Impact of Provincial Drug Policy on Discontinuation.

BACKGROUND: In October 2007, British Columbia started to cover the cost of cholinesterase inhibitors (ChEIs)-donepezil, galantamine, and rivastigmine-for patients with mild to moderate dementia and prominent Alzheimer's disease. OBJECTIVES: To examine the impact of this policy on persistence with ChEIs. METHODS: A population-based cohort study was conducted using British Columbia administrative health data. We examined 45,537 new ChEI users aged 40 years and older between 2001 and 2012; 20,360 (45%) started the treatment after the coverage policy was launched. Patients were followed until treatment discontinuation, defined as a ChEI-free gap of 90 days, death, or December 2013. Persistence on ChEIs was estimated using survival analysis and competing risk approach. Hazards of discontinuation were compared using competing risk Cox regression with propensity adjustment. RESULTS: Patients who started ChEI therapy after the introduction of the coverage policy had a significantly longer persistence. Median ChEI persistence until discontinuation or death was 9.37 months (95% confidence interval [CI] 9.0-39.7) and 17.6 months (95% CI 16.9-18.3) in patients who started therapy before and after the new policy, respectively. The propensity-adjusted hazard ratio for discontinuing therapy was 0.91 (95% CI 0.88-0.94). Similar patterns were observed for persistence with the first ChEI (propensity-adjusted hazard ratio of 0.94; 95% CI 0.91-0.98). In rivastigmine users, the hazard ratio was insignificant (0.98; 95% CI 0.92-1.02). CONCLUSIONS: The British Columbia ChEI coverage policy was associated with significantly prolonged persistence with donepezil and galantamine, but not rivastigmine.

Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy.

BACKGROUND: Isotretinoin, a teratogen, is widely used to treat cystic acne. Although the risks of pregnancy during isotretinoin therapy are well recognized, there are doubts about the level of adherence with the pregnancy prevention program in Canada. Our objective was to evaluate the effectiveness of the Canadian pregnancy prevention program in 4 provinces: British Columbia, Saskatchewan, Manitoba and Ontario. METHODS: Using administrative data, we identified 4 historical cohorts of female users of isotretinoin (aged 12-48 yr) for the period 1996 to 2011. We defined pregnancy using International Statistical Classification of Diseases and billing codes. One definition included only cases with documented pregnancy outcomes (high-specificity definition); the other definition also included individuals recorded as receiving prenatal care (high-sensitivity definition). We studied new courses of isotretinoin and detected pregnancies in 2 time windows: during isotretinoin treatment only and up to 42 weeks after treatment. Live births were followed for 1 year to identify congenital malformations. RESULTS: A total of 59 271 female patients received 102 308 courses of isotretinoin. Between 24.3% and 32.9% of participants received prescriptions for oral contraceptives while they were taking isotretinoin, compared with 28.3% to 35.9% in the 12 months before isotretinoin was started. According to the high-specificity definition of pregnancy, there were 186 pregnancies during isotretinoin treatment (3.1/1000 isotretinoin users), compared with 367 (6.2/1000 users) according to the high-sensitivity definition. By 42 weeks after treatment, there were 1473 pregnancies (24.9/1000 users), according to the high-specificity definition. Of these, 1331 (90.4%) terminated spontaneously or were terminated by medical intervention. Among the 118 live births were 11 (9.3%) cases of congenital malformation. Pregnancy rates during isotretinoin treatment remained constant between 1996 and 2011. INTERPRETATION: Adherence to the isotretinoin pregnancy prevention program in Canada was poor during the 15-year period of this study.

Seasonal effects on the occurrence of nocturnal leg cramps: a prospective cohort study.

BACKGROUND: It has been anecdotally reported that nocturnal leg cramps in pregnant women are worse in summer. We analyzed population-level data to determine whether the symptom burden of nocturnal leg cramps is seasonal in the general population. METHODS: We examined time-series data for 2 independent measures of the symptom burden of leg cramps: (a) new quinine prescriptions (reflecting new or escalating treatment of leg cramps) from December 2001 to October 2007 among adults aged 50 years and older, which were obtained from linked health care databases that contain the prescribing information for the 4.2 million residents of British Columbia, Canada; and (b) the Internet search volume from February 2004 to March 2012 for the term "leg cramps" (reflecting public interest), which we obtained from Google Trends data and geographically limited to the United States and Australia. We assessed seasonality by determining how well a least-squares sinusoidal model predicted variability in the outcomes. RESULTS: New quinine prescriptions and Internet searches related to leg cramps were both seasonal, with highs in mid-summer and lows in mid-winter, and a peak-to-peak variability that was about two-thirds of the mean. Seasonality accounted for 88% of the observed monthly variability in new quinine prescriptions (p < 0.001) and 70% of the observed variability in Internet searches related to leg cramps (p < 0.001). INTERPRETATION: New quinine prescriptions and Internet searches related to leg cramps were seasonal and roughly doubled between the winter lows and summer highs. Why a disorder of peripheral motor neurons displays such strong seasonality warrants exploration.

Pragmatic randomised trial assessing the impact of peer comparison and therapeutic recommendations, including repetition, on antibiotic prescribing patterns of family physicians across British Columbia for uncomplicated lower urinary tract infections.

OBJECTIVE: To evaluate the impact of a personalised audit and feedback prescribing report (AF) and brief educational summary (ES) on empiric treatment of uncomplicated lower urinary tract infections (UTIs) by family physicians (FPs). DESIGN: Cluster randomised control trial. SETTING: The intervention was conducted in British Columbia, Canada between 23 September 2021 and 28 March 2022. PARTICIPANTS: We randomised 5073 FPs into a standard AF and ES intervention arm (n=1691), an ES-only arm (n=1691) and a control arm (n=1691). INTERVENTIONS: The AF contained personalised and peer-comparison data on first-line antibiotic prescriptions for women with uncomplicated lower UTI and key therapeutic recommendations. The ES contained detailed, evidence-based UTI management recommendations, incorporated regional antibiotic resistance data and recommended nitrofurantoin as a first-line treatment. MAIN OUTCOME MEASURES: Nitrofurantoin as first-line pharmacological treatment for uncomplicated lower UTI, analysed using an intention-to-treat approach. RESULTS: We identified 21 307 cases of uncomplicated lower UTI among the three trial arms during the study period. The impact of receiving both the AF and ES increased the relative probability of prescribing nitrofurantoin as first-line treatment for uncomplicated lower UTI by 28% (OR 1.28; 95% CI 1.07 to 1.52), relative to the delay arm. This translates to additional prescribing of nitrofurantoin as first-line treatment, instead of alternates, in an additional 8.7 cases of uncomplicated UTI per 100 FPs during the 6-month study period. CONCLUSION: AF prescribing data with educational materials can improve primary care prescribing of antibiotics for uncomplicated lower UTI. TRIAL REGISTRATION NUMBER: NCT05817253.

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.

Prescription ranitidine use and population exposure in 6 Canadian provinces, 1996 to 2019: a serial cross-sectional analysis.

BACKGROUND: Ranitidine was the most prescribed histamine-2 receptor antagonist (H2RA) in Canada when recalled in 2019 because of potential carcinogenicity. We sought to compare geographic and temporal patterns in use of prescription ranitidine and 3 other HRAs and estimated population exposure to ranitidine in 6 provinces between 1996 and 2019. METHODS: This population-based serial cross-sectional study used prescription claims for H2RAs dispensed from community pharmacies in Nova Scotia, Ontario, Manitoba, Saskatchewan, Alberta and British Columbia. We estimated the period prevalence of ranitidine use per 100 population by province, age category and sex. We estimated exposure to ranitidine between 2015 and 2019 using defined daily doses (DDDs). RESULTS: Overall, 2.4 million ranitidine prescriptions were dispensed to patients aged 65 years and older, and 1.7 million were dispensed to younger adults. Among older adults, the median period prevalence of ranitidine use among females was 16% (interquartile range [IQR] 13%-27%) higher than among males. Among younger adults, the median prevalence was 50% (IQR 37%-70%) higher among females. Among older adults, between 1996 and 1999, use was highest in Nova Scotia (33%) and Ontario (30%), lower in the prairies (Manitoba [18%], Saskatchewan [26%], Alberta [17%]) and lowest in BC (11%). By 2015-2019, use of ranitidine among older adults dropped by at least 50% in all provinces except BC. We estimate that at least 142 million DDDs of prescribed ranitidine were consumed annually in 6 provinces (2015-2019). INTERPRETATION: Over the 24-year period in 6 provinces, patients aged 65 years and older were dispensed 2.4 million prescriptions of ranitidine and younger adults were dispensed 1.7 million prescriptions of ranitidine. These estimates of ranitidine exposure can be used for planning studies of cancer risk and identifying target populations for cancer surveillance.

Comparative health-care cost advantage of ipratropium over tiotropium in COPD patients.

OBJECTIVE: To compare the total direct health-care costs of patients treated with tiotropium and ipratropium. METHODS: We conducted a cohort study of health-care costs in British Columbia, Canada, by comparing new patients on tiotropium with new patients on ipratropium. Direct health-care costs for study patients were measured in the first 2 years after initiating inhaled anticholinergic treatment. Differences in direct health-care costs between tiotropium and ipratropium patients were estimated by using quantile regression. We analyzed cost differences in the 10th percentile, median, and 90th percentile of patients by cost. High-dimensional propensity score analysis was used as a method of adjustment for potential confounding factors. RESULTS: The study population had 3,140 tiotropium patients and 26,182 ipratropium patients. Higher health system costs in patients who started on tiotropium instead of ipratropium were observed in patients in the median and 10th percentile. The magnitude of these increases was comparable to the price difference between the two drugs. Health system costs in the 90th percentile were not significantly different between tiotropium and ipratropium patients. CONCLUSIONS: The results of this study did not support the preferential use of tiotropium over ipratropium as a basis for savings in direct health-care costs.

Rapid monitoring of health services use following a policy to switch patients from originator to biosimilar etanercept-a cohort study in British Columbia.

BACKGROUND: Drug coverage policies that incentivize switching patients from originator to biosimilar products may result in significant health care savings. Our study aimed to detect early impacts on health services utilization following a mandated switch from originator to biosimilar etanercept in British Columbia (BC), Canada. METHODS: We conducted a prospective, population-based cohort study using linked administrative health data from BC (2010-2020). The policy cohort consisted of patients with inflammatory arthritis who used originator etanercept in 2019, prior to BC's Biosimilars Initiative switching policy. Three historical cohorts included patients with inflammatory arthritis who used originator etanercept in the years 2016, 2017, and 2018. We compared the daily cumulative incidences of drug refills and outpatient and inpatient services between the policy and historical cohorts. A likelihood ratio sustained (≥ 31 days) at 7.1 or higher compared with the null hypothesis was chosen a priori as a threshold for a potential impact of the policy. RESULTS: Each cohort contained between 1694 and 1963 patients. We detected several potential impacts: 1) a transient increase in etanercept refills between months three and eight (cumulative incidence difference of + 3.0%); 2) an anticipated increase in visits to physicians of any specialty between months three and eight (+ 2.6%); and 3) an anticipated increase in visits to a rheumatologist from the end of month three onwards (+ 12.8%). The policy had no impact on incidences of switching to a different biologic antirheumatic drug, visits to emergency departments, or admissions to hospitals. CONCLUSIONS: Only transient and/or anticipated increases in drug refills and physician visits were observed during the study period. Additional research on clinical outcomes is recommended to strengthen the evidence that no long-term unintended negative health impacts are associated with BC's Biosimilars Initiative [switching policy].

Treatment pattern trends of medications for type 2 diabetes in British Columbia, Canada.

INTRODUCTION: Several new oral drug classes for type 2 diabetes (T2DM) have been introduced in the last 20 years accompanied by developments in clinical evidence and guidelines. The uptake of new therapies and contemporary use of blood glucose-lowering drugs has not been closely examined in Canada. The objective of this project was to describe these treatment patterns and relate them to changes in provincial practice guidelines. RESEARCH DESIGN AND METHODS: We conducted a longitudinal drug utilization study among persons with T2DM aged ≥18 years from 2001 to 2020 in British Columbia (BC), Canada. We used dispensing data from community pharmacies with linkable physician billing and hospital admission records. Laboratory results were available from 2011 onwards. We identified incident users of blood glucose-lowering drugs, then determined sequence patterns of medications dispensed, with stratification by age group, and subgroup analysis for patients with a history of cardiovascular disease. RESULTS: Among a cohort of 362 391 patients (mean age 57.7 years old, 53.5% male) treated for non-insulin-dependent diabetes, the proportion who received metformin monotherapy as first-line treatment reached a maximum of 90% in 2009, decreasing to 73% in 2020. The proportion of patients starting two-drug combinations nearly doubled from 3.3% to 6.4%. Sulfonylureas were the preferred class of second-line agents over the course of the study period. In 2020, sodium-glucose cotransporter type 2 inhibitors and glucagon-like peptide-1 receptor agonists accounted for 21% and 10% of second-line prescribing, respectively. For patients with baseline glycated hemoglobin (A1C) results prior to initiating diabetic treatment, 41% had a value ≤7.0% and 27% had a value over 8.5%. CONCLUSIONS: Oral diabetic medication patterns have changed significantly over the last 20 years in BC, primarily in terms of medications used as second-line therapy. Over 40% of patients with available laboratory results initiated T2DM treatment with an A1C value ≤7.0%, with the average A1C value trending lower over the last decade.

Trends in health care utilization in British Columbia following public coverage for tiotropium.

OBJECTIVES: To examine the use and cost of health-care services in British Columbia, Canada, before and after public drug coverage for tiotropium bromide. METHODS: A time series analysis was performed using data from British Columbia's centralized administrative health-care databases. Linear regression on data from a stable 3-year prepolicy period was used to predict future use of inhaled anticholinergic (IAC) medications, visits to physicians, emergency hospitalizations, and costs. For each use measure, we estimated the policy effect as the difference between observed use in the postpolicy period and predicted use obtained from the prepolicy period. RESULTS: In total, over the 2.5-year period after public coverage, tiotropium use increased by 24.4% more than predicted (95% confidence interval [CI] 23.9%-24.8%). Visits to physicians were unchanged, but there were between 596 and 948 more emergency admissions for chronic obstructive pulmonary disease, and between 582 and 1940 more hospital admissions of any kind than were predicted from prepolicy data. Total cost of inhaled IAC medications increased slightly more than predicted, by between an additional CDN$1.30 million and CDN$1.71 million, but total out-of-pocket spending by patients on IAC medications was reduced by between CDN$2.83 million and CDN$3.11 million because of public coverage. Hospital costs were between CDN$3.88 million and CDN$12.93 million greater than anticipated based on prepolicy data. CONCLUSIONS: Public drug plan coverage for tiotropium in British Columbia reduced out-of-pocket costs for patients and their private insurers. Before versus after time series analysis did not show a reduction in hospitalizations or physician visits, or costs associated with those services.

Cardiovascular and neuropsychiatric safety of smoking cessation pharmacotherapies in non-depressed adults: a retrospective cohort study.

BACKGROUND AND AIMS: Pharmacotherapies for smoking cessation are widely prescribed, despite substantial concerns being raised regarding the potential increased risk of cardiovascular (CV) and neuropsychiatric adverse events associated with these treatments. This study aimed to assess the relative CV and neuropsychiatric safety between varenicline and bupropion compared with nicotine replacement therapies (NRT) in adults without a recent history of depression. DESIGN: Retrospective new-user cohort study. SETTING: US administrative data from 2006 to 2016 covering more than 100 million individuals. PARTICIPANTS: Three study cohorts of new users, aged 18 years or older, limited to patients with no diagnosis or treatment for depression in the prior 12 months. MEASUREMENTS: Propensity score adjusted log-binomial regression models. The primary outcome was a composite of hospitalized CV events. Secondary outcomes included a composite of hospitalized neuropsychiatric events and individual components of the primary outcome. FINDINGS: A total of 618 497 participants were included in our study cohorts. Compared with NRT (n = 32 237), varenicline (n = 454 698) was associated with a 20% lower 1-year CV risk [adjusted relative risk (RR) = 0.80, 95% confidence interval (CI) = 0.75-0.85], and bupropion (n = 131 562) was associated with a 25% lower 1-year CV risk (RR = 0.75, 95% CI = 0.69-0.81). Varenicline was associated with a 35% lower 1-year risk of neuropsychiatric hospitalization versus NRT (RR = 0.65, 95% CI = 0.59-0.72), and bupropion was associated with a 21% increase in 1-year risk of neuropsychiatric hospitalization (RR = 1.21, 95% CI = 1.09-1.35). CONCLUSION: Varenicline compared with nicotine replacement therapy does not appear to be associated with an increased risk of cardiovascular or neuropsychiatric hospitalizations. Bupropion appears to be associated with a lower risk of cardiovascular hospitalization and a higher risk of neuropsychiatric hospitalization, compared with nicotine replacement therapy.

Comparative effectiveness and safety of direct oral anticoagulants versus vitamin K antagonists in nonvalvular atrial fibrillation: a Canadian multicentre observational cohort study.

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.

Comparison of cholinesterase inhibitor safety in real-world practice.

INTRODUCTION: Cholinesterase inhibitors (ChEIs) are widely used to treat mild to moderate Alzheimer's disease and related dementia. Clinical trials have focused on placebo comparisons, inadequately addressing within-class comparative safety. METHODS: New users of ChEIs in British Columbia were categorized into five study cohorts: low-dose donepezil, high-dose donepezil, galantamine, rivastigmine patch, and oral rivastigmine. Comparative safety of ChEIs assessed hazard ratios using propensity score adjusted Cox regression. RESULTS: Compared with low-dose donepezil, galantamine use was associated with a lower risk of mortality (adjusted hazard ratio: 0.84, 95% confidence interval: 0.60-1.18), cardiovascular serious adverse events (adjusted hazard ratio: 0.78, 95% confidence interval: 0.62-0.98), and entry into a residential care facility (adjusted hazard ratio: 0.72, 95% confidence interval: 0.59-0.89). DISCUSSION: Given the absence of randomized trial data showing clinically meaningful benefit of ChEI therapy in Alzheimer's disease, our study suggests preferential use of galantamine may at least be associated with fewer adverse events than treatment with donepezil or rivastigmine.