No Consensus for Discontinuing Mainstay Alzheimer's Drugs

Nancy A. Melville

March 27, 2017

UPDATED March 30, 2017 // DALLAS – Although guidelines for initiating treatment of symptoms of Alzheimer's disease (AD) with cholinesterase inhibitors are well established, guidance and consensus as to when, how, and even whether to discontinue the treatment are lacking.

"There clearly needs to be more science regarding the issue of discontinuation of cholinesterase inhibitors," first author Brenna N. Renn, PhD, of the University of Washington's Department of Psychiatry and Behavioral Sciences, Seattle, told Medscape Medical News.

"We found that the majority of textbooks offered no guidance on the issue, with two thirds failing to even mention how to discontinue, much less whether to discontinue."

Cholinesterase inhibitors are currently the only drugs approved for the treatment of symptoms of AD, and they are highly valued as the standard of care for improving memory and cognition.

Because AD is an incurable disease, patients ultimately progress to a stage in which the drugs lose their benefit. Yet patients continue to experience side effects, which may include gastrointestinal problems and cardiac effects, and there is a risk for depression. There is also the issue of cost.

"If the patient has become too impaired to benefit, then it's definitely worth considering discontinuing these drugs," Dr Renn said.

The findings were presented here at the American Association for Geriatric Psychiatry (AAGP) 2017 Annual Meeting.

To evaluate the current state of guidance on the question of discontinuation of cholinesterase inhibitors, Dr Renn and her colleagues conducted an extensive search of cholinesterase inhibitor discontinuation trials, as well as leading textbooks and other relevant materials published between 2005 and 2016.

The results were not consistent: Of five randomized controlled trials that met inclusion criteria, three conclusively recommended to not discontinue the drugs, one advised to discontinue in some circumstances, and one indicated that discontinuation was safe, generally well tolerated, and did not compromise neuropsychiatric or functional outcomes.

Of 17 practice guidelines on the issue, 20% offered no guidance, 20% recommended against discontinuation, and 60% offered indications for discontinuation.

Of textbooks reviewed in seven categories, ranging from family medicine and neurology to geriatric psychiatry, 67% offered no guidance, 5% recommended against discontinuation, and 28% offered indications for discontinuation.

Among the leading indications for discontinuation were a lack of response or loss of treatment effectiveness (n = 6), functional level (n = 4), severity of impairment (n = 3), side effects/adverse events (n = 3), and family/caregiver preference (n = 1).

"Overall, in our review of the literature and scientific evidence from randomized, controlled trials, the evidence was very limited in terms the safety of discontinuing cholinesterase inhibitors," Dr Renn said.

"Furthermore, most of the randomized, controlled trials involve patients with mild to moderate Alzheimer's disease, which doesn't tell us much about when patients are in later stages of the disease, when clinicians often grapple with this issue."

The authors note that their review is the first its kind to synthesize available evidence and recommendations across a broad array of sources.

"Further evidence is needed to justify extended treatment and more rigorously inform discontinuation practices among those in more severe stages of the disease," they conclude.

Dr Renn said the consensus is that discontinuation can be considered on an individual basis.

"These drugs are designed primarily to treat short-term symptoms and to forestall some of the acute changes of Alzheimer's disease, so once someone is impaired enough, it is probably worth a trial with the prescriber," she said.

"If the patient does come off the drug safely, then it's one less medication to worry about in terms of cost and side effects and any sort of polypharmacy issues."

"Hoping for a Miracle"

A key factor that weighs heavily in the decision of discontinuing cholinesterase inhibitors is the role of the family and how they view the medication, Rajesh R. Tampi, MD, professor of psychiatry at Case Western Reserve University School of Medicine, in Cleveland, Ohio, told Medscape Medical News.

"The problem is, once you put people on these medications, their families are hoping for a miracle," explained Dr Tampi, program chair for the AAGP meeting.

"Once patients in my practice are at a more severe stage of disease, I usually discuss the options with families," he said. "I leave the decision up to them, and in most cases, if they opt to continue, they are desperately holding on for something to help."

The data, however, show that benefits will likely diminish as the disease worsens.

"For the first 10 to 15 years after the drugs came out, there was concern about taking patients off of the drugs for fear of worsening the pathology, but the data now show that most can be discontinued in more severe forms of the illness," he said.

The study was supported in part by the US Department of Veterans Affairs (VA) Health Services Research and Development Service, the Houston Center for Innovation in Quality, Effectiveness and Safety, the Michael E. DeBakey VA Medical Center in Houston, and the National Institutes of Health. The authors have disclosed no relevant financial relationships.

American Association for Geriatric Psychiatry (AAGP) 2017 Annual Meeting. Abstract EI 19, presented March 25, 2017.

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