Atherosclerosis and Erectile Dysfunction: Is PTA with DES the answer? James P. Zidar, MD, FACC, FSCAI Professor of Medicine Duke University Medical Center Director, Cardiovascular Services Duke Raleigh Hospital

James P. Zidar, MD DISCLOSURES - Jason Rogers, MD of UC- Davis. Consulting Fees Abbott Vascular, Medtronic CardioVascular, Inc., Cordis, a Johnson & Johnson company Grants/Contracted Research EV3, Inc. Special thanks: - Jason Rogers, MD of UC- Davis.

Erectile Dysfunction is Prevalent Massachusetts Male Aging Study 1995-1997 1085 men, ages 40-70 52% of men experienced some degreee of ED ~25 million men in the United States >300 million men worldwide Laumann et al. JAMA 1999:10:281:537. 4

Causes of Erectile Dysfunction Etiology 80% Vasculogenic Traumatic Post-surgical Hormonal Chronic disease- DM, CRI Medication Psychological Lue. NEJM 2000;342:1803 5

ED and CAD Share Risk Factors Age DM HTN Dyslipidemia Smoking Endothelial Dysfunction + Atherosclerosis This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Gazzaruso et al. Circulation 2004;110:22. Rosen et al. J Urol 1991;145:759. 6

Relationship of ED and CAD Up to 70% of men with CAD have ED The development of ED predates the onset of symptomatic cardiovascular atherosclerotic disease by ~ 36 mos Presence of ED is not routinely screened by vascular specialists Thompson: additional risk of CAD with ED is in the range of risk associated with current smoking or family history of MI Chirlia: 70 pts with vascular ED (by penile doppler after intracavernosal PGE-1 with PSV < 35 cm/s or RI < 0.9) vs. 73 controls. CAC by MSCT was more common. Predicts risk independent of traditional risk factors. Thompson et al. JAMA 2005;294:2996. Chiurlia et al. JACC 2005;46: 1503 7

Campbell. J Manag Care Pharm 2005;11:151. Unmet Clinical Need Many men who take PDE-5 inhibitors do not respond adequately There is need for additional therapies for erectile dysfunction not addressed by currently available treatments Therapies that address vascular inflow may in theory improve erectile function This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Campbell. J Manag Care Pharm 2005;11:151. 8

Penile Arterial Inflow

Physiology

Normal Erectile Function is Dependent on Adequate Arterial Inflow

Atherosclerotic Disease Can Result in Erectile Dysfunction

Veno-Occlusive Mechanism cGMP This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 13

Treatment Continuum for ED Sildenafil (Viagra, Pfizer) Vardenafil (Levitra, Bayer) Tadalafil (Cialis, Lilly) PDE-5 Inhibitor Oral Therapy Penile Injection Intraurethral Suppository PDE-5 Inhibitors (treatment method for 97.5% of ED patients) Includes Viagra, Cialis, and Levitra Taken orally Effective treatment window of 4-36 hours 57% discontinuation rate Prevent the release of phosphodiesterase type 5 (PDE-5), which is responsible for degradation of an erection High failure rate (up to 50% failure) Vacuum Constriction Devices (VCDs) (1%) Least invasive ED treatment; uses a vacuum pump to draw blood into the penis and a constriction band to prevent outflow Specifically recommended by the American Urologist Association as a treatment Unfavored by patients because of the necessary interruption to lovemaking Intraurethral Drugs (.7%) Involves depositing a suppository inside the urethra Effective within ten minutes; effects last for up to an hour 65% effective Very low incidence of side effects or complications Injectable Drugs (.6%) Delivered via injection into the base of the penis immediately before sexual activity Highly effective in causing erection (75 – 85% effective) Discontinuation rate of 70% due to invasiveness, delivery method Examples include papaverine, Alprostadil, and phentolamine Implants (.2%) Most invasive procedure available; involved insertion synthetic cylinders within the corpus cavernosum Irreversible; requires the destruction of the normal cavernosum vasculature Considered a last-resort treatment Vacuum Constriction Device Penile Prosthesis

Surgical Revascularization Only potentially “curative” therapy for ED described to date Usually applied to younger patients with a history of perineal or penile trauma Review of prior surgical reports reveals major limitations are: adequate conduit, target and morbidity This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Goldstein et al. Curr Urol Reports 2007;8:491. Lue. NEJM 2000; 342 1802. 15

ILIAC INTERVENTION PTA/stent of the common iliac has resulted in multiple anecdotal reports of improved erectile function

Percutaneous IPA Revascularization Data on PTA of the internal pudendal artery are needed Few published reports (n=10) & studies of either the disease or angioplasty of the IPA - initial improvement Limitations: clinical restenosis (after balloon angioplasty) No publications regarding stenting of the IPA More investigation is required This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Angelini, CCD, 1987; Becker, Indiana Med. J, 1986; Castenada-Zuniga, AJR, 1982; Valji, Cardio & Int. Radio, 1988 17

PANPI Erectile Dysfunction with Poor Response to PDE-5 Inhibitors Pelvic Angiography in Non-Responders to Phosphodiesterase-5 Inhibitors 10 patients undergoing clinically indicated coronary angiography DESIGN: Pilot angiographic study OBJECTIVE: Describe the arterial disease and feasibility of stenting the IPA SITE: University of California, Davis Medical Center- Jason Rogers, MD Erectile Dysfunction with Poor Response to PDE-5 Inhibitors Coronary Angiography and Pelvic Angiography (DSA) Quantitative Coronary and Pelvic Angiography

1st Study to Correlate Angiographic CAD with Pudendal Arterial disease PANPI: Procedure 1st Study to Correlate Angiographic CAD with Pudendal Arterial disease Used standard femoral access Abdominal aortography & iliofemoral angiography Selective angiography of the internal pudendal arteries after intra-arterial nitroglycerin Gonadal shielding Rogers, UCD, 2009.

Baseline Demographics PANPI Baseline Demographics n=10 Age (yrs) 57 BMI 32 IIEF-5 Score 7 Hypertension 60% Hyperlipidemia 90% Diabetes Mellitus 20% Smoking History 80% Rogers, UC-Davis, 2009

PANPI Pelvic Arteriography Stenosis (%) Diameter (mm) Pelvic Arteries Common iliac Left Right 25 ± 31 10 ± 13 10.4 ± 1.4 10.8 ± 1.4 Internal iliac 15 ± 6.5 25 ± 19 6.7 ± 1.7 6.4 ± 1.3 Internal pudendal 60 ± 32 52 ± 30 2.7 ± 0.5 2.7 ± 0.4 Rogers, UC-Davis, 2009

PANPI Coronary Angiography Coronary Arteries Stenosis (%) Diameter (mm) Left main 15 ± 17 4.6 ± 0.9 Left anterior descending 56 ± 28 3.0 ± 0.9 Circumflex 55 ± 33 2.8 ± 0.7 Right coronary artery 65 ± 29 3.5 ± 0.6 Rogers, UC-Davis, 2009

PANPI: Example Rogers, UC-Davis, 2009

PANPI: Conclusions Represents the first angiographic report of coronary artery disease correlated with internal pudendal artery disease in patients with ED. Erectile dysfunction not responsive to PDE-5 inhibitors may be due to severe disease of the IPA and may be a potential target for modern percutaneous intervention, including stenting. This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Rogers, UC-Davis, 2009 24

ZEN Trial Zotarolimus-Eluting Peripheral Stent System for the Treatment of Erectile Dysfunction in Males with Suboptimal Response to PDE5 Inhibitors Enrolling 50 patients at 9 US centers Data expected by 2011 Study will add insight on safety, feasibility, and patient selection

Atherosclerotic Disease Can Result in Erectile Dysfunction

Percutaneous Revascularization Medtronic Zotarolimus-Eluting Platform

ZEN - Key Inclusion Criteria General Angiographic Males > 18 years old Successful completion of “run in phase” In a stable, active sexual relationship baseline and pre-procedure IIEF-5 domain score >6 and < 21 despite PDE5-I use No other organic cause for ED Not diabetic Stenosis of the internal pudendal artery: Severe Unilateral or moderate-severe bilateral vessel treatment Target vessel reference diameter > 2.25 mm and < 4.2 mm Target lesion length < 27 mm

Conclusions Erectile dysfunction largely has a vascular basis Many men are not optimally treated with conventional medical therapies Patients with angiographic CAD who are poor responders to PDE-5i therapy have IPA stenoses The ZEN feasibility study will investigate the identification of the proper patient subset, safety, feasibility and efficacy of percutaneous IPA revascularization with a zotarolimus-based system This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 29