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28 March 2012
A large observational study suggests that haloperidol is associated with a greater relative risk of death than risperidone when used in older people, and quetiapine has a lower risk. However, there is no reliable evidence that quetiapine is effective in managing the behavioural and psychological symptoms of dementia (BPSD), for which it is unlicensed.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Action
Healthcare professionals should follow the NICE/SCIE guideline for the management of patients with dementia who have behavioural and psychological problems. Antipsychotic drugs should be prescribed only when a person is a risk to themselves or others, and when all other methods have been tried. This should be for a short period of up to three months only, while a care plan is put in place. If use of an antipsychotic is unavoidable, this study, in the context of the rest of the evidence, does not provide convincing grounds for choosing an alternative to the only antipsychotic licensed for this use, risperidone.
What is the background to this?
More than 90% of people with dementia will experience BPSD. These symptoms include agitation, aggression, hallucinations and delusions, which are distressing to people with dementia, their families and carers. The Banerjee report on the prescribing of antipsychotic drugs to people with dementia found that the benefits from these drugs on BPSD are limited but that they are associated with an increased risk of stroke and death (see the NPC shared decision aid). Short-term use of antipsychotic drugs can sometimes be appropriate when all other methods have been tried. However, the Banerjee report found that antipsychotic drugs are often used, usually inappropriately so, as first-line treatment for BPSD.
Risperidone is the only antipsychotic drug currently licensed for use in BPSD (see the SPC for details of the licensed indication), but it is not the only antipsychotic used in practice for this. The authors of this study used information from prescribing and other data sets to compare the risk of death associated with the use of antipsychotics in older people. Data were collected relating to 75,445 older people resident in nursing homes in 45 US states between 2001 and 2005. Not all of these people had a formal diagnosis of dementia. People who had a pre-existing diagnosis of cancer, schizophrenia, or bipolar disorder were excluded. Deaths within 180 days of starting different antipsychotics were evaluated
What does this study claim?
Compared with risperidone, and after adjusting for a number of variables, patients treated with haloperidol had double the risk of mortality (hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.89 to 2.26) and patients treated with quetiapine had a reduced risk (HR 0.81, 95%CI 0.75 to 0.88). The effect of haloperidol was strongest during the first 40 days of treatment. No statistically significant differences in risk were observed for aripiprazole, olanzapine or ziprasidone, although the numbers of events and people exposed to aripiprazole or ziprasidone were small. There was no evidence that the effects were modified by the presence of a recorded diagnosis of dementia or behavioural disturbances.
So what?
The NICE/SCIE guideline for dementia recommends that people with dementia who develop non-cognitive symptoms that cause them significant distress or who develop behaviour that challenges should be offered a comprehensive assessment at an early opportunity to establish likely factors that may generate, aggravate or improve such behaviour. Building on these recommendations, a best practice guide, ‘Optimising treatment and care for people with behavioural and psychological symptoms of dementia‘, has been published and is endorsed by the Department of Health. The guide provides advice to health and social care professionals on how to treat behavioural and psychological symptoms (such as agitation and depression) with the aim of preventing inappropriate prescriptions of antipsychotics.
If short-term use of antipsychotics is unavoidable, then (all other things being equal) it is best to choose the drug with the lowest risk of harms and the greatest likelihood of having a beneficial effect. This study suggests that risperidone is preferable to haloperidol in terms of safety. The lower risk associated with quetiapine in this study might suggest that it is preferable to risperidone. However, a recent, large, comprehensive systematic review found no evidence of a statistically significant benefit from quetiapine on BPSD. That review found a small but statistically significant effect on BPSD from aripiprazole, olanzapine and risperidone. Haloperidol was not considered.
A single observational study, such as this one, can prove only association not causation and observational studies are prone to confounding. Unlike in the setting of a randomised controlled trial, in ‘real life’, treatment plans are chosen, changed, or actively not chosen in the light of individual patients’ risk factors, preferences and tolerability or response to other drugs. Thus observed differences in outcomes may be due to differences among the patients, not only the different treatments. In this study the authors adjusted for a number of such possible confounders. However, residual confounding cannot be ruled out, although the authors calculate that an unknown confounder would have to have a large effect and/or be present in a large proportion of the population to explain the results. Another major limitation of the study is the absence of a comparison of mortality risks in people who were not taking antipsychotics, so as to give a comparative measure.
The use of antipsychotics in dementia is included in the QIPP document: ‘Key therapeutic topics – Medicines management options for local implementation’. A set of e-learning resources are also available to support implementation of this topic. More information on dementia can be found within the CNS and mental health NPC e-learning materials and on NHS Evidence.
Design United States 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
Patients 75,445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥65 years, were eligible for Medicaid, and lived in a nursing home in 2001–5
Intervention and comparison 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
Main results
Table: Non-cancer mortality, hazard ratio (HR) versus risperidone
| Drug | Adjusted HR | 95% CI |
| Haloperidol | 2.07 | 1.89 to 2.26 |
| Olanzapine | 1.02 | 0.96 to 1.08 NS* |
| Ziprasidone | 0.92 | 0.72 to 1.17 NS* |
| Aripiprazole | 0.88 | 0.73 to 1.07 NS* |
| Quetiapine | 0.81 | 0.75 to 0.88 |
*NS: not statistically significant
Study sponsorship This study was supported by AHRQ and FDA awards. The lead author and one of the other authors were partly funded by a National Institute of Mental Health award
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