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Risk of Death With Atypical Antipsychotic Drug Treatment for Dementia:  Meta-analysis of Randomized Placebo-Controlled Trials

Lon S. Schneider, MD, MS; Karen S. Dagerman, MS; Philip Insel, MS
JAMA. 2005;294(15):1934-1943. doi:10.1001/jama.294.15.1934.
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Context Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease and other dementia; however, concerns have arisen about the increased risk for cerebrovascular adverse events, rapid cognitive decline, and mortality with their use.

Objective To assess the evidence for increased mortality from atypical antipsychotic drug treatment for people with dementia.

Data Sources MEDLINE (1966 to April 2005), the Cochrane Controlled Trials Register (2005, Issue 1), meetings presentations (1997-2004), and information from the sponsors were searched using the terms for atypical antipsychotic drugs (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), dementia, Alzheimer disease, and clinical trial.

Study Selection Published and unpublished randomized placebo-controlled, parallel-group clinical trials of atypical antipsychotic drugs marketed in the United States to treat patients with Alzheimer disease or dementia were selected by consensus of the authors.

Data Extraction Trials, baseline characteristics, outcomes, all-cause dropouts, and deaths were extracted by one reviewer; treatment exposure was obtained or estimated. Data were checked by a second reviewer.

Data Synthesis Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo. Outcomes were assessed using standard methods (with random- or fixed-effects models) to calculate odds ratios (ORs) and risk differences based on patients randomized and relative risks based on total exposure to treatment. There were no differences in dropouts. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence interval [CI], 1.06-2.23; P = .02; and risk difference was 0.01; 95% CI, 0.004-0.02; P = .01). Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis.

Conclusions Atypical antipsychotic drugs may be associated with a small increased risk for death compared with placebo. This risk should be considered within the context of medical need for the drugs, efficacy evidence, medical comorbidity, and the efficacy and safety of alternatives. Individual patient analyses modeling survival and causes of death are needed.

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Figure 1. Trials Identification and Selection Process
Graphic Jump Location

RCT indicates randomized controlled trial.

Figure 2. Deaths by Individual Comparisons by Drugs and Overall Compared With Placebo
Graphic Jump Location

CI indicates confidence interval; OR, odds ratio.
*Unique identification code which identifies the study or the collection of posters, abstracts, unpublished manuscripts, or published trials of the study drug. The total number of placebo patients is 1757 and deaths, 40. The trial HGGU placebo group is used for both risperidone and olanzapine comparisons.

Figure 3. All-Cause Dropouts by Individual Comparisons by Drugs and Overall Compared With Placebo
Graphic Jump Location

CI indicates confidence interval; OR, odds ratio.
*Unique identification code, which identifies the study or the collection of posters, abstracts, unpublished manuscripts, or published trials of the study drug. The total number of placebo patients is 1757 and dropouts, 551. The trial HGGU placebo group is used for both risperidone and olanzapine comparisons.

Figure 4. Deaths Based on Total Drug and Placebo Exposures Pooled by Drug
Graphic Jump Location

Total population is patient-years exposure to treatment (drug) or placebo. CI indicates confidence interval; RR, relative risk. Exposure time to treatment for 4 risperidone and 3 olanzapine trials was obtained from data presented by the US Food and Drug Administration.23 Exposure time for 1 risperidone trial,46 2 olanzapine trials,8,46 and 1 quetiapine trial33 was estimated from sample sizes, trial lengths, and dropout rates. Exposure time for aripiprazole was calculated from sample sizes and incidence data provided in a letter from Bristol-Myers Squibb (February 10, 2005),32 and for 2 quetiapine trials from data provided in Schneider et al.31 The total number of placebo deaths is 40 and placebo exposure is 303 patient-years (see footnote to Figure 2).

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