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Many adverse effects of medicines only become known after approval, prompting regulatory agencies to issue post-market safety advisories to support safer care. Our team evaluated advisories issued by national regulators in Australia, Canada, Denmark, the United Kingdom, and the United States from 2007 to 2016 inclusive, comparing regulators' decisions to warn, effects on prescribing, doctors' awareness and responses to warnings, relevant regulatory policies, and specific case studies.Based mainly on our research program and a narrative review, this commentary describes how often regulators issue safety advisories and effects on clinical practice. We found extensive differences in decisions to warn, timing and content of warnings. Monitoring advice is often inadequate. The most systematic estimate suggests an average reduction in prescribing of around 6% compared with settings with no advisory. Interviews with doctors suggest limited awareness, uptake, and at times belief in these warnings.Post-market safety advisories are an important intervention aiming to improve prescribing and use of medicines. However, differing warnings mean that some patients may be exposed to riskier prescribing than others. Better integration of safety information into clinical practice is needed, as well as improved transparency, independence, and public engagement in regulatory decision-making.

Approximately 40% of randomized controlled trials are not published, leading to publication bias and less informed clinical decision-making. Qualitative interviews were conducted to understand whether and how industry sponsors of clinical trials of drugs and biologics in Canada influence decisions to report trial results.Participants eligible for an interview included clinical trial investigators and research coordinators with experience in drug research, research ethics board members with at least 1 year of experience in ethical review of trials, research administrators with knowledge of dissemination of clinical trial findings or relations with trial sponsors, and trial participants who had taken part in a drug trial as an adult in the 5 years before their interview. Semi-structured interviews were held in person or by telephone between March 2019 and April 2021 with participants in Alberta, British Columbia, and Ontario, Canada. Qualitative analysis included coding of interview transcripts and identification of key themes.Interviews were conducted with 34 participants, including 17 clinical trial investigators, 1 clinical research coordinator, 3 research administrators, 3 research ethics board members, and 10 clinical trial participants. Participants involved in the conduct, administration, or ethical review of trials represented a range of medical disciplines. Interview participant accounts indicated that in some cases, industry sponsors influence whether results are reported. A core theme was that companies have a weaker incentive to publish trials with unfavorable findings and trials for products that they have decided not to develop further. Companies may influence reporting in various ways, including stopping trials early and not reporting results of stopped trials, owning and controlling access to data, and negotiating clinical trial agreements in multicenter trials that do not fully protect the ability of investigators to publish. Internal company trials represent an additional source of unpublished trials. More broadly, the research system creates a dependency on funding from industry sponsors that may weaken the ability of researchers and research institutions to negotiate terms with industry sponsors that would fully protect publication rights.Interviews with trial investigators and others connected to trial research indicate that in some cases, industry sponsors of clinical trial research in Canada influence whether results are reported. Policies aiming to bring about full reporting of trials could benefit from considering the commercial incentives of companies and the ways in which industry sponsors may influence clinical trial reporting. Future research could examine the generalizability of these findings to other jurisdictions.

In 2019, British Columbia's public drug plan, PharmaCare, was the first in Canada to implement a nonmedical switching policy from originator infliximab to its biosimilar, for patients with inflammatory arthritis or psoriasis. We aimed to detect signals of impact on health services utilization during the first year of policy implementation and to provide early data to policy-makers.We constructed cohorts of users of originator infliximab: 3 historical cohorts (2016-2018) and 1 policy cohort (2019). We extracted data from BC Ministry of Health databases from 2015 to 2020, as we followed each cohort for 365 days from May 27 of each cohort's respective year. We excluded patients with gastrointestinal conditions and those not covered by PharmaCare. We examined the cumulative incidence of infliximab prescription refills, switching to other biologic drugs and use of additional health services. A log-likelihood ratio of 1.96 compared with the null hypothesis was used as the threshold for differences between the policy cohort and the historical cohorts.The study included a total of 572 unique patients: 520 in the 2016 historical cohort, 461 in the 2017 historical cohort, 423 in the 2018 historical cohort and 377 in the policy cohort (with some patients included in multiple cohorts; 335 [58.6%] were included in all 4 cohorts). During months 8 and 9 of follow-up, a transient signal was observed in infliximab refills (7.2% decrease in refilling infliximab for the fourth time for the policy cohort, log-likelihood ratio1.96). An anticipated increase in visits to specialists was observed from month 4 forward (15.0%, log-likelihood ratio1.96). No signal was observed for increased use of other health services (log-likelihood ratio1.96).Early monitoring did not detect signals of negative impacts on health services use during the first year of the policy. Detailed, longer-term cohort studies and hypothesis-testing methods could provide additional assurance about the safety of the policy.

This study aims to understand factors contributing to nonpublication and publication bias in clinical trials in Canada.Qualitative interviews were conducted between March 2019 and April 2021 with 34 participants from the Canadian provinces of Alberta, British Columbia and Ontario, including 17 clinical trial investigators, 1 clinical research coordinator, 3 research administrators, 3 research ethics board members and 10 clinical trial participants. We conducted a thematic analysis involving coding of interview transcripts and memo-writing to identify key themes.Several factors contribute to nonpublication and publication bias in clinical trial research. A core theme was that reporting practices are shaped by incentives within the research system taht favour publication of positive over negative trials. Investigators are discouraged from reporting by experiences or perceptions of difficulty in publishing negative findings but rewarded for publishing positive findings in various ways. Trial investigators more strongly associated positive clinical trials than negative trials with opportunities for industry and nonindustry funding and with academic promotion, bonuses and recognition. Research institutions and ethics boards tended to lack well-resourced, proactive policies and practices to ensure trial findings are reported in registries or journals.Clinical trial reporting practices in Canada are shaped by incentives favouring reporting of positive over negative trials, such as funding opportunities and academic promotion, bonuses and recognition. Research institutions could help change incentives by adopting performance metrics that emphasize full reporting of results in journals or registries.

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.

The US Food and Drug Administration (FDA) and other major regulators regularly issue safety advisories about licensed drugs with new adverse effects that have been documented through observational studies, clinical trials, and spontaneously reported adverse drug events. To assess the possible effects of a representative group of FDA Drug Safety Communications on the reporting of the specific adverse effect featured in the advisory on new cases reported to the FDA Adverse Event Reporting System (FAERS). We examined 16 FDA Drug Safety Communications issued from 2010 to 2015 that had not previously been the focus of advisories from regulators in the UK, Canada, or Australia. We compared the reports of the adverse effect in the 8 calendar quarters preceding the advisory and in the 4 quarters following. We measured change in reporting frequency by calculating the event reporting odds ratio (ROR) for the post-warning compared to the pre-warning periods. We defined a credible association of the advisory with increased reporting as a ROR ≥ 2.0 and p value of

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.

ObjectiveTo understand how the experiences and views of trial participants, trial investigators and others connected to clinical trial research relate to whether researchers have a duty to participants to publicly report research findings.DesignQualitative interview study.SettingSemistructured interviews held in person or by telephone between March 2019 and April 2021 with participants in the Canadian provinces of Alberta, British Columbia and Ontario.Participants34 participants, including 10 clinical trial participants, 17 clinical trial investigators, 1 clinical research coordinator, 3 research administrators and 3 research ethics board members.AnalysisWe conducted a thematic analysis, including qualitative coding of interview transcripts and identification of key themes.Main outcome measuresKey themes identified through qualitative coding of interview data.ResultsMost clinical trial participants felt that reporting clinical trial results is important. Accounts of trial participants suggest their contributions are part of a reciprocal relationship involving the expectation that research will advance medical knowledge. Similarly, comments from trial investigators suggest that reporting trial results is part of reciprocity with trial participants and is a necessary part of honouring informed consent. Accounts of trial investigators suggest that when drug trials are not reported, this may undermine informed consent in subsequent trials by withholding information on harms or efficacy relevant to informed decisions on whether to conduct or enroll in future trials of similar drugs.ConclusionThe views of trial participants, trial investigators and others connected to clinical trial research in Canada suggest that researchers have an obligation to participants to publicly report clinical trial results and that reporting results is necessary for honouring informed consent.

IntroductionSeveral 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 methodsWe 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.ResultsAmong 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%.ConclusionsOral 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.

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.

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., Highlights • Galantamine was associated with fewer adverse events than donepezil or rivastigmine. • Galantamine users experienced longer independent living. • The 3-year risk of cardiovascular events and mortality was lowest with galantamine.

Purpose To use the Canadian Network for Observational Drug Effect Studies (CNODES) to describe drug utilization of antidiabetic medications in four Canadian provinces. Methods With the use of data from CNODES, we constructed cohorts of patients with type 2 diabetes in four Canadian provinces (Manitoba, Ontario, Quebec, and Saskatchewan) who received their first-ever prescription for a noninsulin antidiabetic medication during the study period, defined as the earliest date of data availability in each province (range: 1993-1998) to the latest date of the data extraction in each province (range: 2013-2014). Prescriptions rates were calculated for all prescriptions by class and described over time. Results Across provinces, we identified 650 830 patients who initiated antidiabetic medications during the study period. In most provinces, the overall prescription rate of antidiabetic medications increased during the last two decades. Metformin particularly increased in popularity, surpassing sulfonylureas in all provinces as the most widely prescribed antidiabetic medication by the early 2000s. Thiazolidinediones grew in popularity from the onset of their availability until 2006 to 2007, at which point they rapidly declined. Dipeptidyl peptidase-4 inhibitors saw substantial growth in several provinces following their addition to provincial formularies in 2008 to 2012, while glucagon-like peptide-1 agonists experienced modest growth. Insulin prescription rates remained constant or steadily increased over the last two decades. Conclusions CNODES can be used for cross-jurisdictional drug utilization studies. In Canada, trends in antidiabetic medication prescriptions followed changing guidelines reflecting up-to-date knowledge of drug effectiveness and safety.

Purpose To explore the utility of physician prescribing preference as an instrumental variable. Methods Expert (non‐systematic) review of relevant literature on the appropriate selection of instrumental variables and theoretical exploration of individual physician and physician group prescriber preference. Results An instrumental variable must satisfy three criteria: (1) It must predict the treatment received (strength of the instrument); (2) it cannot influence the outcome other that through the treatment received (exclusion restriction); and (3) it cannot be influenced by any factor that also influences the outcome (independence assumption). Arguments in favor of prescriber preference as an instrumental variable and suggestions for how to approach specific scenarios that may be encountered are offered. Conclusions Prescriber preference, be it of individual physicians or groups of physicians, may, under the right conditions, be powerful instrumental variables. Empiric experimental data are required to determine the appropriateness of combining propensity matching and instrumental variable analysis.

Background The College of Physicians and Surgeons of British Columbia introduced opioid prescribing standards and guidelines in mid-2016 in British Columbia. We evaluated impacts of the standards and guidelines on health outcomes. Methods We conducted a longitudinal study with repeated measures using administrative data from December 2013 to March 2017. The study included BC patients with long-term use of prescription opioids. Those with a history of long-term care, palliative care or cancer were excluded. Patients were followed for a 12-month prepolicy period and 10-month postpolicy period and compared with historical controls. We estimated changes in level (sudden changes) and monthly trend (gradual changes) of rates of opioid overdose hospital admission, and secondary outcomes of all-cause hospital admission, all-cause emergency department visits, opioid overdose mortality and all-cause mortality. Results The study included 68 113 patients in the main cohort and 68 429 historical controls. We did not find significant changes to opioid overdose hospital admissions in level (adjusted rate ratio [RR] 0.83, 95% confidence interval [CI] 0.45-1.54) or in trend (adjusted RR 1.00, 95% CI 0.91-1.10). All-cause hospital admissions declined in level but may have increased in trend, suggesting that a temporary decrease in hospital admissions may have occurred. We found no significant changes in all-cause emergency department visits, opioid overdose mortality or all-cause mortality. Interpretation Among patients with a history of long-term prescription opioid use, the regulatory prescribing standards and guidelines were not associated with changes in opioid overdose hospital admissions, all-cause emergency department visits, opioid overdose mortality or all-cause mortality, or with a sustained reduction in all-cause hospital admissions, over a 10-month period after they were introduced. Future research should investigate whether opioid prescribing standards or guidelines are associated with use of nonopioid analgesic medications or nonpharmacologic treatments.

Importance Ondansetron is frequently used to treat nausea and vomiting during pregnancy. Although some studies reported important safety signals, few studies have been sufficiently large to assess rare pregnancy outcomes. Objective To study the association between ondansetron exposure during pregnancy and the risks of spontaneous abortion, stillbirth, and major congenital malformations. Design, Setting, and Participants This is a cohort study conducted in 3 countries, with a meta-analysis. Participants included women and girls aged 12 to 55 years who experienced spontaneous abortion, induced abortion, stillbirth, or live birth between April 2002 and March 2016, as recorded in administrative data from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, and Ontario), the US IBM MarketScan Research Databases, and the UK Clinical Practice Research Datalink. The statistical analysis was completed in October 2020. Exposures Exposure to ondansetron during pregnancy was compared with exposure to other commonly used antiemetics to minimize confounding by indication. Main Outcomes and Measures The primary outcome was fetal death, defined as either spontaneous abortion or stillbirth. Secondary outcomes were the 2 components of the primary outcome and major congenital malformations identified during the year after a live birth. Adjusted hazard ratios were estimated using Cox proportional hazards models with time-dependent drug exposures and were adjusted using high-dimensional propensity scores. For major congenital malformations, adjusted odds ratios were estimated from logistic models. Site-level results were pooled using random-effects meta-analysis. Sensitivity analyses considered second-line antiemetic exposure and exposure specifically during 4 to 10 weeks of gestation. Results Data from 456 963 pregnancies were included in this study of fetal death (249 787 [54.7%] in Canada, 197 913 [43.3%] in the US, and 9263 [2.0%] in the UK; maternal age, ≤24 years, 93 201 patients [20.4%]; 25-29 years, 149 117 patients [32.6%]; 30-34 years, 142 442 patients [31.2%]; and ≥35 years, 72 203 patients [15.8%]). Fetal death occurred in 12 907 (7.9%) of 163 810 pregnancies exposed to ondansetron, and 17 476 (5.7%) of 306 766 pregnancies exposed to other antiemetics. The adjusted hazard ratios were 0.91 (95% CI, 0.67-1.23) for fetal death with time-dependent ondansetron exposure during pregnancy, 0.82 (95% CI, 0.64-1.04) for spontaneous abortion, and 0.97 (95% CI, 0.79-1.20) for stillbirth. For major congenital malformations, the estimated odds ratio was 1.06 (95% CI, 0.91-1.22). Results of sensitivity analyses were generally consistent with those of the primary analyses. Conclusions and Relevance In this large, multicenter cohort study, there was no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs.

To evaluate the impact of concomitant use of conventional synthetic DMARDs (csCMARD) on adherence, switching and dose of biologic disease modifying antirheumatic drugs (bDMARD) in rheumatoid arthritis (RA) patients treated with bDMARDs.This was a population-based cohort study conducted in five provinces of Canada (Alberta, Manitoba, Ontario, Quebec, and Saskatchewan), and one American database (IBM® MarketScan® Databases). Adult RA patients entered the study after a 3-month initiation period of bDMARDs between 1 January 2007, and 30 March 2014. Concomitant csDMARD exposure was compared to non-csDMARD exposure on the following outcomes: discontinuation of bDMARD therapy, switching of bDMARDs, and percent change in dose of bDMARD compared to initial dose. The effect of the time-varying changes in csDMARD exposure was analyzed using marginal structural models. Dose change was analyzed using linear regression. Results from each participating site were combined using likelihood ratio meta-analysis.The study population comprised 20,221 new users of bDMARDs: adalimumab (7609), etanercept (9809), abatacept (1024), infliximab (1779). Concomitant use of csDMARD therapy was not significantly associated with reduced discontinuation of bDMARD treatment (hazard ratio 0.90, 95% intrinsic confidence interval 0.79 to 1.02) or reduced switching of bDMARDs (hazard ratio 0.95, 95% intrinsic confidence interval 0.80 to 1.11), but was associated with a small increase in bDMARD dose compared to the mean dose over the first three months of treatment (mean percentage change in dose +0.56% mg/day, 95% intrinsic confidence interval +0.14% to +0.97%).In this large study of RA patients using bDMARDs in Canada and the United States, we found no clear evidence that patients who received concomitant csDMARD therapy were less likely to discontinue, switch or increase their dose of bDMARD.

BACKGROUND: The College of Physicians and Surgeons of British Columbia introduced opioid prescribing standards and guidelines in mid-2016 in British Columbia. We evaluated impacts of the standards and guidelines on health outcomes. METHODS: We conducted a longitudinal study with repeated measures using administrative data from December 2013 to March 2017. The study included BC patients with long-term use of prescription opioids. Those with a history of long-term care, palliative care or cancer were excluded. Patients were followed for a 12-month prepolicy period and 10-month postpolicy period and compared with historical controls. We estimated changes in level (sudden changes) and monthly trend (gradual changes) of rates of opioid overdose hospital admission, and secondary outcomes of all-cause hospital admission, all-cause emergency department visits, opioid overdose mortality and all-cause mortality. RESULTS: The study included 68 113 patients in the main cohort and 68 429 historical controls. We did not find significant changes to opioid overdose hospital admissions in level (adjusted rate ratio [RR] 0.83, 95% confidence interval [CI] 0.45–1.54) or in trend (adjusted RR 1.00, 95% CI 0.91–1.10). All-cause hospital admissions declined in level but may have increased in trend, suggesting that a temporary decrease in hospital admissions may have occurred. We found no significant changes in all-cause emergency department visits, opioid overdose mortality or all-cause mortality. INTERPRETATION: Among patients with a history of long-term prescription opioid use, the regulatory prescribing standards and guidelines were not associated with changes in opioid overdose hospital admissions, all-cause emergency department visits, opioid overdose mortality or all-cause mortality, or with a sustained reduction in all-cause hospital admissions, over a 10-month period after they were introduced. Future research should investigate whether opioid prescribing standards or guidelines are associated with use of nonopioid analgesic medications or nonpharmacologic treatments.

Objective To compare the risk of cardiovascular events between sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors among people with type 2 diabetes in a real world context of clinical practice. Design Multi-database retrospective cohort study using a prevalent new user design with subsequent meta-analysis. Setting Canadian Network for Observational Drug Effect Studies (CNODES), with administrative healthcare databases from seven Canadian provinces and the United Kingdom, 2013-18. Population 209 867 new users of a SGLT2 inhibitor matched to 209 867 users of a DPP-4 inhibitor on time conditional propensity score and followed for a mean of 0.9 years. Main outcome measures The primary outcome was major adverse cardiovascular events (MACE, a composite of myocardial infarction, ischaemic stroke, or cardiovascular death). Secondary outcomes were the individual components of MACE, heart failure, and all cause mortality. Cox proportional hazards models were used to estimate site specific adjusted hazards ratios and 95% confidence intervals, comparing use of SGLT2 inhibitors with use of DPP-4 inhibitors in an as treated approach. Site specific results were pooled using random effects meta-analysis. Results Compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with decreased risks of MACE (incidence rate per 1000 person years: 11.4 v 16.5; hazard ratio 0.76, 95% confidence interval 0.69 to 0.84), myocardial infarction (5.1 v 6.4; 0.82, 0.70 to 0.96), cardiovascular death (3.9 v 7.7; 0.60, 0.54 to 0.67), heart failure (3.1 v 7.7; 0.43, 0.37 to 0.51), and all cause mortality (8.7 v 17.3; 0.60, 0.54 to 0.67). SGLT2 inhibitors had more modest benefits for ischaemic stroke (2.6 v 3.5; 0.85, 0.72 to 1.01). Similar benefits for MACE were observed with canagliflozin (0.79, 0.66 to 0.94), dapagliflozin (0.73, 0.63 to 0.85), and empagliflozin (0.77, 0.68 to 0.87). Conclusions In this large observational study conducted in a real world clinical practice context, the short term use of SGLT2 inhibitors was associated with a decreased risk of cardiovascular events compared with the use of DPP-4 inhibitors. Trial registration ClinicalTrials.gov NCT03939624 .

Background Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the day. This review focuses on the subclass of beta-blockers with partial agonist activity (BBPAA). Objectives To assess the degree of variation in hourly BP lowering efficacy of BBPAA over a 24-hour period in adults with essential hypertension. Search methods The Cochrane Hypertension Information Specialist searched the following databases for relevant studies up to June 2020: the Cochrane Hypertension Specialised Register; CENTRAL; 2020, Issue 5; MEDLINE Ovid; Embase Ovid; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. Selection criteria We sought to include all randomised and non-randomised trials that assessed the hourly effect of BBPAA by ambulatory monitoring, with a minimum follow-up of three weeks. Data collection and analysis Two review authors independently selected the included trials and extracted the data. We assessed the certainty of the evidence using the GRADE approach. Outcomes included in the review were end-point hourly systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR), measured using a 24-hour ambulatory BP monitoring (ABPM) device. Main results Fourteen non-randomised baseline controlled trials of BBPAA met our inclusion criteria, but only seven studies, involving 121 participants, reported hourly ambulatory BP data that could be included in the meta-analysis. Beta-blockers studied included acebutalol, pindolol and bopindolol. We judged most studies at high or unclear risk of bias for selection bias, attrition bias, and reporting bias. We judged the overall certainty of the evidence to be very low for all outcomes. We analysed and presented data by each hour post-dose. Very low-certainty evidence showed that hourly mean reduction in BP and HR visually showed an attenuation over time. Over the 24-hour period, the magnitude of SBP lowering at each hour ranged from -3.68 mmHg to -17.74 mmHg (7 studies, 121 participants), DBP lowering at each hour ranged from -2.27 mmHg to -9.34 mmHg (7 studies, 121 participants), and HR lowering at each hour ranged from -0.29 beats/min to -10.29 beats/min (4 studies, 71 participants). When comparing between three 8-hourly time intervals that correspond to day, evening, and night time hours, BBPAA was less effective at lowering BP and HR at night, than during the day and evening. However, because we judged that these outcomes were supported by very low-certainty evidence, further research is likely to have an important impact on the estimate of effect and may change the conclusion. Authors' conclusions There is insufficient evidence to draw general conclusions about the degree of variation in hourly BP-lowering efficacy of BBPAA over a 24-hour period, in adults with essential hypertension. Very low-certainty evidence showed that BBPAA acebutalol, pindolol, and bopindolol lowered BP more during the day and evening than at night. However, the number of studies and participants included in this review was very small, further limiting the certainty of the evidence. We need further and larger trials, with accurate recording of time of drug intake, and with reporting of standard deviation of BP and HR at each hour.

Purpose To provide an overview of altmetrics, including their potential benefits and limitations, how they may be obtained, and their role in assessing pharmacoepidemiologic research impact. Methods Our review was informed by compiling relevant literature identified through searching multiple health research databases (PubMed, Embase, and CIHNAHL) and grey literature sources (websites, blogs, and reports). We demonstrate how pharmacoepidemiologists, in particular, may use altmetrics to understand scholarly impact and knowledge translation by providing a case study of a drug‐safety study conducted by the Canadian Network of Observational Drug Effect Studies. Results A common approach to measuring research impact is the use of citation‐based metrics, such as an article's citation count or a journal's impact factor. “Alternative” metrics, or altmetrics, are increasingly supported as a complementary measure of research uptake in the age of social media. Altmetrics are nontraditional indicators that capture a diverse set of traceable, online research‐related artifacts including peer‐reviewed publications and other research outputs (software, datasets, blogs, videos, posters, policy documents, presentations, social media posts, wiki entries, etc). Conclusion Compared with traditional citation‐based metrics, altmetrics take a more holistic view of research impact, attempting to capture the activity and engagement of both scholarly and nonscholarly communities. Despite the limited theoretical underpinnings, possible commercial influence, potential for gaming and manipulation, and numerous data quality‐related issues, altmetrics are promising as a supplement to more traditional citation‐based metrics because they can ingest and process a larger set of data points related to the flow and reach of scholarly communication from an expanded pool of stakeholders. Unlike citation‐based metrics, altmetrics are not inherently rooted in the research publication process, which includes peer review; it is unclear to what extent they should be used for research evaluation.

Purpose We explored changes in health services utilization associated with the Biosimilars Initiative introduced in British Columbia on May 27, 2019. To maintain drug coverage, the policy requires users of originator infliximab or etanercept to transition to biosimilar versions. We present a three-month interim analysis of this initiative. Methods We conducted a rapid monitoring analysis to evaluate changes in health services utilization three months after the policy was introduced compared with a three-year period before the policy's introduction. Using the administrative claims data of the British Columbia Ministry of Health, we assembled three historical cohorts and one policy cohort of users of each originator drug (8 cohorts in total). Cumulative incidences of medication refills, switching, and visits to physicians were the outcome measures used to compare policy and historical cohorts. Likelihood ratios were used to quantify statistical differences between each policy cohort and its respective historical controls. Likelihood ratios above 7.1 were considered statistically significant. Results The four infliximab cohorts included 436 patients on average, mean age 56 to 59, 53% to 55% females. The four etanercept cohorts included 1826 patients on average, mean age 57 to 58, 60% to 63% females. Three months after the policy's introduction, 21% of patients treated in the policy cohorts transitioned to the biosimilar versions. Health services utilization in the policy cohorts were consistent with the historical cohorts. Conclusions An increase in visits to physicians was expected but not detected in the first three months of the Biosimilars Initiative. The impacts of the policy will continue to be monitored.

Background Emergence coughing can harm the patient following completion of surgery, but it is unclear which medication is most effective at reducing this event. We conducted a systematic review and network meta-analysis of RCTs to determine the medications' relative efficacies on decreasing moderate to severe emergence coughing after general anaesthesia. Medications studied were lidocaine (i.v., intracuff, topical, or tracheal application), dexmedetomidine, remifentanil, and fentanyl. Methods We searched eight different medical literature databases, conference abstracts, and article references. After screening, included citations were evaluated for bias and had their data extracted. Pooled odds ratios and 95% confidence intervals for each treatment comparison were calculated. A surface under the cumulative ranking curve analysis (SUCRA) determined the relative rank of each intervention to decrease moderate to severe emergence coughing. Subgroup analyses included severe coughing only, extubation times, type of maintenance anaesthetic, and dosages. Results The network meta-analysis included 70 studies and 5286 patients. All study medications had favourable odds in reducing moderate and severe peri-extubation coughing compared with either no medication or placebo. No single medication was favoured over another. Dexmedetomidine had the highest SUCRA rank, followed in order by remifentanil, fentanyl, and lidocaine via intracuff, tracheal/topical, and i.v. routes. Remifentanil was ranked highest for decreasing severe coughing only. Intracuff lidocaine had higher odds of prolonging extubation times compared with placebo, dexmedetomidine, fentanyl, and remifentanil. Conclusion All study medications were better than placebo or no medication in reducing moderate to severe emergence cough, with dexmedetomidine ranked the most effective. Systematic review registration PROSPERO registration number: CRD42018102870.

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.

ObjectivesTramadol is a widely prescribed analgesic that influences both opioid and monoamine neurotransmission. While seizures have been reported with its use, the risk in clinical practice has not been well characterised. We examined risk of seizure with tramadol relative to codeine, a comparable opioid analgesic.DesignRetrospective nested case-control study. For each case, we identified up to 10 controls matched on age, sex, US state of residence and date of cohort entry (±365 days). We calculated ORs to determine the association between seizure and exposure to tramadol, codeine (≥15 mg), both or neither, in the preceding 30 days.SettingCohort of patients, who had continuous health coverage and resided in the same state for≥3 years, identified from linked administrative health data in US MarketScan databases from 2009 to 2012.ParticipantsWe identified 96 753 patients with seizure and 888 540 matched controls.Primary and secondary outcome measuresIn the primary analysis, we defined cases using a broad definition of seizure (based on either an outpatient physician claim for seizure disorder or a seizure-related emergency department visit or hospitalisation). In a secondary analysis, we used a more specific definition of seizure restricted to a hospital visit with a principal diagnosis of seizure.ResultsIn the primary analysis, we found no association between risk of seizure and exposure to tramadol compared with codeine (OR 1.03, 95% CI 0.93 to 1.15). However, in the secondary analysis (using a more specific definition of seizure), this association was statistically significant (OR 1.41, 95% CI 1.11 to 1.79).ConclusionsTramadol was not associated with an increased risk of seizure defined by inpatient and outpatient diagnoses. However, this finding was sensitive to the outcome definition used and requires further study.

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.

Background: Emergence coughing and bucking, secondary to endotracheal tube stimulation of the tracheal mucosa, frequently occurs after the general anesthetic recedes. Besides general unpleasantness, coughing has important physiological sequelae that may be detrimental to the postoperative patient. Multiple pharmacological strategies have been published, but prior systematic reviews on this topic have neither been comprehensive enough in their literature or medication search, nor provided us the answer regarding what the best pharmacological method is to prevent or minimize peri-extubation coughing. Our systematic review and network meta-analysis’ primary objective is to determine the relative efficacies of different pharmacological methods on decreasing coughing (none to mild compared to moderate to severe, as defined by the modified Minogue scale) during emergence after a general anesthetic with endotracheal intubation in adult elective surgeries. Medications of interest are lidocaine or lignocaine (intravenous (IV), intracuff alkalinized, intracuff non-alkalinized, topical, endotracheal application), dexmedetomidine IV, remifentanil IV, and fentanyl IV. These medications were selected based on a preliminary review of the literature. Methods: Using a predefined search strategy, we will search MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effects, and the Cochrane Methodology Register, with no date or language restrictions. Gray literature search will encompass conference abstracts, Web of Science, and references from publications selected for full-text review. Two reviewers will independently screen the retrieved literature using predetermined inclusion criteria, process publications selected for full-text review, extract data from publications chosen for study inclusion, and evaluate for bias using the Cochrane risk of bias assessment. Risk ratios and 95% confidence intervals will be calculated for each study, and a surface under the cumulative ranking curve will determine the relative rank of each intervention in its ability to prevent coughing on emergence. Discussion: The proposed systematic review and network meta-analysis will not only provide a more thorough review of common medications used to decrease emergence coughing, but also inform clinicians which of these pharmacological strategies is the best approach. Systematic review registration: PROSPERO CRD42018102870

There is concern that antidiabetic incretin-based drugs, including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, can increase the risk of heart failure. Ongoing clinical trials may not have large enough samples to effectively address this issue.We applied a common protocol in the analysis of multiple cohorts of patients with diabetes. We used health care data from four Canadian provinces, the United States, and the United Kingdom. With the use of a nested case-control analysis, we matched each patient who was hospitalized for heart failure with up to 20 controls from the same cohort; matching was based on sex, age, cohort-entry date, duration of treated diabetes, and follow-up time. Cohort-specific hazard ratios for hospitalization due to heart failure among patients receiving incretin-based drugs, as compared with those receiving oral antidiabetic-drug combinations, were estimated by means of conditional logistic regression and pooled across cohorts with the use of random-effects models.The cohorts included a total of 1,499,650 patients, with 29,741 hospitalized for heart failure (incidence rate, 9.2 events per 1000 persons per year). The rate of hospitalization for heart failure did not increase with the use of incretin-based drugs as compared with oral antidiabetic-drug combinations among patients with a history of heart failure (hazard ratio, 0.86; 95% confidence interval [CI], 0.62 to 1.19) or among those without a history of heart failure (hazard ratio, 0.82; 95% CI, 0.67 to 1.00). The results were similar for DPP-4 inhibitors and GLP-1 analogues.In this analysis of data from large cohorts of patients with diabetes, incretin-based drugs were not associated with an increased risk of hospitalization for heart failure, as compared with commonly used combinations of oral antidiabetic drugs. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT02456428.).

Purpose In distributed data networks, some data sites may be systematically missing important confounders that are captured by other sites in the network (eg, body mass index [BMI]). Multiple imputation may help repair bias in these scenarios. However, multiple imputation has not been described for distributed data networks where data access restrictions prevent centralized analysis. Methods We conducted a simulation study and a real-world analysis using the UK's Clinical Practice Research Datalink to evaluate multiple imputation for confounders that are systematically missing from a subset of data sites in mock distributed data networks. The simulation study addressed univariate missing data, while the real-world analysis addressed multivariate missing data. Both studies were designed as retrospective cohort studies of the effect of current statin use on the risk of myocardial infarction among patients with newly treated type 2 diabetes. Results In our simulation study, multiple imputation repaired bias from missing BMI in all scenarios, with a median bias reduction of 118% in the default scenario. In our real-world study, the multiply imputed analysis (hazard ratio [HR]: 0.86; 95% confidence interval [CI], 0.69-1.08) was closer to the analysis that considered the true confounder values (HR: 0.85; 95% CI, 0.66-1.10) than the analysis that ignored them (HR: 0.93; 95% CI, 0.73-1.20). Conclusions Multiple imputation adapted to distributed data settings is a feasible method to reduce bias from unmeasured but measurable confounders when at least one database contains the variables of interest. Further research is needed to evaluate its validity in real distributed data networks.

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.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.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 (p0.001) and 70% of the observed variability in Internet searches related to leg cramps (p0.001).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.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To analyze the temporal (hourly and 24-hour) blood pressure (BP) lowering efficacy of angiotensin receptor blockers (ARBs).

Cholinesterase inhibitors (ChEIs) are prescribed to dementia patients despite their poor tolerance. Low tolerability potentially reduces persistence and adherence, while inducing switching between medications. Comparisons of these utilization measures contribute to knowledge of the relative tolerability of these medications. The aim was to compare persistence, adherence, and switching between donepezil, galantamine, oral rivastigmine, and rivastigmine patch. A population-based cohort study, using British Columbia claims data (2009–2013), assessed ChEI new users aged 40 and older. We conducted survival analysis to compare persistence and Poisson regression to estimate switching rates. Good adherence, defined as a medication possession ratio of ≥80%, was modeled using log-binomial regression. Analyses were adjusted using propensity scores. Patients on galantamine had longer mean persistence and better adherence compared with patients on donepezil, with a hazard ratio for discontinuation of 0.91 [95% confidence interval (CI) 0.87–0.96] and a relative risk for good adherence of 1.01 (95% CI 1.002–1.03). Rivastigmine was associated with the shortest mean persistence [3.6 months (95% CI 3.0–4.2) and 5.0 (95% CI 4.7–5.3) for oral and patch, respectively] and the highest mean switching rates. Comparing the two rivastigmine preparations, the patch was associated with decreased discontinuation compared with oral [hazard ratio 0.79 (95% CI 0.71–0.89)] and decreased switching [relative risk 0.63 (95% CI 0.46–0.87) during the first 6 months of treatment]. Paradoxically, the patch was also associated with poorer adherence [relative risk for good adherence 0.94 (95% CI 0.91–0.98)] than the oral formulation. Based on estimates of persistence, adherence, and switching, galantamine was the best tolerated ChEI and rivastigmine the least.

ObjectivesTo study the association between accidental opioid overdose and neurological, respiratory, cardiac and other serious adverse events and whether risk of these adverse events was elevated during hospital readmissions compared with initial admissions.DesignRetrospective cohort study.SettingPopulation-based study using linked administrative data in British Columbia, Canada.ParticipantsThe primary analysis included 2433 patients with 2554 admissions for accidental opioid overdose between 2006 and 2015, including 121 readmissions within 1 year of initial admission. The secondary analysis included 538 patients discharged following a total of 552 accidental opioid overdose hospitalizations and 11 040 matched controls from a cohort of patients with ≥180 days of prescription opioid use.Outcome measuresThe primary outcome was encephalopathy; secondary outcomes were adult respiratory distress syndrome, respiratory failure, pulmonary haemorrhage, aspiration pneumonia, cardiac arrest, ventricular arrhythmia, heart failure, rhabdomyolysis, paraplegia or tetraplegia, acute renal failure, death, a composite outcome of encephalopathy or any secondary outcome and total serious adverse events (all-cause hospitalisation or death). We analysed these outcomes using generalised linear models with a logistic link function.Results3% of accidental opioid overdose admissions included encephalopathy and 25% included one or more adverse events (composite outcome). We found no evidence of increased risk of encephalopathy (OR 0.57; 95% CI 0.13 to 2.49) or other outcomes during readmissions versus initial admissions. In the secondary analysis, ConclusionsWe found no evidence that risk of encephalopathy or other adverse events was higher in readmissions compared with initial admissions for accidental opioid overdose. Risk of serious morbidity and mortality may be elevated in the year following an accidental opioid overdose.

Introduction/objective: The Canadian Network for Observational Drug Effect Studies (CNODES), a network of researchers and databases, is a collaborating center of the Drug Safety and Effectiveness Network. CNODES’ main mandate is to conduct observational studies of drug safety based on queries developed and submitted by Health Canada and other federal, provincial, and territorial stakeholders. Through a case study we explore several methodological opportunities and challenges that arise in distributed pharmacoepidemiology networks.Case study: We use as a case study a study of proton pump inhibitors and hospitalization for community-acquired pneumonia. Challenges arise in the design and conduct of studies at individual sites, and then with processes and methods for combining data. On the other hand, distributed networks provide opportunities, such as the ability to detect and understand heterogeneity, in sample sizes that would typically be impossible for a single study.Conclusions: Networks such as CNODES provide the opportunity to detect and quantify important safety signals from administrative data, and provide many challenges for methods research in pharmacoepidemiology using distributed data. As networks increase in size and scope of research questions, the need for methodological developments should continue to grow.

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.

Objective To determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes. Design Population based cohort. Setting Large, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom. Participants A cohort of 972 384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014. Main outcome measures Within each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models. Results During 2 024 441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking. Conclusions In this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas. Although this potential adverse drug reaction will need to be monitored long term owing to the latency of the cancer, these findings provide some reassurance on the safety of incretin based drugs.

Background Comparative performance of the traditional propensity score (PS) and high-dimensional propensity score (hdPS) methods in the adjustment for confounding by indication remains unclear. We aimed to identify which method provided the best adjustment for confounding by indication within the context of the risk of diabetes among patients exposed to moderate versus high potency statins. Method A cohort of diabetes-free incident statins users was identified from the Quebec’s publicly funded medico-administrative database (Full Cohort). We created two matched sub-cohorts by matching one patient initiated on a lower potency to one patient initiated on a high potency either on patients’ PS or hdPS. Both methods’ performance were compared by means of the absolute standardized differences (ASDD) regarding relevant characteristics and by means of the obtained measures of association. Results Eight out of the 18 examined characteristics were shown to be unbalanced within the Full Cohort. Although matching on either method achieved balance within all examined characteristic, matching on patients’ hdPS created the most balanced sub-cohort. Measures of associations and confidence intervals obtained within the two matched sub-cohorts overlapped. Conclusion Although ASDD suggest better matching with hdPS than with PS, measures of association were almost identical when adjusted for either method. Use of the hdPS method in adjusting for confounding by indication within future studies should be recommended due to its ability to identify confounding variables which may be unknown to the investigators. Electronic supplementary material The online version of this article (doi:10.1186/s12874-016-0119-1) contains supplementary material, which is available to authorized users.

Objective We did a systematic review of studies comparing discontinuation of tumor necrosis factor alpha (TNF) antagonists in rheumatoid arthritis (RA) patients, pooled hazard ratios and assessed clinical and methodological heterogeneity. Methods We searched MEDLINE and EMBASE until June 2015 for pairwise hazard ratios for discontinuing infliximab, etanercept, and adalimumab from cohorts of RA patients. Hazard ratios were pooled using inverse variance weighting and random effects estimates of the combined hazard ratio were obtained. Clinical and methodological heterogeneity was assessed using the between-subgroup I-square statistics and meta-regression. Results Twenty-four unique studies were eligible and large heterogeneity (I-square statistics > 50%) was observed in all comparisons. Type of data, location, and order of treatment (first or second line) modified the magnitude and direction of discontinuation comparing infliximab with either adalimumab or etanercept; however, some heterogeneity remained. No effect modifier was identified when adalimumab and etanercept were compared. Conclusion Heterogeneity in studies comparing discontinuation of TNF antagonists in RA is partially explained by type of data, location, and order of treatment. Pooling hazard ratios for discontinuing TNF antagonists is inappropriate because largely unexplained heterogeneity was demonstrated when random effect estimates were calculated.

Purpose The role of administrative databases for research on drug safety during pregnancy can be limited by their inaccurate assessment of the timing of exposure, as the gestational age at birth is typically unavailable. Therefore, we sought to develop and validate algorithms to estimate the gestational age at birth using information available in these databases. Methods Using a population-based cohort of 286,432 mother–child pairs in British Columbia (1998–2007), we validated an ICD-9/10-based preterm-status indicator and developed algorithms to estimate the gestational age at birth on the basis of this indicator, maternal age, singleton/multiple status, and claims for routine prenatal care tests. We assessed the accuracy of the algorithm-based estimates relative to the gold standard of the clinical gestational age at birth recorded in the delivery discharge record. Results The preterm-status indicator had specificity and sensitivity of 98% and 91%, respectively. Estimates from an algorithm that assigned 35 weeks of gestational age at birth to deliveries with the preterm-status indicator and 39 weeks to those without them were within 2 weeks of the clinical gestational age at birth in 75% of preterm and 99% of term deliveries. Conclusions Subtracting 35 weeks (245 days) from the date of birth in deliveries with codes for preterm birth and 39 weeks (273 days) in those without them provided the optimal estimate of the beginning of pregnancy among the algorithms studied. Copyright © 2012 John Wiley & Sons, Ltd.

Introduction: Knowledge translation (KT) initiatives have the potential to improve prescribing quality and produce savings that exceed the cost of the KT program itself, including the cost of evaluation using pragmatic study methods. Our objective was to measure the impact and estimated savings resulting from the distribution of individualized physician portraits of statin prescribing along with therapeutic recommendations in British Columbia, Canada. Methods: A paired community design was used to study 2 725 family physicians in British Columbia. Communities were paired according to number of physicians and geographic location, with one community of each pair randomly assigned to an early (n = 1 349) or delayed (n = 1 376) intervention group. The intervention was a personalized prescribing portrait on statins that included therapeutic recommendations. The primary outcome was the impact on new prescribing (defined as statin naive) for primary prevention (defined as no diagnosis of cardiovascular disease) as recorded in the administrative claims databases of the BC Ministry of Health. Results: Compared to the delayed control group, the relative probability of a new statin prescription for primary prevention decreased by 6% in the 12 months after the Education for Quality Improvement in Patient Care (EQIP) portrait compared to the preceding 12 months (relative risk [RR] 0.94; 95% confidence interval [CI] 0.91–0.98). There was also a non–statistically significant decrease in new prescribing for secondary prevention in patients diagnosed with cardiovascular disease (RR 0.96; 95% CI 0.91–1.01). We estimated that 572 fewer patients started statins for primary prevention in the first year after the portrait was mailed compared to patients in the delayed practices. We estimated the statin cost for those patients as $465,000 in the first two years, while the KT program to provide statin portraits cost less than $100,000. Discussion: The individualized prescribing portrait had a significant beneficial effect on new statin prescribing for primary prevention but not secondary prevention. Provincial drug plan costs appear to have been reduced to a level that exceeded the cost of the program.

Objective To explore the "healthy user" and "healthy adherer" effects—hypothetical sources of bias thought to arise when patients who initiate and adhere to preventive therapies are more likely to engage in healthy behaviors than are other subjects. Methods The authors examined the association between statin initiation and adherence, and the subsequent use of preventive health services and incidence of clinical outcomes unlikely to be associated with the need for, or use of, a statin among older enrollees in two state-sponsored drug benefit programs. Results After adjustment for demographic and clinical covariates, patients who initiated statin use were more likely to receive recommended preventive services than noninitiators matched on age, sex, and state (hazard ratio [HR]: 1.10, 1.06–1.14 for males, HR: 1.09, 1.07–1.11 for females) and appeared to have a lower risk of a range of adverse outcomes (HR: 0.87, 0.85–0.89) thought to be unrelated to statin use. Adherence to a statin regimen was also associated with increased rates of preventive service use and a decreased rate of adverse clinical outcomes (HR: 0.93, 0.88–0.99). Conclusions These results suggest that patients initiating and adhering to chronic preventive drug therapies are more likely to engage in other health-promoting behaviors. Failure to account for this relationship may introduce bias in any epidemiologic study evaluating the effect of a preventive therapy on clinical outcomes.

Purpose Myocardial infarction (MI) survivors benefit from receiving secondary prevention, including beta‐blockers, angiotensin‐blocking agents, and statins, as recommended by guidelines. Compliance with these guidelines is suboptimal. We sought to describe the initiation of secondary prevention in MI survivors, and to describe the variation in initiation by discharging the hospital, the physician, and the physician “responsible” for secondary prevention prescribing decisions in British Columbia in 1997–2004. Methods We assembled a cohort of 28613 patients discharged alive from the hospital after their first MI and were not readmitted within 30days. Physicians responsible for prescribing post‐MI secondary prevention medications were identified as the physicians prescribing the greatest number of cardiac medications (post‐discharge cardiac prescribers). We used multilevel logistic regression to assess the variation in drug initiation at discharging hospital, discharging physician, and post‐discharge cardiac prescriber levels, which were adjusted for patient and provider characteristics during the study period. Results Beta‐blockers initiation increased from 56 to 71% over the 8‐year study period; angiotensin‐converting enzyme/angiotensin II receptor blocker initiation increased from 37 to 70%, and statin initiation increased from 22 to 66% (0–28% for high‐potency statins). The probability for initiating an average patient with the study drugs varied widely in age–sex‐adjusted models at the hospital and physician levels. Further adjustment did not meaningfully change findings. The variation was largest for statins. The maximum between‐provider variance was found for high‐potency statins in 2003–2004 at the post‐discharge cardiac prescriber level. Conclusions Study‐drug initiation is increasing among MI survivors, but the variation in initiation is wide between discharging hospitals and physicians. Copyright © 2011 John Wiley & Sons, Ltd.