Pharmacologic Treatment of Overactive Bladder: Defining a Success and When is Improvement ‘Enough’ Jeffrey P. Weiss, MD, FACS Professor and Chair Department.

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

Blaivas, AUGS, 2006

• 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)

Classification of Urge

DeWachter, Neurourol & Urodynam, 2004Blaivas, J Urol. 2007:177, 199

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,

significancePayne 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 telephonesurvey 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 femalepatients 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