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Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study.

Huybrechts KF, Gerhard T, Crystal S, Olfson M, Avorn J, Levin R, Lucas JA, Schneeweiss S - BMJ (2012)

Bottom Line: To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes.Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88).The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02120 MA, United States. khuybrechts@partners.org

ABSTRACT

Objective: To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes.

Design: Population based cohort study with linked data from Medicaid, Medicare, the Minimum Data Set, the National Death Index, and a national assessment of nursing home quality.

Setting: Nursing homes in the United States.

Participants: 75,445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥ 65, were eligible for Medicaid, and lived in a nursing home in 2001-5.

Main outcome measures: Cox proportional hazards models were used to compare 180 day risks of all cause and cause specific mortality by individual drug, with propensity score adjustment to control for potential confounders.

Results: Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine.

Conclusions: Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need. The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.

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Related in: MedlinePlus

Fig 4 Hazard ratios (adjusted propensity score) for death from causes other than cancer by dose of various antipsychotic drugs with low dose group of each drug as reference. Results for aripiprazole and ziprasidone not presented because of small numbers of events in some dose groups
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fig4: Fig 4 Hazard ratios (adjusted propensity score) for death from causes other than cancer by dose of various antipsychotic drugs with low dose group of each drug as reference. Results for aripiprazole and ziprasidone not presented because of small numbers of events in some dose groups

Mentions: Findings from the Cox regression analyses indicated that, compared with risperidone, patients treated with haloperidol had double the risk of mortality (hazard ratio adjusted for propensity score 2.07, 95% confidence interval 1.89 to 2.26) and patients treated with quetiapine had a reduced risk (0.81, 0.75 to 0.88). No meaningful differences in risk were observed for aripiprazole, olanzapine, and ziprasidone (table 3). Adjusted Kaplan-Meier plots are consistent with these findings (fig 2). The effect of haloperidol was strongest during the first 40 days of treatment (hazard ratio adjusted for propensity score 2.34, 2.11 to 2.60) and reduced to 1.32 (1.02 to 1.71) and 1.46 (1.07 to 2.00) after 40-79 and 80-180 days of treatment, respectively. The corresponding rate ratios for quetiapine were 0.74 (0.66 to 0.82), 0.87 (0.75 to 1.01), and 0.91 (0.79 to 1.05). Analyses stratified by dose confirmed the overall findings (figs 3 and 4), and we did not find evidence that the effect measure was modified by the presence of a recorded diagnosis of dementia or behavioural disturbances (see table D in appendix on bmj.com). Sensitivity analyses indicated that for an unmeasured confounder (such as frailty, severity of dementia) present in 25% of the population, relative risks ≥5.0 linking the hypothetical confounder to both haloperidol use and mortality would be needed to fully explain the observed association with mortality. For confounders present in 10% or 5% of the population, relative risks of >6.0 and 7.5, respectively, would be needed. To fully explain the protective association for quetiapine, relative risks of >2.5, 3.5, and 5.0 would be required for an unmeasured confounder present in 25%, 10%, and 5%, respectively, of the population (see figs A and B in appendix on bmj.com).


Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study.

Huybrechts KF, Gerhard T, Crystal S, Olfson M, Avorn J, Levin R, Lucas JA, Schneeweiss S - BMJ (2012)

Fig 4 Hazard ratios (adjusted propensity score) for death from causes other than cancer by dose of various antipsychotic drugs with low dose group of each drug as reference. Results for aripiprazole and ziprasidone not presented because of small numbers of events in some dose groups
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3285717&req=5

fig4: Fig 4 Hazard ratios (adjusted propensity score) for death from causes other than cancer by dose of various antipsychotic drugs with low dose group of each drug as reference. Results for aripiprazole and ziprasidone not presented because of small numbers of events in some dose groups
Mentions: Findings from the Cox regression analyses indicated that, compared with risperidone, patients treated with haloperidol had double the risk of mortality (hazard ratio adjusted for propensity score 2.07, 95% confidence interval 1.89 to 2.26) and patients treated with quetiapine had a reduced risk (0.81, 0.75 to 0.88). No meaningful differences in risk were observed for aripiprazole, olanzapine, and ziprasidone (table 3). Adjusted Kaplan-Meier plots are consistent with these findings (fig 2). The effect of haloperidol was strongest during the first 40 days of treatment (hazard ratio adjusted for propensity score 2.34, 2.11 to 2.60) and reduced to 1.32 (1.02 to 1.71) and 1.46 (1.07 to 2.00) after 40-79 and 80-180 days of treatment, respectively. The corresponding rate ratios for quetiapine were 0.74 (0.66 to 0.82), 0.87 (0.75 to 1.01), and 0.91 (0.79 to 1.05). Analyses stratified by dose confirmed the overall findings (figs 3 and 4), and we did not find evidence that the effect measure was modified by the presence of a recorded diagnosis of dementia or behavioural disturbances (see table D in appendix on bmj.com). Sensitivity analyses indicated that for an unmeasured confounder (such as frailty, severity of dementia) present in 25% of the population, relative risks ≥5.0 linking the hypothetical confounder to both haloperidol use and mortality would be needed to fully explain the observed association with mortality. For confounders present in 10% or 5% of the population, relative risks of >6.0 and 7.5, respectively, would be needed. To fully explain the protective association for quetiapine, relative risks of >2.5, 3.5, and 5.0 would be required for an unmeasured confounder present in 25%, 10%, and 5%, respectively, of the population (see figs A and B in appendix on bmj.com).

Bottom Line: To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes.Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88).The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02120 MA, United States. khuybrechts@partners.org

ABSTRACT

Objective: To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes.

Design: Population based cohort study with linked data from Medicaid, Medicare, the Minimum Data Set, the National Death Index, and a national assessment of nursing home quality.

Setting: Nursing homes in the United States.

Participants: 75,445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥ 65, were eligible for Medicaid, and lived in a nursing home in 2001-5.

Main outcome measures: Cox proportional hazards models were used to compare 180 day risks of all cause and cause specific mortality by individual drug, with propensity score adjustment to control for potential confounders.

Results: Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine.

Conclusions: Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need. The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.

Show MeSH
Related in: MedlinePlus