Psychiatric News July 16, 2004
Volume 39 Number 14
© 2004 American Psychiatric Association
p. 22
Antipsychotics Do Not Appear To Increase Stroke Risk
Jim Rosack
It is difficult to tease out the real-world risk of taking antipsychotic
medications and having a stroke. But statistically speaking, any relative risk
appears to be quite small.
Olanzapine (Zyprexa) and risperidone (Risperdal) do not appear to be
associated with a statistically significant increased risk of a
cerebrovascular event, or stroke, say Canadian researchers who analyzed
administrative health care data on more than 1.4 million patients over age
65.
Last year, drug regulatory agencies across the globe, including the U.S.
Food and Drug Administration (FDA), issued warnings based on clinical trial
data of the two second-generation antipsychotics in elderly patients with
dementia.
In four clinical trials involving risperidone, the FDA noted that patients
taking the medication appeared to have twice the risk of stroke of subjects
taking placebo. Later in 2003 the same type of warning was issued for
olanzapine, again based on clinical trial data.
The FDA said it was not clear at that time, however, how much of the risk
of stroke was associated with the medication being tested, and how much of the
increased risk might be inherent in the population being studied. The patients
in the clinical trials were elderly, mostly had vascular dementia (itself
associated with stroke), and had high levels of other stroke risk factors such
as diabetes, hypertension, stroke history, and atrial fibrillation.
In the risperidone trials, there was no matching done between drug and
placebo subjects based on these other inherent risk factors to try to
alleviate some of these potentially confounding variables. Thus some
researchers questioned the validity of the risk, given a rare event such as
stroke and a small population (about 1,200 patients were studied in the
risperidone trials).
The new analysis, by Nathan Herrmann, M.D., and colleagues at the
Sunnybrook and Women's College Health Sciences Center at Toronto's Institute
for Clinical and Evaluative Sciences, was published in the June American
Journal of Psychiatry. The report was not supported by funding from the
pharmaceutical industry.
In reviewing data on approximately 1.4 million patients over age 65 from
April 1, 1997 through March 31, 2002, Herrmann and his colleagues found 11,400
patients who were not taking any antipsychotic medication at the beginning of
the observation period but who began taking a first-generation (typical)
antipsychotic (1,015 patients), risperidone (6,964), or olanzapine (3,421)
during the observation period.
All three elderly cohorts were similarly medically frail, although the
risperidone-treated patients were nearly two years older on average than
patients in the other two groups, and those on first-generation antipsychotics
were less likely to be residents of long-term-care facilities.
During the five years of observation, 92 of the 11,400 patients were
admitted to a hospital for stroke, and the crude stroke rate per 1,000 persons
did not significantly differ among the patients treated with first-generation
medications (5.7 strokes per 1,000 patients), risperidone (7.8), or olanzapine
(5.7).
When the researchers adjusted for confounding variables such as age, sex,
and other stroke risk factors, such as hypertension or cardiovascular disease,
or a history of a prior stroke, they came up with relative risk ratios of
having a stroke of 1.1 (or a 10 percent increase) while taking olanzapine,
compared with taking a first-generation medication. For patients taking
risperidone, the relative risk of having a stroke was 1.4 (a 40 percent
increase), compared with patients taking a first-generation medication.
While the relative risk appears greater in the risperidone group, the
authors pointed out that, statistically speaking, the confidence intervals for
the relative risks were wide, and therefore the differences between the three
groups were not statistically significant. While the authors attempted to
adjust for known stroke risk factors, they noted that they "could not
account for other potentially important stroke risk factors, such as obesity
or smoking."
Researchers have noted for decades the difficulty of studying the risk of a
certain outcome that in itself is rare, in this case, a stroke occurring in an
elderly demented patient. In order to study any differences in rates between
the rate of strokes between the three groups—patients on
first-generation antipsychotics versus olanzapine versus risperidone—the
researchers would need to study a much larger population of elderly demented
patients to find statistically significant differences. The authors of the
current report noted this as a limitation of their study. They also noted that
a strength of their analysis lies in the population they studied, of whom
"the vast majority of antipsychotic users in this study were being
treated for behaviors associated with dementia as opposed to
schizophrenia," a factor that closely mirrors the clinical trial
populations previously studied.
Herrmann and his colleagues concluded that there does appear to be an
increased risk of stroke in elderly demented patients treated with
risperidone; however, that risk is quite small. A relative risk of stroke for
patients on risperidone of 1.4, they wrote, "would translate into
approximately two extra strokes per 1,000 person years. The fact that we were
unable to detect [a statistically significant] effect still provides
information on the anticipated effect size," that is, it is indeed very
likely to be small.
"Atypical Antipsychotics and Risk of Cerebrovascular
Accidents" is posted online at
<http://ajp.psychiatryonline.org/cgi/content/abstract/161/6/1113>.
Am J Psychiatry 2004 161 1113[Abstract/Free Full Text]
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