Overactive Bladder: Identifying Patients at Risk, Implementing New Strategies

Transcription

1 Overactive Bladder: Identifying Patients at Risk, Implementing New Learning Objectives Identify patients with OAB risk factors in order to proactively initiate a discussion about bladder symptoms and establish a diagnosis Educate patients on the management of OAB, including pharmacologic and nonpharmacologic strategies and the importance of adherence and follow-up Individualize the pharmacologic treatment of OAB based on the efficacy, dosing, metabolism, and side-effect profiles of available agents 2 OAB = overactive bladder. Virginia, 74, is unhappy with her antimuscarinic therapy for OAB She has taken immediate- and extended-release antimuscarinics but is not satisfied with the results Although she has had some improvement in symptoms, she continues to experience urgency 7-8 times per day She also complains of dry mouth and constipation She takes medications for diabetes, hypertension, and depression 3 1

2 Definitions of Incontinence From the International Continence Society UI Complaint of involuntary leakage of urine UUI Complaint of involuntary leakage associated with urgency SUI Complaint of involuntary leakage upon exertion, effort, sneezing, or coughing Mixed UI Complaint of involuntary leakage associated with urgency and upon exertion, effort, sneezing, or coughing SUI = stress urinary incontinence; UI = urinary incontinence; UUI = urgency urinary incontinence. 4 Abrams P, et al. Neurourol Urodyn. 2002;21: ; Haylen BT, et al. Neurourol Urodyn. 2010;29:4-20. Definitions of Incontinence From the International Continence Society (cont d) Nocturia Complaint that the individual has to wake at night 1 times to void Urgency Complaint of sudden, compelling urge to pass urine that is difficult to defer Increased daytime frequency Complaint that voiding occurs more frequently during waking hours than deemed normal by patient OAB Urinary urgency, usually accompanied by frequency and nocturia, with or without UUI a a In the absence of urinary tract infection (UTI) or other obvious pathology. 5 Abrams P, et al. Neurourol Urodyn. 2002;21: ; Haylen BT, et al. Neurourol Urodyn. 2010;29:4-20. Storage Problem: Incontinence Normal (No Incontinence) Large capacity, relaxed bladder High-resistance urethra Urethra Bladder Urgency/UUI Small capacity, OAB Urine loss, accompanied by urgency Bladder Urethra SUI Low-resistance urethra Urine loss resulting from sudden increased Urethra intra-abdominal pressure (eg, laugh, cough, sneeze) Bladder Mixed Small capacity, hyperactive bladder Urethra Low-resistance urethra Combination of SUI and UUI Bladder OAB 6 Abrams P, et al. The Overactive Bladder: A Widespread and Treatable Condition. 1998; Clare J, et al. Nat Rev Neurosci. 2008;9: ; Gormley EA, et al. J Urol. 2015;193: ; Wein AJ, et al. Urology. 2002;60(5 Suppl 1):

3 OAB Is Very Common in Both Men and Women 1 in 3 US adults aged 40 years reported symptoms of OAB at least sometimes Respondents (%) Men Women Age (Years) 7 Coyne S, et al. Urology. 2011;77: Key Populations: Patients With Diabetes and Obesity Survey of 1359 patients with T2DM: 22.5% had OAB, of whom 48% had UI 1 - Higher A1C levels predict increased risk for OAB/urgency, UUI, and nocturia in patients with T2DM 2 - Women who are overweight or obese and have T2DM: higher prevalence of UI than with other T2DM complications 1,3 - Women with obesity twice as likely to have OAB than women of normal weight 4 A1C = glycated hemoglobin Liu RT, et al. Urology. 2011;78: ; 2. Chiu A-F, et al. Int J Urol. 2012;19: ; 3. Phelan S, et al. Diabetes Care. 2009;32: ; 4. Cheung WW, et al. Open Access J Urol. 2011;3: The Iceberg of Care for Women Aged 40 Years With UI: Underreported and Undertreated Women with UI who seek care tend to be older, have more severe symptoms of longer duration, and have bothersome symptoms that impact QoL Primary care interventions are key to preventing worsening of UI, especially because so few patients ever see pelvic floor specialists Proportion of women with UI receiving subspecialty care: 12% (164/1366) Proportion of women with UI receiving care: 23% (313/1366) Proportion of women with UI seeking care: 25% (339/1366) Prevalence of UI in women aged 40 years based on responses to a bladder health survey: 41% (1366/3316) QoL = quality of life. 9 Minassian VA, et al. Int Urogynecol J. 2012;23:

4 Provider and Patient Perceptions Differ In 85% of cases, female patients have to initiate the discussion about their incontinence symptoms with their clinician Only one-third of patients with a diagnosis of OAB receive treatment 56% of women with OAB wait >1 year to seek treatment (mean 3.1 years) Providers may not recognize the association of OAB and depression, particularly with more severe OAB 10 Dmochowski RR, et al. Curr Med Res Opin. 2007;23:65-76; Dmochowski RR. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17: ; Lai HH, et al. BMC Neurol. 2016;16:60 Why Patients Do or Do Not Seek Help Why not seek help? Embarrassed Not asked by clinician Do not think it is serious Coping mechanisms Misconception about disease/ normal aging process Why seek help? Getting worse Fear of more serious condition Concern of embarrassing accident 11 Dmochowski RR. Int Urogynecol J Pelvic Floor Dysfunct. 2006;15: ; Dmochowski RR, et al. Curr Med Res Opin. 2007;23:65-76; Irwin SDE, et al. BJU Int. 2006;97:96-100; Muller N. Urol Nurs. 2005;25: ; Ricci JA, et al. Clin Ther. 2001;23: ; Sandman D, Trauring A. Survey of Adult Women With Overactive Bladder. 2003; Tyagi S, et al. Urol Clin North Am. 2006;33: Case Study: Mrs Jones Presents for a Follow-up Appointment Mrs Jones, age 73 years, presents for follow-up of T2DM Works part-time as a bookkeeper Medical history: Severe OA, for which she regularly takes ibuprofen T2DM, poorly controlled with metformin Depression, for which she has taken venlafaxine Broke her hip 6 months ago Has recovered well, but worries about falling again Has a part-time job as a bookkeeper What avenues should you be exploring with Mrs Jones? 12 OA = osteoarthritis. 4

5 Let s Meet Mrs Jones 13 Useful Questions to Direct the Diagnosis of OAB In a survey, most patients said they would prefer their clinician to initiate the conversation on OAB, yet only 14% said their clinician asked them about urinary/bladder symptoms Urgency Frequency Nocturia UUI Do you frequently have strong urges to urinate? Do you urinate more often than you think you should? Do you go to the bathroom so often that it interferes with your activities? Are you bothered by waking up at night to go to the bathroom? Do you have uncontrollable urges to urinate that sometimes result in wetting accidents? Do you leak urine on the way to the bathroom? 14 Dmochowski RR, et al. Curr Med Res Opin. 2007;23:65-76; Filipetto FA, et al. BMC Fam Pract. 2014;15:96; Newman DK. Nurse Pract. 2009;34:33-45; Newman DK, et al. Am J Nurs. 2002;102:36-45; Rosenberg MT, et al. Can J Urol. 2014;21(Suppl 2):7-16; Sussman DO. J Am Osteopath Assoc. 2007;107: Typical Bladder Diary Time Voided Activity Leakage Urge Present Fluid Intake (Amount/Type) 4:00 AM In bed/rushed to bathroom Yes Yes 6:30 Morning routine Yes Yes 20 oz coffee 8:40 Waited too long Yes Strong 8 oz water 10:00 Yes 10:15 Yes 6 oz juice 12:35 PM Housework Yes Strong 12 oz cola 2:30 Yes 8 oz water 4:20 Yes 6 oz tea 6:20 Dinner Yes Strong 8 oz beer 7:35 Yes No 8 oz water 10:10 Yes 4 oz water 1:20 AM Yes 15 Frequency = 12; fluid intake = 80 oz. 5

6 Differential Diagnosis: OAB, SUI, and UTI Symptom OAB SUI UTI Urgency Yes No Yes Daytime voiding frequency every >2 hours Yes No Yes Leaking during physical activity No Yes No Amount of urinary leakage Variable Variable Small Ability to reach the toilet following an urge Often no Yes Sometimes no Nocturia Usually Not often Rarely 16 Abrams P, et al. The Overactive Bladder: A Widespread and Treatable Condition Mrs Jones Returns a Month Later Mrs Jones returns with her bladder diary, which is incomplete, but suggests nocturia ~2 times/night and frequent daytime urgency She has a negative urinalysis result Based on her bladder diary, history of T2DM, normal physical exam, and a negative urinalysis, you believe she has OAB Mrs Jones needs education and lifestyle strategies 17 Pelvic Floor Rehabilitation: Pelvic Floor (Kegel) Muscle Exercises Exercises increase muscle tone/strength Help hold urine inside bladder, preventing leakage; decrease median number of voids per day Urge suppression; rapid, active pelvic muscle contractions ( quick flicks ) inhibit unstable bladder contraction once it starts Superior efficacy versus oxybutynin and placebo, with less desire to change therapy Recommended by ACP as first-line treatment for women with SUI and in combination with bladder training in women with mixed UI Repeat in sets of up to 10 3 times/day Locate pelvic muscles Relax completely for at least 10 seconds Yes! There is an App! Squeeze muscles tightly for up to 10 seconds 18 ACP = American College of Physicians. Burgio KL, et al. JAMA. 1998;280: ; Newman DK. Accessed Aug 29, 2017; Qaseem A, et al. Ann Intern Med. 2014;161: ; Urology Care Foundation. Accessed Sep 19,

7 Behavioral Therapy: Multiple Options Less than one-third of patients with OAB or other urinary symptoms are offered behavioral management options Scheduled toileting programs Pelvic floor muscle exercises with biofeedback therapy Education Behavioral interventions Lifestyle interventions Bladder training; urge-suppression strategies 19 Filipetto FA, et al. BMC Fam Pract. 2014;15:96; Gormley EA, et al. J Urol. 2015;193: ; Jayarajan J, et al. Res Rep Urol. 2013;6:1-16. Lifestyle Changes Weight loss Smoking cessation Managing constipation Fluid intake (adequate) Caffeine consumption Physical exercise Awareness of toileting behaviors 20 Moore K, et al. In: Abrams P, et al, eds. Incontinence: Proceedings From the 5th International Consultation on Incontinence. 2013: Behavior Change: Reducing Fluid Intake Reducing fluid intake by 25% significantly improves urgency, frequency, nocturia Water Intake Calculator 21 Hashim H, et al. BJU Int. 2008;102:62-66; Water Intake Calculator. Accessed Oct 12,

8 Mrs Jones Returns 2 Months Later Mrs Jones reports that she is diligently following the lifestyle modifications that you discussed with her She restricts fluid (especially at night) and has given up caffeine and her usual glass of wine in the evening Does kegels regularly Uses suppression strategies to minimize urgency Her bladder diary shows fewer episodes of urgency, but she is still concerned about rushing to the bathroom, the potential for injury, and leaking She is very concerned that people at work are noticing her frequent trips and that it could jeopardize her job 22 Talking to Mrs Jones About Medications 23 AUA Treatment Recommendations Line of Therapy First Second Third a Fourth b Treatment [Evidence Strength Grade] Behavioral therapies [B] Behavioral and pharmacologic therapies [C] Pharmacologic therapy a (antimuscarinics, β 3 -agonists) [B] OnabotulinumtoxinA [B] Peripheral tibial nerve stimulation [C] Sacral neuromodulation [C] Augmentation cystoplasty [Expert Opinion] Urinary diversion [Expert Opinion] a Patients who do not respond to or cannot tolerate first- or second-line therapies should be referred to a specialist for additional therapy; b Severe, refractory, complicated cases. AUA = American Urological Association. 24 Gormley EA, et al. J Urol. 2015;193:

9 Antimuscarinic Treatment Options Drug Dose, mg Frequency 25 Oxybutynin ER 5-15 Once daily Oxybutynin IR times daily Oxybutynin gel 10% 1 g Once daily Oxybutynin transdermal patch a 3.9 Twice weekly Tolterodine 1-2 Twice daily Tolterodine long-acting 2-4 Once daily Darifenacin Once daily Fesoterodine 4-8 Once daily Solifenacin 5-10 Once daily Trospium 20 Twice daily Trospium ER 60 Once daily a Approved for over-the-counter use in women. ER = extended release; IR = immediate release. Prescribers Digital Reference. Accessed Oct 25, Common Side Effects of Antimuscarinics Dry mouth Constipation Headaches Blurred vision Clinicians should manage constipation and dry mouth before abandoning effective antimuscarinic therapy Patient must decide if the efficacy of the medication is worth side effects Some patients Balance tolerate of severe efficacy side and effects tolerability better should than others be considered and discussed with each patient 26 Steers WD. Urol Clin North Am. 2006;33: Erdam N, et al. Am J. Med 2006;119(suppl 1): Gormley EA, et al. American Urological Association (AUA) Guideline. AUA Web site Accessed Oct 25, Contraindications, Warnings, and Precautions for Antimuscarinics Contraindications Urinary or gastric retention Uncontrolled narrow-angle glaucoma Warnings and precautions Clinically significant bladder outlet obstruction Decreased gastrointestinal motility Treated narrow angle glaucoma May have central nervous system effects (eg, somnolence) Use with caution in patients with myasthenia gravis 27 Physicians Desk Reference. 64th ed. Thomson PDR; 2010; Oelke M, et al. Eur Urol. 2013;64:

10 Antimuscarinics: Comments and Concerns All have comparable efficacy Adherence/persistence rates low ER medications preferred over IR formulations: lower rates of dry mouth Use caution in patients taking other medications with anticholinergic properties Antidepressants, medications for Parkinson s disease and Alzheimer s disease, antinausea medications, etc Use caution when prescribing to frail and elderly patients Mobility deficits Cognitive deficits 28 Gormley EA, et al. J Urol. 2015;193: ; Jayarajan J, Radomski SB. Res Rep Urol. 2013;6:1-16. Mirabegron: A Different Mechanism of Action Bladder Activates β 3 -adrenergic receptors on the detrusor smooth muscle Relaxes the muscle during the storage phase of the urinary bladder fill void cycle and increases bladder capacity Pelvic nerve ACh (parasympathetic) NE Hypogastric nerve (sympathetic) M3 receptor (+) β 3 receptor (-) NE Detrusor muscle Urethra α1 receptor (+) Therapeutic Class Dose, mg Frequency β 3-adrenergic agonist 25 and 50 Once daily ACh = acetylcholine; NE = norepinephrine. 29 Bhide AA, et al. Int Urogynecol J. 2012;23: ; Clare J, et al. Nat Rev Neurosci. 2008;9: ; Tyagi P, et al. Drugs. 2010;13: Mirabegron: Incontinence Episodes Per 24 Hours Co-primary end point: mean number of incontinence episodes/24 hours adjusted mean change from baseline to final visit (week 12) a Study 1 Study 2 Study 3 Mean Number of Incontinence Episodes/24 Hours Baseline n = 291 n = 293 n = 325 n = 312 n = 262 n = 254 n = b 1.36b 1.47 b 1.57 b Placebo Mirabegron 25 mg Mirabegron 50 mg a Adjusted mean is for baseline, sex, and geographic location; b P.05 vs placebo with multiplicity adjustments. 30 Herschorn S, et al. Urology. 2013;82: ; Khullar V, et al. Eur Urol. 2013;63: ; Myrbetriq [prescribing information]. Astellas; 2017; Nitti VW, et al. J Urol. 2013;189:

11 Mirabegron: Common Side Effects Hypertension Nasopharyngitis UTIs Headaches Balance of efficacy and tolerability should be considered and discussed with each patient 31 Myrbetriq [prescribing information]. Astellas; Contraindications, Warnings, and Precautions for Mirabegron No contraindications Warnings and precautions: Not recommended for patients with severe uncontrolled hypertension Use with caution in patients: With urinary retention with bladder outlet obstruction Taking antimuscarinic for OAB Taking drugs metabolized by CYP2D6 (mirabegron is moderate inhibitor) 32 Myrbetriq [prescribing information]. Astellas; BESIDE: Combination Therapy When Monotherapy Fails Mean (SE) Adjusted Change From BL to EoT: Incontinence Episodes Baseline (SE) 3.24 (0.11) 3.15 (0.10) 3.31 (0.12) Combination Solifenacin 5 mg Solifenacin 10 mg (n = 706) 1.80 Incontinence Episodes (n = 704) 1.53 Difference vs solifenacin 5 mg 0.26 (95% CI, 0.47 to 0.05) P =.001* (n = 697) 1.67 Difference vs solifenacin 10 mg 0.13 (95% CI, 0.34 to 0.08) P =.008 Combination = solifenacin 5 mg + mirabegron 25 mg (50 mg after 4 weeks) *P <.05 vs solifenacin 5 mg; P <.05 vs solifenacin 10 mg. BL = baseline; CI = confidence interval; EoT = end of treatment; SE = standard error. 33 Drake MJ, et al. Eur J Urol. 2016;70:

12 BESIDE: Combination of Antimuscarinic + β 3 Agonist Therapy Better Tolerated OAB-q Symptom Bother Health-Related QoL Improvement Baseline (SE) Mean (SE) Adjusted Change From Baseline to EoT Combination Solifenacin 5 mg Solifenacin 10 mg (0.76) (0.78) (0.78) (n = 694) (n = 683) (n = 676) Difference vs Difference vs solifenacin 5 mg solifenacin 10 mg (95% CI, 6.88 to 3.04) (95% CI, 5.23 to 1.37) P <.001 P =0.001 Improvement Mean (SE) Adjusted Change From Baseline to EoT Difference vs Difference vs solifenacin 5 mg solifenacin 10 mg (95% CI, ) (95% CI, ) P <.001 P < (n = 694) (n = 683) (n = 676) 0 Baseline (SE) (0.85) (0.89) (0.87) Combination Solifenacin 5 mg Solifenacin 10 mg 34 Drake MJ, et al. Eur J Urol. 2016;70: Safety Results of Combination Therapy a Combination Solifenacin 5 mg Solifenacin 10 mg Treatment-Emergent AE, n (%) (n = 725) (n = 728) (n = 719) Increased BP 12 (1.7) 6 (0.8) 13 (1.8) QT prolongation 1 (0.1) 1 (0.1) 2 (0.3) Increased heart rate, palpitations, 7 (1.0) 5 (0.7) 4 (0.6) tachycardia, atrial fibrillation Tachycardia 2 (0.3) 3 (0.4) 1 (0.1) UTI 17 (2.3) 16 (2.2) 20 (2.8) Urinary retention 2 (0.3) 1 (0.1) 5 (0.7) Acute urinary retention Hypersensitivity reactions 11 (1.5) 6 (0.8) 6 (0.8) Glaucoma Dry mouth 43 (5.9) 41 (5.6) 70 (9.7) Blurred vision 10 (1.4) 10 (1.4) 5 (0.7) Constipation 33 (4.6) 22 (3.0) 34 (4.7) a Treatment-emergent adverse events (AEs) of special interest. 35 Drake MJ, et al. Eur J Urol. 2016;70: Indications for Referral Refractory to behavioral and pharmacologic therapy Neurologic disease or suspicion of neurologic cause of symptoms History of genitourinary trauma Pelvic pain Uncertain diagnosis or patient choice History of recurrent UTIs, other infection Pelvic irradiation Hematuria (microscopic or gross) Prior genitourinary surgery Elevated prostate-specific antigen Abnormal genital exam 36 Rosenberg MT, et al. Int J Clin Pract. 2007;61:

13 Therapy for Refractory OAB OnabotulinumtoxinA: injection 12 weeks; 24 weeks typical Reduces number of incontinence episodes and urgency, improves QoL AEs: UTI (34%-48%); urinary retention (6%) Peripheral tibial nerve stimulation: weekly 30-minute in-office sessions Efficacy in refractory OAB AEs: mild and uncommon Sacral neuromodulation: implanted device Improves OAB symptoms and continence vs standard medical therapy AEs: related to implanted device 37 Botox [prescribing information]. Allergan; 2013; Gormley EA, et al. J Urol. 2015;193: ; Gormley EA, et al. education/clinical-guidance/overactive-bladder.pdf. Accessed Sep 11, 2017; Siegel S, et al. Neurourol Urodyn. 2015;34: Action Plan Initiate discussion about bladder control with patients Use a bladder diary to assist in the diagnosis and monitoring of symptom improvement Institute nonpharmacologic strategies to improve OAB symptoms as a foundation of every treatment program Tailor medication to each patient s comorbidities, response, and tolerability Consider combination therapy with agents from different classes if monotherapy provides insufficient relief PCE Promotes Practice Change 38 13