Sudeep S. Gill

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

Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies

Abstract Objectives To quantify the risk of Alzheimers disease in users of all non-steroidal anti-inflammatory drugs (NSAIDs) and users of aspirin and to determine any influence of duration of use. Design Systematic review and meta-analysis of observational studies published between 1966 and October 2002 that examined the role of NSAID use in preventing Alzheimers disease. Studies identified through Medline, Embase, International Pharmaceutical Abstracts, and the Cochrane Library. Results Nine studies looked at all NSAIDs in adults aged > 55 years. Six were cohort studies (total of 13 211 participants), and three were case-control studies (1443 participants). The pooled relative risk of Alzheimers disease among users of NSAIDs was 0.72 (95% confidence interval 0.56 to 0.94). The risk was 0.95 (0.70 to 1.29) among short term users (< 1 month) and 0.83 (0.65 to 1.06) and 0.27 (0.13 to 0.58) among intermediate term (mostly < 24 months) and long term (mostly > 24 months) users, respectively. The pooled relative risk in the eight studies of aspirin users was 0.87 (0.70 to 1.07). Conclusions NSAIDs offer some protection against the development of Alzheimers disease. The appropriate dosage and duration of drug use and the ratios of risk to benefit are still unclear.

Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study

Abstract Objective To compare the incidence of admissions to hospital for stroke among older adults with dementia receiving atypical or typical antipsychotics. Design Population based retrospective cohort study. Setting Ontario, Canada. Patients 32 710 older adults (≤ 65 years) with dementia (17 845 dispensed an atypical antipsychotic and 14 865 dispensed a typical antipsychotic). Main outcome measures Admission to hospital with the most responsible diagnosis (single most important condition responsible for the patients admission) of ischaemic stroke. Observation of patients until they were either admitted to hospital with ischaemic stroke, stopped taking antipsychotics, died, or the study ended. Results After adjustment for potential confounders, participants receiving atypical antipsychotics showed no significant increase in risk of ischaemic stroke compared with those receiving typical antipsychotics (adjusted hazard ratio 1.01, 95% confidence interval 0.81 to 1.26). This finding was consistent in a series of subgroup analyses, including ones of individual atypical antipsychotic drugs (risperidone, olanzapine, and quetiapine) and selected subpopulations of the main cohorts. Conclusion Older adults with dementia who take atypical antipsychotics have a similar risk of ischaemic stroke to those taking typical antipsychotics.

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.

Nursing Home Profit Status and Quality of Care: Is There Any Evidence of an Association?

This article critically reviews the association between the profit status of North American nursing homes and the quality of care. Studies were identified by searching MEDLINE (January 1990-October 2002), reference lists, letters, commentaries, and editorials. The quality indicator(s) used to measure quality of care, and its relationship to profit status, was extracted from each publication. The study design and risk-adjustment methodologies used were also extracted. The interrater reliability for the extraction of these three items was determined to be 1.0, 0.6, and 0.8, respectively. Aqualitative systematic review was performed using Donabedian’s framework of structure, process, and outcome for analyzing medical quality of care. Empirical research in the past 12 years has found that systematic differences exist between for-profit and not-for-profit nursing homes. Forprofit nursing homes appear to provide lower quality of care in many important areas of process and outcome.

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

BACKGROUND Antipsychotic therapy is widely used to treat behavioral problems in older adults with dementia. Cohort studies evaluating the safety of antipsychotic therapy generally focus on a single adverse event. We compared the rate of developing any serious event, a composite outcome defined as an event serious enough to lead to an acute care hospital admission or death within 30 days of initiating antipsychotic therapy, to better estimate the overall burden of short-term harm associated with these agents. METHODS In this population-based, retrospective cohort study, we identified 20 682 matched older adults with dementia living in the community and 20 559 matched individuals living in a nursing home between April 1, 1997, and March 31, 2004. Propensity-based matching was used to balance differences between the drug exposure groups in each setting. To examine the effects of antipsychotic drug use on the composite outcome of any serious event we used a conditional logistic regression model. We also estimated adjusted odds ratios using models that included all covariates with a standard difference greater than 0.10. RESULTS Relative to those who received no antipsychotic therapy, community-dwelling older adults newly dispensed an atypical antipsychotic therapy were 3.2 times more likely (95% confidence interval, 2.77-3.68) and those who received conventional antipsychotic therapy were 3.8 times more likely (95% confidence interval, 3.31-4.39) to develop any serious event during the 30 days of follow-up. The pattern of serious events was similar but less pronounced among older adults living in a nursing home. CONCLUSIONS Serious events, as indicated by a hospital admission or death, are frequent following the short-term use of antipsychotic drugs in older adults with dementia. Antipsychotic drugs should be used with caution even when short-term therapy is being prescribed.

Intake of vitamin E, vitamin C, and carotenoids and the risk of Parkinson's disease: a meta-analysis

We studied the effect of vitamin C, vitamin E, and beta carotene intake on the risk of Parkinsons disease (PD). We did a systematic review and meta-analysis of observational studies published between 1966 and March 2005 searching MEDLINE, EMBASE, and the Cochrane Library. Eight studies were identified (six case-control, one cohort, and one cross-sectional). We found that dietary intake of vitamin E protects against PD. This protective influence was seen with both moderate intake (relative risk 0.81, 95% CI 0.67-0.98) and high intake (0.78, 0.57-1.06) of vitamin E, although the possible benefit associated with high intake of vitamin E was not significant. The studies did not suggest any protective effects associated with vitamin C or beta carotene. We conclude that dietary vitamin E may have a neuroprotective effect attenuating the risk of PD. These results require confirmation in randomised controlled trials.

Psychotropic medications and the risk of fracture: a meta-analysis.

Background: Older adults throughout the developed world are at significant risk of osteoporotic fractures. Many studies have examined the relationship between the use of psychotropic medications and the risk of fractures, but these studies have reported conflicting results.Purpose: To resolve discrepancies, we carried out a meta-analysis to assess the risk of fractures among users of several classes of psychotropic drugs.Data sources: We retrieved studies published in any language by systematically searching MEDLINE, LILACS, EMBASE and ISI Proceedings databases and by manually examining the bibliographies of the articles retrieved electronically as well as those of recent reviews.Study selection: We included 98 cohort and case-control studies, published in 46 different articles, that reported relative risk (RR) estimates and confidence intervals (CIs) or sufficient data to calculate these values.Data synthesis: Study-specific RRs were weighted by the inverse of their variance to obtain fixed- and random effects pooled estimates. The random effects RR of fractures was 1.34 (95% CI 1.24, 1.45) for benzodiazepines (23 studies), 1.60 (95% CI 1.38, 1.86) for antidepressants (16 studies), 1.54 (95% CI 1.24, 1.93) for non-barbiturate antiepileptic drugs (13 studies), 2.17 (95% CI 1.35, 3.50) for barbiturate antiepileptic drugs (five studies), 1.59 (1.27, 1.98) for antipsychotics (12 studies), 1.15 (95% CI 0.94, 1.39) for hypnotics (13 studies) and 1.38 (95% CI 1.15, 1.66) for opioids (six studies). For non-specified psychotropic drugs (10 studies), the pooled RR was 1.48 (95% CI 1.41, 1.59).Limitations: Main concerns were the potential for residual confounding and for publication bias.Conclusion: Globally, the increase in the risk of fractures among psychotropic drug users is moderate. Further research is needed, especially to examine high-risk populations and newer medications. Future studies should be prospective and emphasise control of confounding bias.

Effects of antihypertensive drug treatments on fracture outcomes: a meta-analysis of observational studies

Objective.  To quantitatively pool findings from observational studies on the risk of fracture outcomes associated with exposure to five antihypertensive drug classes: angiotensin‐converting enzyme (ACE) inhibitors, diuretics (in particular thiazide diuretics), β‐blockers, calcium‐channel blockers and alpha‐blockers.

Effect of regulatory warnings on antipsychotic prescription rates among elderly patients with dementia: a population-based time-series analysis

Background: Three warnings of serious adverse events associated with the use of atypical antipsychotic drugs among elderly patients with dementia were sent to health care professionals in Canada. We assessed the impact of these warnings on prescription rates of antipsychotic drugs in this patient population. Methods: We used prescription drug claims data from Ontario to calculate prescription rates of atypical and conventional antipsychotic drugs among elderly patients with dementia from May 1, 2000, to Feb. 28, 2007. We performed a time-series analysis to estimate the effect of each warning on rates of antipsychotic drug use. Results: Before the first warning, growth in the use of atypical antipsychotics was responsible for an increasing rate of overall antipsychotic use. Each warning was associated with a small relative decrease in the predicted growth in the use of atypical antipsychotic drugs: a 5.0% decrease after the first warning, 4.9% after the second and 3.2% after the third (each p < 0.05). The overall prescription rate of antipsychotic drugs among patients with dementia increased by 20%, from 1512 per 100 000 elderly patients in September 2002, the month before the first warning, to 1813 per 100 000 in February 2007, 20 months after the last warning. Interpretation: Although the warnings slowed the growth in the use of atypical antipsychotic drugs among patients with dementia, they did not reduce the overall prescription rate of these potentially dangerous drugs. More effective interventions are necessary to improve postmarket drug safety in vulnerable populations.