Antimuscarinic Drugs for Overactive Bladder Syndrome Clinical Review Series Part I Introduction to Series, Methods, and Tolterodine vs. Oxybutynin Systematic Review Clinical Review Series Table of Contents for Part I of Series Abbreviations/Glossary ........................................................................................................................ iii Overview Executive Summary ................................................................................................. 1 Chapter 1. Introduction and Background to the Series .......................................................... 50 Introduction ................................................................................................................................... 50 PSD Request ........................................................................................................................................ 50 Organization of the report .................................................................................................................. 50 Background .................................................................................................................................... 50 Overactive Bladder (OAB) Syndrome: Definition and Prevalence ...................................................... 50 Treatment Goals and Options ............................................................................................................. 52 Non‐Pharmaceutical Treatment Options ............................................................................................ 53 Antimuscarinic Drugs .......................................................................................................................... 53 Mechanism of Effect: anti‐muscarinic activity .................................................................................... 56 Cognition, the Elderly and Antimuscarinic Drugs ............................................................................... 58 Antimuscarinic Drugs versus Placebo ................................................................................................. 61 Persistence with Antimuscarinic Drugs ............................................................................................... 70 References ..................................................................................................................................... 72 Chapter 2. Methods ............................................................................................................... 77 Objectives of the review: ............................................................................................................... 77 Research Questions ........................................................................................................................ 77 Selection criteria for studies included in this review (‘PICOS’ format) ............................................. 78 Search Strategy .............................................................................................................................. 80 Assessment of study quality ........................................................................................................... 80 Data analysis .................................................................................................................................. 80 Chapter 3. Overall Search Results .......................................................................................... 82 PRISMA Flowchart Detailing Flow of Studies .................................................................................. 84 Existing Systematic Reviews ........................................................................................................... 85 Chapter 4. Tolterodine vs. Oxybutynin Systematic Review .................................................... 87 Background .................................................................................................................................... 98 Tolterodine L‐tartrate Immediate‐Release Product Data ................................................................... 98 Tolterodine L‐tartrate Extended‐Release Product Data ..................................................................... 98 Q1. Comparative Harms and Benefits ............................................................................................. 98 Results ........................................................................................................................................... 98 Search Findings .............................................................................................................................. 98 Direct Comparator RCTs ................................................................................................................. 98 1. Tolterodine IR vs Oxybutynin IR ...................................................................................................... 99 Table 1. Summary: RCTs Tolterodine IR vs Oxybutynin IR ........................................... 109 2. Other Tolterodine vs. Oxybutynin Comparisons ........................................................................... 109 3. Meta‐analyses Pooling All Formulations of Oxybutynin and Tolterodine .................................... 113 3. Non Randomized Studies .......................................................................................................... 114 4. Other Adverse Event Data ........................................................................................................ 121 5. Discussion and Conclusions Tolterodine vs. Oxybutynin ........................................................... 126 i Clinical Review Series Q2. New Evidence since CDR Review ............................................................................................ 127 Q3. Cognition ............................................................................................................................... 128 References for Included RCTs Tolterodine vs. Oxybutynin ........................................................... 129 Other References ......................................................................................................................... 133 ii Clinical Review Series Abbreviations/Glossary ADL activities of daily living AE adverse event CDR Common Drug Review CI confidence intervals CR controlled release d day DARI darifenacin DB double blind ER extended release FESO fesoterodine h hours IR immediate release IIQ Incontinence Impact Questionnaire ITT intention-to-treat LOCF last observation carried forward M muscarinic MD mean difference MCID minimal clinically important difference NRS non-randomized studies NDA new drug approval (U.S. FDA) OAB overactive bladder syndrome OXY oxybutynin PP per protocol PPBC Patient perception of bladder condition PSD Pharmaceuticals Service Division PSUR Periodic Safety Update Report QoL quality of life RCT randomized, controlled trial RR relative risk SAE serious adverse events SD standard deviation SOL solifenacin TDS transdermal system TOL tolterodine TROS trospium UDI Urogenital Distress Inventory UTI urinary tract infection UI urinary incontinence UUI urge urinary incontinence WDAE withdrawals due to adverse events iii Clinical Review Series Glossary Term Definition Continence Absence of any involuntary leakage of urine, usually measured over a 3 day or 7 day period of time (as recorded in a bladder diary) Cystometry Measurement of the pressure/volume relationship of the bladder during filling and/or pressure flow study during voiding. Detrusor Bladder smooth muscle that contracts on voiding and relaxes upon filling of the bladder Detrusor overactivity Involuntary detrusor contractions during filling cystometry (normally, there is little or no change in detrusor pressure and no involuntary phasic contractions) i.e., a diagnosis made by urodynamics. May or may not be accompanied by symptoms (e.g., urgency or urgency incontinence). Idiopathic detrusor overactivity Detrusor overactivity with no known neurogenic cause. Lower urinary tract symptoms (LUTS) Includes urinary storage symptoms and voiding symptoms Mixed urinary incontinence Incontinence associated with urgency, and also with effort or physical exertion or on sneezing or coughing Neurogenic detrusor activity Detrusor overactivity and evidence of a relevant neurological cause. Nocturia Waking at night to void Overactive bladder syndrome Urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology Post-void residual volume Volume remaining in bladder immediately after voiding Stress urinary incontinence Involuntary loss of urine on effort or physical exertion (or on sneezing or coughing) Urgency A sudden compelling desire to pass urine, which is difficult to defer Involuntary loss of urine associated with urgency; Urge or urgency incontinence ‘Urgency’ has recently replaced ‘urge’ as the accepted terminology to distinguish urgency associated with OAB, which is maximal and episodic, from normal urge (Haylen 2010; Chapple 2005) Urge or Urgency predominant mixed urinary incontinence Mixed urinary incontinence with predominant, more frequent symptoms of urgency urinary incontinence Urinary incontinence Involuntary loss of urine Urodynamics Functional study of the lower urinary tract; Usually involves free (no catheter) uroflowmetry and postvoid residual