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Mortality in AD Rises With Long-Term Antipsychotic Use


 

Antipsychotics appear to significantly increase the risk of death in patients with Alzheimer's disease, especially if taken for more than 12 months, a randomized controlled trial has determined.

Nursing home patients with Alzheimer's disease (AD) who continued taking the drugs for 1 year were 7% more likely to die than were those who discontinued them, and the mortality difference escalated over the 4-year study. By the end of the trial, just 26% of those taking the drugs were still alive, compared with 53% of those taking a placebo, wrote Dr. Clive Ballard of King's College, London, and his associates (Lancet 2009 Jan. 9 [doi:10. 1016/S1474-4422[08] 70295-3]).

The authors did support a limited use of the drugs, particularly in patients with severe dementia-related aggression, geriatrician Karl Steinberg, who is in a group practice in Oceanside, Calif., noted in an interview. But their risks must be carefully considered.

The conclusions seem to support the Omnibus Budget Reconciliation Act of 1987, which mandated gradual dose reductions of antipsychotics in nursing home residents, he added. “This is looking like an increasingly sound idea. We need to keep in mind that the patients for whom we prescribe these medications are suffering from significant dementia and already nearing the end of life, where quality of life should be a major concern.”

The trial comprised 165 nursing home residents with AD (mean age 89). At baseline, all of the patients were taking an antipsychotic medication. Most (93%) were taking either risperidone or haloperidol; other agents included thioridazine, chlorpromaine, and trifluoperazine.

Patients were randomized to either continue treatment (83) or discontinue treatment by taking a placebo. Thirty-seven patients did not start treatment, leaving 64 in each treatment group. The 12-, 24-, 36-, and 42-month survival rates were analyzed in the group of those who began taking their study medication, regardless of whether they stopped at any time during the study.

After 12 months, those taking placebo were more likely to survive than were those taking an active agent (70% vs. 77%); the difference was statistically significant. The disparity was magnified as the trial continued. At 24 months, the cumulative survival rate was 71% in the placebo group vs. 46% in the active group; at 36 months, the rate was 59% vs. 30%; and at 42 months, it was 53% vs. 26%.

Death certificates were available for 78%. More deaths of a probable vascular nature occurred in the placebo group; there was no indication that antipsychotics contribute to cerebrovascular deaths.

The reasons for the biggest difference in mortality occurring after the first 12 months of the trial are unclear. “One possible explanation is that the most frail participants who had the most severe dementia … have a high mortality risk regardless of whichever treatment is assigned,” they noted. However, “the results are consistent in that patients allocated to discontinue antipsychotics seem to benefit from lower mortality during long-term follow-up than [do] those allocated to placebo.”

They noted that up to 60% of nursing home residents with dementia in Europe and North America receive antipsychotic medication, often for extended periods of time, despite data suggesting that the risks outweigh any possible benefit.

“There is clear evidence of a significant increase in adverse events, including parkinsonism, sedation, oedema, chest infections, accelerated cognitive decline, and cerebrovascular events in patients with Alzheimer's treated with antipsychotics,” they noted. Alternative treatments include psychological management, memantine, and antidepressants.

The results confirm those in other trials suggesting a link between the drugs and increased morbidity and mortality in dementia patients, said Dr. Marwan Sabbagh in an interview. “This risk was the impetus for the black box warning issued by the FDA for risk associated with antipsychotic use specifically in dementia.”

“What makes this more compelling is that … this is objective evidence in a randomized, placebo-controlled study that [AD] subjects taking antipsychotics had demonstrable increases in mortality,” said Dr. Sabbagh, chief medical-scientific officer and director of clinical research at the Sun Health Research Institute, Sun City, Ariz.

The study was funded by the U.K. Alzheimer's Research Trust. Dr. Ballard noted financial relationships with many companies that manufacture antipsychotics and Alzheimer's medications.

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