Background: In recent years, medications have been marketed to delay the progression of dementia. No studies have specifically addressed when or if these drugs should be stopped as cognition and function decline in serious illness. Clinicians are frequently asked about the continued role of these drugs in the face of a limited prognosis. This Fast Fact will suggest guidelines for continued use or discontinuation in the hospice/palliative care setting.

Medications:

1. Cholinesterase Inhibitors (ChEIs): e.g. galantamine, donepezil, rivastigmine.

• Indication: usually first-line agents for mild to moderate dementia.
• Evidence: A systematic review indicated that ChEIs lead to cognitive, functional, and global benefits in mild to moderate dementia which wane at about one year after initiation and are of relatively unclear clinical significance (1). Few studies have looked at efficacy in moderate to severe dementia. Some studies suggest ChEIs have a role in controlling dementia-related behavior problems (2) and lessening opioid-related somnolence (3). One study suggested a potential precipitous cognitive decline if ChEIs are stopped suddenly (4).
• Cost: ~ $200-300/month (5).
• Side Effects: diarrhea, nausea, anorexia, insomnia, bradycardia, vivid dreams, nocturia.

2. N-methyl-D-aspartate (NMDA) receptor antagonist: memantine.

• Indication: moderate to severe dementia.
• Evidence: Studies suggest a modest benefit with decreased cognitive and functional decline (clinical significance of this effect is debated) for moderate to severe dementia (6).
• Cost: $366/month at 10mg twice daily (5).
• Side Effects: dizziness, headache, constipation, somnolence, weight gain.

3. Monoclonal antibody against amyloid beta: e.g., aducanumab, donanemab, lecanemab.

• Indication: mild cognitive impairment or mild dementia due to Alzheimer’s disease with goal to reduce beta amyloid plaques in the brain. Of note: they are parenteral infusions provided every 4 weeks and they require ongoing brain MRI monitoring due to risk for cerebral edema.
• Evidence: Lecanemab and donanemab studies show reduced markers of amyloid and moderately less decline in cognition and function when compared to placebo. Aducanumab studies have shown robust reduction in amyloid deposition in the brain however there has been small and inconsistent clinical benefits.
• Cost: $25,000-30,000 annually.
• Side effects: transient infusion reactions like flushing and body aches, asymptomatic swelling or fluid formation in the brain, brain bleed.

Care management recommendations:

1. Use a shared decision-making model with patients/surrogates guided by the goals of care (e.g. life prolongation and/or symptom relief), carefully weighing the expected benefits and burdens (see reference 7 for specific guidance on medication appropriateness late in life).
2. Be prepared to make a clear recommendation based on best available evidence. Due to the advanced dementia status of many patients seen by palliative care or hospice teams, it is reasonable to recommend stopping ChEIs, memantine, or recombinant monoclonal antibodies as the evidence for their benefit is marginal and typically only proven for early stages of dementia.
3. If there is uncertainty, consider a time-limited trial of medication continuation or discontinuation, with serial reassessment of target cognitive or behavioral indicators. Families should be made aware that a decline following discontinuation may not be reversible.
4. In the case of a patient with dementia-related behavior problems, clinicians or family may feel that dementia-related medications play an important role in lessening the behaviors. In these scenarios, continuing the medications would be reasonable. Alternatively, using non-pharmacologic strategies and/or increasing can often help control behavior problems without the use of ChEls or memantine.
5. When the decision is made to stop a medication, common geriatrics wisdom supports a gradual dose taper rather than abrupt discontinuation.
6. Clinicians should inform all involved healthcare team members of a recommendation to discontinue medication along with the rationale for discontinuation (8).

Working with families: The reaction of families to a discussion of discontinuing these drugs is often emotional and may be a source of tension between family members. Some will view these medications as a final hope for prolonged life or improved function and will resist discontinuation. For others, permission to let go, to accept impending death and remove a perceived burden of cost and daily pill taking, will be welcomed. Clinicians can best help families by acknowledging these underlying emotions and focusing discussions around the overall goals of care for the patient (see Fast Fact #29 and Fast Fact #65).

References

1. Buckley JS, Salpeter SR. A risk-benefit assessment of dementia medications: systematic review of the evidence. Drugs Aging. 2015; 32(6):453-467.
2. Wynn ZJ, Cummings JL. Cholinesterase inhibitor therapies and neuropsychiatric manifestations of Alzheimer’s disease. Dement Geriatr Cogn Disord. 2004; 17(1-2):100-8.
3. Slatkin NE, Rhiner M. Treatment of opiate-related sedation: utility of the cholinesterase inhibitors. J Support Oncol. 2003; 1(1):53-63.
4. Minett TS, Thomas A, Wilkinson LM, Daniel SL, Sanders J. Richardson J, Littlewood E, Myint P, Newby J, McKeith IG. What happens when donepezil is suddenly withdrawn? An open label trial in dementia with Lewy bodies and Parkinson’s disease with dementia. Int J Geriatr Psychiatry. 2003; 18(11):988-93.
5. Wolters Kluwer. Lexicomp Online. URL: http://online.lexi.com/lco/action/home. Accessed November 24, 2015. And August 26, 2024
6. Holmes HM, Hayley DC, Alexander GC, Sachs GA. Reconsidering medication appropriateness for patients late in life. Arch Intern Med. 2006;166(6):605-9.
7. Gwyther LP, Weinberg AD. Discontinuing medications for a resident with advanced Alzheimer’s disease. Ann Long-Term Care. 2006:14(5):46-8.
8. Yang Z, Zhou X, Shand Q. Effectiveness and safety of memantine treatment for Alzheimer’s disease. J Alzheimers Dis. 2013; 36(3):445-458.
9. McCleery, J., & Quinn, T. J. (2021). Aducanumab and the certainty of evidence. Age and Ageing, 50(6), 1899-1900.
10. Van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., … & Iwatsubo, T. (2023). Lecanemab in early Alzheimer’s disease. New England Journal of Medicine, 388(1), 9-21.
11. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512–527.

Version History: Originally edited by David E Weissman MD in February 2007; 2nd edition in April 2009. 3rd Edition in November 2015 by Mary G Rhodes, MD; 4th Edition by Elizabeth Bukowy DO in September 2024.
Conflicts of Interest: None to report