JOURNAL TRANSCRIPT
ADHERENCE THERAPY FOR PEOPLE WITH PARKINSON’S DISEASE
By
DAVID JAMES DALEY
Thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Norwich Medical School Faculty of Medicine and Health Sciences University of East Anglia
September 2013
Word Count: 76,414
© This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that use of any information derived there from must be in accordance with current UK Copyright Law. In addition, any quotation or extract must include full attribution.
Abstract
Introduction: Medication non-adherence is prevalent in Parkinson’s disease (PD). However, factors associated with non-adherence are unknown. Despite interventions to improve medication adherence being investigated in long-term conditions, few studies have focused on PD. Adherence Therapy (AT) is a novel, patient-centred approach to maximising adherence that has shown benefit in other chronic conditions.
Aim: To investigate the efficacy of AT for improving medication adherence and quality of Life (QoL) in people with PD.
Methods: To achieve the above aim I conducted a systematic review to identify factors associated with medication non-adherence, followed by a Cochrane systematic review on interventions for improving medication adherence in PD. I then tested the efficacy of AT in PD in a randomised controlled trial (RCT). Semistructured interviews were used to explore patients’ experiences of receiving AT.
Results: Mood disorders, cognition, poor symptom control/QoL, younger age/longer disease duration, regimen complexity/polypharmacy, risk taking
behaviours, poor knowledge of PD/education, lack of spouse/partner, low income, desire to maintain employment and gender were identified as factors associated with non-adherence in PD. Only one study previously investigated an intervention (didactic educational material) for improving medication adherence in PD, according to my Cochrane systematic review.
Seventy-six patients and 46 spouse/carers completed the RCT (CAAT-PARK). At week-12 follow-up the active treatment group significantly improved in adherence and QoL compared to the treatment as usual group. Thematic analysis of interviews from 10 patients and 3 spouse/carers suggested that positive effects and attributes of AT may be important for the success of AT. Furthermore, the findings suggested that the mechanism of AT may be bi-directional and associated with improved confidence and self-efficacy.
Conclusions: Adherence Therapy improved medication adherence and QoL in PD. A larger pragmatic trial to test the efficacy and cost effectiveness of Adherence Therapy with a control group placebo intervention is required. ISRCTN07830951
Contents
List of Tables ................................................................................................................ xi List of Figures ............................................................................................................. xiii List of Appendices ...................................................................................................... xiv List of Abbreviations .................................................................................................. xvi Acknowledgements .................................................................................................... xix Parky’s Time .............................................................................................................. xxi
PART ONE CHAPTER 1 .................................................................................................................. 1 The Necessity of This Work .......................................................................................... 1 1.1 Background .............................................................................................................. 1 1.2 The Aim & Structure of This Thesis ....................................................................... 5
CHAPTER 2 .................................................................................................................. 8 Parkinson’s Disease & Pharmacotherapy ...................................................................... 8 2.1 Introduction ............................................................................................................. 8 2.2 Parkinson’s Disease & The Nigrostriatal Pathway ................................................. 9 2.3 Prevalence and Cost of Parkinson’s Disease ........................................................... 9 2.3.1 Prevalence ............................................................................................................. 9 2.3.2 Cost of Parkinson’s Disease ............................................................................... 10 2.4 Symptoms of Parkinson’s Disease ........................................................................ 11 2.5 Pharmacotherapy for Parkinson’s Disease ............................................................ 14 2.5.1 Levodopa Therapy .............................................................................................. 16 2.5.2 Levodopa Response ............................................................................................ 16 2.5.3 Dopamine Receptor Agonists ............................................................................. 17 2.5.4 Monoamine Oxidase-B Inhibitors ...................................................................... 19 i
2.5.5 Catechol-O-Methyltransferase Inhibitors ........................................................... 20 2.5.6 N-Methyl-D-Aspartate (NMDA) Glutamate Antagonist ................................... 20 2.5.7 Anticholinergics ................................................................................................. 21 2.6 Treatment Complexity in Parkinson’s Disease ..................................................... 21 2.6.1 Early Treatment .................................................................................................. 21 2.6.2 Advancing Treatment ......................................................................................... 24 2.7 Medication Adherence ........................................................................................... 26 2.7.1 Prevalence of Non-adherence in Parkinson’s Disease ....................................... 28 2.7.2 Consequences of Non-adherence in Parkinson’s Disease .................................. 29 2.8 Summary: A Greater Understanding ..................................................................... 32
CHAPTER 3 ................................................................................................................ 34 Factors Affecting Medication Non-adherence in Parkinson’s Disease ....................... 34 3.1 Background ............................................................................................................ 34 3.2 Study Design ......................................................................................................... 36 3.2.1 Search Methods .................................................................................................. 36 3.2.2 Search Terms ...................................................................................................... 36 3.2.3 Selection Criteria ................................................................................................ 37 3.2.4 Data Extraction ................................................................................................... 38 3.3 Risk of Bias/Internal Validity ................................................................................ 39 3.3.1 Terminology ....................................................................................................... 39 3.3.2 Development of the Risk of Bias Appraisal Tool............................................... 40
3.4 Findings ................................................................................................................. 44 3.4.1 Summary of Studies ........................................................................................... 44 3.4.2 Risk of Bias (Threats to Internal Validity) ......................................................... 49 3.4.3 Factors Associated with Medication Non-adherence ......................................... 57 3.4.3.1 Assessing Study Risk of Bias .......................................................................... 57 3.4.3.2 Clinical Factors ................................................................................................ 60 3.4.3.3 Demographic Factors....................................................................................... 66
3.5 Discussion.............................................................................................................. 70 3.5.1 Strengths and Limitations ................................................................................... 84 ii
3.5.2 Summary............................................................................................................. 86
CHAPTER 4 ................................................................................................................ 87 Interventions to Improve Medication Adherence in Parkinson’s disease ................... 87 4.1 Background ............................................................................................................ 87
4.2 Methods ................................................................................................................. 89 4.2.1 Criteria for Considering Studies for this Review (Inclusion Criteria)................ 89 4.2.1.1 Types of Studies: ............................................................................................. 89 4.2.1.2 Types of Participants: ...................................................................................... 89 4.2.1.3 Types of Interventions: .................................................................................... 89 4.2.1.4 Exclusion Criteria ............................................................................................ 91 4.2.1.5 Types of Outcome Measures: .......................................................................... 92 4.2.2 Electronic Search Methods for Identification of Studies.................................... 93 4.2.3 Selection of Studies ............................................................................................ 94 4.2.4 Data Extraction and Management ...................................................................... 94 4.2.5 Assessment of Risk of Bias ................................................................................ 94 4.2.6 Dealing with Missing Data ................................................................................. 95 4.2.7 Measurement of Treatment Effect ...................................................................... 95 4.2.8 Data Synthesis .................................................................................................... 95
4.3 Results ................................................................................................................... 97 4.3.1 Assessment of Risk of Bias .............................................................................. 102 4.3.2 Judging Risk of Bias in Included Studies ......................................................... 103 4.3.3 Description of Adherence Intervention ............................................................ 104 4.3.4 Baseline Measurements and Observations ....................................................... 104 4.3.5 Efficacy of the Intervention .............................................................................. 105 4.3.5.1 Primary Outcomes ......................................................................................... 105 4.3.5.2 Secondary Outcomes Reported ..................................................................... 105 4.3.5.3 Secondary Outcomes Not Reported .............................................................. 106
4.4 Discussion............................................................................................................ 107 4.4.1 Summary of Main Results ................................................................................ 107 iii
4.4.2 Quality of Evidence .......................................................................................... 108 4.4.3 Discussion of Findings ..................................................................................... 108 4.4.4 Type of Intervention ......................................................................................... 111 4.4.5 Alternative Strategies for Enhancing Adherence ............................................. 113 4.4.6 Implications for Research ................................................................................. 114
PART TWO CHAPTER 5 .............................................................................................................. 117 Behaviour Change & Adherence Therapy................................................................. 117 5.1 Introduction ......................................................................................................... 117 5.2 Behaviour Change ............................................................................................... 118 5.3 Theories of Behaviour Change ............................................................................ 119 5.3.1 The Biomedical Perspective ............................................................................. 120 5.3.2 Behavioural (learning) Theory ......................................................................... 121 5.3.3 Communication Perspective ............................................................................. 122 5.3.4 Cognitive Perspective ....................................................................................... 123 5.3.4.1 Health Belief Model ...................................................................................... 124 5.3.4.2 The Protection-Motivation Theory ................................................................ 125 5.3.4.3 Social-Cognitive Theory ............................................................................... 127 5.3.4.4 Theory of Reasoned Action and Planned Behaviour .................................... 128 5.3.4.5 Information-Motivation-Behavioural Skills (IMB) Theory .......................... 130 5.3.5 The Transtheoretical Model (TTM) ................................................................. 132 5.3.5.1 Related Constructs to the TTM ..................................................................... 133 5.4 Summary of Behaviour Change Theories ........................................................... 134
5.5 The Motivational Interviewing Technique .......................................................... 136 5.5.1 Evidence for Motivational Interviewing........................................................... 138
5.6 Cognitive-Behavioural Therapy .......................................................................... 139 5.6.1 Evidence for Cognitive Behavioural Therapy .................................................. 140
5.7 A Need for Adherence Therapy .......................................................................... 142 5.8 Adherence Therapy.............................................................................................. 144 iv
5.8.1 Cornerstones of Adherence Therapy ................................................................ 144 5.8.2 Adherence Assessment ..................................................................................... 145 5.8.3 Key Adherence Therapy Exercises................................................................... 146 5.9 Evidence for Adherence Therapy ........................................................................ 148
CHAPTER 6 .............................................................................................................. 152 Methodology.............................................................................................................. 152 6.1 Introduction ......................................................................................................... 152 6.2 The Randomised Controlled Trial ....................................................................... 153 6.2.1 Advantages of the Randomised Controlled Trial ............................................. 154 6.2.2 Randomisation .................................................................................................. 154 6.2.3 Block Randomisation ....................................................................................... 155 6.2.4 Allocation Concealment ................................................................................... 156 6.2.5 Stratification ..................................................................................................... 156 6.2.6 Other Advantages of the RCT .......................................................................... 158
6.3 Hypothesis and Study Aims ................................................................................ 159 6.3.1 Alternate Hypotheses (H1) – Two-sided:.......................................................... 159 6.3.2 Null Hypothesis (N0) ........................................................................................ 159 6.3.3 Primary Aims .................................................................................................... 160 6.3.4 Secondary Aims ................................................................................................ 160 6.4 Selecting the Outcome Measures ........................................................................ 162 6.4.1 Direct Methods for Measuring Adherence ....................................................... 162 6.4.2 Indirect Methods of Measuring Adherence ...................................................... 163 6.4.3 Clinical Outcome Measures.............................................................................. 165 6.4.4 Deciding Upon the Primary Outcome Measure ............................................... 169 6.4.5 Primary Outcome Measures ............................................................................. 172 6.4.6 Secondary Outcome Measures ......................................................................... 172 6.4.7 Additional Baseline Assessments ..................................................................... 175 6.4.8 Patient Demographics and Clinical Characteristics.......................................... 176
6.5 Methods ............................................................................................................... 177 6.5.1 Study Design .................................................................................................... 177 v
6.5.2 Study Participants ............................................................................................. 178 6.5.3 Inclusion Criteria .............................................................................................. 178 6.5.4 Exclusion Criteria ............................................................................................. 180 6.5.5 Recruitment Procedure ..................................................................................... 180 6.5.6 Randomisation and Allocation Concealment ................................................... 182 6.5.7 Treatment Groups ............................................................................................. 183 6.5.8 Follow-up Outcome Assessment ...................................................................... 185 6.5.9 Adverse Events Monitoring .............................................................................. 186 6.6 Determination of Sample Size ............................................................................. 187
6.7 Analysis ............................................................................................................... 187 6.7.1 Data Entry & Quality Control .......................................................................... 187 6.7.2 Baseline Comparisons ...................................................................................... 188 6.7.3 Efficacy Analyses ............................................................................................. 189 6.7.4 Subgroup Analysis ............................................................................................ 193 6.7.5 Correlation Analyses ........................................................................................ 193
6.8 Ethical Considerations ......................................................................................... 194 6.8.1 Declaration of Helsinki..................................................................................... 194 6.8.2 International Conference of Harmonisation Good Clinical Practice ................ 194 6.8.3 Participant Confidentiality................................................................................ 195 6.8.4 Research Ethics and Governance ..................................................................... 195
6.9 Protocol Amendments ......................................................................................... 196 6.9.1 Amendment to Inclusion Criteria ..................................................................... 196 6.9.2 Protocol Breach ................................................................................................ 197 6.9.2.1 Actions Taken to Rectify ............................................................................... 198 6.9.2.2 Conclusion to Protocol Breach ...................................................................... 199 6.10 Chapter Summary .............................................................................................. 200
PART THREE CHAPTER 7 .............................................................................................................. 201 Trial Results............................................................................................................... 201 vi
7.1 Introduction ......................................................................................................... 201 7.2 Participant Flow ................................................................................................... 202 7.3 Study Population ................................................................................................. 204 7.3.1 Baseline Demographic & Clinical Characteristics ........................................... 204 7.3.2 Baseline Outcome Measures ............................................................................ 205
7.4 Efficacy Analyses ................................................................................................ 207 7.4.1 Primary Outcomes ............................................................................................ 207 7.4.2 Sensitivity Analysis .......................................................................................... 208 7.4.3 Secondary Outcomes ........................................................................................ 209 7.5 Sub-group Analyses ............................................................................................. 214
7.6 Correlation Analyses ........................................................................................... 215 7.6.1 MMAS-4 & Importance, Confidence and Satisfaction .................................... 215 7.6.2 MMAS-4 and MoCA Overall and Sub-domain Scores .................................... 216 7.7 Serious Adverse Events ....................................................................................... 217 7.8 Cost of Adherence Therapy in PD ....................................................................... 218 7.9 Summary of Results ............................................................................................ 219
CHAPTER 8 .............................................................................................................. 220 Discussion of Trial Results ........................................................................................ 220 8.1 Introduction ......................................................................................................... 220 8.2 Discussion of Results .......................................................................................... 222 8.2.1 Efficacy Analyses (Medication Adherence) ..................................................... 222 8.2.2 Efficacy Analyses (QoL) .................................................................................. 225 8.2.3 Sub-group Analyses.......................................................................................... 226
8.3 Correlation Analyses ........................................................................................... 228 8.3.1 Correlation: MMAS-4 & Importance, Confidence and Satisfaction ................ 228 8.3.2 MMAS-4 and MoCA Overall & Sub-domain Scores ...................................... 231 8.4 Implications of the Trial Findings ....................................................................... 232 8.5 Strengths and Limitations .................................................................................... 234 8.6 Adverse Events .................................................................................................... 237 vii
8.7 Cost of Adherence Therapy in PD ....................................................................... 238 8.8 Conclusion ........................................................................................................... 239
CHAPTER 9 .............................................................................................................. 240 Investigating the Experience & Acceptability of Adherence Therapy ...................... 240 9.1 Introduction ......................................................................................................... 240 9.2 Data Collection in Qualitative Research ............................................................. 242 9.2.1 Participant Observation .................................................................................... 242 9.2.2 Interviews ......................................................................................................... 243
9.3 Methods ............................................................................................................... 243 9.3.1 Aim ................................................................................................................... 243 9.3.2 Design ............................................................................................................... 243 9.3.3 Participants ....................................................................................................... 244 9.3.4 Procedure .......................................................................................................... 244 9.3.5 Data Collection ................................................................................................. 245 9.3.6 Thematic Analysis ............................................................................................ 246
9.4 The Analytical Process ........................................................................................ 247 9.4.1 Phase One: Familiarisation of the Data ............................................................ 248 9.4.2 Phase Two: Initial Code Generation ................................................................. 248 9.4.3 Phase Three: Searching for Themes ................................................................. 249 9.4.4 Phase Four: Revising the Themes .................................................................... 249 9.4.5 Phase Five: Defining and Naming Themes ...................................................... 249 9.4.6 Quality Assurance of the Analysis Process ...................................................... 250
9.5 Results ................................................................................................................. 251 9.5.1 Study Population .............................................................................................. 251 9.5.2 Codes and Themes ............................................................................................ 251 9.6 Perceptions Prior to Adherence Therapy ............................................................. 254 9.6.1 Poor Knowledge & Understanding of PD and Medication .............................. 254 9.6.2 Low Mood / Confidence ................................................................................... 255 9.6.3 Decreased Support / Isolation ........................................................................... 256 viii
9.7 Positive Effects of Adherence Therapy ............................................................... 257 9.7.1 Increased Acceptance ....................................................................................... 257 9.7.2 Increased Self-awareness .................................................................................. 259 9.7.3 Increased Confidence ....................................................................................... 260 9.7.4 Increased Knowledge & Understanding of PD Meds ...................................... 261 9.7.5 Increased Control / Self-discipline ................................................................... 264 9.7.6 Improved Relationships .................................................................................... 265
9.8 Attributes of Adherence Therapy ........................................................................ 267 9.8.1 Therapy Attributes ............................................................................................ 267 9.8.1.1 Flexibility, Continuity & Timing .................................................................. 267 9.8.1.2 Involved Spouse ............................................................................................ 269 9.8.1.3 Face to Face / In the Home Environment ...................................................... 269 9.8.1.4 Time to Talk / Openness ................................................................................ 270 9.8.2 Therapist Attributes .......................................................................................... 271 9.8.2.1 Specialist Knowledge .................................................................................... 271 9.8.2.2 Understanding & Interested ........................................................................... 272 9.8.2.3 Equal Relationships ....................................................................................... 273 9.8.2.4 Easy to Understand ........................................................................................ 274 9.9 Summary of Results ............................................................................................ 274
CHAPTER 10 ............................................................................................................ 275 Discussion of Interview Findings .............................................................................. 275 10.1 Introduction ....................................................................................................... 275 10.2 Perceptions Prior to Adherence Therapy ........................................................... 276 10.3 Positive Effects of Adherence Therapy ............................................................. 280 10.3.1 Improving Knowledge and Understanding..................................................... 280 10.3.2 Improving Acceptance of PD and Confidence in Daily Life ......................... 282 10.4 Attributes of Adherence Therapy ...................................................................... 286 10.4.1 Therapy Attributes .......................................................................................... 286 10.4.2 Therapist Attributes ........................................................................................ 290 10.5 Strengths and Limitations .................................................................................. 292 10.6 Summary............................................................................................................ 293 ix
CHAPTER 11 ............................................................................................................ 295 Implications and Conclusions.................................................................................... 295 11.1 Summary of This Thesis .................................................................................... 295 11.2 The Cochrane Systematic Review Including CAAT-PARK............................. 297 11.3 CAAT-PARK within the Wider Adherence Literature ..................................... 299 11.4 Implications of This Work................................................................................. 301 11.4.1 Implications for Clinical Practice ................................................................... 301 11.4.2 Implications for Future Research ................................................................... 302
11.5 Dissemination of This Work.............................................................................. 304 11.5.1 Conference Presentations ............................................................................... 304 11.5.2 Published Papers ............................................................................................. 304 11.5.3 Manuscripts Submitted ................................................................................... 305 11.5.4 Manuscripts in Preparation ............................................................................. 306 11.6 Conclusion ......................................................................................................... 306
References ................................................................................................................. 307
x
List of Tables
Table 2. 1 - Symptoms of Parkinsonism ................................................................. 12 Table 2. 2 - Non-motor Symptoms of Parkinson's disease ...................................... 13 Table 2. 3 - Oral Drug Preparations for Parkinson’s disease .................................. 15 Table 3. 1 - Data Extraction Table .......................................................................... 38 Table 3. 2 - Tool to Appraise Risk of Bias in Non-Interventional Studies ............. 43 Table 3. 3 - Characteristics of Included Studies ...................................................... 46 Table 3. 4 - Study Specific Risk of Bias ................................................................. 50 Table 3. 5 - Calculating Risk of Bias ...................................................................... 58 Table 3. 6 - Factors Associated with Medication Non-adherence ........................... 59 Table 4. 1 - Records Identified by Database ........................................................... 97 Table 4. 2 - Characteristics of Included Study ...................................................... 101 Table 4. 3 - Classification Scheme for Bias .......................................................... 102 Table 4. 4 - Risk of Bias ........................................................................................ 103 Table 5. 1 - Key Principles in Motivational Interviewing ..................................... 136 Table 5. 2 - Adherence Therapy Trials .................................................................. 149 Table 6. 1 - Randomisation by Strata .................................................................... 157 Table 6. 2 - Outcome Measure Assessment Points ............................................... 186
xi
Table 7. 1 - Baseline Demographic & Clinical Characteristics ............................. 205 Table 7. 2 - Baseline Outcome Measure Scores .................................................... 206 Table 7. 3a - Adjusted Outcomes (Baseline to Week-12 Follow-up) ................... 210 Table 7. 3b - Unadjusted Outcomes (Baseline to Week-12 Follow-up) ............... 211 Table 7. 4a - Adjusted Outcomes (Baseline to Week-7 Follow-up) ..................... 212 Table 7. 4b - Unadjusted Outcomes (Baseline to Week-7 Follow-up) ................. 213 Table 7. 5 - Sub-group Interactions with Primary Outcomes ................................ 214 Table 7. 6 - Importance, Confidence and Satisfaction Scores…………………...215 Table 7. 7 - Difference in MMAS-4 from Baseline to Week-12…………..….…216 Table 7. 8 - Association between MMAS-4 and MoCA at Baseline…………….217 Table 9. 1 - Phases of Thematic Analysis ............................................................. 247 Table 9. 2 - Baseline Characteristics of Interview Participants ............................. 252 Table 9. 3 - Themes and Sub-themes .................................................................... 253
xii
List of Figures
Figure 2. 1 - Decision Pathway for Initiating Parkinson's disease Treatment ......... 23 Figure 3. 1 - PRISMA Flow Diagram of Study Identification ................................ 45 Figure 4. 1 - PRISMA Flow Diagram of Study Identification .............................. 100 Figure 5. 1 - Behavioural Learning Theory ........................................................... 121 Figure 5. 2 - The Health Belief Model .................................................................. 124 Figure 5. 3 - Protection Motivation Theory........................................................... 126 Figure 5. 4 - Social-Cognitive Theory ................................................................... 127 Figure 5. 5 - Theory of Reasoned Action .............................................................. 129 Figure 5. 6 - Information-Motivation-Behavioural Skills Model .......................... 131 Figure 5. 7 - The Transtheoretical Model (Stages of Change) .............................. 132 Figure 5. 8 - Adherence Therapy Model ............................................................... 148 Figure 6. 1 - The Basic Structure of a RCT ........................................................... 153 Figure 6. 2 - Outcome Measure Assessment Time Points..................................... 185 Figure 7. 1 - Trial CONSORT Participant Flow Diagram .................................... 203 Figure 10. 1 - Linear Mechanism of Action of Adherence Therapy ..................... 283 Figure 10. 2 - Bi-directional Model of AT Mechanism in PD .............................. 285
xiii
List of Appendices
Appendix 1
Systematic Review Search Strings: Factors for Non-adherence
Appendix 2
Data Extraction for Included Studies
Appendix 3
Cochrane Systematic Review Search Strings
Appendix 4
Criteria for Judging Risk of Bias
Appendix 5
Morisky Medication Adherence Scale-4 (MMAS-4)
Appendix 6
Parkinson’s Disease Questionnaire - 39 items
Appendix 7
MDS - Unified Parkinson’s Disease Rating Scale
Appendix 8
Beliefs about Medication Questionnaire
Appendix 9
EuroQol EQ-5D
Appendix 10 Caregiving Distress Scale Appendix 11 Montreal Cognitive Assessment Scale Appendix 12 Hospital Anxiety & Depression Scale Appendix 13 Information Hand-out for Moderate/Severe Depression Appendix 14 Information Hand-out for Mild Depression Appendix 15 Letter to General Practitioner Regarding Patients Depression Appendix 16 Baseline Demographics Form Appendix 17 Hoehn & Yahr Scale of PD Severity Appendix 18 United Kingdom Brain Bank Criteria Appendix 19 Letter of Invitation Appendix 20 Patient Information Sheet xiv
Appendix 21 Consent Form for MMAS-4 Appendix 22 Carer Information Sheet Appendix 23 Carer Initial Consent Form Appendix 24 Patient Informed Consent Form Appendix 25 Carer Informed Consent Form Appendix 26 Adverse Events Form Appendix 27 Trial Steering Committee Members Appendix 28 Protocol Submitted to Cambridge Central Ethics Committee Appendix 29 Favourable Ethical Opinion Letter Appendix 30 Favourable Ethical Opinion for Inclusion Criteria Amendment Appendix 31 Favourable Ethical Opinion Letter for Re-starting Trial Recruitment Appendix 32 NNUH R&D Letter for Re-starting Trial Recruitment Appendix 33 Patient Information Sheet for Interviews Appendix 34 Spouse/carer Information Sheet for Interviews Appendix 35 Patient Interview Consent Form Appendix 36 Spouse/carer Interview Consent Form Appendix 37 Interview Questions Appendix 38 Example of Codes and Code Descriptions Appendix 39 Extract of an Interview Transcript Appendix 40 Diagram of Dopaminergic Theory Used for Explanation Appendix 41 Published Papers
xv
List of Abbreviations
ADL
-
Activities of Daily Living
AE
-
Adverse Events
CENTRAL
-
Cochrane Central Register of Controlled Trials
CI
-
Confidence Intervals
COMT
-
Catechol-O-Methyl Transferase Inhibitors
CRF
-
Case Record Files
DDS
-
Dopamine Dysregulation Syndrome
DLB
-
Dementia with Lewy Bodies
DRT
-
Dopamine Replacement Therapy
HADS
-
Hospital Anxiety & Depression Scale
HBM
-
Health Belief Model
HIV
-
Human Immunodeficiency Virus
HRQoL
-
Health Related Quality of Life
H&Y
-
Hoehn & Yahr Scale
ICD
-
Impulse Control Disorder
ICH
-
The International Conference of Harmonisation
ICTRP
-
WHO International Clinical Trials Registry Platform
IMB
-
Information-Motivation-Behavioural Skills Theory
IQR
-
Inter Quartile Range
ISRCTN
-
International Standard Randomised Controlled Trial Number xvi
ITT
-
Intension to Treat
LEDD
-
Levodopa Equivalent Daily Doses
MAO-B
-
Monoamine Oxidase-B-Inhibitors
MD
-
Mean Difference
MEMS
-
Medication Electronic Monitoring devises/caps
MeSH
-
Mapped Specific Subject Headings
MFE
-
Medicine For The Elderly Department
MMAS-4
-
Morisky Medication Adherence Scale 4 item
MMSE
-
Mini-Mental State Examination
MoCA
-
Montreal Cognitive Assessment Scale
MOOSE
-
Meta-analysis of Observational Studies in Epidemiology
MI
-
Motivational Interviewing
MPR
-
Medication Possession Ratio
MSA
-
Multiple Systems Atrophy
NICE
-
National Institute for Health and Clinical Excellence
NRR
-
UK National Research Register
NNT
-
Numbers Needed to Treat
NNUH
-
Norfolk and Norwich university Hospital
Non-IMPs
-
Non-Investigational Medicinal Products
NPF
-
National Parkinson’s Foundation
OH
-
Orthostatic Hypotension
OR
-
Odds Ratio
PD
-
Parkinson’s disease
PDD
-
Parkinson’s disease Dementia
PMT
-
Protection Motivation Theory xvii
PP
-
Per Protocol
PSP
-
Progressive Supranuclear Palsy
QALYs
-
Quality Adjusted Life Years
QoL
-
Quality of Life
REM
-
Rapid Eye Movement
SCT
-
Social-Cognitive Theory
SOPs
-
Standard Operating Procedures
STROBE
-
Strengthening the Reporting of Observational Studies
TPB
-
Theory of Planned Behaviour
TRA
-
Theory of Reasoned Action
TSC
-
Trial Steering Committee
TTM
-
Transtheoretical Model of Change
UK
-
United Kingdom
UPDRS
-
Unified Parkinson’s disease Rating Scale
US
-
United States
USPSTF
-
US Preventive Services Task Force
WHO
-
World Health organization
xviii
Acknowledgements
One of the great delights of completion is being able to look back to see how far you have journeyed, how you have developed and who is responsible for guiding you towards attainment. With that I would like to express my heartfelt gratitude to my Ph.D supervisors: Professor Phyo Myint, Dr Katherine Deane and Professor Richard Gray who have been not only great mentors but dear friends. I could not have wished for better role models. I hope that I can one day pass on the same research values to my own students that they have given to me.
Specifically, I immensely thank my primary supervisor Phyo for his wisdom, support and inspiration. It has been an honour to be supervised by him and he has taught me more than he will realise. I thank him greatly for his sincere patience over the last three years. I wish to thank Katherine for her sound advice and contribution to this work. Her expertise has been invaluable and her enthusiasm has been contagious. I thank Richard for being a strong and supportive supervisor and for believing in the project. His supervisory approach and knowledge of current fashion trends were refreshing.
I wish to offer a special thanks to Dr Allan Clark for providing me with statistical support throughout the entirety of this work. I am enormously grateful for Allan’s xix
continued perseverance. I also wish to thank the members of the Trial Steering Committee: Dr Paul Worth, Dr Kanagasabesan Sabanathan, Fiona Reading, Garth Ravenhill and Dr Michael Pfeil who kindly gave up their valuable time to help in the smooth running of the clinical trial. Their knowledge and expertise was unquestionable and I thank them sincerely for their efforts.
I wish to thank the Parkinson’s disease nurse specialists: Fiona Reading, Bronnie Roper, Rachael Rendell, Terri Johns, Michelle Green and especially Debbie Davey for whom without them the clinical trial would not have been possible. It was a joy and privilege to work alongside all of them.
I wish to provide a very special thanks to three wonderful women. Firstly to my Nan who has been a source of everlasting encouragement in whatever endeavour I undertake. Secondly to Lyndsey my landlady who has been more akin to a mother than somebody I pay rent to. I thank her greatly for her kindness over the last few years. Dave’s desk will never be the same. Finally, but by no means least, I sincerely thank one of my dearest friends, Dr Rebekah Hill. Rebekah’s encouragement and support has far surpassed the realms of academic life. I will be ever thankful for her perpetual wisdom in all facets of my life.
Finally, I wish to thank the patients who kindly gave up their time to participate in the research presented within this thesis. I was honoured that they all felt comfortable sharing their homes and experiences with me. Every day they gave me a reason to smile. I will never forget them.
xx
Parky’s Time
“Parky is running around my brain what is he doing there He whizzes round from dawn to dusk and doesn’t seem to care He makes my life quite hard to plan and leaves me feeling down He twits my face this way and that and makes me wear a frown Levodopa is the answer, so all the experts say To put this right I have to take some medicine each day Through studies made it has been proved it’s most important to Not just take them every day, but at the right time too. My morning medications, starts off with good intent The sequence that I follow, is time I think well spent The importance of adherence, is there for all to see It soothes the highs and the lows you see, and leaves me tremor free It may be sometimes tiresome, for a clock to rule my day But all in all it helps me live my life a better way”
Trial Participant: B181 (CRTU 052)
xxi
CHAPTER 1
The Necessity of This Work Background The Structure and Aim of This Thesis
1.1 Background Parkinson’s disease (PD) is a degenerative, neurological disorder that greatly impacts on Quality of Life (QoL). The diagnosis of PD is made based on four key symptoms: rigidity, bradykinesia (slowness of movement), postural instability and resting tremor (Hughes et al., 1992). Alongside motor dysfunction, many people with PD experience a wide variety of non-motor symptoms which can be both highly prevalent and problematic (Chaudhuri et al., 2006, Poewe, 2008).
The symptoms of PD are controllable, although management becomes considerably more complex as the condition progresses. Not only do slowness, rigidity and gait problems respond to treatment, but many non-motor symptoms can also be relieved by PD medications. Healthcare professionals responsible for managing PD have the potential to substantially improve the QoL of patients. Although not all symptoms of PD can be sufficiently managed, anti-parkinsonian medication affords the 1
patient an optimal QoL, allowing many individuals to remain in the mainstream of their lives for many years post diagnosis (Ahlskog, 2009).
Medication management for PD, however, is not straight forward and is complicated by a multitude of factors. There are various pharmaceutical formulations (drugs) available for use with the same therapeutic indications and overlapping pharmacodynamics. Many drugs can induce unique side effects, which may often be confused with the worsening symptoms of PD (Fahn, 1989). Despite a vast body of research, disparity remains in the literature concerning what is the best therapeutic approach to adopt at different stages of disease severity (Schapira, 2007). Furthermore, controversy between expert opinions regarding when to initiate certain treatments remains topical and continues to be a source of debate (Schapira and Obeso, 2006).
Obscuring management decisions further is the fact that PD is progressive, with new problems appearing over the course of the disease that can alter the therapeutic focus. This can result in continuous amendment of doses and class of medications used to control the symptoms. What’s more, as PD is mainly a condition prevalent in older people, age related comorbidities add further to the burden on QoL. In light of the aforementioned factors, it is evident that successful medical management of a person with PD is a complex and on-going pursuit, particularly as the disease progresses.
As with all chronic diseases, adherence to medication is paramount for achieving effective symptom control; drugs do not have the desired therapeutic effect if they 2
are not taken as the prescriber intended (Rigby, 2007). However, reports from the World Health Organization (WHO) and the National Institute for Health and Care Excellence (NICE) in the UK suggest that a third to half of all medications prescribed to people with long term conditions are not taken as recommended (WHO, 2003, NICE, 2009).
In PD more than half of people take two to four anti-parkinsonian medications three to four times daily (Leoni et al., 2002, Tan et al., 2005). This is because multiple drug classes are needed to adequately control symptoms as PD progresses (Schapira et al., 2009a). Adding further prescriptions often parallels dose escalation, resulting in complex polypharmacy (Kulkarni et al., 2008). Therefore, not surprisingly, medication adherence is poor in people with PD (Bainbridge and Ruscin, 2009).
Whilst not taking prescribed medication as recommended will result in ill managed symptoms in many chronic conditions, the ramifications of non-adherence in PD are acutely problematic (Grosset et al., 2005b, Kulkarni et al., 2008, Grosset, 2010). For example, sub-optimal medication adherence in PD can result in the ‘wearing-off’ of the treatment effect which can increase motor dysfunction (Grosset et al., 2005b, Kulkarni et al., 2008, Grosset, 2010). Researchers have shown sub-optimal medication adherence to be associated with poor symptom control, increased unplanned hospital visits for PD related problems and a poorer overall prognosis (Kulkarni et al., 2008).
3
Aside from sub-optimal medication taking, people may also over medicate on antiparkinsonian therapy. This can result in severe motor complications such as peak dose motor fluctuations, dyskinesia (uncoordinated movements) and can even lead to psychosis (Lim et al., 2009, O'Sullivan et al., 2009). Although medication adherence is important in all chronic diseases, due to the intricate relationship between medication taking and both immediate and long-term symptom management, it is clear that sound adherence in PD is essential.
The reasons for non-adherence are likely to be multi-dimensional. Consequentially, there is a need for greater understanding of the factors that are associated with medication non-adherence in PD. With an increased understanding of why patients may not adequately adhere to medication regimens, an intervention that specifically aims to enhance adherence behaviour can be investigated. A targeted therapy that acknowledges factors associated with sub-optimal medication taking may result in overall improvement in rates of adherence. As various motor and non-motor symptoms of PD are sensitive to anti-parkinsonian therapies, improved medication adherence may enhance overall function. Consequentially, improved adherence to medication could theoretically benefit QoL.
4
1.2 The Aim & Structure of This Thesis The main aim of the work presented in this thesis was to investigate the efficacy of an intervention for improving medication adherence in patients with PD. From this aim, several specific objectives were developed as presented below:
1. To identify from the existing literature which factors are associated with medication non-adherence in people with PD.
2. To identify from the literature which interventions have been investigated previously that aimed specifically to improve adherence to medication in PD.
3. To develop a novel intervention aimed at improving medication adherence in people with PD.
4. To investigate the efficacy of this novel intervention.
5. To evaluate patient acceptability and to investigate the potential underlying mechanism of the adherence enhancing intervention.
This thesis is presented in three parts. Part one contains Chapters 2, 3 and 4. In Chapter 2 I provide an introduction to PD, including an overview of the medication used to manage the common symptoms in both early and later stages of the disease. I then discuss the importance of medication adherence in PD, the prevalence of non-adherence and the associated consequences. 5
In Chapter 3 I present the rationale and findings of a systematic review identifying factors associated with medication non-adherence in people with PD. The development of a novel quality appraisal tool for assessing risk of bias is also discussed. Having highlighted factors associated with non-adherence in PD, in Chapter 4 I provide the rationale and findings of a Cochrane systematic review investigating interventions used to improve medication adherence in PD.
Part 2 commences with Chapter 5 where I discuss the common psychological theories of behaviour change. The underlying principles of, and the evidence base for, the disciplines of motivational interviewing and cognitive behavioural therapy are presented. I then conclude by introducing the therapy of interest in this thesis; that is, Adherence Therapy (AT) and by discussing its evidence base from the existing literature.
Chapter 6 outlines the justification and methodology for a randomised controlled trial investigating whether AT is beneficial for improving medication adherence and quality of life. The analyses undertaken and the ethical considerations relating to the conduct of the trial are then discussed. Part 3 starts with Chapter 7 where I present the quantitative findings of the RCT. In Chapter 8 I provide a detailed discussion of the findings.
In Chapter 9 I investigate the acceptability of, and proposed mechanism for, the AT intervention using a qualitative methodological approach. In Chapter 10 a detailed discussion of the findings is provided and the implications for practice and further research are considered. 6
This thesis concludes with Chapter 11. The findings of the Cochrane systematic review, presented in Chapter 4, are considered when the results of the clinical trial are added. The implications of the overall findings within this thesis are considered for both clinical practice and future research. The dissemination of the findings is also outlined.
7
Part 1 CHAPTER 2 Parkinson’s Disease & Pharmacotherapy Introduction Parkinson’s Disease & The Nigrostriatal Pathway Prevalence and Cost of Parkinson’s Disease Symptoms of Parkinson’s Disease Pharmacotherapy for Parkinson’s Disease Treatment Regimens and Complexity in Parkinson’s Disease Medication Adherence Summary: A Greater Understanding
2.1 Introduction This chapter provides an outline of PD. Specifically, I summarise the underlying pathophysiology, characteristic symptoms, prevalence and the cost of PD. Following this I then highlight the typical anti-parkinsonian medications used to treat the symptoms of PD. In the final part of this chapter I discuss medication nonadherence and the associated consequences for people with PD.
8
2.2 Parkinson’s Disease & The Nigrostriatal Pathway The hallmark of PD is the progressive degeneration of the dopamine producing neurons within the substantia nigra (Jankovic, 2008). Microscopically, PD is characterised by the presence of Lewy bodies found within surviving nigral neurons. The protein alpha-synuclein, found in Lewy bodies, characterises PD aside from other forms of Parkinsonism (Ahlskog, 2009).
The nigrostriatal pathway is positioned centrally in the extrapyramidal (basal ganglia) motor control circuits (Ahlskog, 2009). Identifying that the nigrostriatal pathway is dopaminergic resulted in the discovery that replenishing dopamine with levodopa is a very effective treatment for PD (Ahlskog, 2009). Today levodopa remains the foundation of PD treatment and has been recognised as the most effective pharmacological intervention for symptom management (Schapira et al., 2009b).
2.3 Prevalence and Cost of Parkinson’s Disease 2.3.1 Prevalence Parkinson’s disease is the second most prevalent neurodegenerative disorder after Alzheimer’s disease (Mayeux et al., 1995, Bower et al., 1999, Nussbaum and Ellis, 2003) and is anticipated to impose an increasing social and economic burden on society as populations continue to age (De Lau and Breteler, 2006). A report by the National Parkinson Foundation (NPF) in the United States (US) suggested that PD affects an estimated four to six million worldwide (Oberdorf and Schmidt, 2010). 9
In the UK, PD is estimated to affect 100–180 people per 100,000 of the population and has an annual incidence of 4-20 per 100,000 (NICE, 2006). The incidence of the disease rises with increasing age (Findley, 2007, Findley et al., 2003). One in seven are diagnosed before 50 years of age, with a fivefold increase in diagnosis in those aged over 65 (Schrag et al., 2000a).
2.3.2 Cost of Parkinson’s Disease Due to an ageing population the prevalence of PD is forecast to increase substantially in the long term (De Lau and Breteler, 2006). This will result in immense financial dependency on healthcare organisations globally. Current costs are estimated to be $23 billion annually in the US alone and are projected to increase to $50 billion by 2040 (Oberdorf and Schmidt, 2010).
A cross-sectional study of the economic impact of PD on healthcare providers in the UK showed an estimated cost for care of approximately £450 million (Findley et al., 2003). However, this calculation was thought to be the most conservative scenario. Using current and future predicted prevalence rates, cost for healthcare analysis suggests expenditure will reach as high as £3.3 billion annually (Findley, 2007). Furthermore, the fiscal dependency for increased care in patients with PD rises exponentially with the progression of the disease. This is because people become increasingly medicated due to incapacitating motor and non-motor dysfunction.
10
Personalised one-to-one care may also be required for those who develop significant cognitive dysfunction, adding substantial costs for care (Oberdorf and Schmidt, 2010); researchers have shown cognitive impairment and dementia in PD greatly reduce QoL and can be more debilitating to patients and burdensome for carers than motor symptoms (Leroi et al., 2012). It is also well acknowledged that poor cognitive function is a key predictor of nursing home placement and mortality in people with PD (Hou and Lai, 2007, Liepelt et al., 2007).
In light of the reported prevalence’s and findings from cost for healthcare analyses, it is essential that PD medication is closely managed to ensure that treatments are appropriate for each individual suffering from PD.
2.4 Symptoms of Parkinson’s Disease Parkinsonism implies the appearance of PD characteristics and is a broad term used to include other disorders like progressive supranuclear palsy (PSP), multiple systems atrophy (MSA), PD dementia (PDD) and dementia with Lewy bodies (DLB) (Albanese, 2003, Jankovic, 2008, Ahlskog, 2009). Prior to the diagnosis of PD patients may report non-specific symptoms: feelings of depression and/or anxiety, REM (rapid eye movement) sleep disorder, fibromyalgia and olfactory dysfunctions. It is not until PD progresses further that parkinsonian associated symptoms present (Albanese, 2003).
11
For many the onset of PD is insidious and people classically present with the cardinal signs and symptoms associated with the overarching phenomenon of Parkinsonism (Table 2.1). Additionally, a dysfunctional presence of thoracic flexion and freezing during gait have been proposed as characteristically prominent features in advanced Parkinsonism (Albanese, 2003, Jankovic, 2008).
Table 2. 1 - Symptoms of Parkinsonism Symptom Bradykinesia
Description Slowed movements
Rigidity
Resistance as the examiner moves a relaxed limb
Gait
Shortened stride, reduced heel strike, shuffling
Resting tremor
Limbs, chin
Loss of automatic movements
Reduced animation; for example, facial masking, dampened arm swing when walking, gesturing when talking
Poor balance
Often not prominent in early PD
(Ahlskog, 2009)
Diagnostically the motor symptoms of PD characterise the disorder. However, nonmotor symptoms are also significantly debilitating (Chaudhuri et al., 2004, Chaudhuri et al., 2006, Hou and Lai, 2007, Poewe, 2008, Chaudhuri and MartinezMartin, 2008, Löhle et al., 2009, Park and Stacy, 2009). As many as 90% of people with PD are reported to experience non-motor manifestations throughout the disease course (Shulman et al., 2001).
12
Table 2.2 provides an outline of the non-motor symptoms of PD. As PD progresses non-motor symptoms start to become increasingly troublesome and multiple medications can be added (Hou and Lai, 2007). These can be in addition to drugs aimed at treating motor symptoms. For many people with PD this leads to increasing medication complexity and polypharmacy.
Table 2. 2 - Non-motor Symptoms of Parkinson's disease Category of Nonmotor symptom Neuropsychiatric
Specific complaint
Sleep Disorders
Autonomic
Gastrointestinal
Sensory
Other
Depression, apathy, anxiety, anhedonia, attention deficit, hallucinations. Delusions, dementia, obsessive behaviour. Restless legs, periodic limb movements, REM behaviour disorder. Excessive daytime sleepiness, vivid dreaming, nonREM sleep movement disorder, insomnia. Bladder disturbance: urgency, nocturia and frequency, sweating, Orthostatic Hypotension (OH), falls related to OH, coat-hanger pain, sexual dysfunction, hypersexuality, erectile impotence. Dribbling of saliva, ageusia, dysphagia/choking, reflux, vomiting, nausea, constipation, unsatisfactory voiding of bowl, bowl incontinence. Pain, paraesthesia, olfactory disturbance Fatigue, diplopia, blurred vision, seborrhoea, weight loss
Cognitive impairment is estimated to affect up to 85% of patients with PD if executive dysfunction is included (Aarsland and Kurz, 2010). Deficits include dysfunctional planning and organisation, visuospatial difficulties and impaired memory recall, amongst others (Dubois and Pillon, 1997, Hou and Lai, 2007). Even in early PD, subtle decline in cognitive function may be evident (Park and Stacy, 2009). As the disease progresses cognitive decline persists and PD patients 13
may develop dementia (PD dementia (PDD)) (Leroi et al., 2012). Aarsland & colleagues (2005) conducted a meta-analysis including a total of 1767 PD patients with a mean age of 73 years (range 70-76) and found the prevalence of dementia to be 30%. However, estimates suggest dementia affects 50% of PD patients who have had the disease for 15 years or more. It is likely therefore that in advanced PD treatment may be aimed at managing the consequences of dementing illness as opposed to treating motor symptoms which may have been the focus in earlier stages of PD (Dubois and Pillon, 1997, Bosboom et al., 2004, Ahlskog, 2009, Montine, 2010).
The remainder of this chapter focuses on two topics. First I outline the various pharmacological treatments used for the management of PD. I then discuss the issue of medication adherence and the consequences of non-adherence specifically in PD. Finally, I summarise the chapter by placing it within the context of the overall thesis.
2.5 Pharmacotherapy for Parkinson’s Disease Despite much research into strategies to inhibit PD progression, no treatment has yet been shown to offer promising neuroprotective properties (Suchowersky et al., 2006). Currently there is no encouraging evidence that any drug truly modifies the underlying pathophysiology of PD. Therefore, managing and controlling the symptoms of PD is the chief therapeutic goal of current treatment strategies; the aims of which are to keep patients engaged in society, remain ambulatory and 14
maximise QoL (Chaudhuri et al., 2006). Despite medications appearing to lack neuroprotective efficacy, drugs aimed at controlling the symptoms of PD can be substantially beneficial. Table 2.3 outlines the most common orally administered PD preparations.
Table 2. 3 - Oral Drug Preparations for Parkinson’s disease Classification
Drug Names Generic Brand
Preparations
Levodopa
Co-careldopa (carbidopa)*
Sinemet (tablet)
50mg/12.5mg Half Sinemet 100mg/25mg 100mg/10mg Sinemet CR 200mg/50mg 200mg/25mg
Co-beneldopa (benserazide)*
Madopar (capsule)
Co-careldopa + Entacapone
Stalevo
50mg/12.5mg 100mg/25mg 200mg/50mg CR** 100mg/25mg 50mg 70mg 100mg 125mg 150mg 200mg
Entacapone
Comtess
200mg
Tolcapone
Tasmar
100mg
Rasagiline
Azilect
1mg
Selegiline
5mg 10mg
Selegiline
Elderpryl (tbl or syrup) Zelapar
Pramipexole
Mirapexin
0.088 mg base/0.125 mg salt 0.18 mg base/0.25 mg salt 0.35 mg base/0.5 mg salt 0.7 mg base/1 mg salt
Pramipexole
Mirapexin PR**
0.25 0.52 1.05 1.57 2.1 2.62 0.7
Ropinirole Ropinirole
Requip Requip XL** Symmetrel
0.25 mg 0.5mg 1mg 2mg 5mg 2mg 4mg 8mg
Catechol-O-Methyl Transferase Inhibitors
Monoamine Oxidase B Inhibitors
Dopamine Receptor Agonists (Non-ergot derived)
Glutamate Antagonist
Amantadine
(dispersible tbl) 100mg/25mg (dispersible tbl)
10mg/5ml
1.25mg
mg base/0.375 mg base/0.75 mg base/1.5 mg base/2.25 mg base/3.0 mg base/3.75 mg base/1
mg salt mg salt mg salt mg salt mg salt mg salt mg salt
100mg
* Dopa-decarboxylase inhibitor added to Levodopa in a ratio of 1:4 i.e. 4 parts Levodopa to one part inhibitor **CR (continuous release) drugs are complete doses that are released over a prolonged period. Often prescribed for overnight delivery of levodopa
15
2.5.1 Levodopa Therapy Since its discovery more than fifty years ago, levodopa has been by far the most efficacious drug for managing the symptoms of PD (Schapira et al., 2009b). Levodopa is the amino acid precursor of dopamine and its administration has been shown to promptly raise dopamine concentrations in the nigrostriatal pathways, leading to increased QoL and overall life expectancy (Karlsen et al., 2000, Rajput, 2001, Schapira, 2007, Schapira et al., 2009b).
Following the diagnosis of PD careful consideration is required to establish the optimal dose of medication. Traditionally this has awaited the manifestation of significant motor symptoms and reduced QoL (Schapira and Obeso, 2006, Schapira et al., 2009b). However, evidence now suggests that early dopamine replacement therapy (DRT) offers long-term benefit to patients (Schapira and Obeso, 2006). It has been reported that the rate of clinical deterioration can be rapid within the first year post diagnosis of PD, with a significant decline of 8-10 points in the Unified Parkinson’s Disease Rating Scale (typically considered large) observed in this short duration (Fahn et al., 2004). This suggests that early intervention with antiparkinsonian therapies may offer worthwhile benefit for controlling PD symptoms in the long term.
2.5.2 Levodopa Response Early in the course of PD the therapeutic response to levodopa is typically constant; that is, patients are not usually susceptible to response fluctuations (Ahlskog and Muenter, 2001). Some patients can take doses later than the prescribed time or even 16
completely miss doses without noticing a substantial decline in symptom control. This phenomenon has been referred to as the long-duration levodopa response and may partly explain medication underuse in early PD (Lopez et al., 2001).
After a few years some of the benefit offered by levodopa starts to become time locked. Patients may note 20-60 minutes post drug administration that their symptoms improve. However, the therapeutic response often declines after a few hours and people with PD may start to feel their symptoms return sooner than they once did. For example, patients commonly report slowing-up during gait and feeling progressively more rigid. This is referred to as the short-duration response which is reported to represent the underpinning for the ‘wearing-off’ phenomenon in PD (Lopez et al., 2001, Sesar et al., 2011). Once this starts to occur levodopa regimens almost certainly require modification. Doses can be increased or more doses can be added so that the time between each dose is reduced. Adjunctive medications can also be used, however this further complicates the medication regimen (Ahlskog, 2009).
2.5.3 Dopamine Receptor Agonists Dopamine receptor agonists imitate the action of the neurotransmitter dopamine by stimulating dopamine receptors at the post synaptic membrane (Lim et al., 2009). Drugs from this classification do not require enzymatic conversion or a specific transport system to cross the blood-brain barrier, making their successful uptake simpler than levodopa preparations (Gerlach et al., 2003). The main orally
17
administered dopamine agonists are pramipexole (Mirapexin) and ropinirole (Requip).
In contrast to levodopa, the principal benefit of dopamine receptor agonists is that they have a longer duration of action. The half-life of levodopa is only around ninety minutes (Yeh et al., 1989). In contrast, the half-life of pramipexole is substantially longer (8-12 hours) and is around 6 hours for ropinirole (Kvernmo et al., 2006). The prolonged-release formulation of ropinirole, pramipexole MR and the rotigotine transdermal patch each deliver a reasonably constant 24-hour supply which aims to keep dopaminergic tone stable (Pfeiffer, 2005).
In advanced PD levodopa conversion and storage is limited, as is the regulation of synaptic dopamine concentrations. Often in later disease stages functioning nigral cells (i.e. cells still able to convert levodopa to dopamine) are lacking. What’s more, loss of receptor cells at the post synaptic membrane can also be substantial. Consequentially, what dopamine is readily available may become redundant. Due to this the motor response to levodopa can be erratic and pulsatile and in time some patients will experience significant response fluctuations and dyskinesias (Péchevis et al., 2005, Grosset, 2008). In this scenario, longer acting dopamine receptor agonists may be of benefit (Ahlskog, 2009).
There are however limitations to the use of dopamine agonists, such as incomplete receptor agonism. Dopamine receptors are divided into five types: D1-D5. The main motor effects of dopamine have been primarily attributed to D1 and D2 receptor stimulation (Ahlskog, 2009) which are greatly expressed in striatal 18
regions. However, all three dopamine agonists mentioned have specific affinity to D3 receptor cells. Ropinirole and pramipexole for example have a 100-fold affinity to D3 than D2 receptors (Gerlach et al., 2003). Rotigotine has around a 20-fold greater predilection to D3 than D2 (Jenner, 2005). Neither pramipexole nor ropinirole have however demonstrated affinity to D1 receptors (Gerlach et al., 2003) and the affinity of the transdermal patch to D1 receptor site stimulation is 100-fold less than it is for D3 (Jenner, 2005). This continuum of receptor cell stimulation offers two clinically relevant implications when comparing dopamine agonist efficacy to that of levodopa:
(1) Agonists offer reduced capacity for improving motor control than dopamine generated from levodopa because of the specificity and affinity to certain receptors;
(2) There is greater potential for patients developing behavioural problems as a result of D3 receptor stimulation (Joyce, 2001).
2.5.4 Monoamine Oxidase-B Inhibitors Monoamine oxidase (MAO) enzymatically degrades monoamines such as dopamine within the brain tissue. Inhibiting the activity of MAO type-B thus increases brain dopamine concentrations, potentially improving PD symptoms (Henchcliffe et al., 2005, Fernandez and Chen, 2007a, Fernandez and Chen, 2007b). The therapeutic indication for the use of MAO-B inhibitors (selegiline and rasagiline) is still a source of debate. Whilst evidence shows that they do improve
19
the clinical symptoms of PD, they appear to do so only moderately (Ives et al., 2004).
2.5.5 Catechol-O-Methyltransferase Inhibitors As highlighted earlier in Table 2.3, levodopa is mostly prescribed in a ratio of one to four. For example, one part dopa-decarboxylase inhibitor (25mg carbidopa) may be prescribed with four parts levodopa (100mg) to produce Sinemet (125mg). The added carbidopa aims to prevent conversion of levodopa to dopamine outside of the central nervous system in an attempt to optimise brain dopamine concentrations. However, despite the addition of the dopa-decarboxylase inhibitor, levodopa can still be metabolised in the periphery by the enzymatic activity of Catechol-O-Methyltransferase (COMT) (Bonifati and Meco, 1999, Männistö and Kaakkola, 1999). As COMT can reduce the availability of levodopa, one of two COMT inhibitors may also be prescribed: entacopone (Comtess) and tolcapone (Tasmar). Inhibiting COMT helps to reduce the quantity of levodopa metabolised peripherally and thus helps to lengthen the therapeutic effect of levodopa.
2.5.6 N-Methyl-D-Aspartate (NMDA) Glutamate Antagonist Amantadine has been used to treat PD for almost as long as levodopa. Originally the therapeutic indication was for the treatment of early parkinsonism. However, when prescribed today it is mainly used to combat levodopa induced dyskinesias (Metman et al., 1998, Metman et al., 1999). Although amantadine is proposed to attenuate levodopa induced dyskinesias without worsening PD symptoms (Metman 20
et al., 1999), findings from a Cochrane systematic review did not support this claim (Crosby et al., 2003).
2.5.7 Anticholinergics Anticholinergics drugs were the first medications to be routinely prescribed to treat PD. One of the most commonly administered anticholinergics is trihexyphenidyl (Broflex). Drugs from this classification can reduce resting tremor in some PD patients but do little to combat bradykinesia, gait problems or other motor and nonmotor symptoms of PD. Given their vast side effect profile and limited therapeutic benefits, most often a more efficacious anti-parkinsonian agent is prescribed in place of an anticholinergic drug (Ahlskog, 2009).
2.6 Treatment Complexity in Parkinson’s Disease 2.6.1 Early Treatment Optimum medication management typically allows people who are newly diagnosed with PD to remain active in all aspects of their lives. When symptoms impede on working commitments, reduce social interaction, or result in sedentary lifestyles initiating treatment is necessary. The natural progression of PD confers less drug efficacy and more disability later in the disease course (Apaydin et al., 2002). There is no evidence that the best drug response can be saved for later years. By deferring treatment and accepting early disability, the patient may be sacrificing good years of life for no therapeutic gain (Ahlskog, 2009). 21
The pharmacological management of PD is complex. Dopaminergic drugs like levodopa, MAO-B inhibitors and dopamine receptor agonists are the main therapeutic options and represent usual first line treatment strategies (NICE, 2006, Schapira and Obeso, 2006, Schapira, 2007). All of these drugs have supporting clinical data to justify their therapeutic use (Goetz et al., 2005, Pahwa et al., 2006). Typically younger individuals are treated with an MAO-B inhibitor (once daily), especially if symptoms are mild, or a dopamine receptor agonist (three daily doses) as first line intervention. Older individuals (≥75 years), especially those with or at risk of cognitive impairment, may be treated with levodopa as first line therapy (Schapira et al., 2009b, Schapira, 2007). Figure 2.1 shows a decision pathway for initiating PD treatment.
Two studies showed that although the use of levodopa improved the Unified PD Rating Scale by 3-5 points more than a corresponding agonist, motor control was still considered satisfactory by patients and clinicians when treated with the agonist alone (Rascol et al., 2000). Additionally, researchers have shown MAO-B inhibitors are useful as monotherapy in early disease or as adjuvant therapy in later stages of PD (Fernandez and Chen, 2007a, Fernandez and Chen, 2007b). It is well acknowledged, however, that MAO-B inhibitors are not as effective as levodopa or dopamine agonists for the management of PD and thus their therapeutic indications are limited (Ives et al., 2004).
22
Diagnosis
Decision to treat
No
Yes
Review
Evaluate patient characteristics and degree of disability
Moderate to severe disability and age 70+ years or with significant comorbidity including cognitive impairment
Mild to moderate motor disability and no cognitive impairment
Mild motor disability and no cognitive impairment
Begin levodopa
Begin dopamine agonist
Begin MAO-B inhibitor
(Schapira, 2007) Figure 2. 1 - Decision Pathway for Initiating Parkinson's disease Treatment
23
2.6.2 Advancing Treatment As PD progresses, controlling symptoms becomes considerably more challenging. Researchers have shown that more than half of people with PD take two to four anti-parkinsonian medications three to four times daily (Leoni et al., 2002, Tan et al., 2005). This is because multiple drug classes are required as PD progresses (Rascol et al., 2000, Holloway et al., 2004, Bainbridge and Ruscin, 2009, Schapira et al., 2009a). Long-term follow-up studies indicate that of the PD patients who began receiving a dopamine agonist, approximately half at three years and twothirds at five years required levodopa supplementation (Rascol et al., 2000, Holloway et al., 2004).
As levodopa is added, treatment regimens become more complex. The transition from MAO-B inhibitor or dopamine agonist to levodopa marks a significant juncture in PD treatment when considering the specificity of dose timing. A patient previously managed with an MAO-B inhibitor is likely to have only taken one tablet daily. Although a dopamine agonist may have been prescribed in three daily doses to manage symptoms, comparable to levodopa when initiated, the considerably longer half-life of agonists affords the patient a greater time window in which medication needs to be taken. A patient can be more flexible with the time of dosing with little or no ill effect. This phenomenon also stands true for levodopa in the initial years of treatment when the long-duration response predominates. As some patients may be able to omit doses without detrimental consequences to function, this may partly explain medication non-adherence in early PD.
24
However, as the half-life of levodopa is only around 90-120 minutes (Yeh et al., 1989), patients with advanced PD will require a more stringent dosing schedule to maintain steady plasma concentrations and desired therapeutic benefit (Ahlskog, 2009, Schapira et al., 2009b).
Occasionally people with long standing PD will experience responses to therapy lasting only 1-2 hours, reflecting the plasma half-life of levodopa (Yeh et al., 1989). By five years of active levodopa treatment, approximately 40 per cent with PD report experiencing the short-duration response and this becomes increasingly more likely and debilitating over subsequent years (Ahlskog and Muenter, 2001, Rascol et al., 2000). At this juncture, one strategy is to add a further dose to shorten the time interval between each pill taken (Ahlskog, 2009). This however starts to add significant regimen complexity. Around this time, and as PD continues to progress, some patients also begin to experience debilitating motor fluctuations and dyskinesias resulting from long-term use of dopaminergic therapy.
In addition to adding further doses, each drug prescribed may have different dosing schedules, which can complicate treatment regimens (Leoni et al., 2002). COMT inhibitors can supplement levodopa but this approach adds further complexity if given as a separate tablet.
With advancing disease the therapeutic window narrows and becomes dependent on more frequent dosing to maintain the treatment effect (Grosset et al., 2005b, Schapira et al., 2009b). Some people with advanced PD can take as many as ten doses a day in attempt to control symptom fluctuation (Schapira, 2007, 25
Valldeoriola et al., 2010). Dyskinesias (involuntary movements) associated with long-term levodopa use may also require remediation in later PD. This adds even greater treatment complexity to a population already potentially highly medicated (Schapira et al., 2009b, Valldeoriola et al., 2010). Additionally, specific non-motor complications may necessitate further drug use which adds to the polypharmacy in PD (Chaudhuri et al., 2006, Bainbridge and Ruscin, 2009).
Whilst medication use may be consistent in many chronic illnesses, it is evident that in PD treatment strategies can change in order to address a patient’s progressive symptom manifestation. Such amendments to treatment can add considerable complexity and this may make accurate pill taking challenging for even the most cognitively able individuals.
2.7 Medication Adherence The effectiveness of prescribed drugs depends not only on the efficacy of the medications, but also on adherence to the therapeutic regimen. Adherence is defined by the World Health Organisation (WHO, 2003) as:
“the extent to which a person’s behaviour – taking medication, following diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider”.
26
Adherence to medication is paramount for achieving optimal therapeutic benefit. Using medication appropriately is dependent on two factors: ability and motivation (Horne, 2000). Most of the early research on adherence focussed on a patient’s ability to take medication. As a result, non-adherence was assumed to be unintentional (e.g. forgetfulness and poor understanding), or a physical ailment (e.g. poor eyesight or lack of dexterity). These factors are unquestionably important. However, it is also being increasingly acknowledged that non-adherence to medication may result from a decision to avoid medication or to use it in a manner inconsistent with the prescriber’s instructions (Horne and Weinman, 1999, Horne, 2000). Previously such behaviour may have been viewed as disobedient. However, a new view of health has emerged in which patients are encouraged to take a more active role in their healthcare and more specifically in decisions about their treatment (Barber, 1995).
In PD pharmacological management is essential for managing symptoms and maximising QoL. Sound medication adherence therefore cannot be over emphasised (Rigby, 2007). This is especially relevant as motor function becomes progressively worse, requiring increasingly intricate medication regimes to manage symptoms (Davis et al., 2010). Furthermore, as non-motor symptoms have been reported by patients and carers to be more negatively impactful than motor complaints in PD (Martinez-Martin et al., 2011), adequately adhering to prescribed regimens is likely to be important for maximising health related quality of life (HRQoL). However, in spite of the identified importance of medication adherence, non-adherence to treatment is a problem in PD as the next part of this chapter outlines. 27
2.7.1 Prevalence of Non-adherence in Parkinson’s Disease Researchers propose that a third to half of all medicines prescribed to people with long-term conditions are not taken as recommended (Haynes et al., 2002b, WHO, 2003, NICE, 2009). Despite recognising that non-adherence is prevalent in many chronic conditions, it has only recently been acknowledged that people with PD do not take prescribed medication as intended (Grosset et al., 2005b, Bainbridge and Ruscin, 2009, Grosset, 2010).
Dutton et al (1993) were one of the first research groups to identify that elderly people with PD were under-medicating. Soon after Copeland and colleagues (1994) found that many blood samples taken from PD patients were below the lower levodopa concentration limit, indicating poor medication adherence. Additionally, five samples were shown to be above the therapeutic range and understandably dyskinesia was common in this group of patients. Despite medication having the potential to optimise QoL in PD, these early studies suggest that medication nonadherence is prevalent.
More recently researchers have highlighted the prevalence of medication nonadherence in PD using a variety of assessment strategies. Leopold and colleagues (2004) used Medication Electronic Monitoring caps (MEMS), the reported gold standard method, to show that only 10% of PD patients fully adhered to treatment.
A further study identified that 20% of patients with PD were under users of antiparkinsonian medication (Grosset et al., 2005a). In addition, patients who satisfactorily adhered to medication (average total pill taking > 80%) all showed 28
substantial problems with dose timing adherence (number of doses taken at the correct time interval). Furthermore, findings revealed that 56% of patients were more likely to take once-daily drugs on time than drugs that had to be taken more frequently, where as few as 3% adhered satisfactorily (Grosset et al., 2005a). Kulkarni and colleagues (2008) conducted a retrospective longitudinal cohort study in people with PD and found the prevalence of sub-optimal adherence to be 67%.
Collectively these findings indicate that medication non-adherence is a significant problem in people with PD. Specifically, findings to date have revealed that dose timing is poor, even in PD patients with overall satisfactory adherence (those taking greater than 80% of their prescribed dose).
2.7.2 Consequences of Non-adherence in Parkinson’s Disease The consequences of non-adherence to medication in PD can be substantial and should be considered from various perspectives. For the patient, medication does not work if it is not taken as the prescriber intended. However, assumptions by clinicians that non-adherence is a passive process; that is, forgetfulness or resulting from impaired cognition, may be too simplistic and it should be recognised that medication taking behaviour is more complex (Grosset, 2010). Active consideration may in some cases be significant. For example, discontinuing treatment due to perceived side effects, either accurate or fallacious; medication sparing based on the belief of loss of efficacy over time (i.e. becoming immune or unresponsive to treatment); or fear of long-term complications such as peak dose
29
dyskinesias and response fluctuations are all proposed reasons why a patient with PD may not adhere to treatment (Bainbridge and Ruscin, 2009, Grosset, 2010).
Patients with PD should take their medication as prescribed for numerous reasons. Firstly, sudden withdrawal of dopaminergic drugs can result in suppression of central dopamine transmission and thus trigger the neuroleptic malignant syndrome, which may lead to fatality (Mizuno et al., 2003). Secondly, one major theory for the genesis of motor fluctuations is that erratic, pulsatile dopaminergic stimulation is contributory (Juncos et al., 1989, Rascol et al., 2000, Grosset et al., 2005a). Sporadic dopamine levels in blood plasma, partly from inadequate timing of medication taking, correlate with alternating high and low levels in the brain. Such erratic stimulation (the so called peak and trough effect) is proposed to result in motor fluctuations (Bezard et al., 2001).
Researchers evaluating the effect of reduced pill intake in PD showed that nonadherence was associated with the ‘wearing off’ of the treatment effect (Kulkarni et al., 2008). This was shown to result in motor fluctuations and increased risk of worsening symptoms compared to medication adherent individuals. Furthermore, poor adherence to treatment was associated with more unplanned hospital admissions for PD related problems and an overall poorer prognosis (Kulkarni et al., 2008).
Interestingly, and perhaps unique to PD, non-adherence to medication is not specific to sub-optimal pill intake. Patients may also non-adhere by over medicating. Excessive intake of dopaminergic agents was prevalent in 10% of 30
patients diagnosed with PD at a younger age (Grosset et al., 2005a). The consequences of over medicating can be substantial and include severe medication induced dyskinesia, behavioural disturbances and potentially even psychosis (Merims and Giladi, 2008, O'Sullivan et al., 2009).
Medication non-adherence in PD also has serious consequences for other parties involved. From the perspective of family members, their relative’s health is deteriorating leading to poor QoL and increasing care requirements. This can place significant burden on the spouse/carer which can greatly affect their health and QoL. For treating clinicians, future management decisions are based on the premise that the patient is correctly taking the intended treatments. Dose escalation, adjunctive therapy use and, in some cases, diagnostic reconsideration may all result from seeing a patient in clinic who apparently has had a poor response to therapy (Bainbridge and Ruscin, 2009, Grosset, 2010).
Poor drug management in PD is not confined to patients living in the community but is also an acknowledged problem in secondary care. Parkinson’s UK launched a “Get it on time” campaign aiming to ensure people admitted to hospital receive medication at their individual time. Such a campaign emphasises the critical relationship between medication non-adherence and functional deterioration in PD and helps illuminate the importance of ensuring patients adhere to their medication dosing as intended.
31
2.8 Summary: A Greater Understanding The symptoms of PD can be extremely debilitating in all aspects of life. What is considered a small complaint by one individual may be significantly troublesome and impactful to another. However, as stated earlier in this thesis, many of the symptoms of PD are treatable to varying extents. Healthcare professionals therefore have the ability to improve the QoL of many people with PD for several years. Unlike decades previous, today’s arsenal of pharmacological agents is more substantial with clinicians having many treatment options available that can be tailored to the patient’s specific needs.
Despite this, however, it is clear from the evidence that some people with PD are not taking their prescribed anti-parkinsonian medication in accordance with medical advice. Furthermore, it is evident that non-adherence to medication in PD results in many people experiencing a ‘wearing off’ of their treatments therapeutic effect. This has been shown to negatively impact on function and QoL. It is therefore essential for clinicians to be able to identify non-adherent PD patients. With a greater knowledge of who is likely to non-adhere to prescribed medication, targeted interventions can be provided in attempt to improve adherence and thus maximise the therapeutic effect of prescribed treatment.
In the next section of this thesis I present the rationale, methods, results and discussion of two systematic reviews. In Chapter 3 I provide the findings of a systematic review identifying what factors are associated with medication nonadherence specifically in PD. In Chapter 4 I present the findings of a Cochrane 32
systematic review on interventions used to enhance medication adherence in people with PD.
33
CHAPTER 3
Factors Affecting Medication Nonadherence in Parkinson’s Disease Background Study Design Risk of Bias/Internal Validity Findings Discussion
3.1 Background As highlighted in Chapter 2, to achieve optimum symptom control in chronic conditions medication adherence is imperative. Despite this, the World Health Organization (2003) report that as much as half of all medications prescribed for long-term conditions are not taken as intended. Therefore, it is not surprising that medication adherence is poor in PD.
Leopold et al (2004) reported as few as 10% of a PD cohort showed full adherence. Kulkarni et al (2008) found the prevalence of poor adherence ranged between 60% and 70% when followed over 5-years while Grosset et al (2005a) reported complete medication adherence in as few as 3% of PD patients. These findings are concerning when placed in a clinical context. Kulkarni and colleagues (2008) 34
showed that poor medication adherence increased the risk of worsening symptoms compared to medication adherent people with PD. As PD treatments are selfadministered, there is a need for greater understanding of why people do not take their prescribed medications as intended. This theoretical knowledge could help to better understand how best to improve medication adherence in people with PD.
Pharmacological based interventions such as simplifying drug regimens and nonpharmacological approaches such as provision of educational material have been advocated to address non-adherence in PD (Bainbridge and Ruscin, 2009, Grosset and Grosset, 2007). However, whilst these interventions may be beneficial in other chronic conditions, such approaches in a PD population are theoretical because the current evidence on why medication non-adherence develops specifically in PD is limited.
Regardless of the various theories, it remains unclear which factors are associated with non-adherence specifically in PD. The identification of such factors may allow healthcare professionals to identify potentially non-adherent individuals. With this knowledge, the development of targeted interventions to counteract or prevent non-adherence may be possible and could prove beneficial. This is both in terms of symptom management and the clinicians’ understanding of a patient’s treatment response and disease progression.
In the next part of this chapter I outline the processes used to identify which factors are associated with medication non-adherence in people with PD.
35
3.2 Study Design I used the systematic review approach to identify literature relating to medication non-adherence in PD.
3.2.1 Search Methods To ensure that both quantitative and qualitative evidence was identified, I performed a systematic search of online databases in April 2011. The five databases searched were Medline (Ovid, 1948), EMBASE (Ovid, 1980), AMED (Ovid, 1985), PsycINFO (Ovid, 1806) and CINAHL (EbscoH, 1982). In January 2012 I updated the search to capture more recently published articles. I also conducted a supplementary hand search of bibliographies of extracted articles and reviews to acquire records not identified electronically. Next I outline the search strategy for the systematic review.
3.2.2 Search Terms Before conducting the systematic search I reviewed the key words and search strings used by the authors of related articles with the aim of developing a comprehensive set of search terms. When relevant key words were identified I added these to the search string. This practice continued until I was satisfied that I had the key words required to conduct a comprehensive search of the topic. The terms ‘Parkinson’s disease’ and ‘Parkinsonism’ were combined with keywords relating to non-adherence: ‘non-adherence’, ‘non-compliance’, ‘influencing 36
factors’, ‘caregiver compliance’, ‘sub-optimal’, ‘determinants’, ‘drug adherence’, ‘therapy adherence’, ‘drug compliance’, ‘denial psychology’ and ‘therapy compliance’. To make the search strategy more comprehensive, I mapped key terms to database specific subject headings (MeSH). I then ‘exploded’ each MeSH term to include all relevant sub-categories. Truncations and Boolean operators (e.g. ‘and’, ‘or’) were used where necessary to broaden the search window. Exact search strings can be seen in Appendix 1.
3.2.3 Selection Criteria Once identified records had been imported into the Endnote reference manager and duplicated items had been removed, I proceeded by reviewing all relevant titles and abstracts for potential study inclusion. Full text articles were obtained either where abstracts appeared relevant or when insufficient information was provided from which an adequate assessment of relevance could be made from the abstract alone. Studies meeting the following criteria were included:
(1)
English language
(2)
Full-article publication available (accessed directly or requested from the study authors)
(3)
Idiopathic PD population (iPD) (defined by the authors).
(4)
All age ranges and duration of anti-parkinsonian treatments.
(5)
Presented either quantitative or qualitative data on factors associated with medication non-adherence.
37
3.2.4 Data Extraction Having identified potentially eligible records, the full text of each article was reviewed for potential inclusion in the systematic review. I developed a concise, standardised data extraction table (Table 3.1) to acquire information relevant to the review from each included study. Extracted data were checked twice for accuracy. Relevant
study
information
was
tabulated
focusing
on
study
design,
methodological characteristics, included participants and the analytical methods used. Extracted data for each included study can be seen in Appendix 2.
Table 3. 1 - Data Extraction Table
Study Design What was the study design? What were the aims and objectives? Participants What was the sample size? Were participant demographics reported and how were they collected? How were participants recruited and from where? Was there specific inclusion/exclusion criteria? Measurement Tools/Outcomes What was the primary outcome? Was adherence to medication assessed? If so, what method or instruments were used? How was the instrument administered and by whom? Statistical Analysis What analysis was used to determine factors that influence/are associated with medication adherence? Were covariates identified and included in the analysis? Results What were the response rates? What were the main reported determinants of non-adherence to medication in PD?
38
In the next section of this Chapter I will describe the procedure used to assess the risk of bias of the studies included in this systematic review.
3.3 Risk of Bias/Internal Validity 3.3.1 Terminology Bias is defined as the risk of systematic error, or deviation from the truth, when interpreting the findings or inferences of a study. The term ‘risk of bias’ is interchangeable with internal validity, which is often defined as the extent to which the design and conduct of a study are likely to have prevented bias (Higgins and Green, 2009).
Despite the risk of bias assessment being a key phase when conducting a systematic review, the specific term used varies substantially across review groups and specialities. A common alternative term to risk of bias is quality assessment. However, the meaning of quality can vary greatly. For example, one source defines quality as:
“The extent to which all aspects of a study’s design and conduct can be shown to protect against systematic bias, non-systematic bias and inferential error.” (Lohr, 2004)
In the US the Preventive Services Task Force (USPSTF), an independent panel that systematically reviews evidence of effectiveness, equates quality with internal 39
validity and classifies individual studies first according to a hierarchy of study design and then by individual study criteria. In contrast the Cochrane Collaboration argues for a wider use of the phrase risk of bias instead of quality, reasoning that:
“An emphasis on risk of bias overcomes ambiguity between the quality of reporting and the quality of the underlying study’s methodology.” (Higgins and Green, 2009)
Due to the inconsistency and potential confusion of the term ‘quality’, I will refer to validity assessment as ‘risk of bias assessment’ throughout the remainder of this thesis. In the next section of this thesis I describe the development of the appraisal tool that I used for the current systematic review.
3.3.2 Development of the Risk of Bias Appraisal Tool I developed a specific, novel appraisal tool to assess the risk of bias of the studies included in this systematic review. To comprehensively assess the studies I sought to evaluate the impact of bias, confounding and statistical chance on the study findings. Having identified the effect of these risks of bias, I aimed to assess their individual and combined impact on the interpretability of each study’s findings.
Prior to developing the appraisal tool I systematically reviewed existing quality indicator scales and checklists. Medline (Ovid, 1948), EMBASE (Ovid, 1980), AMED (Ovid, 1985), PsycINFO (Ovid, 1806) and CINAHL (EbscoH, 1982) were
40
searched using pre-defined search terms. The following terms/key words were exploded and then combined in each respective database:
‘bias’, ‘confounding’, ‘chance’, ‘internal validity’, ‘threats to validity’, ‘validity’, ‘reliability’, ‘appraisal’ were combined by ‘OR’ during the search. This was then combined by ‘AND’ with the results of the following search string:
‘data collection’, ‘epidemiology’, ‘observational study’, ‘questionnaires’, ‘scales’, ‘checklists’, ‘indexes’, ‘assessments’, ‘tools’, ‘instruments’.
Many of the appraisal tools identified appeared to replicate published reporting guidelines such as the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) (Von Elm et al., 2007) and MOOSE statements (Metaanalysis of Observational Studies in Epidemiology) (Stroup et al., 2000). These statements were developed for use by authors to ensure a high standard of reporting, not for assessing methodological rigor.
Many tools focused on whether authors clearly reported the methodological steps undertaken, instead of providing guidance on how to assess the risk of bias in what was reported. For example, many tools asked whether participant recruitment was described by study authors without providing guidance on whether the methods used to screen and recruit participants were prone to selection bias.
I also reviewed the 47 scales and 51 checklists identified by Shamliyan and colleagues (2010) in a systematic review of tools to assess the quality of 41
observational studies. In comparison to the appraisal tools identified in my independent search, many tools identified by Shamliyan and colleagues (2010) also failed to differentiate between poor reporting and risk of bias.
To this end, I designed a novel, generic use quality indicator tool with the view to detect risk of bias (threats to internal validity) in non-interventional studies (Table 3.2).
Having assessed the methodological performance of each included study using this novel appraisal tool, I was able to create a risk of bias (Threats to Validity) table highlighting the methodological strengths and limitations of each study included in the review.
42
Table 3. 2 - Tool to Appraise Risk of Bias in Non-Interventional Studies
Quality Criteria
Threat to Validity
Source of Threats to Validity
Identification & Evaluation:
Representativeness of population: cases and controls
Selection Bias (misclassification bias)
Diagnosis inaccuracy
Selection Bias
Source and method for sampling
Chance
Sample size
Confounding
Demographics/characteristics of participants
Were eligibility criteria used? Were inclusion/exclusion criteria specified? How were these determined and used? Was screening adequate or bias? Where were participants accessed? Is this representative of the population? How was the sample size determined? Was this sample target reached? Comparability of control to cases: disease severity, duration, medication profile, comorbidity?
Detection Bias (misclassification bias)
Validity/reliability (systematic bias/errors) Instrumentation (e.g. calibration) Measurement biases: Self-report Recall Observer/ interviewer
Are measurement tools valid? Has reliability been determined? Does the instrument have cut-offs or do the authors determine this? Is this consistent? What efforts have been made to minimise measurement biases? Are measurement biases acknowledged and reported?
Detection Bias (Information bias)
Follow-up period time
Were follow-up periods the same for cases and controls?
Detection Bias (Unmasked bias)
Blinded analysis
Was data collection/analysis masked where necessary?
Chance
Attrition Bias
Analysis: -
Did authors conduct appropriate analysis? Was adjustment performed for identified confounders? What was used to control for known effect modifiers and confounders? I.e. randomisation, matching, restriction (exclusion), stratification, multivariate analysis. Could significance be a result of chance? Was missing data discussed and dealt with appropriately?
Reporting Bias
Investigator bias, funding bias
Quality of measurement and outcome
Detection Bias
Appropriate statistical methods and result interpretation
Conflict of interest
Study power & probability value Sub-analysis power Confounders Effect Modification** Missing data
Were conflicts of interest disclosed? Who funded the research? Could this explain findings?
43
3.4 Findings The five databases searched yielded a total of 1880 records. An additional six records were identified through targeted hand searching of reference lists. Figure 3.1 shows the PRISMA diagram depicting the stages of study identification. After discarding duplicates and reviewing abstracts of identified records, 46 articles were suitable for full text retrieval. Of them, six articles met the study inclusion criteria: Leopold et al. (2004), Grosset et al. (2005a), Evans et al. (2005), Banks and Lawrence (2006), Grosset et al. (2009), Valldeoriola et al. (2010). A further study by Drey & colleagues (2012) was later added to the list of included papers providing a total of seven records. This article had not been published at the time of the initial search and therefore it was not originally identified.
3.4.1 Summary of Studies The characteristics of the seven included studies are presented in Table 3.3. The systematic review included a total of 787 PD patients. Five of the studies were observational in design of which four were cross-sectional surveys (Leopold et al., 2004, Grosset et al., 2005a, Grosset et al., 2009, Valldeoriola et al., 2010) and one was a case-controlled study (Evans et al., 2005). Of the remaining two studies one was a postal survey which encompassed one-to-one patient interviews (Banks and Lawrence, 2006) and the other was an exploratory qualitative study using semistructured interviews (Drey et al., 2012).
44
Identification
Potentially relevant records identified through electronic database search: n = 1880
Additional records identified through hand searching: n=6
Included
Eligibility
Screening
Number of duplicates removed: n = 188
Number of records screened: n = 1698
Number of records excluded: n = 1652
Number of full-text records retrieved for detailed evaluation: n = 46
Number of full-text articles excluded with reasons: n=40 - Article not in English (n=1)
Total number of records included in systematic synthesis: n=7 (n= 6 from database search & n=1 later added)
-
Abstract only available (n=1)
-
No data provided on factors influencing nonadherence (n=8)
-
No reference to medication non-adherence (n=5)
-
No assessment of adherence (n=3)
-
Non-adherence to functional activity and exercise (n=1)
-
Review papers on adherence (n=10)
-
Pathogenesis of Dopamine Dysregulation Syndrome review (n=1)
-
No reference to PD (n=9)
-
Commentary (n=1)
Figure 3. 1 - PRISMA Flow Diagram of Study Identification
45
Table 3. 3 - Characteristics of Included Studies Article
Study Design
Study Aims
Source of Participants
Participant Characteristics Intervention/ study group
Control or comparison group
n=
Adherence Assessment
Identified Factors for Nonadherence
Evans et al (2005)
Casecontrol
Identify predisposing factors to DDS in people with PD
Outpatients attending a specialist PD clinic
Dopamine dysregulation syndrome n=25
Patients without identified DDS n=100
125
n/a
Novelty Seeking Depression Alcohol intake Age of PD onset
Grosset et al (2005a)
Crosssectional survey
Compare medication intake and characteristics of patients according to medication intake
Outpatient movement disorder clinics
All participants given MEMs device.
n/a
54
Electronic Event Monitoring (MEMS)
Younger age Depression Poor quality of life More daily tablets
Valldeoriola et al (2010)
Crosssectional survey
Determine demographic, social and clinical aspects modifying therapy adherence
Multiple academic tertiary and secondary hospitals in Spain
All participants assessed by MMAS-4
n/a
418
Physician subject assessment & Morisky-4 scale
Low knowledge of PD Poor clinical control No spouse or partner low income Cognitive Impairment Psychiatric symptoms
Leopold et al (2004)
Crosssectional survey
To report on drug use in PD using MEMS.
PD and movement disorder clinic.
All participants given MEMs devise.
n/a
39
MEMS
Gender (females less accurate at reporting miss-timed doses) Level of education
46
Banks and Lawrence (2006)
Postal survey
Explore the impact of PD on employment from the perspective of the PD patients.
Identified through the PD Society.
339 returned questionnaire.
n/a
24
n/a
Maintaining employment – adjustment of dosing
Grosset et al (2009)
Crosssectional survey
To define the pattern of therapy adherence, to assess factors associated with non-adherence.
Large Multicentre (8 centres in 5 countries)
All assessed with MEMS for adherence.
n/a
112
MEMS
Higher motor impairment assessed by UPDRS and PDQ-39 motor subscore. Timing adherence associated with total tablets, disease duration and age. Complexity of regimens
Drey et al (2012)
Exploratory qualitative study with semistructured interviews
To identify how people with PD adhere to prescribed medication, and what are the antecedents of non-adherence to antiparkinsonian medication.
A specialist PD clinic in an unnamed National Health Service hospital in England.
All participants (9 males and 6 females) interviewed
n/a
15
Self-report
All participants demonstrated at least one type of non-adherent behaviour. Forgetfulness Minor, deliberate amendment of doses Major, deliberate nonadherence - often overuse of mediation.
47
Four of the seven studies recruited from single-centre clinics (Leopold et al., 2004, Grosset et al., 2005a, Evans et al., 2005, Drey et al., 2012). One recruited from secondary and tertiary care hospitals across Spain (Valldeoriola et al., 2010), whilst one multi-centre study identified PD patients from eight centres across five European countries: France, Germany, Italy, Spain and the UK (Grosset et al., 2009). The seventh study recruited from the PD Society register, nurse specialist clinics and the PD Society magazine in the UK (Banks and Lawrence, 2006).
The mean age of the participants in this review was 62 years (range 44 – 74 years) with a mean disease duration of 7.4 years (range < 1 year – 17 years) and a mean Hoehn & Yahr (H&Y) score of 2.2 (a widely used clinical rating scale which defines broad categories of motor function in PD).
Of the studies reporting medication profiles, a mean of two anti-parkinsonian drugs were taken (Grosset et al., 2005a, Grosset et al., 2009, Valldeoriola et al., 2010) with a mean of five daily PD drug doses (Grosset et al., 2005a, Grosset et al., 2009). Combined with other medication use, an average of 6 (range 4-11) prescriptions were taken daily (Leopold et al., 2004, Grosset et al., 2005a, Grosset et al., 2009, Valldeoriola et al., 2010). The mean PD daily tablet intake was eight doses (Grosset et al., 2005a, Grosset et al., 2009). The mean complete medication intake was 9 doses (range 5-11) (Leopold et al., 2004, Grosset et al., 2005a, Grosset et al., 2009).
Four studies assessed cognitive impairment using the Mini-Mental State Examination (MMSE) (Leopold et al., 2004, Evans et al., 2005, Grosset et al., 48
2005a, Grosset et al., 2009). The combined mean was 28/30. One study reported cognitive impairment in 22% of participants but did not report the method of assessment (Valldeoriola et al., 2010).
3.4.2 Risk of Bias (Threats to Internal Validity) The reporting quality was reasonable throughout the seven included studies. One study was accepted for publication prior to version one of the STROBE statement becoming available (Leopold et al., 2004). None of the observational studies published after the release of STROBE acknowledged adhering to the reporting guidelines.
Each article was evaluated against five potential biases using nine sub-bias items, as determined by the novel quality appraisal tool that was specifically developed for this review. Table 3.4 shows each study’s specific risk of bias. The nine quality markers considered are presented below:
Selection Bias
-
1. Diagnostic Inaccuracy 2. Participant Representativeness 3. Sampling
Random variation/chance
-
4. Sampling Size
Detection Bias
-
5. Validity of Adherence Assessment
-
6. Follow-up
-
7. Blinding
Attrition Bias
-
8. Loss to Follow-up
Reporting Bias
-
9. Appropriateness of Analysis 49
Table 3. 4 - Study Specific Risk of Bias Risk of Bias/Threats to Validity
Evans et al (2005)
Grosset et al (2005a)
Valldeoriola et al (2010)
Leopold et al (2004)
Banks & Lawrence (2006)
1.
Selection Bias (Diagnostic Inaccuracy)
2.
Selection Bias (Participant Representativeness)
3.
Selection Bias (Sampling)
4.
Random Variation/Chance (Sample Size)
n/a
5.
Detection bias (Validity of Adherence Assessment)
n/a
6.
Detection Bias (Follow-up)
7.
Detection Bias (Blinding)
8.
Attrition Bias (Loss to Follow-up)
9.
Reporting Bias (Appropriate Analysis)
n/a
n/a
n/a
n/a
Grosset et al (2009)
Drey et al (2012)
n/a
n/a
n/a
n/a
n/a
n/a
n/a
50
In the next part of this chapter I outline the performance of each included study in respect to the nine risk of bias items described.
Selection Bias (Diagnostic Inaccuracy): All authors stated recruiting patients with PD. However, the diagnostic criteria used were only reported in three studies (Evans et al., 2005, Grosset et al., 2005a, Grosset et al., 2009). The accuracy of the PD diagnosis was uncertain in four of the reviewed studies (Leopold et al., 2004, Banks and Lawrence, 2006, Valldeoriola et al., 2010, Drey et al., 2012). As the purpose of the review was to identify factors associated with medication non-adherence in idiopathic PD, I felt the accuracy of PD diagnosis to be imperative. A lack of diagnostic accuracy could have resulted in patients with others forms of parkinsonism being included. These types of patients can have different medication profiles to people with idiopathic PD and may also have different reasons for not adhering to treatment. It is important to note, however, that the uncertainty of PD diagnosis in these four studies was a consequence of poor reporting.
Selection Bias (Participant Representativeness): Five studies showed no evidence of biased participant representation (Leopold et al., 2004, Evans et al., 2005, Grosset et al., 2009, Valldeoriola et al., 2010, Drey et al., 2012). Grosset et al (2005a) excluded PD patients prescribed selegiline or amantadine. I regarded this as selection bias as no justification was given for this exclusion criterion. Banks and Lawrence (2006) provided no information concerning the representativeness of their sample.
51
Selection Bias (Sampling): Only three studies provided sufficient information of sampling methods to discount selection bias (Evans et al., 2005, Grosset et al., 2005a, Drey et al., 2012). Two studies provided no information concerning participant selection and therefore an assessment of bias was not possible due to poor reporting (Leopold et al., 2004, Valldeoriola et al., 2010). Valldeoriola and colleagues (2010) described physicians enrolling three consecutive out-patients. The authors claimed selection bias was avoided in that patients were previously unselected and had to have been attending clinic the same day. I felt this description lacked clarity concerning how selection bias was actually avoided.
Banks and Lawrence (2006) were vague concerning their sampling method. Participants were identified by PD nurses, a PD partners and relatives database and eight participants contacted the research team directly. No further details were provided from which an adequate assessment of risk of bias could be made. I therefore was unable to discount selection bias in this study. Grosset et al (2009) reported selecting participants non-sequentially at the investigator’s discretion. I believed this to represent substantial selection bias as investigators may possess prior knowledge of the patients’ medication taking behaviour.
Chance/random Variation (Sample Size): Of the seven studies included only Valldeoriola et al (2010) described a sample size calculation, reporting standard values for significance (0.05) and the statistical power (0.8) (the probability of finding an effect if one exists). The accuracy of the dependent variable (medication adherence) was reported as ± 4.6%. No clear 52
explanation or justification was given for this value; however, the authors state that no previous data was available to facilitate a more informed sample size calculation.
Evans et al (2005) compared 25 patients with Dopamine Dysregulation Syndrome (DDS) (where patients develop a harmful pattern of compulsive drug use) to 100 PD patients without DDS. Although a sample of 25 is low for observational studies, it must be acknowledged that the prevalence of DDS in the PD population is small. Therefore, high numbers likely yielded from a sample size calculation would likely be problematic from a recruitment perspective. Despite the small sample, a statistically significant association between patient characteristics and non-adherence was identified. As associations were identified, even with a small sample, I felt this substantiated the reliability of the findings.
In support of this, Grimes & Schulz (2005) state that where the prevalence of cases is low compared to controls, increasing the number of controls up to a ratio of four to one is acceptable. As the ratio of patients in the study by Evans et al (2005) was four controls to one DDS case, I felt this sample ratio was acceptable. The lack of an appropriate sample size calculation however predisposes the findings to type 1 error (i.e. rejecting the null hypothesis when it should be accepted). I felt caution should therefore be exercised when interpreting the identified associations in this study.
The postal survey with interviews conducted by Banks and Lawrence (2006) provided no numerical data to warrant a sample size calculation. The same was the 53
case for the exploratory study by Drey et al (2012). As both were qualitative studies, sample size calculations do not apply. The remaining three studies were cross-sectional designs of which no research group calculated a sample size (Leopold et al., 2004, Grosset et al., 2005a, Grosset et al., 2009). As stated earlier, this predisposes to type 1 error and therefore I was cautious when interpreting the identified associations. As statistical significance was established, despite no sample size calculation, type 2 error which relates to statistical power (accepting the null hypothesis when it should be rejected) was not relevant.
Detection Bias (Validity of Adherence Assessment): Three studies assessed adherence using MEMS devices, the reported gold standard method (Leopold et al., 2004, Grosset et al., 2005a, Grosset et al., 2009). Evans et al (2005) used the criteria for DDS as a marker for non-adherence (Evans et al., 2005). As this is clinically diagnosed I felt confident that participants in this study were over-medicating. Valldeoriola et al (2010) assessed adherence with the Morisky Medication Adherence Scale (MMAS-4). Although the interpretation of self-report measures requires caution, the MMAS-4 has been investigated and shown to be moderately comparable to pill counts in PD (Elm et al., 2007).
One study did not report any method for determining non-adherence as this was not the aim (Banks and Lawrence, 2006). Drey et al (2012) used an experienced healthcare interviewer with limited knowledge of PD to question patients on their medication taking behaviours. As non-adherence is often not self-confessed, under or overuse of drugs may not have been identified in many people. In contrast, this method may have encouraged more patients to provide greater insight into their 54
medication taking practices without the worry of disappointing clinical staff. However, due to this uncertainty I was unable to discount bias.
Detection Bias (Follow-up): Three studies had a follow-up assessment phase: two were one month post baseline (Leopold et al., 2004, Grosset et al., 2009) and one was 3 months post baseline (Grosset et al., 2005a). Although the studies were cross-sectional in design, followup assessments were required due to the use of MEMS (i.e. an adequate time interval is required to assess pill bottle opening). The remaining studies did not require a follow-up period.
Detection Bias (Blinding): Four studies did not report whether patients or researchers were blinded (Grosset et al., 2009, Grosset et al., 2005a, Evans et al., 2005, Valldeoriola et al., 2010). As the studies were cross-sectional, I did not feel this represented a suitable risk of bias. Leopold et al (2004) withheld the study aim from participants so that medication adherence could be accurately determined.
Attrition Bias (Loss to Follow-up): Three studies reported numbers lost to follow-up (Grosset et al., 2005a, Grosset et al., 2009, Leopold et al., 2004). In one study, 8 withdrew, 2 lost the MEMS device, 1 died, 1 had a prolonged hospital admission and 3 patients misused MEMS (Grosset et al., 2005a). Grosset et al (2009) enrolled 124 PD participants of which 1 patient died and 10 used MEMS inconsistently. These were therefore withdrawn leaving data for 112 participants. Leopold et al (2004) excluded 1 participant due to 55
symptoms of depression. The remaining three studies had no follow-up assessment phase (Evans et al., 2005, Banks and Lawrence, 2006, Valldeoriola et al., 2010). No researcher group described a method for imputing missing data.
Reporting Bias (Analytical Methods): All seven research groups appropriately analysed their data. Authors used logistic regression analysis (Grosset et al., 2005a), multivariate linear regression (Grosset et al., 2009, Valldeoriola et al., 2010) or Pearson’s correlation coefficients (Leopold et al., 2004) to identify associations between non-adherence and other variables. Interview transcripts were analysed with thematic analysis (Drey et al., 2012) and content analysis (Banks and Lawrence, 2006) techniques, however, in one study no method was reported (Banks and Lawrence, 2006).
56
3.4.3 Factors Associated with Medication Non-adherence Various factors, both clinical and demographic, were found to be associated with medication non-adherence in PD. To transform the findings from a list of factors into something clinically useful, I ranked each factor independently according to the strength of association with medication non-adherence. My main justification for this approach was to aid healthcare professionals in identifying patients at risk of medication non-adherence by informing them of the most salient factors correlated with non-adherence in PD.
3.4.3.1 Assessing Study Risk of Bias For each included article I provided an assessment of overall study quality; that is, high, moderate or low. For example, where the risk of bias in a study appeared to be low, the study was defined as high quality.
The risk of bias in each study was used to determine overall quality. From the risk of bias table presented earlier I divided the number of ‘ticks’ awarded by the total number of risk of bias items to produce a percentile for individual study quality. Studies scoring ≥70% were deemed high quality, 40-69% moderate, and