Canada and Australia are deprescribing cholinesterase inhibitors.
Emphasis mine...
Deprescribing Cholinesterase Inhibitors and Memantine in People With Dementia A Sensitive Issue Linda Brookes, MSc
March 06, 2018
Finally, Guidance on Cholinesterase Inhibitor and Memantine Deprescribing
The latest clinical practice guideline from the Deprescribing Guidelines for the Elderly Project, based at the Bruyère Research Institute, Ottawa, Canada, focuses on the discontinuation of cholinesterase inhibitors and memantine, drugs approved for use in Alzheimer disease.[1] This guideline, which was developed jointly with the University of Sydney and the National Health and Medical Research Council (NHMRC) Cognitive Decline Partnership Centre, Sydney, Australia, is the first anywhere to be dedicated solely to the discontinuation of these drugs and the first to involve consumers in its development. Like the previous guidelines in the Bruyère series, it is accompanied by a summary deprescribing algorithm.[2] Its recommendations follow international criteria and are applicable to clinical practice worldwide.
Medscape spoke with the guideline's lead author, Emily Reeve, PhD, NHMRC-Australian Research Council Dementia Research Fellow, University of Sydney, and Dalhousie University, Halifax, Nova Scotia, Canada, to learn about the unique challenges involved in the preparation of this guideline and its recommendations.
Although there is no known cure for Alzheimer disease, current treatment guidelines generally recommend a cholinesterase inhibitor (ChEI)—for example, donepezil, rivastigmine, or galantamine—as the first-line treatment in mild-to-moderate disease. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be used in later stages.[3] Donepezil is also approved for use in severe Alzheimer disease in the United States and Canada, and can be given in addition to memantine or, in the United States, as a fixed-dose combination with memantine. These drugs have all been shown to delay or slow worsening of symptoms to some degree, but their effectiveness varies from person to person. As many as one third of ChEI prescriptions are inappropriate, according to studies discussed in the guideline.[1] in addition, up to 80% of patients taking ChEIs have been reported to experience adverse drug-related effects (ADRs).[4] In clinical trials, most ADRs (principally gastrointestinal) were reported to be transient, occurring at the start of treatment, but more serious ADRs have been reported in practice. "Although severe side effects are rare, cardiovascular effects, like slowing heart rate and life-threatening dermatologic conditions, have been reported with these drugs," Dr Reeve noted.
One third of ChEI ADRs may be due to drug-drug interactions. People with dementia are likely to be taking five to 10 regular medications, and 9% to 45% of ChEI/memantine users are also prescribed a medication that could reduce its efficacy or result in a drug-drug interaction.
A particular concern is the prescription of anticholinergics to treat urinary incontinence, a potential side effect of ChEIs, Dr Reeve noted. "Since the two drug classes have opposite mechanisms of action, combinations like this need to be carefully considered in the individual," she commented.
Advantages and Disadvantages of Deprescribing Deprescribing ChEIs/memantine can reduce the risk for ADRs and drug-drug and drug-disease interactions. It can also reduce the pill burden for patients and improve adherence to other medications, as well as reduce the medication management burden for caregivers and reduce medication costs. However, abruptly stopping these drugs may also result in a worsening in cognition and/or behavior as well as adverse drug withdrawal reactions in some individuals.
One barrier to deprescribing ChEIs/memantine is that clinicians are not sure when or how to do it, and consequently there is some fear about it. Families and caregivers of people with dementia can feel guilty that they are "giving up" on the patient if the possibility of deprescribing is broached. One of the goals of the guideline is to encourages discussion with the patient and family members or caregivers across all points of care and to increase awareness that optimal medication management involves deprescribing as well as prescribing. "Even when these medications are being started, the discussion should include how, at some point, we are going to try stopping them," Dr Reeve said.
One barrier to deprescribing ChEIs/memantine is that clinicians are not sure when or how to do it, and consequently there is some fear about it, Dr Reeve noted. "A few of the current treatment guidelines mention stopping, but in a very vague way; and there is much less clear information on how to stop the drugs than how to start them," she explained. The new guideline aims to help clinicians identify the most suitable patients for deprescribing—those who are likely to benefit or not experience harm from withdrawal of ChEIs/memantine—and how to withdraw the drugs, what to monitor, and what to do if the symptoms return.
The State of the Evidence
The recommendations are consensus- rather than evidence-based, as a result of limited or low-quality evidence. Like earlier reviewers,[5,6] the guideline authors point to the lack of appropriate study data on ChEIs/memantine withdrawal. Dr Reeve and her colleagues identified only seven randomized controlled trials of withdrawal versus continuation of ChEIs (including six in Alzheimer disease) and none on the discontinuation of memantine. "We don't have a lot of good information outside of the initial randomized clinical treatment trials, which we know aren't really a good representation of the wider population who end up taking these drugs," Dr Reeve cautioned. From their review of the evidence available, including observational data, they concluded that despite the potential for worsened outcomes (especially in cognition) after discontinuation of these drugs in some patients, in others, the risk-benefit ratio favors discontinuation rather than continuation. When and How to Deprescribe
A major challenge for clinicians is determining whether patients using these medications are still benefiting from them. "We chose not to include a specific cutoff in terms of tools like MMSE (Mini-Mental Status Examination) or ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive) for a recommendation to deprescribe because we didn't think the evidence supported doing that. There are limitations of those kinds of tools and there is huge variability in how people respond," Dr Reeve explained. Deprescribing still requires assessment and judgment by the patient's clinician, but it must eventually be a shared decision based on discussion with the patient (if possible) and their family or caregivers, she emphasized. "We talk with them about their treatment goals—that is, what they value most. Is it cognition, quality of life, or staying independent? And we explain that as someone ages, the benefits and harms of the medication can change," she said. "We look at the patients' symptoms over the past 6 months, their present condition, and what real impact this is going to have for the remainder of their life."
The guideline stresses that deprescribing should begin as a trial discontinuation, with close periodic monitoring. The new guideline applies to anyone18 years of age or older who has been taking ChEI/memantine for Alzheimer disease, dementia associated with Parkinson disease, Lewy body dementia, vascular dementia, or for other indications. Consideration of a trial of deprescribing is recommended in patients who have been taking the medication for more than 12 months and have shown significantly worsening cognition or function over the previous 6 months (compared with previous progress) or have not demonstrated benefit from the drug (improvement, stabilization, or decreased rate of decline during treatment), as well as in those with severe/end-stage dementia.
Deprescribing is also suggested in the following circumstances:
The guideline stresses that deprescribing should begin as a trial discontinuation, with close periodic monitoring (eg, every 4 weeks). The dose of ChEI/memantine should be tapered by halving the dose or by stepping down through available dose formulations every 4 weeks to the lowest available dose, followed by discontinuation. "If there seems to be a clear worsening of symptoms at any time up to 3 months after dose reduction or cessation, after exclusion of other causes, then the medication can be restarted," Dr Reeve said. "Based on the limited evidence available, there doesn't appear to be any long-term harm associated with a temporary dose reduction or stopping," she noted. After 3 months, any worsening is likely to be due to disease progression rather than re-emergence of symptoms.
- The patient or family members/caregivers wish to discontinue the medication;
- The patient refuses or is unable to take the medication;
- Nonadherence cannot be resolved;
- Drug-drug or drug-disease interactions make treatment risky;
- Severe agitation/psychomotor restlessness; or
- Non-dementia terminal illness.
Future Guideline Updates
The guideline authors point to "significant gaps in the literature," and they predict that future studies may lead to changes in the recommendations. "Even though we found quite a few studies that we were able to base our recommendations on, one of the major limitations was the wide variability in the different populations studied," Dr Reeve said. "So we would benefit from more evidence for identifying the people in whom we can stop the drugs and then follow up to be able to strengthen those recommendations and more evidence about whether tapering is the best way to go about it." The authors aim to update the guideline online as new evidence emerges. One study that is expected to come under consideration within the next 2 years is the Cholinesterase Inhibitors Discontinuation (CID) trial,[7] sponsored by the US government's Veterans Affairs Office of Research and Development. This study is comparing dose reduction followed by discontinuation versus sham discontinuation in elderly adults taking a daily dose of donepezil ≥ 10 mg or galantamine ≥ 8 mg.[7] "I think the research that is being done now and being started in deprescribing is becoming a lot more strategic, and it really is targeted towards those areas of most uncertainty," Dr Reeve commented.
