Risk of Ischemic Stroke Associated with the Use of Antipsychotic Drugs in Elderly Patients: A Retrospective Cohort Study in Korea

<div><p>Objective</p><p>Strong concerns have been raised about whether the risk of ischemic stroke differs between conventional antipsychotics (CAPs) and atypical antipsychotics (AAPs). This study compared the risk of ischemic stroke in elderly patients taking CAPs and AAPs.</p><p>Method</p><p>We conducted a retrospective cohort study of 71,584 elderly patients who were newly prescribed the CAPs (haloperidol or chlorpromazine) and those prescribed the AAPs (risperidone, quetiapine, or olanzapine). We used the National Claims Database from the Health Insurance Review and Assessment Service (HIRA) from January 1, 2006 to December 31, 2009. Incident cases for ischemic stroke (ICD-10, I63) were identified. The hazard ratios (HR) for AAPs, CAPs, and for each antipsychotic were calculated using multivariable Cox regression models, with risperidone as a reference.</p><p>Results</p><p>Among a total of 71,584 patients, 24,668 patients were on risperidone, 15,860 patients on quetiapine, 3,888 patients on olanzapine, 19,564 patients on haloperidol, and 7,604 patients on chlorpromazine. A substantially higher risk was observed with chlorpromazine (HR = 3.47, 95% CI, 1.97–5.38), which was followed by haloperidol (HR = 2.43, 95% CI, 1.18–3.14), quetiapine (HR = 1.23, 95% CI, 0.78–2.12), and olanzapine (HR = 1.12, 95% CI, 0.59–2.75). Patients who were prescribed chlorpromazine for longer than 150 days showed a higher risk (HR = 3.60, 95% CI, 1.83–6.02) than those who took it for a shorter period of time.</p><p>Conclusions</p><p>A much greater risk of ischemic stroke was observed in patients who used chlorpromazine and haloperidol compared to risperidone. The evidence suggested that there is a strong need to exercise caution while prescribing these agents to the elderly in light of severe adverse events with atypical antipsychotics.</p></div

Sub-group analysis of the risk of ischemic stroke with quetiapine, olanzapine, haloperidol, and chlorpromazine compared with risperidone according to the age group, gender, the presence and type of dementia, and comorbidity.

<p>Adjusted for age, gender, presence or absence of dementia (F00-F03, G30, G31.8), depression (F32–33, F34.1, F41.2), dyslipidemia (E78.0), coronary heart disease (I21-I25), COPD (J40-J44, J47), and the use of antidepressants, benzodiazepine, anticoagulants, or antithrombotic agents during the follow-up period.</p><p>The estimated HRs were finally accepted as the SMR weighted and multivariable adjusted HR after exclusion of the patients whose propensity score is > 99.99 in quetiapine, < 0.05 in olanzapine, > 0.90 in haloperidol, and < 0.05 in chlorpromazine</p><p>* Could not be estimated.</p><p>† P for trend was calculated using likelihood ratio test.</p><p>Sub-group analysis of the risk of ischemic stroke with quetiapine, olanzapine, haloperidol, and chlorpromazine compared with risperidone according to the age group, gender, the presence and type of dementia, and comorbidity.</p

Cumulative hazard rate for ischemic stroke after the initiation of risperidone, quetiapine, olanzapine, haloperidol, and chlorpromazine.

<p>Cumulative hazard rate for ischemic stroke after the initiation of risperidone, quetiapine, olanzapine, haloperidol, and chlorpromazine.</p

General characteristics of new users of conventional and atypical antipsychotic medications.

<p>* The P value was calculated by using the Mantel-Haenszel chi-squared test.</p><p>† The P value was calculated by using an ANOVA test with the Bonferroni correction.</p><p>General characteristics of new users of conventional and atypical antipsychotic medications.</p

Incidence rates and hazard ratios of ischemic stroke after the initiation of conventional and atypical antipsychotic medications.

<p>(SMR, standardized morbidity ratio)</p><p>* (No. of events/total No. of days per 365 days)× 1,000.</p><p>† Adjusted for age, gender, presence or absence of dementia (F00-F03, G30, G31.8), depression (F32–33, F34.1, F41.2), dyslipidemia (E78.0), coronary heart disease (I21-I25), COPD (J40-J44, J47), and the use of antidepressants, benzodiazepine, anticoagulants, or antithrombotic agents during the follow-up period.</p><p>SMR weighted and multivariable adjusted HR after exclusion of the patients whose propensity score was > 99.99 in quetiapine, < 0.05 in olanzapine, > 0.90 in haloperidol, and < 0.05 in chlorpromazine.</p><p>Incidence rates and hazard ratios of ischemic stroke after the initiation of conventional and atypical antipsychotic medications.</p

Dose-response relationship and time-varying risks of ischemic stroke of quetiapine, olanzapine, haloperidol, and chlorpromazine compared with risperidone.

<p>(Mean PDD, mean Prescribed Daily Dose)</p><p>*Adjusted for age, gender, presence or absence of dementia (F00-F03, G30, G31.8), depression (F32–33, F34.1, F41.2), dyslipidemia (E78.0), coronary heart disease (I21-I25), COPD (J40-J44, J47), and the use of antidepressants, benzodiazepine, anticoagulants, or antithrombotic agents during the follow-up period.</p><p>The estimated HRs were finally accepted as the SMR weighted and multivariable adjusted HR after exclusion of the patients whose propensity score is > 99.99 in quetiapine, < 0.05 in olanzapine, >0.90 in haloperidol, and < 0.05 in chlorpromazine</p><p>†Could not be estimated.</p><p>‡P for trend was calculated using the likelihood ratio test.</p><p>§Short- and long-term periods were distinguished by the cross-point using a log-log survival curve.</p><p>Dose-response relationship and time-varying risks of ischemic stroke of quetiapine, olanzapine, haloperidol, and chlorpromazine compared with risperidone.</p