Conflict of interest: I received funding for investigation from BAYER, Lilly, Pfizer, Auxilium and Janssen, and I have fomred part of comittees for Bayer, Lilly, Gebro, Almirall, Janssen, Italpharmaco abd Menarini. I am speaker for Lilly, Pierre Fabre and Bayer. CEO at DocFitSolution.

MANAGEMENT OF COMPLICATIONS AFTER LRP:

HOW TO IMPROVE EARLY CONTINENCE

AND MANAGE ERECTILE DYSFUNCTION

Eduard García Cruz

Urología y Salud del Hombre

Servicio de Urología

Hospital Clínic de Barcelona

ecruz@clinic.ub.es

@drgarciacruz

www.reisho.com

STEP 1. BEFORE

STEP 2. DURING

STEP 3. AFTER

DO WE GIVE REALISTIC AND COMPREHENSIVE INFO TO OUR PATIENTS?

DO WE PREOP STRESS THE IMPORTANCE OF EARLY FUNCTIONAL REHAB?

DO WE HAVE RELIABLE PREDICTING TOOLS?

DO WE USE VALIDATED QUESTIONAIRES?

STEP 1. BEFORENeurovascular preservation indication.Use Validated Questionaires.Assess Risk.Realistic information about options and timing.

STEP 2. DURING

STEP 3. AFTER

STEP 1. BEFOREUse Validated QuestionairesAssess Risk.Neurovascular preservation indication.Realistic information about options and timing.

STEP 2. DURING

STEP 3. AFTER

AGE, URETHRAL LENGTH, ROBOT (NS), NERVE SPARING (NS)

AGE, ROBOT, TESTOSTERONE, D´AMICO RISK GROUPS (NS)

STEP 1. BEFOREUse Validated QuestionairesAssess Risk.Neurovascular preservation indication.Realistic information about options and timing.

STEP 2. DURINGBest possible surgery.

STEP 3. AFTER

STEP 1. BEFOREUse Validated QuestionairesAssess Risk.Neurovascular preservation indication.Realistic information about options and timing.

STEP 2. DURINGBest possible surgery.

STEP 3. AFTER

Efficacy measuresThe primary measure was the percentage of patientswho were responders. A stringent responderdefini ti on was establ ished a priori as those patientswho, at the end of phase 3, had a combined score ofat least 8 for Q3 and Q4 of the International Indexof Erecti le Function, and also answered ‘yes’ tothe question, ‘Over the past 4 weeks, have yourerections been good enough for satisfactory sexualactiv i ty?’

Secondary measures were changes from basel inein the six-i tem Erecti le Function domain of theInternational Index of Erecti le Function and, forthe plethysmography subgroup, the duration ofpenile tumescence and rigidity. The Erecti le Functi ondomain has a score range of 1–30, with ED graded assevere (1–10), moderate (11–16), mi ld to moderate(17–21), mi l d (22–25) and none (26–30).12

StatisticsOn the basis of analyses of Q3 and Q4 of theInternational Index of Erecti le Function in previousstudies, a conservative standard deviation of 2.00was assumed. If the mean si ldenafi l versus placebodi fference for at least one of the si ldenafi l groupswas 1.5 points for both variables, then a sampl e sizeof 44 patients per treatment group would provide90% power to detect a signi ficant di fferencebetween variables singly and 80% power to detectsigni fi cant di fferences for both variables jointly,based on two-sided analysis of variance testsconducted at the 0.05 signi fi cance level wi thDunnett’s adjustment. Assuming that 80% of rando-mized patients would contribute to the intent-to-treatanalyses, a sample size of 55 patients per treatmentgroup was requi red. However, enrol l ment ceasedafter 125 because an interim bl inded review of datafrom the 35 completed patients showed a responserate of only 25% (9 of 35), which was not what was

expected based on rates of spontaneous recovery oferecti le functi on reported in the publ ished l i tera-ture.13–17 After enrol lment ceased, two US studycenters remained acti ve to complete al l the studyvisi ts in the ongoing patients in the plethysmogra-phy subgroup and to provide information to aid inplanning possible future studies.

A l l statistical analyses were performed usingStatist ical Anal ysis System software version 6.12for efficacy analyses and version 8.2 for demo-graphic and safety analyses. Primary and secondaryefficacy variables were analyzed in patients whocompleted the 36-week double-bl ind treatmentperiod and the 8-week drug-free evaluation period.In the original statistical analysis plan, the primaryefficacy measure (percentage of responders) wasto be analyzed using the pai r-wise Cochran–Mantel–Haenszel (CMH) test. However, becausethe Mantel–Fleiss cri teri on was not sati sfied, theCMH test was determined to be inappropriate foranalysis purposes. Therefore, Fisher ’s exact test(two-tai l ed) was used as an al ternative (and appro-priate for the existing number of patients) approach,wi th the Bonferroni adjustment to account formul tipl e compari sons wi th placebo. Secondaryefficacy measures were analyzed using the nonpara-metric Wi lcoxon rank-sum test. Safety was assessedin patients who took at least one dose of studymedication.

Resul ts

Of 238 patients screened, 125 were randomi zed totreatment and 123 received at least one dose of studydrug. In total , 94% (117 of 125) of the randomi zedpatients were enrol led at five North American si tes.Patients were largely simi lar among treatmentgroups wi th respect to demographics (Table 1).Across the groups, a simi lar number of patients

Table 1 Demographics of the patients who took study medication and of the analyzed population

Took study medication (n ¼123)/analyzed (n ¼76)

Placebo Sildenafi l (50 mg) Sildenafi l (100 mg)

Number of patients (n) 42/25a 40/23a 41/28Mean age, year (s.d.) 57 (7)/56 (6) 55 (6)/55 (6) 55 (6)/55 (6)(range) (42–70)/(42–67) (42–67)/(42–63) (38–68)/(38–65)

Race (%)White 88/92 80/83 90/89Black 12/8 17/13 7/11Other 0/0 3/4 3/0

Mean weight, kg (s.d.) 88 (12)/88 (14) 89 (11)/90 (12) 84 (15)/85 (14)(range) (68–123)/(68–123) (68–110)/(71–110) (66–113)/(66–113)

aOne addi tional patient was randomized to this group, but discontinued before receiving study drug.

Sildenafil and ED after radical prostatectomyH Padma-Nathan et al

481

International Journal of Impotence Research

This article is p

rotecte

d b

y cop

yright. A

ll rights reserved

.

This is an open access article under the terms of the Creative Commons

Attribution-NonCommercial-NoDerivs License, which permits use and

distribution in any medium, provided the original work is properly cited, the

use is non-commercial and no modifications or adaptations are made.

22

Fig

ure 1

: The F

ER

TI C

AR

E®

vib

rator. T

he v

ibrato

ry stim

ulatio

n o

f the d

evice is d

elivered

thro

ugh a

reusab

le but d

isposa

ble b

lack p

lastic disc as seen

on th

e righ

t end o

f the p

icture.

Th

e dev

ice was set to

an a

mp

litude o

f 2 m

m an

d a v

ibratio

n fre

quen

cy o

f 100

Hz. P

atients

were in

structed

in stim

ulatin

g th

e frenulu

m o

nce d

aily

with

a sequ

ence co

nsistin

g o

f 10

seconds o

f stimulatio

n fo

llow

ed b

y a 1

0 seco

nd

pau

se repeated

10 tim

es (for a to

tal of 1

00

seconds o

f stimulatio

n ev

ery d

ay).

Accepted Article

This article is protected by copyright. All rights reserved.

This is an open access article under the terms of the Creative Commons

Attribution-NonCommercial-NoDerivs License, which permits use and

distribution in any medium, provided the original work is properly cited, the

use is non-commercial and no modifications or adaptations are made.

23

Figure 2: The flow of patients throughout the study

Acc

epte

d A

rtic

le

This article is protected by copyright. All rights reserved.

This is an open access article under the terms of the Creative Commons

Attribution-NonCommercial-NoDerivs License, which permits use and

distribution in any medium, provided the original work is properly cited, the

use is non-commercial and no modifications or adaptations are made.

1

Title page

Title:

Penile vibratory stimulation in the recovery of urinary continence and erectile function after

nerve sparing radical prostatectomy: A randomized, controlled trial1

Running title:

PVS after Radical Prostatectomy

Authors:

Mikkel Fode, MD 1, Michael Borre, MD, PhD, DSc (Med)

2, Dana A. Ohl, MD

3, Jonas

Lichtbach 4 , Jens Sønksen, MD, PhD, DSc (Med)

1

1. Department of Urology, Herlev University Hospital, Herlev, Denmark

2. Department of Urology, Aarhus University Hospital, Aarhus, Denmark

3. Department of Urology, University of Michigan, Ann Arbor, USA

4. Department of Physiotherapy, Herlev University Hospital, Denmark

This article has been accepted for publication and undergone full peer review but has not been through the copyediting,

typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of

Record. Please cite this article as doi: 10.1111/bju.12501

Acc

epte

d A

rtic

le

This article is protected by copyright. All rights reserved.

This is an open access article under the terms of the Creative Commons

Attribution-NonCommercial-NoDerivs License, which permits use and

distribution in any medium, provided the original work is properly cited, the

use is non-commercial and no modifications or adaptations are made.

25

Table 2: Erectile function outcomes in the two groups after RP. Results reported as median (range) and

proportions respectively.

IIEF-5 at 3

months

IIEF-5 at 6

months

IIEF-5 at 12

months

IIEF-5 ≥ 18

at 3 months

IIEF-5 ≥ 18

at 6 months

IIEF-5 ≥ 18 at

12 months

PVS 5 (0-25) 10.5 (0-25) 18 (0-25) 5/30 (17%) 13/30 (43%) 16/30 (53%)

Control 5 (0-25) 5 (0-25) 7.5 (0-25) 4/38 (11%) 9/38 (24%) 12/38 (32%)

p-value 0.25 0.08 0.09 0.46 0.09 0.07

Acc

epte

d A

rtic

le

This article is protected by copyright. All rights reserved.

This is an open access article under the terms of the Creative Commons

Attribution-NonCommercial-NoDerivs License, which permits use and

distribution in any medium, provided the original work is properly cited, the

use is non-commercial and no modifications or adaptations are made.

26

Table 3: Continence rates and pad use (median and range) after surgery

Continence at 3

months

Continence at 6

months

Continence at

12 months

Pad use at 3

months

Pad use at 6

months

Pad use at 12

months

PVS 65.5% 83.3% 90% 1 (0 - 6) 0 (0 - 3) 0 (0 - 2)

Control 62.9% 91.9% 94.7% 1 (0 - 4) 1/3 (0 - 6)* 0 (0 - 3)

p-value 0.83 0.28 0.46 0.09 0.14 0.56

*One patient reported to use 1/3 of a pad daily. As there was no pre-specified decision on how to deal with

such reporting, it was taken at face-value when analysing the results.

Table 4: DAN-PSS (median and range) after surgery

3 months 6 months 12 months

PVS 1 (0-34) 2 (0-41) 3 (0-36)

Control 5 (0-34) 1 (0-48) 0.5 (0-21)

p-value 0.74 0.74 0.13

Acc

epte

d A

rtic

le

ICI, IUA and VED

TIMING OF THE REHAB

STEP 1. BEFOREUse Validated QuestionairesAssess Risk.Neurovascular preservation indication.Realistic information about options and timing.

STEP 2. DURINGBest possible surgery.

STEP 3. AFTEREarly onset?Multimodal?Optimal strategy unknown.PFMT and lifestyle changes

Tadalafil 5/24MUSE* 3/week

* Minimum dose to get functional erections

AFTER CATHETER REMOVAL

STOP REHAB AND ASSESS3 MONTHS

Tadalafil 5/24

FUNCTIONAL ERECTIONS

Observation

BACK TO BASELINE

Tad 5/24 + MUSE 3/week

NON-FUNCTIONAL ERECTIONS

STOP REHAB AND ASSESS12 MONTHS

Observation

BACK TO BASELINE

Patient preference

FUNCTIONAL ERECTIONS

PDEI-5* vs MUSE*

NON-FUNCTIONAL ERECTIONS

PENILE PROSTHESIS

NON-FUNCTIONAL ERECTIONS

PFMTAFTER CATHETER

REMOVAL

ASSESS3 MONTHS

PFMT

1 PAD

Observation

DRY

PFMT + DULOXETINE

>1 PAD

STOP REHAB AND ASSESS12 MONTHS

RSP + DULOXETINE

1 PAD

SPHINCTER

>2 PADS

SLING

2 PADS

RSP + DULOXETINE*

NOT DRY

Conflict of interest: he recibido fondos para investigación de BAYER, Lilly, Pfizer, Auxilium y Janssen, he formado parte de comités asesores para Bayer, Lilly, Gebro, Almirall, Janssen, Italpharmaco y Menarini. Soy ponente para Lilly, Pierre Fabre y Bayer. CEO en DocFitSolution.

MANAGEMENT OF COMPLICATIONS AFTER LRP:

HOW TO IMPROVE EARLY CONTINENCE

AND MANAGE ERECTILE DYSFUNCTION

Eduard García Cruz

Urología y Salud del Hombre

Servicio de Urología

Hospital Clínic de Barcelona

ecruz@clinic.ub.es

@drgarciacruz

www.reisho.com