lutd debate brussels antagonist mono- 13.06.2014 therapy ... micturition symptoms • feeling of...
TRANSCRIPT
+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