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The Risk of Cerebrovascular Problems in Patients With Dementia Treated With Atypical Antipsychotics

(PSYCHIATRIC TIMES) - Educational Objectives:

After reading this article, you will be familiar with:

* Concerns associated with the use of antipsychotics in patients with dementia
* Amount of risk for cerebrovascular adverse events (CVAEs) associated with various antipsychotics
* Mechanisms that may be involved in increasing the risk of CVAEs in patients with dementia

Who will benefit from reading this article?

Psychiatrists, primary care physicians, neurologists, nurse practitioners, psychiatric nurses, and other mental health care professionals. Continuing medical education credit is available for most specialties. To determine if this article meets the CE requirements for your specialty, please contact your state licensing board.

Dr Bullock is principal investigator and director at the Kingshill Research Centre as well as a consultant and manager of the old age psychiatry department at Swindon in the Avon and Wiltshire Mental Health Care Partnership NHS Trust in the UK. He reports that he has undertaken clinical trials in the field of dementia for numerous pharmaceutical companies, including studies on all the drugs mentioned in this article.

Antipsychotics have been seen as a mainstay of treatment for the behavioral and psychological symptoms of dementia for many years. While their value is fairly obvious in the more positive symptoms, such as agitation, psychosis, and aggression, their widespread prescription for lesser symptoms has caused concern and led to a mistrust of their use. In many countries, the use of antipsychotics for behavioral and psychological symptoms of dementia represents offlabel use, even though it is supported by numerous randomized controlled trials and meta-analyses.

The Omnibus Reconciliation Act of 1987 introduced guidance in the United States to restrict the use of atypical antipsychotics to the most necessary cases and only after nonpharmacologic therapies had been attempted.1 In late 2002, health regulatory agencies in Canada and Switzerland raised concerns about an association of risperidone with cerebrovascular adverse events (CVAEs) in clinical trials in elderly dementia patients. The FDA and the UK Committee for Safety in Medicine (CSM) soon followed and published recommendations restricting the use of risperidone and olanzapine in elderly patients with dementia—citing the reason as a “clear risk of stroke” emerging from the randomized studies.2
The trial data

In the 11 randomized studies of risperidone and olanzapine conducted to date in elderly subjects with dementia, 48 (2.2%) of the 2187 patients treated had CVAEs, compared with 10 (0.8%) of the 1190 patients in the placebo groups.3 The combined relative risk was 2.7 (95% confidence interval, 1.4, 5.3). Of the 1009 patients treated with risperidone, 33 (3.3%) had a CVAE, and of the 1178 treated with olanzapine, 15 (1.3%) had a CVAE; 5 patients treated with risperidone and 4 treated with olanzapine died, compared with 1 in each of the placebo groups. This is a significant finding that merits the warnings—especially considering that the CSM calculated the number of patients needed to be treated to show harm (CVAEs) as 6.

However, as is often the case with pure data, these figures may not really tell the whole story. Cerebrovascular disease increases with age, with a standardized prevalence rate of stroke in persons older than 65 years of 46 to 72 per 1000 patient years.4 Patients with cognitive impairment have an increased risk for cerebrovascular disease,5 independent of vascular risk factors; and studies suggest that patients with Alzheimer disease (AD) died of stroke more frequently than elderly people without AD.6 It seems likely that some of the patients studied in these 11 trials would have CVAEs over a 12-week study period. However, there are still differences between risperidone and olanzapine—and between each of these drugs and placebo—that need explaining.

In 6 studies of risperidone in nursing home residents (n = 1721), patients with dementias other than AD (eg, vascular dementia, AD with cerebrovascular disease) were included. This means that a third of the patients in the CVAEs analysis already had a significant risk for such an event. In clinical trials CVAEs are grouped into a single category that includes serious events, such as stroke and cerebral infarct, but also less serious events, such as transient ischemic attack or cerebrovascular disturbance. If the CVAEs are divided into serious and not serious events, the rates of serious events are not statistically different from those in patients receiving placebo: 15 (1.5%) of the 1009 in the risperidone group, compared with 4 (0.6%) of 712 in the placebo group. Of the subjects with CVAEs, nearly all had major risk factors for stroke, including hypertension and atrial fibrillation; 10 actually had a previous history of stroke.7

Although “not serious” CVAEs were more frequent with risperidone (18 vs 4), issues around misdiagnosis were raised in subsequent reviews that included the recording of orthostatic and sedative side effects and vasovagal faints as CVAEs. This suggests that the rates of CVAEs were lower and the difference between risperidone and placebo may have been an artifact created by imperfect coding of other effects. Thus, claims that the use of risperidone increased the incidence of stroke should be tempered. However, the stroke mortality rate was higher in the risperidone group than in the placebo group (13.9 vs 8.4 per 1000 patient years), compared with no difference on all-cause mortality (182.3 vs 185.0), so the need for suitable caution in this patient group remains, especially in patients with cerebrovascular disease.

The olanzapine data come from 5 trials: 4 involved exclusively AD patients and 1 was a comparison study with risperidone, composed of a mixed group of AD, vascular dementia, and AD with cerebrovascular disease. In the olanzapine group, 15 (1.3%) of 1178 patients were reported to have a CVAE, compared with 2 (0.4%) of 478 subjects in the placebo group. This was statistically significant (p = .016), as was the difference in the mortality data: 42 (3.5%) versus 7 (1.5%). These CVAE data were not reported in the same way as the risperidone data; looking at serious versus not serious CVAEs or stroke incidence is not possible. Not much more can be said about the olanzapine data from these particular studies other than that the rates of CVAEs are low and may look numerically different from risperidone because of shorter study duration and fewer subjects with preexisting vascular disease.3

Currently, no other studies of atypical antipsychotics have been published, although several have been undertaken. Anecdotally, it appears that CVAEs occur at similar rates in quetiapine studies, and there are reports that the rates are the same for aripiprazole as for placebo. These data need to be published before firm conclusions can be drawn, but the FDA has issued a statement about the mortality data and classed all of the atypical antipsychotics as having the potential to increase mortality (odds ratio, 1.57).
Possible explanations for the CVAE findings

There are several potential explanations for the seemingly higher rates of CVAEs with atypical antipsychotics, but these remain hypotheses because no study has ever been undertaken to establish a causal relationship. All antipsychotics have been associated with venous thromboembolism, to the extent that a warning in both the United States and United Kingdom is included in the labelling.8 This applies equally to the older, typical antipsychotics and is probably a result of platelet aggregation, although no data support this from either preclinical or clinical studies. Anticholinergic and α-adrenoceptor blockade may have an effect on cardiovascular homeostasis and may produce tachycardia and orthostatic hypotension, both of which have been associated with an increased risk for stroke.9 This would be a simple rationale, but in all the risperidone studies and all but one of the olanzapine studies, there has been no difference shown between the treatment and placebo groups in these measures or ECG parameters and other vital signs.

Another mechanism may be alteration in vascular tone and reactivity in patients with dementia, leading to less adaptability to physiologic challenges. A large, unpublished German study of risperidone in patients with psychosis, but no dementia, did not find a rate of CVAEs similar to that seen in elderly patients with dementia; so this phenomenon does seem related to dementia. Given that the incidence is higher in those with preexisting vascular damage or risk factors, it is intuitive that a vascular cause may be the explanation.

A mechanism involving endothelial dysfunction could offer an explanation.10 Given that this is also a proposed mechanism of reduced energy in the brains of patients with AD, the question remains: Why would atypical antipsychotics make this differentially worse than placebo? Raised levels of prolactin have been associated with impaired endothelial function and platelet aggregation, leading to increased atherosclerosis.11 Both risperidone and olanzapine have the potential to raise prolactin levels; quetiapine, less so. In most cases this increase in prolactin level is often noticeable but at levels not much above the accepted upper range of normal. Thus, even though levels were not taken in any of these studies in dementia, considerable overlap would be expected between the placebo and active-treatment groups. Even if endothelial function were a mechanism, it would be expected for this to result in longer-term side effects and not something that be seen in a 6- or even 12-week study.

Other known side effects of atypical antipsychotics are weight gain; changes in insulin metabolism; sedation; and the presence of extrapyramidal side effects (EPS), albeit at much lower levels than with typical antipsychotics. The trials were too short for the metabolic effects to have an influence, but sedation and EPS could have contributed to venous stasis and indirectly increased the risk for CVAEs. Risperidone was found to cause dose-dependent EPS in a US study,12 whereas in studies with olanzapine, there were no differences shown with placebo; thus, it is difficult to draw any conclusions about EPS as a contributing mechanism. Sedation featured in all antipsychotic studies and it can be postulated that the resulting dehydration increased the risk for CVAEs (although this was not supported by laboratory tests performed during the studies and so would appear unlikely).
Were the warnings warranted?

The warnings about risperidone and olanzapine grew out of post hoc analyses that suffered from multiple comparisons. The CSM used a random-effects model when the studies they selected were not random, especially for cerebrovascular risk factors, and made assumptions that what happened in a 6-week study continued to be a constant effect over a year when stating their number needed to treat. This is clearly not the case and the error is compounded when the results for all patients, both high and low risk, are pooled. Such an approach may result in spurious conclusions that may preclude all patients with dementia from having a viable treatment option.13

After the warnings appeared, the use of risperidone and olanzapine dropped dramatically. Many patients had these drugs phased out and did not actually require further treatment because their symptoms did not return, which reinforced the need for regular review of a patient’s pharmacotherapy. Others were given alternative antipsychotics, including typical antipsychotics, which had generally fallen into disuse because of their propensity for causing EPS and other harmful side effects.

What was not apparent was whether the typical antipsychotics had the same association with CVAEs. No specific data exist, but several large observational studies included typical antipsychotics in their analyses. Interpretation from these studies is clearly open to certain biases and lacks the control of randomized clinical trials but does allow the study of low frequency events in large numbers of patients.

A review of Medicaid records between 1999 and 2002 looked at more than 18,000 admissions for a stroke-related event in patients with dementia treated with a psychotropic agent in the previous 90 days.14 The results showed no increased risk with the atypical antipsychotics but a doubling of the risk with haloperidol and benzodiazepines. Another case-control study in nursing homes looked at 1130 subjects treated with antipsychotics, compared with 3658 controls, and again found no statistical separation from nonusers.15 A study in Ontario, Canada, compared all adults over 65 years (11,400) on risperidone or olanzapine therapy with those using typical antipsychotics between 1997 and 2002.16 The risk ratios for stroke were the same for the atypical and typical antipsychotics, which suggests that use of typical antipsychotics following the warnings did not confer extra safety. Considered together, these studies suggest that atypical antipsychotics have no more risk than either no treatment or typical antipsychotic treatment and are perhaps safer than haloperidol or benzodiazepines. Properly designed studies are needed to confirm this, but the results of the Canadian studies offer a certain reassurance.

In terms of clinical practice, it would seem that the atypical antipsychotics are not quite as harmful as originally thought and that the warnings, while produced for the correct reasons, may have been premature. At the time, risperidone in particular, and olanzapine were commonly used in the treatment of behavioral and psychological symptoms of dementia, especially if nonpharmacologic methods had failed. The warnings had such a high impact primarily because of a lack of available options for treating a common condition for which some intervention is often expected.

Reviews of nonpharmacologic treatments often show small, methodologically problematic studies with little or no effect on the target symptoms, thus not offering real alternatives, especially in aggression and psychosis. Other treatments that have been suggested, such as trazodone and other antidepressants, mood stabilizers, and benzodiazepines, also have no convincing evidence of reliable effect. The evidence base is firmly with atypical antipsychotics, particularly risperidone.

Guidelines still suggest the use of atypical antipsychotics but with more circumspection. It is clear that with risperidone, the serious CVAEs are associated with those patients who have the most cerebrovascular risk factors; this is likely to be the case with all atypical antipsychotics. Identification and management of these factors should help in the treatment of the underlying dementia and serve to minimize risk should antipsychotics be required. Armed with this information, clinicians should not stop using a class of useful drugs across all patients with dementia.

More important, there is no reason to use typical antipsychotics as an alternative therapy because they have the same incidence of ischemic stroke regardless of which atypical antipsychotic they are compared with, or when different levels of baseline cerebrovascular risk are allowed for.17 Instead, cerebrovascular risk is part of a treatment-decision pathway in which hypertension and atrial fibrillation treatment play an equal role to managing the actual behavioral and psychological symptoms of dementia. In adopting this approach and maintaining close communication with caregivers and families, the best of the current treatments can be used logically and safely to good effect where they are needed most.

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