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To evaluate the impact of personalized prescribing portraits on antibiotic prescribing for treating uncomplicated acute cystitis (UAC) by Family Physicians (FPs). Cluster randomized control trial. The intervention was conducted in the primary care setting in the province of BC between December 2010 and February 2012. We randomized 4 833 FPs by geographic location into an Early intervention arm (n = 2 417) and a Delayed control arm (n = 2 416). 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. Antibiotic prescribing preference to treat UAC. 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. 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.

AbstractObjectiveTo 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.DesignMulti-database retrospective cohort study using a prevalent new user design with subsequent meta-analysis.SettingCanadian Network for Observational Drug Effect Studies (CNODES), with administrative healthcare databases from seven Canadian provinces and the United Kingdom, 2013-18.Population209 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 measuresThe 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.ResultsCompared 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).ConclusionsIn 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 registrationClinicalTrials.gov NCT03939624.

The annual cut-off date of birth for entry to school in British Columbia, Canada, is Dec. 31. Thus, children born in December are typically the youngest in their grade. We sought to determine the influence of relative age within a grade on the diagnosis and pharmacologic treatment of attention-deficit/hyperactivity disorder (ADHD) in children. We conducted a cohort study involving 937 943 children in British Columbia who were 6–12 years of age at any time between Dec. 1, 1997, and Nov. 30, 2008. We calculated the absolute and relative risk of receiving a diagnosis of ADHD and of receiving a prescription for a medication used to treat ADHD (i.e., methylphenidate, dextroamphetamine, mixed amphetamine salts or atomoxetine) for children born in December compared with children born in January. Boys who were born in December were 30% more likely (relative risk [RR] 1.30, 95% confidence interval [CI] 1.23–1.37) to receive a diagnosis of ADHD than boys born in January. Girls born in December were 70% more likely (RR 1.70, 95% CI 1.53–1.88) to receive a diagnosis of ADHD than girls born in January. Similarly, boys were 41% more likely (RR 1.41, 95% CI 1.33–1.50) and girls 77% more likely (RR 1.77, 95% CI 1.57–2.00) to be given a prescription for a medication to treat ADHD if they were born in December than if they were born in January. The results of our analyses show a relative-age effect in the diagnosis and treatment of ADHD in children aged 6–12 years in British Columbia. These findings raise concerns about the potential harms of overdiagnosis and overprescribing. These harms include adverse effects on sleep, appetite and growth, in addition to increased risk of cardiovascular events.

ObjectiveTo estimate the prevalence of potential overtreatment of type 2 diabetes mellitus (T2DM) among older adults and to develop and compare predictive models to identify patient and physician characteristics associated with overtreatment.DesignPopulation-based retrospective cohort study with predictive modelling.SettingA province-wide, publicly funded healthcare system in British Columbia, Canada, using linked administrative health claims data from 2016 to 2023.ParticipantsResidents of long-term care facilities over age 65, and community-dwelling individuals over age 75, with a diagnosis of T2DM and a glycated haemoglobin (A1C) laboratory value ≤7.0%. Participants were required to have ≥365 days of continuous provincial health insurance coverage prior to their index A1C test. Patients receiving palliative care and those with missing physician information were excluded.Primary and secondary outcome measuresPotential overtreatment of T2DM, defined a priori as overlapping prescriptions for ≥2 glucose-lowering medications or ≥1 insulin or sulfonylurea dispensing within 90 days after the index A1C test.Model performance outcomes included discrimination (area under the curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value). Performance metrics were calculated with 95% CIs using a 25% temporally distinct test dataset (2021–2023). No changes were made to outcome definitions after protocol development.ResultsAmong 133 773 patients with an A1C≤7.0%, 38 074 (28.5%) were classified as overtreated. These patients had a mean age of 79.6 years, were 47% female, and had a median A1C of 6.4%. The gradient boost model was the best performing model overall, using a combination of expert-selected variables and data-driven variables, achieving an AUC of 0.87, sensitivity of 0.81 and negative predictive value of 0.89. The top predictors of overtreatment included use of blood glucose test strips, A1C test volume, polypharmacy, specialist involvement and measures of diabetes severity.ConclusionsOvertreatment of T2DM was prevalent among older adults in our cohort. Machine learning algorithms that integrate clinical expertise with data-driven variable selection performed the best in predicting T2DM overtreatment. We identified several patient and physician characteristics as key contributors that may inform future clinical practice and quality improvement initiatives, although external validation is required before clinical implementation.

In this analysis of data from several large cohorts of patients with diabetes, antidiabetic 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. The safety of incretin-based drugs, which include dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, is controversial. Although much attention has been focused on adverse pancreatic events, there are new concerns about an increased risk of heart failure. 1 Indeed, in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, 2 , 3 patients who were randomly assigned to the DPP-4 inhibitor saxagliptin had a 27% increase in the risk of hospitalization for heart failure as compared with those who received placebo. In contrast, the Examination of Cardiovascular Outcomes with . . .

Objective To determine the safety of direct oral anticoagulant (DOAC) use compared with warfarin use for the treatment of venous thromboembolism.Design Retrospective matched cohort study conducted between 1 January 2009 and 31 March 2016.Setting Community based, using healthcare data from six jurisdictions in Canada and the United States.Participants 59 525 adults (12 489 DOAC users; 47 036 warfarin users) with a new diagnosis of venous thromboembolism and a prescription for a DOAC or warfarin within 30 days of diagnosis.Main outcome measures Outcomes included hospital admission or emergency department visit for major bleeding and all cause mortality within 90 days after starting treatment. Propensity score matching and shared frailty models were used to estimate adjusted hazard ratios of the outcomes comparing DOACs with warfarin. Analyses were conducted independently at each site, with meta-analytical methods used to estimate pooled hazard ratios across sites.Results Of the 59 525 participants, 1967 (3.3%) had a major bleed and 1029 (1.7%) died over a mean follow-up of 85.2 days. The risk of major bleeding was similar for DOAC compared with warfarin use (pooled hazard ratio 0.92, 95% confidence interval 0.82 to 1.03), with the overall direction of the association favouring DOAC use. No difference was found in the risk of death (pooled hazard ratio 0.99, 0.84 to 1.16) for DOACs compared with warfarin use. There was no evidence of heterogeneity across centres, between patients with and without chronic kidney disease, across age groups, or between male and female patients.Conclusions In this analysis of adults with incident venous thromboembolism, treatment with DOACs, compared with warfarin, was not associated with an increased risk of major bleeding or all cause mortality in the first 90 days of treatment.Trial registration Clinical trials NCT02833987.

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.

Objective Previous observational studies suggest that the use of proton pump inhibitors (PPIs) may increase the risk of hospitalisation for community-acquired pneumonia (HCAP). However, the potential presence of confounding and protopathic biases limits the conclusions that can be drawn from these studies. Our objective was, therefore, to examine the risk of HCAP with PPIs prescribed prophylactically in new users of non-steroidal anti-inflammatory drugs (NSAIDs). Design We formed eight restricted cohorts of new users of NSAIDs, aged ≥40 years, using a common protocol in eight databases (Alberta, Saskatchewan, Manitoba, Ontario, Quebec, Nova Scotia, US MarketScan and the UK's General Practice Research Database (GPRD)). This specific patient population was studied to minimise bias due to unmeasured confounders. High-dimensional propensity scores were used to estimate site-specific adjusted ORs (aORs) for HCAP at 6 months in PPI patients compared with unexposed patients. Fixed-effects meta-analytic models were used to estimate overall effects across databases. Results Of the 4 238 504 new users of NSAIDs, 2.3% also started a PPI. The cumulative 6-month incidence of HCAP was 0.17% among patients prescribed PPIs and 0.12% in unexposed patients. After adjustment, PPIs were not associated with an increased risk of HCAP (aOR=1.05; 95% CI 0.89 to 1.25). Histamine-2 receptor antagonists yielded similar results (aOR=0.95, 95% CI  0.75 to 1.21). Conclusions Our study does not support the proposition of a pharmacological effect of gastric acid suppressors on the risk of HCAP.

•Industry sponsors in some cases influence decisions on whether to report trials.•Companies may influence reporting through owning and controlling access to data.•Trial agreements may only weakly protect the right of site investigators to publish.•Early phase internal company trials are a source of unpublished clinical trials.•Small biotech firms may cease operations without publishing their results. 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.

Network meta-analysis is increasingly used to allow comparison of multiple treatment alternatives simultaneously, some of which may not have been compared directly in primary research studies. The majority of network meta-analyses published to date have incorporated data from randomized controlled trials (RCTs) only; however, inclusion of non-randomized studies may sometimes be considered. Non-randomized studies can complement RCTs or address some of their limitations, such as short follow-up time, small sample size, highly selected population, high cost, and ethical restrictions. In this paper, we discuss the challenges and opportunities of incorporating both RCTs and non-randomized comparative cohort studies into network meta-analysis for assessing the safety and effectiveness of medical treatments. Non-randomized studies with inadequate control of biases such as confounding may threaten the validity of the entire network meta-analysis. Therefore, identification and inclusion of non-randomized studies must balance their strengths with their limitations. Inclusion of both RCTs and non-randomized studies in network meta-analysis will likely increase in the future due to the growing need to assess multiple treatments simultaneously, the availability of higher quality non-randomized data and more valid methods, and the increased use of progressive licensing and product listing agreements requiring collection of data over the life cycle of medical products. Inappropriate inclusion of non-randomized studies could perpetuate the biases that are unknown, unmeasured, or uncontrolled. However, thoughtful integration of randomized and non-randomized studies may offer opportunities to provide more timely, comprehensive, and generalizable evidence about the comparative safety and effectiveness of medical treatments.