NPC Archive Item: More evidence that antipsychotics increase stroke risk

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Douglas IJ, Smeeth L. Exposure to antipsychotics and risk of stroke: self controlled case series study. BMJ 2008;337:a1227

A recent study adds to evidence that typical and atypical antipsychotics are both associated with an increased risk of stroke in elderly patients. The risk appears to be higher with atypical antipsychotics and in patients with dementia.

Antipsychotic use should be avoided in patients with dementia whenever possible. Although the risk seems lower in patients without dementia, the background risk of stroke in elderly patients is high and, as with all treatment decisions, the potential risks and benefits of antipsychotic treatment should be balanced on an individual patient basis. Typical antipsychotics are likely to be preferable to atypical antipsychotics with regard to stroke risk.

What is the background to this?
In March 2004, the Committee on Safety of Medicines (CSM) advised that olanzapine and risperidone should not be used for the treatment of behavioural symptoms of dementia. There was clear evidence of an increased risk of stroke in elderly patients with dementia who were taking these drugs, and the risk was considered sufficient to outweigh likely benefits. The CSM also advised that if risperidone was used for the management of acute psychotic conditions in elderly patients with dementia, this should be short-term and under specialist advice.

The NICE 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.

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 to people with dementia. The review is due for publication in October 2008.

What does this study claim?
This self-controlled case series study found that all antipsychotics are associated with an increased risk of stroke, but the risk appears to be higher in those receiving atypical, rather than typical, antipsychotics. A 73% relative increase in the risk of stroke was seen in periods of time when patients were exposed to any antipsychotic compared with unexposed periods (rate ratio or relative risk [RR] 1.73, 95% confidence interval [CI] 1.60 to 1.87). The relative increase in stroke risk was similar in patients receiving only typical antipsychotics (RR 1.69, 95% CI 1.55 to 1.84) but it more than doubled with exposure to only atypical antipsychotics (RR 2.32, 95% CI 1.73 to 3.10), both versus unexposed periods.

Also, people with dementia (which was recorded before their stroke) appear to be at a higher risk of an associated stroke than people without dementia. In those receiving any antipsychotic drug, the relative risk of stroke was tripled (RR 3.50, 95% CI 2.97 to 4.12) for those with dementia, whereas a much smaller increase in the risk was seen in those without dementia (RR 1.41, 95% CI 1.29 to 1.55), both versus unexposed periods.

In patients with dementia, the risk of stroke was three times higher while they were treated with typical antipsychotics only, compared with periods of non-exposure (RR 3.26, 95% CI 2.73 to 3.89). Although few people with dementia received only atypical antipsychotics, so the results are less certain, the risk was five times higher during periods of exposure to atypical antipsychotics, compared with periods of non-exposure (RR 5.86, 95% CI 3.01 to 11.38).

So what?
Self-controlled case series studies are less prone to bias and confounding than traditional case-control or cohort studies. This is because differences between patients are largely irrelevant as risk comparisons are made within patients, and controls are not required. This is discussed further in an accompanying editorial. However, the study is still an observational study and can, therefore, only prove that antipsychotics are associated with an increased risk of stroke, not that they are the cause of that increased risk. It is also argued in correspondence to this study that we cannot yet rule out the possibility that the factors that cause a psychotic episode themselves may be associated with an increased risk of stroke. The only way to be sure would be to conduct a prospective randomised controlled trial (RCT) in elderly people having a psychotic episode where one group is given placebo and another group an antipsychotic.

That said, the results of the study are consistent with previous data, suggesting that all antipsychotics, regardless of their type are associated with an increased risk of serious adverse reactions, even when used over the short-term (see previous MeReC Rapid Review Blog). The study provides further support for the CSM recommendations on atypical antipsychotics and the advice on antipsychotics in the NICE guideline on dementia Antipsychotics should only be used in exceptional circumstances in people with dementia, only by specialists, and after full discussion about the risks and benefits with the patient and the people who care for them.

You can find further information on the treatment of dementia on the CNS and mental health floor of NPC

Study details

Design: retrospective self-controlled case series

Patients: 6,790 patients in the UK general practice research database (GPRD) with at least one prescription for an antipsychotic drug and a first diagnosis of stroke, between January 1988 and the end of 2002. 1,423 patients had a recorded diagnosis of dementia prior to their stroke.

Intervention: 6,334 patients were prescribed at least one typical antipsychotic (most commonly phenothiazines), 905 were prescribed at least one atypical antipsychotic (most commonly risperidone) and 449 patients were prescribed both.

Comparison: rate ratios for stroke in periods of time exposed to antipsychotics compared with unexposed periods.


Association between exposure to antipsychotic and stroke
Exposed vs. unexposed periods; rate ratios
(95% confidence intervals)

Any antipsychotic (n=6,790)

Typical only (n=5,885)

Atypical only (n=456)

All patients (n=6,790)

1.73 (1.60 to 1.87

1.69 (1.55 to 1.84)

2.32 (1.73 to 3.10)

Dementia recorded (n=1,423)

3.50 (2.97 to 4.12)

3.26 (2.73 to 3.89)

5.86 (3.01 to 11.38)

Dementia not recorded (n=5,367)

1.41 (1.29 to 1.55)

1.40 (1.26 to 1.54)

1.90 (1.36 to 2.65)

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