Lauren C. Bresee

A review of pharmacoepidemiologic studies of antipsychotic use in children and adolescents.

Objective: In Canada, treatment of children and adolescents with antipsychotics is almost always off label. A single atypical agent, aripiprazole, only recently received regulatory authorization for use in the group aged 15 to 17 years. This regulatory approval was restricted to treatment of schizophrenia. The objective of this review was to summarize pharmacoepidemiologic reports examining the frequency of use of these medications. Methods: A literature search was used to identify English-language studies examining the pharmacoepidemiology of antipsychotics in children and adolescents. The results of identified studies were summarized using narrative review methods. Results: In countries where longitudinal data are available, increased antipsychotic use has been consistently observed. Generally, most or all of this increase can be attributed to second-generation antipsychotics (SGAs). Major international differences are evident in the literature. European studies describe lower overall frequencies of use than North American studies (most of which were conducted in the United States). SGAs in children and adolescents are used more often in boys than in girls, and are increasingly used for treatment of attention-deficit hyperactivity disorder (ADHD) and conduct disorder (CD). Conclusions: Determining the most appropriate frequency of SGA use in children and adolescents will ultimately depend on decisive clarification of risks and benefits. The currently available literature highlights large international differences in the frequency of use. These differences may reflect fundamental dissimilarities in the therapeutic stance adopted toward ADHD and CD by physicians practicing in different countries.

Association Between GFR, Proteinuria, and Adverse Outcomes Among White, Chinese, and South Asian Individuals in Canada

BACKGROUND We investigated the association between proteinuria, estimated glomerular filtration rate (eGFR), and risk of mortality and kidney failure in white, Chinese, and South Asian populations. STUDY DESIGN Population-based cohort study. SETTING & PARTICIPANTS Participants from Alberta, Canada, with a serum creatinine and urine protein dipstick measurement from January 1, 2005, to December 31, 2005. PREDICTOR White, Chinese, or South Asian ethnicity. OUTCOMES Prevalence of proteinuria by level of eGFR (estimated using the MDRD [Modification of Diet in Renal Disease] Study equation) and the association between eGFR, proteinuria, and all-cause mortality and kidney failure. MEASUREMENTS Rates of all-cause mortality and kidney failure per 1,000 person-years were calculated using Poisson regression by ethnicity, eGFR level, and proteinuria level while adjusting for sociodemographic variables and comorbid conditions. RESULTS Of 491,729 participants, 5.3% were Chinese and 4.7% were South Asian. For participants with eGFR <60 mL/min/1.73 m(2), the prevalence of heavy proteinuria was higher in Chinese and South Asians compared with whites. Compared with whites, adjusted rates of death were significantly lower for Chinese and South Asian populations (rate ratios, 0.67 [95% CI, 0.56-0.80] and 0.73 [95% CI, 0.59-0.88], respectively); these rate ratios did not vary by eGFR and proteinuria levels. LIMITATIONS Using surname to identify ethnicity has the potential for misclassification due to name changes and identical last names from different ethnic groups. Also, to be eligible for inclusion, participants had to have a measurement of serum creatinine and urine dipstick proteinuria. CONCLUSIONS Although increasing proteinuria and lower eGFR predicted mortality and progression to kidney failure in all 3 ethnic groups, both Chinese and South Asian populations experienced a lower risk of death and similar risk of kidney failure compared with whites at all eGFR and proteinuria levels. Studies exploring this association further are required.

Substantial changes in prescription recommendations for bipolar disorder in Canada: 2002-2010.

Objectives: We examined trends in prescription recommendations for treatment of bipolar disorder (BD) in Canada during 2002–2010. Methods: Data collected by IMS Brogan in a database known as the Canadian Disease and Therapeutic Index were used for this analysis. These data are collected from a representative physician panel who record each drug recommendation and reason for recommendation in their practices for 2 consecutive days each calendar quarter of the year. Prescription patterns of medications for BD, including lithium, anticonvulsants, antipsychotic agents, anxiolytics, and antidepressants, were evaluated both for general practitioners and for specialists. Results: The number of prescription recommendations for BD increased by 72.1% from 2002 to 2009, and then dropped by 24.8% from 2009 to 2010. This increase from 2002 to 2009, and subsequent decrease from 2009 to 2010, was observed for all classes of medications. The overall increase from 2002 to 2010 was statistically significant for the atypical antipsychotics (P = 0.04). The largest change for an individual drug during this period was a 438% increase in recommendations for quetiapine (P = 0.01). Conclusions: The number of prescription recommendations for BD increased substantially from 2002 to 2009 and sharply dropped in the following year. These results suggest that the infuence of the concept of the bipolar spectrum and its promotion may have resulted in a substantial increase in treatment that has recently begun to wane.

Second-Generation Antipsychotics and Metabolic Side Effects: A Systematic Review of Population-Based Studies

IntroductionThere is strong evidence from randomized controlled trials (RCTs) that second-generation antipsychotic (SGA) medications are associated with metabolic adverse events. However, with the recent increases in the use of SGAs worldwide and frequent off-label use, it is unclear whether these associations are generalizable to populations beyond those included in RCTs.ObjectivesThis review aims to characterize the impact of SGAs on the population through a systematic review of population-based studies of SGA users. Studies could examine the use of any SGA medication and any comparator group. Studies also needed to include at least one metabolic outcome such as type 2 diabetes mellitus, dyslipidemia, obesity, hypertension, or metabolic syndrome.MethodsA systematic search process was used to identify studies for inclusion in this review. Included studies had to be population-based studies of users of any SGA medication with at least one reported metabolic outcome. Study quality was also assessed using the AMSTAR tool, and evidence was synthesized by both metabolic outcome and specific SGA medication.ResultsIn total, 15 studies were included in this review. Type 2 diabetes mellitus was the most frequently reported outcome; clozapine and olanzapine were most strongly associated with type 2 diabetes mellitus. Evidence was mixed for a moderate association between type 2 diabetes mellitus and risperidone or quetiapine. Few studies examined other metabolic outcomes, and therefore it is difficult to estimate the true effect in the population.DiscussionPopulation-based evidence for other SGAs and metabolic outcomes was limited. However, clozapine and olanzapine were consistently more strongly associated with metabolic adverse events than were other SGAs currently available.

Utilization of general and specialized cardiac care by people with schizophrenia.

OBJECTIVE Whether access to primary and specialist care has an impact on treatment for people with schizophrenia and comorbid cardiac disease is unclear. The objective of this study was to compare use of general health care and specialized cardiac care by people with schizophrenia and by the rest of the population. METHODS A population-based period-prevalence study was conducted and included adults (N=2,310,391) in Alberta, Canada, by using administrative databases. People with schizophrenia were identified based on billing codes; all others served as the comparator cohort. Multivariable logistic regression analyses were conducted to compare claims for general (general practitioner visits) health care, urgent and emergent (emergency department visits and hospitalizations) health services, and specialized cardiac (cardiologist visits, revascularization) care. RESULTS Individuals with schizophrenia (N=28,755) had a higher prevalence of coronary artery disease than those without schizophrenia (N=2,281,636) (20% versus 14%) and were more likely than those without schizophrenia to visit a general practitioner more than four times per year (76% versus 47%; adjusted odds ratio [AOR]=3.60, 95% confidence interval [CI]=3.49-3.71). In contrast, individuals with schizophrenia and coronary artery disease were less likely to visit a cardiologist (50% versus 59%; AOR=. 76, 95% CI=.72-.80) or undergo coronary revascularization (6% versus 12%; AOR=. 55, 95% CI=.49-.61). CONCLUSIONS In this large population-based study, individuals with schizophrenia were less likely to visit cardiologists or undergo revascularization than were people without schizophrenia. Opportunities exist for better assessment and management of cardiovascular disease and risk factors among people with schizophrenia.

Likelihood of coronary angiography among First Nations patients with acute myocardial infarction

Background: Morbidity due to cardiovascular disease is high among First Nations people. The extent to which this may be related to the likelihood of coronary angiography is unclear. We examined the likelihood of coronary angiography after acute myocardial infarction (MI) among First Nations and non–First Nations patients. Methods: Our study included adults with incident acute MI between 1997 and 2008 in Alberta. We determined the likelihood of angiography among First Nations and non–First Nations patients, adjusted for important confounders, using the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) database. Results: Of the 46 764 people with acute MI, 1043 (2.2%) were First Nations. First Nations patients were less likely to receive angiography within 1 day after acute MI (adjusted odds ratio [OR] 0.73, 95% confidence interval [CI] 0.62–0.87). Among First Nations and non–First Nations patients who underwent angiography (64.9%), there was no difference in the likelihood of percutaneous coronary intervention (PCI) (adjusted hazard ratio [HR] 0.92, 95% CI 0.83–1.02) or coronary artery bypass grafting (CABG) (adjusted HR 1.03, 95% CI 0.85–1.25). First Nations people had worse survival if they received medical management alone (adjusted HR 1.38, 95% CI 1.07–1.77) or if they underwent PCI (adjusted HR 1.38, 95% CI 1.06–1.80), whereas survival was similar among First Nations and non–First Nations patients who received CABG. Interpretation: First Nations people were less likely to undergo angiography after acute MI and experienced worse long-term survival compared with non–First Nations people. Efforts to improve access to angiography for First Nations people may improve outcomes.

Serotonin-Norepinephrine Reuptake Inhibitors and the Risk of AKI: A Cohort Study of Eight Administrative Databases and Meta-Analysis

BACKGROUND AND OBJECTIVES A safety signal regarding cases of AKI after exposure to serotonin-norepinephrine reuptake inhibitors (SNRIs) was identified by Health Canada. Therefore, this study assessed whether the use of SNRIs increases the risk of AKI compared with selective serotonin reuptake inhibitors (SSRIs) and examined the risk associated with each individual SNRI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Multiple retrospective population-based cohort studies were conducted within eight administrative databases from Canada, the United States, and the United Kingdom between January 1997 and March 2010. Within each cohort, a nested case-control analysis was performed to estimate incidence rate ratios (RRs) of AKI associated with SNRIs compared with SSRIs using conditional logistic regression, with adjustment for high-dimensional propensity scores. The overall effect across sites was estimated using meta-analytic methods. RESULTS There were 38,974 cases of AKI matched to 384,034 controls. Current use of SNRIs was not associated with a higher risk of AKI compared with SSRIs (fixed-effect RR, 0.97; 95% confidence interval [95% CI], 0.94 to 1.01). Current use of venlafaxine and desvenlafaxine considered together was not associated with a higher risk of AKI (RR, 0.96; 95% CI, 0.92 to 1.00). For current use of duloxetine, there was significant heterogeneity among site-specific estimates such that a random-effects meta-analysis was performed showing a 16% higher risk, although this risk was not statistically significant (RR, 1.16; 95% CI, 0.96 to 1.40). This result is compatible with residual confounding, because there was a substantial imbalance in the prevalence of diabetes between users of duloxetine and users of others SNRIs or SSRIs. After further adjustment by including diabetes as a covariate in the model along with propensity scores, the fixed-effect RR was 1.02 (95% CI, 0.95 to 1.10). CONCLUSIONS There is no evidence that use of SNRIs is associated with a higher risk of hospitalization for AKI compared with SSRIs.

Assessment of Serum Creatinine and Kidney Function among Incident Metformin Users

OBJECTIVE Metformin is considered the first-line antihyperglycemic therapy for type 2 diabetes, but should be used with caution in people with renal insufficiency. Our study objective was to describe the proportion of patients who have an assessment of kidney function (serum creatinine [SCr] and estimated glomerular filtration rate [eGFR]) around the time of initiation of metformin in new users. METHODS We used data from the Alberta Kidney Disease Network to identify patients with diabetes (age, ≥66 y) with a new prescription for metformin from November 1, 2002, to March 31, 2008. We assessed whether SCr measurement was completed before and after metformin initiation. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and categorized into CKD stages. Frequency of metformin use based on SCr measurement and CKD stage was reported using descriptive statistics. RESULTS A total of 22 051 subjects were identified as new metformin users. Overall, 25.4% (n=5608) had no measurement of SCr or assessment of eGFR before metformin prescription. In addition, of patients with an eGFR measurement, 38.7% (n=8544) of individuals had an eGFR of less than 60 mL/min/1.73 m(2). CONCLUSIONS One quarter of patients started on metformin did not have a SCr measurement completed beforehand. Also, metformin was used commonly among patients with diabetes and CKD, potentially putting these individuals at risk for adverse events.

Second-generation antipsychotics and metabolic side-effects: Canadian population-based study

Background Use of second-generation antipsychotics (SGA) has increased in recent years; however, their use and effect on metabolic outcomes has been poorly characterised in population-level studies. Aims This study aimed to determine the associations between SGA use and metabolic indicators in a general population. Method We used data from the Canadian Health Measures Survey, a cross-sectional survey of Canadian households. Participants were Canadians aged 3–79 years, living in one of the ten provinces. Several metabolic indicators were examined, including weight, body mass index, waist circumference, hypertension, diabetes and two definitions of metabolic syndrome. Results The proportion of Canadians taking an SGA tripled over the study period. SGA use was significantly associated with hypertension (odds ratio 1.94, 95% CI 1.07–3.55) and abdominal obesity in adults, as defined by the National Cholesterol Education Program–Adult Treatment Panel III (odds ratio 2.62, 95% CI 1.45–4.71). Conclusions Evidence of metabolic dysfunction with SGAs is seen in the Canadian population, along with a rapid increase in prevalence of use since 2007. Declaration of interest None.

Frequency of and Risk Factors for Acute Kidney Injury Associated With Vancomycin Use in the Pediatric Intensive Care Unit

BACKGROUND: Published information evaluating frequency of and risk factors for vancomycin-induced acute kidney injury (AKI) in the pediatric intensive care unit (PICU) population is conflicting. OBJECTIVES: The primary objective was to describe the proportion of our PICU patients who developed AKI with intravenous (IV) vancomycin. The secondary objective was to describe the associated potential risk factors. METHODS: Pediatric patients (0-18 years) who received their first IV vancomycin dose in the PICU were evaluated in this retrospective chart review. AKI was defined based on Pediatric-Modified RIFLE (pRIFLE) criteria. Patient demographics, vancomycin trough concentrations, concomitant nephrotoxins, and estimated creatinine clearance changes were analyzed. RESULTS: Of 265 patients included, the primary outcome of AKI (defined by meeting any pRIFLE criteria) occurred in 62 (23.4%) patients (48 category R, 11 category I, 3 category F). Patients who received vancomycin treatment for = 5 days were more likely to develop AKI (unadjusted odds ratio [uOR]: 2.52; 95% confidence interval [CI]: 1.11-5.73), as were patients with a maximum vancomycin trough level = 20 mg/L (OR: 2.99; 95% CI: 1.54-5.78) and patients on 1 (uOR: 2.29; 95% CI: 1.12-4.66) or more concurrent nephrotoxin (uOR: 3.11; 95% CI: 1.43-6.77). Among nephrotoxins, patients receiving furosemide concomitantly with vancomycin were more likely to develop AKI (uOR: 3.47; 95% CI: 1.92-6.27). After adjustment, only furosemide was a significant predictor of risk of AKI/AKI (adjusted OR: 3.52; 95% CI: 1.88-6.62). The study was limited by its retrospective and observational design, and confounding variables. CONCLUSIONS: Patients who were receiving vancomycin with concurrent furosemide were at highest risk of developing AKI.