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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