Search

Background and ObjectivesNonvalvular atrial fibrillation (NVAF) is associated with an increased risk of dementia. Oral anticoagulants (OACs) are essential for stroke prevention in NVAF, and studies have shown a possible protective effect on dementia. However, findings have been inconsistent and hampered by methodological limitations. Thus, we assessed whether the use of OACs is associated with a decreased incidence of dementia in patients with NVAF. In addition, we explored the impact of the cumulative duration of OAC use on the incidence of dementia.MethodsUsing the UK Clinical Practice Research Datalink, we formed a cohort of all patients aged 50 years or older with an incident diagnosis of NVAF between 1988 and 2017 and no prior OAC use, with a follow-up until 2019. Patients were considered unexposed until 6 months after their first OAC prescription for latency considerations and exposed thereafter until the end of follow-up. We used time-dependent Cox regression models to estimate hazard ratios (HRs), adjusted for 54 covariates, with 95% CIs for dementia associated with OAC use, compared with nonuse. We also assessed whether the risk varied with the cumulative duration of OAC use, compared with nonuse, by comparing prespecified exposure categories defined in a time-varying manner and by modeling the HR using a restricted cubic spline.ResultsThe cohort included 142,227 patients with NVAF, with 8,023 cases of dementia over 662,667 person-years of follow-up (incidence rate 12.1, 95% CI 11.9–12.4 per 1,000 person-years). OAC use was associated with a decreased risk of dementia (HR 0.88, 95% CI 0.84–0.92) compared with nonuse. A restricted cubic spline also indicated a decreased risk of dementia, reaching a low at approximately 1.5 years of cumulative OAC use and stabilizing thereafter. Moreover, OAC use decreased the risk in patients aged 75 years and older (HR 0.84, 95% CI 0.80–0.89), but not in younger patients (HR 0.99, 95% CI 0.90–1.10).DiscussionIn patients with incident NVAF, OACs were associated with a decreased risk of dementia, particularly in elderly individuals. This warrants consideration when weighing the risks and benefits of anticoagulation in this population.Classification of EvidenceThis study provides Class II evidence that in patients with NVAF, OAC use (vs nonuse) is associated with a decreased risk of dementia.

OBJECTIVE The hypoglycemic potential of β-blockers among users of sulfonylureas, drugs that strongly increase the risk of this potentially fatal adverse effect, is not well understood. Our population-based cohort study assessed the potential association between concomitant use of sulfonylureas and β-blockers versus use of sulfonylureas alone and the risk of severe hypoglycemia. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink Aurum, we included patients initiating sulfonylureas between 1998 and 2020, excluding those with β-blocker use in the past 6 months. Time-dependent Cox models estimated hazard ratios (HRs) with 95% CIs of severe hypoglycemia (hospitalization with or death resulting from hypoglycemia; ICD-10 codes E16.0, E16.1, and E16.2) associated with current concomitant use of sulfonylureas and β-blockers compared with current sulfonylurea use alone, adjusted for baseline confounders. We also compared current concomitant use of sulfonylureas and non-cardioselective versus cardioselective β-blockers. RESULTS Our cohort included 252,869 initiators of sulfonylureas (mean age 61.3 years; 43% female). Median follow-up was 7.9 years. The crude incidence rate of severe hypoglycemia was 7.8 per 1,000 per year. Concomitant use of sulfonylureas and β-blockers was associated with an increased risk of severe hypoglycemia compared with sulfonylurea use alone (HR 1.53; 95% CI 1.42–1.65). There was no difference in the risk between concomitant use of sulfonylureas and noncardioselective β-blockers and concomitant use of sulfonylureas and cardioselective β-blockers (HR 0.95; 95% CI 0.74–1.24). CONCLUSIONS β-blockers could further increase the risk of severe hypoglycemia when used concurrently with sulfonylureas. β-blocker cardioselectivity did not seem to play a major role in this regard.

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.

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.

Confounding adjustment is required to estimate the effect of an exposure on an outcome in observational studies. However, variable selection and unmeasured confounding are particularly challenging when analyzing large healthcare data. Machine learning methods may help address these challenges. The objective was to evaluate the capacity of such methods to select confounders and reduce unmeasured confounding bias.A simulation study with known true effects was conducted. Completely synthetic and partially synthetic data incorporating real large healthcare data were generated. We compared Bayesian adjustment for confounding (BAC), generalized Bayesian causal effect estimation (GBCEE), Group Lasso and Doubly robust estimation, high-dimensional propensity score (hdPS), and scalable collaborative targeted maximum likelihood algorithms. For the hdPS, two adjustment approaches targeting the effect in the whole population were considered: Full matching and inverse probability weighting.In scenarios without hidden confounders, most methods were essentially unbiased. The bias and variance of the hdPS varied considerably according to the number of variables selected by the algorithm. In scenarios with hidden confounders, substantial bias reduction was achieved by using machine-learning methods to identify proxies as compared to adjusting only by observed confounders. hdPS and Group Lasso performed poorly in the partially synthetic simulation. BAC, GBCEE, and scalable collaborative-targeted maximum likelihood algorithms performed particularly well.Machine learning can help to identify measured confounders in large healthcare databases. They can also capitalize on proxies of unmeasured confounders to substantially reduce residual confounding bias.

Recent reports have raised concerns about a potential risk of osteonecrosis associated with testosterone treatment (TT). The aim of this pharmacovigilance study was to assess the risk of reporting osteonecrosis associated with the use of TT compared with use of any other medication.We performed a disproportionality analysis to investigate the risk of reporting osteonecrosis with TT using the WHO database VigiBaseAmong men at least 18 years of age between January 1, 2000, and December 31, 2019, we identified 3479 reports of osteonecrosis, 84 of which were associated with TT use, out of a total of 4,667,754 adverse event reports. Reports of osteonecrosis in TT users occurred with both transdermal and injectable forms, and the mean age at report was 55.4 years. TT use was associated with a greater risk of reporting osteonecrosis compared to all other drugs (ROR, 5.13; 95% CI, 4.13-6.37) and compared with use of drugs for BPH (ROR, 3.00; 95% CI, 2.08-4.30). Half of the osteonecrosis reports associated with TT indicated concomitant use of corticosteroids.TT was associated with a greater risk of reports of osteonecrosis compared to use of any other drug and use of drugs for BPH. This signal should be confirmed in complementary studies.

Background: The hypoglycemic potential of beta-blockers among users of sulfonylureas, drugs that strongly increase the risk of this potentially fatal adverse effect, is not well understood. Our population-based cohort study assessed the potential association between concomitant use of sulfonylureas and beta-blockers versus use of sulfonylureas alone and the risk of severe hypoglycemia. Methods: Using the UK's Clinical Practice Research Datalink Aurum, we included patients initiating sulfonylureas between 1998 and 2020, excluding those with beta-blocker use in the past 6 months. Time-dependent Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycemia (hospitalization with or death due to hypoglycemia; ICD-10 codes: E16.0, E16.1, E16.2) associated with current concomitant use of sulfonylureas and beta-blockers compared to current sulfonylurea use alone, adjusted for baseline confounders. We also compared current concomitant use of sulfonylureas and non-cardioselective versus cardioselective beta-blockers. Results: Our cohort included 252,866 initiators of sulfonylureas (mean age 61.3 years, 43% female). Median follow-up was 7.9 years. The crude incidence rate of severe hypoglycemia was 7.8 per 1000/year. Concomitant use of sulfonylureas and beta-blockers was associated with an increased risk of severe hypoglycemia compared to sulfonylurea use alone (HR, 1.53; 95% CI, 1.42-1.65). There was no difference in the risk between concomitant use of sulfonylureas and non-cardioselective beta-blockers and concomitant use of sulfonylureas and cardioselective beta-blockers (HR, 0.95; 95% CI, 0.74-1.24). Conclusion: Beta-blockers could further increase the risk of severe hypoglycemia when used concurrently with sulfonylureas. Beta-blocker cardioselectivity did not appear to play a major role in this regard.

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.

Inverse probability of censoring weights (IPCWs) may reduce selection bias due to informative censoring in longitudinal studies. However, in studies with an active comparator, the associations between predictors and censoring may differ across treatment groups. We used the clinical example of anticoagulation treatment with warfarin or a direct oral anticoagulant (DOAC) in atrial fibrillation to illustrate this. The cohort of individuals initiating an oral anticoagulant during 2010–2016 was identified from the Régie de l’assurance maladie du Québec (RAMQ) databases. The parameter of interest was the hazard ratio (HR) of the composite of stroke, major bleeding, myocardial infarction, or death associated with continuous use of warfarin versus DOACs. Two strategies for the specification of the model for estimation of censoring weights were explored: exposure-unstratified and exposure-stratified. The HR associated with continuous treatment with warfarin versus DOACs adjusted with exposure-stratified IPCWs was 1.26 (95% confidence interval: 1.20, 1.33). Using exposure-unstratified IPCWs, the HR differed by 15% in favor of DOACs (1.41, 95% confidence interval: 1.34, 1.48). Not accounting for the different associations between the predictors and informative censoring across exposure groups may lead to misspecification of censoring weights and biased estimate on comparative effectiveness and safety.

Background Selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressants, are associated with a modestly increased risk of major bleeding. However, in patients treated with both SSRIs and oral anticoagulants (OACs), the risk of major bleeding may be substantial. Objective To assess the risk of major bleeding associated with concomitant use of SSRIs and OACs, compared with OAC use alone. Methods We searched MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials (from inception to December 1, 2021) for clinical trials and observational studies assessing the association between concomitant use of SSRIs and OACs and the risk of major bleeding. Given sufficient homogeneity of studies, we conducted a random-effects meta-analysis to estimate a pooled hazard ratio (HR) of major bleeding associated with concomitant use of SSRIs and OACs, compared with OAC use alone. Results The review comprised 14 studies, including 7 cohort and 7 nested case–control studies. Following assessment of clinical and methodological heterogeneity, eight studies with a total of 98,070 patients were eligible for the meta-analysis. The pooled HR of major bleeding associated with concomitant use of SSRIs and OACs was 1.35 (95% confidence interval [CI]: 1.14–1.58). In secondary analyses, the pooled HR for concomitant use of SSRIs and direct OACs was 1.47 (95% CI: 1.03–2.10). Conclusion Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding. Overall, our findings suggest that physicians may need to tailor treatment according to individual patient risk factors for bleeding when prescribing SSRIs to patients using OACs.

Background: Dipeptidyl peptidase-4 inhibitors (DPP-4i) interact with sulfonylureas (SU) to increase their risk of hypoglycemia. However, it is unclear whether this risk varies with the pharmacologic properties of DPP-4i. Thus, we compared the risk of severe hypoglycemia between concomitant use of SU and peptidomimetic DPP-4i (vildagliptin, saxagliptin) vs. non-peptidomimetic DPP-4i (sitagliptin, linagliptin, alogliptin) in patients with type 2 diabetes. Methods: We conducted a retrospective cohort study using the UK's Clinical Practice Research Datalink linked to hospitalization and vital statistics data of patients with type 2 diabetes initiating SU between 20 and 2020. Time-dependent Cox models estimated hazard ratios (HR) with 95% confidence intervals (CI) of severe hypoglycemia associated with current concomitant use of SU and peptidomimetic DPP-4i compared to current concomitant use of SU and non-peptidomimetic DPP-4i, adjusted for baseline confounders. Secondary analyses stratified by age ( Results: Our cohort included 196,138 SU initiators. The crude incidence rate of severe hypoglycemia was 7.2 per 1000/year. Compared to concomitant use of SU and non-peptidomimetic DPP-4i, concomitant use of SU and peptidomimetic DPP-4i was not associated with the risk of severe hypoglycemia (HR, 0.96; 95% CI, 0.76-1.22) . In female patients, concomitant use of SU and peptidomimetic DPP-4i was associated with a trend towards an increased risk (HR, 1.32; 95% CI, 0.97-1.81) ; in male patients, there was an association with a decreased risk (HR, 0.69; 95% CI, 0.48-0.99) . Age did not modify the association. Conclusion: Our population-based study showed no increased risk of severe hypoglycemia with concomitant use of SU and peptidomimetic DPP-4i compared to concomitant use of SU and non-peptidomimetic DPP-4i. Further research is needed to corroborate the observed effect modification by sex. Disclosure J.Dimakos: None. Y.Cui: None. R.W.Platt: Consultant; Amgen Inc., Biogen, Merck & Co., Inc., Nant Pharma, Pfizer Inc. C.Renoux: None. K.B.Filion: None. A.Douros: None. Funding Canadian Institutes of Health Research (PJT-165882)

Background: Beta-blockers may interact with sulfonylureas (SU) and increase their hypoglycemic risk. Our study assessed the potential association between concomitant use of SU and beta-blockers and the risk of severe hypoglycemia. Methods: We used the UK's Clinical Practice Research Datalink linked to hospitalization and vital statistics data of patients with type 2 diabetes initiating SU between 1998 and 2020, excluding those with beta-blocker use in the past 6 months. Time-dependent Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycemia associated with current concomitant use of SU and beta-blockers compared to current SU use alone, adjusted for baseline confounders. To address potential residual confounding, we repeated the analysis with current concomitant use of SU and thiazide diuretics as reference group. We also compared current concomitant use of SU and non-cardioselective (propranolol, carvedilol, sotalol, labetalol) vs. cardioselective beta-blockers (acebutolol, atenolol, bisoprolol, metoprolol, nebivolol, esmolol) to explore the role of beta-blocker cardioselectivity in this association. Results: Our cohort included 252,869 SU initiators. The crude incidence rate of severe hypoglycemia was 7.8 per 1000/year. Concomitant use of SU and beta-blockers was associated with an increased risk of severe hypoglycemia compared to SU use alone (HR, 1.53; 95% CI, 1.42-1.65) . Changing the reference group led to consistent findings (HR, 1.69; 95% CI, 1.42-2.01) . There was no difference in the risk when comparing concomitant use of SU and non-cardioselective beta-blockers to concomitant use of SU and cardioselective beta-blockers (HR, 0.95; 95% CI, 0.74-1.24) . Conclusion: Our large cohort study showed an increased risk of severe hypoglycemia associated with concomitant use of SU and beta-blockers compared to SU use alone. This association did not vary with beta-blocker cardioselectivity. Disclosure J.Dimakos: None. Y.Cui: None. R.W.Platt: Consultant; Amgen Inc., Biogen, Merck & Co., Inc., Nant Pharma, Pfizer Inc. C.Renoux: None. K.B.Filion: None. A.Douros: None. Funding Canadian Institutes of Health Research (PJT-165882)

Background and Objective: An inconsistent association between exposure to SSRIs and SNRIs and the risk for ASD and ADHD in the Offspring was observed in observational studies. Some suggest that the reported association might be due to unmeasured confounding. We aimed to study this association and to look for sources of bias by performing a systematic review and meta-analysis. Methods: Medline, Embase, and the Cochrane Library were searched up to June 2019 for studies reporting on ASD and ADHD in the Offspring following exposure during pregnancy. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random- effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for each outcome using the adjusted point estimate of each study. Results: Eighteen studies were included in the meta-analysis. We found an association between SSRIs/ SNRIs prenatal use and the risk for ASD and ADHD (OR=1.42, 95% CI: 1.23–1.65, I2=58%; OR=1.26, 95% CI: 1.07-1.49, I2=48%, respectively). Similar findings were obtained in women who were exposed to SSRIs/SNRIs before pregnancy, representing statistically significant association with ASD (OR=1.39, 95% CI: 1.24-1.56, I2=33%) and ADHD (OR=1.63, 95% CI: 1.50-1.78, I2=0%) in the Offspring, although they were not exposed to those medications in utero. Conclusions: Although we found an association between exposure to SSRIs/SNRIs during pregnancy and the risk for ASD and ADHD, an association with those disorders was also present for exposure pre-pregnancy, suggesting that the association might be due to unmeasured confounding. We are aiming to further assess the role of potential unmeasured confounding in the estimation of the association and perform a network meta-analysis.

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.

Introduction The cardiovascular safety of testosterone replacement therapy (TRT) is controversial. While several studies have investigated the association between TRT and the risk of arterial thrombosis, limited information is available regarding its risk of venous thromboembolism (VTE). We aimed to compare the risk of VTE in men randomized to TRT versus placebo or active-comparator in a systematic review. Methods We searched Medline, EMBASE, CINAHL, CENTRAL, and clinical trial registries to identify randomized controlled trials (RCTs) comparing TRT to placebo in men aged ≥18 years. We assessed study quality using the Cochrane Risk of Bias assessment tool and the overall quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Data were pooled across RCTs using random-effects models. Results A total of 13 RCTs (n = 5050) were included in our meta-analysis. In all, 2636 men were randomized to testosterone, and 2414 men to placebo. Sample sizes ranged from 101 to 790 men, and TRT duration from 3 to 36 months. Five studies had a high risk of bias, largely driven by unclear randomization and outcome assessment. When data were pooled across RCTs, testosterone therapy was not associated with VTE compared with placebo (RR: 1.03, 95% CI: 0.49–2.14; I2: 0%; low-quality evidence). Similar estimates were obtained for deep vein thrombosis and pulmonary embolism outcomes. Conclusions Our systematic review suggests that TRT is not associated with an increased risk of VTE. However, estimates were accompanied by a wide 95% CIs, and a clinically important increased risk cannot be ruled out.

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.

Background. Observational economic evaluations (i.e., economic evaluations in which treatment allocation is not randomized) are prone to confounding bias. Prior reviews published in 2013 have shown that adjusting for confounding is poorly done, if done at all. Although these reviews raised awareness on the issues, it is unclear if their results improved the methodological quality of future work. We therefore aimed to investigate whether and how confounding was accounted for in recently published observational economic evaluations in the field of cardiology. Methods. We performed a systematic review of PubMed, Embase, Cochrane Library, Web of Science, and PsycInfo databases using a set of Medical Subject Headings and keywords covering topics in “observational economic evaluations in health within humans” and “cardiovascular diseases.” Any study published in either English or French between January 1, 2013, and December 31, 2017, addressing our search criteria was eligible for inclusion in our review. Our protocol was registered with PROSPERO (CRD42018112391). Results. Forty-two (0.6%) out of 7523 unique citations met our inclusion criteria. Fewer than half of the selected studies adjusted for confounding ( n = 19 [45.2%]). Of those that adjusted for confounding, propensity score matching ( n = 8 [42.1%]) and other matching-based approaches were favored ( n = 8 [42.1%]). Our results also highlighted that most authors who adjusted for confounding rarely justified their methodological choices. Conclusion. Our results indicate that adjustment for confounding is often ignored when conducting an observational economic evaluation. Continued knowledge translation efforts aimed at improving researchers’ knowledge regarding confounding bias and methods aimed at addressing this issue are required and should be supported by journal editors.

Intravitreal anti-vascular endothelial growth factor (VEGF) drugs aflibercept and ranibizumab are used in neovascular retinal diseases but may be associated with non-ocular haemorrhage. Our objective was to compare the risk of non-ocular haemorrhage with intravitreal aflibercept versus intravitreal ranibizumab and with individual intravitreal anti-VEGFs versus intravitreal dexamethasone. A retrospective cohort study was conducted using four Italian claims databases, covering 18 million inhabitants from 2011 to 2016. Incident aflibercept users were matched 1:4 to incident ranibizumab users. The outcome was incident non-ocular haemorrhage requiring hospitalisation. Incidence per 1000 person-years (PYs) was estimated. Patients were followed for 180 days using an intention-to-treat (ITT) approach. An as-treated (AT) approach was also employed, using grace periods of 60 or 90 days. Analyses were repeated for aflibercept versus dexamethasone and ranibizumab versus dexamethasone. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. We identified incident users of intravitreal ranibizumab (n = 21,766), aflibercept (n = 3150) and dexamethasone (n = 3900). The incidence of haemorrhage was four events per 1000 PYs for each drug. Aflibercept was not associated with increased risk versus ranibizumab at 180 days (HR 0.97 [95% CI 0.37–2.56]). Results were consistent in the AT analysis (HR 1.19 [95% CI 0.52–2.75]). No increased risk was found for aflibercept and ranibizumab at 180 days versus dexamethasone (HR 0.70 [95% CI 0.30–2.60] and HR 0.67 [95% CI 0.33–1.38], respectively). No association was identified between intravitreal aflibercept and non-ocular haemorrhage versus ranibizumab. A comparable risk for these intravitreal anti-VEGFs and intravitreal dexamethasone was observed.

A recent study found a decreased risk of Parkinson disease (PD) associated with the β2 adrenergic agonist (β2-agonist) salbutamol. However, other mechanisms might explain this apparent association. Using the UK Clinical Practice Research Datalink, we formed a cohort of 2,430,884 patients aged 50 years or older between 1995 and 2016. During follow-up, 8,604 cases of PD were identified and matched to 86,040 controls on sex, age, date of cohort entry, and duration of follow-up, after applying a 1-year latency time window. Incidence rate ratios of PD associated with use of β2-agonists were estimated using conditional logistic regression. Ever-use of β2-agonists was associated with a 17% decreased rate of PD (rate ratio = 0.83, 95% confidence interval: 0.75, 0.91) compared with no use. However, this association was limited to early short-term use and was no longer observed after more than 2 years of cumulative duration of use (rate ratio = 0.97, 95% confidence interval: 0.80, 1.17). A similar pattern was observed when stratifying by time since first β2-agonist prescription and by duration of follow-up. The apparent association of β2-agonists with a decreased risk of PD is likely the result of reverse causality rather than a biological effect of these drugs on the risk of PD.

The sequential treatment decisions made by physicians to treat chronic diseases are formalized in the statistical literature as dynamic treatment regimes. To date, methods for dynamic treatment regimes have been developed under the assumption that observation times, that is, treatment and outcome monitoring times, are determined by study investigators. That assumption is often not satisfied in electronic health records data in which the outcome, the observation times, and the treatment mechanism are associated with patients’ characteristics. The treatment and observation processes can lead to spurious associations between the treatment of interest and the outcome to be optimized under the dynamic treatment regime if not adequately considered in the analysis. We address these associations by incorporating two inverse weights that are functions of a patient’s covariates into dynamic weighted ordinary least squares to develop optimal single stage dynamic treatment regimes, known as individualized treatment rules. We show empirically that our methodology yields consistent, multiply robust estimators. In a cohort of new users of antidepressant drugs from the United Kingdom’s Clinical Practice Research Datalink, the proposed method is used to develop an optimal treatment rule that chooses between two antidepressants to optimize a utility function related to the change in body mass index.

PURPOSE In clinical practice, warfarin therapy requires frequent dose adjustments. In pharmacy claims, the days supplied value may not reflect the true duration of warfarin dispensation. This may affect the measures of association comparing the safety of direct oral anticoagulants (DOACs) versus warfarin. METHODS Using Quebec healthcare administrative databases, we formed a cohort of 55 230 patients newly treated with oral anticoagulants between 2010 and 2016. The duration of dispensations was defined using two approaches: the recorded days supplied value, and the longitudinal coverage approximation (data-driven) that may account for individual variation in drug usage patterns. Propensity scores adjusted Cox proportional hazards regression models were used to estimate the hazard ratio (HR) of major bleeding with dabigatran or rivaroxaban versus warfarin. RESULTS Using the days supplied, the mean (and standard deviation) dispensation durations for dabigatran, rivaroxaban, and warfarin were 19 (15), 19 (14), and 13 (12) days, respectively. Using the data-driven approach, the durations were 20 (16), 19 (15), and 15 (16) days, respectively. The choice of the approach had no impact on the HR estimates. CONCLUSIONS In our settings, the data-driven approach closely approximated the recorded days supplied value for the standard dose therapies such as dabigatran and rivaroxaban. For warfarin, the data-driven approach captured more variability in the duration of dispensations compared to the days supplied value, which may better reflect the true drug-taking behavior of warfarin. Both approaches may provide valid estimates when comparing the safety of DOACs versus warfarin.

We explored potential differences in time trends of gabapentinoid prescription and of opioid coprescription between 1993 and 2017 in the 4 UK nations using the Clinical Practice Research Datalink, a UK primary care database. There were distinct trends in annual rates of new gabapentin and pregabalin prescriptions in Northern Ireland. The rate of new gabapentin prescriptions rapidly increased after 2010 and exceeded that of the other nations by 2017 (rate of 836 [95% confidence interval: 787-887] per 100 000 person-years). Additionally, the rate of new pregabalin prescriptions was higher during the entire study period, reaching a peak of 1139 (95% confidence interval: 1088-1193) per 100 000 person-years in 2010, 5-fold higher than the other nations. Findings in Northern Ireland may be partly attributable to the high burden of anxiety disorders, an indication for pregabalin. Further exploration of reasons for discrepancies in gabapentinoid prescribing between UK nations is warranted.

Background Use of gabapentinoids is increasing. Following recent case reports, we investigated a putative risk of parkinsonism with pregabalin or gabapentin. Methods A disproportionality analysis of 5,653,547 individual case safety reports in the World Health Organization individual case safety report database, VigiBase, compared all patients with parkinsonism who were receiving gabapentinoids with other patients. Results are shown as reporting odds ratios and the information component, an indicator of disproportionate Bayesian reporting. Sensitivity analyses included comparisons with drugs used for similar indications (amitriptyline, duloxetine) and exclusion of drugs that induce parkinsonism. Results Among 5,653,547 reports, 4925 parkinsonism reports were found with pregabalin and 4881 with gabapentin. Gabapentin and pregabalin were associated with increased reporting odds ratio (2.16 [2.10-2.23], 2.43 [2.36-2.50]). Similar trends were found using information components after excluding drugs that induce parkinsonism and for pregabalin compared with amitriptyline or duloxetine. Conclusions This study found that gabapentinoids (particularly pregabalin) can be associated with parkinsonism. © 2019 International Parkinson and Movement Disorder Society.

PURPOSE The Canadian Network for Observational Drug Effect Studies (CNODES) is a network of Canadian research centres using administrative data to conduct distributed drug safety and effectiveness studies. In this study, we compare the provincial administrative databases and illustrate the potential impact of database differences on a CNODES study about domperidone and the risk of ventricular tachyarrhythmia and sudden cardiac death (VT/SCD). METHODS We assessed the impact of varying versions and precision of the International Classification of Diseases coding system in physician claims data, and the content and completeness of hospital discharge abstracts across CNODES sites, as these variations can introduce differences in the study cohorts formed and affect study results. RESULTS In our study of 214 962 patients, hospital diagnosis type (such as most responsible, admitting, or secondary diagnosis) was missing in some provinces, resulting in misclassification of the outcome and variation in rates and risk estimates. Incidence rates of VT/SCD ranged from 19.8 (95% confidence interval [CI] 17.7-22.2) per 10 000 person-years in British Columbia to 53.4 (95% CI 50.3-56.5) in Quebec. While most provinces reported an increased risk of VT/SCD, a null effect was observed in Quebec (rate ratio 1.06; 95% CI 0.79-1.41). CONCLUSIONS Distributed analyses allow for rapid responses to drug safety signals. However, variation in characteristics of the administrative data across research centres can influence study results. By identifying the sources of database heterogeneity, one can evaluate the potential biases these differences may introduce, highlighting the importance of considering such variation in distributed networks.

Objective To assess whether abatacept as initial biologic disease-modifying antirheumatic drug (DMARD) in the treatment of rheumatoid arthritis is associated with an increased risk of serious infections, including bone and joint, gastrointestinal, respiratory tract, skin and soft tissue, and urinary tract, when compared with other biologic DMARDs. Methods We performed a population-based cohort study among patients newly-treated with biologic DMARDs within the US-based Truven MarketScan® population and Supplemental US Medicare from 2007 to 2014. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of serious infections requiring hospitalisation associated with initiation of abatacept, compared with initiation of other bDMARDs, after controlling for age and deciles of the propensity score. Results The cohort included 5,752 patients who initiated abatacept and 78,556 who initiated another biologic DMARD, of whom 193 and 1531 had a serious infection during follow-up (crude incidence rate 4.45 per 100 person-years and 3.62 per 100 person-years, respectively). Compared with other biologic DMARDs, the use of abatacept was not associated with an increased incidence of serious infections overall (HR 1.04, 95% CI 0.89–1.21). The risk did not vary by duration of use ( 1 year: HR 1.08, 95% CI 0.77–1.52). In addition, the risk was not increased for the site-specific infections. Conclusion The use of abatacept as first biologic DMARD in the treatment of rheumatoid arthritis was not associated with different risks of serious infections compared with other biologic DMARDs.

Background Patients with depression and comorbid obesity may be more prone to weight modulating and cardiovascular side effects of selected antidepressants (AD). It is important to ascertain whether these AD prescriptions differ by patient weight status. Methods Canadian Primary Care Sentinel Surveillance Network (CPCSSN) electronic medical records were used. Participants were adults with depression prescribed an AD in 2000-2016, with weight categories established before the first prescription. Logistic regression and mixed effects models were applied to examine associations between obesity and AD prescribing, adjusted for sex, age, and comorbidities. Machine learning algorithm random forest (RF) was used to evaluate the importance of weight in predicting prescribing patterns. Results Of 26,571 participants, 72.4% were women, mean age was 38.9 years (standard deviation (SD)=14.2) and mean BMI 27.0 kg/m2 (SD=6.5); 9.5% had ≥ 1 comorbidity. Patients with obesity, compared to normal weight patients, were more likely to receive bupropion (adjusted odds ratio (aOR) 1.24, 95%CI: 1.09,1.42), fluoxetine (aOR 1.14, 95%CI : 0.97,1.34), and amitriptyline (aOR 1.13, 95%CI : 0.93,1.36), and less likely to receive mirtazapine (aOR 0.55, 95%CI : 0.44,0.68) and escitalopram (aOR 0.88, 95%CI : 0.80, 0.97). RF analysis showed that weight was among the most important predictors of prescribing patterns, equivalent to age and more important than sex. Conclusions AD prescribing patterns for patients with obesity appear to be different for selected AD types, including AD known for their weight-modulating and cardiovascular side effects. Longitudinal studies are needed to examine whether these prescribing patterns are associated with significant health outcomes.

Objectives To assess the risks of ventricular tachyarrhythmia/sudden cardiac death (VT/SCD) with domperidone use in Parkinson’s disease (PD). Study designs and Settings Using Bayesian methods, results from an observationalstudy were combined with prior beliefs to calculate posterior probabilities of increasedrelative risk (RR)) of VT/SCD with use of domperidone compared to non-use and ofharm, defined as risk exceeding 15%. The analyses were carried with normallydistributed priors (log (RR)): uninformative (N(0,10)) or informative (N(0.53,179)),derived from a meta-analysis (OR (95%CI):1.70 (1.47-1.97)). Sensitivity analyses used:different priors’ strengths, different priors, and Bayesian meta-analysis Results The uninformative prior yielded a RR: 1.23 (95% credible interval (CrI):0.94-1.62), like the published frequentist RR: 1.22 (95% CI:0.99-1.50), with 69% probabilityof harm. With an informative prior weighted at 100%, 50% and 10%, the RR were 1.63(1.41-1.88), 1.57 (1.31-1.91) and 1.39 (1.10-1.93), respectively. The correspondingprobabilities of harm were 100%, 99%, and 94%, respectively. Conclusion While both the frequentist and Bayesian approaches with anuninformative prior were unable to reach a definitive conclusion concerning thearrhythmic risk of domperidone in PD patients, the Bayesian analysis with informativepriors showed a high probability of increased risk that was robust to multiple priorsensitivity analyses.

Background It has been suggested that lipid lowering therapy causes impaired cognitive changes. The association between the use of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk of neurocognitive adverse events remains unclear. This meta-analysis aims to assess neurocognitive safety of PCSK9 inhibitors in randomized controlled trials (RCTs). Methods and results The research was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed (MEDLINE), Embase and Cochrane library were searched through September 2019. Selection criteria included RCTs that addressed to neurocognitive adverse events of participants using Alirocumab, Evolocumab or Bococizumab, with a follow up duration of at least 6 months. The search results were screened by two independent reviewers. Safety data from included papers were extracted. Random effects meta-analysis was used to pool results, and meta-regression was utilized when applicable. Twenty-one studies were included. Among 59,733 patients, 31,611 were treated with PCSK9 inhibitors. The follow-up period ranged from 24 weeks to 48 months. No significant difference in the incidence of neurocognitive adverse effects between the groups was identified (RR = 1.01, 95% CI: 0.86–1.19, I2 = 3%). Similar results were seen in subgroup analysis for each of the medications (alirocumab- RR = 0.88, 95% CI: 0.72–1.08, I2 = 0%, evolocumab- RR = 1.42, 95% CI: 0.74–2.73, I2 = 55%). A meta-regression analysis for evolocumab revealed that prolonged study duration was associated with decreased risk for neurocognitive adverse events (βweek = −0.0037, p-value = 0.03). Conclusions Pooled results of our meta-analysis and meta-regression show that exposure to PCSK9 inhibitors is not associated with an increased risk of neurocognitive adverse effects.

Background There is lack of recent information on the prescribing trends of antidepressants and coprescription with other psychotropic medications in the United Kingdom (UK) pediatric population. Methods Using the Clinical Practice Research Datalink, we estimated the annual rates of patients newly prescribed an antidepressant (selective serotonin reuptake inhibitors (SSRIs), other newer generation antidepressants, and tricyclic antidepressants (TCAs)) and the percentage of new users of antidepressants with a same-day coprescription for other psychotropic medications. We also estimated the prevalence of patients with antidepressant prescriptions and percentage of coprescription for other psychotropic medications. Results After a 42% decline from 2000 to 2005, the rate of patients newly prescribed an antidepressant increased from 2006 onwards. From 2008 to 2018, the rate increased from 254.3 to 471.2 per 100,000 person-years (rate ratio 1.97, 95% confidence interval 1.96-1.99). The rate was higher in females and adolescents aged 15 to 17. SSRIs were most commonly prescribed (70% of all antidepressant prescriptions). Overall, 4.7% of patients newly prescribed an antidepressant had at least one same-day coprescription for another psychotropic medication. During the study period, coprescription rose from 2.6% to 6.4% and was more frequent in males. In 2018, most coprescriptions were anxiolytics and hypnotics (63%) and antipsychotics (26%). Trends in prevalent prescriptions corresponded to trends in new prescriptions. Limitations By using a primary care database, we did not have information on prescriptions from specialists or during hospitalizations. Conclusions During the last decade, antidepressant prescriptions and psychotropic coprescription in primary care increased in UK children and adolescents.

Aims: We characterized the utilization and long-term treatment persistence of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF) and liver disease. Method: Using the UK Clinical Practice Research Datalink, we assembled a population-based cohort of NVAF patients with liver disease initiating oral anticoagulants between 2011 and 2020. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) of the association between patient characteristics and initiation of DOACs vs vitamin K antagonists (VKAs). Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs of the association between patient characteristics and the switch from VKAs to DOACs vs remaining on VKAs. We also assessed the 5-year treatment persistence with DOACs vs VKAs, and whether ischemic stroke or bleeding preceded treatment discontinuation. Results: Our cohort included 3167 NVAF patients with liver disease initiating DOACs (n = 2247, 71%) or VKAs (n = 920, 29%). Initiators of DOACs were more likely to have prior ischemic stroke (OR 1.44, 95% CI 1.12-1.85) than VKA initiators but less likely to have used antiplatelet agents (OR 0.66, 95% CI 0.53-0.82). Patients switching to DOACs were more likely to have used selective serotonin reuptake inhibitors (HR 1.64, 95% CI 1.13-2.37) than those remaining on VKAs. At 5 years, 31% of DOAC initiators and 9% of VKA initiators remained persistent. Only few patients were diagnosed with ischemic stroke or bleeding prior to treatment discontinuation. Conclusion: Most NVAF patients with liver disease initiated treatment with DOACs. Long-term persistence with DOACs was higher than with VKAs but remained relatively low.

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

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for patients with unipolar depression, yet there is little guidance on which SSRI provides the most benefit to a patient, based on personal characteristics. In this work, we explore whether an individualized treatment strategy can be used by health-care providers to adapt their prescription pattern to reduce the risk of a severe depression-related outcome (SDO) when choosing between citalopram and fluoxetine, 2 commonly prescribed SSRIs. Our population-based cohort study used data from the Clinical Practice Research Datalink, the Hospital Episode Statistics repository, and the Office for National Statistics database in the United Kingdom to create a cohort of individuals diagnosed with depression who were prescribed citalopram or fluoxetine between April 1998 and December 2017. Patients were followed from treatment initiation until occurrence of the SDO outcome, treatment discontinuation, or end of study. To find an optimal treatment strategy, we used dynamic weighted survival modeling, considering patient features such as age, sex, body mass index, previous psychiatric diagnoses, and medications. Our findings suggest that using patient characteristics to tailor the antidepressant drug therapy is associated with an increase of 4 days in the median time to SDO (95% confidence interval: 2, 10 days).

There are an infinite number of small decisions to be made in routine clinical practice, and most will never be the subject of prospective research studies. Rather than making these decisions arbitrarily, learning health-care systems leverage experience represented by electronic health record data and other sources to inform decision-making and improve clinical practice. While this approach has been elusive in mental health, Coulombe et al. (Am J Epidemiol. 2021;190(7):1210-1219) use UK National Health Service data to evaluate a decision rule for antidepressant choice created using dynamic weighted survival modeling. Although the results are equivocal in this use case, the work suggests a path forward for data-driven decision-making in routine mental health care. Such approaches will be required to set the stage for a learning mental health care system.

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

The coronavirus disease 2019 pandemic, which was caused by the severe acute respiratory syndrome coronavirus 2, has led to an unprecedented effort to generate real-world evidence on the safety and effectiveness of various treatments. A growing number of observational studies in which the effects of certain drugs were evaluated have been conducted, including several in which researchers assessed whether hydroxychloroquine improved outcomes in infected individuals and whether renin-angiotensin-aldosterone system inhibitors have detrimental effects. In the present article, we review and illustrate how immortal time bias and selection bias were present in several of these studies. Understanding these biases and how they can be avoided may prove important for future observational studies assessing the effectiveness and safety of potentially promising drugs during the coronavirus 19 pandemic.

Aims To determine the risk of fracture associated with direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF), accounting for cumulative duration of use. Methods and results Using Quebec administrative healthcare databases, we formed a cohort of all patients aged 40 years or older newly diagnosed with NVAF, who filled a first prescription for DOACs or VKAs between 2011 and 2014. Exposure was modelled as a time-varying variable whereby patients were considered unexposed up to 180 days of cumulative duration of use (to account for a biologically meaningful exposure) and exposed thereafter. The final cohort included 10 306 new users of DOACs and 15 357 new users of VKAs. After propensity score-based fine stratification and weighting, use of DOACs for 180 days or greater was associated with a 35% decreased risk of fracture [crude incidence rates 7.5 vs. 15.3 per 1000 person-years; adjusted hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.46–0.91] compared to VKA duration ≥180 days. Direct oral anticoagulants use was also associated with a lower risk of hip fracture (HR 0.51, 95% CI 0.31–0.86) compared with VKAs. There was no difference in the rate of fracture for shorter duration of use (HR 1.10; 95% CI 0.79–1.53). The risk was not modified by age, sex, chronic kidney disease, osteoporosis, history of fracture or falls. Conclusion Prolonged use of DOACs is associated with a lower risk of fracture compared with VKAs. These findings support the first-line recommendation for DOACs in patients with NVAF.

Three studies have suggested a potential positive association between the use of tamoxifen in breast cancer and Parkinsonism, mainly after long-term exposure. To explore this potential signal, we performed a case/non-case study using the World Health Organization Global Individual Case Safety Reports (ICSRs) database, VigiBase® between 1979 and 2018. Among women ≥ 55 years, we measured the risk of reporting “Parkinsonism” compared with all other adverse drug reactions [as a reporting odds ratio (ROR 95% CI)] for tamoxifen compared to all other drugs or aromatase inhibitors. During the study period, 356 ICSRs of Parkinsonism reported with tamoxifen were identified. We failed to find a positive association between tamoxifen exposure and Parkinsonism in comparison with exposure to other drugs (ROR = 0.79; 95% CI 0.71–0.88) or aromatase inhibitors (ROR = 0.39; 95% CI 0.33–0.46). This study did not find evidence for Parkinsonism associated with tamoxifen.

Observational studies have suggested an increased risk of intracranial hemorrhage (ICH) associated with selective serotonin reuptake inhibitors (SSRIs) and other antidepressants primarily inhibiting serotonin reuptake. Our aim was to systematically review the available epidemiologic evidence regarding the risk of ICH associated with SSRIs and antidepressants inhibiting serotonin reuptake. MEDLINE/PubMed and EMBASE were searched for all relevant articles in English, French, or German published before April 2017. Observational studies with SSRIs or any antidepressants classified by strength of serotonin reuptake inhibition as primary exposure, a comparison group, and ICH as outcome were eligible. Among twelve identified studies (six nested case-control, three cohort, two case-control, one case-crossover), seven assessed the risk of ICH associated with SSRIs (some also including other antidepressants primarily inhibiting serotonin reuptake), two the risk of ICH associated with inhibitors of serotonin reuptake according to the degree of reuptake inhibition, and three addressed both objectives. Four of ten studies showed an increased risk of ICH associated with SSRIs, with the two largest studies suggesting a moderate effect. Three of five studies showed an increased risk of ICH associated with strong inhibitors of serotonin reuptake. Limitations including residual confounding, inclusion of prevalent users, potentially inappropriate study designs, and lack of power may have influenced these results, especially in studies showing no association or a highly increased risk. This systematic review suggests an increased risk of ICH with antidepressants primarily inhibiting serotonin reuptake, such as SSRIs. An increased risk of ICH with strong inhibitors of serotonin reuptake compared with weak inhibitors is also possible but the available evidence is limited. Antidepressants only moderately or weakly inhibiting serotonin reuptake might be preferred in high-risk patients.

Background Non–vitamin K antagonist oral anticoagulants (NOACs) are relatively new drugs used for stroke prevention in nonvalvular atrial fibrillation (NVAF). However, there are concerns that their use may be associated with hepatotoxic effects. Objectives The purpose of this study was to determine whether the use of NOACs is associated with an increased risk of serious liver injury compared with the use of vitamin K antagonists (VKAs) in NVAF patients with and without prior liver disease. Methods Using the administrative databases of the Canadian province of Quebec’s health insurances, the authors conducted a cohort study among patients newly diagnosed with NVAF between January 2011 and December 2014. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of serious liver injury (defined as either a hospitalization or related death) were estimated using time-dependent Cox proportional hazards models, comparing current use of NOACs to current use of VKAs separately among patients with or without prior liver disease. Results The cohort comprised 51,887 patients, including 3,778 with prior liver disease. During 68,739 person-years of follow-up, 585 patients experienced a serious liver injury. Compared with current use of VKAs, current use of NOACs was not associated with an increased risk of serious liver injury in patients without or with prior liver disease (adjusted HR: 0.99; 95% CI: 0.68 to 1.45; and adjusted HR: 0.68; 95% CI: 0.33 to 1.37, respectively). Conclusions Compared with VKAs, NOACs were not associated with an increased risk of serious liver injury irrespective of baseline liver status. Overall, these results provide reassurance regarding the hepatic safety of NOACs.

Aims Novel oral anticoagulants (NOACs) are alternatives to vitamin-K antagonists (VKAs) for the prevention of thromboembolism. It is unclear how NOACs have been adopted in the UK since first introduced in 2008. The present study was conducted to describe the trends in the prescription of NOACs in the UK, including dabigatran, rivaroxaban and apixaban. Methods Using the UK's Clinical Practice Research Datalink, the rates of new use of NOACs and VKAs from 2009 to 2015 were calculated using Poisson regression. Patient characteristics associated with NOAC initiation were identified using multivariate logistic regression. Results The overall rate of oral anticoagulant initiation increased by 58% over the study period [rate ratio (RR) 1.58; 95% confidence interval (CI) 1.23, 2.03], even as the rate of new VKA use decreased by 31% (RR 0.69; 95% CI 0.52, 0.93). By contrast, the rate of initiation of NOAC increased, particularly from 2012 onwards, with a 17-fold increase from 2012 to 2015 (RR 17.68; 95% CI 12.16, 25.71). In 2015, NOACs accounted for 56.5% of oral anticoagulant prescriptions, with rivaroxaban prescribed most frequently, followed by apixaban and then dabigatran. Compared to VKAs, new NOAC users were less likely to have congestive heart failure, coronary artery disease and peripheral vascular disease, and more likely to have a history of ischaemic stroke. Conclusions In the UK, the rate of initiation of NOACs has increased substantially since 2009, and these agents have now surpassed VKAs as the anticoagulant of choice. Moreover, the characteristics of patients initiated on NOACs have changed over time, and this should be accounted for in future studies comparing NOACs and VKAs.