Extended follow-up of the DART-AD trial found patients with Alzheimer’s disease who continued antipsychotic medication for behavioural or psychiatric problems were twice as likely to die as those switched to placebo.
Prescribers should continue to follow the NICE-SCIE guideline on dementia. This advises that we should avoid using any antipsychotics (atypical or conventional) for non-cognitive symptoms or challenging behaviour of dementia unless the patient is severely distressed or there is an immediate risk of harm to them or others. Any use of antipsychotics should include a full discussion with the patient and/or carers about the possible benefits and risks of treatment.
What is the background to this?
Safety concerns over the use of both typical and atypical antipsychotics in elderly patients with dementia have been well documented. In 2004, the CSM advised that the atypical antipsychotics, olanzapine and risperidone, should not be used for treatment of behavioural symptoms of dementia due to evidence of an increased risk of stroke in elderly patients with such symptoms. More recently, in November 2008, the EMEA published a report which concluded that typical antipsychotics are also likely to be associated with increased mortality when used in elderly patients with dementia (see previous MeReC Rapid Review blog here for details).
It is now thought that all antipsychotics, regardless of their type, are associated with an increased risk of serious adverse reactions. However, this is based on data from short-term randomised controlled trials (RCTs) and observational studies. Here we report data from the longer term, placebo-controlled RCT, DART-AD, which aimed to determine whether continued treatment with antipsychotics in people with Alzheimer’s disease is associated with an increased risk of mortality. DART-AD also considered cognitive and neuropsychiatric symptoms and the results are reported here.
What does this study claim?
In DART-AD, 165 patients were randomised to either continue treatment with antipsychotic medication (mainly risperidone or haloperidol) or to discontinue treatment and receive placebo for 12 months. Of the 128 patients who started their allocated treatment, the cumulative probability of survival during the 12-month trial was 70% (58% to 80%) in patients who continued treatment compared with 77% (64% to 85%) in those who switched to placebo.
During extended follow-up (up to 54 months), there was a significant increase in mortality in patients who continued to receive antipsychotics compared to those receiving placebo. People who took antipsychotics were about twice as likely to die as those taking placebo (hazard ratio [HR] 0.58; 95% CI 0.35 to 0.95). The difference in mortality was more pronounced after the 12-month randomised phase of the trial, with a cumulative survival of 46% vs. 71% at 24 months, 30% vs. 59% at 36 months, and 26% vs. 53% at 42 months for the continued treatment vs. placebo groups, respectively.
This study adds to the ever-growing evidence suggesting that all antipsychotics, regardless of their type, are associated with an increased risk of serious adverse reactions (in this case mortality) in elderly patients with dementia. In some ways this study is more helpful than earlier studies as it involved withdrawing anti-psychotic medication from those who have behavioural problems. This helps address earlier concerns that the behavioural problems themselves were responsible for the increased rate of adverse events seen.
There are limitations with the study, including the small number of patients, particularly at the later time points; and it is unclear why the biggest difference in mortality occurred after the 12-month randomised phase. However, the results are consistent with what we have already seen in shorter-term RCTs and observational studies.
It seems prudent to continue to follow the NICE-SCIE guidance on dementia and only use antipsychotics in exceptional circumstances in such patients (see below). As we reported in a MeReC Stop Press blog, a Department of Health review of antipsychotic prescribing is being conducted as part of the National Dementia Strategy to investigate and suggest actions to reduce the inappropriate prescribing of antipsychotics in people with dementia. This review will be completed after the publication of the National Dementia Strategy in 2009.
The NICE-SCIE guideline on dementia recommends that people with dementia who develop non-cognitive symptoms or behaviours that challenge should only be offered a pharmacological intervention in the first instance if they are severely distressed or there is an immediate risk of harm to the person or others. Antipsychotics should only be offered after a full discussion with the patient and/or their carers about the risks and benefits, especially the risk of stroke or transient ischaemic attack (TIA) and possible adverse effects on cognition. The dose of antipsychotic should be low initially and titrated upwards. It should be treatment time-limited and regularly reviewed (every three months or according to need). Antipsychotics should not be prescribed to people with mild-to-moderate dementia with Lewy bodies, as these people are particularly at risk of serious adverse effects.
You can find further information on the treatment of dementia on the CNS and mental health section of NPC
Ballard C, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurology, Early Online Publication, 9 January 2009, doi:10.1016/S1474-4422(08)70295-3
Design: 12-month randomised, placebo-controlled antipsychotic withdrawal trial, with additional follow-up to 54 months. Allocation concealed.
Patients: 165 patients (mean age 85 years) with dementia due to Alzheimer’s disease who resided in care facilities in four areas of the UK and who were prescribed the antipsychotics thioridazine, chlorpromazine, haloperidol, trifluoperazine or risperidone for behavioural or psychiatric disturbance for at least 3 months.
Intervention and Comparison: 83 patients were randomised to continue treatment (active treatment) and 82 to placebo (discontinue treatment). Active treatment was a dose of antipsychotic that was as close as possible to the one they were already receiving at one of three doses: very low, low or high dose. Placebo capsules were identical. Antipsychotic and placebo treatments were maintained at the same fixed dose throughout the 12-month treatment period.
Outcomes: the primary outcome was mortality at 12 months. The principal analysis included everyone who had received at least one dose of treatment (defined as modified intention-to-treat [mITT]). Intention-to-treat [ITT] analysis was also carried out.
Results: of the 165 patients randomised, 128 started treatment (mITT population). In this population, the cumulative probability of survival during the 12 months was 70% (58% to 80%) in patients who continued to receive antipsychotics compared with 77% (64% to 85%) in those who received placebo. During the whole study period (up to 54 months), there was a significant increase in mortality for patients who continued antipsychotics compared with those receiving placebo. The HR for the mITT population was 0.58 (95% CI 0.35 to 0.95). The difference in mortality was more pronounced after the first year, with a cumulative survival of 46% vs. 71% at 24 months, 30% vs. 59% at 36 months, and 26% vs. 53% at 42 months for the continued treatment and placebo groups, respectively.
Sponsorship: supported by a grant from the UK Alzheimer’s Research Trust