Publications by authors named "Kristian B Filion"

213 Publications

Comparison of Cardiovascular Safety for Smoking Cessation Pharmacotherapies in a Population-Based Cohort in Australia.

JAMA Netw Open 2021 11 1;4(11):e2136372. Epub 2021 Nov 1.

Centre for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada.

Importance: Although concerns exist regarding a potential increased risk of cardiovascular events for smoking cessation pharmacotherapies, there is general consensus that any increased risk associated with their use would be outweighed by the benefits of smoking cessation; thus, clinical guidelines recommend that such pharmacotherapies be offered to everyone who wants to quit smoking. In the interest of minimizing risk to patients, prescribers need evidence indicating how these pharmacotherapies compare with one another in terms of cardiovascular safety.

Objective: To compare the risk of major adverse cardiovascular events (MACE) among individuals initiating varenicline, nicotine replacement therapy (NRT) patches, or bupropion.

Design, Setting, And Participants: This retrospective, population-based cohort study using linked pharmaceutical dispensing, hospital admissions, and death data was conducted in New South Wales, Australia. Participants included adults who were dispensed a prescription smoking cessation pharmacotherapy between 2008 and 2015 or between 2011 and 2015, depending on the availability of the pharmacotherapies being compared. Pairwise comparisons were conducted for risk of MACE among 122 932 varenicline vs 92 148 NRT initiators; 342 064 varenicline vs 10 457 bupropion initiators; and 102 817 NRT vs 6056 bupropion initiators.

Exposure: First course of the smoking cessation pharmacotherapy of interest.

Main Outcomes And Measures: The primary outcome was MACE, defined as a composite of acute coronary syndrome, stroke, and cardiovascular death. Secondary outcomes were the individual components of MACE. Inverse probability of treatment weighting with high-dimensional propensity scores was used to account for potential confounding. Cox proportional hazards regression models with robust variance were used to estimate hazard ratios (HRs) and 95% CIs. Data were analyzed January 24, 2019, to September 1, 2021.

Results: The mean (SD) age of included individuals ranged from 41.9 (14.2) to 49.8 (14.9) years, and the proportion of women ranged from 42.8% (52 702 of 123 128) to 52.2% (53 693 of 102 913). The comparison of 122 932 varenicline initiators and 92 148 NRT patch initiators showed no difference in the risk of MACE (HR, 0.87; 95% CI, 0.72-1.07) nor in the risk of the secondary outcomes of acute coronary syndrome (HR, 0.96; 95% CI, 0.76-1.21) and stroke (HR, 0.72; 95% CI, 0.45-1.14). However, decreased risk of cardiovascular death was found among varenicline initiators (HR, 0.49; 95% CI, 0.30-0.79). The results of comparisons involving bupropion were inconclusive owing to wide confidence intervals (eg, risk of MACE: 342 064 varenicline vs 10 457 bupropion initiators, HR, 0.87 [95% CI, 0.53-1.41]; 102 817 NRT patch vs 6056 bupropion initiators, HR, 0.79 [95% CI, 0.39-1.62]).

Conclusions And Relevance: The finding of this cohort study that varenicline and NRT patch use have similar risk of MACE suggests that varenicline, the most efficacious smoking cessation pharmacotherapy, may be prescribed instead of NRT patches without increasing risk of major cardiovascular events. Further large-scale studies of the cardiovascular safety of varenicline and NRT relative to bupropion are needed.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.36372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630569PMC
November 2021

Effectiveness of interventions for prevention of common infections in people who use opioids: a protocol for a systematic review of systematic reviews.

Syst Rev 2021 Nov 15;10(1):298. Epub 2021 Nov 15.

Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine and Health Sciences, McGill University, Purvis Hall, 1020 Pine Avenue West, Montreal, QC, H3A 1A2, Canada.

Background: The North American opioid crisis is driven by opioid-related mortality and morbidity, including opioid use-associated infections (OUAIs), resulting in a substantial burden for society. Users of legal and illegal opioids are at an increased risk of OUAIs compared to individuals not using opioids. As reported for hepatitis C virus (HCV), human immunodeficiency virus (HIV), bacterial, fungal, and other infections, OUAIs transmission and acquisition risks may be modifiable. Several systematic reviews (SRs) synthetized data regarding interventions to prevent infections in persons using drugs (e.g., opioid substitution therapy, needle and syringes exchange programs, psycho-social interventions); however, their conclusions varied. Therefore, SR of published SRs is needed to synthesize the highest level of evidence on the scope and effectiveness of interventions to prevent OUAIs in people using opioids legally or illegally.

Methods: We will comprehensively search for SRs in the PubMed, Embase, PsycINFO, Cochrane Database of Systematic Reviews, Epistemonikos, and Google Scholar databases from inception to November 2020. Data selection and extraction for each SR will be performed independently by two researchers, with disagreements resolved by consensus. All SRs regarding interventions with evaluated effectiveness to prevent OUAI in legal and/or illegal opioid users will be eligible. Risk of bias assessment will be performed using the AMSTAR2 tool. The results will be qualitatively synthesized, and a typology of interventions' effectiveness with a statement on the strength of evidence for each category will be created.

Discussion: Our pilot search of PubMed resulted in 379 SRs analyzing the effectiveness of interventions to prevent HCV and HIV in persons who inject different types of drugs, including opioids. Of these 379 SRs, 8 evaluated primary studies where participants used opioids and would therefore be eligible for inclusion. The search results thus justify the application of SR of SRs approach. Comprehensive data on the scope and effectiveness of existing interventions to prevent OUAIs will help policy-makers to plan and implement preventive interventions and will assist clinicians in the guidance for their patients using opioids.

Systematic Review Registration: Registered in PROSPERO on 30 July 2020 ( #195929 ).
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http://dx.doi.org/10.1186/s13643-021-01852-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591821PMC
November 2021

Ustekinumab safety in pregnancy: a comprehensive review.

Arthritis Care Res (Hoboken) 2021 Nov 8. Epub 2021 Nov 8.

Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada.

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http://dx.doi.org/10.1002/acr.24813DOI Listing
November 2021

General practitioner prescribing trends among pediatric patients in the United Kingdom: 1998-2018.

Pharmacoepidemiol Drug Saf 2021 Oct 28. Epub 2021 Oct 28.

Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.

Purpose: To describe the prescribing trends of 17 therapeutic drug categories and the specific drug classes of systemic antibiotics, analgesics, and antidepressants in children and adolescents in the United Kingdom between 1998 and 2018.

Methods: A population-based retrospective cohort study including children and adolescents aged 018 years. Overall and annual prescription rates per 10 000 person-years and corresponding 95% confidence intervals (CIs) were calculated. Rate ratios and 95% CIs were calculated to assess changes in prescription rates during the study period using Poisson regression.

Results: Among 4 075 527 children and adolescents during the study period from 1998 to 2018, the prescribing rates increased by 15% for attention deficit hyperactivity disorder drugs (rate ratio: 1.15, 95% CI: 1.12-1.18), 14% for anxiolytics and hypnotics (rate ratio: 1.14, 95% CI: 1.13-1.16), and 8% for drugs for gastroesophageal reflux disease (GERD) (rate ratio: 1.08, 95% CI: 1.07-1.09). Prescribing rates decreased by 6% for cough preparations (rate ratio: 0.94, 95% CI: 0.92-0.95) and by 3% for analgesics (rate ratio: 0.97, 95% CI: 0.96-0.99). No meaningful changes were observed for systemic antibiotics (rate ratio: 1.02, 95% CI: 0.99-1.04). Among specific drug classes, prescribing rates decreased for broad-spectrum penicillins and cephalosporins, and they increased for selective serotonin reuptake inhibitors, opioids, and drugs for migraine.

Conclusions: Between 1998 and 2018, the prescribing of centrally acting drugs and drugs for GERD increased among pediatric patients, whereas prescribing of cough preparations and analgesics declined in this population.
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http://dx.doi.org/10.1002/pds.5377DOI Listing
October 2021

Tramadol versus codeine and the short-term risk of cardiovascular events in patients with non-cancer pain: A population-based cohort study.

Br J Clin Pharmacol 2021 Oct 2. Epub 2021 Oct 2.

Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.

Aims: The effect of tramadol on the cardiovascular system is largely unknown. There is concern that, with its multimodal mechanism of action to increase serotonin and norepinephrine levels in the body, it could increase the risk of arterial ischaemia and cardiovascular events. We aimed to compare the short-term risk of cardiovascular events with the use of tramadol to that of codeine among patients with non-cancer pain.

Methods: We conducted a retrospective population-based cohort study using data from the Clinical Practice Research Datalink (CPRD) with new users of tramadol or codeine from April 1998 to March 2017. Exposure was defined using an approach analogous to an intention-to-treat, with a maximum follow-up of 30 days. The primary endpoint was myocardial infarction, and secondary endpoints were unstable angina, ischaemic stroke, coronary revascularization, cardiovascular death and all-cause mortality. Hazard ratios (HRs) were estimated using Cox proportional hazards models, adjusted for high-dimensional propensity score.

Results: The final cohort included 123 394 tramadol users and 914 333 codeine users. When tramadol was compared to codeine, the adjusted hazard ratio (HR) of myocardial infarction was 1.00 (95% CI 0.81-1.24). There was also no evidence of elevated risks of unstable angina (0.92; 95% CI 0.67-1.27), ischaemic stroke (0.98; 95% CI 0.82-1.17), coronary revascularization (0.97; 95% CI 0.69-1.38), cardiovascular death (1.07; 95% CI 0.93-1.23) or all-cause mortality (1.03; 95% CI 0.94-1.14) when tramadol was compared to codeine.

Conclusions: Short-term use of tramadol, compared with codeine, was not associated with an increased risk of cardiac events among patients with non-cancer pain.
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http://dx.doi.org/10.1111/bcp.15099DOI Listing
October 2021

Evidence reversals in primary care research: a study of randomized controlled trials.

Fam Pract 2021 Sep 23. Epub 2021 Sep 23.

Department of Family Medicine, Tufts University School of Medicine and Cambridge Health Alliance, Boston, MA, United States.

Background: Evidence-Based Medicine is built on the premise that clinicians can be more confident when their decisions are grounded in high-quality evidence. Furthermore, evidence from studies involving patient-oriented outcomes is preferred when making decisions about tests or treatments. Ideally, the findings of relevant and valid trials should be stable over time, that is, unlikely to be reversed in subsequent research.

Objective: To evaluate the stability of evidence from trials relevant to primary healthcare and to identify study characteristics associated with their reversal.

Methods: We studied synopses of randomized controlled trials (RCTs) published from 2002 to 2005 as "Daily POEMs" (Patient Oriented Evidence that Matters). The initial evidence (E1) from these POEMs (2002-2005) was compared with the updated evidence (E2) on that same topic in a summary resource (DynaMed 2019). Two physician-raters independently categorized each POEM-RCT as (i) reversed when E1 ≠ E2, or as (ii) not reversed, when E1 = E2. For all "Evidence Reversals" (E1 ≠ E2), we assessed the direction of change in the evidence.

Results: We evaluated 408 POEMs on RCTs. Of those, 35 (9%; 95% confidence interval [6-12]) were identified as reversed, 359 (88%) were identified as not reversed, and 14 (3%) were indeterminate. On average, this represents about 2 evidence reversals per annum for POEMs about RCTs.

Conclusions: Over 12-17 years, 9% of RCTs summarized as POEMs are reversed. Information alerting services that apply strict criteria for relevance and validity of clinical information are likely to identify RCTs whose findings are stable over time.
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http://dx.doi.org/10.1093/fampra/cmab104DOI Listing
September 2021

The Effect of Overdose Education and Naloxone Distribution: An Umbrella Review of Systematic Reviews.

Am J Public Health 2021 08;111(8):1516-1517

Opioids contribute to more than 60 000 deaths annually in North America. While the expansion of overdose education and naloxone distribution (OEND) programs has been recommended in response to the opioid crisis, their effectiveness remains unclear. To conduct an umbrella review of systematic reviews to provide a broad-based conceptual scheme of the effect and feasibility of OEND and to identify areas for possible optimization. We conducted the umbrella review of systematic reviews by searching PubMed, Embase, PsycINFO, Epistemonikos, the Cochrane Database of Systematic Reviews, and the reference lists of relevant articles. Briefly, an academic librarian used a 2-concept search, which included opioid subject headings and relevant keywords with a modified PubMed systematic review filter. Eligible systematic reviews described comprehensive search strategies and inclusion and exclusion criteria, evaluated the quality or risk of bias of included studies, were published in English or French, and reported data relevant to either the safety or effectiveness of OEND programs, or optimal strategies for the management of opioid overdose with naloxone in out-of-hospital settings. Two reviewers independently extracted study characteristics and the quality of included reviews was assessed in duplicate with AMSTAR-2, a critical appraisal tool for systematic reviews. Review quality was rated critically low, low, moderate, or high based on 7 domains: protocol registration, literature search adequacy, exclusion criteria, risk of bias assessment, meta-analytical methods, result interpretation, and presence of publication bias. Summary tables were constructed, and confidence ratings were provided for each outcome by using a previously modified version of the Royal College of General Practitioners' clinical guidelines. Six systematic reviews containing 87 unique studies were included. We found that OEND programs produce long-term knowledge improvement regarding opioid overdose, improve participants' attitudes toward naloxone, provide sufficient training for participants to safely and effectively manage overdoses, and effectively reduce opioid-related mortality. High-concentration intranasal naloxone (> 2 mg/mL) was as effective as intramuscular naloxone at the same dose, whereas lower-concentration intranasal naloxone was less effective. Evidence was limited for other naloxone formulations, as well as the need for hospital transport after overdose reversal. The preponderance of evidence pertained persons who use heroin. Evidence suggests that OEND programs are effective for reducing opioid-related mortality; however, additional high-quality research is required to optimize program delivery. Community-based OEND programs should be implemented widely in high-risk populations.
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http://dx.doi.org/10.2105/AJPH.2021.306306aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489639PMC
August 2021

Prescription Patterns for the Use of Antihypertensive Drugs for Primary Prevention Among Patients With Hypertension in the United Kingdom.

Am J Hypertens 2022 Jan;35(1):42-53

Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.

Background: Several antihypertensive drugs are available for the primary prevention of cardiovascular disease (CVD). However, existing evidence on prescription patterns was primarily generated among patients at high CVD risk with short-term follow-up, and failed to capture impacts of time and patient characteristics. Our objective was therefore to describe longitudinal prescription patterns for antihypertensive drugs for the primary prevention of CVD among patients with arterial hypertension in the United Kingdom.

Methods: This population-based cohort study used data from the Clinical Practice Research Datalink, included 660,545 patients with hypertension who initiated an antihypertensive drug between 1998 and 2018. Antihypertensive treatments were measured by drug class and described overall and in subgroups, focusing on first-line therapy (first antihypertensive drug(s) recorded after a diagnosis of hypertension) and second-line therapy (antihypertensive drug(s) prescribed as part of a treatment change following first-line therapy).

Results: Angiotensin-converting enzyme (ACE) inhibitors (29.0%), thiazide diuretics (22.1%), and calcium-channel blockers (CCBs) (21.0%) were the most prescribed first-line therapies. ACE inhibitors have been increasingly prescribed as first-line therapy since 2001. Men were more likely to be prescribed ACE inhibitors than women (43.5% vs. 32.1%; difference: 11.4%; 95% confidence interval [CI], 11.0%-11.8%), and Black patients were more likely to be prescribed CCBs than White patients (63.6% vs. 37.0%; difference: 26.6%; 95% CI, 24.8%-28.4%).

Conclusions: Antihypertensive prescription patterns for the primary prevention of CVD among patients with hypertension are consistent with treatment guidelines that were in place during the study period, providing reassurance regarding the use of evidence-based prescribing.
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http://dx.doi.org/10.1093/ajh/hpab137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730500PMC
January 2022

Utilization and long-term persistence of direct oral anticoagulants among patients with nonvalvular atrial fibrillation and liver disease.

Br J Clin Pharmacol 2021 Aug 19. Epub 2021 Aug 19.

Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1111/bcp.15046DOI Listing
August 2021

Use of levothyroxine among pregnant women with subclinical hypothyroidism in the United Kingdom: A population-based assessment.

Pharmacol Res Perspect 2021 10;9(5):e00848

Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.

Our study aimed to describe levothyroxine prescription patterns and trends over time among pregnant women with subclinical hypothyroidism (SCH) in the United Kingdom. We used data from the Clinical Practice Research Datalink linked to its Pregnancy Register and the Hospital Episode Statistics database from 1998 to 2017. The study population included women with a diagnosis of SCH or an abnormal thyroid-simulated hormone (TSH) level one year prior to or during pregnancy. We compared characteristics between women who received a prescription for levothyroxine during pregnancy and those who did not. We further described the timing, dose, duration, and temporal trends of levothyroxine prescriptions. Our cohort included 6,757 pregnancies from 6,287 women with SCH, of whom 10% received levothyroxine during pregnancy. Among women who received levothyroxine, most received their first prescription during the first trimester (median gestational age: 7 weeks; interquartile range [IQR]: 0, 16) with a median daily dosage of 50 mcg (IQR: 50, 73). Levothyroxine prescription varied over time, decreasing from 23% of pregnant women in 1998 to 7.5% in 2003, remaining stable until 2014, and increasing to 12.5% in 2016. Smoking, diabetes, polycystic ovary syndrome, infertility, timing of SCH diagnosis, age, TSH level at diagnosis, and general practice regions were associated with prescription. Few women with SCH received levothyroxine during pregnancy, and treatment varied by patient characteristics and geographical regions. These results highlight the need to increase awareness among healthcare providers and will guide future studies that explore barriers to initiating levothyroxine treatment for women with SCH during pregnancy.
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http://dx.doi.org/10.1002/prp2.848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363773PMC
October 2021

Validity of an algorithm to identify cardiovascular deaths from administrative health records: a multi-database population-based cohort study.

BMC Health Serv Res 2021 Jul 31;21(1):758. Epub 2021 Jul 31.

Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.

Background: Cardiovascular death is a common outcome in population-based studies about new healthcare interventions or treatments, such as new prescription medications. Vital statistics registration systems are often the preferred source of information about cause-specific mortality because they capture verified information about the deceased, but they may not always be accessible for linkage with other sources of population-based data. We assessed the validity of an algorithm applied to administrative health records for identifying cardiovascular deaths in population-based data.

Methods: Administrative health records were from an existing multi-database cohort study about sodium-glucose cotransporter-2 (SGLT2) inhibitors, a new class of antidiabetic medications. Data were from 2013 to 2018 for five Canadian provinces (Alberta, British Columbia, Manitoba, Ontario, Quebec) and the United Kingdom (UK) Clinical Practice Research Datalink (CPRD). The cardiovascular mortality algorithm was based on in-hospital cardiovascular deaths identified from diagnosis codes and select out-of-hospital deaths. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for the cardiovascular mortality algorithm using vital statistics registrations as the reference standard. Overall and stratified estimates and 95% confidence intervals (CIs) were computed; the latter were produced by site, location of death, sex, and age.

Results: The cohort included 20,607 individuals (58.3% male; 77.2% ≥70 years). When compared to vital statistics registrations, the cardiovascular mortality algorithm had overall sensitivity of 64.8% (95% CI 63.6, 66.0); site-specific estimates ranged from 54.8 to 87.3%. Overall specificity was 74.9% (95% CI 74.1, 75.6) and overall PPV was 54.5% (95% CI 53.7, 55.3), while site-specific PPV ranged from 33.9 to 72.8%. The cardiovascular mortality algorithm had sensitivity of 57.1% (95% CI 55.4, 58.8) for in-hospital deaths and 72.3% (95% CI 70.8, 73.9) for out-of-hospital deaths; specificity was 88.8% (95% CI 88.1, 89.5) for in-hospital deaths and 58.5% (95% CI 57.3, 59.7) for out-of-hospital deaths.

Conclusions: A cardiovascular mortality algorithm applied to administrative health records had moderate validity when compared to vital statistics data. Substantial variation existed across study sites representing different geographic locations and two healthcare systems. These variations may reflect different diagnostic coding practices and healthcare utilization patterns.
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http://dx.doi.org/10.1186/s12913-021-06762-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325284PMC
July 2021

The association between glycaemic control during hospitalization and risk of adverse events: A retrospective cohort study.

Endocrinol Diabetes Metab 2021 Jul 27;4(3):e00268. Epub 2021 May 27.

Department of Epidemiology, Biostatistics and Occupational Health McGill University Montreal QC Canada.

Introduction: Hyperglycaemia is common during hospitalization; glycaemic targets in non-critical care settings have not been well studied. We assessed associations between inpatient glycaemic control and adverse events.

Methods: We conducted a retrospective cohort study on non-critically ill medical patients hospitalized in a tertiary care hospital between 2015 and 2018. Mean glycaemia during the first four days of hospitalization was categorized as 4.0-7.0 mmol/L, 7.1-10.0 mmol/L and >10.0 mmol/L. The primary outcome was a composite of adverse events including mortality, infections, acute kidney injury, thromboembolic and cardiovascular events. The secondary outcome was hypoglycaemia, defined as any glycaemia <4.0 mmol/L. Logistic regression was used to assess adverse events, and a Cox proportional hazards model was used to estimate hypoglycaemia risk.

Results: Our cohort included 1,368 patients, of whom 407 (29.8%) experienced an adverse event. We did not find associations between glycaemia of 4.0-7.0 mmol/L (adjusted odds ratio [OR]: 0.88, 95% confidence interval [CI]: 0.63-1.23) or glycaemia of >10.0 mmol/L (adjusted OR: 0.98, 95% CI: 0.75-1.28) and the occurrence of adverse events, compared to a glycaemia of 7.1-10.0 mmol/L. Glycaemia of >10.0 mmol/L was associated with an increased risk of hypoglycaemia (adjusted hazard ratio [HR]: 1.72, 95% CI: 1.21-2.45). Hypoglycaemia was associated with adverse events (adjusted OR 1.85, 95% CI 1.31-2.60).

Conclusions: Neither glycaemia of 4.0-7.0 mmol/L nor glycaemia of >10.0mmol/L during non-critical care hospitalization was associated with increased adverse events. Glycaemia of >10.0 mmol/L was associated with increased hypoglycaemia, likely due to aggressive glucose lowering. These findings highlight the need for further studies to discern optimal inpatient glycaemic targets.
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http://dx.doi.org/10.1002/edm2.268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279636PMC
July 2021

Conduite avec facultés affaiblies après la légalisation du cannabis à usage récréatif.

CMAJ 2021 07;193(27):E1071-E1075

Institut Lady Davis (Windle, Sequeira, Filion, Thombs, Reynier, Grad, Ells, Eisenberg), Hôpital général juif; Département d'épidémiologie, de biostatistique et de santé du travail (Windle, Filion, Thombs, Eisenberg), Université McGill; Faculté de médecine (Filion, Thombs, Eisenberg), Université McGill; Départements de psychiatrie, de psychologie et de psychologie de l'enseignement et du counseling (Thombs), Université McGill; Département de médecine familiale (Grad, Ells), Université McGill; Unité d'éthique biomédicale, Division de médecine expérimentale et Département des sciences sociales en médecine (Ells), Université McGill; Département de cardiologie (Eisenberg), Hôpital général juif, Montréal, Qc.

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http://dx.doi.org/10.1503/cmaj.191032-fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342014PMC
July 2021

The modifying effects of adiposity on the cardiovascular safety of sulphonylureas.

Diabetes Obes Metab 2021 11 3;23(11):2502-2512. Epub 2021 Aug 3.

Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Québec, Canada.

Aims: To determine whether adiposity modified the effect on the cardiovascular safety of sulphonylureas 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 sulphonylurea 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 [MI], ischaemic stroke, cardiovascular mortality), and all-cause mortality, comparing use of sulphonylureas with use of metformin, overall and within BMI categories (≤24.9 kg/m , 25.0-29.9 kg/m , ≥30 kg/m ).

Results: Compared with metformin, sulphonylureas were not associated with an increased risk of MACE either overall (HR 1.08, 95% CI 0.94-1.23) or by BMI category. Similar findings were observed for MI and ischaemic stroke. By contrast, sulphonylureas 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 sulphonylureas and cardiovascular and all-cause mortality compared with metformin.
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http://dx.doi.org/10.1111/dom.14494DOI Listing
November 2021

The Effect of Overdose Education and Naloxone Distribution: An Umbrella Review of Systematic Reviews.

Am J Public Health 2021 08 2;111(8):e1-e12. Epub 2021 Jul 2.

Amir Razaghizad, Sarah B. Windle, Kristian B. Filion, and Mark J. Eisenberg are with the Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada. Genevieve Gore is with the Schulich Library of Physical Sciences, Life Sciences, and Engineering, McGill University, Montreal. Irina Kudrina is with the Department of Family Medicine, Faculty of Medicine, McGill University. Elena Paraskevopoulos is with the Department of Anesthesia, Faculty of Medicine, McGill University. Jonathan Kimmelman is with the Studies of Translation, Ethics, and Medicine Biomedical Ethics Unit, McGill University. Marc O. Martel is with the Faculty of Dentistry, McGill University.

Opioids contribute to more than 60 000 deaths annually in North America. While the expansion of overdose education and naloxone distribution (OEND) programs has been recommended in response to the opioid crisis, their effectiveness remains unclear. To conduct an umbrella review of systematic reviews to provide a broad-based conceptual scheme of the effect and feasibility of OEND and to identify areas for possible optimization. We conducted the umbrella review of systematic reviews by searching PubMed, Embase, PsycINFO, Epistemonikos, the Cochrane Database of Systematic Reviews, and the reference lists of relevant articles. Briefly, an academic librarian used a 2-concept search, which included opioid subject headings and relevant keywords with a modified PubMed systematic review filter. Eligible systematic reviews described comprehensive search strategies and inclusion and exclusion criteria, evaluated the quality or risk of bias of included studies, were published in English or French, and reported data relevant to either the safety or effectiveness of OEND programs, or optimal strategies for the management of opioid overdose with naloxone in out-of-hospital settings. Two reviewers independently extracted study characteristics and the quality of included reviews was assessed in duplicate with AMSTAR-2, a critical appraisal tool for systematic reviews. Review quality was rated critically low, low, moderate, or high based on 7 domains: protocol registration, literature search adequacy, exclusion criteria, risk of bias assessment, meta-analytical methods, result interpretation, and presence of publication bias. Summary tables were constructed, and confidence ratings were provided for each outcome by using a previously modified version of the Royal College of General Practitioners' clinical guidelines. Six systematic reviews containing 87 unique studies were included. We found that OEND programs produce long-term knowledge improvement regarding opioid overdose, improve participants' attitudes toward naloxone, provide sufficient training for participants to safely and effectively manage overdoses, and effectively reduce opioid-related mortality. High-concentration intranasal naloxone (> 2 mg/mL) was as effective as intramuscular naloxone at the same dose, whereas lower-concentration intranasal naloxone was less effective. Evidence was limited for other naloxone formulations, as well as the need for hospital transport after overdose reversal. The preponderance of evidence pertained persons who use heroin. Evidence suggests that OEND programs are effective for reducing opioid-related mortality; however, additional high-quality research is required to optimize program delivery. Community-based OEND programs should be implemented widely in high-risk populations.
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http://dx.doi.org/10.2105/AJPH.2021.306306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489614PMC
August 2021

Depression-related weight change and incident diabetes in a community sample.

Sci Rep 2021 06 30;11(1):13575. Epub 2021 Jun 30.

Department of Epidemiology, Biostatistics, and Occupational Health, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada.

This cohort study aimed to compare the incidence of type 2 diabetes in adults with depression-related weight gain, depression-related weight loss, depression with no weight change, and no depression. The study sample included 59,315 community-dwelling adults in Ontario, Canada. Depression-related weight change in the past 12 months was measured using the Composite International Diagnostic Interview-Short Form. Participants were followed for up to 20 years using administrative health data. Cox proportional hazards models compared the incidence of type 2 diabetes in adults with depression-related weight change and in adults with no depression. Adults with depression-related weight gain had an increased risk of type 2 diabetes compared to adults no depression (HR 1.70, 95% CI 1.32-2.20), adults with depression-related weight loss (HR 1.62, 95% CI 1.09-2.42), and adults with depression with no weight change (HR 1.39, 95% CI 1.03-1.86). Adults with depression with no weight change also had an increased risk of type 2 diabetes compared to those with no depression (HR 1.23, 95% CI 1.04-1.45). Associations were stronger among women and persisted after adjusting for attained overweight and obesity. Identifying symptoms of weight change in depression may aid in identifying adults at higher risk of type 2 diabetes and in developing tailored prevention strategies.
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http://dx.doi.org/10.1038/s41598-021-92963-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245524PMC
June 2021

Interventions to Prevent Drugged Driving: A Systematic Review.

Am J Prev Med 2021 08 5;61(2):267-280. Epub 2021 Jun 5.

Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada; Department of Epidemiology, Faculty of Medicine and Health Sciences, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. Electronic address:

Context: Literature suggests that cannabis legalization may increase fatal motor vehicle collisions. However, evidence on the effectiveness of interventions to prevent drugged driving is limited.

Evidence Acquisition: MEDLINE, PsycINFO, Web of Science, Embase, SafetyLit, Criminal Justice Database, Transport Research International Documentation, bibliographies, and relevant gray literature were searched systematically through May 2020. Randomized and nonrandomized studies of preventive interventions measuring drugged driving outcomes were included. Evidence certainty was judged per Grading of Recommendations Assessment, Development, and Evaluation guidelines to designate quality ratings from very low to high.

Evidence Synthesis: The search identified 11 RCTs and 17 nonrandomized studies conducted predominantly among youth (aged 15-25 years; n=33,711 of 37,117 active research participants). In the public, cannabis packaging with health warnings increases the knowledge about drugged driving effects (high certainty); roadside drug testing can reduce drugged driving among cannabis users (moderate certainty); media campaigns may increase deterrent attitudes and knowledge (low certainty); and state sanctions, including traffic offense criminalization, license withdrawal, and per se drugged driving laws, may have little or no effect on drug-related fatalities or injuries (very low-low certainty). For youth or previous offenders, motivational interviewing can prevent drugged driving and driver education programs can increase knowledge (moderate certainty), whereas drug abuse prevention, substance abuse treatment, and driver rehabilitation may prevent drugged driving (very low certainty).

Conclusions: Overall, there is evidence to support the interventions that may improve drugged driving knowledge, attitudes, and behaviors. However, the impact of such interventions on measures of drugged driving-related morbidity and mortality is uncertain. Further research is urgently required to address these gaps in knowledge.
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http://dx.doi.org/10.1016/j.amepre.2021.03.012DOI Listing
August 2021

Immeasurable time bias in self-controlled designs: case-crossover, case-time-control, and case-case-time-control analyses.

J Epidemiol 2021 May 29. Epub 2021 May 29.

School of Pharmacy, Sungkyunkwan University.

Background: Impact of immeasurable time bias (IMTB) is yet to be examined in self-controlled designs.

Methods: We conducted case-crossover, case-time-control, and case-case-time-control analyses using Korea's healthcare database. Two empirical examples among elderly patients were used: 1) benzodiazepines-hip fracture; 2) benzodiazepines-mortality. For cases, the date of hip fracture diagnosis or death was defined as the index date, and the inherited date of their matched cases for controls or future cases. Exposure was assessed in the 1-30 day (hazard) and 61-90 day (control) windows preceding the index date. A non-missing exposure setting included in- and outpatient prescriptions and the pseudo-outpatient setting included only the outpatients. Conditional logistic regression was done to estimate odds ratio (OR) with 95% confidence intervals (CI), where the relative difference in OR among the two settings was calculated to quantify the IMTB.

Results: The IMTB had negligible impacts in the hip fracture example in the case-crossover (non-missing exposure setting OR 1.27, 95% CI 1.12-1.44; pseudo-outpatient setting 1.21, 1.06-1.39; magnitude 0.05), case-time-control (1.18, 0.98-1.44; 1.13, 0.92-1.38; 0.04), and case-case-time-control analyses (0.99, 0.80-1.23; 0.94, 0.75-1.18; 0.05). In the mortality example, IMTB had significant impacts in the case-crossover (1.44, 1.36-1.52; 0.72, 0.67-0.78; 1.00), case-time-control (1.38, 1.26-1.51; 0.68, 0.61-0.76; 1.03), and case-case-time-control analyses (1.27, 1.15-1.40; 0.62, 0.55-0.69; 1.05).

Conclusions: Although IMTB had negligible impacts on the drug's effect on acute events as these are unlikely to be accompanied with hospitalizations, it negatively biased the drug's effect on mortality, an outcome with prodromal phases, in the three self-controlled designs.
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http://dx.doi.org/10.2188/jea.JE20210099DOI Listing
May 2021

Initiation of four basal insulins and subsequent treatment modification in people treated for type 2 diabetes in the United Kingdom: Changes over the period 2003-2018.

Diabet Med 2021 Aug 31;38(8):e14603. Epub 2021 May 31.

Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada.

Aims: Aim of this study is to describe changes in the utilization of basal insulins (glargine, detemir, degludec, neutral protamine Hagedorn [NPH]) among individuals with type 2 diabetes between 2003 and 2018 in the United Kingdom (UK).

Materials And Methods: Using the UK Clinical Practice Research Datalink (CPRD) Aurum, we created three study cohorts of individuals with type 2 diabetes: (1) all users of antidiabetic drugs (n = 686,170); (2) initiators of antidiabetic drugs (n = 382,247); and (3) initiators of basal insulins (n = 85,369). Trends in prescription rates were determined using Poisson regression overall and stratified by sex, cardiovascular disease history, and obesity. Crude and adjusted Cox proportional hazards models were used to obtain hazard ratios (HRs) and confidence intervals (CI) comparing rates of treatment change between classes of basal insulins, with an intention-to-treat exposure definition.

Results: During the study period, prescription rates of insulin analogues increased in the all-user cohort from 118.3 (95% CI: 116.4, 120.2) prescriptions per 1000 person-years in 2003 to 579.4 (95% CI: 576.9, 582.0) in 2018. Prescription rates of NPH decreased from 770.5 (95% CI: 765.0, 775.3) in 2003 to 457.7 (95% CI: 455.5, 460.0) in 2018. Compared to initiators of NPH, initiators of detemir were more likely to change treatment (adjusted HR: 1.31, 95% CI: 1.25, 1.37) while glargine initiators were less likely to change treatment (adjusted HR: 0.85, 95% CI: 0.82, 0.88).

Conclusions: Basal insulin prescription evolved between 2003 and 2018. Our study provides insight into the evolving use of basal insulin among individuals with type 2 diabetes in the UK.
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http://dx.doi.org/10.1111/dme.14603DOI Listing
August 2021

Off-label postpartum use of domperidone in Canada: a multidatabase cohort study.

CMAJ Open 2021 Apr-Jun;9(2):E500-E509. Epub 2021 May 14.

Centre for Clinical Epidemiology (Moriello, Reynier, Aibibula, Filion), Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Que; ICES (Paterson); Institute of Health Policy, Management and Evaluation (Paterson), University of Toronto, Toronto, Ont.; Manitoba Centre for Health Policy, Department of Community Health Sciences (Dahl, Kuo), Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Man.; Department of Anesthesiology, Pharmacology and Therapeutics (Fisher), University of British Columbia, Vancouver BC; School of Pharmacy (Gamble), University of Waterloo, Kitchener, Ont.; Department of Community Health Sciences (Ronksley), Cumming School of Medicine, University of Calgary, Calgary, Alta.; Saskatchewan Health Quality Council (Winquist); Department of Community Health and Epidemiology (Winquist), College of Medicine, University of Saskatchewan, Saskatoon Sask.; Departments of Medicine and of Epidemiology, Biostatistics, and Occupational Health (Filion), McGill University, Montréal, Que.

Background: Trends in off-label postpartum use of domperidone and the impact of safety advisories on its use remain unknown. Our objectives were to describe postpartum use of domperidone in Canada, to evaluate the impact of Health Canada advisories on prescribing patterns, and to describe the association between domperidone use and a composite end point of sudden cardiac death or ventricular tachycardia (VT) among postpartum patients.

Methods: We conducted a multidatabase cohort study involving pregnant patients with live births between 2004 and 2017 using administrative health databases from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba and Ontario). We excluded patients with less than 1 year of prepregnancy database history and with approved indications for domperidone. We assessed domperidone use in the 6 months postpartum and the impact of the 2012 and 2015 Health Canada advisories on prescribing via interrupted time series analysis. We estimated crude rates of VT and sudden cardiac death.

Results: We included 1 190 987 live births. Mean maternal age was 28.6 (standard error 0.6) years. Domperidone use increased over time, from 7% in 2003-2005 to 12% in 2009-2011, when it plateaued. The 2012 advisory was followed by a drop in use and a reduction in slope, and the 2015 advisory had a more modest impact. Crude analysis suggests that domperidone may be associated with increased VT or sudden cardiac death (0.74 v. 0.37 per 10 000 person-years; difference per 10 000 person-years: 0.37, 95% confidence interval -0.67 to 1.41).

Interpretation: Postpartum domperidone use increased between 2004 and 2017, with prescribing attenuated after Health Canada advisories and a very low absolute rate of VT or sudden cardiac death. These findings suggest that Health Canada advisories affected prescribing; any potential increase in VT or sudden cardiac death with use of domperidone is small and could not be confirmed in this large study STUDY REGISTRATION: ClinicalTrials.gov, no. NCT04024865.
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http://dx.doi.org/10.9778/cmajo.20200084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157989PMC
August 2021

Comparison of Pregnancy Outcomes of Patients Treated With Ondansetron vs Alternative Antiemetic Medications in a Multinational, Population-Based Cohort.

JAMA Netw Open 2021 04 1;4(4):e215329. Epub 2021 Apr 1.

ICES, Toronto, Ontario, Canada.

Importance: Ondansetron is frequently used to treat nausea and vomiting during pregnancy. Although some studies reported important safety signals, few studies have been sufficiently large to assess rare pregnancy outcomes.

Objective: To study the association between ondansetron exposure during pregnancy and the risks of spontaneous abortion, stillbirth, and major congenital malformations.

Design, Setting, And Participants: This is a cohort study conducted in 3 countries, with a meta-analysis. Participants included women and girls aged 12 to 55 years who experienced spontaneous abortion, induced abortion, stillbirth, or live birth between April 2002 and March 2016, as recorded in administrative data from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, and Ontario), the US IBM MarketScan Research Databases, and the UK Clinical Practice Research Datalink. The statistical analysis was completed in October 2020.

Exposures: Exposure to ondansetron during pregnancy was compared with exposure to other commonly used antiemetics to minimize confounding by indication.

Main Outcomes And Measures: The primary outcome was fetal death, defined as either spontaneous abortion or stillbirth. Secondary outcomes were the 2 components of the primary outcome and major congenital malformations identified during the year after a live birth. Adjusted hazard ratios were estimated using Cox proportional hazards models with time-dependent drug exposures and were adjusted using high-dimensional propensity scores. For major congenital malformations, adjusted odds ratios were estimated from logistic models. Site-level results were pooled using random-effects meta-analysis. Sensitivity analyses considered second-line antiemetic exposure and exposure specifically during 4 to 10 weeks of gestation.

Results: Data from 456 963 pregnancies were included in this study of fetal death (249 787 [54.7%] in Canada, 197 913 [43.3%] in the US, and 9263 [2.0%] in the UK; maternal age, ≤24 years, 93 201 patients [20.4%]; 25-29 years, 149 117 patients [32.6%]; 30-34 years, 142 442 patients [31.2%]; and ≥35 years, 72 203 patients [15.8%]). Fetal death occurred in 12 907 (7.9%) of 163 810 pregnancies exposed to ondansetron, and 17 476 (5.7%) of 306 766 pregnancies exposed to other antiemetics. The adjusted hazard ratios were 0.91 (95% CI, 0.67-1.23) for fetal death with time-dependent ondansetron exposure during pregnancy, 0.82 (95% CI, 0.64-1.04) for spontaneous abortion, and 0.97 (95% CI, 0.79-1.20) for stillbirth. For major congenital malformations, the estimated odds ratio was 1.06 (95% CI, 0.91-1.22). Results of sensitivity analyses were generally consistent with those of the primary analyses.

Conclusions And Relevance: In this large, multicenter cohort study, there was no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.5329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065380PMC
April 2021

Impaired driving and legalization of recreational cannabis.

CMAJ 2021 Apr;193(14):E481-E485

Lady Davis Institute (Windle, Sequeira, Filion, Thombs, Reynier, Grad, Ells, Eisenberg), Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational Health (Windle, Filion, Thombs, Eisenberg), McGill University; Department of Medicine (Filion, Thombs, Eisenberg), McGill University; Departments of Psychiatry, of Psychology, and of Educational and Counselling Psychology (Thombs), McGill University; Department of Family Medicine (Grad, Ells), McGill University; Biomedical Ethics Unit, Division of Experimental Medicine, and Department of Social Sciences of Medicine (Ells), McGill University; Division of Cardiology (Eisenberg), Jewish General Hospital, Montréal, Que.

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http://dx.doi.org/10.1503/cmaj.191032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049641PMC
April 2021

Accounting for Repeat Pregnancies in Risk Prediction Models.

Epidemiology 2021 07;32(4):560-568

From the Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada.

Background: In perinatal epidemiology, the development of risk prediction models is complicated by parity; how repeat pregnancies influence the predictive accuracy of models that include obstetrical history is unclear.

Methods: To assess the influence of repeat pregnancies on the association between predictors and the outcomes, as well as the influence of ignoring the nonindependence between pregnancies, we created four analytical cohorts using the Clinical Practice Research Datalink. The cohorts included (1) first deliveries, (2) a random sample of one delivery per woman, (3) all eligible deliveries per woman, and (4) all eligible deliveries and censoring of follow-up at subsequent pregnancies. Using Plasmode simulations, we varied the predictor-outcome association across cohorts.

Results: We found minimal differences in the relative contribution of predictors to the overall predictions and the discriminative accuracy of models in the cohort of randomly sampled deliveries versus the all deliveries cohort (C-statistic: 0.62 vs. 0.63; Nagelkerke's R2: 0.03 for both). Accounting for clustering and censoring upon subsequent pregnancies also had negligible influence on model performance. We found important differences in model performance between the models developed in the cohort of first deliveries and the random sample of deliveries.

Conclusions: In our study, a model including first deliveries had the best predictive accuracy but was not generalizable to women of varying parities. Moreover, including repeat pregnancies did not improve the predictive accuracy of the models. Multiple models may be needed to improve the transportability and accuracy of prediction models when the outcome of interest is influenced by parity.
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http://dx.doi.org/10.1097/EDE.0000000000001349DOI Listing
July 2021

Association between legalization of recreational cannabis and fatal motor vehicle collisions in the United States: an ecologic study.

CMAJ Open 2021 Jan-Mar;9(1):E233-E241. Epub 2021 Mar 17.

Lady Davis Institute (Windle, Eisenberg, Reynier, Cabaussel, Thombs, Grad, Ells, Sequeira, Filion) and Division of Cardiology (Eisenberg), Jewish General Hospital; Departments of Epidemiology, Biostatistics and Occupational Health (Windle, Eisenberg, Thombs, Filion), Medicine (Eisenberg, Thombs, Filion), Psychiatry (Thombs), Psychology (Thombs), Educational and Counselling Psychology (Thombs), Family Medicine (Grad, Ells) and Social Studies of Medicine (Ells), McGill University; Biomedical Ethics Unit (Ells), Division of Experimental Medicine, McGill University, Montréal, Que.

Background: With the recent legalization of recreational cannabis in Canada, cannabis-impaired driving is an important public safety concern. Our aim was to examine the association between recreational cannabis legalization and fatal motor vehicle collisions using data from the United States, which present a timely natural experiment of cannabis legalization.

Methods: We conducted an ecologic study using the number of fatal motor vehicle collisions and the associated number of deaths for US jurisdictions with legalized recreational cannabis (2007-2018) retrieved from the US Fatality Analysis Reporting System. We examined jurisdiction-specific rates of fatal motor vehicle collisions and associated deaths before and after recreational cannabis legalization using Poisson regression and meta-analyzed estimates across jurisdictions using DerSimonian and Laird random-effects models.

Results: After adjustment for calendar year, legalization was associated with increases in rates of fatal motor vehicle collisions (incidence rate ratio [IRR] 1.15, 95% confidence interval [CI] 1.06-1.26) and associated deaths (IRR 1.16, 95% CI 1.06-1.27). Differences between the first 12 months after legalization relative to subsequent months were inconclusive for rates of fatal motor vehicle collisions (IRR 0.92, 95% CI 0.84-1.02) and associated deaths (IRR 0.92, 95% CI 0.84-1.01).

Interpretation: Recreational cannabis legalization in the US was associated with a relative increased risk of fatal motor vehicle collisions of 15% and a relative increase in associated deaths of 16%, with no conclusive difference between the first and subsequent years after legalization. These findings raise concern that there could be a similar increase in fatal motor vehicle collisions and associated deaths in Canada following recreational cannabis legalization.
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http://dx.doi.org/10.9778/cmajo.20200155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096392PMC
July 2021

Use of e-Cigarettes for Smoking Cessation-Reply.

JAMA 2021 03;325(10):1006-1007

Lady Davis Institute, McGill University, Montréal, Québec, Canada.

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http://dx.doi.org/10.1001/jama.2020.27210DOI Listing
March 2021

Levothyroxine and the risk of adverse pregnancy outcomes in women with subclinical hypothyroidism: a systematic review and meta-analysis.

BMC Endocr Disord 2021 Feb 27;21(1):34. Epub 2021 Feb 27.

Department of Medicine, McGill University, Montreal, Quebec, Canada.

Background: Levothyroxine replacement therapy may decrease the risk of adverse pregnancy outcomes among women with subclinical hypothyroidism (SCH). The aim of this study is to conduct a systematic review and meta-analysis to examine the risk of adverse pregnancy, perinatal, and early childhood outcomes among women with SCH treated with levothyroxine.

Methods: A systematic literature search was conducted using Ovid-Medline, Ovid-EMBASE, Pubmed (non-Medline), Ebsco-CINAHL Plus with full text and Cochrane Library databases. Randomized controlled studies (RCTs) and observational studies examining the association between treatment of SCH during pregnancy and our outcomes of interest were included. Studies that compared levothyroxine treatment versus no treatment were eligible for inclusion. Data from included studies were extracted and quality assessment was performed by two independent reviewers.

Results: Seven RCTs and six observational studies met our inclusion criteria. A total of 7342 individuals were included in these studies. RCTs demonstrated several sources of bias, with lack of blinding of the participants or research personnel; only one study was fully blinded. In the observational studies, there was moderate to serious risk of bias due to lack of adjustment for certain confounding variables, participant selection, and selective reporting of results. Pooled analyses showed decreased risk of pregnancy loss (RR: 0.79; 95% CI: 0.67 to 0.93) and neonatal death (RR: 0.35; 95% CI: 0.17 to 0.72) associated with levothyroxine treatment during pregnancy among women with SCH. There were no associations between levothyroxine treatment and outcomes during labour and delivery, or cognitive status in children at 3 or 5 years of age.

Conclusion: Treatment of SCH with levothyroxine during pregnancy is associated with decreased risks of pregnancy loss and neonatal death. Given the paucity of available data and heterogeneity of included studies, additional studies are needed to address the benefits of levothyroxine use among pregnant women with SCH.
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http://dx.doi.org/10.1186/s12902-021-00699-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912520PMC
February 2021

Efficacy and Safety of Metformin for Obesity: A Systematic Review.

Pediatrics 2021 03;147(3)

Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada;

Context: The efficacy and safety of metformin for obesity in children and adolescents remains unclear.

Objective: To assess the efficacy and safety of metformin via systematic review.

Data Sources: Data sources included PubMed, Embase, the Cochrane Library, Scopus, and ClincalTrials.gov (inception to November 2019).

Study Selection: We selected randomized controlled trials (RCTs) in which researchers assessed the efficacy and safety of metformin with lifestyle interventions, compared with a placebo with lifestyle interventions, in children and adolescents with obesity.

Data Extraction: Two researchers independently extracted data and assessed quality. The primary outcomes were mean changes from baseline in BMI, BMI score, homeostatic model assessment of insulin resistance, and gastrointestinal adverse effects.

Results: Twenty-four RCTs (1623 patients; range: 16 to 151) were included. Ages ranged from 4 to 19 years, and follow-up ranged from 2 months to 2 years. Metformin resulted in a modest decrease in BMI (range of mean values: -2.70 to 1.30 vs -1.12 to 1.90), BMI score (range of mean values: -0.37 to -0.03 vs -0.22 to 0.15), and homeostatic model assessment of insulin resistance (range of mean values: -3.74 to 1.00 vs -1.40 to 2.66). Metformin resulted in a higher frequency of gastrointestinal adverse effects (range: 2% to 74% vs 0% to 42%).

Limitations: The available evidence is of varying quality, with high heterogeneity between trials, suggesting some uncertainty in the benefits of metformin in this population.

Conclusions: With this systematic review of RCTs, we suggest that metformin has modest but favorable effects on weight and insulin resistance and a tolerable safety profile among children and adolescents with obesity.
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http://dx.doi.org/10.1542/peds.2020-1610DOI Listing
March 2021

Concurrent prescriptions for opioids and benzodiazepines and risk of opioid overdose: protocol for a retrospective cohort study using linked administrative data.

BMJ Open 2021 02 18;11(2):e042299. Epub 2021 Feb 18.

McGill Clinical and Health Informatics, McGill University, Montréal, Quebec, Canada.

Introduction: Opioid overdoses have increased substantially over the last 20 years, with over 400 000 deaths in North America. While opioid prescribing has been a target of research, benzodiazepine and opioid co-intoxication has emerged as a potential risk factor. Our aim was to assess the risk of opioid overdose associated with concurrent use of opioids and benzodiazepines relative to opioids alone.

Methods And Analysis: A retrospective cohort study will be conducted using medical claims data from adult residents of Montréal, Canada. We will create a cohort of new users of opioids (ie, no opioid dispensations in prior year) in 2000-2014 from people with at least 2 years of continuous health insurance. Those with any diagnosis or hospitalisation for cancer or palliative care in the 2 years before their first opioid dispensation will be excluded. On each person-day of follow-up, exposure status will be classified into one of four mutually exclusive categories: (1) opioid-only, (2) benzodiazepine-only, (3) both opioid and benzodiazepine (concurrent use) or (4) neither. Opioid overdose will be measured using diagnostic codes documented in the hospital discharge abstract database, physician billing claims from emergency department visits and death records. Using a marginal structural Cox proportional hazards model, we will compare the hazard of overdose during intervals of concurrent opioid and benzodiazepine use to intervals of opioid use alone, adjusted for sociodemographics, medical and psychiatric comorbidities, and substance use disorders.

Ethics And Dissemination: This study is approved by the McGill Faculty of Medicine Institutional Review Board and the (Québec privacy commission). Results will be relevant to clinicians, policymakers and other researchers interested in co-prescribing practices of opioids and benzodiazepines. Study findings will be disseminated at relevant conferences and published in biomedical and epidemiological peer-reviewed journals.
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http://dx.doi.org/10.1136/bmjopen-2020-042299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896580PMC
February 2021

Association Between DPP-4 Inhibitors and COVID-19-Related Outcomes Among Patients With Type 2 Diabetes.

Diabetes Care 2021 04 5;44(4):e64-e66. Epub 2021 Feb 5.

School of Pharmacy, Sungkyunkwan University, Suwon, South Korea

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http://dx.doi.org/10.2337/dc20-1824DOI Listing
April 2021

Type 2 diabetes mellitus and risk of community-acquired pneumonia: a systematic review and meta-analysis of observational studies.

CMAJ Open 2021 Jan-Mar;9(1):E62-E70. Epub 2021 Jan 25.

Department of Epidemiology, Biostatistics and Occupational Health (Brunetti, Ayele, Filion), McGill University; Centre for Clinical Epidemiology (Brunetti, Ayele, Yu, Ernst, Filion), Lady Davis Institute for Medical Research, and Divisions of Endocrinology (Yu) and Pulmonary Medicine (Ernst), Jewish General Hospital, McGill University; Department of Medicine (Ernst, Filion), McGill University, Montréal, Que.

Background: People with type 2 diabetes are at greater risk for infections than those without type 2 diabetes. Our objective was to examine the association between type 2 diabetes and the risk of community-acquired pneumonia (CAP).

Methods: In this systematic review and meta-analysis, we searched MEDLINE, Embase, CINAHL, ProQuest theses and dissertations, Global Health, the Global Index Medicus of the World Health Organization, and Google Scholar. We included observational studies published in English or French between Jan. 1, 1946 (start of MEDLINE) and July 18, 2020. Two independent reviewers extracted data and assessed quality using the ROBINS-I tool. DerSimonian-Laird random-effects models were used to pool estimates of the association between type 2 diabetes and CAP.

Results: Our systematic review included 15 articles, reporting on 13 cohort studies and 4 case-control studies (14 538 968 patients). All studies reported an increased risk of pneumonia among patients with type 2 diabetes, and all were at serious risk of bias. When estimates were pooled across studies, the pooled relative risk was 1.64 (95% confidence interval [CI] 1.55-1.73); although there was a substantial amount of relative heterogeneity ( 94.2), the amount of absolute heterogeneity was more modest (T 0.008). The relative risk was 1.70 (95% CI 1.63-1.77, 85.2%, T 0.002) among cohort studies ( = 13), and the odds ratio was 1.54 (95% CI 1.14-2.09, 92.7%, T 0.07) among case-control studies ( = 4).

Interpretation: Type 2 diabetes may be associated with an increased risk of CAP; however, the available evidence is from studies at serious risk of bias, and additional, high-quality studies are needed to confirm these findings.

Prospero Registration: CRD42018116409.
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http://dx.doi.org/10.9778/cmajo.20200013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843079PMC
July 2021
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