Susan E. Bronskill

Antipsychotic Drug Use and Mortality in Older Adults with Dementia

Context Recent reports suggest that antipsychotics are associated with increased risk for death in patients with dementia. Contribution This large, population-based study from Canada assessed the risk for death after dispensation of antipsychotics in older adults with dementia. New use of antipsychotics compared with nonuse was associated with increased risk for death at 30 days. Conventional agents were associated with higher risks than were atypical agents. Caution Sensitivity analyses showed that unmeasured confounders might diminish or erase observed associations. Implication Both conventional and atypical antipsychotics may be associated with an increased risk for death in elderly persons with dementia. The Editors Various challenging behavioral and psychological symptoms commonly develop in older adults with dementia and predispose them and their caregivers to poor outcomes (1). Nonpharmacologic strategies are recommended as first-line management for these symptoms (2), but they may be difficult to implement in clinical practice (3). For many reasons, antipsychotic medications are routinely prescribed in this setting (4, 5). Conventional antipsychotics, such as haloperidol, have been available since the 1950s. Meta-analyses of clinical trials evaluating conventional antipsychotics to treat agitation in dementia show that these agents have modest efficacy and important adverse effects compared with placebo (6, 7). In the past decade, use of newer atypical antipsychotics has been rapidly increasing in clinical practice because these agents were thought to produce fewer adverse effects than conventional agents (2). A Canadian study found that the prevalence of antipsychotic use in older adults increased from 2.2% in 1993 to 3.0% at the end of 2002. In that study, atypical antipsychotics, which were unavailable in 1993, accounted for 82.5% of all antipsychotics dispensed in 2002 (8). Short-term randomized, controlled trials (RCTs) have studied the role of atypical antipsychotics in the management of behavioral and psychological symptoms of dementia (2, 9). An RCT involving 421 outpatients with Alzheimer disease and psychosis, aggression, or agitation concluded that the adverse effects of these newer drugs offset their advantages (10). As a result, improvements in behavioral symptoms with antipsychotic drug treatment do not necessarily lead to improvements in overall quality of life for patients or their caregivers (11). In April 2005, the U.S. Food and Drug Administration (FDA) issued a public health advisory that the use of atypical antipsychotics to treat elderly patients with dementia was associated with an increased risk for death compared with placebo (12). In June 2005, Health Canada issued a similar warning and additional data (13). These warnings stem from reviews of RCTs that involve the atypical agents risperidone, olanzapine, quetiapine, and aripiprazole. The mortality rate was approximately 1.6 to 1.7 times higher than with placebo and was greater with antipsychotics than with placebo in 15 of the 17 trials reviewed by the U.S. FDA (12). The warnings extend to all currently available atypical antipsychotics. Other publications have provided support for these warnings and have raised further safety concerns about older conventional antipsychotics (1416). Important questions remain unanswered. Although RCTs provide the best evidence of treatment efficacy and harm, the individual RCTs in this case had low event rates. Reliable estimates of the mortality risk were generated only when data were combined by meta-analysis (14). Furthermore, these RCTs were generally short in duration and could not provide information about the long-term effect of antipsychotics on mortality (14, 17). Finally, these trials provide estimates of harm primarily for atypical antipsychotics. Relatively few data are available on harms associated with older conventional antipsychotics. Studies suggest that important differences may exist in the safety profiles of conventional and atypical agents (15, 16, 18, 19). Using population-based data, we sought to determine the risk for all-cause mortality in older adults with dementia who received atypical antipsychotics, conventional antipsychotics, or no antipsychotic. Because important baseline differences exist among these groups, we used propensity score matching to improve their comparability. We also evaluated the effect of duration of treatment with antipsychotics on the risk for death. Methods Data Sources Ontario is Canadas most populous province. During our study, Ontario had a population of approximately 12 million people, of whom 1.4 million were 65 years of age or older. A universally funded health program covers nearly all physician services, medications, and hospital services for patients 65 years of age or older in Ontario. Information from 4 administrative health care databases was linked to develop the study cohort: pharmacy records from the Ontario Drug Benefit program, hospitalization records from the Canadian Institute for Health Information Discharge Abstract Database, physician billing information for inpatient and outpatient services from the Ontario Health Insurance Plan, and basic demographic information and vital statistics from the Registered Persons Database. We used encrypted unique identifiers that are common among databases to link anonymous information on demographic characteristics and health services utilization for patients in our study. Little basic information on patients is missing in these databases. For example, the coding accuracy of drug claims in the Ontario Drug Benefit program database is excellent, with an error rate of only 0.7% (20). The study was approved by the ethics review board of Sunnybrook and Womens College Health Sciences Centre, Toronto, Ontario, Canada. Dementia Cohort We identified a cohort of all Ontario residents 66 years of age or older with a diagnosis of dementia (in the Ontario Health Insurance Plan or Discharge Abstract Database) between 1 April 1997 and 31 March 2002. To focus on antipsychotic drug treatment for behavioral and psychological symptoms of dementia, we excluded patients who had evidence of other psychotic disorders (such as schizophrenia) or were receiving palliative care services. To reduce the potential for selection bias, we studied only new users of antipsychotics and excluded those who had received antipsychotics in the year before cohort entry (21). Exposure to Antipsychotics We identified new use of antipsychotics if any agent available through the Ontario Drug Benefit program was dispensed after cohort entry. Cohort entry (that is, the index date) was defined as the date of the first dispensed antipsychotic drug. Available atypical drugs included olanzapine, quetiapine, and risperidone, and available conventional drugs included chlorpromazine, flupenthixol, fluphenazine, haloperidol, loxapine, pericyazine, perphenazine, pimozide, thioridazine, and trifluoperazine. Clozapine was rarely used in Ontario during the study period, and we therefore excluded patients who were receiving this medication. Other atypical antipsychotics (such as aripiprazole and ziprasidone) are not licensed for use in Canada. We decided that exposure to an antipsychotic was discontinued (and we censored follow-up) if the patient did not refill his or her antipsychotic prescription within an interval composed of the days of drug supply plus a grace period of 20%. For example, we censored follow-up for a patient who did not refill his or her 60-day antipsychotic prescription within 72 days. We also censored follow-up for patients who switched from atypical to conventional antipsychotics (or vice versa). However, we continued follow-up for patients who switched from 1 atypical antipsychotic to another, because data suggest no statistically significant difference in the risk for death associated with individual drugs in this class (13, 14, 16). We applied the same rules to conventional antipsychotics. All-Cause Mortality The primary outcome was all-cause mortality, as recorded in the Registered Persons Database (for patients who were not hospitalized at the time of death) or the Discharge Abstract Database (for patients who died while hospitalized). To assess the influence of the duration of antipsychotic exposure on the outcome, we evaluated the risk for death at 30, 60, 120, and 180 days after the initial dispensing of antipsychotic medication. Cohort Matching We stratified the dementia cohort to support separate analyses among persons living in the community and those residing in long-term care at cohort entry. Studies have demonstrated that rates of antipsychotic prescribing are substantial among older adults newly admitted to long-term care facilities (4). Furthermore, long-term care residents typically carry a greater burden of comorbid disease and are more vulnerable to adverse drug events than are their counterparts in the community (22, 23). Our first objective was to determine the risk for death among older adults with dementia who received atypical antipsychotics compared with those who were not exposed to any antipsychotic. Because antipsychotic use was not randomly assigned in the study cohorts, we addressed potential confounding and selection biases by developing a propensity score for antipsychotic use. We then applied this score to match users of atypical antipsychotics with nonusers in the dementia cohort. The rationale and methods underlying the use of a propensity score for a proposed causal exposure variable are described elsewhere (24). Recent studies provide guidance on the selection of variables to include in the propensity score (25, 26). We developed a logistic regression model by using 42 covariates describing patient characteristics. Tables 1 and 2 list many of the characteristics included in the propensity score. After a structured and iterative assessment of the balance of measured covariates betwe

Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review

Abstract Objective To review the role of oral atypical antipsychotic drugs in the management of the behavioural and psychological symptoms of dementia (BPSD). Data sources Medline, Embase, and the Cochrane Library. Reference lists were reviewed and experts were contacted to identify additional trials. Study selection Double blind randomised controlled trials that evaluated the four oral atypical antipsychotic therapies for BPSD. Review methods Two reviewers assessed trial validity independently. Data extraction Demographics of patients, study duration, dose of antipsychotic, primary end points, adverse events. Results 77 abstracts were reviewed. Five randomised trials (1570 patients) evaluating risperidone and olanzapine were identified. The quality of trials was generally good. Most participants were in an institution (> 96%), elderly (weighted mean 82.3 years), and had Alzheimers disease (76.3%). Trials lasted 6-12 weeks. Treatment with atypical antipsychotic drugs was superior to placebo for the primary end point in three of the five trials. Two trials comparing risperidone with haloperidol did not find any differences in the primary measures of efficacy. Adverse events were common and included extrapyramidal symptoms, somnolence, and abnormal gait. Conclusions Although atypical antipsychotic drugs are being used with increasing frequency, few randomised trials have evaluated their use for BPSD. Limited evidence supports the perception of improved efficacy and adverse event profiles compared with typical antipsychotic drugs.

Projected incidence of mechanical ventilation in Ontario to 2026: Preparing for the aging baby boomers

Objective:The aging baby boomers are expected to have a significant impact on the healthcare system. Mechanical ventilation is an age-dependent, costly, and relatively nondiscretionary medical service that may be particularly affected by the aging population. We forecast the future incidence of mechanical ventilation to the year 2026 to understand the impact of aging baby boomers on critical care resources. Design:Population-based, sex-specific, and age-specific mechanical ventilation incidences for adults for the year 2000 were directly standardized to population projections to estimate the incidence of mechanical ventilation, in 5-yr intervals, from 2006 to 2026. Sensitivity analyses were performed by varying population projections and mechanical ventilation incidence for the elderly. Setting:Province of Ontario, Canada. Patients:Noncardiac surgery, mechanically ventilated adults. Interventions:None. Main Results:The projected number of ventilated patients in 2026 was 34,478, representing an 80% increase from 2000. The crude incidence increased 31%, from 222 to 291 per 100,000 adults. The annually compounded projected growth rate during this 26-yr period was 2.3%, similar to the actual growth rate experienced in the 1990s. The projected incidence was relatively insensitive to changes in assumptions, with estimates for 2026 ranging from 31,473 to 36,313 ventilated adults. Conclusions:The incidence of mechanical ventilation projected to the year 2026 will steadily increase and outpace population growth as occurred in the 1990s. In the current environment in which intensive care unit resources are limited and ventilated patients already use a significant proportion of acute care resources, planning for this continued growth is necessary. Existing evidence-based strategies that improve both the efficiency and efficacy of critical care services should be carefully evaluated for widespread implementation.

Inappropriate prescribing before and after nursing home admission

OBJECTIVES: To compare the prevalence of inappropriate prescribing before and after nursing home admission and to determine which patient and physician characteristics are associated with inappropriate prescribing in the nursing home setting.

Frequency and pattern of emergency department visits by long-term care residents--a population-based study.

OBJECTIVES: To obtain population‐based estimates of emergency department (ED) visits by long‐term care (LTC) residents.

Association between tamsulosin and serious ophthalmic adverse events in older men following cataract surgery.

CONTEXT Both benign prostatic hyperplasia (BPH) and cataract formation are common in older men. The alpha-adrenergic receptor blocker tamsulosin is frequently prescribed to treat BPH, and research suggests this drug may increase the intraoperative difficulty of cataract surgery. No studies have documented whether use of tamsulosin or other alpha-blocker drug therapies affect the risk of serious postoperative adverse events. OBJECTIVE To assess the risk of adverse events following cataract surgery in older men prescribed tamsulosin or other alpha-blocking drugs used to treat BPH. DESIGN, SETTING, AND PATIENTS Nested case-control analysis of a population-based retrospective cohort study using linked health care databases from Ontario, Canada. We included all men aged 66 years or older who had cataract surgery between 2002 and 2007 (N = 96 128). MAIN OUTCOME MEASURES A composite of procedures signifying retinal detachment, lost lens or lens fragment, or endophthalmitis occurring within 14 days after cataract surgery. The risk of these adverse events was compared between men treated with tamsulosin or other alpha-blockers and men with no exposure to these medications in the year prior to cataract surgery. We separately examined the association of drug exposure that was either recent (within the 14 days before surgery) or previous (15-365 days before surgery). RESULTS Overall, 3550 patients (3.7%) in the cohort had recent exposure to tamsulosin and 7426 patients (7.7%) had recent exposure to other alpha-blockers. Two hundred eighty-four patients (0.3%) had an adverse event. We randomly matched 280 of the cases to 1102 controls according to their age, surgeon, and year of surgery. Adverse events were significantly more common among patients with recent tamsulosin exposure (7.5% vs 2.7%; adjusted odds ratio [OR], 2.33; 95% confidence interval [CI], 1.22-4.43) but were not associated with recent exposure to other alpha-blockers (7.5% vs 8.0%; adjusted OR, 0.91; 95% CI, 0.54-1.54) or to previous exposure to either tamsulosin (< or = 1.8% vs 1%; adjusted OR, 0.94; 95% CI, 0.27-3.34) or other alpha-blockers (2.9% vs 2.1%; adjusted OR, 1.08; 95% CI, 0.47-2.48). This corresponds to an estimated number needed to harm (NNH) of 255 (95% CI, 99-1666). CONCLUSIONS Exposure to tamsulosin within 14 days of cataract surgery was significantly associated with serious postoperative ophthalmic adverse events. There were no significant associations with exposure to other alpha-blocker medications used to treat BPH.

Changing prescription patterns for lithium and valproic acid in old age: shifting practice without evidence.

Over the past decade, valproic acid (prescribed as divalproex in North America) has been marketed as an alternative to lithium for treating bipolar disorders. For elderly patients, however, there is no clear evidence that valproic acid is more beneficial than lithium. Moreover, the evidence for the superiority of valproic acid in treating bipolar disorders—mixed episodes and rapid cycling—has been challenged in a recent Cochrane review.1 Valproic acid has not benefited patients with manic and psychiatric symptoms in dementia, despite the growing use of the drug in the management of these conditions.2 Recently, the relatively rapid shift in prescription patterns has been questioned.3 We describe trends in the use of lithium and valproic acid in a large population of people over 65. We obtained information on drug use from the Ontario Drug Benefit Program, which provides comprehensive drug benefits to all residents aged 65 or older in Ontario, Canada. …

Analytic Methods for Constructing Cross-Sectional Profiles of Health Care Providers

National effort is currently directed toward developing and disseminating comparative information involving both outcomes and processes of care for health care providers. Univariate provider-specific comparative indices based on posterior summaries as well as indices based on maximum likelihood estimates have been developed for use in the cross-sectional setting. A remaining issue in the dissemination of cross-sectional profiles relates to the multivariate nature of the indices: often many performance measures are used to assess quality for a particular provider. Because this information can often be contradictory and overwhelming, there is a need for measures that summarize quality at a provider level. This article proposes the use of latent variable models for comparing health care providers in the cross-sectional setting when each provider is measured on more than one dimension of care. By combining information across dimensions of care within a provider, an integrated analysis can produce a composite measure of quality and has more statistical power to detect differences among providers. As the number of individual performance measures grows over time, composite measures will become increasingly important tools to support decision making by consumers, payors, and providers.

Mechanical ventilation in Ontario, 1992-2000: incidence, survival, and hospital bed utilization of noncardiac surgery adult patients.

Objective:Mechanical ventilation is a common therapy used in caring for critically ill patients, but its epidemiology is poorly understood. We describe population-based, temporal trends in the incidence, survival, and hospital bed utilization of mechanically ventilated, noncardiac surgery adult patients. Design:Retrospective, observational cohort study using linked administrative databases. Setting:Province of Ontario, Canada. Patients:Subjects were 150,755 unique patients who received mechanical ventilation between 1992 and 2000. Interventions:None. Measurements:Annual measures of mechanical ventilation incidence, 30-day patient mortality rate, and number of mechanical ventilation days and inpatient days for mechanically ventilated patients as a proportion of total adult inpatient bed days. Main Results:From 1992 to 2000, the crude and age- and gender-adjusted incidence of mechanical ventilation increased 9% (p < .001) and 2% (p < .027), respectively, to 217 per 100,000 adults. Crude mortality rate 30 days after initiation of mechanical ventilation increased from 27% to 32% (p < .001). Significant predictors of 30-day mortality rate (adjusted hazard ratio, 95% confidence interval) were calendar year (1.03, 1.02–1.03), age >80 yrs (2.3, 2.2–2.3), Charlson score 3+ (2.0, 2.0–2.1), and specific diagnosis. From 1992 to 2000, the number of mechanical ventilation days and inpatient days for mechanically ventilated patients, as a proportion of total adult inpatient bed days, increased 69% and 30% (both p < .001), respectively, to 1.8% and 6.2%. Conclusions:There was a small, but important, increase in mechanical ventilation incidence and a substantial increase in the proportion of inpatient bed days used by mechanically ventilated patients in Ontario during the 1990s. These trends are important in planning for expansion of health care resources to meet the needs of the aging population. The increase, over time, in risk-adjusted mortality rate of mechanically ventilated patients is concerning and requires further investigation.

A Population-Based Study of Cholinesterase Inhibitor Use for Dementia

OBJECTIVES: To examine current utilization patterns of cholinesterase inhibitor (ChEI) therapy for dementia to determine treatment duration, use in long‐term care, how often patients receive these drugs until death, and frequency of switching between the available ChEIs.