Chaim M. Bell

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

Derivation and validation of an index to predict early death or unplanned readmission after discharge from hospital to the community

Background: Readmissions to hospital are common, costly and often preventable. An easy-to-use index to quantify the risk of readmission or death after discharge from hospital would help clinicians identify patients who might benefit from more intensive post-discharge care. We sought to derive and validate an index to predict the risk of death or unplanned readmission within 30 days after discharge from hospital to the community. Methods: In a prospective cohort study, 48 patient-level and admission-level variables were collected for 4812 medical and surgical patients who were discharged to the community from 11 hospitals in Ontario. We used a split-sample design to derive and validate an index to predict the risk of death or nonelective readmission within 30 days after discharge. This index was externally validated using administrative data in a random selection of 1 000 000 Ontarians discharged from hospital between 2004 and 2008. Results: Of the 4812 participating patients, 385 (8.0%) died or were readmitted on an unplanned basis within 30 days after discharge. Variables independently associated with this outcome (from which we derived the nmemonic “LACE”) included length of stay (“L”); acuity of the admission (“A”); comorbidity of the patient (measured with the Charlson comorbidity index score) (“C”); and emergency department use (measured as the number of visits in the six months before admission) (“E”). Scores using the LACE index ranged from 0 (2.0% expected risk of death or urgent readmission within 30 days) to 19 (43.7% expected risk). The LACE index was discriminative (C statistic 0.684) and very accurate (Hosmer–Lemeshow goodness-of-fit statistic 14.1, p = 0.59) at predicting outcome risk. Interpretation: The LACE index can be used to quantify risk of death or unplanned readmission within 30 days after discharge from hospital. This index can be used with both primary and administrative data. Further research is required to determine whether such quantification changes patient care or outcomes.

Bias in published cost effectiveness studies: systematic review

Abstract Objective To investigate if published studies tend to report favourable cost effectiveness ratios (below

Systematic Overview of Cost-Utility Assessments in Oncology

20 000,

Long-term analgesic use after low-risk surgery: a retrospective cohort study.

50 000, and

Antipsychotic therapy and short-term serious events in older adults with dementia.

100 000 per quality adjusted life year (QALY) gained) and evaluate study characteristics associated with this phenomenon. Design Systematic review. Studies reviewed 494 English language studies measuring health effects in QALYs published up to December 2001 identified using Medline, HealthSTAR, CancerLit, Current Content, and EconLit databases. Main outcome measures Incremental cost effectiveness ratios measured in dollars set to the year of publication. Results Approximately half the reported incremental cost effectiveness ratios (712 of 1433) were below

Metformin Use and All-Cause and Prostate Cancer-Specific Mortality Among Men With Diabetes

20 000/QALY. Studies funded by industry were more likely to report cost effectiveness ratios below

Association of ICU or Hospital Admission With Unintentional Discontinuation of Medications for Chronic Diseases

20 000/QALY (adjusted odds ratio 2.1, 95% confidence interval 1.3 to 3.3),

Gastrointestinal Adverse Events with Sodium Polystyrene Sulfonate (Kayexalate) Use: A Systematic Review

50 000/QALY (3.2, 1.8 to 5.7), and

Risk Factors for Acute Endophthalmitis after Cataract Surgery: A Population-based Study

100 000/QALY (3.3, 1.6 to 6.8). Studies of higher methodological quality (adjusted odds ratio 0.58, 0.37 to 0.91) and those conducted in Europe (0.59, 0.33 to 1.1) and the United States (0.44, 0.26 to 0.76) rather than elsewhere were less likely to report ratios below