Erectile Dysfunction

Treatment of Sexual dysfunction associated with CVD Graham 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 events 1400 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: treadmill 14 minutes to 187 bpm BP response normal End point fatigue: no pain Lateral ST depression 1mm upsloping Resolved 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 rehab 165 age matched controls ED 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 al . Eur Urol 2003 In 67% of the pts, symptoms of ED had started before the symptoms of CAD (mean 39 months) – retrospective assessment Montorsi P, et al. Eur Heart J 2006 In almost all pts, ED comes before CAD by an average of 2 up to 3 years

Recommendation 3 ED is associated with increased all-cause mortality primarily due to increased cardiovascular mortality (Level 1, Grade A).

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 CAD Brother and Sister CAD (aged “forties”) Fasting glucose 6.4 mmol/l Cholesterol 5.1mmol/l 200mg % triglycerides 2.27 110 HDL 1.10 43 LDL 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?

Metabolic Syndrome increases CV morbidity and mortality 21 9 4.8 5.5 2.1 1.4 0 5 10 15 20 25 CHD Previous MI Previous stroke 4.6 2.2 12 18 0 5 10 15 20 25 Total mortality CV mortality Incidence (%) Prevalence (%) 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

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 METS Maximal heart rate 173 bpm No chest pain No 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 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 (Level 1, Grade A).

ASCOT: Baseline Characteristics 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) 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 al JACC 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 1 o endpoint : first acute coronary event, revascularisation or stroke Follow up 3.9 years (stopped 2 years early)

Obesity Diabetes 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 (Level 1, Grade A).

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

“ The same old story…” Cost of Sexual Activity: The case for a distinction “ New fling” Familiar partner Unfamiliar partner + Familiar setting + Unfamiliar setting METS 2-3 METS 5-6 + Familiar meal + Unfamiliar meal

Cardiovascular Changes during Sexual Activity Simple everyday guidelines Walking 1 mile in 20’  3.5 METS Briskly climbing 2 flights of stairs (20 steps in 10 seconds)  3 METS “ The stair-climbing test” (Larson, 1980) Digging in the garden  5 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 (Level 1, Grade A).

Low Testosterone associated with increase CV and all cause mortality Khaw 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 (Level 1, Grade A).

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 (Level 1, Grade A).

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

Take Home Message E.D. E rectile D ysfunction ED ucation E arly D etection E ndothelial D ysfunction E arly D eath

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 .

Erectile Dysfunction

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