Скачать презентацию Learning Objectives Accurately recognize overactive bladder OAB Скачать презентацию Learning Objectives Accurately recognize overactive bladder OAB

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Learning Objectives • Accurately recognize overactive bladder (OAB), with urgency as the core symptom, Learning Objectives • Accurately recognize overactive bladder (OAB), with urgency as the core symptom, in the context of other urinary symptoms that are commonly encountered in men and women • Confidently assess important measures like symptom severity and health-related quality of life (HRQOL) and use this information for patient management • Apply behavioral and lifestyle modifications to treatment strategies using an individualized and patient-centered approach to OAB • Understand the current first-line treatments for OAB in both men and women • Employ a patient-centered treatment strategy that explores the benefits of dosing antimuscarinics to obtain a balance between efficacy and tolerability

Premeeting Survey • ? True or False: The core symptom of OAB is urgency. Premeeting Survey • ? True or False: The core symptom of OAB is urgency. 1. True 2. False

Premeeting Survey • Which of the following are NOT considered comorbidities in patients with Premeeting Survey • Which of the following are NOT considered comorbidities in patients with OAB? 1. 2. 3. 4. Falls and fractures Urinary tract infections (UTIs) Skin infections Kidney stones ?

Premeeting Survey • True or False: Using a flexible-dosing regimen of antimuscarinics results in Premeeting Survey • True or False: Using a flexible-dosing regimen of antimuscarinics results in improved efficacy and patient satisfaction. 1. True 2. False ?

Overactive Bladder: Impact Matt T. Rosenberg, MD Mid. Michigan Health Centers Jackson, MI Overactive Bladder: Impact Matt T. Rosenberg, MD Mid. Michigan Health Centers Jackson, MI

ICS Definition of Overactive Bladder • A symptom syndrome suggestive of lower urinary tract ICS Definition of Overactive Bladder • A symptom syndrome suggestive of lower urinary tract dysfunction 1, 2 • Urgency, with or without urge incontinence, usually with frequency and nocturia 1, 2 • In absence of metabolic or pathologic conditions 1, 2 ICS: International Continence Society 1 Abrams P, et al. Neurourol Urodyn. 2002; 21: 167 -178. 2 Wein AJ, et al. Urology. 2002; 60(5 suppl 1): 7 -12.

Overactive Bladder Definitions Urgency 1, 2 Sudden compelling desire to pass urine that is Overactive Bladder Definitions Urgency 1, 2 Sudden compelling desire to pass urine that is difficult to defer Frequency 1, 2 Patient considers that he/she voids too often by day Normal is < 8 times per 24 hours Nocturia 1, 2 Waking to urinate during sleep hours Considered a clinical problem if frequency is greater than twice a night Urge urinary incontinence (UUI)1 Involuntary leakage accompanied by or immediately preceded by urgency OAB “wet” 1, 2 OAB with UUI OAB “dry” 2 OAB without UUI Warning time 3 Time from first sensation of urgency to voiding 1 Abrams P, et al. Neurourol Urodyn. 2002; 21: 167 -178. Urol. 2006; 175(3 pt 2): S 5 -S 10. 3 Zinner N, et al. Int J Clin Pract. 2006; 60: 119 -126. 2 Wein AJ, et al. J

Healthy Bladder Versus Overactive Bladder • • Holds 300 -500 cc Empties < 8 Healthy Bladder Versus Overactive Bladder • • Holds 300 -500 cc Empties < 8 times per day Holds at night After gradual filling, urge is felt • Empties > 8 times per day • Empties > 2 times per night • Has urgency (sudden compelling desire to void that is difficult to defer) Pfisterer MH-D, et al. Neurourol Urodyn. 2007; 26: 356 -361. Wein AJ. Am J Manag Care. 2000; 6(11 suppl): S 559 -S 564. Wein AJ, et al. J Urol. 2006; 175(3 pt 2): S 5 -S 10.

OAB Symptoms Are as Prevalent in Men as in Women and Increase With Age OAB Symptoms Are as Prevalent in Men as in Women and Increase With Age Population-based prevalence studies: 40 Prevalence (%) 35 30 25 Comparison of data from the SIFO study (1997)*1 and the EPIC study (2005)† 2 Men (SIFO 1997) 16. 6 Women (SIFO 1997) Men (EPIC 2005) Women (EPIC 2005) 11. 8 20 15 10 5 0 18 -29 30 -34 35 -39 40 -44 45 -49 50 -54 55 -59 60 -64 65 -69 > 70 Age (years) SIFO: Sifo/Gallup telephone survey * N = 16, 776 interviews (6 European countries) † N = 19, 165 interviews (4 European countries and Canada) 1 Milsom I, et al. BJU 2 Irwin DE, et al. Eur Int. 2001; 87: 760 -766. Urol. 2006; 50: 1306 -1314.

Urgency Leading to Urgency Incontinence: More Prevalent in Women with OAB Men with OAB Urgency Leading to Urgency Incontinence: More Prevalent in Women with OAB Men with OAB (n = 463) (n = 401) With UUI 16% With UUI 55% Without UUI 45% National Overactive Bladder Evaluation Study Without UUI 84% Stewart WF, et al. World J Urol. 2003; 20: 327 -336.

Overcoming Barriers in OAB: Forming an Accurate Diagnosis Overcoming Barriers in OAB: Forming an Accurate Diagnosis

Patients Suffer Needlessly From OAB • OAB negatively impacts QOL: – – – – Patients Suffer Needlessly From OAB • OAB negatively impacts QOL: – – – – Emotional well-being Social relationships Productivity Physical functioning Anxiety Hostility Depression Avoid activities like travel Patients Would Rather Cope With OAB Than Seek Help Due to: • Fear of embarrassment • Fear resulting from misconceptions • Differences in perception: – Symptom severity – Degree of bother – Willingness to seek treatment Khullar V, et al. Urology. 2006; 68(2 suppl): 38 -48. Dmochowski RR, et al. Curr Med Res Opin. 2007; 23: 65 -76.

Percent of patients OAB Symptoms Negatively Affect Patients HRQOL assessed with King’s Health Questionnaire Percent of patients OAB Symptoms Negatively Affect Patients HRQOL assessed with King’s Health Questionnaire N = 2878 Sand P, et al. BJU Int. 2007; 99: 836 -844.

Percentage of women (agree strongly or completely) Women Prefer Clinicians to Initiate Discussion About Percentage of women (agree strongly or completely) Women Prefer Clinicians to Initiate Discussion About Urinary Symptoms (n = 1046) (n = 386) (n = 271) (n = 389) • Participant question: “I would be more comfortable discussing urinary symptoms if my health care provider brought up the topic. ” SUI: stress urinary incontinence MUI: mixed urinary incontinence Mac. Diarmid S, et al. Curr Med Res Opin. 2005; 21; 1413 -1421.

Look for Comorbidities of OAB P < 0. 0001 • These conditions were 2. Look for Comorbidities of OAB P < 0. 0001 • These conditions were 2. 8 times more likely to occur in patients with OAB compared to controls (95% CI, 2. 6 -2. 9): – Adjusted for neurologic conditions, diuretic use, potentially inappropriate drug use, and UTI risk factors 11, 556 adult patients with OAB and 11, 556 controls matched on propensity score Adapted from Darkow T, et al. Pharmacotherapy. 2005; 25: 511 -519.

How Do You Approach a Conversation About Urinary Problems Like OAB? ? 1. I How Do You Approach a Conversation About Urinary Problems Like OAB? ? 1. I ask 1 or more questions like, “Do you have urinary problems? ” 2. I let the patient bring it up 3. I use a questionnaire 4. I do not routinely ask about urinary problems

How to Optimally Obtain a Patient History: First Line of Questioning • Do you How to Optimally Obtain a Patient History: First Line of Questioning • Do you have urinary problems? 1, 2 • How much do the symptoms bother you? • Do you want medication for your problems? 1 Lavelle JP, et al. Am J Med. 2006; 119(3 suppl 1): 37 -40. Clin J Med. 2005; 72: 149 -156. 2 Rosenberg MT, et al. Cleve

How to Optimally Obtain a Patient History: Second Line of Questioning How are you How to Optimally Obtain a Patient History: Second Line of Questioning How are you handling your urinary symptoms? What is your most distressing symptom? How long have you experienced these symptoms? What is your fluid intake? What have you tried to solve your problems? Urgency • Do you have to rush to go to the toilet? • Do you have to urinate IMMEDIATELY? Frequency • Do you feel that you urinate too often during the day? Nocturia • Do you have to get up during the night to urinate? • Is it the urge to urinate that wakes you? UUI • When you feel the urge to urinate, do you have leaks or wetting accidents? Rosenberg MT, et al. Cleve Clin J Med. 2005; 72: 149 -156. Irwin DE, et al. Eur Urol. 2006; 50: 1306 -1314. Marschall-Kehrel D, et al. Urology. 2006; 68(2 suppl): 29 -37.

How to Optimally Obtain a Patient History: Elements of the Examination • Now that How to Optimally Obtain a Patient History: Elements of the Examination • Now that the urinary problem is identified, inquire about: – – – Lower urinary tract symptoms (LUTS) Medical and surgical history Medications Focused physical examination Laboratory examinations and/or tests: • Voiding diary, pad test Lavelle JP, et al. Am J Med. 2006; 119(3 suppl 1): 37 -40. Rosenberg MT, et al. Cleve Clin J Med. 2005; 72: 149 -156.

Clinical Practice Recommendation • Practice recommendation: – Patient history in combination with pad tests Clinical Practice Recommendation • Practice recommendation: – Patient history in combination with pad tests and urinary diaries is effective in diagnosing OAB • Evidence-based source: – Health Technology Assessment • Web site of supporting evidence: – http: //www. ncchta. org/fullmono/mon 1006. pdf • Strength of evidence: – Of 6009 papers, 121 were relevant for inclusion in the review: • Comparison of 2 or more assessment/diagnostic techniques – Simple investigations (eg, pad test and diary) may offer useful information on severity – Combined with history, process may provide sufficient information to commence primary care interventions (which are low cost and low risk)

Case Study 1: Carol Presentation • Carol, aged 55 years, has been a long-term Case Study 1: Carol Presentation • Carol, aged 55 years, has been a long-term patient of yours and presents to your office to check on her hypertension and get a new prescription • She seems hesitant to leave after the examination and you question her on other troubling symptoms • She admits to experiencing OAB symptoms with great bother: – Frequency has increased in the past 6 months – Nocturia • Medical history: – Previously treated for depression and UTIs – Hypertension treated with diuretic and calcium channel blocker – Atrophic vaginitis testing was unremarkable

What Is Your Initial Approach to Treating Carol? 1. Behavioral modifications 2. Pharmacotherapy 3. What Is Your Initial Approach to Treating Carol? 1. Behavioral modifications 2. Pharmacotherapy 3. Combination of behavioral modifications and pharmacotherapy 4. I ask the patient for her treatment goals and preference first 5. I do not treat OAB ?

Behavioral Modifications Are a Good Starting Point • Bladder training: scheduled voiding/voiding deferment 1, Behavioral Modifications Are a Good Starting Point • Bladder training: scheduled voiding/voiding deferment 1, 2 • Pelvic floor exercises 1 -4: – – Can be easily performed at home with no equipment needed Not associated with significant adverse events Significant impact in women with UUI and MUI Evidence for men lacking • Significantly higher cure rates and satisfaction associated with combined bladder training and pelvic floor exercises than eitherapy alone 4 1 Christofi N, et al. Menopause Int. 2007; 13: 154 -158. J Nurs. 2002; 102: 36 -45. 3 Burgio KL. J Am Acad Nurse Pract. 2004; 16(10 suppl): 4 -7. 4 Milne JL. J Wound Ostomy Continence Nurs. 2008; 35: 93 -101. 2 Newman DK. Am

Clinical Practice Recommendation • Practice recommendation: – Behavioral therapy improves symptoms of UUI and Clinical Practice Recommendation • Practice recommendation: – Behavioral therapy improves symptoms of UUI and MUI • Evidence-based source: – National Guideline Clearinghouse • Web site of supporting evidence: – http: //www. guideline. gov/summary. aspx? doc_id=1093 1&nbr=005711&string=incontinence • Strength of evidence: – Level A – Can be recommended as a noninvasive treatment in many women

Lifestyle Modifications in OAB: Current Evidence Is Sparse and Inconsistent • Caffeine reduction dose Lifestyle Modifications in OAB: Current Evidence Is Sparse and Inconsistent • Caffeine reduction dose dependent 1: – Affects patients consuming ≥ 400 mg caffeine or 2. 5 cups of coffee • Weight loss 1: – Significant reduction in UUI reported: • No data in men or in OAB dry or moderately overweight patients • Adjusting fluid intake 1, 2: – Greater impact than caffeine restriction – For significant improvement in urgency, frequency, and nocturia episodes, modify fluid input by 25% (goal: 1500 -2400 m. L/day) • Few data for smoking cessation and regulation of bowel function 2 1 Milne JL. J Wound Ostomy Continence Nurs. 2008; 35: 93 -101. 2 Newman DK, et al. Am J Nurs. 2002; 102: 36 -45.

Case Study 1: Carol Treatment • Low-dose antimuscarinic with daily dosing • Take diuretic Case Study 1: Carol Treatment • Low-dose antimuscarinic with daily dosing • Take diuretic before bedtime to improve nocturia • Behavioral modifications

OAB in Female Patients OAB in Female Patients

Differential Diagnosis of Symptoms in Women With OAB Women UTI Bladder cancer Diabetes Multiple Differential Diagnosis of Symptoms in Women With OAB Women UTI Bladder cancer Diabetes Multiple sclerosis SUI Recent pelvic surgery Neurogenic bladder Prolapse Urethral obstruction Atrophic vaginitis Postsurgical incontinence Rosenberg MT, et al. Cleve Clin J Med. 2007; 74(suppl 3): S 21 -S 29.

ICI Management of Incontinence in Women Incontinence on physical activity Incontinence with mixed symptoms ICI Management of Incontinence in Women Incontinence on physical activity Incontinence with mixed symptoms Incontinence with urgency/frequency Evaluation SUI MUI UUI Pelvic floor muscle training Bladder retraining Treat most bothersome symptoms for MUI Antimuscarinics ICI: International Consultation on Incontinence Adapted from Kirby M, et al. Int J Clin Pract. 2006; 60: 1263 -1271.

Treatment Strategies and Pharmacotherapy for OAB David R. Staskin, MD New York Presbyterian Hospital Treatment Strategies and Pharmacotherapy for OAB David R. Staskin, MD New York Presbyterian Hospital New York, NY

Treatment Goals for OAB Eliminate or improve UUI Reduce urgency - frequency - incontinence Treatment Goals for OAB Eliminate or improve UUI Reduce urgency - frequency - incontinence - nocturia Improvement in warning time Ensure treatment compliance for multiple long-term benefits: - Consider appropriate dose, comorbidities, cost, and improved QOL Consensus with the patient’s treatment expectations Hegde SS. Br J Pharmacol. 2006; 147(suppl 2): S 80 -S 87. Staskin DR, et al. Am J Med. 2006; 119(3 suppl 1): 9 -15. Cardozo L, et al. J Urol. 2005; 173: 1214 -1218.

Patient and Physician Expectations Overall Expectations of Treatment 1 Physicians Patients Complete Cure 3. Patient and Physician Expectations Overall Expectations of Treatment 1 Physicians Patients Complete Cure 3. 2% 17% Improved QOL 85. 9% 43% Tailor to 2: Not tailoring treatment may lead to 2: • • • Environment Expectations Lifestyle Age Health Disillusionment Avoidable adverse events Unneeded use of time and resources Harmful and unnecessary surgery Morbidity/mortality Worsening symptoms 1 Robinson D, et al. Int Urogynecol J Pelvic Floor Dysfunct. 2007; 18: 273 -279. 2 Cardozo L. BJU Int. 2007; 99(suppl 3): 1 -7.

Clinical Practice Recommendation • Practice recommendation: – Antimuscarinics significantly reduce OAB symptoms • Evidence-based Clinical Practice Recommendation • Practice recommendation: – Antimuscarinics significantly reduce OAB symptoms • Evidence-based source: – Cochrane Database of Systematic Reviews • Web site of supporting evidence: – http: //www. cochrane. org/reviews/en/ab 003781. html • Strength of evidence: – 61 trials included in the review – The use of anticholinergic drugs for OAB results in statistically significant improvements in symptoms

Symptom-Based OAB Management Patient perception of improvement in overall bladder condition at week 12* Symptom-Based OAB Management Patient perception of improvement in overall bladder condition at week 12* 1 Questionnaires used: OAB symptom questionnaire (OAB-q) American Urological Association Symptom Index Patient Perception of Bladder Condition (PPBC) 863 patients from 82 primary care and 16 obstetric/gynecology offices 1, 2 • • OAB symptoms ≥ 3 months; at least moderately bothered by most bothersome symptom 69% of patients had ≥ 1 comorbid condition; none of the patients had retention requiring catheterization * IMPACT: tolterodine extended release (ER) 12 -week, openlabel study 1 Roberts R, et al. Int 2 Elinoff V, et al. Int J Clin Pract. 2006; 60: 752 -758. J Clin Pract. 2006; 60: 745 -751.

Pros and Cons: Antimuscarinics PROS CONS Only approved treatments with grade A recommendation Physiology/uropharmacology Pros and Cons: Antimuscarinics PROS CONS Only approved treatments with grade A recommendation Physiology/uropharmacology still does not provide ideal agent Extensive literature has demonstrated efficacy and improved QOL Adherence to therapy is low Data available from large-scale, randomized controlled trials High placebo rates Alternative surgical treatments limited by morbidity and cost Response to behavioral therapies Good tolerability Anticholinergic side effects Adapted from Chapple C, et al. Eur Urol. 2008; 54: 226 -230.

Potential Adverse Events, Contraindications, and Drug Interactions of Antimuscarinics Most common side effects Dry Potential Adverse Events, Contraindications, and Drug Interactions of Antimuscarinics Most common side effects Dry mouth 1, 2 Constipation 1, 2 Blurred vision 1, 2 Rare/potential adverse events Sedation, cognitive effects 2, 3 Drowsiness, headache 4 Cardiac adverse effects (QT prolongation)4 Heat prostration (decreased sweating)4 Contraindications Urinary or gastric retention 4 Uncontrolled narrow-angle glaucoma 4 Drug interactions Antidepressants*2, 3 Polypharmacy in the elderly 2 CYP 3 A 4 inhibitors† 3, 5 Diuretic effect of alcohol 2 1 Steers WD. Urol Clin North Am. 2006; 33: 475 -482. * eg, paroxetine (SSRI) shares CYP 2 D 6 2 Erdem N, et al. Am J Med. 2006; 119(3 suppl 1): 29 -36. liver metabolism with darifenacin 3 Staskin DR. Drugs Aging. 2005; 22: 1013 -1028. † eg, ketoconazole, fluoxetine (SSRI) 4 Physicians’ Desk Reference. 62 nd ed. Montvale, NJ: Thomson PDR; 2008. 5 Swart PJ, et al. Basic Clin Pharmacol Toxicol. 2006; 99: 33 -36. SSRI: selective serotonin reuptake inhibitor

Percent of patients Adverse Events Decline Over Time* Consistent finding across long-term studies for Percent of patients Adverse Events Decline Over Time* Consistent finding across long-term studies for OAB: adverse events are most common within 3 months of therapy and decline thereafter Treatment duration (months) N = 716 * 24 -month, noncomparative, darifenacin, open-label extension study Haab F, et al. BJU Int. 2006; 98: 1025 -1032.

Enhanced Therapeutic Effects With Combined Pharmacologic and Behavioral Therapy Mean reduction in UUI (%) Enhanced Therapeutic Effects With Combined Pharmacologic and Behavioral Therapy Mean reduction in UUI (%) 0 Behavioral therapy Combined therapy* Pharmacologic Combined therapy* – 10 – 20 – 30 – 40 – 50 – 60 – 57. 5 – 70 – 72. 7 – 80 – 90 – 84. 3 – 88. 5 – 100 P = 0. 034 N = 197 * Behavioral therapy and pharmacotherapy P = 0. 001 Burgio KL, et al. J Am Geriatr Soc. 2000; 48: 370 -374.

Outcome Measures 1. Objective versus subjective measures 2. Metrics for urgency: – Urgency severity Outcome Measures 1. Objective versus subjective measures 2. Metrics for urgency: – Urgency severity – Warning time

Correlation of Subjective and Objective Measures Patient-Reported Outcomes (PROs) • Meaningful improvements for the Correlation of Subjective and Objective Measures Patient-Reported Outcomes (PROs) • Meaningful improvements for the patient • Changes captured by PROs may differ and include more information than those captured by bladder diaries Tools • Bladder diaries • OAB-q: – 8 -item Symptom Bother scale – 25 -item HRQOL scale (concern, sleep, social interaction, and coping) • PPBC: – Single item of 6 statements Coyne KS, et al. Int J Clin Pract. 2008; 62: 925 -931.

Metrics for Urgency: Reduction in Urgency Severity Weeks Reduction in urgency severity score/void (IUSS) Metrics for Urgency: Reduction in Urgency Severity Weeks Reduction in urgency severity score/void (IUSS) from baseline 1 4 12 0 – 0. 1 – 0. 2 P = 0. 0002 – 0. 3 P = 0. 0008 P = 0. 0004 – 0. 4 Trospium 60 mg daily (n = 292) Placebo (n = 300) – 0. 5 Trospium significantly reduced urgency severity episodes in patients with OAB IUSS: Indevus Urgency Severity Scale Staskin D, et al. J Urol. 2007; 178(3 pt 1): 978 -983.

Median change in warning time from baseline (seconds) Antimuscarinics and Warning Time in OAB: Median change in warning time from baseline (seconds) Antimuscarinics and Warning Time in OAB: Impact of Urgency First study to demonstrate significant increase in warning time in a large clinical setting (VENUS) (n = 739; solifenacin vs placebo)1 – More time to reach a toilet – Avoid urge incontinence episodes (n = 367) (5 -10 mg daily) * P = 0. 032 Primary end point: mean reduction in urgency episodes per 24 hours: 3. 91 for solifenacin vs 2. 73 for placebo (P < 0. 001) 1 Toglia M, et al. Neurourol 2 Zinner N, et al. Int – Time from first sensation of urgency to voiding 1 -3 • Increase in warning time significant to patients 1 -3: * (n = 372) • Warning time: Urodyn. 2006; 25: 655. Abstract 123. J Clin Pract. 2006; 60: 119 -126. • Other warning time placebocontrolled studies: – Darifenacin 15 mg daily (P = not significant; N = 432)2 – Darifenacin 30 mg daily (P = 0. 003; N = 67)3 – Oxybutynin 2. 5 mg TID (P < 0. 001; N = 44)4 3 Cardozo L, et al. J Urol. 2005; 173: 1214 -1218. 4 Wang AC, et al. Urology. 2006; 68: 999 -1004.

Optimizing Treatment Success: Using Flexible-Dosing Options Optimizing Treatment Success: Using Flexible-Dosing Options

OAB Patients Frequently Request Dose Adjustments Percent of patients requesting a dose increase at OAB Patients Frequently Request Dose Adjustments Percent of patients requesting a dose increase at 4 weeks*1 48% Solifenacin 10 mg Solifenacin 5 mg (n = 578) Higher dose (10 mg) available 51% Tolterodine ER 4 mg + placebo Tolterodine ER 4 mg (n = 599) Start Higher dose not available 4 weeks 12 weeks • Similar results (59% vs 68%) were obtained after 2 weeks by a 12 -week efficacy, safety, and tolerability study of darifenacin vs placebo 2 * Prospective 12 -week, parallel-group, double-dummy, 2 -arm, double-blind, efficacy and safety study 1 Chapple CR, et al. Eur Urol. 2005; 48: 464 -470. Int. 2005; 95: 580 -586. 2 Steers W, et al. BJU

Antimuscarinic Flexible Dosing (1) Incontinent patients reporting no incontinence episodes (%) STAR Study: Incontinent Antimuscarinic Flexible Dosing (1) Incontinent patients reporting no incontinence episodes (%) STAR Study: Incontinent Patients Reporting No Incontinence Episodes at End Point on a 3 -Day Diary* † Baseline (per 24 hours): 2. 77 episodes 2. 55 episodes * Patients who reported experiencing incontinence episodes per 24 hours at baseline and who did not report any episodes of incontinence for 3 consecutive days prior to the study visit † P = 0. 006 vs tolterodine ER Chapple CR, et al. Eur Urol. 2005; 48: 464 -470.

Antimuscarinic Flexible Dosing (2) Flexible-Dosing Study Reduction in incontinence episodes per week with darifenacin Antimuscarinic Flexible Dosing (2) Flexible-Dosing Study Reduction in incontinence episodes per week with darifenacin Median change from baseline (%) No Dose Escalation 7. 5 mg 15 mg Placebo 0 mg (n = 104) (n = 157) (n = 127) ■ 2 weeks ■ 12 weeks Steers W, et al. BJU Int. 2005; 95: 580 -586.

Antimuscarinic Flexible Dosing (3) Percent of patients Cumulative Response Rate With Increasing Dose N Antimuscarinic Flexible Dosing (3) Percent of patients Cumulative Response Rate With Increasing Dose N = 368 Mac. Diarmid SA, et al. J Urol. 2005; 174(4 pt 1): 1301 -1305.

Dosing Options Comparison Antimuscarinic Dosing Dose Adjustment? Darifenacin 7. 5 and 15 mg Oxybutynin Dosing Options Comparison Antimuscarinic Dosing Dose Adjustment? Darifenacin 7. 5 and 15 mg Oxybutynin IR 5 mg ER 5, 10, 15 mg TDS 3. 9 mg/day system Daily YES BID, TID, QID NO Daily (up to 30 mg/day) New patch twice a week (every 3 -4 days) YES Daily NO BID Daily NO NO NO Solifenacin 5 and 10 mg Tolterodine ER 4 mg Trospium chloride* 20 mg 60 mg * 1 hour before meal or on an empty stomach IR: immediate release TDS: transdermal delivery system Physicians’ Desk Reference. 62 nd ed. Montvale, NJ: Thomson PDR; 2008.

Low Patient Persistence Patients remaining persistent (%)1 Medicaid and Prescription Drug Databases Only 44% Low Patient Persistence Patients remaining persistent (%)1 Medicaid and Prescription Drug Databases Only 44% out of 1637 Medicaid patients remained persistent after 30 days • Low adherence and persistence reported by various clinical studies 2 -4: – Adherence rates reported for OAB similar to other chronic diseases 5 – Low level of education and cultural and social support factors may contribute to poor compliance 6 Tolterodine ER Oxybutynin ER • Antimuscarinic therapy for OAB 3, 5 -6: – Short- and long-term efficacy for significant proportion of users – Therapeutic/patient perceived benefits require at least 4 -8 weeks of continuous therapy Days Persistence: time to discontinuation J Manag Care. 2005; 11(4 suppl): S 121 -S 129. Health. 2004; 7: 366. Abstract PUK 11. 3 Yu YF, et al. Value Health. 2005; 8: 495 -505. 4 Balkrishnan R, et al. J Urol. 2006; 175(3 pt 1): 1067 -1071. 5 Basra RK, et al. BJU Int. 2008. Epub ahead of print. 6 Thomas L, et al. J Manag Care Pharm. 2008; 14: 381 -386. 2 Chui MA, et al. Value 1 Adapted from Shaya FT, et al. Am

Factors Affecting Adherence • Presentation and efficacy of medication • Cost (financial or personal) Factors Affecting Adherence • Presentation and efficacy of medication • Cost (financial or personal) • Dosing frequency • Expectations of treatment • Route of administration of medication • Adequate follow-up after initiation of therapy Follow-up is important to ensure patient adherence to treatment Basra RK, et al. BJU Int. 2008. Epub ahead of print. D’Souza AO, et al. J Manag Care Pharm. 2008; 14: 291 -301.

OAB in Male Patients OAB in Male Patients

Case Study 2: Tom Presentation • Tom, aged 60 years, presents to your office Case Study 2: Tom Presentation • Tom, aged 60 years, presents to your office for his annual physical examination • At the end of the examination, he asks about the definition of normal voiding: – Works at night – Frequent bathroom visits interrupt his work – Slow urine stream and feeling that bladder has not emptied completely • Unremarkable medical history and physical examination: – Checked blood sugar levels • Normal laboratory values

Differential Diagnosis of Symptoms in Men With OAB Men Benign prostatic hyperplasia (BPH) Prostate Differential Diagnosis of Symptoms in Men With OAB Men Benign prostatic hyperplasia (BPH) Prostate cancer Diabetes Postsurgical incontinence Bladder outlet obstruction (BOO) Urethral stricture Neurogenic bladder Bladder stones Rosenberg MT, et al. Cleve Clin J Med. 2007; 74(suppl 3): S 21 -S 29.

Men With OAB: LUTS Storage and Voiding Symptoms Storage 1, 2 Voiding 1, 2 Men With OAB: LUTS Storage and Voiding Symptoms Storage 1, 2 Voiding 1, 2 (afferent, irritative) (efferent/obstructive) Urgency Hesitancy Postvoid dribble Frequency Poor flow/weak stream Nocturia Intermittency Sense of incomplete emptying UUI Straining to pass urine SUI Terminal dribble MUI Prolonged micturition Overflow incontinence Urinary retention Postmicturition 1, 2 1 Abrams P, et al. Neurourol Urodyn. 2002; 21: 167 -178. Urol. 2006; 49: 651 -658. 2 Chapple CR, et al. Eur

Clinical Algorithm for the Management of LUTS in Men Focused history and Unlikely BPH Clinical Algorithm for the Management of LUTS in Men Focused history and Unlikely BPH or OAB physical examination Referral Urinalysis/PSA and/or treat Blood sugar LUTS Watchful waiting No Desires treatment Provisional OAB Check PVR Ineffective < 50 cc PSA: prostate-specific antigen PVR: postvoid residual Provisional BPH Trial α-blocker 50 -200 cc Effective Continue medication > 200 cc Referral Rosenberg MT, et al. Int J Clin Pract. 2007; 61: 1535 -1546.

Clinical Algorithm for the Management of LUTS in Men (Cont. ) Check PVR < Clinical Algorithm for the Management of LUTS in Men (Cont. ) Check PVR < 50 cc Possible OAB Uroflow 50 -200 cc Diagnosis unclear High Low Mixed OAB/BPH Antimuscarinics Ineffective Referral Optional • Titrate α-blocker • Switch medication • Try ARI, combination therapy • Refer > 200 cc Referral Effective Continue therapy Ineffective High Uroflow Low Referral Effective Continue medication ARI: α-reductase inhibitor Rosenberg MT, et al. Int J Clin Pract. 2007; 61: 1535 -1546.

Low Risk of Retention in Men on Antimuscarinics for OAB/LUTS Evidence From Trials Study/Goal Low Risk of Retention in Men on Antimuscarinics for OAB/LUTS Evidence From Trials Study/Goal Result Reference(s) Antimuscarinic No clinically meaningful Abrams P, et al. J Urol. monotherapy in men change in PVR or urinary 2006; 175(3 pt 1): 999 -1004. with BOO/DO versus (Tolterodine ER) retention placebo Combined therapy: α-blocker plus antimuscarinics in men Increased benefit with combination therapy Low incidence of retention Varying results for PVR increase Antimuscarinic Low incidence of therapy in men with retention, no OAB with or without catheterization BPH medication * Not available in the United States DO: detrusor overactivity Kaplan SA, et al. JAMA. 2006; 296: 2319 -2328. (Tolterodine ER plus tamsulosin) Lee K-S, et al. J Urol. 2005; 174(4 pt 1): 1334 -1338. (Propiverine hydrochloride* plus doxazosin ER) Staskin DR, et al. Int J Clin Pract. 2008; 62: 27 -38. (Oxybutynin TDS)

OAB Symptom Improvement in Men: Patient-Reported Outcomes Percent of male respondents ■ PPBC = OAB Symptom Improvement in Men: Patient-Reported Outcomes Percent of male respondents ■ PPBC = 1, 2, or 3 ■ PPBC = 4, 5, or 6 • Antimuscarinic treatment effective and well tolerated in men with OAB: – Regardless of history of “prostate condition” Baseline Month ■ Always ■ Most of the time ■ Sometimes, infrequently, or never Global assessment of OAB severity Percent of male respondents “Within the past month, do you feel that you had enough time to get to the bathroom? ” Baseline Month N = 369 men with PPBC ≥ 4 (condition caused moderate, severe, or many severe problems) MATRIX: open-label study with oxybutynin TDS Staskin DR, et al. Int J Clin Pract. 2008; 62: 27 -38.

Case Study 2: Tom Treatment and Follow-Up • You use a questionnaire to assess Case Study 2: Tom Treatment and Follow-Up • You use a questionnaire to assess Tom’s symptoms • Behavioral modifications • You start him on an α-blocker: – At follow-up, obstruction has improved • He still complains of nocturia and you add antimuscarinic treatment: – After 4 weeks of antimuscarinic treatment, his nocturia episodes have been reduced to 2 times a night

Summary • OAB is a prevalent disease that increases with age • OAB impacts Summary • OAB is a prevalent disease that increases with age • OAB impacts comorbidities and QOL • OAB symptoms can be treated: – Move toward symptom/syndrome-based treatment – Individualized to match patient’s preference and expectations (tolerability and efficacy) – Recognize comorbidities and treatment fluid imbalances – Institute behavioral changes and pelvic floor exercises – Flexible-dosing regimens

Postmeeting Survey • True or false: The core symptom of OAB is urgency. 1. Postmeeting Survey • True or false: The core symptom of OAB is urgency. 1. True 2. False ?

Postmeeting Survey • Which of the following are NOT considered comorbidities in patients with Postmeeting Survey • Which of the following are NOT considered comorbidities in patients with OAB? 1. 2. 3. 4. Falls and fractures UTIs Skin infections Kidney stones ?

Postmeeting Survey • True or False: Using a flexible-dosing regimen of antimuscarinics results in Postmeeting Survey • True or False: Using a flexible-dosing regimen of antimuscarinics results in improved efficacy and patient satisfaction. 1. True 2. False ?

Generic/Brand Name Table Generic Trade Darifenacin Enablex® Doxazosin Cardura ® Fluoxetine Prozac®, Sarafem® Ketoconazole Generic/Brand Name Table Generic Trade Darifenacin Enablex® Doxazosin Cardura ® Fluoxetine Prozac®, Sarafem® Ketoconazole Extina®, Nizoral®, Xolegel® Oxybutynin Ditropan®, Oxytrol® Paroxetine Paxil®, Pexeva® Propiverine Not available in the United States Solifenacin VESIcare® Tolterodine Detrol® Trospium Sanctura XR™