+1-adrenoceptor

antagonist mono-

therapy is the right

first-line treatment

for all men with

bothersome LUTS

LUTD

debate

Brussels

13.06.2014

Mark J

Speakman

Consultant

Urologist

Taunton UK.

+‘Alpha-blocker monotherapy is the right first-line therapy in all men with LUTS’

1. Yes I agree

2. No I don’t agree

+Conflicts of Interest:-

Over the last 5 years I have been involved in

research studies and given lectures for:

Allergan

Astellas

Genprobe

GSK

Lily

Neotract

+1-adrenoceptor antagonist

mono-therapy is

the right first-line treatment

for all men

with bothersome LUTS

However……

+ Individualise patients

Male LUTS – symptom clusters

Storage

symptoms

• Altered bladder

sensation

• Increased daytime

frequency

• Nocturia

• Urgency

• Urinary

incontinence

Post micturition

symptoms

• Feeling of

incomplete bladder

emptying

• Post micturition

dribble

Voiding

symptoms

• Hesitancy

• Intermittency

• Slow stream

• Splitting/spraying

• Straining

• Terminal dribble

Abrams P et al. Urology 2003;61:37-49;

Sexton CC et al. BJU Int 2009;103(Suppl3):12-23

About 2/3 of men with LUTS have symptoms

from more than one symptom group

+

• EpiLUTS 14,139 men ≥ 40 years old: 71% reported LUTS

Adapted from Sexton CC et al. BJU Int 2009;103(Suppl 3):12-23

Voiding + storagesymptoms

Storage symptoms only

Voiding symptoms only

Voiding + storage + post

micturition symptoms

Voiding + post micturition

symptoms

12.1%

10.4%

24.3%

10.3%

9.1%

A majority of men have BOTH

voiding and storage symptoms

+ Treat patients according to

their symptom profile

Voiding LUTS

predominant

Voiding + storage

LUTS

Storage LUTS

predominant

α1-AR

antagonist

α1-AR antagonist +

antimuscarinic

agent

Antimuscarinic

agent

in case of

substantial storage

In case of

persistent storage

after 4-6 weeks

+From BPH to male LUTS

Guidelines

2001

2012

+ What do the guidelines say?

EAU guideline on treatment of non-neurogenic male LUTS LE GR

α1-AR antagonist should be offered to men with moderate to severe

LUTS

1a A

NICE guideline on management of LUTS in men

Offer an α1-AR antagonist (alfuzosin, doxazosin, tamsulosin or

terazosin) to men with moderate to severe LUTS

Oelke M et al. EAU 2011 Guidelines; NICE clinical guideline 97 (May 2010); AUAnet 2010

AUA guideline on management of BPH (2010)

α1-AR antagonist are appropriate and effective treatment … for

patients with bothersome, moderate to severe LUTS

+ 1-AR antagonists improve patients’

QoL

1 Adapted from van Kerrebroeck P et al. Eur Urol 2000;37:306-13; 2 Adapted from Kirby RS et al. BJU Int 2001;87:192-200; 3 Adapted from Chapple CR et al. Eur Urol Suppl 2005;4:33-44

(N = 289) (N = 791) (N = 704)

P < 0.01

1-AR antagonist *

QoL: quality of life

*agents differ between studies

+ 1-AR antagonists relieve

voiding and storage LUTS

1 Adapted from van Kerrebroeck P et al. Eur Urol 2000;37:306-13; 2 Adapted from Chapple CR et al. Eur Urol Suppl 2005;4:33-44

1(N = 289)

2(N = 704)

P < 0.001

1- AR antagonist *

2(N = 704)

P = 0.02

1(N = 289)

Voiding IPSS Storage IPSS

P < 0.001

*agents differ between studies

+

“Long-term studies on … antimuscarinics in men

with LUTS are still missing, therefore these drugs

should be prescribed with caution and

regular re-evaluation of IPSS and

postvoid residual is advised”

Not all patients are treated the same

EAU guidelines on treatment of non-neurogenic male LUTS LE GR

Combination treatment with α1-AR antagonist and antimuscarinic

agent might be considered in patients with moderate to severe LUTS

if symptom relief has been insufficient with the monotherapy of

either drug

1b B

Prescribe cautiously in men suspected of having bladder outlet

obstruction

2b B

NICE guidelines on management of LUTS in men

Consider offering an antimuscarinic agent as well as an α1-AR

antagonist to men who still have storage symptoms after treatment

with an α1-AR antagonist alone

Oelke M et al. EAU 2011 Guidelines; NICE clinical guidelines 97 (May 2010) Chapple ICUD 2013

Recommendation: Prior to initiation of anticholinergic therapy,

baseline PVR urine should be assessed. Anticholinergics should

be used with caution in patients with a post-void residual greater

than 250 to 300 mL.

+ NICE Guideline

there is no evidence to suppport:-

1.1.8 Do not routinely offer cystoscopy to men with

uncomplicated LUTS (that is, without evidence of bladder

abnormality) at initial assessment.

1.1.9 Do not routinely offer imaging of the upper urinary

tract to men with uncomplicated LUTS at initial assessment.

1.1.11 Do not routinely offer a post void residual volume

measurement to men with LUTS at initial assessment.

+1-adrenoceptor antagonist monotherapy is

the right first-line treatment

for all men with bothersome LUTS

Be pragmatic,

Be practical,

Be cost effective & reimbursable,

Be Safe

Vote YES

α-Adrenoceptor Antagonist Monotherapy

Benefits all Men with LUTS

Matthias Oelke

Department of Urology

Global Congress on LUTD, The Egg, Brussels, 13th June 2014

- AGAINST -

Disclosures

Consultant / Speaker / Clinical studies sponsored by / research grants from: • Allergan• Apogepha• Astellas• Bayer• Ferring• GSK• Lilly• Mundipharma• Pfizer • Pohl-Boskamp• Recordati• Sophiris

Storage Symptoms are Prevalent in Men and Women

EpiLUTS survey in USA, UK, and Sweden; men and women ≥40 yrs

27.2%

43.1%

Coyne KS et al. Urology. 2011;77: 1081 – 7.OAB: overactive bladder

Storage symptoms are bothersome

EpiLUTS survey

40,0%

32,2%

27,8%

0%

20%

40%

60%

80%

100%

Men with ≥1 storage symptom (N=2,559)

% o

f m

en

re

po

rtin

g sy

mp

tom

bo

the

r

Quite a bit or agreat deal

Somewhat

Not at all or a littlebit

60.0%

27.2%

4 Coyne KS et al. Urology. 2011;77: 1081 – 7.

1-blocker Monotherapy – Antimuscarinics in Patients with Detrusor Overactivity (DO)

± 60% of men with LUTS respond to monotherapy with 1-AR antagonist

35%

79%

21%

65%

0%

20%

40%

60%

80%

100%

BOO

without DO

BOO with DO

% o

f p

atie

nts

Non-responders

Responders

73%

27%

0%

20%

40%

60%

80%

100%

Non-responders withBOO + DO

1-blocker monotherapy (3 mo) 1-blocker + antimuscarinic agent (+3 mo)

24/68 32/44

(IPSS decrease ≥4 points)

Lee JY et al. BJU Int. 2004; 94: 817 – 20.

60/76

BOO: bladder outlet obstruction; IPSS: International Prostate Symptom Score

12-week, double-blind RCTs in men ≥40 or 45 yr with OAB symptoms after ≥4 w on α1-AR antagonist

• Qmax ≥4 or 5 ml/s; PVR ≤200 ml (type of active agents differs between studies)

-4

-3,5

-3

-2,5

-2

-1,5

-1

-0,5

0

1 2 3

Addition of an Antimuscarinic to an α1-blocker Improves Persistent Storage Symptoms

1 MacDiarmid SA et al. Mayo Clin Proc. 2008; 83: 1002 - 10102 Chapple C et al. Eur Urol. 2009; 56: 534 - 543

3 Kaplan SA et al. J Urol. 2009; 182: 2825 - 2830

α1-AR antagonist + placebo

α1-AR antagonist + antimuscarinic agent

P<0.01

P=0.037

Me

an c

han

ge in

sto

rage

IPSS

fro

m b

ase

line

N=409 N=652 N=398

10.0 10.3 9.2 9.3 8.5 8.9

P<0.01

IPSS: International Prostate Symptom Score;RCT: randomised controlled trial; OAB: overactive bladder; PVR: post-void residual

α-Blocker ± Antimuscarinic- SATURN Study -

van Kerrebroeck P et al. Eur Urol. 2013; 64: 398 – 407.

Combination of α–blocker (tamsulosin) + antimuscarinic (solifenacin) is only effective when the patient has storage (OAB) symptoms

Combination therapy is not more effective than α–blocker if the patient has only/predominent voiding symptoms

IPSS - voiding IPSS - storage Total Urgency Score

α-Blocker ± Antimuscarinic- NEPTUNE Study -

Van Kerrebroeck P et al. Eur Urol. 2013, 64: 1003 – 12.

Primary Endpoint: total IPSS

Secondary Endpoint: IPSS irritative

Secondary Endpoint: # micturitions

Secondary Endpoint: QoL (IPSS)

Treatment According to Patients’ Symptom Profile

Predominantvoiding LUTS

Voiding + storageLUTS

Predominantstorage LUTS

α1-blocker

α1-blocker + antimuscarinic

antimuscarinicα1-blocker

In case of persistent storage LUTS

after 4-6 weeks

In case of persistent storage LUTS

after 4-6 weeks

In case of persistent voiding LUTS

after 4-6 weeks

Recommendations LE GR

Combination treatment with an α1-blocker together with a muscarinic receptor antagonist may be used in patients with bothersome moderate-to-severe LUTS if relief of storage symptoms has been insufficient with monotherapy with either drug

1b B

Combination treatment should be carefully prescribed in men who may have bladder outlet obstruction (BOO)

2b B

α1-blocker + Antimuscarinic Combination Therapy

EAU Recommendations

Oelke M et al. Eur Urol. 2013; 64: 118 – 40.

+Rebuttal

Mark J Speakman

+ Meta-analysis of efficacy & tolerabilityDjavan & Marberger Eur Urol 1999; 36:1-13

“All alpha-blockers seen to have similar

efficacy in improving symptoms and flow”

“Alfuzosin and Tamsulosin [& silodosin] are

better tolerated than doxazosin, terazosin &

prazosin”

+Summary of key points

α1-AR antagonists v anti-muscarinic agents

α1-AR

antagonists

Antimuscarinic agent

Efficacy Good overall Good in subpopulation

(storage)

Tolerability/persiste

nce

Good More bothersome

leading to

discontinuation

Use Recommended

in first line

Not recommended in

particular patients

(LUTS/BOO)

+ “1-adrenoceptor antagonist mono-therapy

is the right first-line treatment for all men

with bothersome LUTS”

Use an 1 blocker FIRST

Adapted from Helfand BT et al. Eur Urol. 2010; 57: 586 – 91.

45–54 years 55–64 years ≥ 65 years

(1,348,901)N patients: (1,270,892) (543,420) (1,201,365) (755,218) (2,124,705) (7,244,501)

Consequences: Undertreatment in Clinical Practice

Most patients with storage LUTS/OAB remain untreated (men more frequently than women)

• Adherence to Guidelines (AUA-BPH) reduces the number of prostate operations (evaluated ≤12 months after initial patient visit)

• 5% random sample analysis of Medicare claims data (n = 10,248 patients aged >65 years treated 1999 - 2007)

Consequences: Increased Number of Prostate Operations

Strope SA et al. Urology 2012; 80: 84-9.

• 675 patients (6.7%) had

surgery:

2% of patients with highestadherance vs. 11% of patients with lowestadherance (91% decrease of receiving surgery withhighest vs. lowest guidelinecompliance)

-91%

Consequences: Peristent LUTS after Prostate Surgery

• In case series, residual/recurrent LUTS after TURP were found in ~ 15-20% of patients (mean time from TURP 3.5 years), especially storage LUTS (OAB)

• Symptoms after TURP:

Seaman EK et al. J Urol. 1994; 152: 935 – 7.

n = 129 men(consecutive series, age 46-90 y, mean 72 y)

32%

33%

40%

42%

52%

68%

Storage LUTS

Voiding LUTS

‘Alpha-blocker monotherapy is the right first-line therapy in all men with LUTS’

1. Yes I agree

2. No I don’t agree