Psychiatr News November 18, 2005
Volume 40, Number 22, page 1
© 2005 American Psychiatric Association
Elderly Patients Show Elevated Mortality Risk on Atypicals
Jim Rosack
Researchers again are noting that along with potential benefit comes
risk, especially for frail, elderly patients with dementia on
antipsychotics.
A new meta-analysis of clinical-trials data appears to confirm a small but
statistically significant increase in risk of death associated with the use of
second-generation (or "atypical") antipsychotic medications (SGAs)
in elderly patients who have dementia.
SGAs have increasingly been prescribed off label in recent years to
patients with dementia to help calm agitation and aggression or treat
delusions and hallucinations, as well as other behavioral disturbances
commonly associated with various forms of dementia, including Alzheimer's
disease.
Concern over the drugs' use in frail, elderly patients has been steadily
growing, however, and this past April the U.S. Food and Drug Administration
ordered revisions to the labels of all SGAs. Each of the drugs' labels now
includes language on the increased risk of death in elderly demented patients
within the labels' black-box warnings (Psychiatric News, May 6).
The new meta-analysis, completed by investigators at the University of
Southern California (USC), appeared in the October 19 Journal of the
American Medical Association. The meta-analysis was funded with grants
from the Alzheimer's Disease Centers of California and the University of
Southern California Alzheimer's Disease Research Center.
The report's lead author, Lon Schneider, M.D., M.S., a professor of
psychiatry and behavioral sciences at USC's Keck School of Medicine, is also
the coprincipal investigator (with the University of Rochester's Pierre
Tarriot, M.D.) of the National Institute of Mental Health's Clinical
Antipsychotic Trials of Intervention Effectiveness–Alzheimer's Disease
(CATIE-AD) study.
CATIE-AD was designed to look at the effectiveness and safety of using
antipsychotic medications to control the behavioral disturbances associated
with dementia in "real-world" practice settings. Although data
collection has been completed in CATIE-AD, results have yet to be published.
Researchers who conducted NIMH's companion CATIE-Schizophrenia study reported
primary results in September (Psychiatric News, October 21).
In the current report, Schneider and his colleagues electronically searched
MEDLINE from 1966 to April 2005 and the Cochrane Controlled Trials Register
(January 1, 2005). In addition, they reviewed conference proceedings,
abstracts, and poster presentations (1999 through April 2005) from geriatric
medicine, psychiatric, neurological, and geriatric psychiatry meetings.
Information was also requested from pharmaceutical manufacturers and the
FDA.
In all, the team identified and analyzed 15 clinical trials in which the
SGAs aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel), or
risperidone (Risperdal) were compared with placebo. (One study included both
olanzapine and risperidone.) The studies encompassed 3,353 patients who
received one of the four SGAs and 1,757 patients who received placebo.
During the active-treatment phase of a clinical trial of patients taking
one of the four drugs, 118 deaths occurred, compared with 40 deaths among
those on placebo. This difference was statistically significant (p=0.02).
Patients taking an SGA were 1.54 times more likely to die (from any cause)
than those patients assigned to receive placebo in the clinical trials
studied. While available details were not plentiful, most of the reported
deaths were cardiovascular in origin or from infections such as pneumonia.
When Schneider and his colleagues analyzed all the data they had available
to estimate patients' total exposure to either drug or placebo (that is, dose
as well as duration of drug/placebo therapy), they found that the overall
relative risk of death was 1.65 times more likely in those taking drug
compared with those taking placebo.
In this pooled, total-exposure analysis, each of the individual medications
was associated with an increased relative risk of death from any cause,
compared with placebo. However, the risk varied among the drugs, with the
highest relative risk of death associated with olanzapine (RR=2.31) and the
lowest with risperidone (RR=1.35). However, while the overall increase was
highly statistically significant (p=0.003), none of the relative risks
calculated for the individual medications reached statistical
significance.
"Although the findings were consistent from trial to trial and from
drug to drug," Schneider and his coauthors concluded in their
JAMA report, "It is only when all trials are combined that a
statistically significant effect is found. No drug is individually responsible
for the effect, but rather each contributes to the overall effect."
In an editorial accompanying the report, Peter Rabins, M.D., M.P.H., and
Constantine Lyketsos, M.D., M.H.S., both in the department of psychiatry and
behavioral sciences at Johns Hopkins University School of Medicine, noted,
"The results do not contraindicate the use of antipsychotic drugs in the
treatment of patients with dementia," but rather, they write, "the
results change the risk-benefit analysis such that antipsychotic drugs should
be used only when there is an identifiable risk of harm to the patient or
others, when the distress caused by the symptoms is significant, or when
alternate therapies have failed, and symptom relief would be
beneficial."
Rabins and Lyketsos also noted the difficulties that Schneider and his
colleagues encountered in trying to identify all available data on the use of
antipsychotics in elderly demented patients. Similar challenges have been
encountered with research efforts involving other drug classes, they
added.
"Because there is a significant likelihood that rare events will not
be identified in the two [studies] required by the FDA for approval,"
Rabins and Lyketsos wrote, "the FDA must put more effort into formal
post-marketing surveillance" and require public registry of all
clinical-trials data.
An abstract of "Risk of Death With Atypical Antipsychotic Drug
Treatment for Dementia" is posted at
<http://jama.ama-assn.org/cgi/content/abstract/294/15/1934>.
The accompanying editorial is posted at
<http://jama.ama-assn.org/cgi/content/extract/294/15/1963>.
JAMA 2005 294 1934[Abstract/Free Full Text]
JAMA 2005 294 1963[Free Full Text]
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