Nocturia - a Significant Symptom of Mul8factorial Nature. Objec8ves of the Talk. Dr. Boris Friedman May 25, 2011

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1 Nocturia - a Significant Symptom of Mul8factorial Nature Dr. Boris Friedman May 25, 2011 Objec8ves of the Talk 1. Review the characteriza8on of nocturia and implica8ons on morbidity and mortality 2. Review various e8ologies of nocturia 3. Update of behavioural and pharmacological treatment op8ons 4. op8onal future research targets 1

2 Defini&on The defini8on of nocturia as proposed by the ICS is the complaint that the individual has to wake at night one or more 8mes to void. Nocturia Frequency, Bother, and Quality of Life: How O>en Is Too O>en? A Popula&on- Based Study Tikkinen et al. European Urology 2010 Objec&ve: To evaluate the associa8on among frequency of nocturia and bother and health- related quality of life (HRQoL). Methods: A survey mailed to a random sample of 6000 subjects aged years Results : Degree of bother increased with nocturia frequency 2

3 Nocturia Frequency, Bother, and Quality of Life: How O`en Is Too O`en? A Popula8on- Based Study Tikkinen et al. European Urology 2010 Nocturia Frequency, Bother, and Quality of Life: How O`en Is Too O`en? A Popula8on- Based Study Tikkinen et al. European Urology

4 Night frequency and QoL Few pa8ents are bothered by waking once per night With an increase in nocturia frequency to two or more voids per night, the bother caused by the condi8on increases, along with nega8ve effects on QoL and day8me func8oning Nocturia characterisa&ons Nocturia is the most prevalent of LUTS in the general community It is as common in women as it is in men Affects a significant propor8on popula8on at all ages Reported to be one of the most bothersome of LUTS with greatest impact on the pa8ent s quality of life as well as difficult to improve Van Kerrebroeck et al. Neurourology and Urodynamics

5 Van Kerrebroeck et al. Neurourology and Urodynamics 2010 Van Kerrebroeck

6 Nocturia a sleep disrup&on Nocturia fragments sleep and is the major cause of sleep disturbance in people over 50 y Sleep disturbance can have profound consequences for health, well- being and func8oning impact of nocturia reach much further due to the sleep- interrup8on Sleep disrup&on Day &me fa&gue Cogni&ve impairment Road /work accidents falls Fractures Mood alterna&ons Immuno- suppression Endocrine / metabolic alterna&ons Depression Quality of Life 6

7 Impact of Nocturia on Bone Fracture and Mortality in Older Individuals: A Japanese Longitudinal Cohort Study Nakagawa et al. J of Urology 2010 Aim: to evaluate the associa8on of nocturia with fracture and death in a large, community based sample of Japanese individuals 70 years old or older. 784 individuals followed for 5 years Nocturia (2 or greater voids per night) was present in 45.7% of par8cipants. Hazard Ra8o for fractures and fall related fractures with nocturia 2.01 and 2.20 For mortality in pa8ents with nocturia the age- gender adjusted HR was 1.91 Impact of Nocturia on Bone Fracture and Mortality in Older Individuals: A Japanese Longitudinal Cohort Study Nakagawa et al. J of Urology 2010 Incidence of all and fall related fractures in 359 pa8ents with (light blue bars) and in 425 without (dark blue bars) nocturia was significantly higher in former (each p = 0.03). 7

8 Impact of Nocturia on Bone Fracture and Mortality in Older Individuals: A Japanese Longitudinal Cohort Study Nakagawa et al. J of Urology 2010 Kaplan- Meier es8mates show significantly lower mortality in pa8ents without (solid curve) than with (doled curve) nocturia (log rank test p = ), defined as 1 or fewer vs 2 or greater voids per night, respec8ve Associa8on of Nocturia and Mortality: Results From the Third Na8onal Health and Nutri8on Examina8on Survey Kupelian et al. J Urology 2011 Third Na8onal Health and Nutri8on Examina8on Survey = na8onal probability survey of the United States between 1988 and 1994 A total of 7,455 men and 8,533 women included in the analysis 134,777 person years of follow up (median follow up 8.8 years) There were 2,711 deaths observed during follow up The overall prevalence of nocturia (2 or more episodes of urina8on at night) was 15.5% in men and 20.9% in women. 8

9 Associa8on of Nocturia and Mortality: Results From the Third Na8onal Health and Nutri8on Examina8on Survey Kupelian et al. J Urology 2011 Survival probability by nocturia Associa8on of Nocturia and Mortality: Results From the Third Na8onal Health and Nutri8on Examina8on Survey Kupelian et al. J Urology 2011 Conclusions Nocturia is a strong predictor of mortality, more so in younger men and women than in the elderly, with a dose- response palern 9

10 Conclusions: Nocturia is posi8vely correlated to poorer overall health status. Predicts significantly increase in mortality in the elderly and in pa8ents with a cardiac history. The associa8on between nocturia and mortality in coronary pa8ents remained a`er adjustment for several other risk factors. POTENTIAL FACTORS UNDERLYING NOCTURIA Global Polyuria Nocturial Polyuria Reduced Bladder Capacity Diabetes Insipidus conges8ve heart failure OAB Diabetes Mellitus HTN BOO (BPE, BPH, BPO) Sleep Disturbance Depression Puritus Polydipsia chronic peripheral edema Infec8on Chronic pain Hypoalbuminemia Inters88al Cys88s Obstruc8ve Sleep Apnea Uterine fibroids 10

11 Global or 24- hr Polyuria 24- hr polyuria: an overproduc8on of urine both during night and day8me 24- hr urine produc8on >2.8 L or >40ml/kg. Global polyuria has been linked to : Primary polydipsia dipsogenic or psychogenic - Diabetes Mellitus (DM) à osmo8c diuresis - Diabetes Insipidus (DI) Diabetes Insipidus Global or 24- hr Polyuria Central DI deficient synthesis of an8diure8c hormone - Nephrogenic DI impaired ability of the kidneys to respond to an8diure8c hormone. 11

12 Global Polyuria Water depriva&on test (WDT) = pa8ent refraining from drinking throughout the night First morning void for osmolality Osmolality > 800 mosm/kg Osmolality < 800 mosm/kg polydipsia DI Abnormal WDT Renal concentra&ng capacity test (RCCT) Intranasal desmopressin (40 mcg) / Oral desmopressin 0.4 mg Water intake restricted Urine sample for osmolality a>er 3-5 h Osmolality > 800 Osmolality < 550 Central DI Nephrogenic DI 12

13 Nocturnal Polyuria nocturnal polyuria (NP): an excessive produc8on of urine during the night- 8me night- 8me urinary produc8on that cons8tutes more than 20% of total output in the young (<65) and more than 33% of total output in the elderly (>65) A link between NP and deficient nocturnal produc8on of arginine vasopressin (AVP) in elderly pa8ents: Lower levels of AVP during the hours of sleep = an appropriate response to reintroduc8on of third- spaced fluids into the circula8on Diseases causing Nocturnal Polyuria Conges&ve Heart Failure / Hypoalbuminemia à day 8me fluid accumula8on in lower extremi8es à at night during supine posi8on fluids are mobilized back to general circula8on à increased vascular filling and arterial stretch à Atrial Natriure8c Pep8de release à increased diuresis 13

14 Diseases causing Nocturnal Polyuria Obstruc&ve sleep apnea (OSA) Muscles that control the tongue and so` palate relax causing the airway to narrow and close during sleep Pa8ent tries to breathe but cannot due to airway obstruc8on Pa8ent stops breathing for more than 10 seconds 14

15 OSA DEFINITIONS Apnea: Cessa8on of Airflow > 10 sec Hypopnea: > 50% reduc8on in airflow for > 10 sec AHI: Severity Defini8ons: Sleep Apnea Syndrome: Apnea Hypopnea Index: the number of apneas and hypopneas per hour of sleep Normal: AHI < 5 Mild: AHI 5 14 Moderate: AHI Severe: AHI > 30 AHI of > 5 with symptoms OSA: Polysomnography 15

16 OSA : polysomnography OSA Prevalence Prevalence in the General Popula8on AHI 5: mild, moderate, or severe sleep apnea 24% of middle aged men 9% of middle aged women These pa8ents stop breathing > 40 8mes per night AHI 15: moderate or severe sleep apnea 15% of middle- aged men 5% of middle- aged women These pa8ents stop breathing >120 8mes per night 16

17 Obstruc8ve Sleep Apnea, Nocturia and Polyuria in Older Adults Umlauf et al. Sleep 2004 Objec&ves: To examine the rela8onship between nocturia and obstruc8ve sleep apnea (OSA) in community dwelling older men and women 17

18 Obstruc8ve Sleep Apnea, Nocturia and Polyuria in Older Adults Umlauf et al. Sleep 2004 Results Nocturia and overnight urine output were posi8vely associated with AHI Nocturia was nega8vely associated with self- rated health Increasing nocturia by one event per night increases the odds of being in a more severe AHI group by mes Con8nuous posi8ve airway pressure reduces nocturia in pa8ents with obstruc8ve sleep apnea Margel et al. Urology 2006 Objec&ves: To examine whether treatment (CPAP) reduces nocturia in pa8ents with obstruc8ve sleep apnea (OSA). Methods: Prospec8ve clinical study, pa8ent recruited from sleep lab. Nocturia was assessed at four 8me points: 1. Baseline (awakenings to urinate per night during one week at home before polysomnography). 2. During a diagnos8c night in the laboratory. 3. During CPAP 8tra8on in the laboratory 4. A`er 1 to 3 months of stable CPAP treatment at home 18

19 Con8nuous posi8ve airway pressure reduces nocturia in pa8ents with obstruc8ve sleep apnea Margel et al. Urology 2006 Correla8on between number of awakenings to void before treatment with respiratory disturbance index (r= 0.25, P = 0.01). Con8nuous posi8ve airway pressure reduces nocturia in pa8ents with obstruc8ve sleep apnea Margel et al. Urology 2006 TABLE II. Mean ± SD awakenings to urinate per night Before CPAP During CPAP P Value Home 2.5 ± ± 0.6 <0.001 Laboratory 1.1 ± ± 0.6 <0.001 KEY: CPAP = con8nuous posi8ve airway pressure. 19

20 Comparison of outcomes of 50 pa8ents with mild to moderate OSA (RDI less than 35/hr) and 47 with severe OSA (RDI greater than 35/hr). Con8nuous posi8ve airway pressure reduces nocturia in pa8ents with obstruc8ve sleep apnea Margel et al. Urology 2006 conclusions : CPAP appears to be an effec8ve treatment for nocturia associated with OSA. CPAP was more effec8ve in pa8ents with severe than in those with moderate OSA. The reduc8on in nocturia was noted even a`er 1 night of CPAP treatment (in the laboratory), sugges8ng that this may be an acute effect rather than a chronic consequence. 20

21 Con8nuous posi8ve airway pressure reduces nocturia in pa8ents with obstruc8ve sleep apnea Margel et al. Urology 2006 Clinical implica&ons: pa8ents with nocturia should be queried about signs and symptoms of snoring and apnea and referred for polysomnography accordingly. Diseases causing nocturia Condi8ons associated with a disturbed sleep - chronic pain - pruritus - depression 21

22 Nocturia Associated With Depressive Symptoms Johnson et al. J Urology 2010 Objec&ves :To assess the rela8onship between nocturia and depression Methods : 547 male pa8ents surveyed using the American Urological Associa8on Symptom Score (AUA- SS) and the Geriatric Depression Scale (GDS) Nocturia Associated With Depressive Symptoms Johnson et al. J Urology 2010 Pa8ent Characteris8cs Depressed Pa8ents (n = 93) Nondepressed Pa8ents (n = 454) Univariate Analysis P Value Average age, years (SD) 55.1 (12.4) 58.3 (15.6).067 Average years of school completed (SD) 13.0 (2.4) 13.9 (3.5).013 Average monthly income, US $ (SD) 1231 (2285) 3820 (6668).002 Race n (%) White 24 (25.8%) 217 (47.8%) <.001 Black/African- American 60 (64.5%) 208 (45.8%).001 Other 9 (9.7%) 29 (6.4%).720 Hispanic n (%) 5 (5.4%) 20 (4.4%).684 Self- reported AUA- SS, mean total (SD) 17.5 (10.1) 10.8 (8.0) <.001 Self- reported nocturia score, mean (SD) 2.7 (1.4) 1.9 (1.4) <.001 Self- reported QOL, mean score (SD) 4.0 (1.9) 2.5 (1.8) <

23 Nocturia Associated With Depressive Symptoms Johnson et al. J Urology 2010 Distribu8on of nocturia frequency (episodes per night) by depression status Nocturia Associated With Depressive Symptoms Johnson et al. J Urology 2010 Results: A`er controlling for demographic variables and overall quality of life, pa8ents with 5 episodes of nocturia / night experienced a 6.5- fold increased risk of depression 23

24 Depressive Symptoms Increase the Incidence of Nocturia: Tampere Aging Male Urologic Study (TAMUS) Häkkinen et al. J of Urology 2008 Purpose : to assess the effects of depressive symptoms on the incidence of nocturia in men Methods: A self- administered ques8onnaire was mailed to 3,143 randomly selected men in 1994 and a second round was mailed to the 2,837 who were alive and eligible in ,580 men had informa8on on nocturia available at baseline and follow up. Depressive Symptoms Increase the Incidence of Nocturia: Tampere Aging Male Urologic Study (TAMUS) Häkkinen et al. J of Urology 2008 Results Men with depressive symptoms at study entry were at 2.8 8mes higher for moderate or severe nocturia than those without depressive symptoms. A dose response rela8on was found between the severity of depressive symptoms at baseline and the incidence of moderate or severe nocturia 24

25 Depressive Symptoms Increase the Incidence of Nocturia: Tampere Aging Male Urologic Study (TAMUS) Häkkinen et al. J of Urology 2008 Only untreated depression increased the incidence of moderate or severe nocturia (adjusted RR 3.3) but not medically treated depression. Nocturia at study entry had no significant effect on depressive symptoms during follow up. Conclusions Findings show a unidirec)onal effect of depressive symptoms on the incidence of moderate or severe nocturia. Nocturia associated with impaired bladder capacity Detrusor overac8vity (DO) Can be idiopathic or neurogenic DO is less apparent in the supine posi8on 25

26 Nocturia associated with LUT reservoir and sensory impairment Reduced bladder compliance steady rise in pressure during bladder filling Compliance should be >20 ml/cmh2o Clinical assessment important considera8ons: 1. Nocturia can be an early feature of poten8ally serious underlying pathology 2. Nocturia can be secondary to obvious pathology or its treatment à systemic approach is needed to give the best prospect of achieving symptoma8c improvement 26

27 Clinical assessment At ini8al consulta8on: - Frequency- volume chart (FVC) Categoriza8on to: 1. Global polyuria - diurnal and nocturnal frequency of good voided volumes, in the absence of other LUTS 2. Nocturnal Polyuria - nocturnal frequency of good voided volumes, in the absence of other LUTS 3. LUT reservoir and sensory impairment- diurnal and nocturnal frequency of poor voided volumes; other LUTS may be present 4. Sleep disturbance - nocturnal frequency of varied volumes Frequency volume Chart (FVC) Representa8ve results from 24 h of a FVC for a 75 Kg 62- year- old man with nocturia. Total voided volume 2360cc Nocturnal volume 890cc (38%) 27

28 History and examina&on Habitual excess fluid intake - absolute excess of fluid intake - inadequate 8ming of fluid intake - excessive use of beverages containing poten8ally diure8c substances (alcohol / caffeine) History and examina&on Global polyuria: presence of polydipsia poorly controlled diabetes mellitus endocrine disorders Nocturnal Polyuria predisposing medical condi8ons: - chronic kidney disease - cardiovascular problems A history of snoring 28

29 History and examina&on LUT reservoir and sensory impairment presence of storage LUTS in addi8on to nocturia - Urgency - dysuria / bladder pain - past history of pelvic mass /malignancy A broad neurological screen is appropriate Sleep disturbance Record the sleep environment (e.g. noise and temperature) habits before selling for sleep anxiety and mental state also Drugs poten&ally contribu&ng to nocturia Increased urine output Insomnia and CNS effects Direct LUT effects Diure8cs SSRIs (Surgam) Calcium channel blockers Tetracycline CNS s8mulants (dextroamphetamine, methylphenidate) An8hypertensives (α- blockers, β- blockers, methyldopa) Respiratory (albuterol, theophylline) Decongestants (phenylephrine, pseudoephedrine) Hormones (cor8costeroids, thyroid) Ketamine Tiaprofenic acid Cyclophosphamide Lithium Psychotropics (MAOIs, SSRIs, atypical an8depressants) Dopaminergic agonists (carbidopa) An8epilep8cs (phenytoin) 29

30 History and examina&on Physical examina8on: Orthosta8c vital signs Evidence of CHF, venous insufficiency Abdominal exam : distended bladder, fecal impac8on Genitourinary exam: prosta8c enlargement in men, uterine fibroids in women, bladder outlet obstruc8on, neurologic deficits. Inves&ga&ons FVC - is the minimum necessary Blood glucose, Urea and electrolytes: electrolyte imbalance or renal dysfunc8on. Lipids and cholesterol Urine analysis : for bacteriuria, leukocyturia or hematuria. Urinary tract ultrasound: pelvic or bladder masses, or urinary tract stones Flow rate and post- void residual measurement 30

31 Management Management is directed at the cause of the problem. Failure to correctly iden8fy the underlying mechanisms = poor treatment outcome + adverse effects and a dissa8sfied pa8ent. Management Main points to consider: Treatment is aimed at improving QoL Symptoms can be refractory Evalua8on of treatment response requires objec8ve : a FVC before and during treatment allows greater sensi8vity when evalua8ng treatment response 31

32 Global Polyuria Nocturnal Polyuria Reduced Bladder Capacity DM : op8miza8on of DM control Central DI : Desmopressin Polydipsia : management of fluid intake Behavioural Treatment Op8mal management of underlying medical cause (CHF, HTN, OSA etc) Desmopressin Diure8cs OAB : An8muscarinic drugs? BOO: Α- adrenergic blocking agents? Combina8on therapy? Sleep Disturbance Op8mal management of underlying medical cause (depression, pain et.) Melatonin HRT? Treatment : Behavioural Improving sleep environment: op8mizing room temperature, noise, ligh8ng and consistent bed8me Managing fluid intake : reduc8on of coffee and alcohol consump8on and restric8ng night- 8me fluid Regular exercise = deeper sleep and increased arousal threshold and bladder volume lower limb eleva&on and compression during the day 32

33 Doc says I ll sleep better if I only drank one cup of coffee a day Efficacy of Nondrug Lifestyle Measures for the Treatment of Nocturia Soda et al. J of Urology 2010 Objec&ve :to test the efficacy of nondrug lifestyle measures as a first step in trea8ng nocturia Lifestyle modifica8ons : 1) restric8on of fluid intake 2) refraining from excess hours in bed 3) moderate daily exercise 4) keeping warm in bed 33

34 Efficacy of Nondrug Lifestyle Measures for the Treatment of Nocturia Soda et al. J of Urology 2010 Evalua&on of efficacy : - The frequency volume chart (FVC) - Interna8onal Prostate Symptom Score - Sleep Quality Index before and 4 weeks a`er the interven8on Results Mean nocturnal voids decreased significantly from 3.6 to 2.7 (p ) Nocturnal frequency before and a`er interven8on 34

35 Efficacy of Nondrug Lifestyle Measures for the Treatment of Nocturia Soda et al. J of Urology 2010 Results Nocturnal urine volume decreased from 923 to 768 ml The treatment was significantly more effec8ve in pa8ents with a larger 24- hour urine produc8on. Conclusions Nondrug lifestyle measures were effec8ve in decreasing the number of nocturia episodes and improving pa8ent quality of life Treatment : Desmopressin a synthe8c analogue of the an8diure8c hormone arginine vasopressin (AVP) has a more powerful and longer- las8ng an8diure8c ac8on than AVP 35

36 Treatment : Dessmopressin Desmopressin: increases reabsorp8on of water in the distal and collec8ng tubules of the kidney via its ac8on on the V2 receptor Different trials of Desmopressin for Nocturia Refs. Pa&ents enrolled Nocturnal voids (change%) Undisturb sleep (min) (change %) Incidence of hyponatremia (%) Mapasson (43%) (59%) 49/224 (22%) Lose (46%) (78%) 14/224 (6%) Van Kerrebroeck (39%) (100%) 6/184 (3%) Fei- Guo Fu (43%) (52%) 5/122 (4%) 36

37 Treatment : Dessmopressin Ma~asson et al. : a series of 3- week RCTs showed effec8veness of oral desmopressin on men with nocturia. 34% of pa8ents experienced clinical response ( 50% reduc8on in nocturnal voids) vs. 3% of pa8ents receiving placebo The mean number of nocturnal voids reduced from 3.0 to 1.7 Ma~asson et al. Efficacy of desmopressin in the treatment of nocturia: a double- blind placebo- controlled study in men. BJU Int 2002 Treatment : Desmopressin Lose et al. RCT for effec8veness of Desmopressin in women 46% of treated pa8ents experienced clinical response vs. 7% placebo. The mean number of nocturnal voids was reduced from 2.9 to 1.6 Long- term studies show that efficacy is maintained during months of treatment a rebound effect is seen when treatment is withdrawn Lose et al.. Efficacy of desmopressin (Minirin) in the treatment of nocturia: a double- blind placebo- controlled study in women. Am J Obstet Gynecol

38 Treatment : Desmopressin Desmopressin was well tolerated in all studies The most frequently AEs: headache, nausea, diarrhea, dizziness and hyponatremia Hyponatremia is the main poten8ally serious AE associated with desmopressin use primary predictor is increasing age. Ini8a8on of desmopressin should be carefully administered for pa8ents 65y by low dose treatment with 8tra8on serum sodium monitoring at baseline and early in treatment required in older pa8ents Reducing Nocturia in the Elderly: A Randomized Placebo- Controlled Trial of Staggered Furosemide and Desmopressin Fei- Guo Fu et al. Neurology and Urodynamics 2011 Objec&ves to inves8gate efficacy, safety, and impact on sleep of staggered furosemide and desmopressin Methods RCT, Pa8ents aged >60 years with nocturnal polyuria A 3- week dose- 8tra8on phase established the op8mum desmopressin dose (0.1, 0.2, or 0.4 mg). A`er a 1- week washout period à randomiza8on to receive staggered furosemide + op8mal dose of desmopressin or placebo in a double- blind design for 3 weeks. Primary end point :50% or greater reduc8on in number of nocturnal voids. Secondary end point : nocturnal urine volume, mean dura8on of first sleep episode, Quality of Life. 38

39 Reducing Nocturia in the Elderly: A Randomized Placebo- Controlled Trial of Staggered Furosemide and Desmopressin Fei- Guo Fu et al. Neurology and Urodynamics 2011 Results 82 pa8ents randomized 46% pa8ents in the study group vs. 10% pa8ents in the control group had a 50% reduc8on in the number of nocturnal voids. The mean number of nocturnal voids decreased from 3.5 to 2.0 in study group vs. 3.3 to 3.0 in control group. The mean dura8on of the first sleep period was improved by 70 min in the study group. Summary of Adverse Events (AEs) Dose 8tra8on Desmopressin Double- blind Furosemide and Desmopressin Placebo N (%) E N (%) E N (%) E Pa8ents enrolled Total AEs 62 (50) (26) 17 8 (20) 13 Serious AEs 3 (3) 5 2 (5) 2 AEs related to study medica8on 37 (39) 49 5 (12) 7 3 (7) 5 Most frequently (>3%) AEs related to study medica8on Headache 10 (8) 11 2 (5) 3 2 (5) 2 Hyponatremia 3 (3) 4 2 (5) 2 Nausea 5 (4) 6 Dry mouth 6 (5) 9 Dizziness 6 (5) 8 Hypertension 4 (3) 4 39

40 Reducing Nocturia in the Elderly: A Randomized Placebo- Controlled Trial of Staggered Furosemide and Desmopressin Fei- Guo Fu et al. Neurology and Urodynamics 2011 Conclusions Staggered dosing of furosemide and desmopressin is safe and efficacious for the short- term treatment of nocturia in the elderly. Longer term, larger scale studies are needed to assess that the efficacy of staggered furosemide and desmopressin Treatment : Pharmacological Impaired bladder capacity An8muscarinic drugs- for pa8ents with OAB Α- adrenergic blocking agents- for men with storage and voiding LUTs. Combina8on of 5- α- reductase and α- adrenergic blocking HRT in post menopausal women All have a mild influence on nocturia 40

41 Outcomes of pharmacological management of nocturia with non- an8diure8c agents: does sta8s8cally significant equal clinically significant? Smith et al. BJU 2011 A comprehensive literature review AIM: to evaluate the sta8s8cal and clinical efficacy of the pharmacological treatments of nocturia Mainly: alpha blockers 5- alpha reductase inhibitors (5ARI) an8muscarinics Outcomes of pharmacological management of nocturia with non- an8diure8c agents: does sta8s8cally significant equal clinically significant? Smith et al. BJU 2011 Johnson et al A secondary analysis of the Veterans Administra8on Coopera8ve Study 1078 men with BPH assessed for a reduc8on in nocturia measured by the IPSS The study had four arms: terazosin, finasteride, combina8on terazosin plus finasteride and placebo A 50% reduc8on in nocturia was defined as a meaningful benefit This defini8on allowed achievement of sta)s)cally significant differences in response rates by treatment arm 41

42 Outcomes of pharmacological management of nocturia with non- an8diure8c agents: does sta8s8cally significant equal clinically significant? Smith et al. BJU 2011 Johnson et al In reality there is only a 17% greater improvement in nocturia for terazosin over placebo The authors termed the effect moderate Outcomes of pharmacological management of nocturia with non- an8diure8c agents: does sta8s8cally significant equal clinically significant? Smith et al. BJU men from the Medical Therapy of Prosta8c Symptoms (MTOPS) trial randomized to one of four groups: - Doxazosin - Finasteride - Combina8on therapy - Placebo The outcome measured : change in self- reported nocturia from baseline at a 1- and 4- year follow- up. 42

43 Outcomes of pharmacological management of nocturia with non- an8diure8c agents: does sta8s8cally significant equal clinically significant? Smith et al. BJU 2011 Changes in nocturia from the medical treatment of prosta8c symptoms trial clinical significance? Outcomes of pharmacological management of nocturia with non- an8diure8c agents: does sta8s8cally significant equal clinically significant? Smith et al. BJU 2011 Cardozo et al 2004 RCT which evaluated efficacy of solifenacin succinate in pa8ents with overac8ve bladder Concluded that : Pa8ents without nocturnal polyuria experienced a sta8s8cally significant reduc8on in nocturia this translated to a numeric difference of only 0.18 episodes of nocturia less per night than placebo 43

44 Outcomes of pharmacological management of nocturia with non- an8diure8c agents: does sta8s8cally significant equal clinically significant? Smith et al. BJU 2011 Rackley et al week RCT of 850 pa8ents given 4 mg tolterodine extended release (TER) or placebo nocturnal voids were divided into : non- OAB, OAB voids and severe OAB voids. The results demonstrated was a sta)s)cally significant improvement For OAB- related nocturnal voids = 30% reduc8on for drug and 22% reduc8on for placebo. For severe OAB- associated nocturia, the reduc8ons were 59% for drug and 43% for placebo Outcomes of pharmacological management of nocturia with non- an8diure8c agents: does sta8s8cally significant equal clinically significant? Smith et al. BJU 2011 when one looks at the absolute reduc8ons in these studies, one realizes that it is hard to argue clinical significance, even in the sta8s8cally significant groups 44

45 Outcomes of pharmacological management of nocturia with non- an8diure8c agents: does sta8s8cally significant equal clinically significant? Smith et al. BJU 2011 Efficacious treatment should result in a clinically meaningful reduc8on in the number of nocturnal voiding episodes = reduc8on that actually malers to the pa8ent reduc8on in nocturnal voiding should improve those condi8ons secondary to nocturia, such as falls, fractures, mood and HRQL Future research Focus on diagnosis and treatment while differen8a8ng nocturia from other LUTs and emphasizing mul8disciplinary approach Basic research: - Role of vasopressin V2 receptors and aquaporins - Sleep and related endocrinological mechanisms Epidemiological studies: - subgroups of pa8ents with nocturia Health economic research - Cost of nocturia to society - Impact and cost effec8veness of different therapeu8c strategies. 45

46 Conclusions Nocturia has mul8factorial e8ologies and consist directly to morbidity and mortality A sub- categoriza8on by precise evalua8on may improve treatment results Conclusions Treatment with vasopressin is effec8ve in nocturnal polyuria but requires a careful moni8oring in elderly popula8on. although in rou8ne use, alpha- blockers and an8muscarinic agents have actually a limited effect on nocturia. 46

47 Thank you! 47