Supplement

Treatment Strategies and Quality-of-Care Indicators for Patients With Parkinson’s Disease Jack J. Chen, PharmD, BCPS, CGP, FASCP Mark F. Lew, MD Andrew Siderowf, MD, MSCE

Supplement April 2009 Vol. 15, No. 3 Continuing Education Activity

F a c u lt y

Editor-in-Chief Frederic R. Curtiss, PhD, RPh, CEBS 830.935.4319, [email protected] Associate Editor Kathleen A. Fairman, MA 602.867.1343, [email protected] Peer Review Administrator Jennifer A. Booker, 703.317.0725 [email protected] Graphic Designer Margie Hunter, 703.297.9319 [email protected] February Supplement Editor Joshua J. Spooner, PharmD, MS [email protected] Account Manager Peter Palmer, 800.486.5454, ext. 13 [email protected] Publisher Judith A. Cahill, CEBS Executive Director Academy of Managed Care Pharmacy This supplement to the Journal of Managed Care Pharmacy (ISSN 1083–4087) is a publication of the Academy of Managed Care Pharmacy, 100 North Pitt St., Suite 400, Alexandria, VA 22314; 703.683.8416; 703.683.8417 (fax). Copyright © 2009, Academy of Managed Care Pharmacy. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without written permission from the Academy of Managed Care Pharmacy. POSTMASTER: Send address changes to JMCP, 100 North Pitt St., Suite 400, Alexandria, VA 22314.

Supplement Policy Statement Standards for Supplements to the Journal of Managed Care Pharmacy

Supplements to the Journal of Managed Care Pharmacy are intended to support medical education and research in areas of clinical practice, health care quality improvement, or efficient administration and delivery of health benefits. The following standards are applied to all JMCP supplements to ensure quality and assist readers in evaluating potential bias and determining alternate explanations for findings and results. 1. Disclose the principal sources of funding in a manner that permits easy recognition by the reader. 2. Disclose the existence of all potential conflicts of interest among supplement contributors, including financial or personal bias. 3. Describe all drugs by generic name unless the use of the brand name is necessary to reduce the opportunity for confusion among readers. 4. Identify any off-label (unapproved) use by drug name and specific off-label indication. 5. Strive to report subjects of current interest to managed care pharmacists and other managed care professionals. 6. Seek and publish content that does not duplicate content in the Journal of Managed Care Pharmacy. 7. Subject all supplements to expert peer review.

Jack J. Chen, PharmD, BCPS, CGP, FASCP, is Associate Professor of Neurology at the Loma Linda University Schools of Medicine and Pharmacy in Loma Linda, California. He serves as the faculty Clinical Neuropharmacologist at the Loma Linda University Movement Disorders Center. Dr. Chen received a doctor of pharmacy degree from the University of Utah. He is board certified as a pharmacotherapy specialist and is certified as a geriatric pharmacy specialist. Additionally, he is a member of several organizations, including the American Academy of Neurology, American College of Clinical Pharmacy, American Society of Consultant Pharmacists, American Society of Health-System Pharmacists, and the Movement Disorders Society. Mark F. Lew, MD, is Professor and Vice Chair of the Department of Neurology and is Director of the Division of Movement Disorders at the Keck School of Medicine at the University of Southern California in Los Angeles, California. He is also Director of the Movement Disorders Clinic at Los Angeles County and the University of Southern California Medical Center. He earned his medical degree from George Washington University in Washington, D.C., where he also completed his internship in internal medicine. He is a Fellow of the American Academy of Neurology and holds board certification from the American Board of Psychiatry and Neurology. He is a Participating Scientist of both the Parkinson’s Study Group and the Dystonia Study Group and is an active member of the Dystonia Medical Research Foundation, American Academy of Neurology, and the Movement Disorder Society. Andrew Siderowf, MD, MSCE, is Associate Professor of Neurology at the Pennsylvania Hospital Department of Neurology in Philadelphia, Pennsylvania. He is also a Senior Fellow at the Leonard Davis Institute for Health Economics and a Fellow of the University of Pennsylvania Institute on Aging. He earned his medical degree from Duke University School of Medicine and received a master of science degree in clinical epidemiology from the University of Pennsylvania. Dr. Siderowf’s clinical interests are in Parkinson’s disease and related disorders. His research focuses on improving clinical trial methods in neurodegenerative disorders, assessment of quality-of-life in patients with Parkinson’s disease, and related economic analysis. He is co-author of the set of quality indicators for patients with Parkinson’s disease in the Veterans Affairs Health System that are discussed in this supplement and is certified by the American Board of Psychiatry and Neurology.

Faculty Disclosures Jack J. Chen, PharmD, BCPS, CGP, FASCP, discloses that he is a member of the speakers’ bureaus for Teva Neuroscience, Schwarz Pharma, and BoehringerIngelheim. He is also a consultant for Kyowa Pharmaceutical, Inc. Mark F. Lew, MD, discloses that he is a member of the speakers’ bureaus for Boehringer-Ingleheim, GSK, Allergan, Solstice, Novartis, Teva, Valeant, and UCB. He is also an advisor/consultant for Bayer, Teva, Boehringer-Ingleheim, GSK, Solstice, Novartis, Valeant, Prestwick, and Vernalis. Additionally, he is a clinical investigator for Teva, Boehringer-Ingleheim, GSK, Kyowa, Solstice, Novartis, Schwarz Pharma/UCB, Ipsen, the National Institutes of Health, Eisai, Mentor, Solvay, and Schering Plough. Andrew Siderowf, MD, MSCE, discloses no potential bias or conflict of interest relating to this supplement.

Off-Label Use Droxidopa has orphan status for the treatment of orthostatic hypotension and is currently not approved for this use in the United States. Currently, donepezil is not FDA approved for treatment of dementia in patients with Parkinson’s disease. While fludrocortisone has been used to treat orthostatic hypotension, it does not have FDA approval. Selegiline does have FDA approval for use as an adjunct to levodopa treatment; however, it is not approved for monotherapy to treat Parkinson’s disease. Additionally, tamsulosin and terazosin are approved for the treatment of benign prostatic hyperplasia but have been used to treat urinary dysfunction, which is a symptom of prostatic hyperplasia. Acknowledgements The authors acknowledge Chris R. Prostko, PhD, and Joanne M. Faysal, BS, from PRIME® (Tamarac, Florida) for their assistance with the development and revision of this supplement.

Table of Contents Treatment Strategies and Quality-of-Care Indicators for Patients With Parkinson’s Disease Jack J. Chen, PharmD, BCPS, CGP, FASCP; Mark F. Lew, MD; and Andrew Siderowf, MD, MSCE

S2 Epidemiology and Pathophysiology of PD S3 Diagnosis and Initial Treatment of PD S4 Treatment Strategies for PD S8 Recommendations for Initial Treatment of PD S9 Treatment Options for Later Stages of PD S12 Nonmotor Symptoms Associated with PD S14 Neuropsychiatric Manifestations of PD S17 Conclusions S20 Continuing Education: CE/CME Submission Instructions and Posttest Questions

Target Audience The target audience for this activity is managed care pharmacists and managed care physicians. This is an applicationbased learning activity. Learning Objectives Upon completion of this program, participants will be able to: 1. Assess current challenges in the management of Parkinson’s disease in managed care. 2. Outline measures used to characterize quality of care for patients with Parkinson’s disease. 3. Identify the impact of quality indicators on Parkinson’s disease management. 4. Describe the role of the managed care pharmacist in each quality domain to improve management and resulting outcomes in Parkinson’s disease. Funding and Original Presentation of This Learning Activity This supplement was sponsored by PRIME® through an independent educational grant from Teva Neuroscience. This supplement is based on the proceedings of a satellite symposium held October 15, 2008, at the Kansas City Convention Center in Kansas City, Missouri, in conjunction with the Academy of Managed Care Pharmacy’s 2008 Educational Conference, which was supported by an independent grant from Teva Neuroscience. Release date: April 1, 2009 Expiration date: March 31, 2010

Continuing Education Credit Participants who attended the satellite symposium “Measures to Improve the Score for Patients With Parkinson’s Disease (PD)” at the AMCP annual meeting and who obtained continuing education credit for that learning activity held on October 15, 2008, are not eligible for continuing education credit for this supplement.

Treatment Strategies and Quality-of-Care Indicators for Patients With Parkinson’s Disease Jack J. Chen, PharmD, BCPS, CGP, FASCP; Mark F. Lew, MD; and Andrew Siderowf, MD, MSCE

Abstract BACKGROUND: Parkinson’s disease (PD) is a chronic, progressive, and debilitating disease, which affects over 1 million people in the United States. PD is characterized by a loss of voluntary and involuntary muscle control. As the disease progresses, additional complications can arise in the form of nonmotor and neurobehavioral symptoms. The traditional pharmacologic treatment for PD has been levodopa. While levodopa is effective for reducing the symptoms of PD, it is associated with long-term complications such as motor fluctuations and dyskinesias. More recently, several pharmacological agents have been implemented for the treatment of PD at various stages in the disease course. Specific indicators have been developed that will allow health care practitioners to improve the diagnosis, treatment, and quality of care for patients with PD. OBJECTIVES: To familiarize managed care professionals with treatment options in the management of PD based on current practice guidelines and clinical evidence, and to consider a set of quality-of-care indicators to improve symptom assessment and treatment strategies for patients with PD. SUMMARY: A variety of treatment options should be evaluated on an individual basis to optimize management of PD at all disease stages. A set of quality-of-care indicators and treatment recommendations have been developed to assist health care providers and managed care professionals in improving and optimizing clinical outcomes for patients with PD. J Manag Care Pharm. 2009;15(3)(Suppl):S1-S21 Copyright © 2009, Academy of Managed Care Pharmacy. All rights reserved.

Authors JACK J. CHEN, PharmD, BCPS, CGP, FASCP, is Associate Professor of Neurology at the Loma Linda University Schools of Medicine and Pharmacy, 11262 Campus Street, West Hall, Loma Linda, CA 92350. Tel.: 909.558.7726; Fax: 909.558.7927; E-mail: [email protected] MARK F. LEW, MD, is Professor of Neurology, Vice Chair of the Department of Neurology, and Director of the Division of Movement Disorders at the Keck School of Medicine of the University of Southern California. USC HCC2, Department of Neurology Ste 3000, Los Angeles, CA 90033. Tel.: 323.442.5728; Fax: 323.442.5794; E-mail: [email protected] ANDREW SIDEROWF, MD, MSCE, is Associate Professor of Neurology at the Pennsylvania Hospital Department of Neurology, 330 South 9th Street, Philadelphia, PA 19107. Tel.: 800.789.PENN (7366); E-mail: [email protected]

S2 Supplement to Journal of Managed Care Pharmacy

JMCP

April 2009

Epidemiology and Pathophysiology of PD Parkinson’s disease (PD) presently affects over 1 million people in the United States. While PD can occur at younger ages, the disorder most commonly affects people over 50 years of age. Global epidemiologic studies have shown that PD affects approximately 1.5% of the population older than 60 years of age and approximately 4%-5% of those 85 years or older.1 Worldwide, PD medications alone cost an average of $11 billion per year.2 Additionally, statistics from 2002 indicate that there were more than 20,000 hospital discharges as a result of PD, at an average cost of $17,000 per patient.3 Since PD affects such a large population and generates substantial health care costs, proper diagnosis and effective disease management are vital for improving outcomes at all levels of care. PD is a chronic, progressive, and often debilitating disease. Many patients with PD will be significantly disabled 10 to 15 years after initial disease onset.4 While the exact cause, or causes, of PD are unknown, there is some understanding of the underlying pathophysiology. In the substantia nigra, dopaminergic neurons are responsible for the proper coordination and movement of muscle groups. In PD, this pathway is disrupted because of dysfunction and/or degeneration of these dopaminergic neurons. The result is loss of normal motor control in voluntary movement.5 Additionally, structures known as Lewy bodies are found within the remaining nigral neurons. Lewy bodies are cytoplasmic inclusions containing the protein α-synuclein. Storage of α-synuclein within these inclusion bodies disrupts normal neuronal function and contributes to the pathology of PD.6 Quality of Care for PD The quality of general health care in the United States has been reported to fall below professional standards in many instances.7 Approaches to addressing the problem of low quality health care include the development of quality indicators and practice guidelines. Quality indicators measure either processes or outcomes of care that can be assessed by review of clinical records or administrative data. Quality indicators may be based on evidence from clinical studies or expert consensus. The main use of quality indicators is to determine whether health care providers are giving quality care to their patients and to identify variations between groups of providers. In contrast, practice guidelines are used to guide individual practitioners in the care of individual patients. They are almost always based on high-level evidence from clinical trials and are promulgated by professional organizations. Cheng et al. have developed a set of PD-specific quality indicators with the Veterans Administration (VA) health care system that may have wider applicability in assessing the quality of

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Treatment Strategies and Quality-of-Care Indicators for Patients With Parkinson’s Disease

TABLE 1

TABLE 2

Quality Indicators for PD Care

Domain Description 1 Initial Diagnosis and Treatment

Example Key Indicators • Assessment of functional status

Level A

• Timing of levodopa • Initial titration of dopamine agonists

2

3

Management of Motor Complications

Management of Non-Motor Complications

• MAO-B inhibitor vs. dopamine agonist as initial therapy • Initial treatment wearing off

B

Management of Dementia, Depression, and Psychosis

• Probably effective, ineffective, or harmful for the given condition in the specified population • Requires one Class I study or 2 consistent Class II studies

• Using entacapone before tolcapone

• Possibly effective, ineffective, or harmful for the given condition in the specified population

• Treatment of orthostatic hypotension

• Requires one Class II study or 2 consistent Class III studies

• Treatment of swallowing difficulty, daytime sleepiness, and constipation

C

U

• Sildenafil for erectile dysfunction 4

Definitions and Criteria a • Established as effective, ineffective, or harmful for the given condition in the specified population • Requires 2 consistent Class I studiesa

• Management of dyskinesias • Using COMT inhibitors with levodopa

American Academy of Neurology (AAN) Recommendation Levels

• Data is inadequate or conflicting; given current knowledge, treatment is unproven • Studies not meeting criteria for Class I through Class III

• Assessment for depression • Quetiapine, clozapine for hallucinations • Monitoring of white blood cells in patients on clozapine

a AAN

classification of research studies is based on study design, scientific rigor, and potential bias. Source: Pahwa R, et al. Neurology. 2006;66(7):983-95.31

Source: Cheng EM, et al. Move Disord. 2004;19(2):136-50.8

PD care and guiding the design of future quality improvement efforts.8 In their analysis, a comprehensive set of 79 potential quality indicators for PD care were first identified based on an extensive review of the medical literature. An expert panel of 7 movement disorder specialists then rated each indicator for several different criteria: validity, feasibility, impact on outcomes, overall utility, and room for improvement. Using thresholds for consensus by the panel members, a subset of 29 quality indicators were identified as having the highest potential for future improvements in the quality of PD care, and 22 separate quality indicators were identified that met thresholds for validity and feasibility. These quality indicators spanned all domains of care in the diagnosis and treatment of patients with PD.8 Table 1 provides selected examples of key quality indicators that were identified for 4 distinct domains of care. Since a consideration of the entire published list of quality indicators for PD care is not feasible, this supplement will focus on key indicators that are shown in Table 1, as well as current practice parameters or guidelines from the American Academy of Neurology (AAN) as the framework for discussion of various aspects of diagnosis and management of patients with PD. Classification of Clinical Evidence and AAN Treatment Recommendations In order to best inform clinicians and other health care providers, clinical studies are evaluated for outcomes in a certain patient population for a specific disease. The AAN has published recommendations for clinical practice based on the number and class www.amcp.org

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of studies conducted.9 Clinical studies were evaluated based on overall design, scientific rigor, and potential bias, and given 1 of 3 different classifications from I-III, with level I having the best study design, highest rigor, and least potential for bias. Four different overall treatment recommendations have been developed: Level A—the treatment is established as effective, ineffective, or harmful; Level B—the treatment is probably effective, ineffective, or harmful; Level C—the treatment is possibly effective, ineffective, or harmful; and Level U—the data are inadequate or too conflicting to determine its effectiveness (Table 2).9 ■■ Diagnosis of and Initial Treatment for PD Since there are no definitive imaging techniques or biomarkers available for testing and detection purposes, diagnosis of PD relies on physical and neurological examination by physicians. The most commonly used diagnostic criteria are those developed by the United Kingdom PD Society Brain Bank.10 The characteristic, or cardinal, symptoms found in PD affect motor skills and include bradykinesia (or slowed movement), tremors when the patient is at rest, muscle rigidity, and postural instability.11 Bradykinesia is a required symptom for diagnosis of PD, and patients must display at least one of the other cardinal symptoms. Symptom onset is typically asymmetrical in patients with PD.11 Additional motor and nonmotor symptoms can occur in patients with PD (Table 3). Nonmotor complications such as behavioral and autonomic disturbances may be observed; these will be discussed in more detail later in this supplement. However, it is important to note that many similar symptoms occur in a variety of other diseases, including essential tremor, multiple system atrophy (MSA), or corticobasal degeneration, April 2009

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TABLE 3 Gait and Posture Shuffling gait

Decreased arm swing

Speech and Swallowing Hypophonia (soft speech)

Turning “en bloc”

Monotonic speech

Stooped, forward flexed posture

Stuttering dysfluency

Festination (peculiar acceleration of gait)

Dysphagia (impaired swallowing)

Gait freezing Dystonia

TABLE 4

Additional Motor and Nonmotor Features of Parkinson’s Disease

Drooling

Other Fatigue “Masked” faces with infrequent blinking Difficulty rolling in bed or rising from seated position Micrographia (small, cramped handwriting) Impaired gross and fine motor movements

Therapeutic Agents for Parkinson’s Disease

Drug Class Anticholinergics

Dopamine precursor plus peripheral dopa-decarboxylase inhibitor Catechol-O-methyltransferase (COMT) inhibitors Monoamine oxidase (MAO)-B inhibitors Dopamine receptor agonists

Sources: Jankovic J. J Neurol Neurosurg Psychiatry. 2008;79(4):368-76.11 Rao SS, et al. Am Fam Physician. 2006;74(12):2046-54.14 NMDA a receptor inhibitor a N-methyl-D-aspartic

and that initial misdiagnosis occurs in about 5%-10% of patients with actual PD.12 Additionally, approximately 20% of patients originally diagnosed with PD are found to have an alternative disease upon autopsy such as progressive supranuclear palsy (PSP), MSA, or Alzheimer disease-type pathology.12,13 Due to overlapping symptoms, it is important to use a differential diagnosis based on a process of elimination to properly diagnose and treat patients with PD. Positive confirmation of PD usually requires a post-mortem diagnosis confirming the presence of Lewy bodies within residual neurons. Several alternative diseases are associated with the presence of Lewy bodies, including diffuse Lewy body disease and Alzheimer’s disease. Summary and Recommendations for the Diagnosis of PD For purposes of diagnosis of PD, the AAN recommends (Level B recommendation) that both levodopa and apomorphine challenge tests should be considered if the diagnosis of PD is in doubt. Although there is a 30% chance of either a false positive or a false negative result, response to an acute levodopa challenge is strongly associated with a diagnosis of PD. Because PD has symptoms similar to other diseases, the AAN recommends (Level B recommendation) evaluation of a set of clinical features that are suggestive of other parkinsonian syndromes: (a) symmetry of motor signs, (b) lack of tremor, (c) poor response to levodopa, (d) falls occurring early in disease, (e) autonomic dysfunction occurring early, and (f) rapid progression of the disease (to Hoehn & Yahr stage III within 1 year). Confirmation of PD can also be determined by assessing symptoms during long-term follow-up such as lack of autonomic symptoms and oculomotor or cognitive dysfunction.12-14 ■■ Treatment Strategies for PD Following a diagnosis of PD, the general paradigm for disease management includes both pharmacological and nonpharmacoS4 Supplement to Journal of Managed Care Pharmacy

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April 2009

Agent(s) Benztropine Trihexyphenidyl Procyclidine Carbidopa-Levodopa Entacapone Tolcapone Rasagiline Selegiline Apomorphine Bromocriptine Pramipexole Ropinirole Amantadine

acid.

logical approaches. Nonpharmacological management of patients with PD prior to dopaminergic therapy should be considered. Generally, this approach includes adjustments to both nutritional and exercise regimens as well as patient education and support.15 Several classes of pharmacologic agents are also available to treat PD (Table 4). Historically, levodopa has been the gold standard for treatment in patients requiring dopaminergic therapy. Carbidopa is now typically coadministered with levodopa in patients with PD to inhibit peripheral metabolism of levodopa. This reduces the side effects caused by dopamine in the periphery such as nausea and orthostasis, as well as increasing the concentration of both levodopa and dopamine in the brain. Additional dopaminergic or dopamine enhancing drugs can be used including catechol-O-methyltransferase (COMT) inhibitors, monoamine oxidase (MAO)-B inhibitors, and dopamine receptor agonists. Anticholinergic drugs may also be used for initial treatment of PD, especially in younger patients where tremor is predominant.15,16 Delaying the Use of Levodopa While levodopa reduces parkinsonian symptoms, it is also associated with the development of motor complications, which may lead to additional significant disability and impairment of patient quality of life. These motor complications include involuntary movements (dyskinesia), involuntary muscle spasms (dystonia), freezing of gait, fluctuations of symptoms (on-off), and wearing off of the beneficial response to treatment.17 In a Parkinson Study Group report, levodopa effectively reduced the symptoms of PD in a dose-dependent manner, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS); however, increasing the dose of levodopa positively correlated with the frequency of motor complications (Figure 1).17 The UPDRS is an

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FIGURE 1

Levodopa Reduces Symptom Worsening in Early Parkinson’s Disease But Is Associated With Motor Complications

Change in Total Score (units)

12 10 8 6 4 2 0 -2 -4 -6 -8

0

2

4

6

8

10

12

14

16

18

20

22 24 Week

Baseline Placebo

150 mg

26

28

30

32

34

36

38

40

42

44

46

Withdraw of study drug

300 mg

600 mg

Levodopa Placebo (n = 90)

150 mg per day (n = 92)

Adverse Event

Dopaminergic effects Dyskinesia Dystonia Freezing of gait On-off Wearing off

300 mg per day (n = 88)

600 mg per day (n = 91) P value for Trend

number (%) 3 (3.3) 19 (21.1) 13 (14.4) 3 (3.3) 12 (13.3)

3 (3.3) 19 (20.7) 9 (9.8) 1 (1.1) 15 (16.3)

2 (2.3) 14 (15.9) 6 (6.8) 0 16 (18.2)

15 (16.5) 12 (13.2) 5 (5.5) 3 (3.3) 27 (29.7)