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27/05/2014
1
ED & LUTS-BPH Making the link – bridging the gap DR JONATHAN REES MD MRCS MRCGP
GP, BACKWELL & NAILSEA MEDICAL GROUP
PROSTATE CANCER UK MASTERCLASS – MANCHESTER Thursday, 22 May 2014
Case study
Mr S
51yr old
Not seen GP for few years
Presents with ED – third complaint of consultation
Case study
Overweight – BMI 32, Waist Circumference 105cm
No exercise, Poor diet
BP 164/100
Fasting glucose 6.4
Total Cholesterol 6.7, Qrisk 26%
Case study
PDE5 INHIBITOR OPTIONS
On demand: Short acting
On demand: Long acting
Daily dosing
Ageing society UK population >50:
◦ 2010 21.5 million
◦ 2030 27.6 million
UK population > 60:
◦ 2010 10.3 million
◦ 2030 15.4 million
◦ 53,000 centenarians in 2030
0
5
10
15
20
25
30
35
40
45
2010 2020 2030
% >50 y.o
% >60 y.o
UK OFFICE FOR NATIONAL STATISTICS‐ NATIONAL POPULATION PROJECTIONS, 2010
Prevalence of ED increases with age
0
10
20
30
40
50
60
20's 30's 40's 50's 60's
ED Prevalence (%)
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Prevalence of BPH increases with age
CG ROEHRBORN. INT J IMPOT RES. 2008; 20: S11 – S18
2 conditions highly prevalent in men >50
ERECTILE DYSFUNCTION1 LOWER URINARY TRACT SYMPTOMS2,3
Approximately 1/3 of men over 50 have moderate to severe LUTS
3.2 million men in UK
Up to 24 million men in the EU
1. MASSACHUSETTS MALE AGEING STUDY FELDMAN ET AL J UROL 1994 2. PROSTATE OF THE NATION REPORT – PROSTATE ACTION 2010
3. HUTCHISON ET AL. EUR UROL 2006; 50: 555–562.
Diseases associated with ED
ED n=4,422
No ED n=23,416
19
7
16
4
13
36
17
29
14
0
5
10
15
20
25
30
35
40
HTN CHD/ angina
High cholesterol
Diabetes Depression/ anxiety
Me
n r
ep
ort
ing
dis
eas
e (%
)
25
p < 0.0001
ROSEN ET AL. CURR MED RES OPIN 2004;20:607-17
Ischaemic stroke
Atherothrombosis affects many vascular beds
1. Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(Suppl 1): 1–6
2. Adapted from Haffner SM et al. N Engl J Med 1998;339:229-234
Transient ischaemic attack
Myocardial infarction
Angina: Stable
Unstable
Peripheral arterial disease: Intermittent claudication
Rest pain
Gangrene
Necrosis
Renovascular disease
Diabetes (type 2)
Often considered vascular
equivalent to a non-diabetic
patient with previous MI2
Atherosclerosis in Coronary Vessels
Atherosclerosis in Penile Arteries
ED and CV Risk ED compared with subjects without ED have a significantly increased risk by:
44% for total CV events
62% for MI
39% for cerebrovascular events
25% for all-cause mortality
19% for CV mortality
Risk conferred by ED on events is of a magnitude similar to that of the risk conferred on events by established risk predictors such as hypertension and dyslipidemia
Consider multiplying CV risk (e.g. on Qrisk) by 1.5 if patient also has ED
CHARALAMBOS V ET AL CIRC CARDIOVASC QUAL OUTCOMES. 2013;6:99-109
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Diseases associated with LUTS/BPH
ROEHRBORN CG ET AL BJU INT. 2007; 100: 813 - 819
15
20
16
17
21
11
18
45
53
36
0 10 20 30 40 50 60
Allergies / cold / flu / congestion
Arthritis
Depression / anxiety / sleep disorder
Diabetes
Digestive Tract Disorder
General Pain / Inflammation
Heart Disease / Heart Failure
High Cholesterol
Hypertension
Erectile or other Sexual Dysfunction
ROSEN ET AL. EUR UROL 2003;44(6):637-49
Correlation between severity of LUTS & ED
MSAM:
Multinational survey of the ageing male
N =12,815 men aged 50-80 years
0
20
40
60
80
100
Mild Moderate Severe
LUTS severity
Inc
ide
nc
e e
rec
tio
n p
rob
lem
s (
%)
LUTS and Male Sexual Dysfunction (MSAM-7)
Inci
den
ce ,
%
2
12
2
25
5
45
17
53
7
33
6
43
12
53
19
64
16
41
20
50
31
52
44 45
0
10
20
30
40
50
60
70 No, I cannot get an erection
Net reduction in stiffness
Rosen et al. Eur Urol 2003;44(6):637-49
LUTS Severity
Age 50 – 59 years
LUTS Severity
Age 60 – 69 years
LUTS Severity
Age 70 – 79 years
Risk Factors for LUTS & ED
KIRBY M ET AL. INT J CLIN PRACT 2013; 67: 606 - 618
LUTS / ED in UK Primary Care UK Primary Care database – 333 practices
Study period: 2000 – 2007. Rising incidence of both conditions during the study
LUTS diagnosis preceded ED in 2/3 of men by a median of 4.8 years
Compared to men with no LUTS – odds ratios for ED (with 95% c.i.):
◦ Storage LUTS: 3.0 (2.6-3.4)
◦ Voiding LUTS: 2.6 (2.4-2.7)
◦ Mixed storage and voiding LUTS: 4.0 (3.4-4.8)
MORANT S J SEX MED 2009; 6: 1103-1110 GACCI ET AL, EUR UROL 2011; 60: 809-825
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Tip of the iceberg......
HAMMARSTEN J, NATURE REVIEWS UROLOGY SEPTEMBER 2011
Lifestyle Intervention - ED
GUPTA B ET AL ARCH INT MED 2011; 171 (20): 1797-1803
Standardised difference in means in International Index of Erectile Function (IIEF) score after lifestyle intervention & cardiovascular risk factor reduction
Lifestyle changes alone Lifestyle changes plus statins
Lifestyle Intervention – LUTS/BPH “In older men, central obesity and higher physical activity associated with increased &
decreased risks of incident LUTS, respectively......”1
“Prevention of chronic urinary symptoms represents another potential health benefit of exercise
in elderly men.....”1
“Statin use associated with 6.5 to 7 year delay in the onset of moderate / severe LUTS....”2
1. KELLOGG PARSONS J ET AL EUR UROL 2011 2. ST SAUVER JL ET AL BJU INT 2010
The prostate: the ‘gateway to men’s health’……
Asking the LUTS patient about ED
DO WE ASK LUTS PATIENTS ABOUT ED?1
UK Audit 100 patients with LUTS
◦ GP’s enquired about ED in <10%
◦ Offered no therapy for ED in >80%
◦ >90% of untreated ED patients would like treatment
WHY DON’T WE ASK?2
Lack of knowledge of the strong association
Embarrassment (GP or patient)
Respecting patient’s privacy
Lack of confidence in assessing and treating ED
Lack of time
Cost of ED Rx
Issues re prescribing LUTS meds that may worsen ED
1. CHITALE S ET AL - J SEX MED 2007; 4: 1713-1725 2. COOMBE & CROCKER, SEX & THE LUTS CONSULTATION, MEN'S HEALTH 2003
Downloaded from www.IJCP.org © 2009 Blackwell Publishing Ltd.
Conclusions
“Evidence suggests a strong link between erectile dysfunction and lower urinary tract symptoms in men that is independent of age. Co-diagnosis of these conditions is therefore important”.
Consensus statement
Erectile dysfunction and lower urinary tract symptoms: A consensus on the importance of co-diagnosis M. Kirby1, C. Chapple2, G. Jackson3, I. Eardley4, D. Edwards5, G. Hackett6, D. Ralph7, J. Rees8, M. Speakman9, J. Spinks10, K. Wylie11
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CO-DIAGNOSIS ALGORITHM FOR ED & LUTS KIRBY M ET AL IJCP 2013; 67: 606 - 618
Example questions: “Many men with LUTS / waterworks symptoms etc also find that they have problems achieving or maintaining an erection – is that a problem for you?” “Many men with erection difficulties also notice problems with their waterworks (or similar phrase) – has that been an issue for you?”
Treatment options for ED Lifestyle measures & Psychosexual Counselling
PDE5 inhibitors
◦ On demand: Tadalafil (Cialis), Sildenafil (Viagra), Vardenafil (Levitra) ◦ Daily dosing: Cialis 5mg od
Vacuum devices
Intra-urethral, Intra-cavernosal & Topical Prostaglandins
Surgery
Treatment Options
1st International Consultation on Erectile Dysfunction, Paris, July 1999
Alteration of
modifiable risk
factors
Sexual counselling
and education
Oral
agents Vacuum
therapies
Surgical
therapy
Hormone Therapy
Injection
therapies Surgical
therapy
Treatment Options
1st International Consultation on Erectile Dysfunction, Paris, July 1999
Alteration of
modifiable risk
factors
Sexual counselling
and education
Vacuum
therapies
Hormone Therapy
Injection
therapies Oral
agents
A third of Men and Women have no set pattern of sexual timing
30%
5%
16%
48%
34%
7%
19%
39%
0
10
20
30
40
50
60 Male Female
Inte
rco
urs
e p
atte
rns
(%)
Night/ Evening No Set Pattern Morning Afternoon
Fisher W, et al. J Sex Med 2005;2:675–84 UKCLS01047a April 2012
Q: Overall, what would you say you miss the most about your sex life before having ED?
Men miss spontaneity
“Living With ED.” Harris Interactive, Eli Lilly & Company Limited data on file, 2003. UKCLS01047a April 2012
*
*
*
* *p<0.05
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Predicted Pharmacokinetic Modeling: 5mg OD vs. Frequent 20-mg On-Demand Dosing
Predicted weekly plasma tadalafil concentrations during 5-mg once daily dosing at steady state or 20-mg on-demand patterns representing twice- or thrice-weekly administration1
"Adapted from Wrishko et al. J. Sex. Med 2009" UKCLS01047a April 2012
Historical Comparison (Long-Term Safety): Adverse Events at 24 Months
Events Reported in ≥5% of Subjects in First Year of OD Open Extension Trial
24-Month Once Daily1 Tadalafil 5 mg (N=238)*
24-Month On-Demand2 Tadalafil 5/10/20 mg
(N=1173)**
Headache 5 (2.1%) 185 (15.8%)
Dyspepsia 9 (3.8%) 139 (11.8%)
Back Pain 12 (5.0%) 96 (8.2%)
Influenza 6 (2.5%) 37 (3.2%)
Discontinuations Due to Adverse Events
16 (6.7%) 74 (6.3%)
Porst H et al. J Sex Med 2008;5:2160–9. Montorsi F et al. Eur Urol 2004;45:339-45.
* One 24-month extension trial of tadalafil 5 mg OD ** Pooled 24-month extension data from five 8- or 12-week double-blind, placebo-controlled on-demand tadalafil studies OD= Once Daily
UKCLS01128a April 2012
Please see the Cialis Summary of Product Characteristics for a full list of Adverse Events, including a full list of common adverse events.
Case study
Men dislike ‘planning’ element of on demand PDE5 inhibitor
Very few currently offered daily dosing
Most are interested if they are offered
Case study
Mr S is treated with on demand PDE5 inhibitor
He doesn’t mention his LUTS
Asked opportunistically: ‘Many men with erection problems also have urinary symptoms – is that a problem for you?...’
Mixed storage and voiding symptoms
Embarrassed and bothered – relieved to be asked
NICE Guidelines 2010: LUTS in men
National Institute for Health and Clinical Excellence (2010) CG 97 The management on lower urinary tract symptoms on men. London: NICE.
Sexual side effects of medical therapy for LUTS
ERECTILE DYSFUNCTION
COMBAT: ED 9% combination vs 7% dutasteride vs 5% tamsulosin
MTOPS: ED 5.1% combination vs 4.5% finasteride vs 3.5% doxazosin vs 3.3% placebo
EJACULATORY DYSFUNCTION
Meta-analysis of 4 RCT’s, 4800 patients
EjD Combination vs Alpha-blocker monotherapy:
◦ 9.2% vs 2.7%, OR 3.75, p<0.0001
EjD Combination vs 5ARI monotherapy: ◦ 9.2% vs 3.5%, OR 2.76, p=0.02
GACCI M ET AL. IMPACT OF MEDICAL TREATMENTS FOR MALE LUTS DUE TO BPH ON EJACULATORY FUNCTION. A SYSTEMATIC REVIEW & META-ANALYSIS. J SEX MED 2014 IN PRESS
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PDE5 Inhibitors for LUTS-BPH Total IPSS: Mean Change from Baseline
• *p<.05, **p<.01, aValues for Week 1 are based on mIPSS
Treatment Baseline
Mean (SD)
12-week Endpoint LS Mean Change (ANCOVA, LOCF)
Placebo 16.6 (6.0) -3.6
Tadalafil 5 mg 17.1 (6.1) -5.6**
Porst et al. Eur Urol 2011;60(5):1105-13.
-6
-5
-4
-3
-2
-1
0
Placebo
Tadalafil 5 mg
LS
Me
an
Ch
an
ge
in
To
tal
IPS
S
** ** *
Baseline Week 4 Week 1a Week 8 Week 12
IIEF-EF: Mean Change from Baseline
Porst et al. Eur Urol 2011;60(5):1105-13.
IIEF EF Domain: Mean Change from Baseline
Egerdie et al. J Sex Med 2011;9: 271 - 281
*Please note, Tadalafil 2.5mg OD is not a licensed dose for the signs and symptoms of BPH. **IIEF-EF = International Index of Erectile Function, Erectile Function domains.
IPSS† Domain: Mean Change from Baseline
Egerdie et al. J Sex Med 2011;9: 271 - 281
*Please note, Tadalafil 2.5mg OD is not a licensed dose for the signs and symptoms of BPH. † IPSS = International Prostate Symptom Score.
*Please note, Tadalafil 2.5mg OD is not a licensed dose for the signs and symptoms of BPH. † IPSS = International Prostate Symptom Score.
IPSS Total: Mean Change from baseline
Oelke et al. Eur Urol 2012;61: 917 - 925
Please note that tamsulosin is an active control. This study was powered for direct comparisons between tadalafil and placebo and between tamsulosin and placebo.
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IIEF-EF Total: Mean Change from Baseline
Oelke et al. Eur Urol 2012;61: 917 - 925
Please note that tamsulosin is an active control. This study was powered for direct comparisons between tadalafil and placebo and between tamsulosin and placebo.
Oelke M, Bachmann A, Descazeaud A et al. EAU Guidelines on the Treatment and Follow-up of Non-neurogenic Male Lower Urinary Tract Symptoms Including Benign Prostatic Obstruction. Eur Urol. 2013 Jul; 64(1):118-40.
EAU Guidelines 2013: LUTS in men
Case study
LUTS assessed – diagnosed as secondary to BPH
Discussion re continued on demand plus addition of alpha blocker
Offered switch to daily dose of Tadalafil 5mg
Conclusions
Your ED patient probably also has LUTS
Your LUTS patient probably has ED
Think CV risk / T2 DM / Metabolic Syndrome in both sets of patients
Diagnosing ED in your LUTS patient might ‘save their life’
Medical treatment for LUTS has potential for adverse impact on sexual function
Once daily Tadalafil 5mg an option for the man with both LUTS & ED