Faculty. Louis Kuritzky, MD Clinical Assistant Professor Department of Community Health & Family Medicine University of Florida Gainesville, FL

Transcription

1 OAB Made Simple for the Primary Care Provider (PCP): Emerging Challenges In Primary Care: 2014! OAB Made Simple for the Primary Care Provider (PCP): How to Identify, When to Treat and When to Refer Faculty Pamela Ellsworth, MD Professor of Urology Department of Urology UMass Memorial Medical Center/University of Massachusetts Medical School Worcester, MA Louis Kuritzky, MD Clinical Assistant Professor Department of Community Health & Family Medicine University of Florida Gainesville, FL Matt T. Rosenberg, MD Medical Director of MidMichigan Health Centers Jackson, MI Section Editor of Urology, International Journal of Clinical Practice FACULTY DISCLOSURES ² Pamela Ellsworth, MD - Speaker/Advisory Board Pfizer, Allergan - Advisory Board Astellas ² Louis Kuritzky, MD - No relevant relationships to disclose ² Matt T. Rosenberg, MD - Speaker/Consultant Astellas, Horizon, Pfizer - Speaker Forest, Ortho-McNeil - Consultant Easai, Ferring, Lilly, Bayer 2 NACE Emerging Challenges in Primary Care: 2014 OAB - 1

2 PRE-TEST QUESTIONS OAB/LUTS 3 PRE-TEST QUESTION 1 OAB On a scale of 1 to 5, please rate how confident you would be in the diagnosis and management of a patient with OAB. 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 4 NACE Emerging Challenges in Primary Care: 2014 OAB - 2

3 PRE-TEST QUESTION 2 OAB Mary is a 80 year old patient who admits during her yearly exam that she wears a diaper just in case she can t make it to the bathroom in time. Which of the following is true regarding OAB? 1. OAB is less prevalent than chronic sinusitis 2. An 80 year old patient should know that it is normal to get up several times per night to empty their bladder 3. At least 50% of symptomatic patients are offered medical treatment for their symptoms of OAB 4. Understanding volume voided is a helpful point of distinction when evaluating LUTS symptoms for OAB 5 PRE-TEST QUESTION 3 OAB When you tell Mary she may have OAB, she asks about the evaluation. Which is test is not recommended by the AUA in the initial evaluation of OAB in the uncomplicated patient? 1. Urinalysis 2. Bladder ultrasound 3. Voiding diary 4. Genital exam 6 NACE Emerging Challenges in Primary Care: 2014 OAB - 3

4 PRE-TEST QUESTION 4 OAB After an appropriate evaluation you discuss treatment options with Mary. Which of the following statements regarding expectations of OAB therapy is false? 1. It is appropriate to tell the patient that urinary urgency may be reduced with the correct therapy 2. It may take titration or changes in the pharmacologic therapy before an adequate response in attained 3. Therapeutic efficacy is enhanced with the combination of behavioral therapy and pharmacologic therapy as opposed to either alone 4. The risk of urinary retention in the male increases with longer duration on pharmacologic therapy for OAB 7 PRE-TEST QUESTION 5 OAB Mary is very interested in efficacy but wants to limit side effects. Which of the following is true regarding OAB pharmacologic therapy with either an antimuscarinic or a beta 3 adenergic agonist? 1. Both classes have a high rate of dry mouth 2. The efficacy of the antimuscarinic medications are higher than the beta 3 adrenergic agonist medication 3. The efficacy of the beta 3 adrenergic agonist medication is higher than the antimuscarinic medication 4. One agent blocks contraction while the other stimulates relaxation 8 NACE Emerging Challenges in Primary Care: 2014 OAB - 4

5 PRE-TEST QUESTIONS LUTS 9 PRE-TEST QUESTION 1 LUTS On a scale of 1 to 5, please rate how confident you would be with diagnosing and treating lower urinary tract symptoms in men. 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 10 NACE Emerging Challenges in Primary Care: 2014 OAB - 5

6 PRE-TEST QUESTION 2 LUTS Fred presents to the clinic complaining of urgency, frequency and decreased stream. Which of the following is true regarding his symptom complex? 1. The cause is always the prostate or bladder 2. Such symptoms are a normal part of aging 3. The source of the symptoms can be prostate, bladder or other 4. The best way to determine the cause is performing urodynamics 11 PRE-TEST QUESTION 3 LUTS In addition to his urinary symptoms, Fred mentions some problems with his love life. Which of the following is true regarding the relationship between Erectile Dysfunction(ED) and Benign Prostatic Hyperplasia (BPH)? 1. There is no relationship as they occur independent of each other 2. They are only seen in the elderly male 3. The severity of one is inversely related to the severity of the other 4. They share many of the same co-morbidities 5. BPH predicts cardiac risk, whereas ED does not 12 NACE Emerging Challenges in Primary Care: 2014 OAB - 6

7 PRE-TEST QUESTION 4 LUTS With an appropriate evaluation you diagnose Fred with BPH. He is worried that his problem could get worse. Which of the following is NOT a risk factor for progression of BPH? 1. Age 2. Urine flow rate (Qmax) 3. Prostate volume 4. Diabetes 5. Post void residual 13 PRE-TEST QUESTION 5 LUTS Instead of Fred having urinary obstruction you recognize that he has overactive bladder (OAB). Which of the following is/are considered appropriate therapy for OAB? 1. Alpha blockers 2. Phosphodiesterase 5 inhibitors 3. 5 alpha reductase inhibitors 4. Beta 3 agonists or antimuscarinics 14 NACE Emerging Challenges in Primary Care: 2014 OAB - 7

8 LEARNING OBJECTIVES OAB After participating in this educational activity, clinicians should be better able to: 1. Recognize the role of simple questioning for identifying patients with overactive bladder (OAB) 2. Discuss the essential components of the evaluation of the patient with OAB symptoms 3. Develop a management plan for patients with OAB that emphasizes the incorporation of behavioral therapy and setting appropriate expectations, optimizes efficacy and minimizes side effects to improve patient compliance and adherence with pharmacologic therapy 4. Describe the role of recently approved second line therapies, third line therapies and future therapies in patients with OAB who are unsatisfied with antimuscarinic therapy 15 DEFINITION OF OAB OAB is syndrome or symptom complex defined as: Urgency, with or without urgency incontinence, usually with frequency and nocturia Urgency is the key symptom of OAB Urgency is defined as a sudden compelling desire to void, which is difficult to defer Abrams P, et al. Urology. 2003;61: Rosenberg MT, et al. Int J Clin Pract. 2007;61: NACE Emerging Challenges in Primary Care: 2014 OAB - 8

9 PREVALENCE OF OAB SYMPTOMS 1 in 3 US adults 40 years of age reported symptoms of OAB at least sometimes Respondents (%) Coyne S, et al. Urology. 2011;77: Age (years) 17 OAB & OTHER DISORDERS Chronic Bronchitis Diabetes Ulcer Asthma Hay Fever/Allergic Rhinitis Heart Disease Chronic Sinusitis Overactive Bladder Arthritic Symptoms Millions Stewart WF, et al. World J Urol. 2003;20(6): Pleis JR, Coles R. Summary health statistics for U.S. adults: National Health Interview Survey, Vital Health Stat ;209: Centers for Disease Control and Prevention/National Center for Health Statistics. Vital and Health Statistics. Hyattsville, MD: U.S. Department of Health and Human Services; DHHS Publication No. (PHS) « 18 NACE Emerging Challenges in Primary Care: 2014 OAB - 9

10 COPING STRATEGIES Use diapers or other absorbent products Carry extra clothes in case of wetting accident Wear dark, baggy clothes to hide wet spots or wear diapers To cope with symptoms of OAB, many patients employ elaborate behaviors aimed at hiding and managing urine loss Try to urinate on a schedule Bathroom mapping Restrict fluid intake Rosenberg MT. Curr Urol Rep Abrams et al. Am J Manag Care Jul;6(11 Suppl):S580-S590. Ricci JA, et al. Clin Ther. 2001;23: OAB IS PREVALENT, UNDIAGNOSED AND UNDERTREATED ² 33.3 million US adults are said to have OAB ² Less than 50% will discuss with healthcare provider ² Only a minority will be diagnosed and offered treatment ² A smaller proportion will stay on therapy Stewart WF et al. World J Urol. 2003;20: Rovner E, Wein A. Curr Urol Rep. 2002;3: Milsom I et al. BJU Int. 2001;87: Benner J et al. J Urol. 2009;181: Rosenberg M et al. Cleve Clinic J Med. 2007;74:S21-S29. Goepel M et al. Eur Urol. 2002;41: Dmochowski RR et al. Curr Med Res Opin. 2007;23: NACE Emerging Challenges in Primary Care: 2014 OAB - 10

11 The Reality is We Can Do Better in the Identification and Treatment of OAB 21 WHY IS OAB UNDERDIAGNOSED AND UNDERTREATED? The answer is education and communication Unfortunately, if we don t understand the disease, we may not identify it even to refer, let alone treat!!!!!! 22 NACE Emerging Challenges in Primary Care: 2014 OAB - 11

12 IDENTIFYING OAB TAKES A VILLAGE Rosenberg MT. Curr Urol Rep. 2008;9: Yu YF, et al. Value Health. 2005;8: PATIENTS DON T DISCUSS BLADDER ISSUES WITH THE PROVIDER ² Embarrassment ² Fear of invasive procedures or need for surgery ² Perception of lack of available and effective treatment Ricci JA, et al. Clin Ther 2001;23: Milsom I, et al. BJU Int 2001;87: NACE Emerging Challenges in Primary Care: 2014 OAB - 12

13 WHAT DO PATIENTS SAY? ² I have had this problem and did not know who to talk to ² My previous doctor told me it was part of aging ² It became a problem only when my diaper overflowed ² I thought it was normal as my sister and mother had this ² You mean going to the bathroom every hour is not normal? ² I am too embarrassed MacDiarmid S, Rosenberg, M. Curr Med Res Opin. 2005; 21: THE UROLOGIST AND THE UROGYNECOLOGIST ROLE IN THE PARTNERSHIP ² Identification and initial evaluation of OAB starts in the office of the PCP ² There is a significant amount of medically related LUTS ² The diagnosis of OAB does not require an extensive or complicated evaluation Stewart WF, et al. World J Urol. 2003;20: Darkov T, et al. Pharmacotherapy. 2005;25: Ailinger RL, et al. J Comm Health Nurs. 2005;22: Rosenberg M et al. Cleve Clinic J Med. 2007;74:S21-S NACE Emerging Challenges in Primary Care: 2014 OAB - 13

14 POTENTIAL MISCONCEPTIONS IN OAB ² OAB is a natural part of aging ² Diagnosis and treatment of genitourinary disease is to be determined by a specialist ² Diagnosis and treatment is outside the realm of the PCP setting MacDiarmid S, Rosenberg, M. Curr Med Res Opin. 2005;21(9): WHAT DO DOCTORS SAY? ² No time ² Treatments are not all that effective ² If it was a problem for the patient, he or she would bring it up ² Your bladder/penis/kidney won t kill you, your heart will, so I need to focus MacDiarmid S, Rosenberg, M. Curr Med Res Opin. 2005;21(9): NACE Emerging Challenges in Primary Care: 2014 OAB - 14

15 NOT SO! ² What is the outcome of an elderly patient falling and breaking a extremity? ² What is one of the primary drivers for nursing home admission? Brown et al. J Am Geriatr Soc. 2000;48: Current Thinking Is a Myth 30 NACE Emerging Challenges in Primary Care: 2014 OAB - 15

16 REALITIES OF OAB MANAGEMENT ² The PCP is the first line of contact ² Diagnosis and treatment is within the realm of the PCP setting ² Current treatments offer significant improvement of patient symptoms and patient quality of life 31 What we have here is a failure to communicate. Initially stated by the Warden in Cool Hand Luke repeated by Jackie Gleason in Smokey and the Bandit And now just shamelessly used by me for lecturing amusement 32 NACE Emerging Challenges in Primary Care: 2014 OAB - 16

17 WHAT DOES THE PCP NEED? ² Keep It Simple 33 WHAT DOES THE PCP NEED? ² Keep It Simple ² Keep It Effective 34 NACE Emerging Challenges in Primary Care: 2014 OAB - 17

18 WHAT DOES THE PCP NEED? ² Keep It Simple ² Keep It Effective ² Keep Us From Harming Our Patients 35 IT ALL COMES DOWN TO NORMAL ² How many times a day does a normal person need to urinate? ² What is the normal volume of urine voided per micturition? ² Is it normal for older people to get up during the night to use the bathroom? 36 NACE Emerging Challenges in Primary Care: 2014 OAB - 18

19 What are the normal functions of the bladder? 37 FUNCTION OF THE BLADDER ² Normal Function - Storage capacity ( ml of fluid) Adequate low pressure urinary storage (bladder) Adequate outlet resistance (sphincter) - Empty to completion (minimal residual) Adequate bladder contraction Absence of outlet obstruction ² Abnormal Function (failure to store or empty) - Voiding frequently small amounts - Uncontrollable urge (urgency) - Incomplete emptying - Hesitancy, poor stream Wein AJ. Pathophysiology and categorization of voiding dysfunction. In: Wein AJ, Kavoussi LR, Novick AC, et al, eds. Campbell-Walsh Urology. 9th ed. Philadelphia, PA: W. B. Saunders/Elsevier; 2007: NACE Emerging Challenges in Primary Care: 2014 OAB - 19

20 What are the normal functions of the prostate? 39 FUNCTION OF THE PROSTATE ² Normal Function - Does not grow (enlarge) into the urethra thereby allowing unobstructed flow - It is intimately associated with the continence mechanism - Produces fluid for seminal emission ² Abnormal Function (failure of flow) - Obstruction of urinary flow ( obstruction retention ) - Sphincteric damage /usually surgical - ( stress incontinence ) Wein AJ. Pathophysiology and categorization of voiding dysfunction. In: Wein AJ, Kavoussi LR, Novick AC, et al, eds. Campbell-Walsh Urology. 9th ed. Philadelphia, PA: W. B. Saunders/Elsevier; 2007: NACE Emerging Challenges in Primary Care: 2014 OAB - 20

21 LOWER URINARY TRACT SYMPTOMS (LUTS): BLADDER OR PROSTATE? Storage (bladder) Urgency Frequency Nocturia Urge incontinence Stress incontinence Mixed incontinence Overflow incontinence Voiding (prostate) Hesitancy Poor flow/weak stream Intermittency Straining to void Terminal dribble Prolonged urination Urinary retention Chapple CR, et al. Eur Urol. 2006;49: It is all about VOLUME VOIDED and FLOW Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4): NACE Emerging Challenges in Primary Care: 2014 OAB - 21

22 Guess What Happens When You Understand What is Normal? 43 Guess What Happens When You Understand What is Normal? ² Your patients will understand what is normal, and subsequently, what is abnormal 44 NACE Emerging Challenges in Primary Care: 2014 OAB - 22

23 Guess What Happens When You Understand What is Normal? ² Your patients will understand what is normal, and subsequently, what is abnormal ² You recognize when you have something to fix 45 Key: LUTS lower urinary tract symptoms HPE history, physical examination UA urinalysis PSA prostate specific antigen BPH benign prostatic hyperplasia OAB overactive bladder SI stress incontinence Provisional OAB/SI THE LUTS ALGORITHM LUTS Focused HPE UA/PSA Blood Sugar Likely OAB/BPH/SI Unlikely OAB/BPH/SI Desires No Treatment? Yes Provisional BPH Treat or Refer Watchful Treat for BPH Assess and Treat OAB/SI Refer Meds Meds Modified from Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9): NACE Emerging Challenges in Primary Care: 2014 OAB - 23

24 DEFINING LUTS Frequency Nocturia Urgency UUI OAB Wet OAB Dry Patient considers that he/she voids too often by day Normal is < 8 times per 24 hours Waking to urinate during sleep hours Considered a clinical problem if frequency is greater than twice a night Sudden compelling desire to pass urine that is difficult to defer Involuntary leakage accompanied by, or immediately preceded by, urgency OAB with UUI OAB without UUI Warning Time Time from first sensation of urgency to voiding Abrams P, et al. Neurourol Urodyn. 2002;21:167-78; Wein A, et al. J Urol. 2006;175:S5-10; Zinner N, et al. Int J Clin Pract. 2006;60:119-26; Wein AJ. Am J Manag Care. 2000;6:S SIMPLE QUESTIONS THE PCP CAN ASK ² Do you have a sudden urge to void and can barely make it to the bathroom? ² Do you wear a pad or diaper? ² Can you sit through a movie without going to the bathroom? ² Do you leak urine? ² Do you get up at night? Abrams P, et al. Neurourol Urodyn. 2002;21:167-78; Wein A, et al. J Urol. 2006;175:S5-10;Zinner N, et al. Int J Clin Pract. 2006;60:119-26; Wein AJ. Am J Manag Care. 2000;6:S NACE Emerging Challenges in Primary Care: 2014 OAB - 24

25 THE EVALUATION OF LUTS ² Medical and surgical history ² Medications ² Focused physical examination ² Voiding diary ² Labs ² Urodynamics, cystoscopy, and diagnostic renal and bladder ultrasound not necessary in initial workup of uncomplicated patients Gormley EA, et al. American Urological Association (AUA) Guideline. AUA Web site media/oab_guideline.pdf. Accessed March 21, EXAMPLES IN THE MEDICAL AND SURGICAL HISTORY THAT MAY CAUSE LUTS ² Diabetes (new onset or poorly controlled) - Causing polyuria/polydipsia ² Congestive heart failure - Nighttime fluid mobilization ² Recent Surgery - Catheterization during surgery, immobilization, constipation from pain medications A recent onset of the symptoms may provide a clue to the etiology 50 NACE Emerging Challenges in Primary Care: 2014 OAB - 25

26 MEDICATIONS AS A CAUSE OF LUTS Sedatives Alcohol, Caffeine, Diuretics Anticholinergics α Agonists ß - Blockers Calcium-Channel Blockers ACE Inhibitors First generation antihistamines Cholinesterase inhibitors Confusion, secondary incontinence Diuresis Impair contractility, voiding difficulty, overflow incontinence Increased outlet resistance, voiding difficulty Decreased urethral closure, stress incontinence Reduce bladder smooth muscle contractility Induce cough, stress urinary incontinence Increase outlet resistance Precipitate urge incontinence Opioids Direct effect, constipation Wyman JF, et al. Int I Clin Pract. 2009;63: Newman DK. Nurse Pract. 2009;34: THE FOCUSED PHYSICAL EXAMINATION ² Abdominal Tenderness, masses, distension ² Neurological Mental and ambulatory status, neuromuscular function ² Genitourinary Meatus and testis Vaginal mucosal integrity, urethral mobility, bladder prolapse ² Rectal Tone Prostate size, shape, nodules and consistency Rosenberg MT, Newman DK, Tallman CT, et al. Cleve Clin J Med. 2007;74(suppl 3):S21-S NACE Emerging Challenges in Primary Care: 2014 OAB - 26

27 LABORATORY TESTS ² Urinalysis Infection, blood The urine is not an adequate screener for diabetes since the blood sugar must be above 180 mg/dl before it spills into the urine ² A random or fasting blood sugar Diabetes ² Prostate specific antigen Prostate specific not cancer specific but can be used in screening Excellent as a surrogate marker for prostate size PSA is more accurate than a DRE when estimating prostate size A PSA of 1.5 ng/ml equates to a prostate volume of at least 30 grams(ml) Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61,9, Bosch J, et al. Eur Urol. 2004;46: Roerborn CG, et al. Urology. 1999;53; THE PURPOSE OF THE VOIDING DIARY ² Identifies voiding frequency and voided volume ² Differentiates behavioral vs LUTS pathology - Voiding frequently excessive volume(behavioral) small amounts as a result of always being in a rush (behavioral) small amounts (OAB) ² Alerts patients to habits /opportunities to modify ² Can monitor effect of treatment Wyman JF, et al. Int J Clin Pract. 2009; 63(8): NACE Emerging Challenges in Primary Care: 2014 OAB - 27

28 THE POST VOID RESIDUAL (PVR) IS ONLY NEEDED IN SELECT PATIENTS ² The fear of patients going into retention when treated for OAB leaves many patients untreated ² If PVR residual is less than 50 ml, causing retention when treating OAB is extremely unlikely - FACT: most PCPs will not have bladder scanner and will not want to catheterize a patient - FACT: most PCPs will have access to a ultrasound unit and can order a post void residual ² Use common sense, if you are treating the patient for voiding too frequently (OAB) and they have not voided in 6 8 hours or have a sense to void but cannot, have them contact you Rosenberg MT. Curr Opin Urol. 2008;9(6): Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9): INDICATIONS FOR REFERRAL ² History of recurrent urinary tract infections or other infection ² Pelvic irradiation ² Microscopic or gross hematuria ² Prior genitourinary surgery ² Elevated prostate-specific antigen ² Abnormal genital exam ² Suspicion of neurological cause of symptoms ² Meatal stenosis ² History of genitourinary trauma ² Pelvic pain ² Uncertain diagnosis or patient choice Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9), NACE Emerging Challenges in Primary Care: 2014 OAB - 28

29 TREATMENT NOW CAN BE EMPIRIC ² No identifiable etiology ² No reversible causes ² Is patient bothered enough for treatment? - No, watchful waiting - Yes, consider algorithm Weak flow think Prostate Poor voiding volumes think Bladder Incontinence think Bladder/Outlet Rosenberg MT. Cur Uro 2008;9: THE MALE (OR PROSTATE) DILEMMA LUTS Focused HPE UA/PSA Blood Sugar Unlikely OAB/BPH/SI Treat or Refer Likely OAB/BPH/SI Provisional OAB/SI Desires Treatment? Yes Provisional BPH No Watchful Wai@ng Key: LUTS lower urinary tract symptoms HPE history, physical examination UA urinalysis PSA prostate specific antigen BPH benign prostatic hyperplasia OAB overactive bladder SI stress incontinence Treat for BPH Assess and Treat OAB/SI Refer Ineffec@ve Ineffec@ve Effec@ve Effec@ve Modified from Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9): Con@nue Meds Con@nue Meds 58 NACE Emerging Challenges in Primary Care: 2014 OAB - 29

30 TREATMENT GUIDELINES FOR OAB ² Behavioral treatment ² Pharmacologic management ² Referral for specialist management/surgery Gormley EA, et al. American Urological Association (AUA) Guideline. AUA Web site media/oab_guideline.pdf. Accessed March 21, Kirby M, et al. Int J Clin Pract. 2006;60: Burgio K, et al. J Am Geriatr Soc. 2000;48: BEHAVIORAL THERAPY FOR OAB Educa:on reinforcement Bladder training Pelvic floor exercises Biofeedback Behavioral Therapy for OAB Timed voiding Diaries Fluid/Dietary management No matter what the treatment course, behavioral modification should be offered to every patient Soda T, et al. J Urol. 2010; 184: NACE Emerging Challenges in Primary Care: 2014 OAB - 30

31 HABIT CHANGES: MANAGING BLADDER HEALTH Technique Lifestyle Modification Diet, fluid, bowel, and weight management Smoking cessation Timed/ Prompted Voiding Urination at a fixed interval that avoids the symptom Useful for urgency and urinary incontinence not associated with frequency Good option in patients with cognitive impairment Wyman JF, et al. Int J Clin Pract. 2009;63: Wagg AS, et al. BJU Int. 2007;99: Lucas MG, et al. Eur Urol 2012;62(6): HOW TO PERFORM PELVIC FLOOR MUSCLE EXERCISES ² Explain location of perineal muscles (anal area) ² Contract perineal muscles, squeezing upward through the pelvis ² Sit or stand with your legs apart, don t hold your breath ² Hold the contraction for 10 seconds, then gradually relax ² Repeat at least 5 times, increase to per day in groups of 10 ² Relaxation is as important as contraction for muscle rehabilitation ² Use exercises to control symptoms - eg, during urge episode, not during urination The exercises can be performed anywhere 62 Harv Womens Health Watch. January/how-toperform-kegel-exercises. NACE Emerging Challenges in Primary Care: 2014 OAB - 31

32 ADDITIVE EFFECT OF COMBINING BEHAVIORAL AND DRUG THERAPY 0 Behavioral Therapy Combined Therapy Drug Therapy Combined Therapy Mean Reduction in UI, % % 88.5% 72.7% 84.3% 100 P <.05 P =.001 Burgio KL, et al. J Am Geriatr Soc. 2000;48: PHARMACOLOGIC MANAGEMENT ² 8 antimuscarinics, 6 are oral and 2 are topical ² 1 beta-3 adrenergic agonist ² Choice is based of efficacy, dose flexibility, adverse event profiles, drug interactions and patient preference ² Trying several medications before referral is appropriate 64 NACE Emerging Challenges in Primary Care: 2014 OAB - 32

33 RECEPTOR PATHWAYS FOR OAB TREATMENT Acetylcholine ACH Antimuscarinics M 3 muscarinic receptor (contraction) Detrusor smooth muscle (relaxation) NE β 3 agonist Norepinephrine + β 3 AR Takeda M, et al. J Pharmacol Sci. 2010;2110: Fowler CJ, et al. Nat Rev Neurosci. 2008;8: ANTIMUSCARINICS IMMEDIATE RELEASE Drug Brand Name Dose Dosing Oxybutynin IR Ditropan 5 mg 1 3 times per day Tolterodine IR Detrol 1-2 mg Twice per day Trospium Chloride Sanctura 20 mg Twice per day Physcians Desk Reference. 64st ed. Montvale, NJ: Thomson PDR; NACE Emerging Challenges in Primary Care: 2014 OAB - 33

34 ANTIMUSCARINICS EXTENDED RELEASE extended release medications have a better tolerability than their immediate release counterparts Drug Brand Name Dose Dosing Darifenacin Enablex 7.5 mg, 15 mg Daily Fesoterodine Toviaz 4 mg, 8 mg Daily Oxybutynin ER Ditropan XL 5 30 mg Daily Oxybutynin TDS Oxytrol 3.9 mg Twice per week Oxybutynin 10% gel Gelnique 100 mg Daily Solifenacin Vesicare 5 mg, 10 mg Daily Tolterodine ER Detrol LA 2, 4mg Daily Trospium Chloride Sanctura XR 60 mg Daily Physcians Desk Reference. 64st ed. Montvale, NJ: Thomson PDR; COMMON SIDE EFFECTS OF ANTIMUSCARINICS ² Dry Mouth ² Constipation ² Headaches ² Blurred vision Clinicians should manage constipation and dry mouth before abandoning effective antimuscarinic therapy. Balance of efficacy and tolerability should be considered and discussed with each patient. 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 March 21, NACE Emerging Challenges in Primary Care: 2014 OAB - 34

35 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS FOR ANTIMUSCARINICS ² Contraindications- - Urinary or gastric retention - Uncontrolled narrow-angle glaucoma ² Warnings & Precautions - Angioedema of face, lips, tongue and/or larynx - Clinically significant bladder outlet obstruction - Decreased gastrointestinal motility - Treated narrow angle glaucoma - May have CNS effects i.e., somnolence - Use with caution in patients with myasthenia gravis Physicians Desk Reference. 64st ed. Montvale, NJ: Thomson PDR; Oelke M, et al. Eur Urol. 2013;64(1): BETA-3 ADRENERGIC AGENTS Drug Brand Name Dose Dosing Mirabegron Myrbetriq 25 mg, 50 mg Daily Myrbetriq (mirabegron) prescribing information, Astellas Pharma US, Inc. June NACE Emerging Challenges in Primary Care: 2014 OAB - 35

36 COMMON SIDE EFFECTS OF MIRABEGRON ² Hypertension ² Nasopharyngitis ² Urinary Tract Infections ² Headaches Balance of efficacy and tolerability should be considered and discussed with each patient. Myrbetriq (mirabegron) prescribing information, Astellas Pharma US, Inc. June CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS FOR MIRABEGRON ² Contraindications NONE ² Precautions & Warnings - Not recommended for use in severe uncontrolled hypertensive patients - Use with caution in patients with urinary retention or bladder outlet obstruction - Use with caution in patients taking antimuscarinic drugs for overactive bladder - Caution with use in patients taking drugs metabolized by CYP2D6 as mirabegron is a moderate inhibitor of CYP2D6 Myrbetriq (mirabegron) prescribing information, Astellas Pharma US, Inc. June NACE Emerging Challenges in Primary Care: 2014 OAB - 36

37 FOLLOW UP ON THE PATIENT TREATED FOR OAB ² Review the patient after 2 4 weeks - Be prepared to titrate as studies show > 50 % will increase dose if given the option - Be prepared to try different agent or class ² Consider checking PVR to ensure volume not increasing significantly in the complex patient - Studies on medication usage in males show safety and minimal increase in post void residual over time of follow up - The risk of urinary retention (although low) is highest during the first 30 days of treatment Chapple CG, Rosenberg MT, Brenes FJ. Brit J Urol. 2009;104(7): Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9): Martin-Merino E, et al. J Urol. 2009; 182(4): Rosenberg M, Newman DK, Tallman CT, et al. Cleve Clin J Med. 2007;74(suppl 3):S21-S29. Myrbetriq (mirabegron) prescribing information, Astellas Pharma US, Inc. June HIGH DISCONTINUATION RATE FOR PATIENTS ON OAB THERAPY Discontinuation Rate (%) From Anticholinergics for OAB (95% CI)* Adapted from Gopal et al. Months to Discontinuation Study Design: UK study. Overall drug discontinuation for all women prescribed anticholinergic medications (N=29,369). Unadjusted cumulative incidence of discontinuation (95% CI). *Cumulative incidence of discontinuation was determined using the Kaplan-Meier method. Gopal M, et al. Obstet Gynecol. 2008;112: NACE Emerging Challenges in Primary Care: 2014 OAB - 37

38 IMPROVING PATIENT ADHERENCE BY ADDRESSING EXPECTATIONS ² Effects on urgency ² Limiting incontinence ² Decreasing nocturia ² Improved quality of life ² Tolerability of medication Rosenberg MT. Cur Uro 2008, 9: DeCastro J, et al. Am J Med. 2008;121:S27-S OPTIONS FOR THE UNSATISFIED PATIENT ² Sacral Nerve Stimulation ² Percutaneous Tibial Nerve Stimulation ² Onabotulinum Toxin A Gormley EA, et al. American Urological Association (AUA) Guideline. AUA Web site media/oab_guideline.pdf. Accessed March 21, NACE Emerging Challenges in Primary Care: 2014 OAB - 38

39 TAKE HOME MESSAGE ² Overactive bladder doesn t take your life it steals it from you ² The untreated 85% is in the PCP office ² OAB can be diagnosed and treated in the primary care office efficiently, effectively and safely 77 TREATING OAB TAKES A VILLAGE Be willing to discuss his/her symptoms Make recommended lifestyle changes Adhere to prescribed medication Diagnose OAB Set realistic patient expectations/goals Provide initial treatment of OAB Refer appropriate patients Treat refractory or complicated OAB Educate PCPs to better manage OAB Rosenberg MT. Curr Urol Rep. 2008;9: Yu YF, et al. Value Health. 2005;8: NACE Emerging Challenges in Primary Care: 2014 OAB - 39

40 POST-TEST QUESTIONS OAB 79 POST-TEST QUESTION 1 OAB Mary is a 80 year old patient who admits during her yearly exam that she wears a diaper just in case she can t make it to the bathroom in time. Which of the following is true regarding OAB? 1. OAB is less prevalent than chronic sinusitis 2. An 80 year old patient should know that it is normal to get up several times per night to empty their bladder 3. At least 50% of symptomatic patients are offered medical treatment for their symptoms of OAB 4. Understanding volume voided is a helpful point of distinction when evaluating LUTS symptoms for OAB 80 NACE Emerging Challenges in Primary Care: 2014 OAB - 40

41 POST-TEST QUESTION 2 OAB When you tell Mary she may have OAB, she asks about the evaluation. Which is test is not recommended by the AUA in the initial evaluation of OAB in the uncomplicated patient? 1. Urinalysis 2. Bladder ultrasound 3. Voiding diary 4. Genital exam 81 POST-TEST QUESTION 3 OAB After an appropriate evaluation you discuss treatment options with Mary. Which of the following statements regarding expectations of OAB therapy is false? 1. It is appropriate to tell the patient that urinary urgency may be reduced with the correct therapy 2. It may take titration or changes in the pharmacologic therapy before an adequate response in attained 3. Therapeutic efficacy is enhanced with the combination of behavioral therapy and pharmacologic therapy as opposed to either alone 4. The risk of urinary retention in the male increases with longer duration on pharmacologic therapy for OAB 82 NACE Emerging Challenges in Primary Care: 2014 OAB - 41

42 POST-TEST QUESTION 4 OAB Mary is very interested in efficacy but wants to limit side effects. Which of the following is true regarding OAB pharmacologic therapy with either an antimuscarinic or a beta 3 adenergic agonist? 1. Both classes have a high rate of dry mouth 2. The efficacy of the antimuscarinic medications are higher than the beta 3 adrenergic agonist medication 3. The efficacy of the beta 3 adrenergic agonist medication is higher than the antimuscarinic medication 4. One agent blocks contraction while the other stimulates relaxation 83 POST-TEST QUESTION 5 OAB On a scale of 1 to 5, please rate how confident you would be in the diagnosis and management of a patient with OAB. 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 84 NACE Emerging Challenges in Primary Care: 2014 OAB - 42

43 OAB Made Simple for the Primary Care Provider (PCP): POST-TEST QUESTION 6 OAB Which of the statements below describes your approach to diagnosing and treating patients with OAB? 1. I do not diagnose or treat patients with OAB, nor do I plan to this year. 2. I did not diagnose or treat patients with OAB before this course, but as a result of attending this course I m thinking of managing them now. 3. I do diagnose and treat patients with OAB and I now plan to change my treatment methods based on completing this course. 4. I do diagnose and treat patients with OAB and this course confirmed that I don t need to change my treatment 85 methods. Emerging Challenges In Primary Care: 2014! Evaluating and Treating LUTS in the Primary Care Setting Faculty Pamela Ellsworth, MD Professor of Urology Department of Urology UMass Memorial Medical Center/University of Massachusetts Medical School Worcester, MA Louis Kuritzky, MD Clinical Assistant Professor Department of Community Health & Family Medicine University of Florida Gainesville, FL NACE Emerging Challenges in Primary Care: 2014 Matt T. Rosenberg, MD Medical Director of MidMichigan Health Centers Jackson, MI Section Editor of Urology, International Journal of Clinical Practice OAB - 43

44 LEARNING OBJECTIVES LUTS After participating in this educational activity, clinicians should be better able to: 1. Understand that lower urinary tract symptoms in a male could be caused by medical issues, the bladder or the prostate and that a simple history and physical can help delineate the problem 2. Recognize that erectile dysfunction (ED) and BPH share many of the same co-morbidities. 3. Discuss the different classes of medications available for OAB and BPH 4. Recognize the risk factors for progression of BPH 87 DAVID 65 Y/O MALE WITH DM ² 65 yr old obese male with type 2 DM ² At the encouragement of his wife he admits that he has some issues down there - Urinary urgency, a poor stream, frequency and nocturia - Poor erections ( not hard enough ) - Symptoms for many years that he thought was a natural part of aging ² Meds metformin, lisinopril and atorvastatin ² Physical exam contributory only for obesity ² Labs - HgA1C 6.7% - PSA 2.8 ng/dl - Urinalysis - normal 88 NACE Emerging Challenges in Primary Care: 2014 OAB - 44

45 WHAT ARE THE CLUES? ² 65 yr old obese male with type 2 DM ² At the encouragement of his wife he admits that he has some issues down there - Urinary urgency, a poor stream, frequency and nocturia - Poor erections ( not firm enough ) - Symptoms for many years that he thought was a natural part of aging ² Meds metformin, lisinopril and atrovastatin ² Physical exam contributory only for obesity ² Labs - HgA1C 6.7% - PSA 2.8 ng/ml - Urinalysis - normal 89 FUNCTION OF THE PROSTATE NORMAL FUNCTION ² Produces fluid for seminal emission ² Does not grow into the urethra thereby allowing unobstructed flow ABNORMAL FUNCTION ² Obstruction of urinary flow ² Poor function seen as failure to void Rosenberg MT, et al. Int J Clin Pract. 2007;61(9): NACE Emerging Challenges in Primary Care: 2014 OAB - 45

46 NATURAL HISTORY OF PROSTATE GROWTH ² A common condition as men age - By sixth decade: > 50% have some degree of hyperplasia - By eighth decade: > 90% will have hyperplasia ² ±10% will require surgical or medical intervention ² A 55-year old man who is experiencing symptoms, has a PSA of 1.5 ng/ml and a 30 ml prostate volume can expect his prostate to approximately double in size over the next 15 years. McVary KT, et al. J Urol. 2011;185(5): Roehrborn C, et al. J Urol. 2000;163(1): RISK EVALUATION OF BPH-LUTS PROGRESSION Baseline Factors as Predictors Five risk factors 1. Total prostate volume 31 ml 2. PSA 1.6 ng/ml 3. Age 62 Not usually evaluated by the PCP 4. Q max <10.6 ml/s 5. PVR 39 ml PVR, post-void residual; Q max, maximum flow rate. Crawford ED, et al. Urology. 2006;175(4): Rosenberg MT, et al. Current Urology Reports Dec;14(6): NACE Emerging Challenges in Primary Care: 2014 OAB - 46

47 ASSESSMENT: DRE VS. PSA ² There is a strong and clinically useful relationship between serum PSA and prostate volume. ² Digital rectal examination (DRE) is quite inaccurate in estimating the correct prostate size when compared to either transrectal ultrasound (TRUS) or other imaging modalities. Roehrborn CG. Int J Impot Res. 2008;20 Suppl 3:S FUNCTION OF THE BLADDER NORMAL FUNCTION ² Storage capacity of ml of fluid ² Empty to completion after a gentle urge Rosenberg MT, et al. Int J Clin Pract. 2007;61(9): ABNORMAL FUNCTION ² Voiding frequently of small amounts (less than capacity) ² Uncontrollable urge (urgency) to empty ² Incomplete emptying ² Poor function seen as failure to store or empty 94 NACE Emerging Challenges in Primary Care: 2014 OAB - 47

48 DEFINITION OF OAB OAB is syndrome or symptom complex defined as: Urgency, with or without urgency incontinence, usually with frequency and nocturia Urgency is the key symptom of OAB Urgency is defined as a sudden compelling desire to void, which is difficult to defer Abrams P, et al. Urology. 2003;61: Rosenberg MT, et al. Int J Clin Pract. 2007;61: USING SYMPTOMS TO DISTINGUISH THE ORIGIN OF THE PROBLEM Urine Storage Urine Voiding Urgency Hesitancy Frequency Weak stream Urgency incontinence Intermittent Nocturia Straining Kapoor A. Can J Urol. 2012;19 Suppl 1: Abrams P, et al. Neurourol Urodyn. 2002;21: NACE Emerging Challenges in Primary Care: 2014 OAB - 48

49 DIFFERENTIATING THE ETIOLOGY OF LUTS? ² Weak flow think prostate ² Voiding small amounts think bladder ² Leakage of urine think bladder or sphincter ² Good flow, normal volume think too much fluid production and evaluate accordingly It is all about volume and flow Rosenberg MT, et al. Int J Clin Pract. 2007;61(9): OAB AND BPH CAN COEXIST LUTS OAB BPH Rosenberg MT, et al. Int J Clin Pract. 2007;61,9, NACE Emerging Challenges in Primary Care: 2014 OAB - 49

50 BACK TO DAVID Upon questioning David s symptoms are consistent with BPH-LUTS. Which would you consider to be the three most prevalent co-morbid conditions associated with BPH-LUTS? 1. Heart disease, diabetes, arthritis 2. Hypertension, high cholesterol, ED 3. Diabetes, pain, depression 4. Digestive tract disorders, allergies, arthritis 99 COMMON COMORBIDITIES IN BPH-LUTS Comorbidity with BPH-LUTS (N = 6,909) Hypertension 53 High cholesterol 45 Erectile or other sexual dysfunction % 36 Digestive tract disorder 21 Arthritis 20 Heart disease/heart failure 18 Diabetes 17 Depression/Anxiety/Sleep disorder 16 Allergies/cold/flu/congestion 15 General pain/inflammation 11 Roehrborn CG, et al. BJU Int. 2007;100(4): NACE Emerging Challenges in Primary Care: 2014 OAB - 50

51 LINKING LUTS-BPH AND ED Risk Factors LUTS-BPH Increasing LUTS severity or symptom worsening Increasing serum dihydrotestosterone Enlarged prostate; >30 ml Inflammation Elevated IPSS Refractory to treatment Poor flow Genetics History of AUR High waist circumference Increasing age PSA >1.5 ng/dl PVR >50 ml Increasing bother Reduced physical activity Comorbidities Cardiovascular disease Diabetes/Disrupted glucose homeostasis Erectile dysfunction Metabolic syndrome Obesity Risk Factors Increasing age Smoking High waist circumference ED Comorbidities Lee RK and Chung D, et al. BJU Int. 2012;110(4): Parsons JK. Curr Bladder Dysfunct Rep. 2010;5(4): Robert G. Curr Opin Urol. 2011;21(1): Roehrborn CG. BJU Int. 2006;97(S2):7-11. Rosen R. Eur Urol. 2003;44(6): Shabsigh R, et al. BMC Urol. 2010;10:18. Woo HH, et al. Med J Aust. 2011;195(1): Cardiovascular disease Depression Diabetes Hypercholesterolemia Lower urinary tract symptoms Metabolic syndrome Obesity LUTS-BPH AND ED AND DIRECTLY RELATED Mean IIEF Erectile Function Domain Better Erectile Function LUTS Effect Age Effect LUTS Effect LUTS Severity No Mild Moderate Severe LUTS Effect Worse Erectile Function 0 N=10,636 men who had been sexually active within the last 4 weeks. IIEF, International Index of Erectile Function Years Years Years McVary KT. BJU Int. 2006;97: NACE Emerging Challenges in Primary Care: 2014 OAB - 51

52 BPH-LUTS AND ED COMMON PATHOPHYSIOLOGIC MECHANISMS Reduced NO cgmp signaling Increased RhoA ROCK signaling Autonomic hyperactivity Pelvic atherosclerosis FUNCTIONAL CONSEQUENCES AT TISSUE LEVEL (corpora cavernosa, prostate, urethra, and bladder functional alterations) Reduced function of nerves and endothelium Altered smooth muscle relaxation or contractility Arterial insufficiency, reduced blood flow, and hypoxia-related tissue damage BPH-LUTS ED Chronic inflammation Steroid hormone unbalance Comorbidities Hypertension, Metabolic Syndrome, Diabetes, etc. cgmp, cyclic guanosine monophosphate; NO, nitric oxide; ROCK, Rho-associated protein kinase. Gacci M, et al. Eur Urol. 2011;60(4): WHAT TO KEEP IN MIND IN THE EVALUATION OF LUTS ² Lower Urinary Tract Symptoms (LUTS) can be of urologic origin, which includes the prostate and bladder, or can be medical in nature ² A comprehensive history, physical and lab evaluation will generally provide the needed clues Rosenberg MT, et al. Int J Clin Pract. 2007;61(9): NACE Emerging Challenges in Primary Care: 2014 OAB - 52

53 EXAMPLES IN THE MEDICAL OR SURGICAL HISTORY THAT CAN CAUSE OR CONFOUND LUTS ² Poorly controlled diabetes causing polyuria/ polydipsia ² Antihypertensive diuretics can frequency and urgency whereas some cold medications (e.g., α- agonists) can cause urinary retention or hesitancy ² Nocturia associated with CHF ² Recent surgery causing immobilization or constipation ² Poor urinary hygiene The temporal relationship may offer a clue 105 Rosenberg MT, et al. Int J Clin Pract. 2007;61(9): Burgio KL, et al. Int J Clin Pract. 2013;67(6): A FOCUSED PHYSICAL EXAMINATION ² Abdominal Tenderness, masses, distension ² Neurological Mental and ambulatory status, neuromuscular function ² Genitourinary Meatus and testes ² Rectal Tone Prostate size, shape, nodules and consistency Rosenberg MT, et al. Int J Clin Pract. 2007;61(9): Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4): NACE Emerging Challenges in Primary Care: 2014 OAB - 53

54 LABORATORY TESTS ² Urinalysis - Infection, blood, crystals - The urine is not an adequate screener for diabetes since the blood sugar must be above 180 mg/dl before it spills into the urine ² A random or fasting blood sugar - Diabetes ² Prostate specific antigen - Prostate specific not cancer specific but can be used in screening - Excellent as a surrogate marker for prostate size PSA is more accurate than a DRE when estimating prostate size A PSA of 1.5 ng/ml equates to a prostate volume of at least 30 grams(ml) Rosenberg MT, et al. Int J Clin Pract. 2007;61,9, Bosch J, et al. Eur Urol. 2004;46(6): Roerborn CG, et al. Urology. 1999;53; OPTIONAL TESTS ² International Prostate Symptom Score (IPSS) ² Voiding Diary ² Post Void Residual (PVR) ² Urine Flow Rate (Qmax) Rosenberg MT, et al. Int J Clin Pract. 2007;61(9): Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4): NACE Emerging Challenges in Primary Care: 2014 OAB - 54

55 INTERNATIONAL PROSTATE SYMPTOM SCORE (IPSS) McVary KT, et al. J Urol. 2011;185(5): Available at THE PURPOSE OF THE VOIDING DIARY ² Identifies voiding frequency and voided volume ² Differentiates behavioral vs LUTS pathology - Voiding frequently excessive volume(behavioral) small amounts as a result of always being in a rush (behavioral) small amounts (OAB) ² Alerts patients to habits /opportunities to modify ² Can monitor effect of treatment Wyman JF, et al. Int J Clin Pract. 2009; 63(8): NACE Emerging Challenges in Primary Care: 2014 OAB - 55

56 POST-VOID RESIDUAL ² FACTS - 50 ml or less represents adequate emptying ml or more is consistent with clinically significant inadequate emptying ² WHEN TO CHECK - Clinical suspicion - Refractory to therapy for BPH - Prior to pharmacologic treatment of OAB Rosenberg MT, et al. Int J Clin Pract. 2010;64(4): AUA Guidelines available at: URINE FLOW RATE It is all about the arc of the void Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4): NACE Emerging Challenges in Primary Care: 2014 OAB - 56

57 LUTS AND INDICATIONS FOR REFERRAL ² Suspicion of neurologic cause of symptoms ² History of recurrent UTI or other infection ² Findings or suspicion of urinary retention ² Abnormal prostate exam (nodules) ² Microscopic or gross hematuria ² History of genitourinary trauma ² Prior genitourinary surgery ² Uncertain diagnosis ² Meatal stenosis ² Elevated PSA ² Pelvic pain Rosenberg MT, et al. Int J Clin Pract. 2007;61(9): Rosenberg MT, et al. Int J Clin Pract. 2010;64(4): THE NEXT STEP Rosenberg MT, et al. Current Urology Reports Dec;14(6): NACE Emerging Challenges in Primary Care: 2014 OAB - 57

58 THE NEXT STEP: STEP 1 Rosenberg MT, et al. Current Urology Reports Dec;14(6): STEP 1: INFORMED SURVEILLANCE. If the patient has symptoms but no bother and no complications Patients who opt for this may benefit from: ² Education and reassurance ² Lifestyle changes (exercise, weight management) ² Fluid management ² Bladder training: timed and complete voiding ² Medication modification ² Validation: LUTS:BPH significant QoL impact Yap T, et al. Curr Opin Urol. 2010;20: Burgio KL, et al. Int J Clin Pract. 2013;67(6): NACE Emerging Challenges in Primary Care: 2014 OAB - 58

59 THE NEXT STEP: STEP 2 Rosenberg MT, et al. Current Urology Reports Dec;14(6): RATIONALE FOR ALPHA-BLOCKER OR PDE5I THERAPY Alpha-blockers PDE5is Dynamic component Rapidly relieve symptoms by inhibiting contraction of prostate smooth muscle Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4): Roehrborn CG. Rev Urol. 2009;11(Suppl 1):S1-8. Rosenberg MT, et al. Current Urology Reports Dec;14(6): NACE Emerging Challenges in Primary Care: 2014 OAB - 59

60 STEP 2: ALPHA BLOCKERS (AB) Single medication therapy with an AB is appropriate for the symptomatic patient who has identified bother and has a PSA of < 1.5 ng/ml ² Generally fast acting, relieving symptoms within hours ² Does not affect progression of prostate growth Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4): STEP 2: ALPHA BLOCKERS Non - Uroselective Terazosin 1, 2, 5, 10 mg daily Doxazosin 1,,2, 4, 8 mg daily Uroselective Tamsulosin 0.4 mg daily Alfuzosin 10 mg daily Silodosin 8 mg daily Potential side effects (decreased incidence with uroselective agents) ² Asthenia, fatigue, dizziness ² Postural hypotension ² Congestion, rhinitis, cough ² Abnormal ejaculation ² Edema ² Headache Physician s Desk Reference, 64 ed. Montvale, NJ:Thomson PDR; Lepor H. Rev Urol. 2007;9: Roehrborn CG. Rev Urol. 2009;11(Suppl 1):S NACE Emerging Challenges in Primary Care: 2014 OAB - 60

61 STEP 2: PHOSPHODIESTERASE 5 INHIBITORS(PDE5I) Monotherapy with a PDE5-I is appropriate for the symptomatic patient who has identified bother and has a PSA of < 1.5 ng/ml. The potential favorable impact of this therapy on male sexual function should be considered ² It is believed that the PDE5i increase the signaling of the NO/cGMP pathway, which reduces smooth muscle tone in the lower urinary tract ² It is not believed that use of a PDE5i will reduce progression of prostate growth 121 Roehrborn CG, et al. J Urol. 2008;180(4): Rosenberg MT, et al. Current Urology Reports Dec;14(6): STEP 2: PHOSPHODIESTERASE TYPE 5 INHIBITORS Medication Dose Indication Tadalafil 2.5 mg per day ED Tadalafil 5.0 mg per day BPH and ED Common side effects: headache, back pain, myalgia, dizziness, flushing and dyspepsia. Contraindicated in patients who use nitrates. Patients should not use tadalafil if sex is inadvisable due to cardiovascular status. Roehrborn CG, et al. J Urol. 2008;180(4): Oelke M, et al. Eur Urol. 2013;64(1): Nehra A, et al. Mayo Clin Proc. 2012;87(8): Cialis (product insert). Indianapolis, IN; Eli Lilly and Company, NACE Emerging Challenges in Primary Care: 2014 OAB - 61

62 PDE-5 Inhibitors Pharmacokinetics Parameters Available doses, mg T max, hours T ½, hours Sildenafil 1 25, 50, Vardenafil 2 5, 10, Tadalafil 3 2.5, 5, 10, Avanafil 4 50, 100, See Drugs@FDA ( 2. See Drugs@FDA ( 3. See Drugs@FDA ( 4. See Drugs@FDA ( 123 TADALAFIL IN BPH-LUTS ONCE-DAILY DOSING Total IPSS Change From Baseline IPSS-HRQoL Change From Baseline N=427 men who completed a 12-week, placebo-controlled, dose-finding study assessing once-daily tadalafil for BPH-LUTS. HRQoL, health-related quality of life. Donatucci CF, et al. BJU Int. 2011;107: NACE Emerging Challenges in Primary Care: 2014 OAB - 62

63 ADVERSE EVENTS WITH TADALAFIL ONCE-DAILY VS ON-DEMAND DOSING Adverse Event 5 mg Once Daily a N=238 5/10/20 mg On Demand b N=1173 Headache 2.1% 15.8% Dyspepsia 3.8% 11.8% Nasopharyngitis 5.9% 11.4% Back pain 5.0% 8.2% Influenza-like illness 2.5% 3.2% Discontinuation due to adverse events possibly related to the study drug 0.8% 3.1% a 24-month extension trial of tadalafil 5 mg once daily for erectile dysfunction. b Pooled 24-month extension trial data from five 8- or 12-week studies examining on-demand tadalafil for erectile dysfunction. Montorsi F, et al. Eur Urol. 2004;45: ; Porst H, et al. J Sex Med. 2008;5; WHAT ABOUT PDE5IS AND ABS? ² Recent studies show benefit of PDE5i/AB combination therapy over AB monotherapy - Improvement in IPSS - No added benefit in urodynamic parameters ² Concerns over hemodynamics effects of combination therapy not demonstrated Bechara A, et al. J Sex Med. 2008;5: Giuliano F, et al. Urology. 2006;67: Liguori G, et al. J Sex Med. 2009;6: Kaplan SA, et al. Eur Urol. 2007;51: Gacci M, et al. Eur Urol. 2012;61(5): NACE Emerging Challenges in Primary Care: 2014 OAB - 63

64 PDE-5 INHIBITORS AND Α-BLOCKERS Effects on IPSS, Erectile Dysfunction, and Flow Rate Source IPSS Mean Differences IIEF Score Mean Differences Qmax Mean Differences Kaplan et al, 2007 Bechara et al, 2008 Liguori et al, 2009 Tuncel et al, 2009 Gacci et al, 2012 Overall α-blocker + PDE-5 inhibitor α-blocker alone α-blocker + PDE-5 inhibitor α-blocker α-blocker alone + PDE-5 inhibitor Compared with α-blockers alone, the combination regimens significantly improved IPSS (P=0.05), IIEF scores (P<0.0001), and Qmax (P<0.0001) These studies examined the PDE-5 inhibitors tadalafil, sildenafil, and vardenafil, and the α-blockers alfuzosin and tamsulosin. Gacci M, et al. Eur Urol. 2012;61: THE NEXT STEP: STEP 3A Rosenberg MT, et al. Current Urology Reports Dec;14(6): NACE Emerging Challenges in Primary Care: 2014 OAB - 64

65 RATIONALE FOR COMBINING AB/PDE5I WITH ANTIMUSCARINIC/BETA - 3 Antimuscarinics Alpha-blockers PDE5s Blocks contraction of detrusor Dynamic component Rapidly relieve symptoms + Beta 3 Agonists Facilitates bladder storage Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4): Rosenberg MT, et al. Current Urology Reports Dec;14(6): STEP 3A: ADDITION OF AN ANTIMUSCARINIC OR BETA-3 AGONIST If the patient has symptoms of both obstruction and irritation as well as bother ² In multiple studies the addition of an antimuscarinic to an α-blocker was more efficacious in reducing voiding frequency, nocturia, or IPSS compared to α- blockers or placebo alone. ² Not yet studied - β3 agonists+ α-blocker - β3 agonist + PDE5i - Antimuscarinic + PDE5i Oelke M, et al. Eur Urol. 2013;64(1): Rosenberg MT, et al. Current Urology Reports Dec;14(6): NACE Emerging Challenges in Primary Care: 2014 OAB - 65

66 ANTIMUSCARINICS IMMEDIATE RELEASE Drug Brand Name Dose Dosing Oxybutynin IR Ditropan 5 mg 1 3 times per day Tolterodine IR Detrol 1-2 mg Twice per day Trospium Chloride Sanctura 20 mg Twice per day Physcians Desk Reference. 64st ed. Montvale, NJ: Thomson PDR; ANTIMUSCARINICS EXTENDED RELEASE extended release medications have a better tolerability than their immediate release counterparts Drug Brand Name Dose Dosing Darifenacin Enablex 7.5 mg, 15 mg Daily Fesoterodine Toviaz 4 mg, 8 mg Daily Oxybutynin ER Ditropan XL 5 30 mg Daily Oxybutynin TDS Oxytrol 3.9 mg Twice per week Oxybutynin 10% gel Gelnique 100 mg Daily Solifenacin Vesicare 5 mg, 10 mg Daily Tolterodine ER Detrol LA 2, 4 mg Daily Trospium Chloride Sanctura XR 60 mg Daily Physcians Desk Reference. 64st ed. Montvale, NJ: Thomson PDR; NACE Emerging Challenges in Primary Care: 2014 OAB - 66

67 COMMON SIDE EFFECTS OF ANTIMUSCARINICS ² Dry Mouth ² Constipation ² Headaches ² Blurred vision Clinicians should manage constipation and dry mouth before abandoning effective antimuscarinic therapy. Balance of efficacy and tolerability should be considered and discussed with each patient. 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 March 21, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS FOR ANTIMUSCARINICS ² Contraindications- - Urinary or gastric retention - Uncontrolled narrow-angle glaucoma ² Warnings & Precautions - Angioedema of face, lips, tongue and/or larynx - Clinically significant bladder outlet obstruction - Decreased gastrointestinal motility - Treated narrow angle glaucoma - May have CNS effects i.e., somnolence - Use with caution in patients with myasthenia gravis Physicians Desk Reference. 64st ed. Montvale, NJ: Thomson PDR; Oelke M, et al. Eur Urol. 2013;64(1): NACE Emerging Challenges in Primary Care: 2014 OAB - 67

68 BETA-3 ADRENERGIC AGONISTS Drug Brand Name Dose Dosing Mirabegron Myrbetriq 25 mg, 50 mg Daily Myrbetriq (mirabegron) prescribing information, Astellas Pharma US, Inc. June COMMON SIDE EFFECTS OF MIRABEGRON ² Hypertension ² Nasopharyngitis ² Urinary Tract Infections ² Headaches Balance of efficacy and tolerability should be considered and discussed with each patient. Myrbetriq (mirabegron) prescribing information, Astellas Pharma US, Inc. June NACE Emerging Challenges in Primary Care: 2014 OAB - 68

69 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS FOR MIRABEGRON ² Contraindications NONE ² Precautions & Warnings - Not recommended for use in severe uncontrolled hypertensive patients - Use with caution in patients with urinary retention or bladder outlet obstruction - Use with caution in patients taking antimuscarinic drugs for overactive bladder - Caution with use in patients taking drugs metabolized by CYP2D6 (i.e., metoprolol or desipramine) as mirabegron is a moderate inhibitor of CYP2D6 Myrbetriq (mirabegron) prescribing information, Astellas Pharma US, Inc. June THE NEXT STEP: STEP 3B Rosenberg MT, et al. Current Urology Reports Dec;14(6): NACE Emerging Challenges in Primary Care: 2014 OAB - 69

70 RATIONALE FOR COMBINING AB/ PDE5I WITH 5ARI Alpha-blockers PDE5s 5-alpha-reductase inhibitors (5ARIs) Dynamic component Rapidly relieve symptoms Static component Arrest disease progression Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4): Rosenberg MT, et al. Current Urology Reports Dec;14(6): STEP 3B: ADDING A 5 ALPHA REDUCTASE INHIBITOR (5ARI) The addition of a 5ARI is appropriate for the symptomatic patient with BPH-LUTS who has identified bother and has a PSA of 1.5 ng/ml or greater ² Prostate growth may result in symptom progression, AUR and surgery ² Prostate growth is stimulated by dihydrotestosterone (DHT) with is converted from testosterone by the 5-alpha reductase enzyme ² Decreasing DHT may induce prostatic epithelial apoptosis and atrophy which can lead to approximately 18% 28% reduction in prostate size and approximately a 50% reduction in PSA levels after 6-12 months Naslund MJ, et al. Clin Ther. 2007;29(1): Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4): NACE Emerging Challenges in Primary Care: 2014 OAB - 70