Psychiatric News April 1, 2005
Volume 40 Number 7
© 2005 American Psychiatric Association
p. 32
New Analysis Questions Antipsychotics' Stroke Risk
Aaron Levin
Off-label use of antipsychotic drugs in older patients with dementia is
associated with higher risk of strokes, but higher baseline risk or
mis-classification of events may account for the difference.
Using atypical antipsychotic medications in elderly demented patients to
control agitation and aggression is a standard—if
off-label—practice, but one tempered by warnings in recent years that
they raise the risk of stroke.
Now several recent studies complicate that issue. One reanalysis of earlier
clinical trials found that increased rates of stroke in one trial may have
been due to inclusion of patients at higher cerebrovascular risk or the
mislabeling of the events they experienced. A large, population-based cohort
study reported no difference in risk of ischemic stroke between those taking
typical and atypical antipsychotics, while a systematic review of four drug
classes concluded that atypicals showed modest efficacy but with an increased
risk of stroke.
No randomized controlled studies testing atypical antipsychotics in this
population have been carried out, according to Nathan Herrmann, M.D., an
associate professor of psychiatry and medicine, and Krista L. Lanctôt,
Ph.D., an associate professor of psychiatry and pharmacology at the University
of Toronto, and Sunnybrook and Women's College Health Sciences Centre. That
has not kept the drugs from playing an important role, especially in
institutional settings. Guidelines issued by the American Academy of
Neurology, American Geriatrics Society, and others recommend their use once
behavioral methods have failed.
Herrmann and Lanctôt reanalyzed results from 11 randomized controlled
trials of risperidone and olanzapine. Beginning in 2002, drug regulators in
Canada and Switzerland, and then in the United States, issued warnings about
elevated risks of stroke on the basis of those trials. Although these warnings
were first published for risperidone and olanzapine, the FDA recommended a
similar warning about stroke for aripiprazole in December 2004.
The initial conclusions were based on a review of six studies of
risperidone indicating that 3.3 percent of risperidone-treated subjects
experienced strokes, compared with 1.1 percent of those on placebo. Five
persons (0.5 percent) on risperidone died, as did one (0.1 percent) subject on
placebo. In olanzapine trials, 1.3 percent of patients recorded a
cerebrovascular event (with four deaths), compared with 0.4 percent on placebo
(and one death).
"Taken at face value, without critical review, these are disturbing
figures," wrote Herrmann and Lanctôt in the February issue of
CNS Drugs. However, their detailed analysis found less clarity below
the surface of the numbers. For one, the definition of cerebrovascular adverse
events included unclear or overlapping terms: "stroke, transient
ischemic attacks, cerebrovascular accidents, cerebral ischemia, cerebral
infarct, cerebrovascular disturbance, and cerebrovascular disorder."
Comparing the risperidone and olanzapine trials, they found that the
risperidone trials had included disproportionately large numbers of patients
who had vascular dementia and mixed dementia and thus would have begun the
trials at higher risk for cerebrovascular events. Trial subjects were not
stratified by stroke risk factors. Eleven patients who experienced
cerebrovascular events in these trials had hypertension, eight had atrial
fibrillation, and 10 had prior strokes, all important risk factors for
stroke.
Then, by dividing events into the serious (death, needing hospitalization,
leading to serious disability) and nonserious, Herrmann and Lanctôt
found that the rate of serious events (15 of 1009, or 1.5 percent) was not
significantly different statistically from the rate of those on placebo (4 of
712, or 0.6 percent, p=0.27). The rate of nonserious events of subjects on
risperidone (18 of 1009, or 1.8 percent) was significant compared with the
rate of those on placebo (4 of 172, or 0.6 percent, p=0.026).
"Given that the frequency of cerebrovascular adverse events differs
only for the nonserious events, it is possible that miscoding of events might
explain the differences," the authors stated.
Statistically different event and mortality rates were also found in
olanzapine trials, but differences between serious and nonserious outcomes
were not recorded. Several small, unpublished trials found olanzapine and
risperidone had similar event and mortality rates, as did trials comparing
olanzapine and typical antipsychotics.
"This is a group of patients prone to having strokes anyway,"
said William Regenold, M.D., an assistant professor and director of the
Division of Geriatric Psychiatry at the University of Maryland in Baltimore.
The majority of strokes occur in patients over 75 years of age, and cognitive
impairment is an independent risk factor. Low absolute rates of stroke in
these drug trials make it hard to tease out the causes.
A population-based retrospective cohort study examined 32,710 older adults
with dementia living in Ontario, Canada, from 1997 to 2002. Of those, 17,845
received atypical antipsychotics, and 14,865 were prescribed typical
antipsychotic medications. The adjusted hazard ratio for incidence of
admission to hospital with stroke of those using atypical compared to typical
antipsychotics was 1.01. Although the risk of stroke was the same, clinicians
should weight other risks and benefits of typical or atypical antipsychotics,
wrote Gill, Rochon, Herrmann, and colleagues in the February 26 BMJ
(British Medical Journal).
Authors of a systematic review published in the February 2 JAMA
examined efficacy and adverse effects among typical antipsychotics, atypical
antipsychotics, mood stabilizers, and cholinesterase inhibitors in older
patients with dementia.
"Pharmacological therapies are not particularly effective for
management of neuropsychiatric symptoms of dementia," wrote Kaycee M.
Sink, M.D., Karen F. Holden, M.D., and Kristine Yaffe, M.D. "Of the
agents reviewed, the atypical antipsychotics risperidone and olanzapine
currently have the best evidence for efficacy. However, the effects are modest
and further complicated by an increased risk of stroke."
"Clinicians may be using medications in place of more supportive
environments," said University of Maryland's Regenold. "A lot of
patients are on antipsychotic drugs when other causes should be investigated.
Patients may be in pain, fearful, or confused by their surroundings. Modifying
the conditions that produce symptoms should be the first step."
Sink, Holden, and Yaffe came to the same conclusion in their report and
recommended that physicians and caregivers should try nonpharmacological
treatment first. If that does not alleviate behavioral problems, they
suggested beginning drug treatment with a cholinesterase inhibitor unless the
patient is already receiving one, while avoiding typical antipsychotics and
benzodiazepines. They presented a more complete algorithm for managing
neuropsychiatric symptoms of dementia in their article.
"Do Atypical Antipsychotics Cause Stroke?" is posted
online at
<www.ingentaconnect.com/content/adis/cns/2005/00000019/00000002/art00001>.
"Atypical Antipsychotic Drugs and Risk of Ischaemic Stroke: Population
Based Retrospective Cohort Study" is posted at
<http://bmj.bmjjournals.com/cgi/content/full/330/7489/445>.
An abstract of "Pharmacological Treatment of Neuropsychiatric Symptoms
of Dementia" is posted at
<http://jama.ama-assn.org/cgi/content/abstract/293/5/596>.
BMJ 2005 330 445[Abstract/Free Full Text]
JAMA 2005 293 596[Abstract/Free Full Text]
Get information about faster international access.
Privacy Policy
Copyright © 2005
American Psychiatric Association.
All rights reserved.
Home
| Search
| Current Issue
| Past Issues
| Subscribe
| All APPI Journals
| Help
| Contact Us
| 
