Educational Partner:
Asante Communications, LLC
Conduct an initial and ongoing assessment of patients with benign prostatic hyperplasia (BPH), addressing lower
urinary tract symptoms (LUTS), coexisting disorders, and patient quality of life and function.
Evaluate the risk of BPH disease progression and complications.
Teach patients with BPH-LUTS practical self-management approaches and behavioral modifications to slow disease
progression.
Evaluate the clinical profiles and utility of 5- reductase inhibitors (5-ARIs),
-1 adrenergic receptor blockers, and phosphodiesterase-5 (PDE-5) inhibitors for patients with BPH-LUTS with and
without erectile dysfunction (ED).
Tailor monotherapy and multidrug regimens for patients with BPH-LUTS based in part on signs and symptoms, prior
medication history, ED and other common comorbidities, risk of disease progression, and patient goals.
Faculty
Session 2
Association, the Sexual Medicine Society of North America, and the European Society for Sexual Medicine. He is a reviewer
for several national and international journals and was recently selected to be the section editor of urology for the
International Journal of Clinical Practice.
Dr Rosenberg was honored as the most recent recipient of the Continence Care Champion award by the National
Association For Continence (NAFC). This nationwide award is bestowed by the NAFC board of directors to a healthcare
provider who has distinguished himself in research, clinical practice, and education with accomplishments meaningful to
continence care.
In the summer of 2006, Dr Rosenberg was featured in a PBS documentary on interstitial cystitis as part of the Healthy Body,
Healthy Mind series, which focused on some of his research findings in this clinical area.
Martin M. Miner, MD, serves as a consultant for Abbott Laboratories and receives research grants from Auxilium
Pharmaceuticals, Inc.
Matt T. Rosenberg, MD, serves as a consultant for Astellas Pharma US, Inc.; Eli Lilly and Company; Ferring
Pharmaceuticals Inc.; Horizon Pharma; and Pfizer Inc. He is on the speakers bureau for Astellas Pharma US, Inc.; Forest
Laboratories, Inc.; Horizon Pharma; Ortho-McNeil-Janssen Pharmaceuticals, Inc; and Pfizer Inc.
The content collaborators at Asante Communications, LLC, have reported the following:
Christopher S. Ontiveros, PhD, Group Scientific Supervisor, has no financial relationships to disclose.
Session 2
Trade
Alfuzosin
Doxazosin
Dutasteride
Finasteride
Uroxatral
Cardura, Cardura XL
Avodart
Propecia, Proscar
Fortamet, Glucophage, Glucophage XR,
Glumetza, Riomet
Actos
Revatio, Viagra
Rapaflo
Adcirca, Cialis
Flomax
Hytrin
Levitra, Staxyn
Metformin
Pioglitazone hydrochloride
Sildenafil
Silodosin
Tadalafil
Tamsulosin
Terazosin
Vardenafil
Benign Prostatic
Hyperplasia
Optimizing Management in
the Primary Care Setting
Faculty
Educational Objectives
Upon completion of this CME initiative, participants should be better
prepared to:
Matt T. Rosenberg, MD
Medical Director
Mid-Michigan Health Centers
Chief, Department of Family Medicine
Foote Health System
Jackson, Michigan
Martin M. Miner, MD
Clinical Associate Professor Family
Medicine and Urology
The Warren Alpert Medical School of
Brown University
Co-Director, Mens Health Center
Chief of Family and Community Medicine
Miriam Hospital
Providence, Rhode Island
Pre-Activity Evaluation
In men with LUTS, frequency and nocturia are usually
associated with bladder problems whereas hesitancy and
poor flow are usually associated with prostate problems.
1.
2.
3.
4.
5.
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Pre-Activity Evaluation
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Pre-Activity Evaluation
1.
2.
3.
4.
5.
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Pre-Activity Evaluation
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Pre-Activity Evaluation
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Pre-Activity Evaluation
Pre-Activity Evaluation
1.
2.
3.
4.
5.
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Pre-Activity Evaluation
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Pre-Activity Evaluation
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Establishing BPH-LUTS
as a Clinical Construct
Prostate Function
Normal Function
100
Prevalence, %
80
Abnormal Function
Obstruction of urinary flow
Sphincteric damage/usually surgical
(stress incontinence)
Baron, 1941
Harbitz, 1972
Karube, 1961
Franks, 1954
Moore, 1943
Holund, 1980
Pradhan, 1975
Fang-Lui, 1991
Swyer, 1944
60
40
20
Normal Prostate
0
20-29 30-39 40-49 50-59 60-69 70-79 80-89
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: WB Saunders/Elsevier; 2007:1973-1985.
Bladder Function
Abnormal function
Voiding frequently small amounts
Uncontrollable urge (urgency) to empty
with frequency
Age, y
Overactive Bladder
Syndrome that includes urinary urgency (intense, sudden
desire to void) with or without incontinence, urinary
frequency, and nocturia
Present without any pathologic or metabolic disorders that
might otherwise result in symptoms
Etiology is heterogeneous and may result from abnormal
signaling, a sensory amplification (afferent), or increased
motor output (efferent)
Incomplete emptying
Hesitancy, poor stream, feeling of incomplete emptying
Abrams P, et al. Neurol Urodyn. 2002;21(2):167-178; Ouslander JG. N Engl J Med. 2004;350(8):786-799;
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
Storage (bladder/OAB)
Urgency
Frequency
Nocturia
Urge incontinence
Stress incontinence
Mixed incontinence
Overflow incontinence
Voiding (prostate/BPH-LUTS)
Hesitancy
Poor flow/weak stream
Intermittency
Straining to void
Terminal dribble
Prolonged urination
Urinary retention
Frequency
Bladder Pain
Urge Incontinence
Straining
Post-mict. Dribbling
Frequency
Nocturia
Urgency
Incomplete Emptying
Hesitancy
Intermittency
Reduced Stream
Terminal Dribbling
10
20
30
Post-mict, post-micturition.
Peters TJ, et al. J Urol. 1997;157(3):885-889.
40
50
60
70
80
Common Comorbidities
Erectile or Other
Sexual Dysfunction
36
Hypertension
53
High Cholesterol
45
EP
Histologic
BPH
18
General Pain/Inflammation
11
21
Diabetes
BOO
17
Depression/Anxiety/
Sleep Disorder
16
Arthritis
20
Allergies/Cold/Flu/Congestion
LUTS
Incidence, %
22.3
14.9
15.3
12.4
13.2
10.3
10
7.5
Reduced NO
cGMP signaling
Increased RhoA
ROCK signaling
FUNCTIONAL
CONSEQUENCES AT
TISSUE LEVEL
(corpora cavernosa,
prostate, urethra, and
bladder functional
alterations)
0
50-59 Years
60-69 Years
50
60
70-79 Years
Autonomic
hyperactivity
Pelvic
atherosclerosis
BPH-LUTS
ED
Chronic inflammation
Normal ED
40
BPH-LUTS and ED
18.3
15.8
30
21.1
19.2
20
No
Mild
Moderate
Severe
18.9
10
20
15
0
BOO, bladder outlet obstruction; EP, enlarged prostate; LUTS, lower urinary tract symptoms.
Emberton M, et al. Int J Clin Pract. 2008;62(7):1076-1086; Roehrborn CG. Rev Urol. 2005;7(suppl 9):S3-S14;
Roehrborn CG. Med Clin N Am. 2011;95(1):87-100.
30
100
BPH-LUTS
Complex Interrelationship
Severe ED
90
BPH-LUTS Patients, %
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):809-825.
Dennis
LUTS Evaluation
Presentation to PCP
Unlikely OAB/BPH/SI
Focused HPE
Treat or Refer
Likely OAB/BPH/SI
No
Desires
Treatment
Watchful
Waiting
Yes
Provisional BPH
Provisional
OAB/SI
Effective
Continue
Medication
Effective
Continue
Medication
Ineffective
Assess and
Treat OAB/SI
Ineffective
Refer
HPE, history and physical exam; PSA, prostate-specific antigen; SI, stress incontinence; UA, urinalysis.
Rosenberg MT, et al. Int J Clin Pract. 2007;61(9):1535-1546.
LUTS Evaluation
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.
LUTS-Related Effect
Confusion, secondary incontinences
Diuresis
Impaired 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
Constipation
DeBeau CE. J Urol. 2006;175(3, pt 2):S11-S15; Gill SS, et al. Arch Intern Med. 2005;165(7):808-813; Lavelle JP, et al.
Am J Med. 2006;119(3, suppl 1):37-40; Newman DK. Nurse Pract. 2009;34(12):33-45;
Wyman JF, et al. Int J Clin Pract. 2009;63(8):1177-1191.
Voiding Diary
Relationship Between
PSA and Prostate Size
DRE tends to
underestimate prostate
size in larger prostates
PSA is more accurate than
a DRE when estimating
prostate size
PSA 1.5 ng/mL suggests
a prostate volume >30 mL
Age
65
75
60
Prostate Volume, mL
70
65
60
55
50
55
50
45
40
35
30
1
Dennis
Bladder cancer
Prostate cancer
Prostatitis
Bladder stones
Interstitial cystitis
Radiation cystitis
Urinary tract infection
Diabetes mellitus
Patient Evaluation
Parkinsons disease
Primary bladder neck
hypertrophy
Congestive heart failure
Lumbosacral disc disease
Multiple sclerosis
Nocturnal polyuria
Personal history
Medical history
Diagnosed 6 years earlier with type 2
diabetes controlled with medication
and diet
Metformin ER: 1000 mg daily
Pioglitazone hydrochloride: 30 mg daily
Laboratory tests
Fasting serum glucose: 98 mg/dL
Serum HbA1c: 6%
Urinalysis: clear, no growth with
midstream specimen culture
PSA: 1.7 ng/mL
Creatinine*: 1 mg/dL
Patient Interview
Not at
All
Less Than
One Time
in Five
Less Than
Half the
Time
About
Half the
Time
More Than
Half the
Time
Almost Always
Never
1 time
2 times
3 times
4 times
5 times
18
HR: 87 bpm
BP: 138/85 mm Hg
Height: 5 11; Weight: 235 lbs
BMI: 32.8 (obese)
Abdominal exam: unremarkable
Neurologic exam: unremarkable
Genital exam: unremarkable
DRE: 50 mL, smooth, nontender
Dennis
*Not uniformly recommended as part of laboratory evaluation in patients with possible LUTS; however, this test
provides information about the status of renal function.
BP, blood pressure; BMI, body mass index; bpm, beats per minute; HR, heart rate; UTI, urinary tract infection.
Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496.
Urinary Symptoms
Physical exam
62 years old
Married 35 years
Worsening of symptoms
Deterioration of urinary flow rate
Increase in prostate volume
Outcomes such as AUR and need for surgery
Renal insufficiency
Recurrent urinary tract infection
Age
55 yrs
60 yrs
65 yrs
70 yrs
PV
PSA
30 mL
1.5 ng/mL
>40 mL
>50 mL
>61 mL
30
Cumulative Incidence, %
25
20
15
Either
Surgery
10
5
AUR
0
>0.0 >0.5 >1.0 >1.5 >2.0 >2.5 >3.0 >3.5 >4.0 >4.5 >5.0 >5.5 >6.0 >6.5 >7.0 >7.5 >8.0
Conclusions
BPH is a histologic construct; BPH-LUTS is a clinical
construct
BPH-LUTS is often comorbid with other disorders (eg, ED)
BPH-LUTS is a progressive disease
Assessment of BPH-LUTS is based primarily on a focused
physical exam and history, laboratory tests, and evaluation
of symptom bother
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.
Formulating an Approach to
Initial and Ongoing
Management of BPH-LUTS in
Primary Care
Martin M. Miner, MD
Clinical Associate Professor Family Medicine and Urology
The Warren Alpert Medical School of Brown University
Co-Director, Mens Health Center
Chief of Family and Community Medicine
Miriam Hospital
Providence, Rhode Island
100
Worse IPSS
Same IPSS
Better IPSS
84
75
Patients, %
80
65
60
60
40
20
20
13
17
9
11
10
12 Months
24 Months
36 Months
48 Months
87% of men with mild symptoms had symptom worsening, while 13% had
reduced or stabilized symptoms
N=397 men who presented with mild LUTS suggestive of BOO (IPSS score <8). IPSS, International Prostate Symptom Score.
American Urological Association (AUA) defines BOO as the generic term for all forms of obstruction to the bladder outlet (eg, urethral
stricture). AUA Clinical Practice Guidelines. Benign Prostatic Hyperplasia. Chapter 1: Guideline on the Management of Benign Prostatic
Hyperplasia (BPH). http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines/main-reports/bphmanagement/chap_1_GuidelineManagementof(BPH).pdf; Djavan B, et al. Urology. 2004;64(6):1144-1148.
100
80
Treatment
failure
SC
SM
60
40
20
20
IPSS Score
Subjects, %
BPH Impact
Index
SC
SM
0
3 months
6 months
Moderate
Vigorous
AUA QoL
12 months
SC
SM
3 months
6 months
12 months
12 months
Source
Gann et al, 1995
4
2
3 months
12 months
AUA-QoL Score
BII Score
6 months
4
2
SM
0
3 months
SC
IPSS
Newman S, et al. Lancet. 2004;364(9444):1523-1537; Rosenberg MT, et al. Int J Clin Pract. 2010;64(4):488-496;
Yap T, Emberton M. Curr Opin Urol. 2010;20(1):20-27.
BII, BPH Impact Index; IPSS, international prostate symptom score; QoL, quality of life; SC, standard care;
SM, self-management.
*P<0.05 vs SC; N= 140 men >40 with LUTS (n=67 for SC; n=73 for SM); SC began with watchful waiting. Escalation to
medical treatment and surgery was left to the discretion of the clinician and patient. The SM group included SC as well
as 3 small group sessions comprising education, lifestyle advice, and training in problem solving and goal setting.
Brown CT, et al. BMJ. 2007;334(7583):25.
Dennis
P=0.006
2.0
0.74
95% CI, 0.60-0.92
0.18
Odds Ratio
0.74
95% CI, 0.59-0.92
3.1
Odds Ratio
Physical activity was divided into low, moderate, and vigorous levels corresponding to intensity categories
within the individual studies.
Parsons JK, Kashefi C. Eur Urol. 2008;53(6):1228-1235.
P=0.005
0.9
Predominant
Bladder Outlet
Obstruction
PDE5 Inhibitor?
*PSA
1-Blocker
1-Receptor Selectivity
Side Effects*
Doxazosin
1A=1D=1B
Terazosin
1A=1D=1B
Alfuzosin
1A=1D=1B
Tamsulosin
1A=1D>1B
Silodosin
1A>1D>1B
Retrograde ejaculation
*Adverse
20
16.8
11.7
P=0.82
Symptom Progression
Combination Therapy
25
Finasteride (P=0.002)
15
Doxazosin (P<0.001)
10
Finasteride+Doxazosin (P<0.001)
0
3.0
3.5
4.0
4.5
5.0
5.5
Years
Doxazosin or finasteride monotherapy and the two drugs in combination reduce the
risk of overall clinical progression of BPH
Combination therapy is significantly more effective at reducing clinical progression
than either drug alone
MTOPS, Medical Therapy of Prostatic Symptoms.
Progression was defined by an increase of 4 points vs baseline in the AUA Symptom Index score, acute urinary
retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection.
McConnell JD, et al. N Engl J Med. 2003;349(25):2387-2398.
Incidence, %
Cumulative Incidence of
Progression, %
Placebo
2.5
Type II
5 weeks
<1 day
Half-life
Serum DHT
~95% reduction
~70% reduction
Intraprostatic
DHT
~98% reduction
68%-85% reduction
PSA
~50% reduction
Prostate volume
~25% reduction
Reduced libido,
impotence
Abnormal ejaculation,
decreased ejaculate
volume, impotence,
reduced libido
CombAT Study
20
2.0
Finasteride
Type I and II
RRR=65.8%
(54.7%, 74.1%)
25
1.5
Dutasteride
5-Reductase
specificity
Combination Therapy
MTOPS Study
1.0
BPH-Related Surgery
0.5
AUR
Adverse events*
5.1
PDE5 Inhibitor?
6.5
2.1
1.8
Predominant
Bladder Outlet
Obstruction
0.0
P=0.18
10
Alfuzosin 10 mg OD (n=749)
P=0.0013
15
Placebo (n=757)
25
Cumulative Incidence, %
20
15
RRR=44.1%
(33.6%, 53.0%)
RRR=19.6%
(-10.9%, 41.7%)
RRR=31.2%
(17.7%, 42.5%)
21.5
17.8
Combination (n=1610)
Dutasteride (n=1623)
Tamsulosin (n=1611)
11.9
12.6
n=191
n=203
10
5
0
4.2
n=67
5.2
n=84
n=289
n=347
Phosphodiesterase 5 Inhibitors
PDE5 Inhibitor
Sildenafil
Erectile dysfunction
Tadalafil
Erectile dysfunction
Signs and symptoms of BPH
Erectile dysfunction and the
signs and symptoms of BPH
Erectile dysfunction
Vardenafil
Erectile function
Orgasmic function
Sexual desire
Intercourse satisfaction
Overall satisfaction
20
15.9
15.9
13.2
13.4
10
Baseline
12 Weeks
IPSS Score,
Mean Change From Baseline
20
-3.00
20
16.8
16.8
15
13.2
11.0
10
0
Baseline
8 Weeks
Baseline
8 Weeks
vs placebo;
vs placebo. EF, erectile function.
Vardenafil is not FDA approved for the treatment of BPH-LUTS.
Increasing IIEF-EF denotes improvement in erectile function; Decreasing IPSS denotes reduced LUTS.
Stief CG, et al. Eur Urol. 2008;53(6):1236-1244.
P=0.0013
Sildenafil (n=179)
0.00
23.5*
17.4
-1.9
-6.00
-6.3*
IIEF-EF Score,
Mean Change From Baseline*
Placebo (n=162)
15.9
10
Placebo (n=110)
Vardenafil (n=105)
23.4*
*P=0.0001
Barry MJ, et al. J Urol. 1992;148(5):1549-1557; Rosen RC, et al. Urology. 1997;49(6):822-830.
30
25
Vardenafil (n=105)
Placebo (n=110)
30
5.9
20
4
2
1.1
*P<0.0001 vs placebo.
Sildenafil is not FDA approved for the treatment of BPH-LUTS.
Increasing IIEF-EF denotes improvement in erectile function; Decreasing IPSS denotes reduced LUTS.
McVary KT, et al. J Urol. 2007;177(3):1071-1077.
18.1 17.8
13.8 14.0
15
12.7 13.2
10
0
Week 0-64
-9.00
25
Incomplete emptying
Frequency
Intermittency
Urgency
Weak stream
Straining
Nocturia
Quality of life
Adverse Events*
Abnormal vision, diarrhea,
dyspepsia, flushing, headache,
nasal congestion
ANS, autonomic nervous system; cGMP, cyclic guanosine monophosphate; NO, nitric oxide.
Andersson KE, et al. Neurourol Urodyn. 2011;30(3):292-301.
Indication
Week 12-64
Baseline
12 Weeks
64 Weeks
*N=219
10
5
4
IPSS Score,
LS Mean Change From Baseline
IIEF-EF Score,
LS Mean Change From Baseline
BPH-LUTS and ED
3
2
1
0
-1
Tadalafil 5 mg
Tamsulosin 0.4 mg
Source
Placebo
Tadalafil 5 mg
Tamsulosin 0.4 mg
-1
-2
-2
-5
-6
0 1
12/EP
-blocker
+ PDE5 inhibitor
-blocker
alone
-blocker
+ PDE5 inhibitor
Conclusions
-blocker
+ PDE5 inhibitor
PDE5 inhibitors included in the meta-analyses are sildenafil, tadalafil, vardenafil, and UK-369003; -blockers
included in the meta-analyses are alfuzosin and tamsulosin.
Gacci M, et al. Eur Urol. 2012;61(5):994-1003.
Dennis
Post-Activity Evaluation
-blocker
alone
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Qmax
Mean Differences
0 2 4 6 8 10 12
-2
-4
1.
2.
3.
4.
5.
IIEF Score
Mean Differences
-4
-3
-7
IPSS Score
Mean Differences
-6
Post-Activity Evaluation
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
11
Post-Activity Evaluation
1.
2.
3.
4.
5.
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Post-Activity Evaluation
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Post-Activity Evaluation
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Post-Activity Evaluation
Post-Activity Evaluation
1.
2.
3.
4.
5.
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Post-Activity Evaluation
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
12
Post-Activity Evaluation
I now plan to consider combination pharmacotherapy for my
patients with BPH-LUTS.
1.
2.
3.
4.
5.
Strongly Disagree
Disagree
Neutral
Agree
Strongly agree
Audience
Question & Answer Session
13