Antipsychotics Do Not Appear To Increase Stroke Risk

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