REVIEW OF CLINICAL GUIDELINES ON USE OF ANTIPSYCHOTIC DRUGS IN THE TREATMENT OF

BEHAVIORAL SYMPTOMS IN ALZHEIMER’S DISEASE AND THEIR IMPACT ON PATIENT OUTCOMES

Myrlene Sanon Aigbogun, MPH1

Milena Anatchkova2, Anne Brooks2, Laura Swett2, Ann Hartry3, Ruth Duffy1, Ross Baker1

1Otsuka Pharmaceutical Development & Commercialization, Inc., 2Evidera & 3Lundbeck LLC

Funding for this research was provided by Otsuka Pharmaceutical Development & Commercialization, Inc., and Lundbeck LLC

Key Events That Have Shaped the Environment of Neuropsychiatric Symptoms Management

Two quality measures related to antipsychotic agents added to CMS Nursing Home Compare

2

Nursing Home Reform Act (a.k.a. OBRA ‘87)

Implemented the Minimum Data Set requirement

Unnecessary physical restraint use warranted citation from state inspectors

Physical restraint use dropped substantially. Including bedrails.

Continued utilization of psychiatric drugs for behavioral issues

2011 • 14% of elderly nursing home residents

are prescribed atypical antipsychotics • 83% of use was for off-label conditions;

88% were used for the condition specified in the FDA boxed warning.

• 51% of use considered "erroneous" (mostly because use was off-label), amounting to $116 M.

• 22% of these drugs were not administered in accordance with the Centers for Medicare & Medicaid Services (CMS) standards regarding unnecessary drug use in nursing homes.

1986

2009 / 2010 / 2013

Billions of $$ in fines for marketing of atypical antipsychotics for off-label uses in nursing homes

FDA Black Box Warnings

2015

Objective

• Study objectives were-

• To review the literature evaluating professional clinical guidelines on antipsychotic drug usage for Neuropsychiatric symptoms (NPS) in Alzheimer’s disease and

• To evaluate the impact of clinical guidelines on patient outcomes

Methods • Two literature review searches conducted in MEDLINE and Embase over 2006-2016 focused on:

– Professional clinical guidelines of antipsychotic use in AD treatment – Publications reporting on the impact of published guidelines related to antipsychotic use on patient clinical

and humanistic outcomes

• Adult patients with AD and agitation; agitation symptoms identified per the 2015 International Psychogeriatric Association (IPA) working group definition1

• Outcomes: Search 1 {Clinical practice treatment guidelines in AD Off-label usage of APs for behavioral symptoms (e.g., agitation) in AD} Search 2 {agitation burden, clinical outcomes, humanistic burden; quality of life, patient-reported outcomes, and utilities}

• Abstracts screened by three reviewers; studies meeting predetermined inclusion criteria were summarized

1Agitation symptom buckets determined by Cummings, et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr. 2015 Jan;27(1):7-17

Excessive Motor Activity

Verbal Aggression

Physical Aggression

pacing yelling biting shoving

pointing Screaming pacing pushing

Restless Shouting rocking resisting

rocking using profanity gesturing scratching

fidget grabbing biting

hitting kicking

16 Guidelines reviewed spanning across US, Canada, and EU

0 20 40 60 80 100

Target Specific Behavioral Symptoms

Practice of Minimal Dosing

Dose Reduction

Full withdrawal

Dose Monitoring

Limit to Moderate/Severe Symptoms

Limit to Severe Symptoms

Agitation-Related Behavioral Symptoms**

Agitation/Other NPS target

Initiate to Target Specific Symptoms

NP Intervention continued

Alternative Treatment*

Underlying Cause Rule-Out

NP intervention first line

Drug Use Minimization

Recommendation Type Recommendation

General

Antipsychotic Treatment

Best Practices Defined for AP Administration

AP= Antipsychotic; NP= Non-pharmacologic; NPS= Neuropsychiatric Symptoms

• acetylcholinesterase (AChEI), or, if not tolerant, memantine, benzodiazepines, cholinergics, selective serotonin reuptake inhibitors (SSRIs), and/or beta-adrenergic

antagonist drugs for the treatment of behavioral disturbances in persons with AD; zoplicone, an anti-depressant and adjunct to AP’s, for treatment of night-time

agitation.

** psychomotor agitation, agitation with anxiety, night-time agitation, wandering, verbal agitation, physical aggression and combativeness

Percent including

88%

94%

44%

No studies were identified that directly assessed the impact of AP guidelines on patient outcomes

5% (11/209) of potential studies met abstraction criteria with variable designs including: Guideline-based interventions, Staff Education, Qualitative study, Retrospective review of reasons for AP use, Expert opinion survey

0 20 40 60 80 100

Decreased Agitation Levels

Reduction in AP Use/Dosage

Cohen-Mansfield Agitation Inventory

Neuropsychiatric Inventory

Agitation

AP Use/Use Patterns

Behavioral Symptoms

Pain Intervention

NP Intervention

Guidelines Based Interventions

Community Dwelling Veterans

Psychiatrists

Nursing home/long-term care or staff

Outcomes

Interventions

Populations

Findings

Measures

AP= Antipsychotic; NP= Non-pharmacologic

82%

55%

55%

Conclusions • Overall, clinical guidelines discussed alternative clinical approaches as a

first-line intervention including ruling out underlying causes and initiating and attempting non-pharmacological interventions such as behavioral interventions.

• The most recently published guideline (Reus 2016 American Psychiatric Association) recommended a comprehensive, person-centered non-pharmacological approach prior to initiating the use of AP.

• Agitation and other NPS explicitly noted as potentially appropriate symptoms for treatment with an antipsychotic.

• Assessments of the impact of guidelines have focused solely on prescription patterns but have not addressed issues of patient outcomes.

• Limited data exists evaluating the impact of safety warnings of antipsychotic treatment on patient outcomes.

• Formal research should be conducted to determine impact of guidelines on patient/caregiver satisfaction and broader patient outcomes like activities of daily living and mortality/morbidity.

Guidelines Reviewed 1. Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association Practice Guideline on the Use of Antipsychotics to Treat Agitation or

Psychosis in Patients With Dementia. Am J Psychiatry. May 01 2016;173(5):543-546.

2. American Association for Geriatric Psychiatry Statement on the Use of Antipsychotic Medications for the Treatment of Agitation and Psychosis in Persons with Dementia; Marc E. Agronin, M.D., Susan K. Schultz, M.D., Gary W. Small, M.D. and the Board of Directors of the American Association for Geriatric Psychiatry (2016).

3. Levinson DR, Inspector General. Medicare Atypical Antipsychotic Drug Claims for Elderly Nursing Home Residents. Department of Health and Human Services: Office of Inspector General; 2011.

4. Centers for Medicare & Medicaid Services. Update Report on the National Partnership to Improve Dementia Care in Nursing Homes; 2016.

5. Centers for Medicare & Medicaid Services. Advanced Copy: Dementia Care in Nursing Homes: Clarification to Appendix P State Operations Manual (SOM) and Appendix PP in the SOM for F309 - Quality of Care and F329 – Unnecessary Drugs.. Available at: https://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/Downloads/Survey-and-Cert-Letter-13-35.pdf. Accessed February 8, 2017.

6. Raskind MA, Barnes RF. Alzheimer's disease: treatment of noncognitive behavioral abnormalities. In: Kupfer DJ, Bloom FE, eds. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press; 1995:1427-1435.

7. Maglione M, Maher AR, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Rockville, MD: Agency for Healthcare Research and Quality; 2011.

8. Bergert FW, Conrad D, Ehrenthal K, et al. Pharmacotherapy guidelines for the aged by family doctors for the use of family doctors. International Journal of Clinical Pharmacology and Therapeutics. 2009;47(1):11-22.

9. American Association for Geriatric Psychiatry. AAGP Position Statement: Principles of Care for Patients With Dementia Resulting From Alzheimer Disease. Available at: http://www.aagponline.org/index.php Accessed February 8, 2017.

10. Sadowsky CH, Galvin JE. Guidelines for the management of cognitive and behavioral problems in dementia. J Am Board Fam Med. May-Jun 2012;25(3):350-366.

11. Pathway-Dementia N. I. C. E. Dementia: supporting people with dementia and their careers in health and social care NICE guidelines [CG42]; 2014.

12. Herrmann N, Gauthier S. Diagnosis and treatment of dementia: 6. Management of severe Alzheimer disease. CMAJ. Dec 02 2008;179(12):1279-1287.

13. Ihl R, Frolich L, Winblad B, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of Alzheimer's disease and other dementias. World J Biol Psychiatry. Feb 2011;12(1):2-32.

14. Hort J, O'Brien JT, Gainotti G, et al. EFNS guidelines for the diagnosis and management of Alzheimer's disease. Eur J Neurol. Oct 2010;17(10):1236-1248.

15. Kales, H. C., Gitlin, L. N. and Lyketsos, C. G. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatric Soc 2015: 62(4): 762-9.

16. Benoit, M., Arbus, C., Blanchard, F, et al. Professional consensus on the treatment of agitation, aggressive behavior, oppositional behavior and psychotic disturbances in dementia. J Nutr Health Aging 2006: 10(5): 410-5.

Studies Reviewed 1. Ballard, C, Orrell, M, YongZhong, S, et al. Impact of antipsychotic review and nonpharmacological intervention on antipsychotic use,

neuropsychiatric symptoms, and mortality in people with dementia living in nursing homes: a factorial cluster-randomized controlled trial by the Well-Being and Health for People With Dementia (WHELD) Program (2015): American Journal of Psychiatry.

2. Bonner, Alice F, et al. Rationales that providers and family members cited for the use of antipsychotic medications in nursing home residents with dementia. Journal of the American Geriatrics Society 63.2 (2015): 302-308.

3. Cervo, F, et al. The role of the CNA Pain Assessment Tool (CPAT) in the pain management of nursing home residents with dementia. Geriatric Nursing 33.6 (2012): 430-438.

4. Dhawan, N, Steele, A, Morgan, R,et al. Documentation of antipsychotic use and indications for newly diagnosed, nonaggressive dementia patients. Primary Care Companion to the Journal of Clinical Psychiatry (2008): 10(2), 97.

5. Husebo, Bettina S, et al. The response of agitated behavior to pain management in persons with dementia. The American Journal of Geriatric Psychiatry 22.7 (2014): 708-717.

6. Kovach, C, et al. Effects of the Serial Trial Intervention on discomfort and behavior of nursing home residents with dementia. American Journal of Alzheimer's Disease and Other Dementias 21.3 (2006): 147-155.

7. McCabe, Marita P, et al. An RCT to evaluate the utility of a clinical protocol for staff in the management of behavioral and psychological symptoms of dementia in residential aged-care settings. Aging & Mental Health 19.9 (2015): 799-807.

8. Monette, J, et al. Effect of an interdisciplinary educational program on antipsychotic prescribing among nursing home residents with dementia. International Journal of Geriatric Psychiatry 23.6 (2008): 574-579.

9. Rapp, M, et al. Agitation in nursing home residents with dementia (VIDEANT trial): effects of a cluster-randomized, controlled, guideline implementation trial. Journal of the American Medical Directors Association 14.9 (2013): 690-695.

10.Stacpoole, M, et al. The Namaste Care program can reduce behavioral symptoms in care home residents with advanced dementia. International Journal of Geriatric Psychiatry 30.7 (2015): 702-709.

11.Bishara, D, Taylor, D, Howard, R, et al. Expert opinion on the management of behavioral and psychological symptoms of dementia (BPSD) and investigation into prescribing practices in the UK. International Journal of Geriatric Psychiatry (2009): 24(9), 944-954.

Back-up

Clinical Guidelines Targeted Literature Review: Data Sources, Search Limits, and Inclusion Criteria

Guidelines Review

Literature Databases

• MEDLINE (via PubMed) • Excerpta Medica Database (Embase)

Guideline Reports

• Centers for Medicare & Medicaid Services Guideline Report • American Health Care Association • Alzheimer’s Association • Other Professional Organization Websites

Limits

Language English language

Time Period Past 10 years (since 2006-2016)

Geography No limits

PICOS Inclusion Criteria

Population Adult patients with AD with agitation

Intervention/ Comparator

Not applicable

Outcomes • Clinical practice treatment guidelines in AD • Off-label usage of APs for behavioral symptoms (e.g., agitation) in AD

Study Design Treatment guidelines, Consensus documents

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Abbreviations: AD = Alzheimer’s disease; PRO = Patient-reported outcome; QOL = Quality of life; RCT = Randomized controlled trial; US = United States

Abbreviations: AD = Alzheimer’s disease; PRO = Patient-reported outcome; QOL = Quality of life; RCT = Randomized controlled trial; US = United States

Impact on Patient Outcomes Targeted Review: Data Sources, Search Limits, and Inclusion Criteria

Patient Outcome Review

Literature Databases

• MEDLINE (via PubMed)

• Excerpta Medica Database (Embase)

Limits

Language English language

Time Period Past 10 years (since 2006-2016)

Geography No limits

PICOS Inclusion Criteria

Population Adult patients with AD with agitation

Intervention/ Comparator

Clinical guidelines specific to use of antipsychotic use in AD patients

Outcomes

• Agitation burden

• Clinical and economic outcomes (costs, comorbidity, and resource use)

• Humanistic burden; QoL/PROs/utilities

Study Design RCTs, observational cohort studies, epidemiologic studies

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