OAB Made Simple for the Primary Care Provider (PCP): How...

OAB Made Simple for the Primary Care Provider (PCP): How to Identify, When to Treat and When to Refer

NACE – Emerging Challenges in Primary Care: 2014 OAB - 1

Emerging Challenges In Primary Care: 2014

!

Faculty

OAB Made Simple for the Primary Care Provider (PCP):

How to Identify, When to Treat and When to

Refer

Matt T. Rosenberg, MD Medical Director of Mid-Michigan Health Centers

Jackson, MI Section Editor of

Urology, International Journal of Clinical

Practice

Louis Kuritzky, MD Clinical Assistant

Professor Department of

Community Health & Family Medicine

University of Florida Gainesville, FL

Pamela Ellsworth, MD Professor of Urology

Department of Urology UMass Memorial Medical

Center/University of Massachusetts Medical

School Worcester, MA

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

FACULTY DISCLOSURES

2



PRE-TEST QUESTIONS OAB/LUTS

3

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

PRE-TEST QUESTION 1 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


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?

5

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



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

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



PRE-TEST QUESTIONS LUTS

9

On a scale of 1 to 5, please rate how confident you would be with diagnosing and treating lower

urinary tract symptoms in men.


10

PRE-TEST QUESTION 1 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


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




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


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




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;61:37-49. Rosenberg MT, et al. Int J Clin Pract. 2007;61:1535-1546. 16



PREVALENCE OF OAB SYMPTOMS

Coyne S, et al. Urology. 2011;77:1081-1087.

1 in 3 US adults ≥40 years of age reported symptoms of OAB at least “sometimes”

Age (years)

Resp

onde

nts

(%)

17

Stewart WF, et al. World J Urol. 2003;20(6):327-336. Pleis JR, Coles R. Summary health statistics for U.S. adults: National Health Interview Survey, 1998. Vital Health Stat 10. 2002;209:1-113. 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; 1997. DHHS Publication No. (PHS) 97-1522. «http://www.cdc.gov/nchs/data/series/sr_10/sr10_194.pdf».

Overactive Bladder Chronic Sinusitis

Arthritic Symptoms

Hay Fever/Allergic Rhinitis Heart Disease

Asthma

Chronic Bronchitis Diabetes

Ulcer

0 10 20 30 40Millions

OAB & OTHER DISORDERS

18



To cope with symptoms of OAB, many patients

employ elaborate behaviors aimed at hiding and managing urine loss

Rosenberg MT. Curr Urol Rep. 2008. Abrams et al. Am J Manag Care. 2000 Jul;6(11 Suppl):S580-S590. Ricci JA, et al. Clin Ther. 2001;23:1245-1259.

Restrict fluid intake

Carry extra clothes in case of wetting accident

Try to urinate on a schedule

Bathroom mapping

Wear dark, baggy clothes to hide wet

spots or wear diapers

Use diapers or other

absorbent products

COPING STRATEGIES

19

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;20:327-336. Rovner E, Wein A. Curr Urol Rep. 2002;3:434-438. Milsom I et al. BJU Int. 2001;87:760-766. Benner J et al. J Urol. 2009;181:2591-2598. Rosenberg M et al. Cleve Clinic J Med. 2007;74:S21-S29. Goepel M et al. Eur Urol. 2002;41:234-239. Dmochowski RR et al. Curr Med Res Opin. 2007;23:65-76.

OAB IS PREVALENT, UNDIAGNOSED AND UNDERTREATED

20



The Reality is We Can Do Better in the Identification

and Treatment of OAB

21

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!!!!!!

WHY IS OAB UNDERDIAGNOSED AND UNDERTREATED?

22



Rosenberg MT. Curr Urol Rep. 2008;9:428-432.Yu YF, et al. Value Health. 2005;8:495-505.

IDENTIFYING OAB TAKES A VILLAGE

23

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;23:1245–1259. Milsom I, et al. BJU Int 2001;87:760–766. 24



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; 21:1413-1421.

WHAT DO PATIENTS SAY?

25

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;20:327-336. Darkov T, et al. Pharmacotherapy. 2005;25:511-519. Ailinger RL, et al. J Comm Health Nurs. 2005;22:135-142. Rosenberg M et al. Cleve Clinic J Med. 2007;74:S21-S29. 26



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):1413-1421. 27

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):1413-1421. 28



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;48:721-725. 29

Current Thinking Is a Myth

30



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



WHAT DOES THE PCP NEED?

²  Keep It Simple

33



²  Keep It Effective

34





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



What are the normal functions of the bladder?

37

²  Normal Function -  Storage capacity (300 – 500 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; 2007:1973-1985.

FUNCTION OF THE BLADDER

38



What are the normal functions of the prostate?

39

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; 2007:1973-1985.

FUNCTION OF THE PROSTATE

40



LOWER URINARY TRACT SYMPTOMS (LUTS): BLADDER OR PROSTATE?

Storage (bladder) Voiding (prostate) Urgency Hesitancy

Frequency Poor flow/weak stream Nocturia Intermittency

Urge incontinence Straining to void Stress incontinence Terminal dribble Mixed incontinence Prolonged urination

Overflow incontinence Urinary retention

Chapple CR, et al. Eur Urol. 2006;49:651-658. 41

It is all about VOLUME VOIDED

and FLOW

Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4):488-496. 42



Guess What Happens When You Understand

What is Normal?

43


What is Normal? ²  Your patients will understand what is normal, and

subsequently, what is abnormal

44




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

Treat or Refer

LUTS

Focused HPE UA/PSA Blood Sugar

Desires Treatment?

Watchful Wai@ng

Treat for BPH Con@nue Meds

Assess and Treat OAB/SI

Con@nue Meds

Refer

Unlikely OAB/BPH/SI

Likely OAB/BPH/SI

No

Yes Provisional BPH Provisional OAB/SI

Effec@ve

Ineffec@ve

Effec@ve

Ineffec@ve

Modified from Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9):1535-1546.

THE LUTS ALGORITHM 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

46



DEFINING LUTS

Frequency •  Patient considers that he/she voids too

often by day •  Normal is < 8 times per 24 hours

Nocturia •  Waking to urinate during sleep hours •  Considered a clinical problem if

frequency is greater than twice a night

Urgency •  Sudden compelling desire to pass urine that is difficult to defer

UUI •  Involuntary leakage accompanied by, or immediately preceded by, urgency

OAB “Wet” •  OAB with UUI

OAB “Dry” •  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:S559-64.

47

SIMPLE QUESTIONS THE PCP CAN ASK

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:S559-64.

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?

48



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

49 Gormley EA, et al. American Urological Association (AUA) Guideline. AUA Web site. 2012. http://www.auanet.org/content/media/OAB_guideline.pdf. Accessed March 21, 2014.

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



MEDICATIONS AS A CAUSE OF LUTS

Sedatives Confusion, secondary incontinence

Alcohol, Caffeine, Diuretics Diuresis

Anticholinergics Impair contractility, voiding difficulty, overflow incontinence

α – Agonists Increased outlet resistance, voiding difficulty

ß - Blockers Decreased urethral closure, stress incontinence

Calcium-Channel Blockers Reduce bladder smooth muscle contractility

ACE Inhibitors Induce cough, stress urinary incontinence

First generation antihistamines

Increase outlet resistance

Cholinesterase inhibitors Precipitate urge incontinence

Opioids Direct effect, constipation

Wyman JF, et al. Int I Clin Pract. 2009;63:1177-1191. Newman DK. Nurse Pract. 2009;34:33-45. 51

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-S29. 52



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;61,9,1535-1546. Bosch J, et al. Eur Urol. 2004;46:753-759 Roerborn CG, et al. Urology. 1999;53;381-9. 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):1177-91 54



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):428-32. Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9):1535-1546. 55

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),1535-1546 56



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;9:428–432. 57

Treat or Refer

LUTS

Focused HPE UA/PSA Blood Sugar

Desires Treatment?

Watchful Wai@ng

Treat for BPH Con@nue Meds

Assess and Treat OAB/SI

Con@nue Meds

Refer

Unlikely OAB/BPH/SI

Likely OAB/BPH/SI

No

Yes Provisional BPH Provisional OAB/SI

Effec@ve

Ineffec@ve

Effec@ve

Ineffec@ve

Modified from Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9):1535-1546.

THE MALE (OR PROSTATE) DILEMMA

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

58



TREATMENT GUIDELINES FOR OAB

Kirby M, et al. Int J Clin Pract. 2006;60:1263-1271.Burgio K, et al. J Am Geriatr Soc. 2000;48:370-374 .

²  Behavioral treatment ²  Pharmacologic management ²  Referral for specialist management/surgery

59

Gormley EA, et al. American Urological Association (AUA) Guideline. AUA Web site. 2012. http://www.auanet.org/content/media/OAB_guideline.pdf. Accessed March 21, 2014.

BEHAVIORAL THERAPY FOR OAB

Behavioral Therapy for OAB

Bladder training

Educa:on reinforcement

Pelvic floor exercises

Biofeedback

Diaries

Timed voiding

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: 1000-1004 60



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;63:1177-91. Wagg AS, et al. BJU Int. 2007;99:502-9. Lucas MG, et al. Eur Urol 2012;62(6):1130-42.

61

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 30-40 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

Harv Womens Health Watch. www.health.harvard.edu/newsletters/Harvard_Womens_Health_Watch/2011/ January/how-to-perform-kegel-exercises.

The exercises can be performed anywhere 62



–100

–80

–60

–40

–20

0

Mea

n R

educ

tion

in U

I, %

Behavioral Therapy

Combined Therapy

Drug Therapy

Combined Therapy

P < .05 P = .001

–57.5%

–88.5%

–72.7%

–84.3%

ADDITIVE EFFECT OF COMBINING BEHAVIORAL AND DRUG THERAPY

Burgio KL, et al. J Am Geriatr Soc. 2000;48:370-374. 63

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



Antimuscarinics ACH

NE

M3 muscarinic receptor

Detrusor smooth muscle

(relaxation) Norepinephrine

β3 AR

β3 agonist

–

+

Acetylcholine

(contraction)

RECEPTOR PATHWAYS FOR OAB TREATMENT

Takeda M, et al. J Pharmacol Sci. 2010;2110:121-127. Fowler CJ, et al. Nat Rev Neurosci. 2008;8:453-466. 65

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; 2010. 66



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


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;33:475-482. Erdam N, et al. Am J. Med 2006;119(suppl 1):29-36. Gormley EA, et al. American Urological Association (AUA) Guideline. AUA Web site. 2012. http://www.auanet.org/content/media/OAB_guideline.pdf. Accessed March 21, 2014. 68



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; 2010. Oelke M, et al. Eur Urol. 2013;64(1):118-140. 69

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 2012. 70



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.


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




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):960-7. Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9):1535-1546. Martin-Merino E, et al. J Urol. 2009; 182(4):1442-8. 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 2012. 73

HIGH DISCONTINUATION RATE FOR PATIENTS ON OAB THERAPY

*Cumulative incidence of discontinuation was determined using the Kaplan-Meier method.

Gopal M, et al. Obstet Gynecol. 2008;112:1311-1318.

Study Design: UK study. Overall drug discontinuation for all women prescribed anticholinergic medications (N=29,369). Unadjusted cumulative incidence of discontinuation (95% CI).

Months to Discontinuation

Dis

cont

inua

tion

Rat

e (%

) Fr

om

Ant

icho

liner

gics

for

OA

B (9

5% C

I)*

Adapted from Gopal et al.

74



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, 9:428–432. DeCastro J, et al. Am J Med. 2008;121:S27-S33. 75

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. 2012. http://www.auanet.org/content/media/OAB_guideline.pdf. Accessed March 21, 2014

76



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

•  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;9:428-432.Yu YF, et al. Value Health. 2005;8:495-505.

TREATING OAB TAKES A VILLAGE

78



POST-TEST QUESTIONS OAB

79

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

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?

80



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

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



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

On a scale of 1 to 5, please rate how confident you would be in the diagnosis and management

of a patient with OAB.


84




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 methods. 85

Faculty

Emerging Challenges In Primary Care: 2014

!

Evaluating and Treating LUTS in the Primary Care Setting

Matt T. Rosenberg, MD Medical Director of Mid-Michigan Health Centers

Jackson, MI Section Editor of

Urology, International Journal of Clinical

Practice

Louis Kuritzky, MD Clinical Assistant

Professor Department of

Community Health & Family Medicine

University of Florida Gainesville, FL

Pamela Ellsworth, MD Professor of Urology

Department of Urology UMass Memorial Medical

Center/University of Massachusetts Medical

School Worcester, MA



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



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 ABNORMAL FUNCTION

² Produces fluid for seminal emission

² Does not grow into the urethra thereby allowing unobstructed flow

² Obstruction of urinary flow

² Poor function seen as failure to void

90 Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.



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.

91 McVary KT, et al. J Urol. 2011;185(5):1793-1803. Roehrborn C, et al. J Urol. 2000;163(1):13–20.

RISK EVALUATION OF BPH-LUTS PROGRESSION

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.  Qmax <10.6 mL/s 5.  PVR ≥39 mL

92

PVR, post-void residual; Qmax, maximum flow rate. Crawford ED, et al. Urology. 2006;175(4):1422-1427. Rosenberg MT, et al. Current Urology Reports. 2013 Dec;14(6):595-605.

Baseline Factors as Predictors



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.

93 Roehrborn CG. Int J Impot Res. 2008;20 Suppl 3:S19-26.

FUNCTION OF THE BLADDER

NORMAL FUNCTION ABNORMAL FUNCTION

²  Storage capacity of 300 – 500 ml of fluid

²  Empty to completion after a gentle urge

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 Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.



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;61:37-49. Rosenberg MT, et al. Int J Clin Pract. 2007;61:1535-1546. 95

USING SYMPTOMS TO DISTINGUISH THE ORIGIN OF THE PROBLEM

96

Urine Storage

Urgency

Frequency

Urgency incontinence

Nocturia

Urine Voiding

Hesitancy

Weak stream

Intermittent

Straining

Kapoor A. Can J Urol. 2012;19 Suppl 1:10-17. Abrams P, et al. Neurourol Urodyn. 2002;21:167-178.



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

97

It is all about volume and flow

Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.

OAB AND BPH CAN COEXIST

98

BPH OAB

Rosenberg MT, et al. Int J Clin Pract. 2007;61,9,1535-1546.

LUTS



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

100 Roehrborn CG, et al. BJU Int. 2007;100(4):813-819.



Lee RK and Chung D, et al. BJU Int. 2012;110(4):540-545. Parsons JK. Curr Bladder Dysfunct Rep. 2010;5(4):212-218. Robert G. Curr Opin Urol. 2011;21(1):42-48. Roehrborn CG. BJU Int. 2006;97(S2):7-11. Rosen R. Eur Urol. 2003;44(6):637-649. Shabsigh R, et al. BMC Urol. 2010;10:18. Woo HH, et al. Med J Aust. 2011;195(1):34-39.

LINKING LUTS-BPH AND ED 101 LUTS-BPH

Risk Factors Comorbidities •  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

• Cardiovascular disease

• Diabetes/Disrupted glucose homeostasis

• Erectile dysfunction • Metabolic syndrome • Obesity

ED Risk Factors Comorbidities

•  Increasing age • Smoking • High waist

circumference

• Cardiovascular disease

• Depression • Diabetes • Hypercholesterolemia • Lower urinary tract

symptoms • Metabolic syndrome • Obesity

22.3

19.2

15.3

21.1

18.3

13.2

18.9

15.8

10.3

14.912.4

7.5

0

10

20

30

50-59 Years 60-69 Years 70-79 Years

NoMildModerateSevere

LUTS-BPH AND ED AND DIRECTLY RELATED

102

N=10,636 men who had been sexually active within the last 4 weeks. IIEF, International Index of Erectile Function. McVary KT. BJU Int. 2006;97:23-28.

Worse Erectile

Function

Better Erectile

Function Age Effect

Mea

n IIE

F Er

ectil

e

Func

tion

Dom

ain

LUTS Effect LUTS Effect LUTS Effect

LUTS Severity



BPH-LUTS AND ED COMMON PATHOPHYSIOLOGIC MECHANISMS

103 cGMP, cyclic guanosine monophosphate; NO, nitric oxide; ROCK, Rho-associated protein kinase. Gacci M, et al. Eur Urol. 2011;60(4):809-825.

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

Comorbidities Hypertension, Metabolic Syndrome, Diabetes, etc.

Chronic inflammation Steroid hormone unbalance

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

WHAT TO KEEP IN MIND IN THE EVALUATION OF LUTS

Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546. 104



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

105

Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546. Burgio KL, et al. Int J Clin Pract. 2013;67(6):495-504.

The temporal relationship may offer a clue

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

106 Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546. Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4):488-496.



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)

107 Rosenberg MT, et al. Int J Clin Pract. 2007;61,9,1535-1546. Bosch J, et al. Eur Urol. 2004;46(6):753-759. Roerborn CG, et al. Urology. 1999;53;581-589.

OPTIONAL TESTS

²  International Prostate Symptom Score (IPSS)

² Voiding Diary

² Post Void Residual (PVR)

² Urine Flow Rate (Qmax)

108 Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546. Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4):488-496.



INTERNATIONAL PROSTATE SYMPTOM SCORE (IPSS)

109 McVary KT, et al. J Urol. 2011;185(5):1793-1803. Available at http://www.urospec.com/uro/Forms/ipss.pdf

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):1177-91 110



POST-VOID RESIDUAL

² FACTS -  50 ml or less represents adequate emptying

-  200 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

111 Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-96.. AUA Guidelines available at: http://www.auanet.org/education/guidelines/benign-prostatic-hyperplasia.cfm .

URINE FLOW RATE

112

It is all about the “arc” of the void

Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4):488-496.



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

113 Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546. Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.

THE NEXT STEP

114 Rosenberg MT, et al. Current Urology Reports. 2013 Dec;14(6):595-605.



THE NEXT STEP: STEP 1


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

116 Yap T, et al. Curr Opin Urol. 2010;20:20-27. Burgio KL, et al. Int J Clin Pract. 2013;67(6):495-504.





RATIONALE FOR ALPHA-BLOCKER OR PDE5I THERAPY

118

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):488-496. Roehrborn CG. Rev Urol. 2009;11(Suppl 1):S1-8. Rosenberg MT, et al. Current Urology Reports. 2013 Dec;14(6):1595-605.



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

119 Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4):488-496.

STEP 2: ALPHA – BLOCKERS Non - Uroselective Uroselective

Terazosin 1, 2, 5, 10 mg daily Tamsulosin 0.4 mg daily

Doxazosin 1, ,2, 4, 8 mg daily Alfuzosin 10 mg daily

Silodosin 8 mg daily

120

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; 2010. Lepor H. Rev Urol. 2007;9:181-190. Roehrborn CG. Rev Urol. 2009;11(Suppl 1):S1-8.



STEP 2: PHOSPHODIESTERASE 5

INHIBITORS(PDE5I)

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):1228-1234. Rosenberg MT, et al. Current Urology Reports. 2013 Dec;14(6):595-605.

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

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.

122 Roehrborn CG, et al. J Urol. 2008;180(4):1228-1234. Oelke M, et al. Eur Urol. 2013;64(1):118-140. Nehra A, et al. Mayo Clin Proc. 2012;87(8):766-778. Cialis (product insert). Indianapolis, IN; Eli Lilly and Company, 2011.



PDE-5 Inhibitors

Pharmacokinetics

1. See Drugs@FDA (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020895s036lbl.pdf); 2. See Drugs@FDA (http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021400s011lbl.pdf); 3. See Drugs@FDA (http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021368s012lbl.pdf); 4. See Drugs@FDA (http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202276s001lbl.pdf);

Parameters Available doses, mg Tmax, hours T½, hours

Sildenafil1 25, 50, 100 1 4

Vardenafil2 5, 10, 20 1 4-5

Tadalafil3 2.5, 5, 10, 20 2 17.5

Avanafil4 50, 100, 200 0.5-0.75 5

123

TADALAFIL IN BPH-LUTS ONCE-DAILY DOSING

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;107:1110-1116.

Tot

al IP

SS C

hang

e F

rom

Bas

elin

e

IPSS

-HR

QoL

Cha

nge

Fr

om B

asel

ine

124



ADVERSE EVENTS WITH TADALAFIL ONCE-DAILY VS ON-DEMAND DOSING

Adverse Event 5 mg

Once Dailya N=238

5/10/20 mg On Demandb

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%

a24-month extension trial of tadalafil 5 mg once daily for erectile dysfunction. bPooled 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;45:339-344; Porst H, et al. J Sex Med. 2008;5;2160-2169. 125

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

126 Bechara A, et al. J Sex Med. 2008;5:2170–2178. Giuliano F, et al. Urology. 2006;67:1199–1204. Liguori G, et al. J Sex Med. 2009;6:544–552. Kaplan SA, et al. Eur Urol. 2007;51:1717–1723. Gacci M, et al. Eur Urol. 2012;61(5):994-1003.



PDE-5 INHIBITORS AND Α-BLOCKERS Effects on IPSS, Erectile Dysfunction, and Flow Rate

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;61:994-1003.

Kaplan et al, 2007

Bechara et al, 2008

Liguori et al, 2009

Gacci et al, 2012

Overall

Source IPSS Mean Differences

-6 -4 -2 0 2

Tuncel et al, 2009

α-blocker + PDE-5 inhibitor

α-blocker alone

IIEF Score Mean Differences

0 6 8 10 12


4 2

Qmax Mean Differences

-2 0 2 4 6


α-blocker alone

Compared with α-blockers alone, the combination regimens significantly improved IPSS (P=0.05), IIEF scores (P<0.0001), and Qmax (P<0.0001)

127

THE NEXT STEP: STEP 3A




RATIONALE FOR COMBINING AB/PDE5I WITH ANTIMUSCARINIC/BETA - 3

129

Alpha-blockers

PDE5s

Dynamic component Rapidly relieve symptoms

Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4):488-496. Rosenberg MT, et al. Current Urology Reports. 2013 Dec;14(6):595-605.

Antimuscarinics

Blocks contraction of detrusor

Beta 3 Agonists

Facilitates bladder storage

+

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

130 Oelke M, et al. Eur Urol. 2013;64(1):118-140. Rosenberg MT, et al. Current Urology Reports. 2013 Dec;14(6):595-605.



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


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




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;33:475-482. Erdam N, et al. Am J. Med 2006;119(suppl 1):29-36. Gormley EA, et al. American Urological Association (AUA) Guideline. AUA Web site. 2012. http://www.auanet.org/content/media/OAB_guideline.pdf. Accessed March 21, 2014.

133

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; 2010. Oelke M, et al. Eur Urol. 2013;64(1):118-140. 134



BETA-3 ADRENERGIC AGONISTS

Drug Brand Name Dose Dosing Mirabegron Myrbetriq 25 mg, 50 mg Daily


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.




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


THE NEXT STEP: STEP 3B




RATIONALE FOR COMBINING AB/PDE5I WITH 5ARI

139

5-alpha-reductase inhibitors (5ARIs)

Static component Arrest disease progression

Alpha-blockers

PDE5s

Dynamic component Rapidly relieve symptoms

Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4):488-496. Rosenberg MT, et al. Current Urology Reports. 2013 Dec;14(6):595-605.

STEP 3B: ADDING A 5 ALPHA REDUCTASE

INHIBITOR (5ARI)

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

140 Naslund MJ, et al. Clin Ther. 2007;29(1):17-25. Rosenberg MT, et al. Int J Clin Pract. 2010; 64(4):488-496.

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



5 ARIS

Drug Dosage

Finasteride Dutasteride

5 mg daily 0.5 mg daily

Potential side effects ²  Diminished ejaculatory volume ²  Erectile dysfunction ²  Decreased libido ²  Gynecomastia ²  Increase risk of high-grade prostate cancer *

* Conflicting data in the literature Physicians’ Desk Reference. 64th ed. Montvale, NJ: Thomson PDR; 2010. Andriole G, et al. J Urol. 2004;172(4 Pt 1):1399-1403. Thompson, IM, et al. N Engl J Med. 2013;369(7):603-610.

141

COMBINATION THERAPY

²  Starting with combination therapy may allow immediate symptom relief from the AB or a PDE51 while facilitating prostate reduction from the 5ARI

²  Two prolonged studies (MTOPS and CombaT) using a AB and a 5ARI have shown that combination therapy is better than either monotherapy alone

²  One 26 week study showed that use of tadalafil with finasteride was better than finasteride alone

142

Crawford ED, et al. Urology. 2006;175:1422-1427. Roehrborn CG, et al. Eur Urol. 2009;55(2): 461-471. Kaplan S. J Urol. 2006;175(1):217-220. Roehrborn CG, et al. 28TH Annual EAU Congress; Milan, Italy; 15-19 March 2013



α-BLOCKER PLUS 5 ARI OUTPERFORMS MONOTHERAPY

IPSS = Interna@onal Prostate Symptom Score LOCF = last observa@on carried forward

IPSS -‐ Adjusted Mean Change From Baseline (LOCF)

Tamsulosin (n = 1582) Dutasteride (n = 1592) Combina:on (n = 1575)

-‐6.3 P<0.001 Combina:on vs Tamsulosin

P<0.001 Combina:on vs Dutasteride

Roehrborn CG, et al. Eur Urol. 2010;57(1):123-31.

-‐3.8

-‐8

-‐7

-‐6

-‐5

-‐4

-‐3

-‐2

-‐1

0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Treatment month

Chan

ge (u

nits)

-‐5.3

143

PDE5I PLUS 5 ARI OUTPERFORMS MONOTHERAPY

Roehrborn CG, et al. 28TH Annual EAU Congress; Milan, Italy; 15-19 March 2013

IPSS Total Score— LS Mean Changes at 4, 12,and 26 Weeks

144



EARLY VS DELAYED COMBINATIONS 5-ARI and α-Blocker

aClinical progression, defined as the occurrence of AUR or prostate surgery during the 12 months after first prescription fill. bDelayed combination therapy, initiation of a 5-ARI >30 days and <180 days after initial α-blocker treatment. cEarly combination therapy, initiation of an α-blocker and a 5-ARI on the same day, or a 5-ARI within 30 days of initial α-blocker treatment OR, odds ratio. N=13,551 men ≥50 years of age and treated for BPH-LUTS with a 5-ARI and an α-blocker. Morlock R, et al. Clin Ther. 2013;35:624-633.

Better Outcomes With Delayed Combination Therapyb

Better Outcomes With Early Combination Therapyc

1.0 0.0 3.0 2.0 5.0 4.0 7.0 6.0

Clinical Progressiona

AUR

Surgery

Total Costs

All Patients Patients with PSA values Patients with 1.5< PSA value <10 All Patients Patients with PSA values Patients with 1.5< PSA value <10 All Patients Patients with PSA values Patients with 1.5< PSA value <10 All Patients Patients with PSA values Patients with 1.5< PSA value <10

OR=1.70 OR=1.82

OR=2.33

OR=1.82

OR=1.54 OR=1.96

OR=1.75 OR=2.50

OR=3.45

OR=1.79 OR=1.75

OR=2.63

145





STEP 4: REFERRAL

For the patient with symptoms and bother who is

refractory to therapy

²  “Alarm symptoms” or “red flags” ² Failure to respond in a reasonable amount

of time -  Alpha blockers, PDE5is, antimuscarinics and β3

agonists should work quickly -  5 ARIs work slowly


SUMMARY

²  The cause of LUTS-BPH can be medical, the prostate or the bladder

²  A simple evaluation in the office of the PCP can elicit the cause in most cases

²  There appears to be a shared pathophysiology that underlies benign prostatic hyperplasia (BPH) and erectile dysfunction (ED)

²  The treatment of LUTS-BPH should occur in a step-wise fashion that depends on symptom severity, sexual function and risk factors

148



POST-TEST QUESTIONS LUTS

149

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

150

POST-TEST QUESTION 1 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

151


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

152




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

153


On a scale of 1 to 5, please rate how confident you would be with diagnosing and treating lower

urinary tract symptoms in men.


154




Which of the statements below describes your approach to participating in diagnosing and treating lower urinary tract

symptoms in men? 1.  I do not participate in the diagnosis and treatment of lower

urinary tract symptoms in male patients, nor do I plan to this year.

2.  I did not participate in the diagnosis and treatment of lower urinary tract symptoms in male patients before this course, but as a result of attending this course I’m thinking of doing this now.

3.  I do participate in the diagnosis and treatment of lower urinary tract symptoms in male patients and I now plan to change my treatment methods based on completing this course.

4.  I do participate in the diagnosis and treatment of lower urinary tract symptoms in male patients and this course confirmed that I don’t need to change my methods.

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OAB Made Simple for the Primary Care Provider (PCP): How...

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