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Selective serotonin reuptake inhibitors (SSRIs) have been associated with type 2 diabetes mellitus (T2DM) in youths, possibly via 5-HTUsing the UK Clinical Practice Research Datalink, we assembled a cohort of patients aged 5-24, newly prescribed a strong-affinity SSRI (citalopram, escitalopram, fluoxetine) or weak affinity (paroxetine, sertraline, fluvoxamine) between 1990 and 2019. We controlled for confounding using standardized mortality ratio weighting, estimated from calendar time-specific propensity scores. We used weighted Cox proportional hazards models to estimate hazard ratios (HRs) of incident T2DM with 95 % confidence intervals (CIs).The cohort included 347,368 new users of strong-affinity SSRIs and 131,359 of weak-affinity SSRIs. Strong-affinity SSRIs were not associated with an increased T2DM risk compared with weak-affinity SSRIs (incidence rate 2.8 vs 2.7 per 1000 person-years; HR 1.03, 95 % CI 0.85-1.25). T2DM risk did not vary with duration of use, age or sex. However, the HR was numerically higher in youths with normal or low weight (HR 1.30, 95 % CI 0.85-1.98) and with prior antipsychotic use (HR 1.62, 95 % CI 0.83-3.18).Median duration of SSRI use, in line with real-world SSRI prescribing, was relatively short.T2DM risk did not differ between strong- and weak-affinity SSRIs, providing reassurance for clinicians when choosing between SSRIs in youths.

PurposeWith the increasing utilization of medications worldwide, coupled with the increasing availability of long-term data, there is a growing opportunity and need for robust studies evaluating drug–cancer associations. One methodology of importance in such studies is the application of lag times.MethodsIn this narrative review, we discuss the main reasons for using lag times.ResultsNamely, we discuss the typically long latency period of cancer concerning both tumor promoter and initiator effects and outline why cancer latency is a key consideration when choosing a lag time. We also discuss how the use of lag times can help reduce protopathic and detection bias. Finally, we present practical advice for implementing lag periods.ConclusionsIn general, we recommend that researchers consider the information that generated the hypothesis as well as clinical and biological knowledge to inform lag period selection. In addition, given that latency periods are usually unknown, we also advocate that researchers examine multiple lag periods in sensitivity analyses as well as duration analyses and flexible modeling approaches.

Randomized controlled trials (RCTs) continue to be the basis for essential evidence regarding the efficacy of interventions such as cancer therapies. Limitations associated with RCT designs, including selective study populations, strict treatment regimens, and being time-limited, mean they do not provide complete information about an intervention’s safety or the applicability of the trial’s results to a wider range of patients seen in real-world clinical practice. For example, recent data from Alberta showed that almost 40% of patients in the province’s cancer registry would be trial-ineligible per common exclusion criteria. Real-world evidence (RWE) offers an opportunity to complement the RCT evidence base with this kind of information about safety and about use in wider patient populations. It is also increasingly recognized for being able to provide information about an intervention’s effectiveness and is considered by regulators as an important component of the evidence base in drug approvals. Here, we examine the limitations of RCTs in oncology research, review the different types of RWE available in this area, and discuss the strengths and limitations of RWE for complementing RCT oncology data.

Current guidelines recommend the treatment of hormone receptor-positive breast cancer with aromatase inhibitors (AIs) and tamoxifen in the adjuvant setting. Some observational studies have raised concerns that tamoxifen may be associated with an increased risk of Parkinson disease (PD). However, no studies have directly compared the risk of PD between AIs and tamoxifen in women diagnosed with breast cancer.Using the UK Clinical Practice Research Datalink, the authors assembled a cohort of women newly diagnosed with breast cancer and newly treated with either AIs or tamoxifen between January 1, 1995, and December 31, 2017. Patients were followed 1 year after treatment initiation (ie, a 1-year lag) until an incident diagnosis of PD or were censored at death from any cause, the date of transfer out of the practice, or the end of the study period (December 31, 2018). Cox proportional hazards models with inverse probability of treatment weights were used to estimate weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for PD comparing AIs with tamoxifen and accounting for more than 30 confounders.In all, 30,140 women with nonmetastatic breast cancer were identified: 13,838 initiated AIs, and 16,302 initiated tamoxifen. Compared with tamoxifen, AIs were not associated with an increased risk of PD (HR, 0.94; 95% CI, 0.60-1.47). Consistent results were observed across all secondary and sensitivity analyses.In this large observational study, the use of AIs, in comparison with tamoxifen, was not associated with an increased risk of PD in women diagnosed with nonmetastatic breast cancer in a real-world setting.Previous studies have indicated that tamoxifen may increase the risk of Parkinson disease in the treatment of breast cancer. However, no studies have directly compared the risk of Parkinson disease between aromatase inhibitors and tamoxifen. This study included 30,140 women diagnosed with breast cancer and treated with aromatase inhibitors or tamoxifen. Overall, compared with tamoxifen, aromatase inhibitors were not associated with an increased risk of Parkinson disease in women diagnosed with breast cancer. This study provides an important addition to the comparative safety profile of aromatase inhibitors and tamoxifen in the treatment of breast cancer.

Aims To evaluate the effectiveness and safety of apixaban versus rivaroxaban among patients with nonvalvular atrial fibrillation (NVAF) and type 2 diabetes mellitus (T2DM). Methods and Results Using the United Kingdom's Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository, and the Office for National Statistics database, we identified a cohort of patients with NVAF and T2DM newly treated with apixaban or rivaroxaban between 2013 and 2020. Propensity scores with standardized mortality ratio weighting were used to control for confounding. We used weighted Cox proportional hazards models to estimate separately the hazard ratios (HRs) with 95% confidence intervals (CIs) of ischemic stroke, major bleeding, and major adverse limb events associated with the use of apixaban compared with rivaroxaban. We also evaluated whether the risk was modified by age, sex, duration of diabetes, microvascular and macrovascular complications of diabetes, nephropathy, CHA2DS2-VASc and HAS-BLED scores, and by dose (standard vs. low dose). Results The cohort included 11,561 apixaban and 8,265 rivaroxaban users. Apixaban was associated with a similar risk of stroke (HR: 0.99, 95% CI: 0.79–1.23), and a 32% reduced risk of major bleeding (HR: 0.68, 95% CI: 0.59–0.78), compared with rivaroxaban. The risk of major adverse limb events was similar between apixaban and rivaroxaban (HR: 0.75, 95% CI: 0.54–1.04). Overall, the risk of ischemic stroke and major bleeding was consistent in stratified analyses. Conclusion Among patients with NVAF and T2DM, apixaban was associated with a similar risk of stroke and a lower risk of major bleeding compared with rivaroxaban.

Case reports and a pharmacovigilance analysis have linked glucagon-like peptide 1 receptor agonists (GLP-1 RAs) with anaphylactic reactions, but real-world evidence for this possible association is lacking. Using databases from the United Kingdom (Clinical Practice Research Datalink) and the United States (Medicare, Optum (Optum, Inc., Eden Prairie, Minnesota), and IBM MarketScan (IBM, Armonk, New York)), we employed a new-user, active comparator study design wherein initiators of GLP-1 RAs were compared with 2 different active comparator groups (initiators of dipeptidyl peptidase 4 (DPP-4) inhibitors and initiators of sodium-glucose cotransporter 2 (SGLT-2) inhibitors) between 2007 and 2019. Propensity score fine stratification weighted Cox proportional hazards models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for an anaphylactic reaction. Database-specific HRs were pooled using random-effects models. Compared with the use of DPP-4 inhibitors (n = 1,641,520), use of GLP-1 RAs (n = 324,098) generated a modest increase in the HR for anaphylactic reaction, with a wide 95% CI (36.9 per 100,000 person-years vs. 32.1 per 100,000 person-years, respectively; HR = 1.15, 95% CI: 0.94, 1.42). Compared with SGLT-2 inhibitors (n = 366,067), GLP-1 RAs (n = 259,929) were associated with a 38% increased risk of anaphylactic reaction (40.7 per 100,000 person-years vs. 29.4 per 100,000 person-years, respectively; HR = 1.38, 95% CI: 1.02, 1.87). In this large, multisite population-based cohort study, GLP-1 RAs were associated with a modestly increased risk of anaphylactic reaction when compared with DPP-4 inhibitors and SGLT-2 inhibitors.

OBJECTIVE To determine whether glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium–glucose cotransporter 2 (SGLT-2) inhibitors, separately, are associated with a decreased risk of nonalcoholic fatty liver disease (NAFLD) compared with dipeptidyl peptidase 4 (DPP-4) inhibitors among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We assembled two new-user, active comparator cohorts using the U.K. Clinical Practice Research Datalink. The first included 30,291 and 225,320 new users of GLP-1 RA and DPP-4 inhibitors, respectively. The second included 41,184 and 148,421 new users of SGLT-2 inhibitors and DPP-4 inhibitors, respectively. Cox proportional hazards models weighted using propensity score fine stratification were fit to estimate hazard ratios (HRs) with 95% CIs of NAFLD. We also determined whether the study drugs were associated with a decreased risk of hepatic transaminase elevation within restricted subcohorts. RESULTS GLP-1 RA were associated with a lower incidence of NAFLD with a wide CI compared with DPP-4 inhibitors (3.9 vs. 4.6 per 1,000 person-years, respectively; HR 0.86, 95% CI 0.73–1.01). SGLT-2 inhibitors were associated with a decreased risk of NAFLD (5.4 vs. 7.0 per 1,000 person-years, respectively; HR 0.78, 95% CI 0.68–0.89). In the restricted subcohorts, both GLP-1 RA and SGLT-2 inhibitors were associated with a decreased risk of hepatic transaminase elevation (HR 0.89, 95% CI 0.83–0.95, and HR 0.66, 95% CI 0.61–0.71). CONCLUSIONS SGLT-2 inhibitors, and possibly GLP-1 RA, may be associated with a decreased incidence of NAFLD and hepatic transaminase elevation among patients with type 2 diabetes.

Background:Preclinical evidence suggests that 5α-reductase inhibitors (5ARi), commonly used to treat benign prostatic hyperplasia (BPH), are associated with reduced incidence of certain urologic cancers, yet epidemiologic studies are conflicting. This study aimed to determine whether 5ARi's are associated with a reduced risk of kidney and bladder cancers.Methods:We conducted a new-user active-comparator cohort study in the United Kingdom Clinical Practice Research Datalink. From a base cohort of patients with incident BPH, new users of 5ARi's and α-blockers were identified. Patients were followed up until a first ever diagnosis of kidney or bladder cancer, death from any cause, end of registration, or December 31, 2017. Cox proportional hazards models were used to calculate HRs and 95% confidence intervals (CI) for incident kidney and bladder cancer.Results:There were 5,414 and 37,681 new users of 5ARi's and α-blockers, respectively. During a mean follow-up of 6.3 years, we found no association between the use of 5ARi's and kidney (adjusted HR, 1.26; 95% CI, 0.74–2.12; n = 23) or bladder (adjusted HR, 0.89; 95% CI, 0.64–1.23; n = 57) cancer risk compared with α-blockers. Similar results were observed across sensitivity analyses.Conclusions:In this study, we found no association between the use of 5ARi's and kidney or bladder cancer incidence in men with BPH when compared with α-blocker use.Impact:The findings of this study indicate that 5ARi's are unlikely to reduce kidney or bladder cancer risk.

Objective To determine whether the use of glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, separately, is associated with a decreased risk of exacerbations of chronic obstructive pulmonary disease among patients with chronic obstructive pulmonary disease and type 2 diabetes. Design Population based cohort study using an active comparator, new user design. Setting The United Kingdom Clinical Practice Research Datalink linked with the Hospital Episode Statistics Admitted Patient Care and Office for National Statistics databases. Participants Three active comparator, new user cohorts of patients starting the study drugs (GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT-2 inhibitors) or sulfonylureas with a history of chronic obstructive pulmonary disease. The first cohort included 1252 patients starting GLP-1 receptor agonists and 14 259 starting sulfonylureas, the second cohort included 8731 patients starting DPP-4 inhibitors and 18 204 starting sulfonylureas, and the third cohort included 2956 patients starting SGLT-2 inhibitors and 10 841 starting sulfonylureas. Main outcome measures Cox proportional hazards models with propensity score fine stratification weighting were fitted to estimate hazard ratios and 95% confidence intervals of severe exacerbation of chronic obstructive pulmonary disease (defined as hospital admission for chronic obstructive pulmonary disease), separately for GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors. Whether these drugs were associated with a decreased risk of moderate exacerbation (defined as a co-prescription of an oral corticosteroid and an antibiotic along with an outpatient diagnosis of acute chronic obstructive pulmonary disease exacerbation on the same day) was also assessed. Results Compared with sulfonylureas, GLP-1 receptor agonists were associated with a 30% decreased risk of severe exacerbation (3.5 v 5.0 events per 100 person years; hazard ratio 0.70, 95% confidence interval 0.49 to 0.99) and moderate exacerbation (0.63, 0.43 to 0.94). DPP-4 inhibitors were associated with a modestly decreased incidence of severe exacerbation (4.6 v . 5.1 events per 100 person years; hazard ratio 0.91, 0.82 to 1.02) and moderate exacerbation (0.93, 0.82 to 1.07), with confidence intervals including the null value. Finally, SGLT-2 inhibitors were associated with a 38% decreased risk of severe exacerbation (2.4 v 3.9 events per 100 person years; hazard ratio 0.62, 0.48 to 0.81) but not moderate exacerbation (1.02, 0.83 to 1.27). Conclusions In this population based study, GLP-1 receptor agonists and SGLT-2 inhibitors were associated with a reduced risk of severe exacerbations compared with sulfonylureas in patients with chronic obstructive pulmonary disease and type 2 diabetes. DPP-4 inhibitors were not clearly associated with a decreased risk of chronic obstructive pulmonary disease exacerbations.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors might increase the risk of intestinal obstruction, but real-world evidence for this severe adverse event is lacking. Thus, the objective of this study was to determine whether GLP-1 RAs and DPP-4 inhibitors are associated with an increased risk of intestinal obstruction compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. We used the United Kingdom Clinical Practice Research Datalink and linked databases to assemble two new-user, active comparator cohorts (2013-2019). The first included 25,617 and 67,261 GLP-1 RA and SGLT-2 inhibitor users, respectively. The second included 131,927 and 40,615 DPP-4 inhibitor and SGLT-2 inhibitor users, respectively. Propensity score fine stratification weighted Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of intestinal obstruction requiring hospitalization. GLP-1 RAs were associated with an increased risk of intestinal obstruction compared with SGLT-2 inhibitors (1.9 vs. 1.1 per 1,000 person-years, respectively; HR: 1.69, 95% CI: 1.04-2.74). The highest HR was observed after 1.6 years of use (HR: 3.48, 95% CI: 1.79-6.79). DPP-4 inhibitors were also associated with an increased risk (2.7 vs. 1.0 per 1,000 person-years; HR: 2.59, 95% CI: 1.52-4.42), with the highest HR observed after 1.8 years of use (HR: 9.53, 95% CI: 4.47-20.30). The number needed to harm after 1 year of use was 1,223 and 603 for GLP-1 RAs and DPP-4 inhibitors, respectively. In this large real-world study, GLP-1 RAs and DPP-4 inhibitors were associated with an increased risk of intestinal obstruction.

OBJECTIVE Irregular menstrual cycles are associated with increased cardiovascular mortality. Polycystic ovary syndrome (PCOS) is characterized by androgen excess and irregular menses; androgens are drivers of increased metabolic risk in women with PCOS. Combined oral contraceptive pills (COCPs) are used in PCOS both for cycle regulation and to reduce the biologically active androgen fraction. We examined COCP use and risk of dysglycemia (prediabetes and type 2 diabetes) in women with PCOS. RESEARCH DESIGN AND METHODS Using a large U.K. primary care database (The Health Improvement Network [THIN]; 3.7 million patients from 787 practices), we carried out a retrospective population-based cohort study to determine dysglycemia risk (64,051 women with PCOS and 123,545 matched control subjects), as well as a nested pharmacoepidemiological case-control study to investigate COCP use in relation to dysglycemia risk (2,407 women with PCOS with [case subjects] and without [control subjects] a diagnosis of dysglycemia during follow-up). Cox models were used to estimate the unadjusted and adjusted hazard ratio, and conditional logistic regression was used to obtain adjusted odds ratios (aORs). RESULTS The adjusted hazard ratio for dysglycemia in women with PCOS was 1.87 (95% CI 1.78–1.97, P < 0.001; adjustment for age, social deprivation, BMI, ethnicity, and smoking), with increased rates of dysglycemia in all BMI subgroups. Women with PCOS and COCP use had a reduced dysglycemia risk (aOR 0.72, 95% CI 0.59–0.87). CONCLUSIONS In this study, limited by its retrospective nature and the use of routinely collected electronic general practice record data, which does not allow for exclusion of the impact of prescription-by-indication bias, women with PCOS exposed to COCPs had a reduced risk of dysglycemia across all BMI subgroups. Future prospective studies should be considered for further understanding of these observations and potential causality.

Aims To determine whether adiposity modified the effect on the cardiovascular safety of sulfonylureas as a first-line therapy compared with metformin among patients with type 2 diabetes. Materials and methods Using the UK Clinical Practice Research Datalink, we conducted a cohort study among 13 862 new sulfonylurea users matched on body mass index (BMI) and propensity score, in a 1:1 ratio, to new metformin users between April 1, 1998 and December 31, 2016. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of major adverse cardiovascular events (MACE), individual components of MACE (myocardial infarction, ischemic stroke, cardiovascular mortality), and all-cause mortality, comparing use of sulfonylureas with use of metformin overall, and within BMI categories (≤ 24.9 kg/m2 , 25.0-29.9 kg/m2 , ≥ 30 kg/m2 ). Results Compared with metformin, sulfonylureas were not associated with an increased risk of MACE either overall (HR: 1.08; 95% CI: 0.94-1.23) or by BMI categories. Similar findings were observed for myocardial infarction and ischemic stroke. In contrast, sulfonylureas were associated with an increased risk of cardiovascular mortality (HR: 1.24; 95% CI: 1.04-1.48), primarily among obese patients (HR: 1.52; 95% CI: 1.08-2.13), and not among normal-weight patients (HR: 1.00; 95% CI: 0.72-1.39; p-interaction: 0.21). Similar results were observed for all-cause mortality (HR: 1.47; 95% CI: 1.32-1.62), where an increased risk was observed among obese patients (HR: 1.83; 95% CI: 1.49-2.25), but not normal-weight patients (HR: 1.18; 95% CI: 0.99-1.42; p-interaction: 0.006). Conclusion The findings of this study suggest that adiposity may have a modifying effect on the association between sulfonylureas and cardiovascular and all-cause mortality compared with metformin. This article is protected by copyright. All rights reserved.

Objective: To determine whether sodium-glucose co-transporter 2 (SGLT2) inhibitors, compared with glucagon-like peptide-receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 (DPP4) inhibitors are associated with an increased risk of early bladder cancer events. Research Design & Methods: We conducted a multi-site, population-based, new-user active comparator cohort study using the United Kingdom Clinical Practice Research Datalink, Medicare fee-for-service, Optum© Clinformatics® Data Mart, and MarketScan Health from January 2013 through December 2020. We assembled two cohorts of adults with type 2 diabetes initiating (1) SGLT2 inhibitors or GLP-1RAs, and (2) SGLT2 inhibitors or DPP4 inhibitors. Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident bladder cancer. The models were weighted using propensity score fine stratification. Site-specific HRs were pooled using random-effects models. Results: SGLT2 inhibitor (n=453,560) and GLP-1RA (n=375,997) users had a median follow-up ranging from 1.5-2.2 years. Overall, SGLT2 inhibitors were not associated with an increased risk of bladder cancer, compared with GLP-1RAs (HR=0.90; 95% CI: 0.81-1.00). Similarly, when compared with DPP-4 inhibitors (n=853,186), SGLT2 inhibitors (n=347,059) were not associated with an increased risk of bladder cancer (HR: 0.99, 95% CI: 0.91-1.09) over a median follow-up ranging from 1.6-2.6 years. Results were consistent across sensitivity analyses. Conclusions: Contrary to previous randomized controlled trials, these findings indicate that the use of SGLT2 inhibitors is not associated with an increased risk of bladder cancer when compared with GLP-1RAs or DPP4 inhibitors. This should provide reassurance on the short-term effects of SGLT2 inhibitors on bladder cancer incidence.

ObjectiveTo determine whether the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, compared to dipeptidyl peptidase 4 (DPP-4) inhibitors, is associated with a decreased risk of incident lung cancers among patients with type 2 diabetes.MethodsWe assembled a new-user, active comparator cohort of SGLT-2 inhibitor and DPP-4 inhibitor users using the United Kingdom Clinical Practice Research Datalink. We fit Cox proportional hazards models with propensity score fine stratification weighting to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for incident lung cancers.ResultsCrude lung cancer incidence rates were 0.92 and 1.37 per 1,000 person-years among 47,517 SGLT-2 inhibitor and 129,807 DPP-4 inhibitor users, respectively. No reduced risk of lung cancer was observed among SGLT-2 inhibitor users after weighting (HR 1.08, 95% CI 0.78–1.48). Conclusions: In this large cohort study, the use of SGLT-2 inhibitors was not associated with a decreased risk of lung cancer.

ObjectiveTo determine whether proton pump inhibitors (PPIs) are associated with an increased risk of colorectal cancer, compared with histamine-2 receptor antagonists (H2RAs).DesignThe United Kingdom Clinical Practice Research Datalink was used to identify initiators of PPIs and H2RA from 1990 to 2018, with follow-up until 2019. Cox proportional hazards models were fit to estimate marginal HRs and 95% CIs of colorectal cancer. The models were weighted using standardised mortality ratio weights using calendar time-specific propensity scores. Prespecified secondary analyses assessed associations with cumulative duration, cumulative dose and time since treatment initiation. The number needed to harm was calculated at five and 10 years of follow-up.ResultsThe cohort included 1 293 749 and 292 387 initiators of PPIs and H2RAs, respectively, followed for a median duration of 4.9 years. While the use of PPIs was not associated with an overall increased risk of colorectal cancer (HR: 1.02, 95% CI 0.92 to 1.14), HRs increased with cumulative duration of PPI use (ConclusionWhile any use of PPIs was not associated with an increased risk of colorectal cancer compared with H2RAs, prolonged use may be associated with a modest increased risk of this malignancy.

Background As in other jurisdictions, the demographics of people infected with SARS-CoV-2 changed in Quebec over the course of the first COVID-19 pandemic wave, and affected those living in residential care facilities (RCFs) disproportionately. We evaluated the association between clinical characteristics and outcomes of hospitalized patients with COVID-19, comparing those did or did not live in RCFs. Methods We conducted a retrospective case series of all consecutive adults (≥ 18 yr) admitted to the Jewish General Hospital in Montreal with laboratory-confirmed SARS-CoV-2 infection from Mar. 4 to June 30, 2020, with in-hospital follow-up until Aug. 6, 2020. We collected patient demographics, comorbidities and outcomes (i.e., admission to the intensive care unit, mechanical ventilation and death) from medical and laboratory records and compared patients who did or did not live in public and private RCFs. We evaluated factors associated with the risk of in-hospital death with a Cox proportional hazard model. Results In total, 656 patients were hospitalized between March and June 2020, including 303 patients who lived in RCFs and 353 patients who did not. The mean age was 72.9 (standard deviation 18.3) years (range 21 to 106 yr); 349 (53.2%) were female and 118 (18.0%) were admitted to the intensive care unit. The overall mortality rate was 23.8% (156/656), but was higher among patients living in RCFs (36.6% [111/303]) compared with those not living in RCFs (12.7% [45/353]). Increased risk of death was associated with age 80 years and older (hazard ratio [HR] 2.39, 95% confidence interval [CI] 1.35-4.24), male sex (HR 1.74, 95% CI 1.25-2.41), the presence of 4 or more comorbidities (HR 2.01, 95% CI 1.18-3.42) and living in an RCF (HR 1.62, 95% CI 1.09-2.39). Interpretation During the first wave of the COVID-19 epidemic in Montreal, more than one-third of RCF residents hospitalized with SARS-CoV-2 infection died during hospitalization. Policies and practices that prevent future outbreaks of SARS-CoV-2 infection in this setting must be implemented to prevent high mortality in this vulnerable population.

Background: Previous studies suggested a link between various infectious pathogens and the development of Alzheimer’s disease (AD), posing the question whether infectious disease could present a novel modifiable risk factor. Objective: To assess whether infectious disease burden due to clinically apparent infections is associated with an increased risk of AD. Methods: We conducted a population-based nested case-control study using the United Kingdom Clinical Practice Research Datalink. We included all dementia-free subjects ≥50 years of age enrolling in the database between January 1988 and December 2017. Each case of AD identified during follow-up was matched with up to 40 controls. Conditional logistic regression estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with ≥1 infection diagnosed > 2 years before the index date compared with no infection during the study period. We further stratified by time since first infection and cumulative number of infections. Results: The cohort included overall 4,262,092 individuals (mean age at cohort entry 60.4 years; 52% female). During a median follow-up of 10.5 years, 40,455 cases of AD were matched to 1,610,502 controls. Compared with having no burden of infectious disease, having a burden of infectious disease was associated with an increase in the risk of AD (OR, 1.05; 95% CI, 1.02 to 1.08). The risk increased with longer time since first infection, peaking after 12–30 years (OR, 1.11; 95% CI, 1.05–1.17). The risk did not increase with cumulative number of infections. Conclusion: The overall risk of AD associated with infectious disease burden was small but increased gradually with longer time since first infection.

OBJECTIVE: To determine whether the use of dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), separately, is associated with an increased risk of acute liver injury compared with the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors. RESEARCH DESIGN AND METHODS: We used the United Kingdom Clinical Practice Research Datalink linked with the Hospital Episode Statistics Admitted Patient Care and the Office for National Statistics databases to assemble two new-user, active comparator cohorts. The first included 106,310 initiators of DPP-4 inhibitors and 27,277 initiators of SGLT-2 inhibitors, while the second included 9470 initiators of GLP-1 RAs and 26,936 initiators of SGLT-2 inhibitors. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of acute liver injury. RESULTS: Compared with SGLT-2 inhibitors, DPP-4 inhibitors were associated with a 53% increased risk of acute liver injury (HR: 1.53, 95% CI: 1.02-2.30). In contrast, GLP-1 RAs were not associated with an overall increased risk of acute liver injury (HR: 1.11, 95% CI: 0.57-2.16). However, an increased risk was observed among female users of both DPP-4 inhibitors (HR: 3.22, 95% CI: 1.67-6.21) and GLP-1 RAs (HR: 3.23, 95% CI: 1.44-7.25). CONCLUSIONS: In this population-based study, DPP-4 inhibitors were associated with an increased risk of acute liver injury compared with SGLT-2 inhibitors in patients with type 2 diabetes. In contrast, an increased risk of acute liver injury was observed only among female GLP-1 RA users.

ObjectivesTo describe the prescribing trends of antihypertensive drugs in primary care patients and assess the trajectory of antihypertensive drug prescriptions, from first-line to third-line, in patients with hypertension according to changes to the United Kingdom (UK) hypertension management guidelines.DesignPopulation-based cohort study.Setting and participantsWe used the UK Clinical Practice Research Datalink, an electronic primary care database representative of the UK population. Between 1988 and 2018, we identified all adult patients with at least one prescription for a thiazide diuretic, angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker, beta-blocker or calcium channel blocker (CCB).Primary and secondary outcome measuresWe estimated the period prevalence of patients with antihypertensive drug prescriptions for each calendar year over a 31-year period. Treatment trajectory was assessed by identifying patients with hypertension newly initiating an antihypertensive drug, and treatment changes were defined by a switch or add-on of a new class. This cohort was stratified before and after 2007, the year following important changes to UK hypertension management guidelines.ResultsThe cohort included 2 709 241 patients. The prevalence of primary care patients with antihypertensive drug prescriptions increased from 7.8% (1988) to 21.9% (2018) and was observed for all major classes except thiazide diuretics. Patients with hypertension initiated thiazide diuretics (36.8%) and beta-blockers (23.6%) as first-line drugs before 2007, and ACE inhibitors (39.9%) and CCBs (31.8%) after 2007. After 2007, 17.3% were not prescribed guideline-recommended first-line agents. Overall, patients were prescribed a median of 2 classes (IQR 1–2) after first-line treatment.ConclusionNearly one-quarter of primary care patients were prescribed antihypertensive drugs by the end of the study period. Most patients with hypertension initiated guideline-recommended first-line agents. Not all patients, particularly females, were prescribed recommended agents however, potentially leading to suboptimal cardiovascular outcomes. Future research should aim to better understand the implication of this finding.

SGLT2 inhibitors (SGLT2is) have been shown to reduce the risk of cardiovascular and mortality events in large cardiovascular outcome trials in patients with type 2 diabetes. However, their safety profile is controversial, with some trials reporting imbalances in bladder cancer events, all of which occurred relatively soon after randomization. To address this safety concern, we used 3 US healthcare claims databases and 1 UK primary care database (01/2013-12/2020) . In each database, we identified adults newly treated with either SGLT2is (total n=453,726) or GLP-1 receptor agonists (GLP1RAs, n=375,990) (comparison #1) , and SGLT2is (n=347,055) or DPP-4 inhibitors (DPP4is, n=854,141) (comparison #2) . Propensity score-based fine stratification was used to reweigh the cohorts, adjusting for a wide range of patient characteristics at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for bladder cancer in each database using Cox proportional hazards models. After a median follow-up of 1.8 years, use of SGLT2is may slightly reduce the risk of bladder cancer, compared to GLP1RAs [HR (95% CI) =0.90 (0.81-1.00) ]. Compared to use of DPP4is, SGLT2is are not associated with bladder cancer incidence [HR (95% CI) : 1.00 (0.91-1.11) ] after a median follow-up of 2.0 years (Table) . Overall, the results of this large international cohort study provide reassurance on the short-term effects of SGLT2is on bladder cancer incidence. Disclosure D.Abrahami: None. H.Tesfaye: None. H.Yin: None. O.Yu: None. R.W.Platt: Consultant; Amgen Inc., Biogen, Merck & Co., Inc., Nant Pharma, Pfizer Inc. S.Schneeweiss: None. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute. L.Azoulay: Consultant; Pfizer Inc. Funding Canadian Institutes of Health Research (PJT-169040)

Background Although there are concerns that inadequate breast positioning in mammographic examinations may lead to cancers being missed, few studies have examined the quality of breast positioning, especially in the Canadian context. Our objective was to assess the quality of breast positioning in mammographic examinations in a Quebec-wide representative sample of technologists. Methods This quality improvement study was part of a professional inspection launched by the Ordre des technologues en imagerie medicale, en radio-oncologie et en electrophysiologie medicale du Quebec among its members. The inspection was conducted between May and July 2017 on a proportionate stratified random sample of all active technologists certified in mammography in Quebec. Each technologist provided images from 15 consecutive mammographic examinations they performed in the previous 6 months. The quality of positioning was then evaluated by senior technologists using a quality assessment tool specifically developed for this inspection. A technologist was deemed to have failed the professional inspection when at least 7 of the 15 mammographic examinations were scored as critical failures. Proportions were calculated accounting for sampling weights and correction for finite population. Results Among the 520 technologists certified in mammography in Quebec, 76 technologists (14.6%) were randomly selected for the professional inspection and contributed images from 1127 mammographic examinations. Thirty-eight technologists (weighted percentage 50.3%, 95% confidence interval [CI] 37.6% to 63.0%) failed the professional inspection. Overall, 492 mammographic examinations (43.7%, 95% CI 38.6% to 48.8%) had at least 1 image scored as a critical failure. Interpretation Half of the technologists performing mammographic examinations in Quebec who participated in this study failed the inspection, and a substantial proportion of their mammographic examinations demonstrated critical failures in breast positioning. Overall, our findings are concordant with those of previous studies and highlight the need for additional investigations assessing the quality of breast positioning in mammographic examinations in other jurisdictions.

Objectives To evaluate if induction of labor (IOL) in obese women at 39 weeks of gestation decreases the risk of cesarean delivery (CD). Methods We conducted a retrospective propensity score matched study using the Center for Disease Control’s (CDC’s) Period Linked Birth-Infant Death data. The study population consisted of cephalic singleton births to women with BMI greater or equal to 30.0 kg/m2 who delivered at or beyond 39 weeks between 2013 and 2017. Women with prior CD were excluded. Women who underwent IOL at 39 weeks were propensity score matched 1:5 on the basis of CD risk factors to women who did not undergo IOL at 39 weeks but may have had an IOL at a later gestational age. Conditional logistic regression compared CD rates and maternal outcomes between obese women induced at 39 weeks with those not induced at 39 weeks. Results Our cohort consisted of 197,343 obese women induced at 39 weeks and 986,715 obese women not induced at 39 weeks. Overall, the risk of CD among women who had an IOL at 39 weeks was lower than those without an IOL at 39 weeks, 0.59 (0.58–0.60). The decrease in CD risk was more pronounced in multiparas, 0.47 (0.46–0.49) than nulliparas, 0.81 (0.79–0.83). When stratified by BMI, the effect of IOL on lowering CD risk was similar across all obesity classes. Aside from an increased risk of instrumental deliveries, morbidities were comparable in both groups. Conclusions IOL at 39 weeks among obese women appears to lower the risk of CD, without compromising maternal outcomes.

Background Randomized studies have shown low compliance to adjuvant chemotherapy in rectal cancer patients receiving preoperative chemotherapy and external beam radiation (CT/EBRT) with total mesorectal excision. We hypothesize that giving neoadjuvant CT before local treatment would improve CT compliance. Methods Between 2010–2017, 180 patients were randomized (2:1) to either Arm A (AA) with FOLFOX x6 cycles prior to high dose rate brachytherapy (HDRBT) and surgery plus adjuvant FOLFOX x6 cycles, or Arm B (AB), with neoadjuvant HDRBT with surgery and adjuvant FOLFOX x12 cycles. The primary endpoint was CT compliance to ≥85% of full-dose CT for the first six cycles. Secondary endpoints were ypT0N0, five-year disease free survival (DFS), local control and overall survival (OS). Results Patients were randomized to either AA (n = 120, median age (MA) 62 years) or AB (n = 60, MA 63 years). 175/180 patients completed HDRBT as planned (97.2%). In AA, two patients expired during CT; three patients post-randomization received short course EBRT because of progression under CT (n = 2, AA) or personal preference (n = 1, AB). ypT0N0 was 31% in AA and 28% in AB (p = 0.7). CT Compliance was 80% in AA and 53% in AB (p = 0.0002). Acute G3/G4 toxicity was 35.8% in AA and 27.6% in AB (p = 0.23). With a median follow-up of 48.5 months (IQR 33–72), the five-year DFS was 72.3% with AA and 68.3% with AB (p = 0.74), the five-year OS 83.8% for AA and 82.2% for AB (p = 0.53), and the five-year local recurrence was 6.3% for AA and 5.8% for AB (p = 0.71). Conclusion We confirmed improved compliance to neoadjuvant CT in this study. Although there is no statistical difference in ypT0N0 rate, local recurrence, and DFS between the two arms, a trend towards favourable oncological outcomes is observed.

Purpose Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have been associated with an increased risk of genitourinary tract infections. Through similar biological mechanisms, they may also increase the risk of community-acquired pneumonia. Our objective was to compare the rate of hospitalization for community-acquired pneumonia (HCAP) with SGLT-2i compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) among patients with type 2 diabetes. Methods We used the United Kingdom's Clinical Practice Research Datalink Gold, linked to hospitalization data, to construct a cohort of patients with type 2 diabetes. Using a time-dependent Cox proportional hazards model, we estimated the adjusted hazard ratio (HR) for HCAP with current use of SGLT-2i versus DPP-4i. Results Among 29 896 patients, 705 HCAPs occurred over a mean follow-up of 1.7 years (standard deviation: 1.2). Incidence rates for SGLT-2i and DPP-4i users were 6.2 (95% confidence interval [CI]: 3.7, 10.2) and 17.8 (95% CI: 15.3, 20.7) per 1000 person-years, respectively. Current use of SGLT-2i was associated with a decreased risk of HCAP compared to current use of DPP-4i (adjusted HR: 0.48, 95% CI: 0.28, 0.82). However, a comparison of SGLT-2i versus glucagon-like peptide-1 receptor agonists (GLP-1 RA) found no difference in risk of HCAP (adjusted HR: 0.94, 95% CI: 0.44, 1.89). Conclusions SGLT-2i are associated with a decreased rate of HCAP compared to DPP-4i, but not when compared to GLP-1 RA, among patients with type 2 diabetes.

Summary Background Many immigrants are susceptible to varicella on arrival to Canada because of different transmission dynamics in their countries of origin and scarcity of vaccination. Universal childhood vaccination programmes decrease varicella incidence rates through herd immunity, but the accumulating number of susceptible adult immigrants could remain at risk for severe varicella. Our aim was to describe the epidemiology of varicella among immigrants and non-immigrants before and after childhood varicella vaccination. Methods We did a population-based, retrospective cohort study of all varicella cases in Quebec, Canada, diagnosed between 1996 and 2014 in administrative health databases linked to immigration data. Cases of varicella met diagnostic codes in the International Classification of Diseases, Ninth and Tenth Revision Canadian modifications. Cases with a co-occurring zoster diagnostic code and immigrants from Australia, New Zealand, the USA, and western European countries were excluded. Vaccination periods included pre-vaccination (1996–98), private vaccination (1999–2005), and public vaccination (2006–14). Incidence rate and comparative rate ratios were estimated using census data. Findings A total of 231 339 varicella cases diagnosed between Jan 1, 1996, and Dec 31, 2014, were linked to 1 115 696 immigrants who arrived between Jan 1, 1980, and Dec 31, 2014. 1444 herpes zoster cases and 1276 immigrants from Australia, western Europe, New Zealand, and the USA were excluded. Among 228 619 varicella cases, 13 315 (5·8%) occurred in immigrants. In pre-vaccination versus public vaccination periods, varicella incidence declined in immigrants by 87% (95% CI 86·6–87·9; 324·3 cases per 100 000 person-years to 40·9 cases per 100 000 person-years) and in non-immigrants by 93% (92·4–92·7; 484 cases per 100 000 person-years to 36 cases per 100 000 person-years). Mean age at diagnosis increased in both groups (15·1 vs 19·4 years in immigrants and 8·4 vs 12·0 years in non-immigrants). In the public vaccination period, immigrants younger than 50 years had higher varicella rates than non-immigrants, with relative risk ranging from 1·53 (95% CI 1·37–1·72) to 4·64 (3·90–5·53) with the highest risk in adolescents and young adults, and people from Latin America and the Caribbean (age-specific incidence rate ratio [aIRR]I-NI pre-vaccination 2·19 and post-vaccination aIRRI-NI6·07) and south Asia (aIRRI-NI pre-vaccination 3·41 and aIRRI-NI post-vaccination 4·46) and in childbearing women (15–40 years; IRRI-NI 2·48). Interpretation Immigrant adolescents, young adults, and women of childbearing age had higher age-standardised rates of varicella than non-immigrants, with increasing disparities following vaccine introduction. Immigrants younger than 50 years of age would benefit from targeted vaccination upon arrival to host countries. Funding The Canadian Institutes of Health Research and The Department of Medicine, Jewish General Hospital, Montreal, QC, Canada.

The use of observational data to assess drug effectiveness and safety can provide relevant information, much of which may not be feasible to obtain through randomized clinical trials. Because observational studies provide critical drug safety and effectiveness information that influences drug policy and prescribing practices, transparent, consistent, and accurate reporting of these studies is critical.We provide recommendations to extend existing reporting guidelines, covering the main components of primary research studies (methods, results, discussion).Our recommendations include extending drug safety and effectiveness guidelines to include explicit checklist items on: study registration, causal diagrams, rationale for measures of effect, comprehensive assessment of bias, comprehensive data cleaning steps, drug equivalents, subject-level drug data visualization, sex and gender-based analyses and results, patient-oriented outcomes, and patient involvement in research.

Background Recent interest has been geared towards the potential therapeutic and chemopreventive benefit of androgen deprivation therapy (ADT) for bladder cancer. As a result, several observational studies have investigated this potential association. Given the important side effects associated with ADT treatment, understanding the methodological strengths and weaknesses of the current evidence is warranted. Objectives The objective of this systematic review was to examine the heterogeneity of the current observational studies on the association between ADT and bladder cancer by assessing the methodological strengths and limitations of these studies. Material and methods We systematically searched Medline, EMBASE, Healthstar, Cochrane Library Online, Science Citation Index, and Dissertation Abstracts Online, from inception to August 2019 to identify all observational studies investigating the association between ADT and bladder cancer. We assessed overall study quality using the ROBINS-I tool and evaluated the presence of other key pharmacoepidemiologic biases. Results Overall, our systematic review included 7 observational studies. Five studies reported a decreased risk of bladder cancer with ADT use, 1 study reported no association, and 1 study reported an increased risk. All studies had time-related biases, did not consider a lag period, and had potential residual confounding. Moreover, 1 study had potential detection bias, 6 included prevalent users, 3 had inadequate follow-up durations, 6 had exposure misclassification, and 5 used an inappropriate comparator. Conclusion Taken together, future methodologically-rigorous studies addressing the limitations underlined in this systematic review are needed to evaluate the important potential association between ADT and bladder cancer.

Background Ethnoracial groups in high-income countries have a 2-fold higher risk of SARS-CoV-2 infection, associated hospitalizations, and mortality than Whites. Migrants are an ethnoracial subset that may have worse COVID-19 outcomes due to additional barriers accessing care, but there are limited data on in-hospital outcomes. We aimed to disaggregate and compare COVID-19 associated hospital outcomes by ethnicity, immigrant status and region of birth. Methods Adults with community-acquired SARS-CoV-2 infection, hospitalized March 1–June 30, 2020, at four hospitals in Montréal, Quebec, Canada, were included. Age, sex, socioeconomic status, comorbidities, migration status, region of birth, self-identified ethnicity [White, Black, Asian, Latino, Middle East/North African], intensive care unit (ICU) admissions and mortality were collected. Adjusted hazard ratios (aHR) for ICU admission and mortality by immigrant status, ethnicity and region of birth adjusted for age, sex, socioeconomic status and comorbidities were estimated using Fine and Gray competing risk models. Results Of 1104 patients (median [IQR] age, 63.0 [51.0–76.0] years; 56% males), 57% were immigrants and 54% were White. Immigrants were slightly younger (62 vs 65 years; p = 0.050), had fewer comorbidities (1.0 vs 1.2; p Conclusions Data disaggregated by region of birth identified subgroups of immigrants at increased risk of COVID-19 ICU admission, providing more actionable data for health policymakers to address health inequities.

OBJECTIVE To determine whether the use of dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs), separately, is associated with an increased risk of acute liver injury compared with the use of sodium–glucose cotransporter 2 (SGLT-2) inhibitors. RESEARCH DESIGN AND METHODS We used the U.K. Clinical Practice Research Datalink linked with the Hospital Episode Statistics Admitted Patient Care and the Office for National Statistics databases to assemble two new-user, active-comparator cohorts. The first included 106,310 initiators of DPP-4 inhibitors and 27,277 initiators of SGLT-2 inhibitors, while the second included 9,470 initiators of GLP-1 RAs and 26,936 initiators of SGLT-2 inhibitors. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate hazard ratios (HRs) and 95% CIs of acute liver injury. RESULTS Compared with SGLT-2 inhibitors, DPP-4 inhibitors were associated with a 53% increased risk of acute liver injury (HR 1.53, 95% CI 1.02–2.30). In contrast, GLP-1 RAs were not associated with an overall increased risk of acute liver injury (HR 1.11, 95% CI 0.57–2.16). However, an increased risk was observed among female users of both DPP-4 inhibitors (HR 3.22, 95% CI 1.67–6.21) and GLP-1 RAs (HR 3.23, 95% CI 1.44–7.25). CONCLUSIONS In this population-based study, DPP-4 inhibitors were associated with an increased risk of acute liver injury compared with SGLT-2 inhibitors in patients with type 2 diabetes. In contrast, an increased risk of acute liver injury was observed only among female GLP-1 RA users.

There is some evidence that glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have chemopreventive effects on prostate cancer cells but real-world evidence for this possible effect is lacking. Thus, the objective of this study was to estimate whether use of GLP-1 receptor agonists and DPP-4 inhibitors, separately, is associated with a decreased risk of prostate cancer among patients with type 2 diabetes.We assembled two new-user, active-comparator cohorts using the UK Clinical Practice Research Datalink (2007 to 2019). The first cohort included 5,063 initiators of GLP-1 receptor agonists and 112,955 of sulfonylureas. The second cohort included 53,529 initiators of DPP-4 inhibitors and 114,417 of sulfonylureas. We fit Cox proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer. We weighted the models using propensity score fine stratification, which considered over 50 potential confounders.GLP-1 receptor agonists were associated with a decreased risk of prostate cancer when compared with sulfonylureas (incidence rates = 156.4 vs. 232.0 per 100,000 person-years, respectively; HR = 0.65; 95% CI = 0.43, 0.99). DPP-4 inhibitors were also associated with a decreased risk of prostate cancer when compared with sulfonylureas (incidence rates = 316.2 vs. 350.5 events per 100,000 person-years, respectively; HR = 0.90; 95% CI = 0.81, 1.00).The results of this study are consistent with the hypothesis that the use of GLP-1 receptor agonists and DPP-4 inhibitors, separately, may decrease the risk of prostate cancer when compared with the use of sulfonylureas.

To describe trends in the pharmacological treatment of BPH in the United Kingdom (UK) from 1998 to 2016. We created a cohort of men with a diagnosis of BPH between 1998 and 2016 using the Clinical Practice Research Datalink. Using Poisson regression, we estimated annual prescription rates of 5αRIs, α-blockers, and combination therapy (5αRIs + α-blockers). Adherence was defined by a proportion of days covered > 80%. Our cohort included 192,640 men with BPH who generated 1,176,264 person-years (PYs) of follow-up. The mean age was 68.0 (standard deviation: 10.7) years. The prescription rate of all BPH medications during the study period was 347.6 per 100 PYs (95% CI 347.2–347.9). α-Blockers had the highest prescription rate (222.9 per 100 PYs, 95% CI 222.7–223.2); prescription rates of 5αRIs and combination therapy were 69.1 per 100 PYs (95% CI 69.0–69.3) and 55.5 per 100 PYs (95% CI 55.4–55.7), respectively. The prescription rate for combination therapy was 19 times greater in 2013–2016 than in 1998–2000 (rate ratio: 19.2, 95% CI 18.6–19.7), while the prescription rates for 5αRIs and α-blockers each doubled during this period (rate ratio: 1.86, 95% CI 1.84–1.88 and rate ratio: 2.02, 95% CI 2.01–2.04, respectively). The proportion of patients who were adherent at 1 year to 5αRIs (32.3%), α-blockers (44.0%), and combination therapy (45.6%) was low. The prescription rate of BPH medications increased substantially between 1998 and 2016 in the UK, with the greatest relative increase observed with combination therapy. Adherence to BPH medications was low in this population-based study.

Objective Existing evidence on the association between vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) and cancer is limited and contradictory. No observational studies have been conducted to simultaneously address the cancer safety of VKAs and DOACs. The objective of this study was to determine whether use of VKAs and DOACs, separately, when compared with nonuse, is associated with cancer overall and prespecified site-specific incidence. Methods Using the United Kingdom Clinical Practice Research Datalink, we identified patients newly diagnosed with nonvalvular atrial fibrillation (NVAF) between 2011 and 2017. Using a time-varying exposure definition, each person-day of follow-up was classified as use of (1) VKAs, (2) DOACs, (3) VKAs and DOACs (drug switchers), and (4) nonuse of anticoagulants (reference). We also conducted a head-to-head comparison of new users of DOACs versus VKAs using propensity score fine stratification weighting. Hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer overall and prespecified subtypes were estimated using Cox proportional hazards models. Results Compared with nonuse, use of VKAs was not associated with cancer overall (HR: 1.05, 95% CI: 0.91–1.22) or cancer subtypes. Similarly, use of DOACs was not associated with cancer overall (HR: 1.13, 95% CI: 0.93–1.37), but an association was observed for colorectal cancer (HR: 1.73, 95% CI: 1.01–2.99), and pancreatic cancer generated an elevated, though nonsignificant HR (HR: 2.15, 95% CI: 0.72–6.44). Results were consistent in the head-to-head comparison. Conclusion Use of oral anticoagulants is not associated with the incidence of cancer overall among patients with NVAF. Possible associations between DOACs and colorectal and pancreatic cancer warrant further study.

The association between use of aromatase inhibitors (AIs) and cardiovascular outcomes is controversial. While some observational studies have assessed the cardiovascular safety of AIs as upfront treatments, their cardiotoxicity as sequential treatments with tamoxifen remains unknown. Thus, we conducted a population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. We employed a prevalent new-user design to propensity-score match, in a 1:2 ratio, patients switching from tamoxifen to AIs with patients continuing tamoxifen between 1998 and 2016. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). Overall, 1,962 patients switching to AIs were matched to 3,874 patients continuing tamoxifen. Compared with tamoxifen, AIs were associated with an increased risk of myocardial infarction (hazard ratio (HR) = 2.08, 95% confidence interval (CI): 1.02, 4.27). The hazard ratios were elevated for ischemic stroke (HR = 1.58, 95% CI: 0.85, 2.93) and heart failure (HR = 1.69, 95% CI: 0.79, 3.62) but not cardiovascular mortality (HR = 0.87, 95% CI: 0.49, 1.54), with confidence intervals including the null value. The elevated hazard ratios observed for the cardiovascular outcomes should be corroborated in future large observational studies.

Aim To assess whether dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are associated with an increased lung cancer risk among individuals with type 2 diabetes. Methods We conducted a population-based cohort study using the UK Clinical Practice Research Datalink. We identified 130 340 individuals newly treated with antidiabetes drugs between January 2007 and March 2017, with follow-up until March 2018. We used a time-varying approach to model use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists compared with use of other second- or third-line antidiabetes drugs. We used Cox proportional hazards models to estimate the adjusted hazard ratios, with 95% CIs, of incident lung cancer associated with use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, separately, by cumulative duration of use, and by time since initiation. Results A total of 790 individuals were newly diagnosed with lung cancer (median follow-up 4.6 years, incidence rate 1.5/1000 person-years, 95% CI 1.4-1.6). Compared with use of second-/third-line drugs, use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists was not associated with an increased lung cancer risk (hazard ratio 1.07, 95% CI 0.87-1.32, and hazard ratio 1.02, 95% CI 0.68-1.54, respectively). There was no evidence of duration-response relationships. Conclusions In individuals with type 2 diabetes, use of incretin-based drugs was not associated with increased lung cancer risk.

Background: The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern. Methods: We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). Results: The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14–3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11–2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88–2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82–1.72]). Conclusions: In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.

Several observational studies have examined the potential protective effect of angiotensin-converting enzyme inhibitor (ACE-I) use on the risk of age-related macular degeneration (AMD) and have reported contradictory results owing to confounding and time-related biases. We aimed to assess the risk of AMD in a base cohort of patients aged 40 years and above with hypertension among new users of ACE-I compared to an active comparator cohort of new users of calcium channel blockers (CCB) using data obtained from IQVIA Medical Research Data, a primary care database in the UK.In this study, 53 832 and 43 106 new users of ACE-I and CCB were included between 1995 and 2019, respectively. In an on-treatment analysis, patients were followed up from the time of index drug initiation to the date of AMD diagnosis, loss to follow-up, discontinuation or switch to the comparator drug. A comprehensive range of covariates were used to estimate propensity scores to weight and match new users of ACE-I and CCB. Standardized mortality ratio weighted Cox proportional hazards model was used to estimate hazard ratios of developing AMD.During a median follow-up of 2 years (interquartile range 1-5 years), the incidence rate of AMD was 2.4 (95% confidence interval 2.2-2.6) and 2.2 (2.0-2.4) per 1000 person-years among the weighted new users of ACE-I and CCB, respectively. There was no association of ACE-I use on the risk of AMD compared to CCB use in either the propensity score weighted or matched, on-treatment analysis (adjusted hazard ratio: 1.07 [95% confidence interval 0.90-1.27] and 0.87 [0.71-1.07], respectively).We found no evidence that the use of ACE-I is associated with risk of AMD in patients with hypertension.

ObjectiveTo determine whether the use of proton pump inhibitors (PPIs) compared with the use of histamine-2 receptor antagonists (H2RAs) is associated with an increased risk of inflammatory bowel disease (IBD).DesignPopulation-based cohort study designed to address the impact of protopathic bias.SettingGeneral practices contributing data to the UK Clinical Practice Research Datalink GOLD.Participants1 498 416 initiators of PPIs and 322 474 initiators of H2RAs from 1 January 1990 to 31 December 2018, with follow-up until 31 December 2019. Patients were analysed according to the timing of the IBD diagnosis after treatment initiation (early vs late).Main outcome measuresStandardised morbidity ratio weighted Cox proportional hazards models were used to estimate marginal HRs and 95% CIs. In the early-event analysis, IBD diagnoses were assessed within the first 2 years of treatment initiation, an analysis subject to potential protopathic bias. In the late-event analysis, all exposures were lagged by 2 years to account for latency and minimise protopathic bias.ResultsIn the early-event analysis, the use of PPIs was associated with an increased risk of IBD within the first 2 years of treatment initiation, compared with H2RAs (HR 1.39, 95% CI 1.14 to 1.69). In contrast, the use of PPIs was not associated with an increased risk of IBD in the late-event analysis (HR 1.05, 95% CI 0.90 to 1.22). The results remained consistent in several sensitivity analyses.ConclusionsCompared with H2RAs, PPIs were not associated with an increased risk of IBD, after accounting for protopathic bias.

The association between long-acting insulin analogs and colorectal cancer is uncertain, with previous studies reporting discrepant findings. To determine whether the use of long-acting insulin analogs is associated with an increased risk of colorectal cancer, when compared with use of intermediate-acting human insulins among patients with type 2 diabetes. We conducted a population-based study using the United Kingdom Clinical Practice Research Datalink (CPRD). We identified patients newly treated with either a long-acting insulin analog or an intermediate-acting human insulin between September 1, 2002 and January 31, 2018, with follow-up until January 31, 2019. Each long-acting insulin analog user was propensity score-matched to one intermediate-acting human insulin user, and a lag of 1 year was imposed. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of colorectal cancer, comparing long-acting insulin analogs with intermediate-acting human insulin. Secondary analysis was conducted to assess whether there was a duration–response relationship. A total of 10,734 new long-acting insulin analog users were matched to 10,734 new intermediate-acting human insulin users. After a median follow-up of 2.8 years, the use of long-acting insulin analogs was not associated with an increased risk of colorectal cancer, compared with intermediate-acting human insulin (1.80 vs. 1.87 per 1000 person-years, respectively; HR 0.96, 95% CI 0.70–1.34). There was no evidence of a duration–response relationship. The results of this population-based study indicate that use of long-acting insulin analogs is not associated with an overall increased risk of colorectal cancer.

The US Sentinel System and the Canadian Network for Observational Drug Effect Studies (CNODES) are two medical product safety surveillance networks. Using Sentinel's preprogrammed, parameterizable analytic tools, we reproduced two protocol-based studies conducted by CNODES to assess the risks of acute pancreatitis and heart failure (HF) associated with the use of incretin-based drugs, compared with use of ≥ 2 oral hypoglycemic agents. Results from the replication new-user cohort analyses aligned with those from the CNODES nested case-control studies. The adjusted hazard ratios were 0.95 (0.81-1.12; vs. 1.03 (0.87-1.22) in CNODES) for acute pancreatitis and 0.91 (0.84-1.00; vs. 0.82 (0.67-1.00) in CNODES) for HF among patients without HF history. The CNODES's common protocol approach allows studies tailored to specific safety questions, whereas the Sentinel's common data model plus pretested program approach enables more rapid analysis. Despite these differences, it is possible to obtain comparable results using both approaches.