June 8, 2007 — Atypical antipsychotic drugs are associated with an increased risk for death in elderly patients with dementia, according to the results of a retrospective cohort study published in the June 5 issue of the Annals of Internal Medicine.
"Antipsychotic drugs are widely used to manage behavioral and psychological symptoms in dementia despite concerns about their safety," write Sudeep S. Gill, MD, MSc, from the Queen's University in Kingston, Ontario, Canada, and colleagues. "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.... 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."
Using population-based data from Ontario, Canada, the current study aimed to determine the risk for all-cause mortality in older adults with dementia who received atypical antipsychotic drugs, conventional antipsychotic drugs, or no antipsychotic drug and who were followed up between April 1, 1997, and March 31, 2003.
Mortality risk was calculated at 30, 60, 120, and 180 days after the initial dispensing of antipsychotic medication. There were 2 pairwise comparisons: atypical vs no antipsychotic drug use and conventional vs atypical antipsychotic drug use. The investigators stratified groups by residence in the community or in long-term care, and they used propensity score matching to adjust for differences in baseline health status.
Using 27,259 matched pairs, new use of atypical antipsychotic drugs was associated with a statistically significant increase in the risk for death at 30 days compared with nonuse in both the community-dwelling population (adjusted hazard ratio [HR], 1.31; 95% confidence interval, 1.02 - 1.70; absolute risk difference, 0.2 percentage point) and the long-term care population (adjusted HR, 1.55; 95% confidence interval, 1.15 - 2.07; absolute risk difference, 1.2 percentage points).
Although excess risk seemed to persist to 180 days, unequal rates of censoring with time may have affected these results. Compared with use of atypical antipsychotic drugs, use of conventional antipsychotic drugs was associated with a higher risk for death at all time points. Unmeasured confounders increasing the risk for death could decrease or abolish the observed associations, according to the results of sensitivity analysis.
"Older adults with dementia who are exposed to atypical antipsychotics have a small but significant increase in overall mortality that is evident as early as 1 month after initiation of treatment, and this risk may persist for 6 months," the authors write. "The risk for death may be greater with conventional antipsychotics than with atypical antipsychotics."
Study limitations include lack of data on causes of death, lack of continuation of initial treatments after 1 month of therapy in many patients, possible unmeasured confounders, use of administrative data and observational study techniques, risk estimates being relatively small, inability to examine the risk for death posed by individual antipsychotic drugs or dose–response relationships, inability to match all potentially eligible patients, and the sample being restricted to older adults with dementia.
"These findings highlight the need to carefully balance potential risks and benefits when considering antipsychotic treatment for older adults with dementia and emphasize the need to limit use of these drugs to situations in which nonpharmacologic measures have provided an inadequate response," the authors conclude.
A Canadian Institutes for Health Research operating grant; a Chronic Disease New Emerging Team program grant; the Canadian Diabetes Association; the Kidney Foundation of Canada; the Heart and Stroke Foundation of Canada; the Canadian Institutes for Health Research Institutes of Nutrition, Metabolism & Diabetes and Circulatory & Respiratory Health; an Ontario Ministry of Health and Long-Term Care Career Scientist Award; a New Investigator Award through the New Emerging Team program; a Chair in Health Management Strategies from the University of Toronto; a Canadian Institutes for Health Research Investigator Award; and a fellowship grant from Eli Lilly supported this study. Some of the authors have disclosed various financial relationships with Pfizer Canada, Janssen-Ortho, Janssen, Novartis, Pfizer Inc, Eli Lilly, and/or AstraZeneca.
Ann Intern Med. 2007;146:775-786.
