Risk of Cerebrovascular Accident and Use of Antipsychotics
Risk of Cerebrovascular Accident and Use of Antipsychotics
Objectives: To explore the association between use of antipsychotics and risk of cerebrovascular accident (CVA) in individuals with dementia aged 65 and older.
Design: Population-based case–control study.
Setting: UK-based electronic primary care records in the General Practice Research Database (GPRD).
Participants: Individuals with dementia aged 65 and older registered in the database between January 1, 1995, and June 22, 2007.
Measurements: Odds ratio (OR) of CVA in users versus nonusers of antipsychotics (typical or atypical) and in users of typical versus atypical antipsychotics. Multivariate analyses were performed using logistic regression models to adjust for potential confounders: demographic variables, comorbidity, and concomitant treatments.
Results: After adjusting for confounding variables, the OR of CVA associated with use of only typical antipsychotics versus no antipsychotics in individuals with dementia aged 65 and older was 1.16 (95% confidence interval (CI)=1.07–1.27) and for use of only atypical antipsychotics versus no antipsychotics was 0.62 (95% CI=0.53–0.72). In the comparison of typical versus atypical antipsychotics, the OR was 1.83 (95% CI=1.57–2.14).
Conclusion: No reasons were found to question the cerebrovascular safety of atypical antipsychotics in older adults with dementia. The typical antipsychotics appear to be associated with a higher risk of CVA, although the risk disappears after use is discontinued.
Antipsychotic drugs are a highly heterogeneous group of medications from a chemical point of view, but they have a similar mechanism of action. These drugs are used for the treatment of a number of mental illnesses such as dementia in older adults, acute psychosis, schizophrenia, delirium, confusion syndromes, depression, psychomotor agitation, and other behavioral disorders.
The introduction in the 1950s of chlorpromazine, the first antipsychotic drug to be used in clinical practice, revolutionized the world of psychiatry and neurology. The first antipsychotics approved for clinical use, also called classic, first-generation, conventional, or typical antipsychotics, have been shown over time to be effective in controlling these diseases, with largely similar results in the different drugs in this group, but the secondary extrapyramidal effects linked to their pharmacological action has greatly impeded their use. Moreover, up to 20% of people are refractory to these types of antipsychotics, and their use in older adults with dementia increases the risk of mortality. These are the main factors limiting the use of this group of medications.
In the early 1990s, a new group of antipsychotic drugs was developed, also known as atypical or second-generation antipsychotics, with effectiveness outcomes similar to those of conventional antipsychotics, although a recent review questions their efficacy. Their main advantage is the reduction, in large measure, of extrapyramidal effects, although their use in elderly persons with dementia has been questioned in recent years because of the possibility of risk of mortality and cerebrovascular accidents (CVAs). In 2002, Health Canada, based on a meta-analysis of data from randomized clinical trials of risperidone versus placebo in people with dementia (incidence of CVA in the risperidone group was 4%, vs 2% in the placebo group), warned Canadian physicians of a possible association between use of risperidone and adverse cerebrovascular events. In 2004, it issued a similar warning on the use of olanzapine (incidence of CVA in the olanzapine group was 1.3%, vs 0.4% in the placebo group). Despite these warnings, prescription of atypical antipsychotics in this group of individuals in Canada has not been reduced. Several other countries have also cautioned regarding possible contraindications to use of this group of drugs. In 2003, the U.S. Food and Drug Administration issued a similar alert, advising that risperidone was not indicated in the treatment of dementia. In 2004, the UK Committee on Safety of Medicines, based on a meta-analysis, concluded that elderly persons with psychotic or behavioral disorders associated with dementia treated with atypical antipsychotics (olanzapine or risperidone) had a risk of CVA three times as high as that of those treated with placebo and advised that these antipsychotics should not be used in such people. These warnings generated controversy among physicians. A subsequent randomized clinical trial concluded that treatment with olanzapine was safe and effective in elderly persons with dementia.
Observational epidemiological studies have been unable to confirm that use of atypical antipsychotics is associated with more CVA than the use of typical antipsychotics, except for a study conducted in the region of Lombardy, Italy. The results of studies comparing the risk of CVA in users and nonusers of antipsychotics are also inconsistent. In light of this situation, population-based epidemiological studies would be useful to clarify whether these drugs increase the risk of CVA in elderly persons with dementia.
The general objective of the current study was to estimate the risk of CVA associated with exposure to antipsychotics in individuals with dementia aged 65 and older. The specific objectives were to compare the risk in people exposed to any kind of antipsychotic (and separately to only atypical or only typical antipsychotics) with that of those who had not used any antipsychotics and to estimate the above-mentioned risk in individuals exposed to atypical versus typical antipsychotics.
Abstract and Introduction
Abstract
Objectives: To explore the association between use of antipsychotics and risk of cerebrovascular accident (CVA) in individuals with dementia aged 65 and older.
Design: Population-based case–control study.
Setting: UK-based electronic primary care records in the General Practice Research Database (GPRD).
Participants: Individuals with dementia aged 65 and older registered in the database between January 1, 1995, and June 22, 2007.
Measurements: Odds ratio (OR) of CVA in users versus nonusers of antipsychotics (typical or atypical) and in users of typical versus atypical antipsychotics. Multivariate analyses were performed using logistic regression models to adjust for potential confounders: demographic variables, comorbidity, and concomitant treatments.
Results: After adjusting for confounding variables, the OR of CVA associated with use of only typical antipsychotics versus no antipsychotics in individuals with dementia aged 65 and older was 1.16 (95% confidence interval (CI)=1.07–1.27) and for use of only atypical antipsychotics versus no antipsychotics was 0.62 (95% CI=0.53–0.72). In the comparison of typical versus atypical antipsychotics, the OR was 1.83 (95% CI=1.57–2.14).
Conclusion: No reasons were found to question the cerebrovascular safety of atypical antipsychotics in older adults with dementia. The typical antipsychotics appear to be associated with a higher risk of CVA, although the risk disappears after use is discontinued.
Introduction
Antipsychotic drugs are a highly heterogeneous group of medications from a chemical point of view, but they have a similar mechanism of action. These drugs are used for the treatment of a number of mental illnesses such as dementia in older adults, acute psychosis, schizophrenia, delirium, confusion syndromes, depression, psychomotor agitation, and other behavioral disorders.
The introduction in the 1950s of chlorpromazine, the first antipsychotic drug to be used in clinical practice, revolutionized the world of psychiatry and neurology. The first antipsychotics approved for clinical use, also called classic, first-generation, conventional, or typical antipsychotics, have been shown over time to be effective in controlling these diseases, with largely similar results in the different drugs in this group, but the secondary extrapyramidal effects linked to their pharmacological action has greatly impeded their use. Moreover, up to 20% of people are refractory to these types of antipsychotics, and their use in older adults with dementia increases the risk of mortality. These are the main factors limiting the use of this group of medications.
In the early 1990s, a new group of antipsychotic drugs was developed, also known as atypical or second-generation antipsychotics, with effectiveness outcomes similar to those of conventional antipsychotics, although a recent review questions their efficacy. Their main advantage is the reduction, in large measure, of extrapyramidal effects, although their use in elderly persons with dementia has been questioned in recent years because of the possibility of risk of mortality and cerebrovascular accidents (CVAs). In 2002, Health Canada, based on a meta-analysis of data from randomized clinical trials of risperidone versus placebo in people with dementia (incidence of CVA in the risperidone group was 4%, vs 2% in the placebo group), warned Canadian physicians of a possible association between use of risperidone and adverse cerebrovascular events. In 2004, it issued a similar warning on the use of olanzapine (incidence of CVA in the olanzapine group was 1.3%, vs 0.4% in the placebo group). Despite these warnings, prescription of atypical antipsychotics in this group of individuals in Canada has not been reduced. Several other countries have also cautioned regarding possible contraindications to use of this group of drugs. In 2003, the U.S. Food and Drug Administration issued a similar alert, advising that risperidone was not indicated in the treatment of dementia. In 2004, the UK Committee on Safety of Medicines, based on a meta-analysis, concluded that elderly persons with psychotic or behavioral disorders associated with dementia treated with atypical antipsychotics (olanzapine or risperidone) had a risk of CVA three times as high as that of those treated with placebo and advised that these antipsychotics should not be used in such people. These warnings generated controversy among physicians. A subsequent randomized clinical trial concluded that treatment with olanzapine was safe and effective in elderly persons with dementia.
Observational epidemiological studies have been unable to confirm that use of atypical antipsychotics is associated with more CVA than the use of typical antipsychotics, except for a study conducted in the region of Lombardy, Italy. The results of studies comparing the risk of CVA in users and nonusers of antipsychotics are also inconsistent. In light of this situation, population-based epidemiological studies would be useful to clarify whether these drugs increase the risk of CVA in elderly persons with dementia.
The general objective of the current study was to estimate the risk of CVA associated with exposure to antipsychotics in individuals with dementia aged 65 and older. The specific objectives were to compare the risk in people exposed to any kind of antipsychotic (and separately to only atypical or only typical antipsychotics) with that of those who had not used any antipsychotics and to estimate the above-mentioned risk in individuals exposed to atypical versus typical antipsychotics.
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