Medical Management of Erectile Dysfunction. Maarten Albersen MD PhD University Hospitals Leuven,

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1 Medical Management of Erectile Dysfunction Maarten Albersen MD PhD University Hospitals Leuven,

2 COI Consultancy/speaker for: Ferring, Sanofi, BSCI, Coloplast, Pfizer, Lilly, Menarini, Berlin-Chemie

3 1. Aytaç IA, et al. BJU International 1999;84: Vlachopoulos C V, et al. Circ Cardiovasc Qual Outcomes 2013;6: Fan Yet al. World J Urol Erectile Dysfunction Is the inability to develop and maintain an erection for satisfactory sexual intercourse or activity. < Age 1 Endocrine Vascular Neurogenic Psychogenic Drugs & abuse Mixed Cardiovascular events 2 All cause mortality 3

4 Erectile dysfunction: BURDEN Negative consequences for sexual experience and emotional wellbeing 1 Unsatisfactory sexual life 2 frustration and lack of spontaneity Affected emotional well being 1 concern over severe ongoing pathologies (cardiovascular disease, hypertension, diabetes, consequences of prostatectomy) 2 Can cause embarrassment, hindering communication, 3 and create concerns for both patients and partners 4, with reduced quality of life 2 1. Becher Cuzin 2016; 3. Hedon 2003 (figure) 4. DiMeo 2006

5 Diagnostic Work-up Patient with ED (self-reported) Medical and psychosexual history (use of validated instruments, e.g. IIEF) Identify other than ED sexual problems Identify common causes of ED Identify reversible risk factors for ED Assess psychosocial status Focused physical examination Penile deformities Prostatic disease Signs of hypogonadism Cardiovascular and neurological status Laboratory tests Glucose-lipid profile (if not assessed in the last 12 months) Total testosterone (morning sample) if indicated, bio-available or free testosterone Algorythm derived from EAU guidelines

6 Diagnostic Work-up: IIEF-EF How often were you able to get an erection during sexual activity? When you had erections with sexual stimulation, how often were your erections hard enough for penetration? During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? When you attempted sexual intercourse, how often was it satisfactory for you? How do you rate your confidence that you could get and keep an erection? Range 6-30 points, MCID = 4 points SEP 2 (%) SEP 3 (%)

7 Medical Management EAU GL

8 Medical Management Lifestyle Pharmacotherapy PDE5i Testosterone Alprostadil (and injectables) Shockwave therapy (Surgical therapy)

9 Lifestyle (association) There is a wealth in evidence on association of lifestyle factors and risk of ED: Smoking: adjusted odds ratio: 1.43 ( ) Becomes apparent after 20 PY Alcohol intake: 0.93 ( ) Physical excercise: 0.68 ( ) Diet: 0.93 ( ) (NS, unadjusted significant) Allen et al. JSM 2018

10 Lifestyle (intervention) Diet: DM2 patients allocated to meditteranean vs low-fat diet had less decrease of IIEF-scores over 8 year period (difference 1.22 points) 1 Exercise: addition of a prespecified exercise program to standard treatment (PDE5i) results in less ED following myocardial infarction 2, and a 2 point increase in IIEF-EF 3 Weight loss in overweight/obese (exercise & diet): 3 RCTs: +1.4 (IIEF-5) (IIEF-EF) (IIEF-EF) 6 OSAS: Addition of PEEP therapy to standard treatment for ED results in improved erectile function and increased PDE5i response 7 Smoking cessation: 25% of ex-smokers and no persistent smokers noted improvement in erectile function. 8 Effect not observed in severe ED. Effect size not reported. Thus: lifestyle modifications are recommended, but effect size is very small However: poor complicance is an issue (exercise 47%, diet 15-24%) 8 1. Maiorino et al. J. Diab. Compl Begot et al. Am J Cardiol Maio et al. JSM Collins et al. Obes Res Clin Pract Wing et al. JSM Moran et al. Plos One Campos-Juanatey, Asian J Androl Plourmand et al. BJUI Mulhall JSM 2018

11 Phosphodiesterase 5 - inhibitors Phosphodiesterase type 5 (PDE5) inhibitors are effective, safe, and welltolerated therapies for the treatment of men with ED (level of evidence = 1; grade of recommendation = A). PDE5 inhibitors are first-line therapy for most men with ED who do not have a specific contraindication to their use (level of evidence = 3; grade of recommendation = C). There are no significant differences in efficacy, safety, and tolerability among PDE5 inhibitors (level of evidence = 1; grade of recommendation = A). Dose titration of PDE5 inhibitors to the maximum tolerated dose is strongly recommended because it increases efficacy and satisfaction from treatment (level of Sexual stimulus needed! ICSM Hatzimouratidis K. JSM 2016

12 PDE5i PRN: pharmacokinetics

13 PDE5i PRN: adverse events Adverse event (%) Sildenafil Tadalafil Vardenafil Avanafil Headache Flushing Upper respiratory disorders Dyspepsia <1 Dizziness <1 Abnormal vision 2 <1 <2 <1 Back pain 7 <1 <1 Myalgia <1 6 <1 Penile pain/burning Genital/testicular pain Urethral burning/bleeding/spotting Penile erythema/infection Injection site reactions Penis disorder Prolonged erection Penile rash/oedema

14 Comparative efficacy/tolerability No randomized controlled trial has directly compared all currently available PDE5Is. Outcome measures differ between studies (IIEF- EF, GAQ-1, SEP2, SEP3) No hard conclusions can be reached. Network meta-analysis gives clues: tolerability differs, efficacy overlapping CIs. Chen et al. Eur Urol 2015

15 PDE5i PRN: efficacy Forest plot of overall efficacy (from 82 trials, patients) for phosphodiesterase 5 inhibitors at different dosages. Chen et al. Eur Urol 2015

16 PDE5i PRN: adverse events Forest plot of any adverse event (from 72 trials, patients) for phosphodiesterase 5 inhibitors at different dosages. Chen et al. Eur Urol 2015

17 PDE5i OAD 400 Tadalafil plasma concentration (ng/ml) Time (hours) Brock et al. JSM 2016, Wrishko R et al. JSM 2009

18 My $0.02 on PDE5i Considerations in my personal practice (not EBM!): NO data are available provideing direct comparison between either of the four drugs in terms of efficacy or patient preference (one study on adherence: TAD better than SIL*) Patients get full info on all options Tadalafil PRN, OAD and Avanafil PRN have pharmacokinetic unique selling points IMO. Sildenafil and Vardenafil are short acting alternatives. *Buvat et al. JSM 2013

19 My $0.02 on PDE5i Don t want to take a pill when not needed Don t want to wait an hour/two before effects kick in / spontaneity Side effects on previous PDE5-i use >>> Avanafil 200 mg. 100 mg. 50 mg. Psychogenic predominance / performance anxiety Spontaneity Weekender/night out Comorbidity (LUTS, mainly) >>> Tadalafil 5 mg OAD (increasing interval over time), Tadalafil 20 mg PRN. Tadalafil 10 mg Short acting, effective and cheap although at the cost of adverse events: Sildenafil or Vardenafil

20 What if PDE5i don t work? 1.Jiann et al. Int J Impot Res 2006; 2.Carvalheira et al. J Sex Med 2012

21 Alprostadil Topical/intra-urethral/intracavernous Alprostadil camp production via adenylate cyclase via GCPR

22 Options for PDE5-i nonresponders? Alprostadil 300 μg produced statistically and clinically significant improvements in IIEF-EF scores ( 4 points), and positive GAQ responses, in patients with comorbidities (e.g. cardiac disease) and those with sildenafil failure N= 74, NNS RP IIEF-5: 18.1 SEP 2: 90% SEP 3: 78% Moncada & Cuzin 2015, Della Camera et al. Urologia 2015

23 PDE5i PRN: adverse events Adverse event (%) Sildenafil Tadalafil Vardenafil Avanafil Alprostadil (topical) Headache Flushing Upper respiratory disorders Dyspepsia <1 Dizziness <1 <1 Abnormal vision 2 <1 <2 <1 Back pain 7 <1 <1 Myalgia <1 6 <1 Penile pain/burning 23 Genital/testicular pain 18 Urethral burning/bleeding/spotting Penile erythema/infection 16 Injection site reactions Penis disorder 4 Prolonged erection Penile rash/oedema 1

24 Testosterone? Snyder, NEJM 2016

25 Testosterone? Effects on erectile function 1 PDE5i nonresponders 2 1.Corona et al. Eur Urol Corona et al. JSM 2014

26 Low-intensity Shockwave Rx

27 Low-intensity Shockwave Rx Fode et al. Nat Rev Urol 2017

28 Does it work: single-arm studies Consistent beneficial effects In spite of varying protocols In spite of varying devices used Benefits in the realm of 0-9 points on IIEF-EF score (MCID 4) Mostly short-term benefits

29 RCT data Author n Patients FU Rate EHS 3-4 IIEF-EF/5 change Risk of bias (mo) % (rate) vs sham Vardi et al. 40 Vasculogenic (56%) Low 2012 Olsen et al. 112 Vasculogenic (5 wk FU) NS Low (3 m FU) 19 (6 m FU) NS NS Yee et al. 58 Vasculogenic 1 NS Low 2014 Srini et al. 60 Vasculogenic High * 2015 Kitrey et al. 37 PDE5inonresponders (MCID 40.5%) Low 2016 Fojecki et al. 126 Vasculogenic NS Low NS Motil et al. 125 Vasculogenic (MCID 81.33%) High ** 2016 Kalyvianakis et al Vasculogenic (75%) Low Fojecki et al Vasuclogenic (NS) (NS) Low Power analysis: to detect MCID with baseline IIEF of 12: randomization of > 70!

30 Meta-analyses Meta-analysis Included studies IIEF-EF increase (sign in bold) Lu et al. 14 (7 RCT) 2.0 Clavijo et al. 7 RCT 4.17 Man et al Zou et al. 15 NR Angulo et al Inclusion of severly biased studies in meta-analysis Inclusion of studies on pelvic pain, peyronie s Double inclusion of positive data Either showing result < MCID, or not significant 1 Lu Z, et al: 2017 Eur Urol 2 Clavijo RI, et al: 2017 JSM 3 Man, L, et al: 2017 Urology 4 Zou Z, et al: 2017 Int Braz J Urol 5 Angulo JC, et al: 2017 Actas Urol Esp

31 Conclusions PDE5 inhibitors are the mainstay first line medical therapy. Efficacy comparable, different profiles for different patients Alternatives include alprostadil topical, intra-urethral or intracavernous, and penile implant. Testosterone has modest effects on erectile function. Low-intensity shockwave therapy has modest effects on erectile function, better studies are needed.