Conventional Antipsychotic Medications Linked to Increased Cardiovascular Death in Elderly Patients
Conventional Antipsychotic Medications Linked to Increased Cardiovascular Death in Elderly Patients
August 28, 2008 — Elderly patients prescribed a conventional, first-generation antipsychotic have a 30% increased risk of dying compared with those prescribed atypical, second-generation antipsychotics, new research suggests.
Half of this increased risk is from cardiovascular disease, and these patients also have a significantly higher risk for death from respiratory causes.
"This paper and 2 previous papers from our group suggest that conventional antipsychotics are not safer than atypical antipsychotics," study investigator Soko Setoguchi, MD DrPH, from Brigham and Women's Hospital, in Boston, told Medscape Psychiatry.
However, she cautioned, the findings need to be confirmed, and residual confounding ruled out.
The study is published online August 6 in the Journal of the American Geriatrics Society.
FDA Warnings
In 2005, the Food and Drug Administration (FDA) issued an advisory warning that atypical antipsychotics were associated with a significantly greater risk for death than placebo in elderly people with dementia.
In June 2008, the warning was extended to both conventional and atypical antipsychotics, based on the results of 2 studies, including 1 from the current group of investigators.
That study looked at a cohort of all residents of British Columbia who were aged 65 years and older when they began taking an antipsychotic (Schneeweiss S et al. CMAJ 2007;176:627-632). The investigators found a 30% increase in 180-day all-cause mortality among those prescribed conventional vs atypical antipsychotics.
The current study, in the same cohort, looked at causes of death.
The study subjects had mean age of 80 years. Participants included 12,882 seniors who started taking conventional antipsychotics, including loxapine (69%), haloperidol (11%), and chlorpromazine (7%).
Another 24,359 seniors began taking the atypical antipsychotics risperidone (75%), quetiapine (15%), and olanzapine (10%).
Of 3821 deaths in the 6-month study period, 49% were due to cardiovascular causes. Of these, more than 60% were out-of-hospital cardiovascular deaths and included cardiac arrhythmias, myocardial infarction, pulmonary embolism, or stroke. Another 10% of deaths were due to infections, mostly pneumonia, and 9% of deaths were from respiratory causes other than pneumonia.
The risk for cardiovascular death, out-of-hospital cardiovascular death, and death from respiratory causes was significantly higher in elderly patients taking conventional vs atypical antipsychotics.
Interestingly, said Dr. Setoguchi, among the subgroup of elderly patients with dementia, there was no significantly increased risk for cardiovascular or out-of-hospital cardiovascular deaths in patients taking conventional vs atypical antipsychotics. This suggests that in patients with dementia, who are generally sicker than other patients, increased mortality might be due to causes other than cardiovascular-related causes.
Clearer Warnings Needed
In another study, researchers, led by Elmira Valiyeva, PhD, from the University of Toronto, in Ontario, assessed the impact of 3 warning letters sent to Canadian healthcare professionals about dangers of prescribing atypical antipsychotic drugs to elderly patients with dementia.
Although prescribing rates for these drugs slowed after each warning, the overall rate increased over the study period from 1512 per 100,000 elderly patients in 2000 to 1813 per 100,000 elderly patients in 2007.
The study is published in the August 26 issue of the Canadian Medical Association Journal.
"If the goal of new information on risk is to motivate prescribers to rethink their therapeutic options, perhaps the warnings should be clear about alternatives and their safety and efficacy," the group writes.
Warnings for atypical antipsychotic drugs should include comments on the safety and efficacy of conventional antipsychotics and at least a summary of nonpharmacologic interventions for dealing with aggression and agitation, such as those in the current clinical practice guidelines for the treatment of dementia, they add.
All 3 new atypical drugs — risperidone, olanzapine, and quetiapine — were approved by Health Canada in the 1990s for treatment of schizophrenia, and risperidone was also approved for short-term management of psychotic or aggressive behavior in patients with dementia.
The 3 safety warnings relating to risperidone, olanzapine and quetiapine were issued between October 2002 and June 2005.
Prescribing Practices Largely Unchanged
The investigators analyzed prescription drug claims in Ontario from May 1, 2000, to February 28, 2007, in patients aged 65 years and older.
About 70% of individuals receiving antipsychotics lived in nursing homes, and 40% were over age 85 years.
The first 2 warnings were associated with substantial relative decreases in prescription rates of 11.8% and 14.6%, respectively, in the predicted growth of risperidone and olanzapine. However, prescribers generally switched to another antipsychotic medication. The bottom line, say the researchers, is these warnings did not reduce overall prescription rates of these potentially dangerous drugs.
"More effective interventions are necessary to improve postmarket drug safety in vulnerable populations. . . . A comprehensive, coordinated approach involving Health Canada, drug manufacturers, private and public drug insurers, and physicians is needed," the authors write.
In an accompanying commentary, Laurence Y. Katz, MD, from the University of Manitoba, in Winnipeg, says the study results highlight the fact that physicians will return to the familiar, even in the presence of documented risks, if they are not given other options.
"Healthcare warnings should provide accurate, explicit, and complete information about the risks and efficacy of the identified treatment in addition to providing the same information on alternative treatments," he writes.
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