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膀胱过度活动症的药物治疗

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膀胱过度活动症的药物治疗,同时还介绍了几个与OAB有关的临床试验。更多精彩教程,请访问缤果网(http://www.bingomed.com)

膀胱过度活动症的药物治疗

  1. 1. 膀胱过度活动症的药物治疗 —— 治疗选择原则 Pharmacotherapy for Overactive Bladder -- Rationale for Treatment Choice David A. Ginsberg, M.D. Assistant Professor of Urology, USC Keck School of Medicine Powered by
  2. 2. Two Funny Pictures 免费小便 · 运动咖啡馆 这里是泌尿科。你能忍一下吗 ? Powered by 缤果网 (http://www.bin.co)
  3. 3. Table Of Contents <ul><li>Overactive Bladder Terminology 5 </li></ul><ul><li>Spectrum of Voiding Dysfunction 6 </li></ul><ul><li>OAB Prevalence and Incidence 7 </li></ul><ul><li>Impact of Urinary Incontinence on Quality of Life 11 </li></ul><ul><li>Diagnosis of Overactive Bladder 14 </li></ul><ul><li>Differential Diagnosis (Stress Incontinence, </li></ul><ul><li>Overactive Bladder, Mixed Symptoms) 23 </li></ul><ul><li>Treatment for Overactive Bladder 28 </li></ul><ul><li>Pharmacologic Therapy for Treatment of OAB 35 </li></ul>Powered by 缤果网 (http://www.bin.co)
  4. 4. Table Of Contents (cont’d) <ul><li>Tolterodine SR Registration Trial 40 </li></ul><ul><li>Registration Trial – 12 Months Extension 50 </li></ul><ul><li>STAT – Speed (of onset) Therapeutic </li></ul><ul><li>Assessment Trial 55 </li></ul><ul><li>Efficacy and Tolerability of Tolteordine SR </li></ul><ul><li>vs. Oxybutylin 64 </li></ul><ul><li>MERIT - Mixed Incontinence Effectiveness </li></ul><ul><li>Research Investigating Tolterodine 68 </li></ul><ul><li>Summary 77 </li></ul>Powered by 缤果网 (http://www.bin.co)
  5. 5. Overactive Bladder Terminology <ul><li>OAB = bladder contracting w/o pt’s permission </li></ul><ul><li>OAB definition per ICS based on symptoms </li></ul><ul><li>Urgency, with or without urge incontinence, usually with frequency and nocturia </li></ul><ul><li>In the absence of pathologic or metabolic conditions that might explain these symptoms </li></ul>ICS = International Continence Society (www.icsoffice.org) Powered by 缤果网 (http://www.bin.co)
  6. 6. Spectrum of Voiding Dysfunction z <ul><li>Urgency </li></ul><ul><li>Frequency </li></ul><ul><li>Nocturia </li></ul>SUI Mixed (UUI+SUI) UUI Powered by 缤果网 (http://www.bin.co) Overactive Bladder Overactive Bladder
  7. 7. OAB Affects 11% to 22% of Adults Older Than 40 Years of Age in Europe, Asia, and the United States Milsom I et al. BJU Int . 2001;87:760-766. Stewart WF et al. World J Urol . 2003;20:327-336. Homma Y et al. ICS Abstract 2003. Prevalence of OAB in adults  40 years of age Male Female Prevalence (%) France Germany Italy Spain Sweden UK Japan Country USA 25 20 15 10 5 0 Powered by 缤果网 (http://www.bin.co)
  8. 8. Prevalence of OAB by Age and Gender 0 5 10 15 20 25 <25 25-34 35-44 45-54 55-64 65+ Prevalence (%) Age (years) Stewart WF et al. World J Urol. 2003;20:327-336. In a US national telephone survey (N = 5,204). Powered by 缤果网 (http://www.bin.co) Men: 2.4% (Incontinent) Men: 13.6% (Continent) Women: 9.3% (Incontinent) Women: 7.6% (Continent)
  9. 9. Incidence Underreported <ul><li>“ Tip of the iceberg” </li></ul><ul><li>Increasing incidence in an aging population </li></ul>Powered by 缤果网 (http://www.bin.co)
  10. 10. Incontinence - Underreported <ul><li>Less than half with bladder control problems report it to their health care provider </li></ul><ul><li>WHY? </li></ul><ul><li>Embarrassment </li></ul><ul><li>Low expectation for therapy </li></ul><ul><li>“ Normal” part of aging </li></ul><ul><li>Availability of absorbent products/pads </li></ul>Powered by 缤果网 (http://www.bin.co)
  11. 11. Impact of Urinary Incontinence on Quality of Life Quality of Life <ul><li>Psychological </li></ul><ul><li>Guilt/depression </li></ul><ul><li>Loss of self-respect and dignity </li></ul><ul><li>Fear of: </li></ul><ul><ul><li>being a burden </li></ul></ul><ul><ul><li>lack of bladder control </li></ul></ul><ul><ul><li>urine odor </li></ul></ul><ul><li>Apathy/denial </li></ul>Powered by 缤果网 (http://www.bin.co) <ul><li>Physical </li></ul><ul><li>Limitations or cessation of physical activities </li></ul><ul><li>Sexual </li></ul><ul><li>Avoidance of sexual contact and intimacy </li></ul><ul><li>Occupational </li></ul><ul><li>Absence from work </li></ul><ul><li>Decreased productivity </li></ul><ul><li>Social </li></ul><ul><li>Reduction in social interaction </li></ul><ul><li>Alteration of travel plans </li></ul><ul><li>Increased risk of institutionalization of frail older persons </li></ul><ul><li>Domestic </li></ul><ul><li>Requirements for specialized underwear, bedding </li></ul><ul><li>Special precautions with clothing </li></ul>
  12. 12. Falls and Fractures <ul><li>In women over 65 years... </li></ul><ul><li>OAB, falls, and fractures are common </li></ul><ul><li>19–42% sustain falls </li></ul><ul><li>Fractures occur in 4–9% of falls </li></ul><ul><li>Hip fractures associated with a high rate of morbidity and mortality </li></ul>Brown, JAGS 48: 721-725 Powered by 缤果网 (http://www.bin.co)
  13. 13. Distribution of Disease Among Women Seeking Care for Pelvic Floor Disorders (N = 602) 67 66 65 72 0 0 5 2 9 6 50 58 77 82 65 56 51 52 33 30 31 34 43 35 0 10 20 30 40 50 60 70 80 90 30-39 40-49 50-59 60-69 70-79 80-89 Age Range (Years) Women Affected (%) Urgency/detrusor instability SUI/GSI Pelvic organ prolapse Intrinsic sphincter deficiency Luber KM, et al. Am J Obstet Gynecol . 2001;184:1496-1503. GSI = genuine stress incontinence. Powered by 缤果网 (http://www.bin.co)
  14. 14. Diagnosis of Overactive Bladder <ul><li>Most cases of overactive bladder can be diagnosed based on: </li></ul><ul><ul><li>patient history, symptom assessment </li></ul></ul><ul><ul><li>physical examination </li></ul></ul><ul><ul><li>urinalysis </li></ul></ul><ul><li>Initiation of noninvasive treatment does not require an extensive further workup </li></ul>Powered by 缤果网 (http://www.bin.co)
  15. 15. Routine Screening <ul><li>Do you frequently limit your fluid intake or map out restrooms when you are away from home? </li></ul><ul><li>Do you urinate more than 8 times in a 24-hour period? </li></ul><ul><li>Do you frequently get up 2 or more times at night to go to the bathroom? </li></ul><ul><li>Do you have uncontrollable urges to urinate, resulting in wetting accidents? </li></ul><ul><li>Do you use pads to protect your clothes? </li></ul><ul><li>Are you bothered or concerned about bladder control? </li></ul>Questions to Consider Powered by 缤果网 (http://www.bin.co)
  16. 16. History <ul><li>How long? How old when started? </li></ul><ul><li>How much (volume)? Degree of bother? </li></ul><ul><li>Characteristics of leakage? </li></ul><ul><ul><li>Activity related? </li></ul></ul><ul><ul><li>Day and night, wet pads at night = instability </li></ul></ul><ul><ul><li>Urgency? </li></ul></ul><ul><ul><ul><li>Suppressible = probably SUI </li></ul></ul></ul><ul><ul><ul><li>not suppressible (urge incontinence) = instability </li></ul></ul></ul><ul><li>Other: fluid intake, UTI’s, pain, hematuria, LE swelling, medications </li></ul>Powered by 缤果网 (http://www.bin.co)
  17. 17. Medications Influencing LUT Function Medication Class Effect Powered by 缤果网 (http://www.bin.co) Alcohol Polyuria, frequency, urgency α-Receptor agonists Urethral constriction and urinary retention (males) α-Receptor antagonists Urethral relaxation ACE inhibitors Cough -> SUI Anticholinergics Urinary retention, overflow incontinence, fecal impaction Antidepressants, tricyclic Anticholinergic effect, α-receptor antagonist effect
  18. 18. Medications Influencing LUT Function (cont) <ul><li>Medication Class </li></ul>Effect Powered by 缤果网 (http://www.bin.co) β-Receptor antagonists Urinary retention Calcium channel blockers Urinary retention, fecal impaction Opioids Urinary retention, fecal impaction Sedative-hypnotics Sedation, delirium, muscle relaxation Diuretics Polyuria, frequency, urgency Methylxanthines Polyuria, bladder irritation Neuroleptics Anticholinergic effect, sedation
  19. 19. <ul><li>Abdomen </li></ul><ul><ul><li>Masses: palpable bladder, etc. </li></ul></ul><ul><li>Pelvis/perineum </li></ul><ul><ul><li>External genitalia: atrophic vaginitis </li></ul></ul><ul><ul><li>vaginal </li></ul></ul><ul><ul><ul><li>Prolapse (assoc. 50% of SUI patients) </li></ul></ul></ul><ul><ul><ul><li>GYN malignancy, fistula </li></ul></ul></ul><ul><li>Rectal: </li></ul><ul><ul><li>tone, masses, teach Kegels during exam </li></ul></ul><ul><ul><li>prostate </li></ul></ul><ul><li>Neurological (reflexes, LE’s, sensory, motor) </li></ul>Physical Examination Powered by 缤果网 (http://www.bin.co)
  20. 20. Physical Examination <ul><li>Rule out possible causes of LUTS </li></ul><ul><ul><li>Atrophic vaginitis </li></ul></ul><ul><ul><li>Estrogen deficiency </li></ul></ul><ul><ul><li>Pelvic floor dysfunction </li></ul></ul><ul><ul><li>Pelvic organ prolapse </li></ul></ul><ul><ul><li>Potentially serious pathologic conditions </li></ul></ul>Conditions Associated With Vaginal Relaxation <ul><li>Cystocele </li></ul><ul><li>Rectocele </li></ul><ul><li>Enterocele </li></ul><ul><li>Uterine prolapse </li></ul>Signs of Hypoestrogenation Agglutination of labia minora Prominent caruncle Powered by 缤果网 (http://www.bin.co)
  21. 21. Laboratory Tests <ul><li>Urinalysis </li></ul><ul><ul><li>Dipstick </li></ul></ul><ul><ul><li>Culture </li></ul></ul><ul><ul><li>Microscopic examination </li></ul></ul><ul><ul><li>Look for hematuria, pyuria, bacteriuria, glucosuria, proteinuria </li></ul></ul><ul><li>Appropriate blood work </li></ul><ul><ul><li>Glucose </li></ul></ul><ul><ul><li>Electrolytes </li></ul></ul><ul><ul><li>Prostate specific antigen (PSA) in men </li></ul></ul>Fantl JA, et al. Agency for Healthcare Policy and Research; 1996. AHCPR publication 96-0686. Powered by 缤果网 (http://www.bin.co)
  22. 22. Laboratory Tests <ul><li>Rule out possible causes of LUTS </li></ul><ul><ul><li>Urinary tract infection (UTI) or sexually transmitted disease (STD) </li></ul></ul><ul><ul><li>Diabetes mellitus </li></ul></ul><ul><ul><li>LUT tumor or kidney stones </li></ul></ul><ul><ul><li>Potentially serious pathologic conditions </li></ul></ul>Refer to appropriate specialist. Powered by 缤果网 (http://www.bin.co)
  23. 23. Stress Incontinence, Overactive Bladder, and Mixed Symptoms Powered by 缤果网 (http://www.bin.co)
  24. 24. Distribution of Urinary Incontinence by Type: United States Total estimated number of people with urinary incontinence: 17.5 million* *Based on 2000 US Census. Adapted from Stewart WF, et al. World J Urol . 2003;20:327-336. Powered by 缤果网 (http://www.bin.co) Urge 6.9 million Stress 5.1 million Mixed 5.5 million
  25. 25. Differentiating OAB With Urge Incontinence From Stress Incontinence OAB and UUI SUI Fantl A, et al. Urinary Incontinence in Adults: Acute and Chronic Management. Clinical Practice Guidelines No. 2, 1996 Update. Rockville, MD: Agency for Health Care Policy and Research: March 1996. AHCPR publication 96-0682. Powered by 缤果网 (http://www.bin.co)
  26. 26. Differential Diagnosis: Overactive Bladder, Stress Incontinence, and Mixed Symptoms Medical History and Physical Examination Symptom Assessment Abrams P, Wein AJ. The Overactive Bladder—A Widespread and Treatable Condition. 1998. Powered by 缤果网 (http://www.bin.co) Symptoms OAB SUI Mixed Symptoms Urgency (strong, sudden desire to void) Yes No Yes Frequency with urgency (> 8 times/24 h) Yes No Yes Leaking during physical activity (eg, coughing, sneezing, lifting) No Yes Yes Amount of urinary leakage with each episode of incontinence Large (if present) Small Variable Ability to reach the toilet in time following an urge to void Often no Yes Variable Waking to pass urine at night Usually Seldom Maybe
  27. 27. Mixed Incontinence is the Most Bothersome Coyne KS, et al. BJU Int. 2003;92:731-735. OAB-q Subscale Scores 0 10 20 30 40 50 60 SUI OAB wet* OAB wet + SUI* * P  .05 versus SUI. Powered by 缤果网 (http://www.bin.co) BOTHER (Quality- of- Life Survey)
  28. 28. Treatment for Overactive Bladder <ul><li>Pads </li></ul><ul><li>Behavioral therapy </li></ul><ul><li>Medications </li></ul><ul><li>Neuromodulation </li></ul><ul><li>Surgery </li></ul>Powered by 缤果网 (http://www.bin.co)
  29. 29. Behavioral Modification Behavioral Modification Education/Log Delayed voiding Timed voiding Diet Pelvic floor exercises Powered by 缤果网 (http://www.bin.co)
  30. 30. Diet Modification <ul><li>Avoid food/beverages irritating to the bladder (coffee, caffeine, etc.) </li></ul><ul><li>Manage fluid intake </li></ul><ul><li>Stop evening fluids </li></ul><ul><li>Avoid constipation </li></ul>Powered by 缤果网 (http://www.bin.co)
  31. 31. Bladder Training <ul><li>Modify bladder function </li></ul><ul><li>Methods </li></ul><ul><ul><li>bladder diary </li></ul></ul><ul><ul><li>gradually increase void interval </li></ul></ul><ul><ul><li>teach coping strategies </li></ul></ul><ul><li>Strengthen pelvic floor muscles and improving bladder stability </li></ul>Powered by 缤果网 (http://www.bin.co)
  32. 32. Management of Overactive Bladder <ul><li>Behavioral therapies 1 </li></ul><ul><li>Pharmacologic therapy </li></ul><ul><li>Combined pharmacologic and behavioral therapy provides improved outcomes 2,3 </li></ul>1. Mattiasson A. Urology. 2000;55(suppl 5a):12-13. 2. Mattiasson A. Neuro Urodyn . 2001;20:403-404. 3. Burgio et al. JAGS. 2000;48:370-374. Powered by 缤果网 (http://www.bin.co)
  33. 33. Behavioral Modification <ul><li>Burgio, et al </li></ul><ul><li>197 women with urge incontinence </li></ul><ul><li>Modified crossover design </li></ul><ul><li>Initially on monotherapy of either </li></ul><ul><ul><li>Behavioral therapy </li></ul></ul><ul><ul><li>Drug therapy (oxy 2.5-15 mg/d) </li></ul></ul><ul><li>Combined therapy offered after 8 weeks if not content with monotherapy alone </li></ul>Burgio et al. JAGS. 2000;48:370-374 Powered by 缤果网 (http://www.bin.co)
  34. 34. Behavioral Modification <ul><li>Behavioral therapy </li></ul><ul><ul><li>57.5% reduction in incontinence </li></ul></ul><ul><ul><li>8 pts crossed over </li></ul></ul><ul><ul><li>88.5% reduction in incontinence when meds added (p=0.034) </li></ul></ul><ul><li>Medical therapy </li></ul><ul><ul><li>72.7% reduction in incontinence </li></ul></ul><ul><ul><li>27 pts crossed over </li></ul></ul><ul><ul><li>84.3% reduction in incontinence when meds added (p=0.001) </li></ul></ul><ul><li>Conclusion: combining drug & behavioral therapy in a stepped program can produce added benefit for patients with UUI </li></ul>Burgio et al. JAGS. 2000;48:370-374 Powered by 缤果网 (http://www.bin.co)
  35. 35. Pharmacologic Therapy for the Treatment of OAB <ul><li>Antimuscarinic agents are the mainstay for treating OAB </li></ul><ul><li>OAB symptoms relieved by </li></ul><ul><ul><li>inhibition of involuntary bladder contractions </li></ul></ul><ul><ul><li>increased bladder capacity </li></ul></ul><ul><li>Treatment can be limited by side effects such as dry mouth, GI effects (eg, constipation), and CNS effects </li></ul>Powered by 缤果网 (http://www.bin.co)
  36. 36. Muscarinic Receptor Distribution Abrams P, Wein AJ. The Overactive Bladder— A Widespread and Treatable Condition. 1998. CNS Powered by 缤果网 (http://www.bin.co) Bladder (detrusor muscle) Salivary glands Dry mouth Colon Constipation Heart Stomach and esophagus Dyspepsia Iris/ciliary body Lacrimal gland Blurred vision Dry eyes Tachycardia <ul><li>Dizziness </li></ul><ul><li>Somnolence </li></ul><ul><li>Impaired memory and cognition </li></ul>
  37. 37. Ideal Muscarinic Receptor Antagonist <ul><li>Efficacious </li></ul><ul><ul><li>inhibits involuntary bladder contractions </li></ul></ul><ul><ul><li>does not adversely affect volitional detrusor activity </li></ul></ul><ul><li>Organ selective </li></ul><ul><ul><li>preferentially affects the bladder over other organs </li></ul></ul><ul><ul><li>results in minimal side effects and improved tolerability </li></ul></ul><ul><li>Durable effects </li></ul><ul><ul><li>improves compliance and/or persistency </li></ul></ul><ul><li>Provides clinical effectiveness </li></ul><ul><ul><li>the optimal balance of efficacy, tolerability, and compliance/persistency </li></ul></ul>Powered by 缤果网 (http://www.bin.co)
  38. 38. Anticholinergics A Delicate Balance <ul><li>Efficacy </li></ul><ul><li>Less frequency </li></ul><ul><li>Less UUI </li></ul><ul><li>Increased voided volume </li></ul><ul><li>Adverse effects </li></ul><ul><li>Dry mouth </li></ul><ul><li>Constipation </li></ul><ul><li>CNS </li></ul>Powered by 缤果网 (http://www.bin.co)
  39. 39. Antimuscarinic Agents <ul><li>Oxybutynin (immediate-release and extended release) </li></ul><ul><li>Propiverine </li></ul><ul><li>Tolterodine (immediate-release and extended release) </li></ul><ul><li>Oxybutynin transdermal delivery system </li></ul><ul><li>Darifenacin </li></ul><ul><li>Solifenacin </li></ul><ul><li>Trospium </li></ul>Powered by 缤果网 (http://www.bin.co)
  40. 40. Tolterodine SR Registration Trial Van Kerrebroeck P et al. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology . 2001;57:414-421. Powered by 缤果网 (http://www.bin.co)
  41. 41. Tolterodine SR in the Treatment of OAB: Study Design and Inclusion Criteria <ul><li>Multicenter (167 sites across North America, Europe, Australia, and New Zealand), randomized, double-blind, active- and placebo-controlled trial in adult patients with symptoms of OAB </li></ul><ul><li>Adult patients aged 18 or older with symptoms of OAB for >6 months </li></ul><ul><li>Symptoms of urinary frequency (average of >8 micturitions/24 h) and urge incontinence (>5 incontinence episodes/wk) </li></ul>Van Kerrebroeck P et al. Urology . 2001;57:414-421. Detrol ® LA (tolterodine tartrate extended release capsules) Registration Trial: Van Kerrebroeck et al Powered by 缤果网 (http://www.bin.co)
  42. 42. Tolterodine SR in the Treatment of OAB: Reduction in Incontinence Episodes Van Kerrebroeck P et al. Urology . 2001;57:414-421. – 80 – 60 – 50 – 30 – 20 – 10 0 – 70 – 40 * † * * P < 0.01 vs placebo † P < 0.05 vs tolterodine – 71% – 60% – 33% Median Change From Baseline (%) Placebo Tolterodine Tolterodine SR Detrol ® LA (tolterodine tartrate extended release capsules) Detrol ® (tolterodine tartrate tablets) Registration Trial: Van Kerrebroeck et al Powered by 缤果网 (http://www.bin.co)
  43. 43. Tolterodine SR in the Treatment of OAB: Reduction in Total Micturitions/24 Hours – 30 – 25 – 20 – 15 – 10 – 5 0 Mean Change From Baseline (%) * * – 25% – 22% – 15% Placebo * P < 0.001 vs placebo Van Kerrebroeck P et al. Urology . 2001;57:414-421. Tolterodine Tolterodine SR Detrol ® LA (tolterodine tartrate extended release capsules) Detrol ® (tolterodine tartrate tablets) Registration Trial: Van Kerrebroeck et al Powered by 缤果网 (http://www.bin.co)
  44. 44. Tolterodine SR in the Treatment of OAB: Increase in Mean Volume Voided/Micturition * P = 0.0001 vs placebo. 0 5 10 15 20 25 30 Placebo Change From Baseline (%) * * 24% 21% 10% Tolterodine SR Tolterodine Detrol ® LA (tolterodine tartrate extended release capsules) Detrol ® (tolterodine tartrate tablets) Van Kerrebroeck P et al. Urology . 2001;57:414-421. Registration Trial: Van Kerrebroeck et al Powered by 缤果网 (http://www.bin.co)
  45. 45. Tolterodine SR in the Treatment of OAB: Reduction in Incontinence Pad Usage – 40 – 35 – 30 – 25 – 20 – 15 – 10 – 5 0 * * – 36% – 36% – 13% Change From Baseline (%) Placebo Tolterodine Tolterodine SR * P < 0.02 vs placebo. Detrol ® LA (tolterodine tartrate extended release capsules) Detrol ® (tolterodine tartrate tablets) Van Kerrebroeck P et al. Urology . 2001;57:414-421. Registration Trial: Van Kerrebroeck et al Powered by 缤果网 (http://www.bin.co)
  46. 46. Tolterodine SR in the Treatment of OAB: Incidence of Dry Mouth <ul><li>The incidence of any dry mouth was: </li></ul><ul><ul><li>Tolterodine– 30% </li></ul></ul><ul><ul><li>Tolterodine SR – 23% </li></ul></ul><ul><li>The rate of dry mouth with tolterodine SR was significantly less than that with tolterodine (P < 0.02) </li></ul>Patients (%) 0 10 20 30 40 50 60 Tolterodine SR Tolterodine Placebo 23%* * P < 0.02 vs Detrol ® 30% 8% Detrol ® LA (tolterodine tartrate extended release capsules) Detrol ® (tolterodine tartrate tablets) Van Kerrebroeck P et al. Urology . 2001;57:414-421. Registration Trial: Van Kerrebroeck et al Powered by 缤果网 (http://www.bin.co)
  47. 47. Tolterodine SR in the Treatment of OAB: Incidence of Common Adverse Events 0 2 4 6 8 10 12 14 16 18 20 Constipation Headache Somnolence Patients (%) 5.9% 6.8% 4.3% 6.3% 3.7% 4.6% 2.8% 2.6% 1.8% Placebo Tolterodine SR Tolterodine Detrol ® LA (tolterodine tartrate extended release capsules) Detrol ® (tolterodine tartrate tablets) Van Kerrebroeck P et al. Urology . 2001;57:414-421. Registration Trial: Van Kerrebroeck et al Powered by 缤果网 (http://www.bin.co)
  48. 48. Tolterodine SR in the Treatment of OAB: Withdrawals Due to Adverse Events 0 10 20 30 40 50 60 70 80 90 100 Withdrawal Patients (%) 5% 5% 6% Placebo Tolterodine SR Tolterodine Detrol ® LA (tolterodine tartrate extended release capsules) Detrol ® (tolterodine tartrate tablets) Van Kerrebroeck P et al. Urology . 2001;57:414-421. Registration Trial: Van Kerrebroeck et al Powered by 缤果网 (http://www.bin.co)
  49. 49. Tolterodine SR in the Treatment of OAB: Study Conclusions <ul><li>A 12-week multinational study comparing tolterodine SR 4 mg once daily, and tolterodine 2 mg twice daily with placebo in 1,529 patients </li></ul><ul><li>Compared with placebo, tolterodine SR and tolterodine were significantly more effective in improving: </li></ul><ul><ul><li>Incontinence episodes/week </li></ul></ul><ul><ul><li>Total micturitions/24 hours </li></ul></ul><ul><ul><li>Mean volume voided/micturition </li></ul></ul><ul><ul><li>Incontinence pad usage/24 hours </li></ul></ul>Detrol ® LA (tolterodine tartrate extended release capsules) Detrol ® (tolterodine tartrate tablets) Van Kerrebroeck P et al. Urology . 2001;57:414-421. Registration Trial: Van Kerrebroeck et al Powered by 缤果网 (http://www.bin.co)
  50. 50. 007 Registration Trial: 12-Month Extension Kreder K et al. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol . 2002;41:588-595. Powered by 缤果网 (http://www.bin.co)
  51. 51. Study Design <ul><li>12-Month open-label, uncontrolled, nonrandomized extension (N = 1,337) </li></ul><ul><ul><li>759 patients completed 12-month extension </li></ul></ul><ul><li>Eligibility </li></ul><ul><ul><li>Those who completed the 12-week double-blind phase </li></ul></ul><ul><li>Primary end point </li></ul><ul><ul><li>Safety and tolerability of tolterodine SR 4 mg qd </li></ul></ul><ul><li>Secondary end points </li></ul><ul><ul><li>Efficacy </li></ul></ul><ul><ul><li>Persistency </li></ul></ul>Kreder K et al. Eur Urol . 2002;41:588-595. Detrol ® LA (tolterodine tartrate extended release capsules) 007 Registration Trial 12-Month Extension: Kreder et al Powered by 缤果网 (http://www.bin.co)
  52. 52. Tolterodine SR: Efficacy Maintained Through 12 Months of Treatment – 100 – 80 – 60 – 40 – 20 0 20 40 12 Weeks 12 Months Median Change From Baseline (%) Urge Incontinence Episodes/Week Micturitions/Week Volume Voided/ Micturition – 18.8 Detrol ® LA (tolterodine tartrate extended release capsules) Detrol ® (tolterodine tartrate tablets) Kreder K et al. Eur Urol . 2002;41:588-595. 12-Month Extension: Kreder et al Powered by 缤果网 (http://www.bin.co) – 80 – 83.1 – 21.3 25 25.4
  53. 53. Tolterodine SR: Exhibited Positive Long-term Safety and Tolerability Profile <ul><li>*Incidence of adverse events with onset during the 12-month open-label study period. </li></ul>Detrol ® LA (tolterodine tartrate extended release capsules) Kreder K et al. Eur Urol . 2002;41:588-595. 12-Month Extension: Kreder et al Powered by 缤果网 (http://www.bin.co) Adverse Event Patients (%)* Dry mouth 12.9% Constipation 3.3% Headache 2.4% Somnolence 1.0% Dizziness 1.2%
  54. 54. Conclusions <ul><li>Efficacy of tolterodine SR was maintained for at least 1 year with continued treatment </li></ul><ul><li>Improvements from baseline in all micturition variables comparable to those observed in the 12-week double-blind phase </li></ul><ul><li>Long-term treatment with tolterodine SR was well tolerated </li></ul><ul><li>71% of patients completed 12 months of therapy </li></ul>Detrol ® LA (tolterodine tartrate extended release capsules) 12-Month Extension: Kreder et al Kreder K et al. Eur Urol . 2002;41:588-595. Powered by 缤果网 (http://www.bin.co)
  55. 55. STAT Speed of Onset Therapeutic Assessment Trial Powered by 缤果网 (http://www.bin.co)
  56. 56. Questions <ul><li>How rapidly does medication work? </li></ul><ul><li>Does effectiveness increase over time? </li></ul><ul><li>Is there a difference between patients naïve and non-naïve to prior anticholinergic therapy? </li></ul>Powered by 缤果网 (http://www.bin.co)
  57. 57. Patients <ul><li>1138 patients </li></ul><ul><ul><li>302 men, 836 women </li></ul></ul><ul><ul><li>735 naïve, 403 non-naïve </li></ul></ul><ul><li>Minimum age of 18 years (range 19-91) </li></ul><ul><li>Diagnosis of OAB </li></ul><ul><ul><li>Frequency ( > 8 voids/24 hours) </li></ul></ul><ul><ul><li>Urgency </li></ul></ul><ul><ul><li>With or without urge incontinence </li></ul></ul><ul><li>911 patients (79.4%) completed the study </li></ul>Powered by 缤果网 (http://www.bin.co)
  58. 58. Methods <ul><li>Prospective </li></ul><ul><li>Multicenter </li></ul><ul><li>12-weeks duration </li></ul><ul><li>Efficacy assessed at 1, 4 & 12 weeks using </li></ul><ul><ul><li>Micturition diary </li></ul></ul><ul><ul><li>Patient perception of improvement </li></ul></ul><ul><ul><li>Physician perception of improvement </li></ul></ul>Powered by 缤果网 (http://www.bin.co)
  59. 59. Medication <ul><li>Treated with tolterodine extended-release (ER) </li></ul><ul><li>4 mg daily for 12 weeks </li></ul><ul><li>If previously on anticholinergics then had 7-day washout </li></ul>Powered by 缤果网 (http://www.bin.co)
  60. 60. Reduction in Urge Incontinence Episodes Over Time – 0 – 10 – 20 – 30 – 40 – 50 – 60 – 70 – 80 – 90 0 1 4 12 Naïve patients Experienced patients Median % Change from Baseline Intent-to-treat analysis Siami P, et al. Clin Ther. 2002;24:616-628. Week Powered by 缤果网 (http://www.bin.co)
  61. 61. Reduction in Micturition Frequency Over Time – 0 – 5 – 10 – 15 – 20 – 25 – 30 0 1 4 12 Naïve patients Experienced patients Intent-to-treat analysis Siami P, et al. Clin Ther. 2002;24:616-628. Median % Change from Baseline Week Powered by 缤果网 (http://www.bin.co)
  62. 62. Patients Reporting Positive Treatment Benefit at 1 & 12 Weeks Intent-to-treat analysis Powered by 缤果网 (http://www.bin.co)
  63. 63. STAT Summary <ul><li>Improvements in efficacy based on patients’ bladder diaries were seen at 1 week, with further improvements noted at 12 weeks </li></ul><ul><li>Perception of treatment benefit by both patients and physicians was maintained at 12 weeks </li></ul><ul><li>After only 1 week of treatment, ~85% of patients and physicians reported benefit from treatment </li></ul><ul><ul><li>half of those patients who reported no treatment benefit at 1 week reported benefit at 12 weeks </li></ul></ul>Powered by 缤果网 (http://www.bin.co)
  64. 64. Efficacy and Tolerability of Tolterodine SR Versus Oxybutynin IR in Japanese and Korean Patients Powered by 缤果网 (http://www.bin.co)
  65. 65. Efficacy <ul><li>Significant reduction between treatment and placebo group </li></ul><ul><li>No significant difference between Detrol ® LA and oxybutynin IR </li></ul>Homma Y et al. BJU Int. 2003;92:741-747. Powered by 缤果网 (http://www.bin.co) Change in Mean Voiding Diary End Points Tolterodine SR (n = 239) Tolterodine IR (n = 244) Placebo (n = 122) Incontinence episode/wk – 78.6% – 76.5% – 46.4% No. voids/24 h – 2.0 – 2.1 – 1.1
  66. 66. Treatment Withdrawal <ul><li>Total 102 withdrawals (n = 605) </li></ul><ul><li>Dry mouth accounted for 9.4% of withdrawals in oxybutynin IR and 0.4% in tolterodine SR </li></ul>0 5 10 15 20 25 Tolterodine SR Oxybutynin IR Placebo Patients Discontinued, % Withdrawals due to dry mouth Homma Y et al. BJU Int. 2003;92:741-747. Powered by 缤果网 (http://www.bin.co)
  67. 67. Japanese and Korean Study: Conclusions <ul><li>Tolterodine SR has similar efficacy but is better tolerated than oxybutynin IR in Japanese and Korean patients with OAB </li></ul><ul><li>Improved tolerability of tolterodine SR resulted in fewer discontinuations of therapy compared with oxybutynin IR </li></ul>Homma Y et al. BJU Int. 2003;92:741-747. Powered by 缤果网 (http://www.bin.co)
  68. 68. MERIT M ixed Incontinence E ffectiveness R esearch I nvestigating T olterodine Powered by 缤果网 (http://www.bin.co)
  69. 69. Effect of Tolterodine on Urge-Predominant Mixed Incontinence Episodes – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 0 1 8 Median Change From Baseline (%) Week * * * P < .01 – 50.5% – 77.2% Khullar V, et al. Urology . 2004;64:269-275. 0 Tolterodine ER 4 mg qd Placebo Intent-to-treat analysis. Powered by 缤果网 (http://www.bin.co)
  70. 70. MERIT: Additional Efficacy Endpoints at Week 8 Khullar V, et al. Urology . 2004;64:269-275. Intent-to-treat analysis. Powered by 缤果网 (http://www.bin.co) Endpoint Change from baseline, (%) Tolterodine ER 4 mg Placebo P-value Urinary frequency/24h – 20.0 – 13.8 < .0001 Urgency episodes/24h – 37.2 – 19.2 < .0001 Volume voided/micturition +20.5 +9.0 < .0001
  71. 71. Patient Assessment of Treatment Benefit After 1 and 8 Weeks Week 1 Week 8 0 10 20 30 40 50 60 70 80 % Improved Tolterodine SR 4 mg qd Placebo * 70% 64% 76% 55% * P < .001 Khullar V, et al. Urology . 2004;64:269-275. Intent-to-treat analysis. Powered by 缤果网 (http://www.bin.co)
  72. 72. MERIT: Tolerability Khullar V, et al. Urology . 2004;64:269-274. Powered by 缤果网 (http://www.bin.co) Tolterodine SR 4 mg Placebo Adverse events 39% 34% Withdrawal due to adverse events 4.6% 5.6% Dry mouth 19.7% 8.1%
  73. 73. Tolterodine: Comparable Efficacy in Urge Predominant Mixed and Urge Incontinence – 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 0 MUI (n = 239) UUI (n = 755) Median Decrease in Incontinence Episodes 67 75 P = NS Kreder K, et al. BJU Int . 2003;92:418-421. Powered by 缤果网 (http://www.bin.co)
  74. 74. Tolterodine in the Treatment of MUI and UUI: Summary of Results *Significant difference versus baseline, but not between MUI and UUI groups Kreder K, et al. BJU Int . 2003;92:418-421. Powered by 缤果网 (http://www.bin.co) MUI (%) UUI (%) Pad usage* (%) – 40 – 50 No pad usage (%) 21 27 Voiding frequency/24 h* (%) – 15 – 17 < 8 voids/24 h 24 24 Volume voided* (mL) 27 27 Nocturia* (%) – 50 – 33 < 2 episodes nocturia (%) 83 76 Total dryness (%) 39 44
  75. 75. Tolerability: Clinical Trial Continuation Rates With Tolterodine SR Van Kerrebroeck P et al. Urology . 2001;57:414-421. Siami P et al. Clin Ther . 2002;24:616-628. Khullar V et al. Urology . 2004;64:269-274. Kreder K et al. Eur Urol . 2002;41:588-595. Powered by 缤果网 (http://www.bin.co) Clinical Study Study Duration, wk No. Patients Patient Continuation Rate, % Registration Trial 12 507 95 Kreder K et al 52 1077 71 STAT 12 1138 80 MERIT 8 569 92
  76. 76. Tolerability: Incidence of Adverse Events* With Tolterodine SR Van Kerrebroeck P et al. Urology. 2001;57:414-421. *Reported by ≥5% of patients in any treatment group or relevant to antimuscarinic therapy during 12 weeks of treatment. Powered by 缤果网 (http://www.bin.co) Body System Adverse Event Placebo, % (n = 507) Tolterodine SR, % (n = 505) Autonomic nervous Dry mouth 8 23 General Headache 5 6 Fatigue 1 2 Central/Peripheral nervous Dizziness 1 2 Gastrointestinal Constipation 4 6 Abdominal pain 2 4 Dyspepsia 1 3 Vision Xerophthalmia 2 3 Vision abnormal 0 1 Psychiatric Somnolence 2 3 Respiratory Sinusitis 1 2 Urinary Dysuria 0 1
  77. 77. Summary <ul><li>OAB is a highly prevalent condition </li></ul><ul><li>As our population ages, rates will increase </li></ul><ul><li>OAB has a large impact on our patient’s quality of life </li></ul><ul><li>Tolterodine SR is an effective therapy shown to significantly reduce incontinence episodes, reduce urgency and frequency, increase void volume, and reduce pad usage </li></ul><ul><li>The efficacy of tolterodine SR can be seen as early as 1 week and the effect is maintained with long-term therapy </li></ul><ul><li>Patients perceive benefit with therapy and improvements in quality of life have been demonstrated </li></ul>Powered by 缤果网 (http://www.bin.co)

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