DOCUMENTED ADVERSE EFFECTS
Analysis of CVAE risk: prospective trials. The current FDA-approved product labeling for olanzapine(Drug information on olanzapine), risperidone(Drug information on risperidone), and aripiprazole(Drug information on aripiprazole) includes cautionary language about increased rates of CVAE observed in some dementia trials. Although previous analyses of pooled clinical trial data linked atypical antipsychotic treatment of behavioral symptoms in patients with dementia to an increased risk of CVAE, there were no differences in the rates of stroke noted between the groups receiving atypical antipsychotic treatment and placebo-treated patients in CATIE-AD.7
In a post hoc analysis of pooled data from 6 dementia trials that compared olanzapine with placebo, risperidone, or haloperidol(Drug information on haloperidol), Kryzhanovskaya and colleagues analyzed the CVAE data and reported that the incidence of CVAE was nearly 3 times higher in olanzapine-treated patients (1.3%) than in placebo-treated patients (0.4%).11 However, exposure-adjusted CVAE rates were not significantly different for olanzapine versus risperidone or olanzapine versus haloperidol.
Analysis of mortality risk: prospective trials. The discovery of the increased risk of death in pooled data from risperidone, olanzapine, quetiapine(Drug information on quetiapine), and aripiprazole placebo-controlled dementia trials led the FDA to add a black box warning to the product labeling for all atypical antipsychotics in April 2005. The warning was added for all atypicals, despite that one of these medications (ziprasidone) had never been studied in dementia trials.20
Schneider and colleagues19 published a meta-analysis of 15 short-term placebo-controlled trials of risperidone, olanzapine, quetiapine, and aripiprazole for dementia-related behavioral symptoms. Risk of death was increased relative to placebo (odds ratio, 1.54; 95% confidence interval [CI], 1.06 to 2.23) for patients randomly selected to receive 1 of the 4 antipsychotics. This report confirmed the FDA analysis that found a similarly increased risk of death among dementia patients treated with risperidone, olanzapine, or quetiapine in placebo-controlled trials.
In contrast to the previous analyses, CATIE-AD failed to demonstrate increased risk of mortality associated with treatment compared with placebo or between treatment groups assigned to risperidone, olanzapine, or quetiapine.7 The lack of significance for incidence of stroke or increased rate of death during the trial is not surprising considering some important differences between the AD population studied in CATIE-AD and the heterogeneity of some of the populations under study in the short-term (6- to 12-week) antipsychotic dementia trials, which included both patients with AD and those with mixed dementia.8,12
A number of trials of atypical antipsychotic agents included patients with dementia and significant cardiovascular risk factors; others studied the effects of treatment in frail nursing home patients who may be at higher risk for adverse medication-related outcomes and all-cause mortality.8,12,13
Analysis of mortality risk: retrospective claims data. Examination of the mortality rates for 2 of the studies with a haloperidol comparator included in the FDA analysis revealed that although the risk of death in patients treated with haloperidol was increased compared with the placebo group, the differences were not significant after adjustment for exposure (relative risk [RR], 2.07; 95% CI, 0.78 to 5.51; P = .15).9
Wang and colleagues21 used US claims data to investigate death rates in a large cohort of older adults receiving either conventional or atypical antipsychotic therapy and found that compared with users of atypical antipsychotics, a significantly greater risk of death in patients for whom older antipsychotics were prescribed was seen. Rates of fatal events were greatest (conventional agents, 17.9%; atypical agents, 14.6%) in the first 40 days after starting therapy and remained significant even after adjusting for diagnosis of dementia or nursing home residence.
Using Canadian claims data and a similar study design, Schneeweiss and colleagues22 also demonstrated an increased risk of death associated with conventional antipsychotics that significantly exceeded event rates in patients receiving newer agents. Choice of conventional antipsychotic had an impact on the risk of mortality in patients with dementia.22 Compared with risperidone, haloperidol was associated with the greatest increase in mortality (RR, 2.14; 95% CI, 1.86 to 2.45) and loxapine(Drug information on loxapine) with the lowest (RR, 1.29; 95% CI, 1.19 to 1.40).
Despite high background mortality rates, use of either a conventional or atypical antipsychotic was associated with greater risk of dying for patients residing in either community or nursing home settings in the most recently published case-control study according to US claims data.23 Within 30 days of starting an atypical antipsychotic, nursing home residents with a dementia diagnosis were more likely to die (hazard rate [HR], 1.55; 95% CI, 1.15 to 2.07) than untreated patients with dementia still residing in the community (HR, 1.31; 95% CI, 1.02 to 1.70).