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)
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膀胱过度活动症的药物治疗
- 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 缤果网 (http://www.bingomed.com)
- 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 ?
- 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
- 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). Men: 2.4% (Incontinent) Men: 13.6% (Continent) Women: 9.3% (Incontinent) Women: 7.6% (Continent)
- 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.
- 17. Medications Influencing LUT Function Medication Class Effect 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
- 23. Stress Incontinence, Overactive Bladder, and Mixed Symptoms
- 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. Urge 6.9 million Stress 5.1 million Mixed 5.5 million
- 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.
- 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. 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. 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. BOTHER (Quality- of- Life Survey)
- 29. Behavioral Modification Behavioral Modification Education/Log Delayed voiding Timed voiding Diet Pelvic floor exercises
- 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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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.
- 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 – 80 – 83.1 – 21.3 25 25.4
- 55. STAT Speed of Onset Therapeutic Assessment Trial
- 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
- 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
- 62. Patients Reporting Positive Treatment Benefit at 1 & 12 Weeks Intent-to-treat analysis
- 64. Efficacy and Tolerability of Tolterodine SR Versus Oxybutynin IR in Japanese and Korean Patients
- 68. MERIT M ixed Incontinence E ffectiveness R esearch I nvestigating T olterodine
- 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.
- 70. MERIT: Additional Efficacy Endpoints at Week 8 Khullar V, et al. Urology . 2004;64:269-275. Intent-to-treat analysis. 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. 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.
- 72. MERIT: Tolerability Khullar V, et al. Urology . 2004;64:269-274. 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. 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.
- 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. 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. 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. 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. 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. 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
Editor's Notes
- At the ICS meeting in Seoul Korea in September 2001, a consensus definition of OAB was derived This definition focuses on the symptoms of OAB rather than on urodynamic parameters and is much more clinically useful for physicians, because most do not do urodynamic studies on patients with OAB In addition, it improves communication between physicians and their patients, since the definition includes terms that are much more intuitive and less likely to confuse or even alarm the patient (many patients have been quite bothered with the old term “unstable” bladder) Thus, the new definition encompasses all of the important clinical aspects of OAB, without using terminology that is only interpretable by a specialist in urology
- At the ICS meeting in Seoul Korea in September 2001, a consensus definition of OAB was derived This definition focuses on the symptoms of OAB rather than on urodynamic parameters and is much more clinically useful for physicians, because most do not do urodynamic studies on patients with OAB In addition, it improves communication between physicians and their patients, since the definition includes terms that are much more intuitive and less likely to confuse or even alarm the patient (many patients have been quite bothered with the old term “unstable” bladder) Thus, the new definition encompasses all of the important clinical aspects of OAB, without using terminology that is only interpretable by a specialist in urology
- At the ICS meeting in Seoul Korea in September 2001, a consensus definition of OAB was derived This definition focuses on the symptoms of OAB rather than on urodynamic parameters and is much more clinically useful for physicians, because most do not do urodynamic studies on patients with OAB In addition, it improves communication between physicians and their patients, since the definition includes terms that are much more intuitive and less likely to confuse or even alarm the patient (many patients have been quite bothered with the old term “unstable” bladder) Thus, the new definition encompasses all of the important clinical aspects of OAB, without using terminology that is only interpretable by a specialist in urology
- This slide shows the overlap of symptoms for OAB Patients with OAB experience urgency with or without urge incontinence (in fact, only 30% of people with OAB have urge incontinence) Frequency and nocturia are usually associated with urgency; however; these symptoms occurring individually do not constitute a diagnosis of OAB Some women may experience mixed symptoms of stress incontinence and OAB; stress symptoms often resolve with OAB therapy
- Why should physicians care about OAB? There are several compelling reasons. More patients have OAB than you realize. Overall, 1 out of 6 adults over 40 years of age in Europe has OAB. In France, Germany, Italy, Spain, Sweden, the United Kingdom, Japan, and the United States, the prevalence of OAB ranges from 11% to 22%. Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int. 2001;87:760-766. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20:327-336. Homma Y, Yamaguchi O, Hayashi K, et al. Nation-wide epidemiologic survey on lower urinary tract symptoms in Japan. Presented at: Annual Meeting of the International Continence Society; October 5-9, 2003; Florence, Italy.
- Psychological —People with OAB often feel guilty about their symptoms, and some become depressed. The embarrassment of leaking or smelling of urine leads to a loss of self-respect and dignity. Social —Overactive bladder sufferers might restrict social activity outside the home for fear of leaking urine or because of the frequent need to use a toilet. Domestic —Some individuals with OAB use disposable pads on the bed during the night or undergarments for incontinence. These items can be costly and are not covered by medical insurance. Occupational —Overactive bladder may lead to decreased productivity in the workplace. Some patients may avoid going to work for fear of leaking urine. Sexual —Women with overactive bladder have reported avoiding dating and sexual intimacy because of overactive bladder symptoms and fear of leaking urine. Physical —Some physical activities like exercising might be limited because of the frequent need to urinate or fear of leaking urine.
- Women with urge incontinence have an increased diurnal and nocturnal voiding Urge incontinence urgency to rush to bathroom Inability of older women to divide attention.
- The reasons women seek care for symptoms of pelvic floor disorders vary by age. According to a study within the Kaiser Permanente Health Care program in Southern California, which evaluated the reasons for pelvic floor disorders among 2070 women seeking care, stress urinary incontinence (SUI) was significantly more common among younger women than older women (78% vs 57%, respectively; P .05). Detrusor instability urge urinary incontinence (UUI) was more common among older vs younger women (67% vs 56%, respectively; P < .05), as was intrinsic sphincter deficiency (5.7% vs 0%, respectively; P < .05). Symptomatic pelvic organ prolapse occurred with equal frequency in older and younger women. Luber KM, Boero S, Choe JY. The demographics of pelvic floor disorders: current observations and future projections. Am J Obstet Gynecol. 2001 ;184:1496-1503.
- In most cases, a diagnosis of OAB can be made based on patient history, symptoms assessment, physical examination , and urinalysis These assessments are usually sufficient to initiate noninvasive therapy provided you have ruled out the following: Local pathological factors such as infection, bladder stones, bladder tumor/CIS, interstitial cystitis Metabolic factors such as diabetes or polydipsia Medications that may cause OAB symptoms such as diuretics, narcotics, antidepressants, hypnotics, analgesics, sedatives, OTC sleep aids and cold remedies Other factors such as pregnancy or psychologic issues Reasons to refer to a specialist include: Evidence of difficulty in emptying Recurrent urinary tract infection Hematuria Prostate problems Symptomatic prolapse Unsuccessful prior treatment Unsuccessful prior surgery Planned surgery Radical pelvic surgery
- The challenge rests with primary care physicians to dispel the fears and misconceptions that keep many patients, especially female patients, from seeking treatment for bladder symptoms. Physicians can detect urinary symptoms in reluctant patients during routine medical examination. Additionally, simple questions (such as those listed on the slide) can be used to elicit information needed for diagnosis.
- This slide and the next list classes of medications that have been shown to influence LUT function.
- In women, a physical examination can rule out several possible causes of LUTS, including Atrophic vaginitis Estrogen deficiency Pelvic floor dysfunction Prolapse Potentially serious pathologic conditions, such as malignancy Patients with prolapse or other potentially serious conditions should be referred to the appropriate specialist for further evaluation.
- Urinalysis is an essential component of the patient workup and is used to rule out conditions that may be responsible for LUTS. Laboratory testing on blood is also essential. A prostate-specific antigen test should be administered to adequately informed men older than 50 years of age in accordance with the American Urological Association guidelines. Fantl JA, et al. Urinary incontinence in adults: acute and chronic management. Rockville, MD: US Department of Health and Human Services, Agency for Healthcare Policy and Research; 1996. AHCPR publication 96-0686.
- Specifically, the appropriate laboratory tests should rule out urinary tract infection, sexually transmitted diseases, diabetes, renal disease (including kidney stones), and more serious conditions, such as malignancies. Patients with tumors, kidney stones, or other potentially serious conditions should be referred to the appropriate specialist for further evaluation.
- Recent data from the NOBLE Program revealed the prevalence of OAB in the United States. A total of 5.1 million people with incontinence have SUI, 6.9 million have UUI, and 5.5 million have MUI (both SUI and UUI). Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol . 2003;20:327-336.
- OAB is associated with involuntary detrusor contractions. Detrusor instability can cause symptoms of urgency of the sudden loss of urine (UUI). Conversely, SUI can be caused by urethral hypermotility; significant displacement of the urethra and bladder neck during exertion and increased abdominal pressure; or urethral sphincter weakness, in which the bladder sphincter cannot generate enough resistance to retain urine during stress maneuvers. In women, urethral sphincter weakness can occur after trauma, hypoestrogenism, aging, or surgical procedures. Fantl JA, et al. Urinary incontinence in adults: acute and chronic management. Rockville, MD: US Department of Health and Human Services, Agency for Healthcare Policy and Research; 1996. AHCPR publication 96-0686.
- This slide demonstrates the findings that differentiate OAB from SUI and patients with mixed symptoms or MUI. Pertinent points include the following: Urgency and frequency are associated with OAB and MUI, but not with SUI SUI and MUI share symptomatology of leakage during physical activity The amount of urinary leakage typically is much greater in OAB than in SUI Patients with OAB rarely have enough time to reach a toilet compared with patients with SUI, but this varies in patients with MUI Nocturia is more closely associated with OAB than with SUI, and may be present in patients with MUI Abrams P, Wein AJ. The Overactive Bladder. A Widespread and Treatable Condition . Stockholm, Sweden: Erik Sparre Medical AB; 1998.
- The NOBLE study identified respondents with incontinence based on telephone survey responses. Further investigation (a nested case-controlled study) was conducted on respondents who reported symptoms of OAB. Respondents completed multiple questionnaires (OAB-q, the Medical Outcomes Study [MOS] Short-Form-36 [SF-36], the MOS Sleep Scale, and the Center for Epidemiological Studies—Depression [CES-D] scale) and were categorized according to the primary cause of incontinence: UUI, SUI, or MUI. One hundred seventy-one respondents reported incontinence (UUI: 69; SUI: 62, MUI: 40). Of the respondents, 82.5% were women and the average age was 55.9 years. The findings showed OAB-q subscale scores were significantly worse P < .01) among those with MUI than among those with SUI. In terms of symptom bother, MUI was reported as most bothersome, followed by UUI; respondents with SUI were bothered the least. Coyne KS, Zhou Z, Thompson C, Versi E. The impact on health-related quality of life of stress, urge and mixed urinary incontinence. BJU Int. 2003;92:731-735 .
- Optional Slide Behavioral modification includes patient education, timed or delayed voiding, pelvic floor exercises, and reinforcement Pelvic floor exercises have been shown to be very useful for women with primarily stress incontinence
- Bladder Training Bladder training focuses on modifying bladder function by reviewing the bladder diary; the voiding interval should be increased gradually by 15- to 30-minute intervals based on the voiding pattern, and the patient should be taught bladder coping strategies Bladder training is used primarily for urge incontinence, urgency, and frequency Bladder training can be very effective, but it requires ongoing commitment by the patient
- It has been shown that behavioral therapy alone can improve the symptoms of OAB However, it is often difficult to achieve high compliance with behavioral therapies, and optimal success is dependent on how intense the program is and, in many cases, also requires a high input of caregiver time Studies have shown that the best outcomes are achieved with a combination of pharmacologic and behavioral therapy
- Currently, antimuscarinic agents are the gold standard for the pharmacologic treatment of OAB Antimuscarinic agents inhibit involuntary bladder contractions and increase bladder capacity, thereby relieving the symptoms of OAB, including urgency, frequency, and urge urinary incontinence However, some antimuscarinic agents, particularly the older ones, are associated with typical anticholinergic side effects that may limit treatment
- This is a “build” slide showing the distribution of peripheral cholinergic (ie, muscarinic) receptors throughout the body Muscarinic receptors are located in the CNS, iris and ciliary body, lachrymal gland, salivary glands, heart, gallbladder, stomach, colon, and bladder Agents that are selective for the bladder are preferable over agents that may potentially target other regions of the body Blockade of muscarinic receptors outside the bladder may result in undesired side effects such as dry mouth (the most common side effect), constipation, and CNS side effects (such as dizziness, somnolence, and cognitive impairment), and effects on the stomach and eyes
- In broad terms, the ideal muscarinic agent would provide efficacy by inhibiting involuntary bladder contractions, while having no adverse effect on normal bladder contractions be selective for the bladder over other organs innervated by the parasympathetic system have durable effects, ie, have effects that do not diminish over time Clinically, the ideal agent would provide a balance between efficacy, tolerability, and compliance (persistency); together, these factors comprise “clinical effectiveness”
- The inclusion criteria consisted of age and OAB symptomatology requirements. Prior therapy was not considered. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57:414-421.
- Patients were randomized 1:1:1 to receive double-blind Detrol ®, 2 mg twice daily; Detrol ® LA, 4 mg once daily; or placebo for 12 weeks. This slide shows the reduction in incontinence episodes after 12 weeks of therapy. Reductions with both Detrol ® treatments were significantly greater than with placebo, with Detrol ® LA being of significantly greater magnitude than Detrol ® . Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57:414-421. This slide to be used in conjunction with the following slide
- Urinary frequency also was reduced 22% to 25% with both Detrol ® formulations, which was significantly greater than with placebo, but there was no significant difference between active treatments. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57:414-421.
- The mean volume voided also increased significantly with both Detrol ® treatments compared with placebo. The difference between active treatments was not significant. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57:414-421.
- Incontinence pad usage was reduced 36% with Detrol ® LA and Detrol ® compared with a 13% reduction with placebo. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57:414-421. This slide to be used in conjunction with the following slide
- Detrol ® LA was better tolerated than Detrol ® . Dry mouth was the most commonly reported side effect for each treatment. Detrol ® LA produced a significant 23% reduction in dry mouth in patients compared with Detrol ® . Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57:414-421.
- This slide shows the incidences of other common anticholinergic adverse events. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57:414-421.
- The percentage of patients who withdrew from the study early because of adverse events was similar among treatment groups and comparable with placebo. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57:414-421. This slide to be used in conjunction with the following slide
- The registration trial was a 12-week multinational study comparing Detrol ® LA 4 mg once daily, and Detrol ® 2 mg twice daily, with placebo in 1,529 patients. Compared with placebo, Detrol ® LA and Detrol ® were significantly more effective in improving: Incontinence episodes/week Total micturitions/24 hours Mean volume voided/micturition Incontinence pad usage/24 hours For the primary efficacy parameter, Detrol ® LA was also shown to provide significantly greater improvement compared with Detrol ® . In addition, both active treatment groups were associated with positive tolerability and safety profiles. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology . 2001;57:414-421. Key Messages: Detrol ® LA was efficacious in improving all symptoms of OAB Detrol ® LA exhibited a positive tolerability and safety profile Detrol ® LA was shown to produce significantly better improvements in efficacy and tolerability compared with Detrol ®
- After completion of the phase 3, double-blind, randomized trial of Detrol ® LA, a 12-month open-label extension was performed. This extension was not controlled or randomized. The 1,337 patients who completed the 12-week double-blind phase of the trial were eligible to participate in the open-label extension. Of these patients, 1,077 chose to continue tolterodine treatment; 759 completed the 12-month extension. The primary end point was safety and tolerability of Detrol ® LA, 4 mg qd, and secondary end points were efficacy and persistency. The majority of the participants were women (82.3%), and the mean age was 60.3 years. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol . 2002;41:588-595.
- Of the 1,077 patients who chose to remain on Detrol ® LA, 1,075 received treatment and were included in the safety population. Of these patients, 759 completed the 12-month extension. Diary data reported indicate that patients who remained on Detrol ® LA maintained the level of efficacy achieved at 12 weeks through 1 year of treatment. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol . 2002;41:588-595.
- The low percentage of adverse events associated with Detrol ® LA treatment at 12 weeks was maintained throughout the12-month open- label study. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol . 2002;41:588-595.
- The 12-month open-label extension of the phase 3 trial of Detrol ® LA showed that treatment was well tolerated. Efficacy was maintained for at least 1 year with continued Detrol ® LA treatment. Improvements from baseline in all micturition variables were comparable to those observed at the completion of the 12-week double-blind phase. Seventy-one percent of patients entering the long-term, open-label phase of the pivotal trial were still on Detrol ® LA at 12 months. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol . 2002;41:588-595.
- This slide shows the reduction in urge incontinence episodes for naïve and experienced patients at each time point (week 1, week 4, and week 12) There is a substantial reduction from baseline in urge incontinence episodes after only 1 week of treatment in both groups, with further reductions observed at weeks 4 and 12 The reduction in urge incontinence was rapid and significant, and showed a continued benefit over time. These swift results encourage patients to remain on therapy. Median percent reduction from baseline 1 week 4 weeks 12 weeks Naïve patients -61.5 -80.0 -85.7 Experienced patients -53.9 -75.0 -75.0
- This slide shows the reduction in micturition frequency (micturitions/24h) for naïve and experienced patients at each time point (week 1, week 4, and week 12) There is a substantial reduction from baseline in micturition frequency after only 1 week of treatment in both groups, with further reductions observed at weeks 4 and 12 Median percent reduction from baseline 1 week 4 weeks 12 weeks Naïve patients -17.1 -25.6 -28.6 Experienced patients -13.9 -20.0 -21.3
- Percentage of Patients and Physicians Reporting Positive Treatment Benefit at 1 Week Approximately 85% of both naïve and previously treated patients reported benefit from treatment after only 1 week Similarly, physicians independently rated the perception of treatment as beneficial in approximately 85% of patients at 1 week in naïve and experienced patients Yes/little vs. yes/lot vs. none
- This slide summarizes the results and conclusions from STAT OAB symptoms, as measured by micturition diary parameters, were improved after 1 week of treatment and showed further improvements throughout the 12-week study; these results are consistent with patient perception of treatment benefit Both patients and physicians had a high perception of treatment benefit with tolterodine ER 4 mg once daily as early as 1 week, which was maintained at 12 weeks Most patients will report treatment benefit within 1 week; those who do not will likely report benefit at 4 or 12 weeks
- Higher incidence of withdrawals reported for oxybutynin IR. This was explained by the higher frequency of withdrawals for adverse events with oxybutynin than with placebo or tolterodine. Other reasons for withdrawal were similar between treatment groups: - lack of efficacy (tolterodine 1.3%, oxybutynin 1.6%, placebo 3.3%) - consent withdrawn - loss to follow-up - protocol violation
- Compared with placebo, tolterodine ER significantly reduced the median number of mixed incontinence episodes at weeks 1 and 8 (primary endpoint). This reduction was significantly greater than the reduction with placebo as early as 1 week. Further reductions were apparent at 8 weeks. Khullar V, Hill S, Laval K-U, et al. Treatment of urge predominant mixed urinary incontinence with tolterodine: a randomized, placebo-controlled trial. Urology . 2004;64:269-275.
- Tolterodine therapy also improved other micturition variables compared with placebo; this included significant reductions in the median change from baseline in urinary frequency episodes per day and urgency episodes per day. Volume voided per micturition significantly increased in tolterodine-treated patients compared with those receiving placebo. Khullar V, Hill S, Laval K-U, et al. Treatment of urge predominant mixed urinary incontinence with tolterodine: a randomized, placebo-controlled trial. Urology . 2004;64:269-275.
- This slide shows the percentage of subjects in both groups reporting treatment benefit at 1 and 8 weeks. At week 8, the percentage of subjects reporting treatment benefit was statistically significantly higher in the tolterodine group compared with the placebo group. Note that the percentage of subjects reporting treatment benefit increased from week 1 to week 8 in the tolterodine group (from 70% to 76%), whereas in the placebo group, the percentage of subjects reporting treatment benefit decreased from week 1 to week 8 (from 64% to 55%). Perception of bladder condition and response to treatment were assessed at baseline after 1 and 8 weeks. Patients rated their bladder condition severity using a validated 6-point rating scale (1 = no problems, 2 = very minor problems, 3 = minor problems, 4 = moderate problems, 5 = severe problems, and 6 = many severe problems). Improvement was defined as a decrease of 1 point or more from baseline. Khullar V, Hill S, Laval K-U, et al. Treatment of urge predominant mixed urinary incontinence with tolterodine: a randomized, placebo-controlled trial. Urology . 2004;64:269-275.
- Tolterodine was tolerated well and involved fewer withdrawals because of adverse events than placebo. Adverse events were similar between the tolterodine group and the placebo group. The most common adverse event in each treatment group was dry mouth. Khullar V, Hill S, Laval K-U, et al. Treatment of urge predominant mixed urinary incontinence with tolterodine: a randomized, placebo-controlled trial. Urology . 2004;64:269-274.
- Compared with baseline, statistically significant reductions in incontinence episodes were observed in patients with MUI or UUI treated with tolterodine. There was no significant difference in tolterodine efficacy in patients with MUI compared with UUI. Kreder KJ, Brubaker L, Mainprize T. Tolterodine is equally effective in patients with mixed incontinence and those with urge incontinence alone. BJU Int . 2003;92:418-421
- Similarly, with all other voiding diary variables, the differences from baseline were significantly improved with tolterodine, but there was no difference in tolterodine efficacy between patients with MUI or UUI. Therefore, tolterodine was equally efficacious in patients with UUI or MUI. Kreder KJ, Brubaker L, Mainprize T. Tolterodine is equally effective in patients with mixed incontinence and those with urge incontinence alone. BMJ Int. 2003;92:418-421.
- Studies indicate that patients taking Detrusitol ® SR are likely to continue taking it. The longest Detrusitol SR has been studied was in a 1-year open-label continuation study. In this study, 71% of patients were still taking Detrusitol SR at 1 year. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A, on behalf of the Tolterodine Study Group. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology . 2001;57:414-421. Siami P, Seidman LS, Lama D. A multicenter, prospective, open-label study of tolterodine extended-release 4 mg for overactive bladder: the Speed of Onset of Therapeutic Assessment Trial (STAT). Clin Ther . 2002;24:616-628. Khullar V, Hill S, Laval K-U, Schiøtz HA, Jonas U, Versi E. Treatment of urge-predominant mixed urinary incontinence with tolterodine extended release: a randomized, placebo-controlled trial. Urology . 2004; 64:269-274. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol . 2002;41:588-595.
- As noted in the registration trial, except for dry mouth, adverse events—including those representing other anticholinergic effects—were similar between Detrusitol ® SR and placebo. There was no difference from placebo in reported events such as dizziness, constipation, or abnormal vision. In a 6-year safety review, Detrusitol SR had no known association with cardiac events. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A, on behalf of the Tolterodine Study Group. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology . 2001;57:414-421. Garely AD, Burrows L. Benefit-risk assessment of tolterodine in the treatment of overactive bladder in adults. Drug Saf . 2004;27:1043-1057.