1. State of the Art in Nocturia
Jeffrey P. Weiss, MD, FACS
Professor and Chair
Department of Urology
SUNY Downstate College of Medicine
Brooklyn, NY
Symposium agenda:
Nocturia/Minirin Symposium
Saturday, Feb 25 , 17h45-19h15, Room Bordeaux
Nocturia Now and in the Future
17: :55 Welcome and introduction,
Philip van Kerrebroeck (Belgium, Chair)
17: :15 State of the art in nocturia
Jeffrey Weiss (USA)
18: The impact of nocturia on sleep
Neil Stanley (UK)
18: :05 Future research directions in nocturia
Charlotte Graugaard-Jensen (Denmark)
19: Panel discussion
All

2. Agenda Evolution Recent reviews/guidelines
Definitions, related issues and prevalence
Consequences
Causes, diagnosis and treatment 2

3. Evolution of nocturia: nocturia in 2000
Not a distinct condition but rather part of an array of symptoms associated with other diseases such as OAB or BPH
A normal factor of aging
Only important for the male population
No standardized definition and terminology of nocturia
Important studies during the last decade
ICS standardization of terminology (2002)
Japan mortality study ( )
EpiLUTS study (2009)
TAMUS study ( )
Population based study in Finland (FINNO) (2003 / 2004)
NERI analysis of nocturia and mortality (2010 / 2011) based on NHANES III results
The Krimpen study (starting 1995) 3

4. Evolution of nocturia: nocturia in 2012
Nocturia Think Tank established under ICI-RS
Understanding of nocturia as a distinct medical condition, rather than as a symptom of BPH, OAB or other diseases
Nocturnal polyuria a common finding in all nocturia patients
Clearly correlated with age, but problem seems larger for younger patients
Not only a male disease but also similarly prevalent among females
Better understanding of quality of life effects of nocturia:
Decreased daytime productivity due to sleep disruption
Higher associated mortality and morbidity
Preliminary suggestions for treatment and diagnostic algorithms are available
Better perspective on ineffectiveness of some treatments (especially in primary nocturia) such as anti-muscarinics and alpha blockers 4

5. Most recent publications summarising nocturia state of the art5

6. Many guidelines address nocturia
Slide shows:
ICI UI paper
EAU UI guideline
EAU UI paper
EAU non-neur. Male LUTS
NICE LUTS in men guideline
NICE IU (women) guideline
AUA BPH guideline
A later slide highlights the actual ICI and EAU recommendations for desmopressin in nocturia 6

7. Definition and related issues
Definition: voiding during (nocturnal) sleep time
Preceded and followed by sleep (ICS guidelines)
Normal: nocturia <1x1
Scientific problems:
How to define sleep time
Is patient awakened by the need to void? or
Do patients void because they’re awake?
“the complaint that the individual has to wake at night one or more times to void … each void is preceded and followed by sleep”
1. van Kerrebroeck et al Neurourol and Urodyn 2002; 21:179-83 7

8. What triggers nocturia?
50 men and women
Mean number of nocturia events = 2.6
Nocturia awakenings attributed to urge or not?1
78% nocturic voids were preceded by urge to void
In the remainder, the patient awakened for some other reason, then voided out of habit or convenience before going back to sleep
The aetiology and treatment of these two groups is likely to be different
1. Blaivas JG, Amirian M, Weiss JP et al: SUFU abstract 2010 8

9. What degree of nocturia is important?
Results from multiple studies of mortality, fractures and QoL all show ≥2 voids/night is a ‘threshold’ for significant negative impact from nocturia
One void/night is less likely to have serious consequences
If treatment can reduce nocturia frequency to <2 voids/night on average, risks and bother to patients may be significantly reduced
Impact zone
Comfort zone 9

10. Nocturia: prevalence (≥2 voids/night)
Meta-analysis of 43 studies
Gender (age range)
Prevalence
Men (20–40 years)
2–17%
Women (20–40 years)
4–18%
Men (>70 years)
29–59%
Women (>70 years)
28–62%
Bosch and Weiss. J Urol 2010;184(2): 10

11. Nocturia: consequences
Mediated by sleep deprivation 12

12. Nocturia disrupts sleep
Nocturia is the major cause of disrupted sleep
Sleep is crucial for well-being, health, vitality and essential biological rhythms. Disrupted sleep impairs all of these
Reduced slow wave sleep (SWS) and sleep efficiency, and short/long sleep duration may:
Increase mortality
Reduce health (including hypertension, glucose homeostasis, immunity)
Reduce QoL and productivity
Night-time urology must take sleep and the impact of its disruption into account
just a very short summary as next speaker will talk about impact of nocturia on sleep for 25 min 13

13. Nocturia reduces QoL and improvement in nocturia improves QoL
Reduced QoL (based on HR-QoL) is specifically associated with nocturia in LUTS patients1,2
Burden of nocturia increases with severity (based on N-QoL3)
Nocturia is associated with significant decreases in 14/15 dimensions of HR-QoL4 (all except eating)
Nocturia’s impact on sleep and QoL is more pronounced in younger compared with older patients5, 6, 7
QoL (based on N-QoL) increases significantly with each void reduced (~5 points) and with each hour gained in the first period of undisturbed sleep (~4 points)8
1. Hernández et al. Curr Med Res Opin 2008;24:1033– Asplund & Aberg. Maturitas 1996;24:73–81
2. Van Dijk et al. BJU Int 2010;105:1141 – Hunskaar. BJU Int 2005;96(suppl 1):4–7
3. Yu et al. Urology 2006;67:713– Irwin et al. Eur Urol 2006;50:1306–1314
4. Tikkinen et al. Eur Urol 2010;57:488– Daneshgari et al. Abstract 212 at ICS/IUGA 2010 14

14. Each void reduced/hour gained in FPUS increases QoL in nocturia patients
Change in N-QoL per void reduction (95% confidence limits)
Change in N-QoL per hour gained in FPUS (95% confidence limits)
<65 y
Total score
5.6 (4.1, 7.1)*
4.0 ( 3.1, 4.9 )*
≥65 y
3.8 (2.3, 5.3)*
3.3 ( 2.3, 4.4 )*
Methodology/comments as per Daneshgari abstract/slides:
At baseline and Day 28 patients were asked to complete a 3-day voiding diary, with information on number of voids, a sleep diary, including information on initial period of undisturbed sleep, and a disease-specific QoL questionnaire, the N-QoL. The N-QoL is a 13-item questionnaire consisting of 12 core items arranged in two domains (sleep/energy and bother/concern) and a total score.
The impact on QoL of a change in number of nocturnal voids was investigated by an ANCOVA model using the change from baseline in QoL as outcome (dependent) variable. Age (<65, ≥65 years) was included as a factor and change from baseline in nocturnal voids and the baseline QoL score were used as covariates. This analysis was performed for the overall N-QoL score and for each of the two domains. A similar model was used for exploring the relationship between change in initial period of undisturbed sleep (hours) and QoL. Estimates are presented with 95% confidence limits. 717 subjects providing data at both baseline and end of study are included in this analysis.
Comments
Statistical vs. clinical significance:
The clinically relevant change in the N-QoL scale has yet to be established
The improvements found in this study are comparable to those found by others (Abraham et al. 2004, Yu et al. 2006, Hernandez et al. 2008, Chen et al. 2007)
Age-difference:
The numerically larger N-QoL improvements and statistical difference in the bother/concern domain in the younger compared to the older patients may reflect a superior benefit of treatment for patients who are still active in the workforce
NOTE: in the submitted NAU manuscript, we only show overall analyses, not split by age-group
* ANCOVA; p<
¤The increase in QoL was significantly larger for patients <65 years
FPUS: first period of undisturbed sleep
Daneshgari et al. Abstract 212 at ICS/IUGA 2010 15 15

15. Each void reduced/hour gained in FPUS increases QoL in nocturia patients
Change in N-QoL per void reduction (95% confidence limits)
Change in N-QoL per hour gained in FPUS (95% confidence limits)
<65 y
Total score
5.6 (4.1, 7.1)*
4.0 ( 3.1, 4.9 )*
≥65 y
3.8 (2.3, 5.3)*
3.3 ( 2.3, 4.4 )*
Methodology/comments as per Daneshgari abstract/slides:
At baseline and Day 28 patients were asked to complete a 3-day voiding diary, with information on number of voids, a sleep diary, including information on initial period of undisturbed sleep, and a disease-specific QoL questionnaire, the N-QoL. The N-QoL is a 13-item questionnaire consisting of 12 core items arranged in two domains (sleep/energy and bother/concern) and a total score.
The impact on QoL of a change in number of nocturnal voids was investigated by an ANCOVA model using the change from baseline in QoL as outcome (dependent) variable. Age (<65, ≥65 years) was included as a factor and change from baseline in nocturnal voids and the baseline QoL score were used as covariates. This analysis was performed for the overall N-QoL score and for each of the two domains. A similar model was used for exploring the relationship between change in initial period of undisturbed sleep (hours) and QoL. Estimates are presented with 95% confidence limits. 717 subjects providing data at both baseline and end of study are included in this analysis.
Comments
Statistical vs. clinical significance:
The clinically relevant change in the N-QoL scale has yet to be established
The improvements found in this study are comparable to those found by others (Abraham et al. 2004, Yu et al. 2006, Hernandez et al. 2008, Chen et al. 2007)
Age-difference:
The numerically larger N-QoL improvements and statistical difference in the bother/concern domain in the younger compared to the older patients may reflect a superior benefit of treatment for patients who are still active in the workforce
NOTE: in the submitted NAU manuscript, we only show overall analyses, not split by age-group
* ANCOVA; p<
¤The increase in QoL was significantly larger for patients <65 years
FPUS: first period of undisturbed sleep
Daneshgari et al. Abstract 212 at ICS/IUGA 2010 16 16

16. Nocturia is associated with significant decreases in 14/15 dimensions of HRQoL
H. Sintonen
The 15D instrument of health-related quality of life: properties and applications
Ann Med, 33 (2001), pp. 328–336.
n=3597 Finnish women & men
*p <0.05; **p <0.001 (test for trend)
Tikkinen et al. Eur Urol 2010;57:488– D instrument: Sintonen. Ann Med 2001;33: 328–336 17

17. Nocturia increases the risk of falls and fractures
Parsons et al : Nocturia is the LUTS most strongly associated with falls and the risk increases with number of voids/night
Fractures:
Temml et al : Nocturia (≥2 voids/night) is an age-independent risk factor for hip fractures
Nakagawa et al : In elderly patients (70–97 yrs), nocturia (≥2 voids/night) HR for fall-related fractures was 2.20 (1.04–4.68)
1. Parsons et al. BJU Int 2009;104:63–68; 2. Temml et al. Neurourol Urodyn 2009;28:949–95; 3. Nakagawa et al. J Urol 2010;184: 18

18. Nocturia is associated with increased mortality
Summary of three recent key studies:
Nakagawa et al.1 (788 men and women, aged 70–97 years): significantly increased mortality risk in elderly patients with 2, 3, and 4 vs. 1 voids/night
Kupelian et al.2 (15,988 men and women, aged ≥20 years):
significantly increased mortality risk with ≥2 vs. <2 voids/night
Magnitude of the nocturia and mortality association was greater in those aged <65 years and in those without baseline comorbidities
Lightner et al.3 (2,447 men, aged 40–79 years): significantly increased mortality risk and CHD risk in younger patients
(40–59 years) with ≥3 voids/night
The impact is greater in younger patients
The impact increases with number of voids
1. Nakagawa et al. J Urol 2010;184: ; 2. Kupelian et al. J Urol 2011;185, ; 3. Lightner et al. BJU Int 2012; Jan (epub/early view) 19

19. Nocturia is a socio-economic burden
US analysis (based on 2008 wages and ≥2 voids/night)1
Economic value of productivity lost estimated at
$61 billion/year
Estimated medical cost of nocturia-associated falls estimated at $1.5 billion/year
European analysis (based on 2007 wages in EU-15 and ≥3 voids/night)2
€29 billion/year
Estimated medical cost of nocturia-associated hip fractures estimated at €1 billion/year
Holm-Larsen T, Weiss JP, Langkilde LK. ECONOMIC BURDEN OF NOCTURIA IN THE US ADULT POPULATION. J Urol 2010;183 (4): e1. Abstract 2 presented at AUA 2010.
van Kerrebroeck P, Holm-Larsen T. The cost of nocturia in Europe. Abstract 373 presented at ICS Non-discussion poster; will not be published.
NOTE: the pharmaco-economic estimates are VERY conservative
Details from abstracts:
Ref 1 RESULTS: Based on the BACH study, 28 million people ≥30 years in the US regularly suffer from ≥2 voids/night. Adjusted for age and gender, a conservative estimate suggests that productivity loss is equivalent to 127 hours per individual per year. With an average US wage of $17.38/h (conservatively based on small-size, private industry salaries), the economic value of the productivity lost in 2008 was $61 billion.
In the elderly (≥65 years), the proportional population attributable risk of falling due to nocturia (≥2 voids/night) is 16.2%. The estimated medical cost of associated falls in 2008 was $1.5 billion.
REF 2 results:
Based on prevalence rates from the EpiLUTS study, approximately 7 million men and 8 million women aged between 40 and 65 years have ≥3 voids/night in Europe (defined as EU-15: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, the Netherlands, Portugal, Spain, Sweden and the UK).
Table 1 shows the estimated loss of productivity per year for men and women living with severe nocturia based on a reduction in work productivity of 9.19%. In total, nocturia costs approximately €29 billion per year. Of the 24 million men and 33 million women ≥65 living in EU-15, approximately 3 million men and 5 million women suffer from ≥3 voids/night (severe nocturia) according to the EpiLUTS data. Applying the proportional population risk of breaking the hip due to severe nocturia (≥3 voids/night) approximately 43,000 men and 76,000 women per year will break a hip in EU-15 due to nocturia (see Table 2). The estimated total cost of hospitalization for hip fractures due to severe nocturia per year in EU-15 is approximately €1 billion.
Holm-Larsen et al. J Urol 2010;183: e1.
Van Kerrebroeck et al. Abstract 373 at ICS/IUGA 2010 21

20. In summary: nocturia (≥ 2 voids/night) is a very common condition and associated with multiple negative outcomes
Consequently, underlying causes should be diagnosed and treated appropriately 22

21. Causes and treatment of nocturia

22. Nocturia is a multifactorial condition
Nocturnal polyuria
Psychological sleep problems
Nocturia
Benign prostatic obstruction
Primary polydipsia
Detrusor overactivity
Oestrogen deficiency
Untreated diabetes mellitus or insipidus
Reduced bladder capacity
Uncompensated heart disease 24 24

23. Potential factors underlying nocturia
Urological evaluation reveals:
Nocturnal polyuria
Reduced nocturnal bladder capacity
24-hour polyuria
Definition:
Nocturnal urine volume >20–30% of total 24-hour urinary volume (dependent on age)
Urine production within normal limits; increased frequency, small voided volumes
24-hour urinary output exceeding 40 mL/kg body weight
Possible causes:
Impaired circadian rhythm of AVP secretion
Congestive heart failure
Renal insufficiency
Excessive evening fluid/caffeine intake
Diuretic medication
Oestrogen deficiency
Sleep apnoea
Venous insufficiency
Oedema
Hypoalbuminemia
Overactive bladder
Bladder outlet obstruction (including benign prostatic enlargement)
Infection
Interstitial cystitis
Bladder hypersensitivity
Calculi
Cancer
Neurogenic detrusor overactivity (e.g. multiple sclerosis)
Poorly-controlled diabetes mellitus (type 1 or type 2)
Diabetes insipidus
Polydipsia
Van Kerrebroeck P. Curr Opin Obstet Gynecol 2011;23(5): 25

24. Nocturia: classification/aetiology by frequency–volume charts (FVC)
FVC/voiding diaries provide invaluable guidance. DDx:
NP (NUV >33% by ICS guideline criterion)
Krimpen study: proposes NUV cutpoint >90 ml/hr sleep
Decreased bladder capacity (global/night – distinction difficult)
Mixed (1+2)
Global polyuria (24-hour output >40 ml/kg) 26

25. Nocturnal polyuria is present in the majority of nocturia patients
Europe1 n=845 NP
Without NP
74%
26%
Asia3 n=41 (males only)
83%
17%
USA2 n=934
12%
88%
The kidneys, rather than the bladder, have a key role in nocturia
1. Abrams et al. Neurourol Urodyn 2004;23:466; 2. Weiss et al. J Urol 2011;186: ;
3. Chang et al. Urology 2006;67:541–4 27 27

26. OAB/BPH therapies have limited effect on nocturia
BPH/OAB therapy
Net advantage vs. placebo (reduction in number of voids or % reduction)
BPH
Terazosin 1
0.3 voids
Tamsulosin OCAS2
Doxazosin + finasteride3
~0.2 voids
OAB
Solifenacin4
0.16 voids
Solifenacin5
0.08 voids (NP)
0.18 voids (No NP)
Tolterodine ER6
~0.75 voids/week (severe urgency nocturnal. voids only)
BPH + OAB
Tolterodine ER + tamsulosin 8
Combination therapy
0.2 voids
OCAS, oral-controlled absorption system; NP, nocturnal polyuria; ER, extended release
1. Johnson et al. J Urol 2003;170:145–148; 2. Djavan et al. Eur Urol Suppl 2005;4:61–68; 3. Johnson et al. J Urol 2007;178:2045–2050; 4. Yamaguchi et al. BJU Int 2007;100:579–587; 5. Brubaker & FitzGerald. Int Urogynecol J Pelvic Floor Dysfunct 2007;18:737–741; 6. Nitti et al. BJU Int 2006;97:1262–1266; 7. Rackley et al. J Urol 2006;67:731–736; 8. Kaplan et al. JAMA 2006;296:2319–2328

27. Desmopressin: mechanism of action
Desmopressin is a selective V2-receptor agonist:
Retains the antidiuretic properties of vasopressin1
Lacks the unwanted pressor activity of vasopressin
When bound to V2-receptors in the kidney, it:
Increases tubular water permeability
Enhances water reabsorption
Extracellular fluid becomes more dilute
Urine becomes more concentrated2
1. Vilhardt H. Drug Investigation 1990; 2(Suppl. 5):2–8; 2. Hammer M & Vilhardt H. J Pharmacol Exp Ther 1985; 234:754–60. 29 29

28. Desmopressin: key recommendations
ICI: Grade A (level 1)1,2
EAU: Grade A (level 1b)3,4,5.
As agreed, slide only shows ICI and EAU recommendations.
The following points could be mentioned:
-That overall, current guidelines and recommendations still reflect the notion that nocturia is not considered a condition in its own right but rather a symptom accompanying other diagnoses (i.e. when looking for recommendations, these are included under topics like incontinence, OAB and BPH).
-That NICE (national institute for clinical excellence; UK) and AUA guidelines also mention/endorse use of desmopressin for nocturia in some OAB/BPH patients.
In Abrams et al. (eds) Incontinence; 4th International Consultation on Incontinence. Paris: Health Publication Ltd, Available at: p://
Abrams et al. Neurourol Urodyn 2010 ; 29 : 213–40
Schröder et al. Guidelines on Urinary Incontinence. © European Association of Urology Available at:
Thüroff et al. EAU Guidelines on Urinary Incontinence. Eur Urol 2011;59:
Oelke et al. Guidelines on the Treatment of Non-neurogenic Male LUTS. © European Association of Urology Available at: 30

29. Summary of key desmopressin data
Nocturia patients experience significant and clinically meaningful reduction in night-time voiding and prolongation of initial sleep period with short- and long-term desmopressin treatment1–5
Desmopressin is well tolerated in the short- and long-term; cessation causes nocturia severity to revert to baseline at
1 year1–5
Both patient QoL and productivity at work improve with desmopressin treatment4,6
Data is available for conventional tablets and the newer melt formulation, which has higher bioavailability and can be taken without water
Gender-specific and lower dosing with the new formulation (especially in women) may further reduce the low but important risk of hyponatremia without reducing efficacy7
1. Lose et al. Am J Obstet Gynecol 2003;189:1106–1113; 2. Mattiasson et al. BJU Int 2002;89:855–862;
3. Lose et al. J Urol 2004;172:1021–1025; van Kerrebroeck et al. Eur Urol 2007;52:221–229; Weiss et al. Abstract 198/ ICS Daneshgari et al. Abstract 212/ ICS Juul et al. Am J Physiol Renal Physiol 2011; 300(5): F 31

30. Gender difference in antidiuretic response to desmopressin
Dose (µg)
Decrease in nocturnal urine volume (mL)
100
200
300
400 20 40 60 80 *
Male
Female
ABSTRACT: Increased age and female gender are well-known risk factors for the development of desmopressin-induced hyponatremia. However, little focus has been on exploring gender differences in the antidiuretic response to desmopressin. Based on an exploratory analysis from three clinical trials, we report a significant gender difference in the effects of desmopressin on nocturnal urine volume that could not be explained by pharmacokinetic differences. Mean desmopressin concentration profiles were tested for covariates, and age and gender were not statistically significant and only weight was significant for log(Cmax) (P = ) and borderline significant for log(AUC) (P = ). The decrease in nocturnal urine volume in nocturia patients treated with desmopressin over 28 days was significantly larger for women at the lower desmopressin melt doses of 10 and 25 μg than for men. The ED50 for men was modeled to be 43.2 μg and 16.1 μg for women, with the ED50 men/women estimated to be 2.7 ( % CI), corresponding to significantly higher sensitivity to desmopressin in women. An increasing incidence of hyponatremia with increasing dose was found, and at the highest dose level of 100 μg decreases in serum sodium were approximately twofold greater in women over 50 yr of age than in men. A new dose recommendation stratified by gender is suggested in the treatment of nocturia: for men, 50- to 100-μg melt is an efficacious and safe dose, while for women a dose of 25 μg melt is recommended as efficacious with no observed incidences of hyponatremia. Areas for further research are proposed to uncover pathophysiological mechanism(s) behind these gender differences.
Means (±SE) observed decrease in nocturnal urine volume vs dose by gender. Results shown are for women (n = 60, 66, 61, 66 and 60) and men (n = 80, 71, 83, 71, and 75) for desmopressin doses of 0, 10, 25, 50, and 100 µg, respectively. In tests of “no gender effect,” *p = 0.36, 0.085, , and 0.74 for doses of 0, 10, 25, 50 and 100 µg, respectively
Juul et al. Am J Physiol Renal Physiol 2011; 300(5): F 34

31. Example of a potential simple algorithm to differentiate night-time urination
LUTS / NOCTURIA
Exclude and treat non-urological causes (such as cardiac, OSA)
Lifestyle changes
Daytime LUTS (predominantly daytime symptoms)
Mixed LUTS (mixed daytime and night-time symptoms)
Night-time LUTS (predominantly night-time symptoms)
OAB
BPO
BPO and OAB
Address daytime symptoms
anticholinergic
a1-blocker
combinations
anticholinergic
a1-blocker
5-a RI
combination
outlet reducing surgery
a1-blocker + anticholinergic
Persistent night-time symptoms
desmopressin
desmopressin
LUTS, lower urinary tract symptoms; BPO, benign prostatic obstruction; 5-a RI, 5-alpha reductase inhibitor 35

32. To take away…
Nocturia is highly prevalent and a leading cause of sleep disruption
Many studies have demonstrated a multifactorial aetiology
for nocturia
Diagnosis and treatment must be differentiated between day-
and night-time LUTS. Nocturia is caused by NP (alone or in combination with OAB/BPO) in a majority of cases; diagnosing
NP is simple, and desmopressin the Grade A recommended pharmacologic intervention
Two episodes of nocturia constitute meaningful nocturia
Nocturia affects sleep and quality of life and is associated with
an increased risk of morbidity and mortality
Left untreated, nocturia affects productivity at work and
represents a significant socio-economic burden 36

33. Challenges… Epidemiology: the key data are there
Causes and targeted therapies:
Differentiating day-time vs. night-time LUTS (diagnosis and treatment)
Differentiating patients?
Treatment irrespective of bother?
Desmopressin
Hyponatraemia: explore risk populations
Doses: clear communication
Education
NP, consequences in younger patients (eg bother and mortality)
Get nocturia/desmopressin into more guidelines (eg. AUA) 37

34. Nocturia: discussion 38