erectile dysfunction

Treatment of Sexual dysfunction

associated with CVDGraham Jackson

Consultant Cardiologist Guy’s & St Thomas’

Hospital, London, UK.

Recommendation 1

• A significant proportion of men with erectile dysfunction (ED) exhibit early signs of coronary artery disease (CAD), and this group may develop more severe CAD than men without ED

• (Level 1, Grade A).

ED Predicts coronary events1400 men 40-75, with no known CAD 10yr follow up

Inman et al Mayo Clin Pr 2009;84:108-113

Age Group ED at baseline No baseline ED

40-49 48.52 (1.23-269.26)

0.94 (0.02-5.21)

50-59 27.15 (7.40-69.56) 5.09 (3.38-7.38)

60-69 23.97 (11.49-44.10) 10.72 (7.62-14.66)

70+ 29.63 (19.37-43.75) 23.30 (17.18-30.89)

CAD events per 1000 pt years with CI interval

Inman et al Mayo Clin Pr 2009

ED As A Predictor for Subsequent CVD Events: A Linked Data Study

• Retrospective 10-15 year study • ED and no CVD prior to ED v general

population• 1660 men with ED• CVD events doubled in men with ED (RR2.2)• 12.3% in 5 years, 37.3% in 10 years, 76% in

15 years• 7 fold increase in men < 40 years of

age (P<0.0001)

Chew et al JSM 2010;7:192-202

Meet Jorge

• Age 38• Never smoked• Doesn’t drink (he’s a chauffeur)• No family history• No symptoms• ED 6 months

Exercise ECG: treadmill14 minutes to 187 bpmBP response normalEnd point fatigue: no painLateral ST depression 1mm upslopingResolved by less than 1 minute

Investigations

• Examination normal• Slightly overweight; waist 38 inches• BP 130/88• Testosterone 16.6 nmol/l• Cholesterol 5.8, triglycerides 1.18,

HDL 0.99, LDL 4.31 mmol/l• Uric acid 488 umol/l (<416)• Glucose 5.8 mmol/l

Radiologist’s Comment

“ In the distal RCA there is a short focal non-calcified stenotic lesion

which appears to be causing a significant narrowing”

Recommendation 2

• The time interval among the onset of ED symptoms and the occurrence of CAD

• symptoms and cardiovascular events is estimated at 2–3 years and 3–5 years

• This interval allows for risk factor reduction

• (Level 2, Grade B).

The Temporal Relationship Between ED and CVD

207 CVD men attending cardiac rehab165 age matched controlsED in 66% with CVD – discussed in 53%ED in 37% controls – discussed in 43%ED on average 5 years before CVD

Hodges et al Int J Clin. Pract 2007;61:2019-25

In half the men there were missed opportunities to assess CVD risk

“Men with ED should be specifically targeted for CVD preventative strategies in terms of lifestyle changes and pharmacological treatments”

ED Prevalence, Time of Onset in 300 consecutive men with acute chest pain and CAD

• Mean age 62.5 years

• ED prevalence 49% (147/300)

• ED before CAD symptoms 99 (67%)

• Mean time interval ED to CAD 38.8 months (1-168)

Montorsi et al Eur Urol 2003;44:360-5

Time interval between ED onset and CAD

Montorsi F, et alMontorsi F, et al.. Eur Urol 2003 Eur Urol 2003

InIn 67% 67% of the pts, symptoms of ED had of the pts, symptoms of ED had started started beforebefore the symptoms of CAD the symptoms of CAD (mean 39 months) – (mean 39 months) – retrospective retrospective assessmentassessment

Montorsi P, et al. Eur Heart J Montorsi P, et al. Eur Heart J 20062006

In almost all pts, In almost all pts, ED comes ED comes

before CAD by an average ofbefore CAD by an average of

2 up to 3 years2 up to 3 years

Recommendation 3

• ED is associated with increased all-cause mortality primarily due to increased cardiovascular mortality


Erectile Dysfunction and Mortality

• 1655 men prospective study aged 40-70 years

• 15 years follow up• ED absent 1317(D 75=6%) Present 338

baseline (D 50=15%)• 403 died, 371 complete data• ED 1.26 HR all cause mortality

(D1.95<0.001)• ED 1.43 HR CVD mortality (D 1.64=0.04)

Araujo et al JSM 2009;6:2445-54

ED predicts CVD events in high risk patients receiving Telmisartan, Ramipril or both

• 1,549 patients with CVD• ED at baseline, 2 years, finish• ED predicted all cause death HR 1.84

– CVD death HR 1.93 (p=0.005)– MI HR 2.02 (p=0.16)– Composite HR 1.42 (p=0.029)

• “ED is a potent predictor of all cause death and the composite of CVD death, MI, stroke and heart failure in men with CVD”

Bohm Circulation 2010;121:1439-46

Clinical perspective

“...erectile function is a predictor of cardiovascular morbidity and mortality. These results remained after adjustment for possible confounders. Thus ED represents an early symptom of endothelial dysfunction and atherosclerosis and patients with ED are at particularly high cardiovascular risk. The identification of these patients with ED offers an opportunity for early risk-adjusted treatment with the goal of further reducing cardiovascular events”

Circulation 2010;121:1446

Recommendation 4

• All men with ED should undergo a thorough medical assessment, including testosterone, fasting lipids, fasting glucose and blood pressure measurement.

• Following assessment, patients should be stratified according to the risk of future

• cardiovascular events. • Those at high risk of cardiovascular disease should

be evaluated by stress testing with selective use of computed tomography (CT) or coronary angiography (Level 1, Grade A).

Figure 1. Management of man with ED and no known CVD

*Determine ED severity based on International Index of Erectile Function (IIEF): mild 17-21; mild to moderate 12-16; moderate 8-11; severe 1-7 Consider cardiac evaluation if severe irrespective of Framingham score.†Incorporate age, gender, total cholesterol, HDL cholesterol, smoking, systolic BP, BP therapy (see appendix sample calculation)

Sexual Enquiry of All Men

E.D. (No known CVD)*

Essential Checks: Age, BP, glucose, lipids, testosterone, smoking

Additional Checks:BMI, waist circumference,

exercise, alcohol, diet, family history

Framingham Risk†

Low (<10%) Intermediate (10-20%) High (>20%)

Lifestyle Advice Lifestyle advice, medication and non-

invasive risk evaluation (e.g. stress testing)

Lifestyle advice, medication, and

cardiologist

Meet David aged 50

• Normally fit and well• ED for 15months: SHIM 16.• Non smoker; Alcohol < 21 units /

week• Weight 106Kg (233lbs)• Waist 104cms (41 inches)• BP 120/90 mmHg• On no medication

What else would you like to know?

David

• Family History: Father died aged 51 CADBrother and Sister CAD (aged “forties”)

• Fasting glucose 6.4 mmol/l

• Cholesterol 5.1mmol/l 200mg %triglycerides 2.27 110HDL 1.10 43LDL 3.41 132

What could he have?

Metabolic Syndrome

• Abdominal Obesity > 94cms (37 inches)Plus: Any two of the following

• Triglycerides > 1.7 mmol/l (150mg%)• HDL < 1.0 mmol/l (40mg%)• BP treated or > 130/85mm/Hg• Fasting glucose > 6.1 mmol/l (USA 5.6)

Increased risk of CAD, stroke and future diabetes

Any other information or tests?

21

9

4.85.5

2.1 1.40

5

10

15

20

25

CHD PreviousMI

Previousstroke

4.6

2.2

12

18

0

5

10

15

20

25

Totalmortality

CV mortality

Inci

dence

(%

)

Pre

vale

nce

(%

)

Metabolic syndrome present

Metabolic syndrome absent

Isomaa B, et al. Diabetes Care 2001; 24: 683–689.

p<0.001

p<0.001

p<0.001

p<0.001

p<0.001

Morbidity Mortality

Metabolic Syndrome increases CV morbidity and mortality

Exercise ECG

• Sex is equivalent to 4min of the standard Bruce treadmill exercise ECG (5-6 METS)

• Useful evaluation for safety e.g post MI, CABG, PCI

• David managed: 13mins 26secs = 16.3 METSMaximal heart rate 173 bpmNo chest painNo ECG changes

ED exercise ECG and CT angio

•52 patients with ED and no cardiac symptoms•Prospective study: aged 38-73 yrs•LDL>3.0mmol/l or on statins – 100%•Not diabetic: 3 metabolic syndrome•Testosterone < 12nmol/l in 2 (replaced)•SHIM < 22

Results

•Exercise ECG borderline in 3, normal in 49•CT calcium in 41•Non-calcified plaque in 7 (regression 2)•Normal CT angio in 4•All treated with PDE5i and statin•4 stented•No events up to 3 years

Recommendation 5

• Improvement in cardiovascular risk factors such as weight loss and increased

• physical activity has been reported to improve erectile function

• (Level 1, Grade A).• Esposito et al 2004, Revnic 2007,

Risk Factor Modification and ED

• Single blind trial of 110 obese men (BMI>30) aged 35-55

• All men had erectile dysfunction

• Men with diabetes, hypertension, hyperlipidaemia excluded

• Men randomised to – Receive advice (and fairly intensive support) on how to

achieve 10% weight loss– or receive general information about healthy food

choices and exercise

• 2 year follow-up

Esposito et al, JAMA, 2004, 291: 2978-3012

Risk Factor Modification and ED

Baseline Control change over

2 years

I ntervention change over

2 years

Corrected Diff erence in Mean

change (95% CI )

P value

BMI 36.7 -0.7 -5.7 -5 (-7.5 to –2.5) <0.001

Erectile f unction score

13.7 0.1 3.01 3 (1.2 to 4.8) 0.008

BP systolic 127 -1 -3 -2 (-3 to –1) 0.01

Total cholesterol

(mg/ dl)

211 2 -11 -13 (-23 to –3) 0.02

HDL cholesterol

(mg/ dl)

39 0 9 9 (5 to 13) 0.01

Esposito et al, JAMA, 2004, 291: 2978-3012

Recommendation 6

• In men with ED, hypertension, diabetes and hyperlipidaemia should be treated

• aggressively, bearing in mind the potential side effects


Age* (years)

Male (%)

Caucasian (%)

SBP* (mm Hg)

DBP* (mm Hg)

TC* (mmol/L [mg/dL])

LDL-C* (mmol/L [mg/dL])

TG* (mmol/L [mg/dL])

HDL-C* (mmol/L [mg/dL])

Number of risk factors*

63.1 ± 8.5

81.1

94.6

164.2 ± 17.7

95.0 ± 10.3

5.5 ± 0.8 (213 ± 31)

3.4 ± 0.7 (131 ± 27)

1.7 ± 0.9 (150 ± 80)

1.3 ± 0.4 (50 ± 27)

3.7 ± 0.9

Characteristic Atorvastatin (n=5168)

ASCOT: Baseline Characteristics

63.2 ± 8.6

81.3

94.7

164.2 ± 18.0

95.0 ± 10.3

5.5 ± 0.8 (213 ± 31)

3.4 ± 0.7 (131 ± 27)

1.6 ± 0.9 (142 ± 80)

1.3 ± 0.4 (50 ± 27)

3.7 ± 0.9

Placebo (n=5137)

*Mean ± SD

Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

ASCOT-LLA was Terminated Early

•The lipid arm of ASCOT was terminated after a median follow-up of 3.3 years due to a highly significant reduction in the primary end point, as well as a significant reduction in stroke

Sever PS, et al, and the ASCOT Investigators. Lancet. 2003;361:1149-1158.

• Does 3 years sound familiar?

Confirmation that ED increases risk of CVD in Diabetes

• 2306 diabetic men average age 54 years• No clinical CVD. Prospective study• 27% ED• After 4 years incidence CVD 1.6 fold

increase in ED vs no ED (p=0.018)• Only microalbuminuria stronger risk

(2.2 p=0.001)

Ma et alJACC 2008;51:2045-50

CARDS (n=2838)

• Atorvastatin 10 mg v Placebo for primary prevention CVD in type 2 diabetes with LDL 4.14 mmol/L or lower

• At least one of: retinopathy, albuminuria, smoker, hypertension

• 1o endpoint : first acute coronary event, revascularisation or stroke

• Follow up 3.9 years (stopped 2 years early)

37

ObesityDiabetes Hypertension Dyslipidemia

ED: BAROMETER OF MEN’S HEALTH:The Deadly Quartet

Recommendation 7

• Management of ED is secondary to stabilising cardiovascular function, and controlling cardiovascular symptoms and exercise tolerance should be established prior to initiation of ED therapy


Metabolic equivalent (METs) of Selected Daily Metabolic equivalent (METs) of Selected Daily Activity compared to Sexual ActivityActivity compared to Sexual Activity

“ “ The same old story…”The same old story…”

Cost of Sexual Activity: Cost of Sexual Activity: The case for a distinctionThe case for a distinction

““New fling”New fling”

Familiar partnerFamiliar partner

Unfamiliar partnerUnfamiliar partner

+Familiar settingFamiliar setting

+

Unfamiliar settingUnfamiliar setting

METSMETS2-32-3

METSMETS5-65-6

+Familiar mealFamiliar meal

+

Unfamiliar mealUnfamiliar meal

Cardiovascular Changes during Sexual ActivityCardiovascular Changes during Sexual ActivitySimple everyday guidelinesSimple everyday guidelines

Walking 1 mile in 20’ Walking 1 mile in 20’ 3.5 METS3.5 METS

Briskly climbing 2 flights Briskly climbing 2 flights of stairs (20 steps in 10 of stairs (20 steps in 10 seconds) seconds) 3 METS3 METS““The stair-climbing test”The stair-climbing test”(Larson, 1980)(Larson, 1980)

Digging in the garden Digging in the garden 5 METS5 METS

Figure 2. Management of ED in patient with known CVD

*Based on patient history per Princeton II (Kostis et al. 2005)†Sexual activity equivalent to walking 1 mile on the flat in 20 minutes, briskly climbing 2 flights of stairs (10 seconds)‡Sexual activity equivalent to 4 minutes of the Bruce treadmill protocol

Sexual Enquiry of All Men

E.D. and known CVD

Clinical evaluation to determine CV risk with sexual

activity*

Low CV risk Intermediate or indeterminate risk

High risk

Exercise ability†Exercise stress testing‡

Sexual activity deferred; see cardiologist

Initiate/resume sexual activity, treat ED

Low risk High risk

Recommendation 8

• Clinical evidence supports the use of phosphodiesterase 5 (PDE5) inhibitors as

• first-line therapy in men with CAD and co-morbid ED and those with diabetes and ED

• (Level 1, Grade A).• PDE5Is are contra-indicated in patients taking nitrates and where the

cardiac condition precludes sexual activity.

Recommendation 9

• Total testosterone and selectively free testosterone levels should be measured in

• all men with ED in accordance with contemporary guidelines and particularly in

• those who fail to respond to PDE5 inhibitors or have a chronic illness associated with low testosterone


Low Testosterone associated with increase CV and all cause mortalityKhaw et al (Circulation. 2007;116:2694-2701.)

• Figure. Multivariate-adjusted survival by quartile group of endogenous testosterone concentrations (1 is lowest, 4 is highest) in 2314 men 42 to 78 years old in EPIC-Norfolk 1993 to 2003.

• Conclusions— In men, endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes. Low testosterone may be a predictive marker for those at high risk of cardiovascular disease.

•

Recommendation 10

• Testosterone replacement therapy may lead to symptomatic improvement

• (improved wellbeing) and enhance the effectiveness of PDE5 inhibitors


IPASS – 763 men receiving 2788 injections on NEBIDO 1,000mg

• Mean PSA inc 0.9 to 1.2 and stable*• 11 men with PSA>4 – NO CA PROSTATE• Mean Waist circumference reduced from 101to 96cm*• Marked improvement in symptoms of mood, energy,libido, concentration*• ED rate down 61%-25%*• PDE5I response rate inc 37% - 60%• * p<0.0001 (Zitzman et al 2009)

• * (p<0.0001)

Recommendation 11

• Review of cardiovascular status and response to ED therapy should be performed at regular intervals


Conclusion

•ED is a cardiovascular equivalent

•We have a time window of 2-5 years to reduce the risk

•Getting it right involves team work between the family doctor, nurse, diabetologist, sexologist, urologist and cardiologist

E.D.

Erectile Dysfunction

EDucation

Early Detection

Endothelial Dysfunction

Early Death

Take Home Message

A final thought.....

Just because the penis is heading in the wrong direction it does not mean the heart has to follow – we can, and should, prevent it from doing so.

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