Effect of statin use for the primary prevention of cardiovascular disease among older adults: a cautionary tale concerning target trials emulation.

OBJECTIVES: Evidence concerning the effect of statins in primary prevention of cardiovascular disease (CVD) among older adults is lacking. Using Quebec population-wide administrative data, we emulated a hypothetical randomized trial including older adults >65 years on April 1, 2013, with no CVD history and no statin use in the previous year. STUDY DESIGN AND SETTING: We included individuals who initiated statins and classified them as exposed if they were using statin at least 3 months after initiation and nonexposed otherwise. We followed them until March 31, 2018. The primary outcome was the composite endpoint of coronary events (myocardial infarction, coronary bypass, and percutaneous coronary intervention), stroke, and all-cause mortality. The intention-to-treat (ITT) effect was estimated with adjusted Cox models and per-protocol effect with inverse probability of censoring weighting. RESULTS: A total of 65,096 individuals were included (mean age = 71.0 ± 5.5, female = 55.0%) and 93.7% were exposed. Whereas we observed a reduction in the composite outcome (ITT-hazard ratio (HR) = 0.75; 95% CI: 0.68-0.83) and mortality (ITT-HR = 0.69; 95% CI: 0.61-0.77) among exposed, coronary events increased (ITT-HR = 1.46; 95% CI: 1.09-1.94). All multibias E-values were low indicating that the results were not robust to unmeasured confounding, selection, and misclassification biases simultaneously. CONCLUSION: We cannot conclude on the effectiveness of statins in primary prevention of CVD among older adults. We caution that an in-depth reflection on sources of biases and careful interpretation of results are always required in observational studies.

Marginal structural models with latent class growth analysis of treatment trajectories: Statins for primary prevention among older adults.

Latent class growth analysis is increasingly proposed as a solution to summarize the observed longitudinal treatment into a few distinct groups. When latent class growth analysis is combined with standard approaches like Cox proportional hazards models, confounding bias is not properly addressed because of time-varying covariates that have a double role of confounders and mediators. We propose to use latent class growth analysis to classify individuals into a few latent classes based on their medication adherence pattern, then choose a working marginal structural model that relates the outcome to these groups. The parameter of interest is defined as a projection of the true marginal structural model onto the chosen working model. Simulation studies are used to illustrate our approach and compare it with unadjusted, baseline covariates adjusted, time-varying covariates adjusted, and inverse probability of trajectory groups weighted adjusted models. Our proposed approach yielded estimators with little or no bias and appropriate coverage of confidence intervals in these simulations. We applied our latent class growth analysis and marginal structural model approach to a database comprising information on 52,790 individuals from the province of Quebec, Canada, aged more than 65 and who were statin initiators to estimate the effect of statin-usage trajectories on a first cardiovascular event.

Sex-specific medication trajectories in older adults newly diagnosed with diabetes.

Background: People with diabetes tend to use many medications to treat diabetes and comorbidities. Nevertheless, the evolution of polypharmacy in newly diagnosed males and females has been little studied. Objective: The objective of this paper was to identify and describe medication trajectories in incident diabetes cases according to sex. Methods: Data were obtained from the Quebec Integrated Chronic Disease Surveillance System. We built a population-based cohort of community-dwelling individuals aged >65 years diagnosed with diabetes in 2014 who were alive and covered with the public drug plan until March 31, 2019. Latent class models were used to identify medication trajectory groups in males and females separately. Results: Of the 10,363 included individuals, 51.4% were males. Females were older and more likely to have more medication claims than males. Four trajectory groups were identified for males and five for females. Most trajectories showed sustained and stable number of medications over time. For each sex, only one of the trajectory groups included a mean annual number of medications lesser than five. Slight increasing trends of medication use were detected in the trajectories composed of very high users, which included older, more comorbid individuals frequently exposed to potentially inappropriate medications. Conclusions: Most males and females with incident diabetes had a high burden of medication following the year of diagnosis and were classified in a group of sustained medication use over time. The largest increase in medication was among those who had higher level of polypharmacy of questionable quality at baseline, raising concerns about the innocuity of such medication trajectories.

Associations between environmental noise and myocardial infarction and stroke: Investigating the potential mediating effects of hypertension.

BACKGROUND: We investigated whether hypertension may be a mediator in the pathway linking environmental noise exposure to incident MI and stroke. METHODS: Separately for MI and stroke, we built two population-based cohorts from linked health administrative data. Participants were residents of Montreal (Canada) between 2000 and 2014, aged 45 years and older who were free of hypertension and MI or stroke at time of entry. MI, stroke and hypertension were ascertained from validated case definitions. Residential long-term environmental noise exposure, expressed as the annual mean level acoustic equivalent 24 h (LAeq24h), was estimated from a land use regression model. We performed mediation analysis based on the potential outcomes framework. We used a Cox proportional hazards model for the exposure-outcome model and a logistic regression for the exposure-mediator model. In sensitivity analysis we applied a marginal structural approach to estimate the natural direct and indirect effects. RESULTS: Each cohort included approximately 900 000 individuals, with 26 647 incident cases of MI and 16 656 incident cases of stroke. 36% of incident MI and 40% of incident stokes had previously developed hypertension. The estimated total effect per interquartile range increase (from 55.0 to 60.5 dB A) in the annual mean LAeq24h was 1.073 (95% confidence interval (CI): 1.070-1.077) for both MI for stroke. We found no evidence of exposure-mediator interaction for both outcomes. The relationships between environmental noise and MI and stroke was not mediated by hypertension. CONCLUSIONS: This population-based cohort study suggests that the main route by which environmental noise exposure may cause MI or stroke is not through hypertension.

Evolution in Trends of Primary Lower-Extremity Amputations Associated With Diabetes or Peripheral Artery Disease From 2006 to 2019.

BACKGROUND: Given the importance in prevention of lower extremity amputations (LEAs) associated with diabetes or peripheral artery disease (PAD), we sought to document the trends of primary LEA in Québec, Canada, from years 2006 to 2019. METHODS: Using the Québec Integrated Chronic Disease Surveillance System, we calculated crude and age-standardized annual incidence rates of primary LEA associated with diabetes and PAD among adults ≥ 40 years (99% confidence intervals [CI]), and all-cause 1-year mortality proportion trends following a primary LEA (95% CI), stratified by minor or major as the highest level of LEA during the same hospital stay and age groups. Trends were assessed using multivariate regression models. RESULTS: In 2019, the crude rate of primary LEA was 116.0 per 100,000 (n = 825) with 93.7 and 21.9 per 100,000 of minor (n = 665) and major (n = 160) LEA, respectively. A tendency of decrease by 8% (-15.0 to 0.4%) of age-standardized incidence of primary LEA was observed between 2006 and 2019, while the absolute number of primary LEA increased from 610 to 825 cases. Minor LEA increased by 14.2% (3.7 to 25.9%) and major LEA decreased by 49.5% (-57.1 to -40.5%). Incidence trends remained stable among the 40 to 64 years, and declined by 14.6% and 20.1% for the 65 to 79 and ≥ 80 years of age groups, respectively. Major LEA decreased in all age groups, whereas minor LEA increased by 26.2% among the patients 40 to 64 years of age only. Age-standardized 1-year mortality decreased by 35.1% (95% CI, -43.4 to -25.7%) between 2006 and 2019, with a crude 1-year mortality of 11.3% in 2019. CONCLUSIONS: The reduction of major LEA and 1-year mortality are encouraging, although increased minor LEA, especially in younger age groups, emphasizes the importance to improve preventive care further.

Great diversity in the utilization and reporting of latent growth modeling approaches in type 2 diabetes: A literature review.

Introduction: The progression of complications of type 2 diabetes (T2D) is unique to each patient and can be depicted through individual temporal trajectories. Latent growth modeling approaches (latent growth mixture models [LGMM] or latent class growth analysis [LCGA]) can be used to classify similar individual trajectories in a priori non-observed groups (latent groups), sharing common characteristics. Although increasingly used in the field of T2D, many questions remain regarding the utilization of these methods. Objective: To review the literature of longitudinal studies using latent growth modeling approaches to study T2D. Methods: MEDLINE (Ovid), EMBASE, CINAHL and Wb of Science were searched through August 25th, 2021. Data was collected on the type of latent growth modeling approaches (LGMM or LCGA), characteristics of studies and quality of reporting using the GRoLTS-Checklist and presented as frequencies. Results: From the 4,694 citations screened, a total of 38 studies were included. The studies were published beetween 2011 and 2021 and the length of follow-up ranged from 8 weeks to 14 years. Six studies used LGMM, while 32 studies used LCGA. The fields of research varied from clinical research, psychological science, healthcare utilization research and drug usage/pharmaco-epidemiology. Data sources included primary data (clinical trials, prospective/retrospective cohorts, surveys), or secondary data (health records/registries, medico-administrative). Fifty percent of studies evaluated trajectory groups as exposures for a subsequent clinical outcome, while 24% used predictive models of group membership and 5% used both. Regarding the quality of reporting, trajectory groups were adequately presented, however many studies failed to report important decisions made for the trajectory group identification. Conclusion: Although LCGA were preferred, the contexts of utilization were diverse and unrelated to the type of methods. We recommend future authors to clearly report the decisions made regarding trajectory groups identification.

The State of Heart Failure Care in Canada: Minimal Improvement in Readmissions Over Time Despite an Increased Number of Evidence-Based Therapies.

Background: An unanswered question is whether the combination of advances in medical and device therapy over the past decade has translated into improved outcomes for patients with heart failure (HF) in Canada. Methods: The Canadian Institute for Health Information (CIHI) Hospital Morbidity Database was used to identify hospitalizations for HF among patients aged 18 years and older in Canadian hospitals during fiscal years 2009/2010 and 2018/2019. We assessed interprovincial differences in age, sex, length of stay (LOS), discharge disposition, type of admitting hospital, and most responsible service, for all HF admissions. National and provincial rates of HF admissions and all-cause 30-day readmissions were calculated. Results: After adjusting for age, the rate of HF admissions in Canada was 216 per 100,000 population in 2009/2010 and 2018/2019. The majority of patients with HF were admitted to general internal medicine and community hospitals in both 2009/2010 and 2018/2019. The national, crude, all-cause 30-day readmission rate stayed constant at 20.6%, and the majority of patients were readmitted with the diagnosis of HF in both 2009/2010 (62.5%) and 2018/2019 (59.0%). Median and interquartile range of HF LOS also remained unchanged at 7 days (3-14). Conclusions: The national rate of HF admissions, 30-day readmissions, and HF LOS have remained unchanged from 2009/2010 to 2018/2019, despite advances in medical and device therapy during this timeframe.

Introduction: La question demeure de savoir si, au cours de la dernière décennie au Canada, la combinaison des avancées dans les traitements médicaux et à l'aide d'un dispositif s'est traduite par de meilleurs résultats cliniques chez les patients atteints d'insuffisance cardiaque (IC). Méthodes: Nous avons utilisé la base de données sur la morbidité hospitalière de l'Institut canadien d'information sur la santé (ICIS) pour recenser les hospitalisations de patients atteints d'IC âgés de 18 ans et plus dans les hôpitaux du Canada au cours des années financières 2009/2010 et 2018/2019. Nous avons évalué les différences interprovinciales selon l'âge, le sexe, la durée du séjour (DDS), l'état à la sortie, le type d'hôpital à l'admission et le service le plus tenu à la prise en charge du patient, de toutes les admissions liées à l'IC. Nous avons calculé les taux provinciaux et national des admissions liées à l'IC et les réadmissions toutes causes confondues dans les 30 jours. Résultats: Après ajustement en fonction de l'âge, le taux d'admissions liées à l'IC au Canada était de 216 pour 100 000 habitants en 2009/2010 et en 2018/2019. La majorité des patients atteints d'IC avaient été admis en médecine interne générale et dans les hôpitaux communautaires en 2009/2010 et en 2018/2019. Le taux national, brut, toutes causes confondues de réadmissions dans les 30 jours était resté constant à 20,6 %, et la majorité des patients avaient eu des réadmissions liées au diagnostic d'IC en 2009/2010 (62,5 %) et en 2018/2019 (59,0 %). L'écart interquartile et la médiane de la DDS liée à l'IC étaient aussi demeurés inchangés après 7 jours (3-14). Conclusions: Le taux national des admissions liées à l'IC, les réadmissions dans les 30 jours et la DDS liée à l'IC étaient demeurés inchangés de 2009/2010 à 2018/2019, malgré les avancées des traitements médicaux et à l'aide d'un dispositif durant cette période de temps.

Relationships between long-term residential exposure to total environmental noise and stroke incidence.

Background: Noise has been related to several cardiovascular diseases (CVDs) such as coronary heart disease and to their risk factors such as hypertension, but associations with stroke remain under-researched, even if CVD likely share similar pathophysiologic mechanisms. Aim: The objective of the study was to examine the association between long-term residential exposure to total environmental noise and stroke incidence in Montreal, Canada. Materials and Methods: We created an open cohort of adults aged ≥45years, free of stroke before entering the cohort for the years 2000 to 2014 with health administrative data. Residential total environmental noise levels were estimated with land use regression (LUR) models. Incident stroke was based on hospital admissions. Cox hazard models with age as the time axis and time-varying exposures were used to estimate associations, which were adjusted for material deprivation, year, nitrogen dioxide, stratified for sex, and indirectly adjusted for smoking. Results: There were 9,072,492 person-years of follow-up with 47% men; 26,741 developed stroke (21,402 ischemic; 4947 hemorrhagic; 392 had both). LUR total noise level acoustic equivalent for 24 hours (LAeq24h) ranged 44 to 79 dBA. The adjusted hazard ratio (HR) for stroke (all types), for a 10-dBA increase in LAeq24h, was 1.06 [95% confidence interval (CI): 1.03-1.09]. The LAeq24h was associated with ischemic (HR per 10 dBA: 1.08; 95% CI: 1.04-1.12) but not hemorrhagic stroke (HR per 10 dBA: 0.97; 95% CI: 0.90-1.04). Conclusion: The results suggest that total environmental noise is associated with incident stroke, which is consistent with studies on transportation noise and other CVD.

Polypharmacy among older individuals with heart failure: trends between 2000 and 2017 in the province of Quebec, Canada.

OBJECTIVE: Pharmacological management of heart failure and comorbidities may result in polypharmacy, but there are few population-based studies that portray the use of medications over time. We aimed to describe the trends in polypharmacy and medication use in older adults with heart failure. METHODS: We performed a study including all adults >65 years with heart failure between 2000 and 2017 using health administrative databases in Quebec, Canada. Medication use was ascertained by the presence of at least one claim in each year. We defined three levels of polypharmacy: ⩾10, ⩾15 and ⩾20 different medications/year, and evaluated the use of guideline-recommended and potentially inappropriate medications. We calculated age- and sex-standardized proportions of users each year. RESULTS: The use of ⩾10, ⩾15 and ⩾20 medications increased from 62.2%, 30.6% and 12.2% in 2000 to 71.9%, 43.9% and 22.7%, respectively, in 2017. The combination of ß-blocker and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) was used by 30.4% of individuals in 2000 and 45.5% in 2017. ACEI/ARB users decreased from 65.8% in 2000 to 62.1% in 2017. Potentially inappropriate medication use decreased over time. CONCLUSION: Polypharmacy is significant among older adults with heart failure. Implications of such medication burden should be investigated.

Temporal trends of aortic stenosis and comorbid chronic kidney disease in the province of Quebec, Canada.

OBJECTIVE: To investigate temporal trends of chronic kidney disease (CKD) among patients with incident aortic stenosis (AS) and to compare these trends with that of a matched control population. METHODS: Using the Quebec Integrated Chronic Disease Surveillance System, we performed a population-based nested case-control study including 108 780 patients newly hospitalised with AS and 543 900 age-matched, sex-matched and fiscal year-matched patients without AS from 2000 to 2016 in Quebec (Canada). Three subgroups were considered. Dialysis subgroup had at least two outpatient billing codes of dialysis. The predialysis subgroup had at least one hospital or two billing diagnostic codes of CKD. The remaining individuals were included in the non-CKD subgroup. We estimated overall and sex-specific standardised annual proportions of CKD subgroups through direct standardisation using the 2016-2017 age structure of the incident AS cohort. The trends overtime were estimated through fitting robust Poisson regression models. Age-specific distribution of AS and control population were assessed for each subgroup. RESULTS: From 2000 to 2016, age-standardised proportions of patients with AS with dialysis and predialysis increased by 41% (99% CI 12.0% to 78.1%) and by 45% (99% CI 39.1% to 51.6%), respectively. Inversely, age-standardised proportions of dialysis and pre-dialysis among non-AS patients decreased by 63% (99% CI 55.8% to 68.7%) and by 32% (99% CI 29.9% to 34.6%), respectively, during the same study period. In patients with and without AS, age-standardised annual proportions of males in predialysis were significantly higher than females in most of the study period. Patients with AS on dialysis and predialysis were younger than their respective controls (dialysis: 29.6% vs 45.1% had ≥80 years, predialysis: 60.8% vs 72.7% had ≥80 years). CONCLUSIONS: Over time, the proportion of patients with CKD increased significantly and remained consistently higher in incident AS individuals compared with controls. Our results highlight the need to investigate whether interventions targeting CKD risk factors may influence AS incidence in the future.

Comparison of Socioeconomic Disparities in Pump Uptake Among Children With Type 1 Diabetes in 2 Canadian Provinces With Different Payment Models.

Importance: Insulin pumps improve glycemic control and quality of life in children with type 1 diabetes (T1D). Canada's provinces have implemented universal pediatric programs to improve access. However, these programs provide differing financial coverage, allowing for unique cross-jurisdictional comparisons. Objective: To evaluate possible socioeconomic status (SES) disparities in pump uptake in Québec, where pumps are fully funded, with those in Manitoba, where pumps are partially funded. Design, Setting, and Participants: Using health administrative databases and a clinical registry, parallel, population-based cohort studies of children with diabetes were conducted from April 1, 2011, in Québec, and April 1, 2012, in Manitoba, until March 31, 2017. In analysis conducted from July 1, 2019, to November 30, 2021, multivariable Cox proportional hazards regression models were applied to study the association between pump uptake and SES, defined using validated area-based material and social deprivation indices. Children aged 1 to 17 years with T1D were identified using a validated definition in administrative data (Québec) and a clinical registry (Manitoba). Those using pumps before the initiation of provincial programs were excluded. Exposures: Socioeconomic status. Main Outcomes and Measures: Insulin pump uptake. Results: A total of 2919 children with T1D were identified in Québec: 1550 male (53.1%), mean (SD) age at diagnosis, 8.3 (4.4) years, and 1067 (36.6%) were using a pump. In Manitoba, 636 children were identified: 364 male (57.2%), mean (SD) age at diagnosis, 8.8 (4.4) years, and 106 (16.7%) were using a pump. In Québec, the mean age at diagnosis of T1D was lower in children using the pump compared with those not using a pump (7.6 [4.1] vs 8.7 [4.5] years); sex distribution was similar (562 [52.7%] vs 988 [53.3%] male). No differences in mean (SD) age at diagnosis (8.8 [4.4] vs 8.8 [4.3] years) or sex (57 [53.8%] vs 307 [57.9%] male) were noted in both groups in Manitoba. Increasing material deprivation was associated with decreased pump uptake in both Québec (adjusted hazard ratio [aHR] 0.89; 95% CI, 0.85-0.93) and Manitoba (aHR, 0.70; 95% CI, 0.60-0.82). Inclusion of ethnic concentration did not change this association. Socioeconomic disparities in pump uptake were greater in Manitoba than Québec (P = .006 by t test; Cochran Q, 8.15; P = .004; I2 = 87.7%; 95% CI, 52.5%-96.8%). Conclusions and Relevance: The results of this study suggest that the program of full coverage for pumps available in Québec partially mitigates observed SES disparities in uptake and may be a model to improve access for all children with T1D.

Evolution of the burden of aortic stenosis by sex in the province of Quebec between 2006 and 2018.

OBJECTIVES: To evaluate the evolution of the burden of aortic stenosis (AS) by sex in the province of Quebec from 2006-2007 to 2018-2019 and compare the percentage of mortality between people who underwent aortic valve intervention and those who did not. METHODS: Persons aged ≥20 years were identified from the Quebec Integrated Chronic Disease Surveillance System using International Classification of Diseases and intervention codes in the hospital files. RESULTS: In 2018, the crude prevalence and incidence of AS were 0.89% (99% CI 0.89 to 0.90) (n=59 025) and 1.39 per 1000 (1.35 to 1.43) (n=9105), respectively. Age-standardised prevalence and incidence of AS diagnosis increased between 2006 and 2018 from 0.67% (0.66 to 0.68) to 0.75% (0.74 to 0.76) and from 0.91 per 1000 (0.88 to 0.95) to 1.20 per 1000 (1.17 to 1.23), respectively. Among incident AS, the age-standardised percentage of valve interventions increased from 11.7% (10.9 to 12.6) to 14.5% (13.9 to 15.3). This increase was only observed in men. The 30-day mortality was stable among patients with incident AS treated conservatively, from 6.9% (6.5 to 7.4) to 7.3% (6.9 to 7.6), and decreased from 7.6% (6.1 to 9.3) to 3.8% (3.1 to 4.7) among operated patients with incident AS. This decrease was only observed in women. However, from 2010, the age-adjusted mortality among prevalent AS tended to be higher in women. CONCLUSIONS: In the province of Quebec, age-standardised prevalence and incidence of AS diagnosis increased between 2006 and 2018. Among incident AS, there was an increase in valve intervention in men and a decrease in 30-day mortality in women who underwent valve intervention. Overall and age-standardised mortality remained higher in women.

Manuscript title: Long─term residential exposure to environmental/transportation noise and the incidence of myocardial infarction.

BACKGROUND: Cardiovascular effects of environmental noise are a growing concern. However, the evidence remains largely limited to the association between road traffic noise and hypertension and coronary heart diseases. OBJECTIVES: To investigate the association between long-term residential exposure to environmental/transportation noise and the incidence of myocardial infarction (MI) in the adult population living in Montreal. METHODS: An open cohort of adults aged 45 years old and over, living on the island of Montreal and free of MI before entering the cohort was created for the years 2000-2014 with the Quebec Integrated Chronic Disease Surveillance System; a systematic surveillance system from the Canadian province of Quebec starting in 1996. Residential noise exposure was calculated in three ways: 1) total ambient noise levels estimated by Land use regression (LUR) models; 2) road traffic noise estimated by a noise propagation model CadnaA and 3) distances to transportation sources (roads, airport, railways). Incident MI was based on diagnostic codes in hospital admission records. Cox models with time-varying exposures (age as the time axis) were used to estimate the associations with various adjustments (material deprivation indicator, calendar year, nitrogen dioxide, stratification for sex). Indirect adjustment based on ancillary data for smoking was performed. RESULTS: 1,065,414 individuals were followed (total of 9,000,443 person-years) and 40,718 (3.8%) developed MI. We found positive associations between total environmental noise, estimated by LUR models and the incidence of MI. Total noise LUR levels ranged from ~44 to ~79 dBA and varied slightly with the metric used. The adjusted hazard ratios (HRs) (also adjusted for smoking) were 1.12 (95% Confidence Intervals [CI]: 1.08-1.15), 1.11 (95%CI: 1.07-1.14) and 1.10 (95%CI: 1.06-1.14) per 10 dBA noise levels increase respectively in Level Accoustic equivalent 24 h (LAeq24 h), Level day-evening-night (Lden) and night level (Lnight). We found a borderline negative association between road noise levels estimated with CadnaA and MI (HR: 0.99 per 10 dBA; 95%CI: 0.98-1.00). Distances to major roads and highways were not associated with MI while the proximity to railways was positively associated with MI (HR for ≤100 vs > 1000 m: 1.07; 95%CI: 1.01-1.14). A negative association was found with the proximity to the airport noise exposure forecast (NEF25); HR (<1 vs >1000 m) = 0.88 (95%CI: 0.81-0.96). CONCLUSIONS: These associations suggest that exposure to total environmental noise at current urban levels may be related to the incidence of MI. Additional studies with more accurate road noise estimates are needed to explain the counterintuitive associations with road noise and specific transportation sources.

Public Health Outcomes May Differ After Switching from Brand-Name to Generic Angiotensin II Receptor Blockers.

BACKGROUND: It is unclear whether generics are as safe as brand-name drugs in cardiology. For public health surveillance purposes, we evaluated if switching from the brand-name losartan, valsartan, or candesartan impacted the occurrence of the following outcomes: emergency room (ER) consultations, hospitalizations, or death. STUDY DESIGN: This was a retrospective cohort study. METHODS: This study was conducted in the Quebec Integrated Chronic Disease Surveillance System, including healthcare administrative data of the population of Quebec, Canada. We included brand-name users of losartan, valsartan, or candesartan aged ≥ 66 years who had undergone ≥ 30 days of stable treatment on the brand-name drug prior to cohort entry (substitution time-distribution matching was used to prevent immortal time bias). Outcomes up to 1 year were compared between groups using multivariable Cox proportional hazards regression models (validity assumptions were verified). RESULTS: In our cohorts (losartan, n =15,783; valsartan, n =16,907; candesartan, n =26,178), mean age was 76-78 years, 59-66% were female, 90-92% had hypertension, and 13-15% had heart failure. Validity assumptions were violated for losartan only. For patients switched to generic valsartan, the hazard ratio (95% confidence interval) was 1.07 (0.99-1.14) for ER consultation, 1.26 (1.14-1.39) for hospitalization, and 1.01 (0.61-1.67) for death. The corresponding rates for candesartan were 1.00 (0.95-1.05), 0.96 (0.89-1.03), and 0.57 (0.37-0.88), respectively. CONCLUSIONS: We observed an increased risk of hospitalizations for patients switched to generic valsartan, and a decreased risk of death for patients switched to generic candesartan, compared with those who continued taking the brand-name drug. The differences between generic and brand-name drugs may lead to some differences in public health outcomes, but this safety signal must be further studied using other cohorts and settings.

Complex Evolution of Epidemiology of Vascular Diseases, Including Increased Disease Burden: From 2000 to 2015.

BACKGROUND: Vascular diseases, encompassing coronary heart disease (CHD), cerebrovascular disease (CVD), and peripheral artery disease (PAD), are leading causes of the global mortality and morbidity burdens. Our objective was to evaluate the temporal trends in the burden of vascular diseases in the province of Quebec from 2000 to 2015. METHODS: We identified subjects aged ≥ 20 years with vascular diseases in the Quebec Integrated Chronic Disease Surveillance System (a combination of 5 provincial health administrative datasets). We identified Quebecers with CHD, CVD, or PAD by tracking codes identifying vascular diseases (and interventions for CHD) in the hospitalization datasets. We used the 2011 Quebec standard population for age standardization. RESULTS: In 2015, the crude prevalence of vascular diseases was 7.3% (n = 473,305), and the all-cause crude mortality rate was 6.6% (n = 31,320). Age-standardized prevalence of vascular diseases increased relatively by 21.4% between 2000 (5.6%; 99% confidence interval [CI], 5.5-5.6) and 2015 (6.8%; 99% CI, 6.7-6.8), whereas the age-standardized incidence and mortality rates showed relative decreases of 46.2% and 32.6%, respectively. PAD and CVD had lower prevalence and incidence but higher mortality than CHD. Most patients with CHD only had this vascular disease in contrast to patients with PAD who generally had diseases involving more than 1 vascular bed. CHD only and CHD with PAD ranked first and second, respectively, in mortality burdens. CONCLUSIONS: During the last decade, the age-standardized incidence and mortality rate of vascular diseases declined, but their prevalence increased with the overall burden of vascular diseases remaining substantial in Quebec, Canada.

Exposure to guideline-recommended drugs after a first acute myocardial infarction in older adults: does deprivation matter?

BACKGROUND: Inequities between guideline-recommended drugs (GRD) exposure and socioeconomic status might exist. The objective was to assess the association between a material and a social deprivation index and GRD exposure following a first acute myocardial infarction (AMI) in older adults in the province of Quebec. METHODS: We conducted a retrospective cohort study using the Quebec Integrated Chronic Disease Surveillance System. Elderly ≥66 years, hospitalized for a first AMI between January 1, 2006, and December 31, 2011 and covered by the public drug plan were identified. Exposure to GRD (i.e. simultaneous use of 1) antiplatelet, 2) beta-blocker, 3) lipid-lowering and 4) angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker drugs) was assessed 30 and 365 days following hospital discharge. Associations between deprivation index and GRD exposure were estimated with log-binomial regressions adjusting for potential confounders. RESULTS: Exposure to GRD was 52.2% and 48.0%, 30 and 365 days after hospital discharge, respectively. No statistically significant association was observed in multivariate analysis for both time points. Thirty days post hospital discharge, adjusted prevalence ratio of non-exposure to GRD was 0.98 (95% confidence interval [CI]: 0.95-1.02) for most materially deprived vs. least deprived and 1.04 (95% CI: 0.99-1.08) for most socially deprived vs. least deprived. Similar results were observed for 365 days. CONCLUSION: Exposure to GRD after a first urgent AMI among older adults insured by the public drug plan in the province of Quebec is relatively low. Reasons and risk groups for this low exposure should be studied to improve secondary prevention. However, results suggest equitable access to GRD, regardless of deprivation.

Did Generic Clopidogrel Commercialization Affect Trends of ER Consultations and Hospitalizations in the Population Treated with Clopidogrel?

BACKGROUND: Clopidogrel has been widely used to prevent atherothrombotic events. Since 2011, pharmacists have offered their patients the opportunity to switch to generic clopidogrel, an economic alternative. Whether bioequivalence of generic cardiovascular drugs translates into clinical equivalence at a population level remains unclear and needs to be further documented. OBJECTIVE: We aimed to evaluate the impact of generic clopidogrel commercialization on adverse events (AEs): hospitalizations or emergency room (ER) consultations. METHODS: This is an interrupted time series analysis using the Quebec Integrated Chronic Disease Surveillance System. We included all patients ≥ 66 years old who were users of the brand-name clopidogrel or a generic version (n = 6) 24 months before and up to 12 months after generics commercialization. Rates of AEs were computed, and periods before and after generics commercialization were analyzed by segmented regression models along with exploratory analyses (generic vs. brand name). Sensitivity analyses were also performed using stratification of the time series by (1) sex, (2) the number of prevalent cardiovascular comorbidities, and (3) socioeconomic status. RESULTS: Time series were constituted of 89,525 clopidogrel users (mean age 78 years, 45% women, 71% ischemic heart disease, 34% stroke). For all users, there was a mean rate of 157 AEs per 1000 user-months, stable trend before (-0.1% [95% confidence interval -0.3 to 0.1] and after (0.0% [- 0.5 to 0.6]) generics commercialization. In exploratory analyses, once generic clopidogrel versions were commercialized, rates of AEs were 19.2% (95% CI 11.7-26.7) higher for generic versus brand-name users. This difference persisted up to 1 year. Sensitivity analyses yielded similar results. CONCLUSIONS: The population treated with clopidogrel had similar rates of hospitalizations or ER consultations before and after generics commercialization. However, differences in rates of hospitalizations or ER consultations between generic and brand-name clopidogrel users may represent a drug safety signal which remains to be validated. Using a different study design, permitting adjustment for potential confounders, could be useful in this regard.

Trends in Hospital Visits for Generic and Brand-Name Warfarin Users in Québec, Canada: A Population-Based Time Series Analysis.

BACKGROUND: Federal standards authorize the commercialization of generic medicines after bioequivalence versus the brand-name originator has been demonstrated. For drugs with narrow therapeutic indexes, such as warfarin, the accepted difference in bioavailability is ≤ 10%. No systematic pharmacovigilance studies are conducted once generics become available. OBJECTIVE: We aimed to assess the impact of the arrival of generic warfarin on hospital visit trends (hospital admissions or emergency room consultations) in warfarin users. METHODS: This was an observational interrupted time series analysis (2 January 1996 to 1 January 2016). Using the Québec Integrated Chronic Disease Surveillance System, we included all patients who were aged ≥ 66 years, publicly covered and using brand-name or generic warfarin (N = 280,158). We estimated rates of hospital visits in 6-month periods, 5 years before and up to 15 years after the arrival of generic warfarin. Periods before and after were compared using segmented regression models for all users along with exploratory (generic vs. brand name)/subgroup analyses (cardiovascular comorbidities and socioeconomic status). RESULTS: Generic warfarin arrived on the market on 2 January 2001. Over the 20-year period of the study, the mean rate of hospital visits was 113 for 100 brand-name or generic users per 6-month period and was similar before and after the arrival of the generics. Up to 15 years after the arrival of the generics, the rates of hospital visits were 10% higher for generic than for brand-name users, which was confirmed by subgroup analyses. CONCLUSIONS: Overall, we observed no impact on hospital visits after the arrival of generic warfarin in all the population treated with any type of warfarin. However, a higher crude rate of hospital visits among generic users than brand-name users remains to be validated using a different methodology and specific outcomes.

Impact of the Commercialization of Three Generic Angiotensin II Receptor Blockers on Adverse Events in Quebec, Canada: A Population-Based Time Series Analysis.

BACKGROUND: Once the patent of a brand-name drug expires, generic drugs are commercialized, and substitution from brand-name to generics may occur. Generic drug equivalence is evaluated through comparative bioavailability studies. Few studies have assessed outcomes after generic drug commercialization at a population level. We evaluated the impact of 3 generic angiotensin II receptor blockers commercialization on adverse events: hospitalizations or emergency room consultations. METHODS AND RESULTS: This is an interrupted time series analysis using the Quebec Integrated Chronic Disease Surveillance System. Rates of adverse events for losartan, valsartan, and candesartan users (N=136 177) aged ≥66 years were calculated monthly, 24 months before and 12 months after generics commercialization. Periods before and after generics commercialization were compared by negative binomial segmented regression models. Sensitivity analyses were also conducted. For all users, there was a monthly mean rate of 100 adverse events for 1000 angiotensin II receptor blocker users before and after generic commercialization. Among generic users of losartan, valsartan, and candesartan, there was an increase in rates of adverse events of 8.0% (difference of proportions versus brand-name, 7.5% [95% confidence interval, -0.9% to 15.9%]; P=0.0643), 11.7% (difference of proportions, 17.1% [95% confidence interval, 9.9%-24.3%]; P<0.0001), and 14.0% (difference of proportions, 16.6% [95% confidence interval, 7.9%-25.3%]; P<0.0001), respectively, the month of generic commercialization. The monthly trend of adverse events was affected for generic versus brand-name losartan users only (difference of proportions, 2.0% [0.7%-3.4%]; P=0.0033) ≤1 year after generics commercialization. Similar results were found in sensitivity analyses. CONCLUSIONS: Among generic users, immediate or delayed differences in adverse events rates were observed right after generic commercialization for 3 antihypertensive drugs. Rates of adverse events remained higher for generic users. Increases were more pronounced for generic candesartan, which is the studied product with the largest difference in comparative bioavailability. Risk and survival analysis studies controlling for several potential confounding factors are required to better characterize generic substitution.