Pharmacologic Treatment of Overactive Bladder: Defining a Success and When is Improvement ‘Enough’ Jeffrey P. Weiss, MD, FACS Professor and Chair Department of Urology SUNY Downstate College of Medicine VA NY Harbor Healthcare System Brooklyn, NY

OAB: Definition Urgency, with or without urge incontinence, usually with frequency and nocturia

Two Types of Urgency Urgency is comprised of at least two different sensations: An intensification of the normal urge to void (69%) A sudden urge that is a different sensation (31%) May have different etiologies May respond differently to treatment In contradistinction Blaivas, AUGS, 2006

Classification of Urge Type 0 - no urge Type 1 - mild urge (delay for > 1H) Type 2 - moderate (delay for 10 – 60 m) Type 3 - severe (delay for < 10 m) Type 4 - precipitous urge (must void immediately) Blaivas, J Urol. 2007:177, 199 DeWachter, Neurourol & Urodynam, 2004

OAB: Urodynamic Classification Type I: symptoms of overactive bladder, no IDC at urodynamics Type II: IDC present; patient is aware and can abort the IDC Type III: IDC patient aware, cannot abort but can temporarily maintain continence by contracting the sphincter Type IV: IDC, no awareness or control

Urodynamic classification of OAB So far there is no data available to determine the validity or usefulness of this new classification as regards outcome of therapy of OAB

PRO as outcomes in medical research* “While we can measure a biological response, we may not be able to determine whether that response makes a noticeable difference to the patient” *Fairclough DL: Stat Methods Med Res 13: 115-138, 2004

OAB: Outcome analysis OAB is a syndrome, with several symptoms together determining the severity of this condition. Clinical trials typically report single-outcome variables Endpoints including multiple key symptoms including QoL would better reflect Rx outcome

OAB: Evaluable endpoints Urgency (# episodes/24 hours, grading) Incontinence (# episodes/24 hours, grading) Nocturia severity Voiding frequency/24 h HRQoL specific to bladder symptoms

OAB: outcomes analysis Great challenge pertaining to health-related QoL research is to translate statistically significant HRQoL changes into those of clinical, not just statistical, significance Payne CK and Kelleher C: BJUI 9 9 , 101 – 10 6, 2007

OAB Diagnosis Does not rely on urodynamic evaluations, but arises solely from patient symptoms Urgency is recognized as the hallmark symptom of OAB Clinical trials do not normally report reductions in urgency as a primary outcome variable, mainly because there is no commonly agreed method for evaluating this key symptom (so far)

Kings Health Questionnaire Multi-dimensional questionnaire Part of the International Consultation on Incontinence Questionnaire (ICIQ) The KHQ is fully validated to assess HRQoL in both women and men with lower urinary tract dysfunction, including OAB Consists of 29 items across 9 domains; 7 of these domains contain items for which there are multiple questions (role limitations, physical limitations, personal relationships, emotions, sleep/energy and severity measures) Remaining 2 domains are single-question items (incontinence impact and general health perception)

Kings Health Questionnaire Δ 12–15 points represents a moderately clinically meaningful difference for all domains except symptom severity; this domain only requires a difference of ≥2 points to be considered minimally clinically meaningful Kelleher CJ, Pleil AM, Reese PR, Burgess SM, Brodish PH. How much is enough and who says so? BJOG 2004; 111: 605–12

OABq: overactive bladder questionnaire 33-item, condition-specific measure developed to assess the impact of OAB on HRQoL Consists of a symptom bother scale (8 items) and four HRQoL subscales (coping, concern, sleep and social interaction; 25 items). All items are scored on a 6-point Likert scale, and scores are transformed to a 0-to 100-point scale. Higher symptom bother scores indicate greater symptom severity, while lower HRQoL subscale scores indicate greater impact. Threshold of 10 points thought to represent MID on OAB-q* *Khullar V: Int Urogynecol J (2012) 23:179–192

Urogenital distress inventory (UDI) Assesses the impact of incontinence on the HRQoL in women UDI consists of 19 symptom items and a 4-point Likert scale (0-3, total 57) to assess the level of bother to the patient (not at all, slightly, moderately and greatly) UDI-6 (shortened version) uses the four point Likert scale to assess the impact of LUTS in women: incontinence, lower abdominal pain, difficulty emptying the bladder UDI-6 often used in conjunction with the Incontinence Impact Questionnaire (IIQ), which provides information on the impact of LUTS on activities, roles and emotional status UDI (entire form): statistically significant improvements of ≥11 points (MID) have been considered clinically important Barber MD, et al. Am J Obstet Gynecol 200:580–587

EPIC: population-based, cross-sectional telephone survey of adults aged ≥18 OAB cases divided into five subgroups (SG) based upon symptom report: Continent OAB (SG1); OAB+UI Sxs(SG2), OAB + post-micturition Sxs (SG3), OAB+voiding Sxs (SG4), or OAB+post-micturition+voiding Sxs(SG5) PPBC: single item assesses patients’ subjective impression of current urinary problems Patients rate their perceived bladder condition on a six-point scale ranging from 1 (‘no problems at all’) to 6 (‘many severe problems’) 36% of SG5 reported that their bladder condition caused ‘moderate- very severe problems’, vs 21.0% in SG4, 18.0% in SG3, 18.4% in SG2 and 3.9% in SG1 Coyne KS et al: BJUI 101: 1388-95, 2008

Effect of solifenacin on male and female patients with OAB: Re Nocturia Assessed utilizing pooled data from four phase III randomized clinical trials 3032 patients included in the analysis; 2534 reported nocturia at baseline Patients without nocturnal polyuria experienced a statistically significant reduction in nocturia Translated to a numeric difference of only 0.18 episodes of nocturia less per night than placebo Statistical significance clearly not same as clinical significance Brubaker L et al: Int Urogynecol J Pelvic Floor Dysfunct 2007;18: 737–41

IPSS: MID Studied 150 consecutives patients treated for LUTS associated with BPH* Related the change in the IPSS at 3 months to a global rating scale of change made of 5 categories: worse, stable, slight, moderate and marked improvement Mean absolute MID could be estimated approximatelly 3 points on the IPSS Results similar to those presented by Barry MJ et al J Urol. 154: 1770-4, 1995 *Ruffion A et al: Eur Urol Suppl: S1569-9056(08)60232-8

Oxybutynin IR cf propantheline cf placebo* Oxy-IR but not propantheline: significant reduction in voids/24 hrs and increases in volume at first involuntary contraction and max cystometric capacity vs placebo Pt responses to VAS re: symptom severity 58% improvement for Oxy-IR, 45% for propantheline and 43% for placebo. Thus subjective results mirrored objective endpoints through diaries and UDS *Thuroff et al J Urol 145: 813-16, 1991

Detrol-ER cf Oxy-IR cf placebo* Perception of bladder condition improvements: Detrol 72%; Oxy-IR 73%; placebo 59% Both active treatments significantly reduced weekly UUI and #24 hour voids and increased volume/void cf placebo King’s Health Questionnaire, validated for assessment of QoL in patients with LUTS: None of the KHQ domains could distinguish between active Rx groups Hence objective outcomes via diaries or UDS do not always agree with subjective outcomes *Kelleher CJ et al: Br J Obst Gyn 104: 1374-9, 1997

Conclusions Ultimately, patient satisfaction and improved QoL define success in therapy of OAB Currently it is impossible to determine the ideal outcome measure for use in OAB Endpoints should focus on changes in urgency [grade], with or without other symptoms, and QoL* Payne CK and Kelleher C. BJUI 99: 101-6, 2007