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Cholinesterase Inhibitors and Memantine: Best Practices


Rachelle S. Doody, MD, PhD


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CNS Spectr. 2008;13:10(Suppl 16):34-35

 

An expert panel review of clinical challenges in neurology and psychiatry

Funding for this activity has been provided by educational grants from Forest Pharmaceuticals, Inc., Eisai Inc., Medivation, Inc., and Elan Pharmaceuticals, Inc.

 

Accreditation Statement

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. 

Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 6 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer reviewed and approved by James C.-Y. Chou, MD, associate clinical professor of Psychiatry at the Mount Sinai School of Medicine. Review Date: September 24, 2008.

Statement of Need and Purpose

Alzheimer’s disease (AD) is a progressive brain disorder that affects cognitive, behavioral, and functional abilities. Patients progress from mild cognitive impairment to death in a span of ~10 years, with increasing functional disability, cognitive impairment, and behavioral symptoms. AD currently affects 4.5 million Americans, and its prevalence is rapidly rising. In addition, many patients are not diagnosed until late in their disease progression, and available treatments are underutilized. Research advances must be translated into clinical practice to maximally impact the care of patients.


New technologies are evolving to assist clinicians in dementia recognition, including screening exams, computerized neuropsychological test batteries, and neuropsychological testing. Neuroimaging and biomarkers play a growing role in research and clinical practice. Knowing when to apply these new techniques in clinical practice and how to interpret their results is increasingly important to clinicians and patients. AD therapeutics is poised to change dramatically in the next few years. There have been new indications for the use of cholinesterase inhibitors. Improved understanding of the pathophysiology of AD has presented well-informed targets for therapeutic intervention, and disease-modifying agents are currently being tested in clinical trials. Anti-amyloid strategies, neuroprotective strategies, immunotherapies, enzyme inhibitors, and neuroprotective approaches are some of the directions being explored. Practitioners need information about the changing landscape of AD research to respond to patient questions, anticipate new therapeutic directions, and refer to clinical trials.


The Alzheimer’s Disease Summit (ADS), held on May 3, 2008, in Washington, DC, translated cutting-edge research into day-to-day practice. Leading experts discussed the latest research advances in four critical areas—diagnosis, imaging and biomarkers, current treatment, and evolving treatment approaches—and related this new knowledge to clinical practice. This supplement, based on information presented at the ADS, presents valuable clinical content to a broad audience of primary care physicians, psychiatrists, geriatricians, and neurologists.

Target Audience

This activity is designed to meet the educational needs of neurologists and psychiatrists.

Acknowledgment of Commercial Support

Funding for this activity has been provided by educational grants from Forest Pharmaceuticals, Inc., Eisai Inc., Medivation, Inc., and Elan Pharmaceuticals, Inc.

Peer Reviewer

James C.-Y. Chou, MD, reports no affiliation with or financial interesst in any organization that may pose a conflict of interest.

To Receive Credit for this Activity

Read this Expert Review Supplement, reflect on the information presented, and complete the CME posttest and evaluation. To obtain credit, you should score 70% or better. Early submission of this posttest is encouraged. Please submit this posttest by October 1, 2010 to be eligible for credit.

Release date: October 1, 2008
Termination date: October 31, 2010

The estimated time to complete this activity is 6 hours.

A related audio CME PsychCastTM will also be available online in November 2008 at: cmepsychcast.mblcommunications.com and via iTunes.

Learning Objectives

At the end of this activity, the participant should be able to:
• Understand how evidence is used in creating guidelines.
• Understand the range of recommendations regarding treatment of mild, moderate, and severe Alzheimer’s disease.

Affiliations and Disclosures

Dr. Doody is Effie Marie Cain chair of Alzheimer’s disease research, director of the Alzheimer’s Disease and Memory Disorders Center, and professor of neurology at Baylor College of Medicine in Houston, Texas.

Dr. Doody is a consultant to Novartis and Pfizer, and has received honoraria from Eisai, Forest, and Pfizer.

 

Introduction

Today’s therapies must be put in the context of both currently available treatments as well as treatment trials with exciting potential for use in the near future. Current clinical trial methodologies do not allow for clear separation of symptomatic treatments from disease-modifying therapies; it may be unproductive to maintain this distinction given the current range of treatments available. A more currently relevant focus is added value. Therapies should aim to provide added value through incremental benefits above and beyond existing treatments, as well as enduring benefits.

Alzheimer’s disease (AD) treatment guidelines are not used by physicians only. Healthcare payers often make use of these guidelines to delimit coverage. Cost concerns will also impact AD treatments after generic cholinesterase inhibitors are made available; it is widely believed that a great number of patients will switch to generics. Therefore, treatment guidelines must account for the possible adverse effects of switching therapies as well as the desirability of persistent treatment. There are many AD treatment guidelines, among them the American Academy of Neurology (AAN) Management of Dementia Guidelines,1 which are currently being revised. The Institute for the Study on Aging (ISOA) Management of Alzheimer’s Disease in Managed Care Guideline2 also presents a different approach for a different audience.

The first step to creating evidence-based best practices guidelines is to determine what is meant by “evidence.” A system of classification exists for examining forms of evidence: Class I evidence is provided by one or more well-designed, randomized, controlled clinical trials, including overviews or meta-analyses of such trials. Class II evidence is provided by well-designed observational studies with concurrent controls; for example, case-control studies that generate hypotheses about epidemiologic associations. Class III evidence is provided by expert opinion, case series, case reports, and studies with historical controls.

American Academy of Neurology Management of Dementia Guidelines

The AAN Guidelines define what is meant by a standard of care. A standard must reflect a high degree of clinical certainty, which usually requires at least one Class I study. Overwhelming Class II evidence may be used when circumstances preclude randomized clinical trials because not all questions lend themselves to Class I studies. AAN’s strongest recommendations for the management of dementia require Class I evidence. Less well-supported recommendations are called guidelines—recommendations for patient management that reflect moderate clinical certainty. Guidelines are not as restrictive as standards of care, usually requiring Class II evidence or a strong consensus of Class III evidence. The AAN Guidelines for the Management of Dementia, however, do not make any recommendations based upon Class III evidence.

The AAN’s guidelines were designed around several central questions. The first question was: Does pharmacotherapy for cognitive symptoms improve outcomes in patients with dementia compared with no therapy? The standard of care established in answer to this question was: Cholinesterase inhibitors should be considered in mild-to-moderate AD patients, although studies suggest a small average degree of benefit. The wording for this standard was agreed upon by various practitioners on the AAN Guidelines committee trying to represent many points of view. Although everyone was convinced that the Class I evidence base was present to make cholinesterase inhibitors a standard of care, there was concern about the wording of the statement. “Should be considered” was employed instead of “must be considered” and “small average degree of benefit” is acknowledged. This standard was based on studies available at the time. Treatment trials of memantine and of cholinesterase inhibitors for severe AD were not yet completed or in the public domain. The following guideline was also proposed in response to this question: Vitamin E (1,000 IU BID) should be considered in an attempt to slow the progression of AD.

The second question asked: Does pharmacotherapy for noncognitive symptoms improve outcomes for patients with dementia and/or their caregivers compared with no therapy? “Noncognitive symptoms” refers to behavioral symptoms but not to function scales, which were included in the first question. A few instructional points based on a literature review are presented before answering the question: For example, practitioners should always seek triggers and environmental factors to explain behavioral changes. Psychosis, agitation, and aggression are the behavioral or noncognitive symptoms most often studied in the literature, so the weight of the evidence centers on those particular phenomena. These questions were often studied in mixed dementia populations, and at the time the AAN’s best practices guide was compiled, no studies had addressed anxiety, disinhibition, sleep disturbance, wandering, shadowing, compulsive behaviors, or apathy.

In response to question two, the standard of care was that antipsychotics should be used to treat agitation or psychosis in demented patients where environmental manipulation fails. Atypical agents might be better tolerated compared to traditional agents (guideline), and selected tricyclics, monoamine oxidase-B inhibitors, and selective serotonin reuptake inhibitors should be considered in the treatment of depression in individuals with dementia, with side-effect profiles guiding the choice of agent (guideline).

A third question asked: Do nonpharmacologic interventions other than education improve outcomes for patients and their caregivers compared with no such interventions? Nonpharmacologic interventions were divided into four categories: interventions to improve functional performance, interventions to improve behavior, Alzheimer’s special care units, and psychosocial interventions for caregivers. The following standard was established: Behavioral modification, scheduled toileting, and prompted voiding should be used to reduce urinary incontinence. Consistently enacting this recommendation can eliminate daytime incontinence as a major issue. Guidelines addressing this question proposed that graded assistance, practice, and positive reinforcement should be used to increase functional independence in persons with dementia. Assistance should be provided at the level required, neither more nor less. Persons with dementia may experience decreased problem behaviors with the following interventions: music, particularly utilized during meals and bathing, walking, or other forms of light exercise. Comprehensive psychoeducational caregiver training and support groups may benefit caregivers of persons with dementia and delay nursing home placement.

Updating Guidelines

The AAN guidelines are currently being updated to incorporate new data. Memantine was Food and Drug Administration-approved for monotherapy and combination therapy in moderate-to-severe AD. Donepezil has been approved for the treatment of severe AD. A number of meta-analyses with cholinesterase inhibitors and memantine have taken place, and some naturalistic studies have been conducted.3-5 Additionally, several antipsychotic drug trials, including a large trial that was negative,6 have taken place. A vitamin E meta-analysis, which was conducted in people with cardiovascular diseases, suggested a 5% increased chance of mortality with doses of vitamin E >400 units per day.7 At the time the meta-analysis was conducted, many physicians routinely suggested that AD patients take 1,000 units of vitamin E BID. A recent paper presented at the AAN showed that prolonged vitamin E use led to an increase in the survival of AD patients.8 These data will all impact the AAN’s revised guidelines.

The Institute for the Study on Aging Management of Alzheimer’s Disease in Managed Care Guidelines

The ISOA Management of Alzheimer’s Disease in Managed Care Guidelines were prompted by a need for updated guidelines on patients care.2 It is important to remember that these guidelines were funded by an educational grant from Forest. These guidelines were assembled by a 12-member expert panel. Unlike the AAN guidelines, the ISOA guidelines allowed for consensus recommendations.

Several non-medication recommendations about early detection and diagnosis were produced from a literature review. Screening was recommended for people ≥75 years of age. Although screening would benefit younger patients, it was determined that patients in managed care settings would be less likely to receive screenings at <75 years of age. It was recommended that cognition, function, and behavior be considered part of the baseline, and neuroimaging was suggested unless the Mini-Mental State Examination score was <10 and there was a very unremarkable and typical clinical course.

Treatments were recommended by disease stage. Mild AD should be treated with cholinesterase inhibitors. Memantine monotherapy could be tried if the cholinesterase inhibitors were not tolerated. (There was no evidence base to fully support the use of memantine for mild AD, and the drug is not FDA-approved for this indication.) For moderate disease, cholinesterase inhibitors and memantine were recommended. If a mild patient advanced to moderate AD, it was recommended that memantine be added to their treatment regimen. For severe AD, it was recommended that patients be treated with memantine and an added cholinesterase inhibitor. The only cholinesterase inhibitor currently FDA-approved for severe AD is donepezil. Re-evaluation is recommended at 2 months after the initial visit, and then at every 6 months following. Patients should be counseled on realistic expectations for disease progression, and delirium should be considered and evaluated.

Nothing in the literature aided doctors in the decision regarding when to discontinue treatment. The ISOA guidelines recommended that physicians discontinue antidementia drugs if patients reach profound stages of dementia, and it was suggested that drugs also be stopped if the patients has no cognitive or functional skills to preserve. A distinction was made between “severe” and “profound” dementia. Drugs should be continued during acute illnesses, and adjusted as appropriate for hepatic and renal failure. Care management and counseling should be introduced to patients as well. Many physicians already practice in this way, but these guidelines were written to outline best practices for healthcare payers’ policies as well.

The ISOA guidelines made specific drug formulary recommendations as well: Cholinesterase inhibitors and memantine should be distinguished as two separate classes of drugs. Antidementia drugs should have preferred status. The ISOA guidelines strongly objected to discrimination by the administrative burden on selections of drug or drug class, such as preauthorizations and appeals. In fact, the Alzheimer’s Association worked to reverse a number of the preauthorization requirements of Medicare prescription drug plans (Leslie Fried, Alzheimer’s Association Medicare Advocacy Project, oral communication).

Conclusion

There is a role for guidelines, and guidelines can be constructed in many different ways. When guidelines are published, the methodologies and the intended audiences are important to the utility of the final product. Even after extensive searches of the medical literature, there remain many research questions. For example, some data suggest that persistence of treatment, even by quartile, is associated with a better outcome over the whole course of the disease, but persistence is not consistently addressed in guidelines. High doses of vitamin E may prolong survival, or may cause higher mortality rates. Currently, the treatment guidelines have blurry edges that will be clarified only with additional studies, and all guidelines will likely be revised and improved with time.

References

1. Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56(9):1154-1166.
2. Fillet HM, Doody R, Binaso K, et al. Recommendations for Best Practice in the Treatment of Alzheimer’s Disease in Managed Care. Am J Geriatric Psychopharm. 2006;4(suppl A):S9-S24.
3. Cholinesterase inhibitors for AD (Review). The Cochrane Collaboration. John Wiley and Sons. 2006. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;(1):CD005593.
4. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. JAMA. 2003;289(2):210-216.
5. Doody RS, Tariot PN, Pfeiffer E, et al. Meta-analysis of six-month memantine trials in Alzheimer’s disease. Alzheimers Dement. 2007;3(1):7-17.
6. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525-1538.
7. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007;297(8):842-857.
8. Pavlik V, Doody R, Rountree S, Darby E. Vitamin E use is associated with improved survival in an AD cohort [abstract]. Neurology. 2008;70(suppl 1):A146.



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