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Introduction: Published data on the safety of natural medical cannabis (MC) when used in the real-world clinical practice setting are lacking. This study aimed to describe adverse events (AEs) reported across three years following MC initiation. Methods: The Quebec Cannabis Registry (QCR) was a prospective registry of adults enrolled through participating physicians when they initiated MC between May 2015 and October 2018. Follow-up ended at MC discontinuation, loss to follow-up, three years, or end of data collection (May 2019). Data were collected at baseline and at follow-up visits every three months for the first two years, then once in the third year. Physicians filled adverse event (AE) reports, which were coded using MedDRA® preferred terms (PTs), and descriptive analyses were conducted. Results: A total of 2991 patients were enrolled (mean age 50.9 years, 50.2% females). During follow-up, 108 patients (3.6%) experienced moderate or severe AEs, yielding 111 AE reports (three patients had two reports) and 214 AEs (average 1.9 AEs per report). Mild AEs were recorded as a reason for MC discontinuation for nine patients, but no AE reports were available. The most common PTs for ingested MC (62 reports) were dizziness (12.9%), nausea (11.3%), somnolence (9.7%), and vomiting (8.1%), and for inhaled MC (23 reports), headache (13.0%) was the most common. The most frequent PTs associated with tetrahydrocannabinol (THC)-dominant MC (25 reports) were dizziness and somnolence (12.0% each); for cannabidiol (CBD)-dominant MC (20 reports), vomiting (20.0%) was most common; and dizziness (17.2%), nausea (13.8%), somnolence (10.3%), and headache (8.6%) were the most frequent for balanced MC (58 reports). Conclusion: No new safety concerns were identified relative to the published literature, although notable differences in AE profile between modes of administration and cannabinoid content ratios should be considered by health professionals. Further work identifying and managing risk factors for AEs is warranted to maintain a favorable benefit-risk balance for MC. [ABSTRACT FROM AUTHOR]

Introduction: Although hereditary von Willebrand disease (VWD) is the most common bleeding disorder, its epidemiology is not well understood. A systematic review (PROSPERO CRD42020197674/CRD42021244374) on the epidemiology/burden of illness of VWD was conducted to better understand patients' unmet needs. Methods: Observational studies (published January 1, 2010 to April 14, 2021) were identified in MEDLINE and Embase databases, using free-text keywords and thesaurus terms for VWD and outcomes of interest. Pragmatic web-based searches of the gray literature, including conference abstracts, were performed, and reference lists of retained publications were manually searched for additional sources. Case reports and clinical trials (phase 1– 3) were excluded. Outcomes of interest were incidence, prevalence, mortality, patient characteristics, burden of illness, and therapeutic management/treatments currently used for VWD. Results: Of the 3095 identified sources, 168 were included in this systematic review. Reported VWD prevalence (22 sources) ranged from 108.9 to 2200 per 100,000 in population-based studies and from 0.3 to 16.5 per 100,000 in referral-based studies. Reported times between first symptom onset and diagnosis (two sources; mean 669 days; median 3 years) highlighted gaps in timely VWD diagnosis. Bleeding events reported in 72– 94% of the patients with VWD (all types; 27 sources) were mostly mucocutaneous including epistaxis, menorrhagia, and oral/gum bleeding. Poorer health-related quality of life (three sources) and greater health care resource utilization (three sources) were reported for patients with VWD than in general populations. Conclusion: Available data suggest that patients with VWD experience high disease burden in terms of bleeding, poor quality of life, and health care resource utilization. [ABSTRACT FROM AUTHOR]

Incidence and prevalence estimates for Gaucher disease (GD) are scarce for this rare disease and can be variable within the same region. This review provides a qualitative synthesis of global GD incidence and prevalence estimates, GD1–3 type-specific and overall, published in the last 10 years. A targeted literature search was conducted across multiple databases from January 2011 to September 2020, including web-based sources and congress proceedings to May 2021. Searches yielded 490 publications, with 31 analyzed: 20 cohort studies (15 prospective, 5 retrospective), 6 cross-sectional studies, 5 online reports (most from Europe (n = 11) or North America (n = 11); one multiregional). Across all GD types, incidence estimates ranged 0.45–25.0/100,000 live births (16 studies), lowest for Asia-Pacific. Incidence of GD1: 0.45–22.9/100,000 live births (Europe and North America) and GD3: 1.36/100,000 live births (Asia-Pacific only). GD type-specific prevalence estimates per 100,000 population were GD1: 0.26–0.63; GD2 and GD3: 0.02–0.08 (Europe only); estimates for GD type unspecified or overall ranged 0.11–139.0/100,000 inhabitants (17 studies), highest for North America. Generalizability was assessed as "adequate"or "intermediate" for all regions with data. GD incidence and prevalence estimates for the last 10 years varied considerably between regions and were poorly documented outside Europe and North America. Data for GD2 and GD3 were limited. [ABSTRACT FROM AUTHOR]

Abstract: Background: In a real-life setting, differences across newer antidepressants in patterns of use remain poorly explored, particularly in the older patients despite the high prevalence of late-life depression. Methods: An observational retrospective cohort study was conducted in the community-dwelling elderly population of Quebec using health databases to compare the newer antidepressants with respect to non-persistence, associated health care costs and cost/persistence ratio. A random sample of 12,825 outpatients who initiated an antidepressant treatment in 2000 were followed for 12 months. Non-persistence was defined as treatment duration of less than 180 days. Economic variables included direct costs of prescribed medications, medical services and hospitalizations assessed through RAMQ claims databases and Med-Echo hospitalization database. Cost/persistence ratio and incremental cost/persistence ratio were obtained for each antidepressant product; persistence being considered as an indicator of effectiveness. Results: 55.6% of antidepressant treatments were non-persistent. Products associated with low antidepressant costs were often associated with high costs of other medications and health care services, and vice versa. Paroxetine was associated with the lowest non-persistence (50.5%; 95%CI 48.5–52.5) and one of the most favourable cost/persistence ratios (CDN$4869 per persistent treatment). Fluoxetine was associated with the most favourable incremental cost/persistence ratio. Limitations: Some services and hospitalizations are not included in the administrative databases. No data on indication for treatment were available. These were likely to be non-differential across newer antidepressants. Conclusion: As found in other populations, non-persistence with antidepressant treatment is very frequent in the Quebec elderly population. Products associated with poor persistence result in increased health care costs. Hence, intervention programs aimed at improving persistence would optimize the use of health care resources and result in economic advantages. [Copyright &y& Elsevier]

Purpose: To assess the effect of visual impairment (VI) on the risk of depression or death in the community-dwelling elderly population. Methods: A population-based, retrospective fixed cohort study was conducted in the community-dwelling elderly (age ≥ 65 years) outpatient population of Quebec. The cohort was assembled through the Quebec medical services database and consisted of the 5063 patients aged ≥ 65 years who received a diagnosis of VI during the years 2000–2004. The reference cohort consisted of 16 932 elderly subjects who were randomly selected among members of the public drug programme. The outcome variables were depression and death. The main independent variable was VI and covariates included age, gender, chronic disease score, fracture and diabetes. Results: Controlling for covariates, VI was associated with an increased risk of depression although the effect was not modified by severity (hazard ratio [HR] = 1.35, 95% confidence interval [CI] 1.10–1.66 for severe VI; HR = 1.35, 95% CI 1.09–1.69 for moderate VI). Visual impairment was associated with an increased risk of mortality; patients with moderate vision loss had a higher risk of death (HR = 1.70, 95% CI 1.55–1.87) than those with severe vision loss (HR = 1.34, 95% CI 1.21–1.48). Conclusions: Given the ageing of the population, VI in elderly subjects is becoming a public health concern. These findings enhance the need to detect and treat VI in order to improve the quality of life and to prevent premature mortality in the elderly population. [ABSTRACT FROM AUTHOR]

Abstract: Background: Age-related macular degeneration (AMD) is characterized by loss of central vision and is the leading cause of blindness among persons over the age of 50 years in Canada. The wet form of AMD has 3 subtypes—occult, minimally classic, and predominantly classic. Photodynamic therapy (PDT) with verteporfin is indicated only for the category of predominantly classic wet AMD. Currently, there are no treatments available for the other AMD subtypes. Pegaptanib sodium was the first pharmacologic therapy approved in Canada for the treatment of subfoveal wet AMD regardless of subtype. Objective: The aim of this study was to examine the cost-effectiveness of pegaptanib versus PDT with verteporfin and versus standard care for the treatment of subfoveal wet AMD in patients aged ⁥65 years in Canada. Methods: A Markov model based on visual acuity in the better-seeing eye was developed. Clinical efficacy was taken from the clinical trials. Costs of treatment, comorbidities (eg, depression, fractures, need for assisted living), vision rehabilitation, visual aids, and adverse events were considered. Costs, utilities, and mortality were estimated from data from the available published literature. Costs were reported in 2004 Canadian dollars, and costs and outcomes were discounted at 3% per annum. Lifetime costs, quality-adjusted life-years (QALYs), and vision years gained (VYGs) were estimated. Sensitivity analyses were performed to determine model robustness. Results: Patients who received pegaptanib experienced more QALYs gained (4.17) and VYGs (3.83) compared with patients who received PDT (3.87 and 3.01, respectively) or standard care (3.96 and 3.26). Mean total costs per patient were greater in patients who received pegaptanib compared to those who received PDT or standard care ($20,016 vs $15,345 or $7669, respectively). The incremental cost per QALY in patients receiving pegaptanib compared to those receiving PDT was $49,052 and $59,039 for patients receiving pegaptanib versus standard care. The incremental cost per VYG was $20,401 and $21,559 with pegaptanib versus PDT and standard care, respectively. Sensitivity analyses found that the model was relatively robust to changes in various model parameters. Conclusion: The results of this analysis suggest that in Canada, pegaptanib is a cost-effective treatment for subfoveal wet AMD in elderly patients, regardless of lesion subtype, compared to PDT with verteporfin and to standard care. [Copyright &y& Elsevier]

Abstract: Objective: To develop the infant and toddler disease score (IDS), a population-based predictive tool of morbidity status in infants and toddlers, based on data from administrative claims. Study Design and Setting: A prospective cohort study was conducted, including 35,580 children less than 2 years of age in June 2003 from the French “ERASME” database (mean follow-up 13 months). The outcome variable was incident hospitalization during the follow-up year, that is, before the second birthday for infants and before the third for toddlers. Risk factors before inclusion (age, health care use, medications) were assessed in a 50% random sample (construction sample) by a logistic regression model. Beta coefficients were summed up to obtain the IDS. The IDS was then validated for the remaining 50% of the study population (validation sample). Results: The major variables significantly associated with the outcome were long-term disability, younger age, and ≥1 hospitalization before inclusion. The risks of hospitalization estimated by the IDS were concordant in the construction and validation samples. Conclusion: The IDS is a useful index for the risk of hospitalization of infants and toddlers in relation to their morbidity status and may be used for adjustment in pharmacoepidemiologic studies using administrative claims databases. [Copyright &y& Elsevier]

OBJECTIVES: To assess the association between selected physician characteristics and suboptimal duration of antidepressant use in the older outpatient population. DESIGN: Follow-up of patients who were prescribed an antidepressant treatment by a cohort of physicians in Quebec. SETTING: Community-based older outpatient population in Quebec. PARTICIPANTS: Retrospective cohort of 1,301 general practitioners (GPs) and 236 psychiatrists followed from 1991 to 1997. MEASUREMENTS: Treatment duration of less than 180 days in 1996/97. RESULTS: Premature interruption of antidepressant treatment was very frequent (44.7%). GPs, physicians who practice in metropolitan or urban regions, and those who have a proportion of older patients in their practice of less than 50% show a higher rate of premature interruption. These associations could not be accounted for by the choice of products, dosage, or patient characteristics. CONCLUSION: We have identified physician characteristics that are associated with suboptimal duration of antidepressant use and conclude that further interventions should target subgroups of physicians. [ABSTRACT FROM AUTHOR]

Background: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency in arylsulfatase A (ASA) activity arising primarily from ASA gene (ARSA) variants. Late-infantile, juvenile and adult clinical subtypes are defined by symptom onset at ≤ 2.5, > 2.5 to < 16 and ≥ 16 years, respectively. Epidemiological data were sought to address knowledge gaps and to inform decisions regarding the clinical development of an investigational drug. Methods: To synthesize all available estimates of MLD incidence and birth prevalence worldwide and in selected countries, Ovid MEDLINE and Embase were searched systematically (March 11, 2022) using a population, intervention, comparator, outcome, time and setting framework, complemented by pragmatic searching to reduce publication bias. Where possible, results were stratified by clinical subtype. Data were extracted from non-interventional studies (clinical trials, non-clinical studies and case reports were excluded; reviews were used for snowballing only). Results: Of the 31 studies included, 14 reported birth prevalence (13 countries in Asia–Pacific, Europe, the Middle East, North America and South America), one reported prevalence and none reported incidence. Birth prevalence per 100,000 live births ranged from 0.16 (Japan) to 1.85 (Portugal). In the three European studies with estimates stratified by clinical subtypes, birth prevalence was highest for late-infantile cases (0.31–1.12 per 100,000 live births). The distribution of clinical subtypes reported in cases diagnosed over various time periods in 17 studies varied substantially, but late-infantile and juvenile MLD accounted for at least two-thirds of cases in most studies. Conclusions: This review provides a foundation for further analysis of the regional epidemiology of MLD. Data gaps indicate the need for better global coverage, increased use of epidemiological measures (e.g. prevalence estimates) and more stratification of outcomes by clinical and genetic disease subtype. [ABSTRACT FROM AUTHOR]

Global adoption of risk management principles outlined in the International Conference on Harmonisation (ICH) E2E guideline and the Council for International Organizations of Medical Sciences (CIOMS) Working Group VI guidance introduced greater proactivity and consistency into the practice of pharmacovigilance and benefit–risk management throughout the lifecycle of a drug. However, following the release of these guidelines there have been important advances in the science and practice of risk minimisation itself, especially in terms of how risk minimisation measures (RMMs) are designed, implemented, disseminated and evaluated for effectiveness in real-world healthcare settings. In this article, we describe how the field of design, implementation, dissemination and evaluation of RMMs has advanced in recent years while highlighting current areas of challenge and possible solutions. Where possible we cite global examples to demonstrate how evidence-based approaches have informed the development of RMMs. In this context, while taking into consideration local healthcare system policies and national legislations, we conclude with a call for a global effort to harmonise certain areas that focus on, but are not limited to, standardising certain terms and definitions, consistent application of robust methodologies, and outline of best practices for risk minimisation design, implementation, and dissemination. [ABSTRACT FROM AUTHOR]

Introduction: Some adverse drug reactions (ADRs) may involve direct social issues, such as impaired quality of life, work productivity, or social functioning, as opposed to being social consequences of medical adverse events. Data on ADRs with a direct social impact remain scarce in the literature.Objective: Our objective was to describe the ADRs consisting of direct social issues that have been recorded in the Canadian national spontaneous reporting system (Canada Vigilance).Methods: We conducted an analysis of the online Canada Vigilance spontaneous reporting database from 1 January 1965 (inception) to 31 December 2015 (last date available). We manually examined all Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) found in the Canada Vigilance database to identify those that involved direct social issues. We then used those PTs to search for relevant individual case safety reports (ICSRs). We conducted a descriptive analysis of the following ICSR characteristics: patient and reporter characteristics, type of ADR, seriousness (as assessed by the reporter and according to the International Conference on Harmonisation criteria of seriousness), and suspected drug(s). We compared the characteristics of ADRs with and without direct social impact.Results: Among the 11,946 MedDRA PTs recorded in Canada Vigilance, we retained 40 that had a direct social impact. Using these PTs, we identified 9557 relevant ICSRs (corresponding to 6670 patients). The proportion of ADRs consisting of direct social issues increased over time, with a sharp transient peak in 2008. The majority were reported by healthcare professionals and consumers (56.7 and 37.8%, respectively). The mean age of patients was 45.4 years, and 53.3% were females. Direct social issues consisted of personality disorders and behaviour disturbances (41.6%) followed by neurological disorders (34.2%). The majority of ADRs were considered serious by reporters (76.5%), with 26.8% resulting in hospitalization. Commonly suspected health products included nervous system drugs (63.3%) and antineoplastic and immunomodulating agents (23.6%). Compared with other ADRs, those with a direct social impact were more often reported by consumers, involved patients who were on average 5 years younger, and were more frequently assessed as being serious by the reporters.Conclusions: Findings from this study support the consideration of direct social issues as ADRs in the detection of drug safety signals. [ABSTRACT FROM AUTHOR]

The article investigates the potential association between long-term use of benzodiazepines and risks of developing Alzheimer's disease among older people. Topics discussed include the correlation between the length of time that a patient has been using the drug and the patient's chances of developing Alzheimer's disease and the experts' warning that benzodiazepine may not be the cause of Alzheimer's disease but may just be an early marker of increased risk.

Background: Recently in France, primary pulmonary hypertension developed in a cluster of patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control. We investigated the potential role of anorexic agents and other suspected risk factors for primary pulmonary hypertension. Methods: In a case–control study, we assessed 95 patients with primary pulmonary hypertension from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the patients' sex and age. Results: The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95 percent confidence interval, 3.4 to 29.9). When anorexic drugs were used for a total of more than three months, the odds ratio was 23.1 (95 percent confidence interval, 6.9 to 77.7). We also confirmed an association with several previously identified risk factors: a family history of pulmonary hypertension, infection with the human immunodeficiency virus, cirrhosis, and use of cocaine or intravenous drugs. Conclusions: The use of anorexic drugs was associated with the development of primary pulmonary hypertension. Active surveillance for this disease should be considered, particularly since the use of anorexic drugs is expected to increase in the near future. (N Engl J Med 1996;335:609-16.) [ABSTRACT FROM AUTHOR]

Although relapse is an important outcome to measure the effectiveness of schizophrenia treatment, no standard definition exists. This review aimed at identifying definitions and measurements of schizophrenia relapse in observational studies of long‐acting injectables (LAIs) versus oral antipsychotics (OAPs) and at determining their impact on heterogeneity of comparative effectiveness estimates. A systematic review was conducted using MEDLINE and Embase (01 January 2010–11 November 2019 [date last searched]). Pragmatic searches of gray literature and snowballing were also conducted. Search outputs were screened independently by two assessors at first stage, and full‐text of potentially eligible sources at second stage. For each retained source, definition and measurement of relapse, study methods, and comparative effectiveness estimates were extracted. Heterogeneity of estimates was assessed using I2 statistic with a threshold of 50% for substantial heterogeneity. Literature search yielded 543 sources and pragmatic searches, 21, of which 35 were eligible. Twelve definitions of relapse were found based on hospitalization/emergency department (ED) data (28 studies) or clinical assessment (5 studies). No definition was provided in five studies. According to quantitative analyses, in studies defining relapse as schizophrenia‐related hospitalization and/or ED visits over 1‐year follow‐up, LAIs were significantly more effective than OAPs. For studies measuring relapse based on all‐cause hospitalization, heterogeneity was too high for pooling; yet this definition is the most frequently found in pooled estimates published in the literature. Schizophrenia relapse definitions led to substantial heterogeneity of comparative effectiveness estimates of LAIs versus OAPs. Creating study subgroups based on relapse definition effectively reduces statistical heterogeneity. [ABSTRACT FROM AUTHOR]

This systematic review and meta-analysis aimed to determine the effectiveness of brentuximab vedotin (BV) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) in the clinical practice setting using most recent results. A total of 32 observational studies reporting on treatment patterns, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and adverse events were found. After four cycles, a random-effect model yielded pooled ORR and CR rates of 62.6% (95% confidence interval (CI): 56.0–68.9; I2 = 9.7%) and 32.9% (95% CI, 20.8–46.3, I2 = 64.8%), respectively. Regarding survival, 1-year, 2-year, and 5-year PFS ranged from 52.1% to 63.2%, 45.2% to 56.2%, and 31.9% to 33.0%, respectively. OS rates were 68.2–82.7%, 58.0–81.9%, and 58.0–62.0%, respectively. Most common adverse events were hematological toxicities (neutropenia: 13.3–23%, anemia: 8.8–39.0%, and thrombocytopenia: 4–4.6%), and grade ≥3 peripheral neuropathy (3.3–7.3%). This study supports the effectiveness and safety of BV in R/R cHL patients in the real-world setting. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Compliance with alendronate and risedronate is suboptimal. • Few studies have specifically evaluated the impact of noncompliance with alendronate or risedronate on the incidence of osteoporotic fractures in community-dwelling elderly women. WHAT THIS STUDY ADDS • Among community-dwelling elderly women, noncompliance [defined as medication possession ratio (MPR) < 80%] with alendronate or risedronate was associated with a 27% increased risk of nonvertebral fracture [rate ratio (RR) 1.27, 95% confidence interval (CI) 1.12, 1.44]. • This study is the first to assess the impact of noncompliance with bisphosphonates in a subgroup of women aged > 80 years. • Among women aged > 80 years, MPR < 80% was associated with a 48% greater risk of sustaining a nonvertebral fracture (RR 1.48, 95% CI 1.19, 1.85), compared with women with a MPR ≥ 80%. AIMS To evaluate the association between noncompliance with alendronate and risedronate and the risk of nonvertebral osteoporotic fracture in community-dwelling elderly women. METHODS A nested case–control study was conducted using the Quebec administrative health databases. To be included in the cohort, women needed to be aged ≥ 68 years and to have initiated treatment with alendronate or risedronate between 1 January 2002 and 31 March 2005. Cases consisted of all women with an incident nonvertebral osteoporotic fracture occurring ≥ 1 year after initiation of therapy. Each case was matched with up to 20 controls using incidence density sampling, according to age (± 1 year) and follow-up duration. A woman was noncompliant if she had a medication possession ratio (MPR) <80% for total follow-up duration. Rate ratios (RR) for fracture were estimated through conditional logistic regression analysis, adjusting for potential confounders. RESULTS Among the 30 259 women included in the cohort, 1036 nonvertebral fracture cases were identified and were matched to 20 069 controls. Compared with women with a MPR ≥ 80%, those with a MPR < 80% had a greater risk of nonvertebral fracture [adjusted RR 1.27, 95% confidence interval (CI) 1.12, 1.44]. Considering hip fracture only, the multivariate model yielded similar results, (adjusted RR 1.28, 95% CI 1.02, 1.61). CONCLUSIONS Among community-dwelling elderly women, noncompliance with alendronate or risedronate is associated with an increased risk of nonvertebral fracture. [ABSTRACT FROM AUTHOR]

• Reporting of AEFIs is central to vaccine safety surveillance. • Vaccine hesitancy in India curtails AEFI surveillance efforts. • Only a minority of paediatricians received formal training in AEFI surveillance. • Main barrier in AEFI reporting is difficulties with reporting processes. The role of health care professionals (HCPs) is central to adverse event following immunisation (AEFI) surveillance. A cross–sectional survey was conducted among paediatricians practising in Kerala, India, to assess their knowledge and reporting behaviour in AEFI surveillance as well as to identify barriers to reporting. A random sample of 380 paediatricians were contacted of whom, 243 (63.9%) participated in the survey. The understanding scores were distributed as follows: 30.9% very high or high, 40.3% moderate, and 28.8% low. Formal training was significantly associated with higher understanding scores, and increased AEFI detection and reporting. Only 42.0% of respondents had formal training; paediatricians in the public sector had higher access to training than those in the private sector. There were 141 respondents (58.0%) who identified an AEFI in the previous year, of whom 66 (46.8%) reported it. The main barriers to AEFI reporting were: difficulties with reporting process (28.9%); fear of raising public alarm (28.1%); time constraints (22.3%); fear of personal consequences (15.7%); and belief that health authorities rarely take useful action (11.6%). Training in AEFI surveillance should be prioritised for HCPs with greater emphasis in medical education programmes. Study showed that a user–friendly reporting mechanism and a blame–free culture are crucial to improve AEFI reporting practices. [ABSTRACT FROM AUTHOR]

Background: Long-term opioid use is a known risk factor for opioid-related harms. We aimed to identify risk factors for and predictors of long-term use of prescription opioids in the community-dwelling population of adults without a diagnosis of cancer, to inform practice change at the point of care. Methods: Using Quebec administrative claims databases, we conducted a retrospective cohort study in a random sample of adult members (≥ 18 yr) of the public drug plan who did not have a cancer diagnosis and who initiated a prescription opioid in the outpatient setting between Jan. 1, 2012, and Dec. 31, 2016. The outcome of interest was long-term opioid use (≥ 90 consecutive days or ≥ 120 cumulative days over 12 mo). Potential predictors included sociodemographic factors, medical history, characteristics of the initial opioid prescription and prescriber's specialty. We used multivariable logistic regression to assess the association between each characteristic and long-term use. We used the area under the receiver operating characteristic curve to determine the predictive performance of full and parsimonious models. Results: Of 124 664 eligible patients who initiated opioid therapy, 4172 (3.3%) progressed to long-term use of prescription opioids. The most important associated factors in the adjusted analysis were long-term prescription of acetaminophen–codeine (odds ratio [OR] 6.30, 95% confidence interval [CI] 4.99 to 7.96), prescription of a long-acting opioid at initiation (OR 6.02, 95% CI 5.31 to 6.84), initial supply of 30 days or more (OR 4.22, 95% CI 3.81 to 4.69), chronic pain (OR 2.41, 95% CI 2.16 to 2.69) and initial dose of at least 90 morphine milligram equivalents (MME) per day (OR 1.24, 95% CI 1.04 to 1.47). Our predictive model, including only the initial days' supply and chronic pain diagnosis, had area under the curve of 0.7618. Interpretation: This study identified factors associated with long-term prescription opioid use. Limiting the initial supply to no more than 7 days and limiting doses to 90 MME/day or less are actions that could be undertaken at the point of care. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article concerning the risk of cognitive impairment in older community-dwelling women after benzodiazepine use.

Background: Fentanyl buccal tablet (FBT), a potent opioid, was approved in Canada in 2013 for breakthrough pain in opioid-tolerant adult cancer patients. Additional risk minimization measures (aRMMs), consisting of communications to patients and healthcare providers (HCPs), were implemented from November 2014 through September 2015.Objectives: The aim of this study was to assess the effectiveness of FBT aRMMs as measured by prescriber knowledge, understanding, and behavior regarding key safety concerns (off-label use, use in non-opioid-tolerant patients, misuse/abuse/diversion, and drug-drug interaction) and to evaluate illicit FBT use.Methods: The study included three components: (1) a knowledge and understanding (KAU) survey of FBT prescribers conducted in two waves: November 2016-February 2017 and April-September 2018; (2) a retrospective prescription study of medical records of patients treated with FBT by a subgroup of prescribers from the KAU survey; and (3) Web surveillance of illicit FBT use in Canada using the search term FENTORA (May 2014-September 2018). The aRMMs were considered effective if the lower bound of the 95% confidence interval indicated that at least 65% of respondents met or partly met the knowledge objective for each key safety concern.Results: KAU survey: Of 46 eligible HCPs, 97.8% met or partly met the knowledge objective on use in breakthrough pain cancer patients, 97.8% on use in opioid-tolerant patients, 89.1% on dose and titration, 100% on abuse/addiction, and 58.7% on drug-drug interaction. Retrospective prescription study: Of 22 FBT-treated patients identified from 14 HCPs, 45.5% had cancer, 50.0% recorded a breakthrough pain indication, and 36.4% reported opioid tolerance; however, only 13.6% of patients were prescribed FBT according to the approved indication. Web surveillance: Of 932 FBT posts in Canada, only 40 (4.3%) mentioned illicit use.Conclusions: The aRMMs as measured by the prescriber KAU were effective for most key safety messages; however, not all key messages of the aRMMs were stringently followed in routine practice. [ABSTRACT FROM AUTHOR]

In an era when the number of expedited and conditional review pathways for newly available brand-name drugs and biosimilar medicines to treat serious and life-threatening diseases is increasing, defining pharmacovigilance has never been more crucial. 21st century pharmacovigilance is not merely about uncovering, reporting, and addressing adverse events associated with already approved and marketed agents, but can be described as the systematic monitoring of the process of pre-market review and post-market surveillance, which includes the use of medicines in everyday practice. Pharmacovigilance identifies previously unrecognised adverse events or changes in the patterns of these effects, the quality and adequacy of drug supply, and should ensure effective communication with the public, health-care professionals, and patients about the optimum safety and effective use of medicines. In this paper, the first in a Series of three about drug safety in oncology, we discuss evolving challenges in the purview, roles, and responsibilities of the US Food and Drug Administration and the European Medicines Agency with respect to pharmacovigilance efforts, with a special emphasis on oncology treatment. [ABSTRACT FROM AUTHOR]

Introduction: An often key component to coordinating surveillance activities across distributed networks is the design and implementation of a common data model (CDM). The purpose of this study was to evaluate two drug safety surveillance CDMs from an ecosystem perspective to better understand how differences in CDMs and analytic tools affect usability and interpretation of results.Methods: Humana claims data from 2007 to 2012 were mapped to Observational Medical Outcomes Partnership (OMOP) and Mini-Sentinel CDMs. Data were described and compared at the patient level by source code and mapped concepts. Study cohort construction and effect estimates were also compared using two different analytical methods--one based on a new user design implementing a high-dimensional propensity score (HDPS) algorithm and the other based on univariate self-controlled case series (SCCS) design--across six established positive drug-outcome pairs to learn how differences in CDMs and analytics influence steps in the database analytic process and results.Results: Claims data for approximately 7.7 million Humana health plan members were transformed into the two CDMs. Three health outcome cohorts and two drug cohorts showed differences in cohort size and constituency between Mini-Sentinel and OMOP CDMs, which was a result of multiple factors. Overall, the implementation of the HDPS procedure on Mini-Sentinel CDM detected more known positive associations than that on OMOP CDM. The SCCS method results were comparable on both CDMs. Differences in the implementation of the HDPS procedure between the two CDMs were identified; analytic model and risk period specification had a significant impact on the performance of the HDPS procedure on OMOP CDM.Conclusions: Differences were observed between OMOP and Mini-Sentinel CDMs. The analysis of both CDMs at the data model level indicated that such conceptual differences had only a slight but not significant impact on identifying known safety associations. Our results show that differences at the ecosystem level of analyses across the CDMs can lead to strikingly different risk estimations, but this can be primarily attributed to the choices of analytic approach and their implementation in the community-developed analytic tools. The opportunities of using CDMs are clear, but our study shows the need for judicious comparison of analyses across the CDMs. Our work emphasizes the need for ongoing efforts to ensure sustainable transparent platforms to maintain and develop CDMs and associated tools for effective safety surveillance. [ABSTRACT FROM AUTHOR]

Abstract: Following reports of a potential association between antidepressants (ADs) and suicidal behaviour in youth, regulatory warnings were issued in May 2004, and clinical recommendations on medical follow-up were published in November 2007. Our study aimed at assessing the association between these communication interventions and medical follow-up of children (age 10–14) and adolescents (age 15–19) who initiate an AD treatment. A retrospective cohort study (1998–2008) was conducted among youth members of the Quebec public drug plan. Study outcomes consisted of adequate follow-up practice, defined as at least 1 medical visit per month during the first 3 months of treatment. The effect of each intervention on follow-up practices was determined through multivariate logistic regression analysis. The cohort included 4576 children and 12,419 adolescents. Two thirds of both children and adolescents had at least one medical visit during the first trimester of treatment, but only 20% had a frequency of at least one visit per month (i.e. adequate). The occurrence and frequency of visits did not change after either the warning nor the publication of the guidelines. Further interventions designed to optimize monitoring practices should be envisaged. [Copyright &y& Elsevier]

Background Comorbidity scores based on medical or prescription claims data are frequently used to control for confounding in pharmacoepidemiological studies. Performance of such scores in predicting the risk of death in community-dwelling elderly adults may be compromised by the absence of mental health and socioeconomic characteristics not captured in claims data. Objective The aim of the study was to assess the impact of adding mental health status and sociodemographic characteristics to the Geriatric Comorbidity Score (GCS), a score derived from prescription claims data in the Quebec community-dwelling elderly population. Methods We used the cohort study from the longitudinal Quebec Seniors' Health Survey (n = 1,494) conducted between 2005 and 2006. For each participant, we obtained mental health and socioeconomic characteristics through validated questionnaires, which we linked with the medical and prescription claims databases of the Quebec Health Insurance Agency [Régie de l'assurance maladie du Québec (RAMQ)]. The main study outcome was death within 1 year, ascertained using the Quebec death registry. The GCS was calculated from prescription claims data, with the c statistic as a measure of performance. Using backward stepwise selection, external variables (marital status, region, family income, social support, daily hassles, perceived physical and mental health status, presence of mental health disorders) were added to the logistic regression model and the marginal effect assessed by comparing the c statistic with and without each covariate. Results Over 1 year, 77 deaths (5.15 %) were reported. The c statistic for the GCS was calculated as 0.67 (95 % confidence interval 0.64, 0.70). Addition of sex and age to the score yielded a 2.4 % increase. The variable with the greatest impact on the c statistic was marital status (6.1 % increase). Though important contributors, social support and perceived mental health status did not significantly improve performance of the score. Conclusions While sex, age and marital status significantly improved performance of a predictive score in the community-dwelling elderly population, the absence of data on mental and physical health status did not appear to compromise the validity of claims-based scores. Combining comorbidity scores with other methods to control for confounding thus remains a useful tool in pharmacoepidemiological research. [ABSTRACT FROM AUTHOR]

Background: Therapeutic risk management has received growing interest in recent years, particularly since the publication of regulatory guidances in 2005 and 2006, paralleled with a change in drug regulation. The characteristics of risk minimization interventions (RMIs) that have been implemented or approved remain inadequately explored.Objective: The aim of this study was to review RMIs published in the literature or posted on regulatory agency websites over the past 10 years, and to assess whether publication of regulatory guidances on risk management is associated with changes in the number and types of interventions.Methods: Sources were searched for RMIs published/posted between 1 January 2000 and 31 December 2009. For the literature search, MEDLINE and EMBASE databases were used using key words related to drug safety (i.e. 'drug toxicity') and the individual RMI names. The website review involved searches of major regulatory authority websites such as the European Medicines Agency, US FDA, Health Canada, the UK's Medicines and Healthcare products Regulatory Agency, Japan's Pharmaceutical and Medical Devices Agency and Australia's Therapeutic Goods Administration. The following eligibility criteria were applied for inclusion in the review: published/posted between the years 2000 and 2009, inclusive; involving drug products; use in humans; and involving RMIs, or tools used to increase the reporting of adverse events (AEs). Natural healthcare products, devices, diagnostic chemicals, pregnancy registries without follow-up, medication errors and products not used as therapy for illness were not retained. For each source, the following characteristics were extracted: nature of the intervention, target population, therapeutic area, AE(s) of special interest, country/regulatory agency and year of publication.Results: A total of 119 unique interventions were identified in the literature (54 published in 2000-4 and 65 published in 2005-9). Interventions included educational material (n = 37; 31%), black-box warnings (n = 22; 19%) and therapeutic drug monitoring (n = 11; 9%). The website review produced a total of 1112 interventions: 326 posted between the years 2000 and 2004, and 786 between the years 2005 and 2009. The main interventions observed were: educational material (n = 956; 86%), black-box warnings (n = 45; 4%) and withdrawals (n = 39; 4%).Limitations: Additional regulatory resource websites were available in the post-guidances periods that were not available in the earlier years of the pre-guidances periods, and may bias the post-guidances results. Also, not all global regulatory websites were searched. Finally, only English-language websites were searched, limiting the variation of RMIs observed. Classification and categorizing for this particular review may not be consistent with future reviews by other researchers.Conclusion: The US is the sole region with a substantial increase in published RMIs during the post-guidances period, while the EU, Japan and the US all indicated an increase in the number of interventions on their websites. [ABSTRACT FROM AUTHOR]

The article discusses a study on antipsychotic use and myocardial infarction (MI) in older patients with treated dementia. The researchers conducted a retrospective cohort of community-dwelling older patients who initiated cholinesterase inhibitor treatment between January 1, 2001 and December 31, 2009 using the Quebec, Canada prescription claims database. The results indicate that antipsychotic use is associated with a modest and time-limited increase in the risk of MI.

Abstract: Objective: The primary aim of this study was to compare the impact of risperidone long-acting injectable (R-LAI) to other antipsychotics on rates of hospitalisation in real-life settings. Method: The Cohort for the General study of Schizophrenia (CGS) followed 1859 patients diagnosed with schizophrenia (DSM-IV) from 177 psychiatric wards of public and private hospitals across France over a mean period of 12months. These patients were ambulatory or had been hospitalised for less than 93days at study entry. Recruitment was stratified for long-acting second-generation antipsychotic use. A multivariate Poisson regression adjusted for confounding with propensity scores and allowing for autocorrelation was used for the calculation of relative rates of hospitalisation with 95% confidence intervals. Results: The mean age of participants was 37.65years, 68.3% were male and 36.7% were hospitalised for less than 93days at study entry. Altogether, participants accumulated 796 hospital stays (53.4 per 100 person-years). R-LAI patients were slightly younger and had been hospitalised more often in the past 12months compared to non-R-LAI users. The adjusted Poisson regression analysis showed R-LAI use to be associated with a lower rate of future hospitalisation: 0.66 [0.46–0.96] compared to non-R-LAI use, and 0.53 [0.32–0.88] compared to use of other LAIs. Conclusion: Use of R-LAI was associated with lower rates of hospitalisation compared to non-use of R-LAI. [Copyright &y& Elsevier]

Background Sleep disturbances are frequently reported in the older adult population and benzodiazepines are the drugs most often prescribed to treat these problems. Nearly 25% of the older adult population uses these drugs and 83% of benzodiazepine users report sleep problems. Although the Collège des Médecins du Québec suggests a maximum length of use of 3 months, according to most studies the mean length of benzodiazepine use is longer. The goal of this study was to document the association between length of benzodiazepine use and sleep quality as reported by adults 65 years older and over. Methods Data used in this study came from the Seniors' Health Survey (ESA) conducted in a representative sample of the community-dwelling older population in Quebec, Canada. Inclusion criteria included the ability to speak and understand French. Data were analyzed using a structural equation modeling strategy. Results Long-term benzodiazepine users were more likely to report poor sleep quality. Sleep quality of initial probable problematic sleepers tended to increase over 1 year but sleep quality in benzodiazepines users increased less rapidly than in non-users. Also, women were more likely to report using benzodiazepines and having poorer sleep quality. Conclusion Longitudinal studies using incident cases of benzodiazepine use should be conducted to better determine the causal relationship between sleep quality and benzodiazepine use in the older population. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Background: Although for the great majority of indications, practice guidelines recommend that antidepressants (ADs) be used for at least 6 months, premature discontinuation is very frequent in a “real-life” setting. Previous studies have assessed the economic impact of such nonpersistence, but differences across antidepressant products remain inadequately explored. Objective: To compare treatment persistence and incremental cost/persistence ratios (ICPRs) across individual new ADs (selective serotonin reuptake inhibitors and atypical ADs) as well as the associated direct health-care costs in the adult population covered by the public drug program of Quebec. Methods: A retrospective cohort study was conducted in 13,936 adults aged 18 to 64 years who started an AD treatment in 2003. Persistence was defined as treatment duration of at least 6 months regardless of whether a product switch had occurred. Economic impact was assessed over the first year of treatment through drug, medical services, hospitalization, and total health-care costs. Comparisons across products were conducted using the ICPR. Results: Adjusting for confounders, treatment nonpersistence ranged from 60.4% (paroxetine) to 65.1% (citalopram). The product associated with the highest total health-care costs was citalopram (CDN$2653) and the lowest was venlafaxine (CDN$2168). Fluvoxamine had the lowest mean AD costs (CDN$215) and venlafaxine (CDN$309) the highest. Conclusions: Total health-care costs were similar across products except for citalopram, which was more costly. Comparisons based on the ICPR revealed that paroxetine, fluoxetine, and venlafaxine were more favorable than the other AD alternatives. [Copyright &y& Elsevier]

Case series and case reports are a cornerstone of drug safety research; however, the characteristics of case series published in the literature remain poorly examined. A narrative review of case series addressing drug safety, published in the literature between 1 January 2003 and 15 July 2009, and identified through a PubMed search, was conducted in order to determine their characteristics and quality according to the criteria found in the US FDA Pharmacovigilance Guidance 2005. Of 130 publications that met the search criteria, 11.5% included an analytical component and 88.5% were descriptive. The median number of cases included in a given case series was 7 (range 2-2195) and the median time period for recruitment of the cases was 23 months (range 0.5-96). Overall, 43.1% of case series consisted of individual case reports, while 24.6% originated from cohorts and 21% from pharmacovigilance databases. Of the case series, 65.1% concerned adults (age ≥18 years), 11.6% elderly (age ≥65 years) and 8.5% youth (<18 years). Adverse effects involved mainly the skin (18.5%) and the circulatory system (13.8%). The main suspected drug classes (Anatomical Therapeutic Chemical classification) were nervous system drugs (23.1%) and antineoplastic and immunomodulating agents (20.0%). On average, six out of the possible nine US FDA Pharmacovigilance Guidance Criteria were fulfilled, with 27% of publications fulfilling at least seven criteria. Only 10% reported data on co-morbidity. In conclusion, this review highlights the reporting gaps and heterogeneity in published case series with respect to size, recruitment period and quality. [ABSTRACT FROM AUTHOR]

Background: About 50% of the elderly population report being dissatisfied with their sleep. Although benzodiazepines are the most prescribed drugs to treat sleep complaints, the effectiveness of their use on the quality of sleep is not well documented. Objectives: This study aimed to assess the association between benzodiazepine use and global sleep quality, as well as six components of sleep quality. Methods: Data from the cross-sectional Quebec Survey on Seniors' Health (n = 2798) conducted in 2005-2006 were used. Quality of sleep was self-reported and use of benzodiazepines was assessed during the previous year. Results: Benzodiazepine users reported poorer quality of sleep than non-users. The association between benzodiazepine use and each of the six quality of sleep components studied were similar except for the daytime dysfunction component. Conclusion: The results suggest that there is no evidence that using benzodiazepines is associated with better quality of sleep than non-users in the elderly population. Future longitudinal population-based studies are needed to assess improvements in quality of sleep in the elderly associated with the use of benzodiazepines. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Determining bacterial aetiology of acute sinusitis is difficult without employing invasive procedures. • Most episodes of acute sinusitis resolve spontaneously. • Antibiotics have demonstrated efficacy for the treatment of acute bacterial sinusitis in clinical trials yet little is known of their effectiveness in real-life treatment settings. WHAT THIS STUDY ADDS • Most cases of untreated acute sinusitis resolved spontaneously. Antibiotics were more effective when given within the first 10 days of treatment. This had no effect on later recurrence. • Patients with poor oro-dental condition or recent antibiotic use may derive the most benefit from an antibiotic prescription and this should be considered by prescribers. • The antibiotics used were found to be equally effective. • Existing recommendations to identify acute sinusitis with high probability of bacterial origin, such as the French recommendations, fever or duration of symptoms fail to identify patients in whom antibiotics are more effective. AIMS To assess the effectiveness of antibiotics in acute bacterial sinusitis. METHODS This was a prospective cohort study with 2 months follow-up of 5640 patients with acute sinusitis included by a random sample from 1174 GPs and 120 ENT specialists. Main outcomes were short-term initial success, defined as the absence of prescription of (another) antibiotic or sinus lavage within 10 days, and lack of recurrence between the 11th and 60th day, after initial success. RESULTS Initial success was found in 88.7% (95% CI 85.1, 91.4%) of patients without antibiotic prescription at inclusion and 96.2% (95% CI 95.7, 96.7%) of patients prescribed antibiotics. The 10 day adjusted hazard ratio (HR) for treatment failure (new antibiotic prescription or sinus drainage) with initial antibiotics compared with no antibiotics was 0.30 (95% CI 0.21, 0.42) with no difference between antibiotics. Antibiotics were more effective in patients with poor oro-dental condition (HR 0.04, 95% CI 0.01, 0.20) and in patients who had already used antibiotics during the previous 2 months (HR 0.09, 95% CI 0.03, 0.28). For patients without failure at 10 days, recurrence between the 11th and 60th day was similar whether or not they had initially been prescribed an antibiotic, 94.1% (95% CI 93.4, 94.7%) and 93.4% (95%CI 90.3, 95.5%), respectively. CONCLUSION Most acute sinusitis cases not prescribed antibiotics resolve spontaneously. Antibiotics reduced by 3.3-fold the risk of failure within 10 days, without impact on later recurrence. The greatest benefit of antibiotics was found for patients with poor oro-dental condition or with antibiotic use within the previous 2 months. [ABSTRACT FROM AUTHOR]

Abstract: Antidepressants are highly prescribed in youth although most products have not been approved for use in this population. Furthermore, regulatory warnings have led to changes in antidepressant use that might have differed across various countries. Our study aimed at determining factors associated with antidepressant prescribing practices and at assessing trends in use from 1997 to 2005 in Quebec youth.A retrospective cohort study was conducted through claims databases of the Quebec public health care program (RAMQ). The study included 5094 children (age 2–14) and 11,121 adolescents (age 15–19) who were incident users of antidepressant between 1997 and 2005. The characteristics of users and prescribers were the main independent variables.Tricyclics were the most frequently dispensed products among children (50.9%) and selective serotonin reuptake inhibitors among adolescents (58.8%). Selection of an antidepressant class was associated with patient characteristics and with prescriber specialty. The number of antidepressant users increased from 1997 until 2001 then decreased thereafter.The selection of an antidepressant class was associated with clinical and non-clinical characteristics. Although antidepressant use decreased after regulatory warnings, there appears to be a care gap between the evidence generated by efficacy studies and the products prescribed in a real-life setting. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Traditional or COX-2-specific (coxib) nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used. • Their use is associated with gastrointestinal toxicity and cardiovascular events. WHAT THIS STUDY ADDS • The low event rates observed for gastrointestinal bleeding and myocardial infarction in the real-life conditions of NSAID use (traditional and coxib) in France preclude their exploration using realistic field studies. • Large population healthcare databases are required to study such risks. AIMS To assess hospital admission rates for gastrointestinal (GI) or cardiovascular (CV) events in real-life use of nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS CADEUS is a real-life population-based cohort study of 23 535 coxib (celecoxib or rofecoxib) and 22 919 traditional NSAID (tNSAID) users. Each hospitalization reported between index day (NSAID delivery) and questionnaire submission (median = 75 days) was explored using hospital discharge summaries. An expert committee validated blindly serious GI and CV events according to predefined criteria. RESULTS Coxib users were older and had more GI history than tNSAID users. There were 21 hospitalizations for GI events, 12 in the coxib cohort and nine in the tNSAID cohort (respectively one and three upper GI haemorrhages and no ulcer perforations). Rates of GI events were 0.39 per 1000 patients [95% confidence interval (CI) 0.18, 0.75] for tNSAID users and 0.51 per 1000 patients (95% CI 0.26, 0.89) for coxib users. There were 21 hospitalizations for CV events, 13 in the coxib cohort and eight in the tNSAID cohort. None was fatal. Rates of CV events were, respectively, 0.59 (95% CI 0.24, 1.22), 0.51 (95% CI 0.19, 1.11) and 0.35 (95% CI 0.15, 0.69) per 1000 patients for celecoxib, rofecoxib and tNSAIDs. GI or CV event rates were not different between products even for patients >60 years old. CONCLUSIONS Hospitalization rates for GI bleeding were 10–20 times lower than expected from published randomized clinical trials, probably because of differences in drug usage and concomitant gastroprotection. CV event rates conformed to those expected from general population data. These results emphasize the necessity of developing population healthcare databases to explore such low event rates. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • To our knowledge, no study has ever described the intensity of nonsteroidal anti-inflammatory drug (NSAID) utilization in an employed population by occupation. • As the use of NSAIDs carries a well-known risk of adverse effects, this risk adds to the burden of musculoskeletal disorders in employed populations. • Information on utilization of NSAIDs in this context will help to better characterize and prevent this risk. WHAT THIS STUDY ADDS • In spite of a previous history of dyspepsia, blue collar workers had the highest rate of chronic and continuous utilization of nonselective NSAIDs. • No clustering of cyclooxygenase-2 selective NSAID utilization according to a previous history of dyspepsia was observed among blue collar workers. • The association between chronicity of NSAID utilization and occupation was independent of medical indication for the prescription and other lifestyle factors. AIM The aim of this study was to compare patterns of utilization of NSAIDs for musculoskeletal disorders (MSD) by occupation in a general employed population. METHODS This was a secondary analysis of the CADEUS cohort study on 5651 actively employed patients, who submitted at least one claim for the reimbursement of a NSAID dispensation for a MSD between August 2003 and July 2004, in the French National Healthcare Insurance database. Questionnaires were sent to prescribing physicians to obtain diagnoses and the medical history, and to patients for their occupation, height and weight and smoking status. Multivariate logistic regression was used to study the determinants of a heavy use of NSAIDs defined as ‘over four dispensations in one year with less than two months between any two’. RESULTS Factors associated with heavy use of NSAIDs were age (Odds ratio (OR): 1.8 (ten years), 95% confidence interval (CI): 1.6–1.9), osteoarthritis (versus back pain) (OR: 1.8, 95% CI: 1.5–2.1), body mass index (superior to 30) (OR: 1.8, 95% CI: 1.5–2.2), and occupation (blue collar versus white collar workers) (OR: 1.4, 95% CI: 1.2–1.6). Blue collar workers also had a 20% higher prevalence of 5-year history of dyspepsia. No difference was observed between sexes or in the use of COX-2 selective inhibitors between occupations. CONCLUSION Factors associated with occupational constraints that contribute to the severity of MSDs, may explain the heavier use of NSAIDs among blue collar workers in spite of a concurrent and past medical history of adverse reactions to this type of medication. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine whether prevalent delirium is an independent predictor of mortality in older patients seen in emergency departments (EDs) and discharged home without admission. DESIGN: Prospective study with 18 months of follow-up. SETTING: EDs in two Montreal hospitals. PARTICIPANTS: From a cohort study of prognosis for delirium (107 delirious and 161 nondelirious subjects), 30 delirious and 77 nondelirious subjects aged 66 and older who were discharged home without admission were identified. MEASUREMENTS: Detailed interviews with patients and their proxies and review of medical charts were performed at enrollment. Trained lay interviewers determined delirium status using the Confusion Assessment Method. Subjects were followed up at 6-month intervals for a total of 18 months. Dates of death were obtained from the Ministère de la Santé et des Service Sociaux (Ministry of Health and Social Services). Survival analysis was performed using the Cox proportional hazards modeling adjusting for potential confounding variables. RESULTS: The analysis revealed a statistically significant association between delirium and mortality after adjustments for age, sex, functional level, cognitive status, comorbidity, and number of medications for the first 6 months of follow-up (hazard ratio = 7.24; 95% confidence interval = 1.62–32.35). The subjects whose delirium was not detected by the ED physician or nurse had the highest mortality over 6 months (30.8%). The mortality of delirious subjects detected in the ED was similar to that of the nondelirious subjects (11.8 vs 14.3%). CONCLUSION: The results of this study suggests that nondetection of delirium in the ED may be associated with increased mortality within 6 months after discharge. Further research is necessary to examine the effectiveness of improving detection on subsequent prognosis of older patients with delirium. [ABSTRACT FROM AUTHOR]

Background: Various drugs have been approved for the treatment of Alzheimer''s disease (AD) in the United States and Canada, including donepezil and rivastigmine, although questions remain as to their efficacy, effectiveness, and long-term benefits.Objective: The goal of this study was to conduct a best-evidence synthesis of data on the efficacy and cost-effectiveness of donepezil and rivastigmine in the treatment of AD.Methods: Relevant published randomized controlled trials (RCTs) and Phase IV open-label extension studies (excluding abstracts) were identified through searches of MEDLINE, HealthSTAR, and PsycINFO for the period January 1984 to October 2001. The bibliographies of retrieved articles were searched for additional publications. For inclusion in the best-evidence synthesis, clinical trials had to pass a blinded quality assessment (score ≥5 on the Jadad scale) and use National Institute of Neurological and Communicative Disease and Stroke—Alzheimer''s Disease and Related Disorders Association diagnostic criteria. Economic studies were selected using National Health Service Centre for Reviews and Dissemination criteria for reporting critical summaries of economic evaluations.Results: Nine RCTs of donepezil and 2 of rivastigmine were identified and met inclusion criteria for the best-evidence synthesis. Eight donepezil trials and both rivastigmine trials included patients with mild AD (Mini—Mental State Examination [MMSE] score, 15–27) or moderate AD (MMSE score, 8–14); 1 donepezil trial included patients with moderate or severe AD (MMSE score, 0–7). In the RCTs of donepezil, the mean decrease in scores on the Alzheimer''s Disease Assessment Scale—cognitive subscale (ADAS-cog) was greater with active treatment than with placebo (lower scores indicate less cognitive deterioration). In the RCTs of rivastigmine, ADAS-cog scores decreased over the follow-up period with both active treatment and placebo; however, scores decreased more with active treatment. Three Phase IV studies of donepezil and 1 Phase IV study of rivastigmine were identified. Their results were consistent with those of the RCTs. Ten economic studies (7 donepezil, 3 rivastigmine) were identified and reviewed. In 4 of the donepezil studies and all 3 rivastigmine studies, use of the drug cost less than a no-drug strategy.Conclusions: The efficacy data indicate that both donepezil and rivastigmine can delay cognitive impairment and deterioration in global health for at least 6 months in patients with mild to moderate AD. Patients receiving active treatment will have more favorable ADAS-cog scores for at least 6 months, after which their scores will begin to converge with those of patients receiving placebo. Differences in methodology, types of direct or indirect costs included, and sources of cost data made it difficult to compare and synthesize findings of the economic studies; therefore, the cost-effectiveness data are inconclusive. [Copyright &y& Elsevier]

The objective of this article was to examine the possible association between benzodiazepine use and the risk of dementia in the elderly. This was a nested case–control study set in community settings in Bordeaux area, France. The participants were a representative sample of 3,777 elderly persons (65 years of age and older) followed from 1989 to 1997. The main outcome measures were the use of benzodiazepines in incident cases of dementia versus nondemented controls. On the basis of medical and psychological data, 150 patients were diagnosed with dementia according to the criteria of the third revision of the Diagnostic and Statistical Manual of Mental Disorders. Information on benzodiazepine use was obtained by face-to-face interview and visual assessment of patient''s medicine chest by a trained neuropsychologist. After controlling for age, gender, education level, living alone, wine consumption, psychiatric history, and depressive symptomatology, ever use of benzodiazepines was associated with a significantly increased risk of dementia [adjusted odds ratio (OR), 1.7; 95% confidence interval, 1.2–2.4]. Former use was associated with a significantly increased risk of dementia (adjusted OR, 2.3; 95% CI,1.2–4.5). No association was found between dementia and the current use of benzodiazepines (adjusted OR, 1.0; 95% CI, 0.6–1.6). Our finding suggest that former use of benzodiazepines could be a risk factor for dementia, but more detailed investigation are needed. [Copyright &y& Elsevier]

Convulsive status epilepticus (CSE) is a life-threatening neurologic emergency, which is defined by the International League Against Epilepsy (ILAE) as bilateral tonic–clonic seizure activity lasting longer than 5 min, while absence status epilepticus (SE) and focal SE are specified as exceeding 10 min. Epidemiological evidence on SE is currently lacking, and the incidence is not well-known, especially in light of changes in the ILAE criteria for SE. The objectives of this systematic literature review were to describe the epidemiology of SE in the US population and the associated burden of illness. A systematic review, including literature and pragmatic searches, was conducted. Literature searches were performed using MEDLINE, Embase, BIOSIS, and Web of Science electronic databases from inception to February 2019. Pragmatic searches of the gray literature were carried out using Google, Google Scholar, conference proceedings, and ClinicalTrials.gov to identify additional sources. Only US-based studies or multinational studies reporting US data of interest were included. In total, 69 sources were identified. The incidence of all SE in patients of all ages in the USA ranged from 18.3 to 41 per 100,000 people per year. Incidence of all-age CSE rose from 3.5 (1979) to 12.5 (2010) per 100,000 people per year. Status epilepticus incidence followed a bimodal (U-shaped) distribution, with the highest estimates in the first years of life (0–4 years) and after 60 years. Mortality associated with SE varied from 21% over 30 days to 31.2% over 10 years. For CSE, two studies reported similar in-hospital mortalities (9.2% and 10.7%). Median healthcare costs related to SE admission were approximately US$14,500 per adult (17–45 years) and US$8000 per child (0–16 years). There is a lack of recent data on the epidemiology and healthcare burden associated with SE. Reports of SE incidence in the USA are highly variable and predate the 2015 ILAE definition of SE. However, the available data suggest a high burden of illness. • There is a lack of recent data on the epidemiology and burden of status epilepticus. • The incidence of status epilepticus in the USA is 18.3–41/100,000 people per year. • The variable incidence rates of status epilepticus predate the 2015 ILAE definition. • Available data suggest a high burden of illness. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on the role of antipsychotic agents in causing myocardial infarction.

Presents a letter to the editor about the delusion of reducing sample size in clinical trials.

Background:Recent evidence suggests that proton pump inhibitors (PPIs) might be linked with adverse cardiac events, but a causal relationship is unproven. Methods:We applied the self-matched case series method to two studies using population-based health care data from Ontario, Canada between 1996 and 2008. The first included subjects aged 66 years or older hospitalized for acute myocardial infarction within 12 weeks following initiation of PPI, while the second included subjects hospitalized for heart failure. In both studies we designated the primary risk interval as the initial 4 weeks of therapy and the control interval as the final 4 weeks. To test the specificity of our findings we examined use of histamine H2 receptor antagonists and benzodiazepines, drugs with no plausible causal link to adverse cardiac events. Results:During the 13-year study period, we identified 5550 hospital admissions for acute myocardial infarction and 6003 admissions for heart failure within 12 weeks of commencing PPI therapy. In the main analyses, we found that initiation of a PPI was associated with a higher risk of acute myocardial infarction (odds ratio 1.8; 95% confidence interval 1.7 to 1.9) and heart failure (odds ratio 1.8; 95% confidence interval 1.7 to 1.9). However, secondary analyses revealed similar risk estimates histamine H2 receptor antagonists and benzodiazepines, drugs with no known or suspected association with adverse cardiac events. Conclusion:PPIs are associated with a short-term risk of adverse cardiac events, but similar associations are seen with other drugs exhibiting no known cardiac toxicity. Collectively these observations suggest that the association between PPIs and adverse cardiac events does not represent reflect cause-and-effect. [ABSTRACT FROM AUTHOR]