Criteria for prescribing / using cholinesterase inhibitors
Updated Criteria for Use: Cholinesterase Inhibitors to Treat Dementia
VHA Pharmacy Benefits Management Service and the Medical Advisory Panel
The following recommendations are based on current medical evidence. The content of the document is dynamic and will be revised as new clinical data become available. The purpose of this document is to assist practitioners in clinical decision making, to standardize and improve the quality of patient care, and to promote cost-effective drug prescribing. The clinician, however, must make the ultimate judgment regarding the propriety of any course of treatment in light on individual patient situations.
Initial Prescription (all of the following must be met):
* A diagnosis of Alzheimer’s disease (AD), mixed (AD and vascular) dementia, Lewy Body Dementia, or dementia associated with Parkinson’s disease
* The patient is able to perform >1 activity of daily living with minimal assistance
* For patients with a FAST Score of 5 or 6, the patient has a regular caregiver(s) to assist with medication and care or resides in a setting where assistance with medication administration is provided such as a nursing home. FAST link: http://www.pbm.va.gov/monitoring/Functional%20Assessment%20Staging%20FAST%207.31.08.doc.
* The patient’s medication regimen has been reviewed and all unnecessary anticholinergic medications have been discontinued.
* No exclusion criteria are met.
Renewal Every 6 Months (all must be met with the noted exception):
* The dementia diagnosis has not changed
* The patient is taking a therapeutic dose
* The patient is able to perform >1 activity of daily living with minimal assistance
* For patients with a FAST Score of 5 or 6, the patient has a regular caregiver(s) to assist with medication and care http://www.pbm.va.gov/monitoring/Functional%20Assessment%20Staging%20FAST%207.31.08.doc
* The patient and/or caregiver and prescriber agree that the patient has benefited from the cholinesterase inhibitor and wish to continue, i.e., continuation is still in line with the goals of treatment and treatment targets. This discussion and decision are documented in the patient’s medical record.
* The patient’s medication regimen has been reviewed and all unnecessary anticholinergic medications have been discontinued.
* No exclusion criteria are met.
Exception: If during a trial off a cholinesterase inhibitor, rapid deterioration or worsening of psychiatric symptoms or behavioral disorders is noted, then the activities of daily living criterion is not relevant.
Combination Treatment with Memantine (all of the following must be met):
* The patient is determined to have moderate to severe Alzheimer’s disease (FAST Stage 5 or 6)
* Has been on a therapeutic dose of cholinesterase inhibitor or memantine for >6 months
* The patient is able to perform >1 activity of daily living with minimal assistance
* The patient has a regular caregiver(s) to assist with medication and care
Exclusion Criteria (any of the following):
* Bradycardia (<50 bpm)
* Chronic alcoholism
* Chronic diarrhea
* Serious liver disease
* FAST Stage 7a-f
Discontinuation Criteria (any of the following):
* Poor compliance
* Persistent side effects, including morbid weight loss
* Mutual agreement between patient and/or caregiver and prescriber.
* Permanent loss of caregiver (for patients with FAST score of 5 or 6)
* FAST Stage 7a-f
July 2008
Updated versions may be found at http://vaww.pbm.va.gov or http://www.pbm.va.gov
Prepared by Todd Semla, MS, Pharm.D., BCPS
Background and Evidence for Cholinesterase Inhibitor
Criteria for Use
VHA Pharmacy Benefits Management Service and the Medical Advisory Panel
The following recommendations are based on current medical evidence. The content of the document is dynamic and will be revised as new clinical data become available. The purpose of this document is to assist practitioners in clinical decision making, to standardize and improve the quality of patient care, and to promote cost-effective drug prescribing. The clinician, however, must make the ultimate judgment regarding the propriety of any course of treatment in light on individual patient situations
Indications and Extent of Cholinesterase Inhibitor Use
Cholinesterase inhibitors (CI) are considered a standard of care by many who care for patients with Alzheimer’s disease (AD), dementia with Lewy bodies, Parkinson’s disease dementia, and other forms of dementia.[1, 2] Donepezil is the only CI inhibitor currently with FDA labeling for treatment of mild, moderate and severe AD; rivastigmine and galantamine are labeled for mild to moderate AD. Rivastigmine is also labeled for the treatment of Parkinson’s disease dementia. The use of CI for the treatment of cognitive and functional loss in patients with pure vascular dementia (non-mixed) is discouraged. None of the CIs has FDA labeling for vascular dementia. Systematic reviews and practice guidelines have not found a consistent or clinically significant treatment effect.[1, 3, 4] At least one trial has raised safety concerns and the potential for increased mortality in this patient population.[5] The routine or continued use of CI across all stages of illness has been questioned, particularly in AD.[6] A PBM drug class review previously concluded that the three CI were considered equivalent in efficacy. Since that review, no new information is available to disprove this assumption.[7]
Use of CI is reported to be extensive by patients in the community and nursing home settings. Data from the 2002 US Medicare Beneficiaries Survey determined that ~25% of all beneficiaries in the community and long term care (LTC) settings with a diagnosis of dementia were treated with a CI.[8] When LTC users were stratified by severity of illness 11% were mild, 36% were moderate, and 53% were severe. In Ontario, Canada a cohort of all in patients 65 years and older started on a CI in 2000-2002 were followed until 2005 or death, whichever came first.[9] Overall, 55% discontinued the CI during the follow-up period; the average duration of use was 866 days with the longest duration by nursing home residents started on a CI while in the nursing home: 1021 days. Overall, 25% continued to use a CI through out the entire follow-up period and19% of patients started on a CI died using a CI.
Staging Dementia
Previous criteria-for-use (CFU) for the CI were based on diagnosis, contraindications and severity or stage of the illness as determined by the Mini Mental Status Exam (MMSE); a cognitive measure. Issues of copyright regarding the MMSE and donepezil’s labeling for severe dementia have caused the PBM to reevaluate the CFU. Alternatives to the MMSE include global severity scales used in clinical trials including the Clinical Dementia Rating (CDR) scale, the Global Deterioration Scale (GDS), and the Functional Assessment Staging (FAST) procedure.[10] Global scales assess cognition, functioning and progression. The 2007 APA practice guidelines[1] suggest the following alternatives to stage dementia:
Stage of Corresponding Scale
Impairment
Mild MMSE >18
GDS or FAST stage 4
CDR = 1
Description: Difficulty balancing a checkbook, preparing a complex meal, or managing a difficult medication schedule.
Moderate MMSE = 10 – 18
GDS or FAST stages 5 & 6
CDR = 2
Description: Above plus difficulties with simpler food preparation, household cleanup, and yard work; may require some assistance with some self-care
Severe MMSE <10
GDS or FAST stages 6 & 7
CDR = 3
Description: Require considerable or total assistance with ADLs such as dressing, bathing and toileting
Terminal Often unable to complete
GDS or FAST stage 7
Description: Noncommunicative, nonambulatory or bed bound, require constant care, develop contractures, susceptible to infections, pressure sores and accidents.
MMSE = Mini Mental Status Exam; GDS = Global Deterioration Scale; FAST = Functional Assessment Staging; CDR= Clinical Dementia Rating; ADLs = Activities of Daily Living
Discontinuing Cholinesterase Inhibitors
When to discontinue a CI due to progression of the illness has not been well studied, nor addressed in many guidelines. One guideline panel stated that CI and memantine “may be discontinued in patients who advance to ‘profound’ disease and who have lost all cognitive and functional abilities.”[2] “Profound disease” was defined as the progression to the state where there was no preserved cognition or function. The guidelines from the American College of Physicians and the American Academy of Family Physicians recognize that there is no evidence to support when to discontinue treatment with a CI based on progression of the dementia. However, the guidelines state that “if slowing decline is no longer a goal, treatment with a CI is no longer appropriate.”[3] Others have stated CI treatment should be withdrawn at the point were a patient is entirely dependent in all basic ADLs, or if the family and physician believe that “meaningful social interactions and quality of life benefits are no longer possible.”[11]
Impact and Extent of Concurrent Anticholinergic Use
The use of medications with anticholinergic effects has been shown to be associated with decreased physical and cognitive function in healthy older adults and nursing home residents.[12, 13]
Little research has been conducted to determine the impact of anticholinergic medications on the functional and cognitive effects of patients taking a CI. A retrospective study of patients taking donepezil 10 mg per day found that the MMSE score of those taking an anticholinergic medication was 2 points lower at baseline compared to nonusers (22.6 vs. 20.6).[14] After one year, the average change from baseline in MMSE score was -2.25 for nonusers and -4.19 among users of anticholinergic medications; after 2-years the average changes from baseline were -3.08 and -7.0, respectively. A prospective cohort study stratified 3536 nursing home residents taking a cholinesterase inhibitor by whether they were taking an immediate or extended-release anticholinergic bladder medication (n=376), oxybutynin or tolterodine.[15] Residents using other anticholinergic medications were excluded. At baseline, 52.2% of residents had severe or very severe cognitive impairment (Minimum Data Set Cognitive Subscale, MDS-COGS) and 47.2% had severe, complete or nearly complete dependence in ADLs. The median duration of dual use was 141 (77-262) days. Residents with no or little dependence (the most functional quartile) taking only a CI declined in ADL score by an average of 1.08 points per quarter; residents taking dual therapy declined an additional 0.54 points per quarter. For residents whose baseline functional status was in the lower three quartiles, dual use was not associated with greater decline in ADL scores. The rates of decline in MDS-COGS did not differ between residents taking CI-alone or CI and a bladder anticholinergic regardless of the degree of impairment at baseline.
Approximately one-third of patients taking a CI have been reported to receive a medication with anticholinergic properties.[16, 17] While data addressing this issue specifically within the VA are not available, a retrospective analysis of national VA outpatient data determined that 23% of veterans had been prescribed at least one inappropriate medication (a category largely composed of medications with anticholinergic properties).[18] Another study of outpatients at one VA found that 27% of veterans 65 years and older used at least one anticholinergic medication.[15] In the interest of gaining the most benefit from CI, the use of inappropriate and nonessential anticholinergic medications should be avoided in patients with AD and in patients taking a CI.
Treatment of Agitation and Behavioral Disorders
Behavioral and neuropsychiatric symptoms can occur at any stage of dementia.[1,2] Two meta-analyses have concluded that the CI have demonstrated efficacy in the management of agitation and behavioral disorders.[7, 20] Only 3 clinical trials, out of 13 and 16 in total, included in each meta-analysis studied CI widely used or available in the U.S. (galantamine and donepezil). A recent double-blind trial randomized patients with AD who had not responded to a non-pharmacologic intervention to donepezil 10 mg or placebo.[21] At the end of 12-weeks, there were no differences in agitation or other measures of neuropsychiatric symptoms between the donepezil and the placebo groups.
Cholinesterase Inhibitor Dosing
Drug Initial Dose Titration Recommended Minimum Formulations
Schedule Dose Therapeutic
Every Dose
Donepezil 5 mg daily 4 weeks 10 mg daily 5 mg daily 5 and 10 mg
Galantamine
IR 4 mg 2x/day 4 weeks 12 mg 2x/day 8 mg 2x/day 4, 8, 12 mg
Galantamine
ER 8 mg daily 4 weeks 24 mg daily 16 mg daily 8, 12, 24 mg
Rivastigmine 1.5 mg 2x/day 4 weeks 6 mg 2x/day 3 mg 2x/day 1.5, 3, 4.5, 6 mg
Rivastigmine
patch 4.6 mg daily 4 weeks 9.5 mg/day 9.5 mg/day 4.6, 9.5 mg
Warnings: Cholinesterase Inhibitors
Prescribers should consider the following warnings prior to prescribing a CI:
* Cholinergic stimulation of the vagus nerve may result in bradycardia, heartblock, or syncope.
* Increased cholinergic activity may increase gastric acid secretion. Patients should be monitored for symptoms of g.i. bleeding, particularly those with a history of peptic ulcer disease or who are taking nonsteroidal anti-inflammatory drugs.
* Cholinergic stimulation is believed to be on potential cause of generalized seizures.
* Patients with a history of asthma or chronic obstructive pulmonary disease (COPD) potentially can experience increased airway reactivity following cholinergic stimulation.
* Cholinergic stimulation can potentially cause bladder outflow obstruction.
* Exaggerated the muscle relaxation with succinylcholine-type and other neuromuscular-blocking anesthetics may occur in patients taking a CI.
Treatment of dementia should take into account concerns about quality of life for the patient and for members of his/her family. Therefore, it is important to respect patient and family preferences when making treatment recommendations. Since these agents are costly and are sometimes associated with side effects, their role in the management of persons with dementia must be clearly defined by the prescriber in consultation with the patient, family and caregiver.
References
1. Practice Guideline for the Treatment of Patients with Alzheimer’s Disease and Other Dementias. From the American Psychiatric Association’s Workgroup on Alzheimer’s Disease and Other Dementias and Steering Committee on Practice Guidelines. APA October 2007.
2. Fillit HM, Doody RS, Binaso K, et al. Recommendations for best practices in the treatment of Alzheimer’s disease in managed care. Am J Geriatr Pharamcother 2006;4 Supp A:S9-S24.
3. Qaseem A, Snow V, Cross Jr. TJ, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2008; 143:370-8.
4. Parminer R, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008;148:379-97.
5. Eisai Inc: Press Release: Eisai reports results from latest donepezil study in vascular dementia. Tokyo, Eisai Corporate Communications Department, March 16, 2006.
6. National Institute for Health and Clinical Excellence (NICE). Alzheimer’s disease – donepezil, galantamine, rivastigmine (review) and memantine (amended). Available at www.nice.org.uk/TA111 Accessed January 20, 2008.
7. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005593. DOI: 10.1002/14651858.CD005593.
8. Gruber-Baldini AL, Stuart B, Zuckerman IH, et al. Treatment of dementia in community-dwelling and institutionalized medicare beneficiaries. J Am Geriatr Soc 2007;
9. Herrmann N, Gill SS, Bell CM, et al. A population-based study of cholinesterase inhibitor use for dementia. J Am Geriatr Soc 2007;
10. Reisberg B. Global measures: utility in defining and measuring treatment response in dementia. International Psychogeriatrics 2007;19:421-57.
11. Farlow MR, Cummings JL. Effective pharmacologic management of Alzheimer’s disease. Am J Med 2007;120:388-97.
12. Hilmer SN, Mager DE, Simonsick EM, et al. A drug burden index to define functional burden of medications in older people. Arch Intern Med 2007;167:781-7.
13. Carnahan RM, Lund BC, Perry PJ, et al. The anticholinergic drug scale as a measure of drug-related anticholinergic burden: Associations with serum anticholinergic activity. J Clinical Pharmacology 2006;46:1481-6.
14. Lu C, Tune LE. Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer’s disease. Am J Geriatr Psychiatry 2003;11:458-61.
15. Sink KM, Thomas J, Xu H, et al. Dual use of bladder anticholinergics and cholinesterase inhibitors: Long-term functional and cognitive outcomes. J Am Geriatr Soc DOI: 10.1111/j.1532-5415.2008.01681.x Accessed online April 21, 2008
16. Roe CM, Anderson MJ, Spivack B. Use of anticholinergic medications by older adults. J Am Geriatr Soc 2002;50:836-42.
17. Carnahan RM, Lund BC, Perry PJ, et al. The concurrent use of anticholinergics and cholinesterase inhibitors: rare events or common practice? J Am Geriatr Soc 2004;52:2082-7.
18. Pugh MJ, Fincke BG, Bierman AS, et al. Potentially inappropriate prescribing in elderly veterans: are we using the wrong drug, wrong dose, or wrong duration? J Am Geriatr Soc 2005;53:1282-89.
19. Ness J, Hoth A, Barnett MJ, et al. Anticholinergic medications in community-dwelling older veterans: prevalence of anticholinergic symptoms, symptom burden and adverse drug events. Am J Geriatr Pharmacother 2006;4:42-51.
20. Trinh N-H, Hoblyn J, Mohanty S, et al. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. JAMA 2003, 289:210-6.
21. Howard RJ, Juszczak E, Ballard CG, et al. Donepezil for the treatment of agitation in Alzheimer’s disease. N Engl J Med 2007;357:1382-92.
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July 2008
Prepared by Todd Semla, MS, Pharm.D., BCPS
Updated versions may be found at www.pbm.va.gov or http://vaww.pbm.va.gov
