Download Nocturia

Medical management of BPH
Sender Herschorn, MD, FRCSC
Division of Urology
University of Toronto
Disclosures






Astellas
Allergan
Pfizer
Ferring
Boston Scientific
Ipsen
University of Toronto Hospitals
Toronto General
Sunnybrook
Mount Sinai
Princess Margaret
Sick Kids
Saint Michael’s
Changing paradigm
Abrams P.
Gravas
et al.
2016
Gravas et al. EAU
Guidelines
2015
Patient-centred care model
Medical
(diseasecentred)
model
Patientcentred
model
Levenstein et al. Family Practice 1986; 3: 24-30.
Gravas et al.
EAU Guidelines 2016
LUTS Are a Constellation of
Storage and Voiding Symptoms
Storage
Voiding
Post-voiding
Urgency
Hesitancy
Post-void dribble
Frequency
Poor flow
Sense of
incomplete emptying
Nocturia
Intermittency
Urgency
incontinence
Straining
Other
incontinence
Terminal dribble
Abrams P, et al. Neurol Urodyn 2002;21:167–178.
Incidence and progression
of LUTS (1992-2008)
Incidence rate of
moderate or worse LUTS
Progression rate of
severe LUTS
 Incidence cohort: 25,879 men in U.S.
 Progression cohort: 9628 men
Platz et al. J Urol 2012; 188:496-501
EAU guideline: symptom- oriented, take into
account underlying pathophysiology and risk of
disease progression
If other diseases/conditions could be excluded
Benign conditions of bladder and/or prostate
with baseline values
TREATMENT
Based on individual patient characteristics incl.
type of LUTS
Predominant Predominant
Storage +
voiding
voiding
storage
LUTS
LUTS
LUTS
Oelke M et al. EAU Guideline on Male LUTS. Update February 2012
Storage LUTS:
Overactive Bladder
 Symptom complex




Urgency
Frequency (>8/day)
Nocturia (>2)
+/- Urgency incontinence
 Associated with other conditions
Abrams et al. Neurourology and Urodynamics 2002; 21:167-178
Rovner and Wein. Clinical Geriatrics, 2002
Prevalence, %
Prevalence of OAB by Age
40
35
30
25
20
15
10
5
0
Comparison of data from the SIFO study 1997
and the EPIC study 2005
Men – SIFO 1997
Men – 2005
Women – SIFO 1997
Women
16.6%
̶ 2005
11.8%
18-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69
70+
Age, years
Milsom I et al. BJU Int. 2001;87:760-766.
Irwin et al. Eur Urol 2006; 50:1906-1915.
Management of OAB
Initial Presentation,
History, Physical,
Urinalysis
Patient Education and
Behavioural Modification
Medical Therapy
(Antimuscarinics or β3
agonist)
OnabotulinumtoxinA
Percutaneous Tibial
Nerve Stimulation
Sacral Neuromodulation
Bartley et al. Curr Urol Rep, 2013; 14:541-8
Antimuscarinics for OAB
Rationale for Treatment
Blockade of muscarinic receptors at both
detrusor and non-detrusor sites may
prevent OAB symptoms and detrusor
overactivity without depressing the
contraction during voiding
Antimuscarinics
Generic
name
Trade name
Dose supplied
Recommended dose
Oxybutynin
Generic
2.5 mg, 5mg, 10 mg
5 mg 2-3 times per day, up to 4
times per day
Transdermal
oxybutynin
Oxytrol
Gelnique
3.9 mg
10% solu’n 100mg)
3.9mg per day (twice weekly)
Daily
Oxybutynin ER
Ditropan XL
5 mg, 10 mg
Dose escalation from
5 mg to 30 mg once daily
Tolterodine IR
Detrol
1 mg, 2 mg
1 or 2 mg twice a day
Tolterodine ER
Detrol LA
2 mg, 4 mg
2 or 4 mg once daily
Solifenacin
Vesicare
5 mg, 10 mg
Dose escalation from 5 to 10
mg once daily
Darifenacin
Enablex
7.5 mg, 15 mg
Dose escalation from 7.5 to 15
mg once daily
Trospium
IR
Sanctura XR
20 mg
30 mg
20 mg twice daily
30 mg once daily
Fesoterodine
Toviaz
4mg, 8 mg
Dose escalation from 4 to 8 mg
once daily
Combined
Non-specific
M3 Specific
Antimuscarinic monotherapy in men
with predominantly storage symptoms
12-wk placebo-controlled studies in men with predominant storage LUTS
(N=163)
(N=745)
(N=425)
(N=745)
(N=235)
*
*
*
* Sign. vs. placebo (P<0.05)
Oelke M et al. EAU Guideline on Male LUTS. Update February 2012
OAB and BOO
 Men with LUTS also have OAB
symptoms
 Benefit of adding an anticholinergic
to an alpha blocker in the treatment
of patients with symptomatic BOO
from BPH who have persistent
storage symptoms
Antimuscarinics in males






Tolterodine
Oxybutynin ER
Propiverine
Solifenacin
Fesoterodine
Darifenacin
 Mainly 12-week trials with alpha-blockers
 Significant improvement in storage symptoms
 Non-significant improvement in many
outcome measures in add-on trials
 Low risk of retention
TIMES: Primary End Point: Treatment
Benefit at Week 12
†
‡
*
*P < .0001 between group comparisons
†P = .001 between group comparisons
‡P = .001 between group comparisons
Kaplan SA et al. JAMA 2006;296:2319-2328.
Mirabegron and BOO


200 men ≥45 years with LUTS and BOO were randomized to daily mirabegron
50 mg (70) or 100 mg (65), or placebo (65) for 12 weeks.
Primary UD parameters were change from baseline to end of treatment in
maximum urinary flow and detrusor pressure at maximum urinary flow
(noninferiority margins 3 ml per second and 15 cm H2O, respectively).
Nitti et al. J Urol. 2013,190:1320-7.
EAU Male LUTS Guidelines
Male LUTS
Symptom bother,
IPSS >7?
-
with or without
α1-AR antagonist
Residual storage
symptoms
Watchful waiting
with or without
Edu/Lifestyle
Add muscarinic
receptor antagonist
+ continue with
Edu/Lifestyle
-
Nocturnal polyuria
only?
Storage symptoms
predominant/only?
Prostate volume
>40 ml?
Edu/Lifestyle
+
+
+
+
Long-term
treatment?
+
Edu/Lifestyle
with or without
5-ARI
± α1-AR
antagonist
Oelke M et al. EAU Guideline on Male LUTS. Update February 2012
Edu/Lifestyle
with or without Muscarinic
receptor antagonist / Beta
3 agonist
Edu/Lifestyle
with or without
Desmopressin
Alpha adrenergic
blockers
• The rationale for α-adrenergic blockers in the
treatment of LUTS is based on the hypothesis that the
pathophysiology of LUTS is in part caused by BOO,
which is mediated by α1 adrenoceptors associated
with prostatic smooth muscle
α1-adrenergic receptors
Caine et al. 1976, 1978
Classification of α-blockers
Anderson CE. Campbell-Walsh 2016
1-AR antagonist is first-line treatment
for men with bothersome LUTS
α1-AR antagonist
Total IPSS
↓ 35-40%
Qmax
↑ 20-25%
Onset of action
Rapid (days)
Prostate volume
No effect
Duration of efficacy
Long-term risk of AUR or
BPH-related surgery
Long-term (years)
No effect
AUR: acute urinary retention; BPH: benign prostatic hyperplasia;
IPSS: International Prostate Symptom Score; Qmax: maximum urinary flow rate
Oelke M et al. EAU Guideline on Male LUTS. Update February 2012
Alpha adrenergic
blockers
 RCTs demonstrated the safety and efficacy of αblockers for the treatment of LUTS.
 Rapid and dose dependent clinical response.
 Long-term durability.
 The long-acting α1-blockers well tolerated.
 Terazosin and doxazosin significantly lower BP only
in hypertensive patients.
 Direct comparison studies of the α-blockers are
sparse and involve small numbers of patients,
and therefore any claims of superiority cannot be
justified.
Anderson CE. Campbell-Walsh 2016
5α-Reductase inhibitors
 Induce apoptosis of prostate epithelial cells –
prostate size reduction of about 18-28% and
circulating PSA levels of about 50% after 6-12
months of treatment
 More pronounced after long-term treatment.
 Continuous treatment reduces the serum DHT
concentration by approximately 70% with finasteride
and 95% with dutasteride. However, prostate DHT
concentration is reduced to a similar level (85-90%)
by both 5-ARIs.
http://uroweb.org/wp-content/uploads/EAU-Guidelines-Management-of-nonneurogenic-male-LUTS-2016.pdf
-AR antagonists and 5-ARIs: more effective than
either monotherapy in patients at high risk of
disease progression
CombAT trial:
4-yr double-blind RCT in 4,844 men ≥50 yrs with mean prostate volume 55 ml and
mean IPSS 16.4
§
§
#
16.6 16.4 16.4
9.3
9.2
9.2
7.3
7.2
7.2
Baseline
*
*
*
Montorsi F et al. BJU Int 2011;107:1426-31
*P<0.001 vs. either monotherapy
# secondary analysis
§ post-hoc analysis
α1-AR antagonist (N=1,611)
5-ARIs in combination with α-AR
antagonists for men at risk of disease
progression
Men with enlarged prostate (>40 ml) and reduced Qmax
Only recommended for long-term treatment (>1 year)
5-ARI
Total IPSS
Qmax
↓ ~15-30%
↑ ~1.5-2.0 ml/s
Onset of action
Very slow (6-12 mo)
Prostate volume
↓ ~18-28%
Duration of efficacy
Long-term risk of AUR or
BPH-related surgery
Long-term (years)
↓
Oelke M et al. EAU Guideline on Male LUTS. Update February 2012
Oelke M et al. EAU Guideline on Male LUTS. Update February 2012
Impact of combination 5-ARI
and AB on sexual function
 Systematic review and meta-analysis
 5 RCTs with 6131 men
ED
Combination
AB
7.93%
4.66%
5ARI
<0.0001
6.47%
LA*
3.69%
2.36%
3.51%
P value
0.04
0.003
3.37%
0.84
 Combination associated with
 significantly higher risk of sexual dysfunction compared with
single agent monotherapy.
 Similar risk of LA as 5ARI monotherapy
*Libido
Abnormalities
Favilla et al. The Aging Male, 2016 epub
Medical treatment and
ejaculatory dysfunction (EjD)
 Meta-analysis of 23 studies
 EjD sig. more common with AB than with placebo
(OR: 5.88; P<0.0001)




Tamsulosin (OR 8.58; P<0.006)
Silidosin (OR 32.5; P<0.00001)
Tamsulosin sig. lower than Silodosin (OR 0.09; P<0.00001)
Doxazosin and terazosin similar to placebo
 EjD independently associated with IPSS and
Qmax improvements
 EjD more common with 5ARIs than placebo
 Finasteride = Dutasteride
Gacci et al. J Sex Med 2014; 11:155-66
Phosphodiesterase-5 Inhibitors
affect LUT smooth muscle
X
ED and LUTS may
share common
etiology
X
Kanai et al. N & U 2012, 31:300-8
PDE-5 inhibitor results
Systematic review and meta-analysis
7 RCTs (N=3,214): PDE-5 inhibitor vs.
placebo
Group
difference
P value
IIEF
+5.5
<0.0001
IPSS
-2.8
<0.0001
Qmax
-0 ml/s
NS
5 RCTs (N=216): α1-AR antagonist + PDE-5
inhibitor vs. α1-AR antagonist monotherapy
Group
difference
P value
IIEF
+3.6
<0.0001
IPSS
-1.8
0.05
Qmax
+1.5 ml/s
<0.0001
IIEF: International Index of Erectile Function score; higher score = better function;
NS: not significant
Gacci M et al. Eur Urol 2012;61:994-1003
PDE5-Inhibitor + finasteride
Change in IPSS total score


350 with tadalafil/finasteride vs. finasteride alone for 26 weeks
Combination provides early improvement
Casabe et al. J Urol 2014; 191:727-33
PDE-5 Inhibitors




Undetermined link between LUTS-BPH and ED.
Improve symptoms scores.
Do not improve flow rates.
Combination with α-adrenergic blockers may be synergistic
and improve LUTS and flow rates.
 The combination with doxazosin may be associated with
hypotension
 PDEIs alone or in combination α-adrenergic blockers may be
of value for men with both ED and LUTS.
Anderson CE. Campbell-Walsh 2016
Nocturia
Nocturia is defined by the International Continence
Society (ICS) as:
“The complaint that the individual has to
wake at night one or more times to void…
each void is preceded and followed by sleep”
~Van Kerrebroeck et al. 2002
Van Kerrebroeck et al. Neurourol Urodyn 2002;21:179–183.
Nocturia in Canada
 In a survey of 1000 adults ≥18 years of age, 43% of men and 57% of
women reported one or more LUTS
Nocturia was the most common LUTS at 36.4%
% Incidence of nocturia ≥1 void/night
Age
Men
Women
Total
All
33.2
39.4
36.4
18-40
23.5
30.3
27
41-64
40.4
45.9
43.2
≥65
44.7
53.4
49.5
Herschorn et al. BJU Int 2008 Jan;101:52-8.
ICUD Male LUTS
Consultation
5 causative categories of nocturia
 Bladder storage problems
 24h global polyuria (>40 mL/kg urine
output over 24 h)
 Nocturnal polyuria
 Sleep disorders
 Mixed etiology
Marshall et al. Urology 2015; 85:1291-9
Obstructive
sleep apnea
 Intermittent occlusion of the airway during sleep leads to
profound hypoxia
 Relieved by a gasping respiratory pattern
 Fluctuating hypoxia pattern impairs sleep patterns directly.
 Gasping intakes of breath substantially raise intrathoracic
pressures.
 Increased right atrial transmural pressure resulting from
hypoxia-induced pulmonary vasoconstriction leads to
an elevation in atrial natriuretic peptide (ANP), which
precipitates increased urine output
Yalkut et al. J Lab Clin Med 1996; 128:322-8
Nocturnal polyuria
 Nocturnal polyuria or nighttime urine overproduction is a major
contributing factor of nocturia
 Defined by the International Continence Society as production of
an abnormally large volume of urine during sleep:
– Young: >20% of daily total output
– Elderly: >33% of daily total output
Nocturnal Polyuria index (NPi) =
nocturnal urine volume/24-hr
urine volume
Van Kerrebroeck et al. Neurourol Urodyn 2002;21:179–183.
Non-pharmacologic options
 Lifestyle advice
 Often given as a first-line option, although no RCTs
evaluating the efficacy of these measures on nocturia as a
primary outcome were conducted
 Advice includes:
 Preemptive voiding immediately before going to bed
 Dietary and fluid restrictions (e.g., avoidance of
caffeinated beverages and alcohol)
 Medication timing (taking diuretics in the midafternoon)
 Evening leg elevation to mobilize fluids
 Use of sleep medications/aids
 Level of evidence – 3; GOR – 3 (ICUD)
1.Weiss et al. J Urol 2011;186:1358–1363;
2. Smith A and Wein A. Expert Opin Pharm 2013;14:885-894.
Antidiuretics in the treatment
of nocturia
 There are currently 2 formats of desmopressin
indicated for nocturia:


Oral tablets and the newly released orally disintegrating tablets1
Compared to the other options, it has been the most frequently
tested for the specific management of nocturia2
 It is a synthetic analogue of the human hormone
arginine vasopressin, concentrating the urine at night
by acting on V2 receptors present in the distal
collecting tubules of the kidneys2
1. Cornu J-N et al. Eur Urol 2012;62(5):877-890. 2. Weiss et al. BJUI 2013;111:700-716.
Desmopressin for nocturia:
Tablet Format
PROS
•
•
•
Demonstrated efficacy
Response observed within
a week
Prolongs initial sleep
period
CONS
•
•
•
Risk of hyponatremia associated with higher
doses of desmopressin
Dosing titration may be required
–
–
0.1 mg (~60 μg ODT) at bedtime x 7days
0.2 mg (~120 μg ODT) at bedtime x 7 days
–
0.4 mg (~240 μg ODT) at bedtime
Serum sodium monitoring
–
–
–
–
Baseline
3 days after initiation of therapy or increase in dosage
At other times during treatment as deemed necessary
by the treating physician
> 65 years or at risk of hyponatremia, as above and
either monthly or every 2-3 months depending on
patient’s risk of hyponatremia
Yazici. Res Rep Urol 2015; 7:57-63
Orally Disintegrating Tablet
(Desmopressin ODT)
 A freeze-dried lyophilisate for sublingual
administration
 Dissolves in the mouth and does not require
ingestion of water for swallowing
 Shorter duration of action
ODT has a higher bioavailability than the conventional
tablet, allowing for lower dosing1
Weiss JP et al. Neurourol Urodyn 2012;31:441–447
Desmopressin ODT
 Male study: 119 men on 50μg vs. 145 placebo
 Serum Na ≤125 mmol/L - 1/119
 Female study: 133 women on 25μg vs. 128 placebo
 Serum Na: 126-129 mmol/L – 3/135
Weiss et al. N&U 2014; 33:S19-24
Desmopressin ODT in
combination with other agents
 Many patients have both daytime and nighttime
LUTS
 Both may be treated
 Desmopressin, in combination with other agents,
such as α-blockers, has been shown to provide
additional clinical benefits in patients with LUTS
 Reduced nocturnal voids
 Increased duration of initial sleep period
 Improved IPSS scores
Wang et al. J Urol 2011;185:219–223.
Berges R et al. World J Urol. 2014;32(5):1163-70.
Medical management of BPH:
population based study
 Case-control population for CaP in Montreal
 1120 of 1994 controls reported BPH history
 Medical therapy in 53.7%
 Older at index date and at diagnosis of BPH
 Longer duration of BPH history
 Monotherapy (87.6%) vs. Combination (12.4%)
(P<0.001)
 Monotherapy: AB (69.9%) and then 5ARIs (26.6%)
 Combination: AB and 5ARIs (97.3%)
Bishr et al. CUAJ 2016; 10:55-9
Conclusions
 Prostate focus has changed to Male LUTS
 Disease focus has changed to patient-centred
 Treatment aimed at storage and voiding
symptoms
 Single agent therapy is effective and
combinations have additional value
 Nocturia can be troublesome and specific
therapy may be considered