Mystery about Nocturia Anything we can do?

Transcription

1 Mystery about Nocturia Anything we can do? 2016 Annual Scientific Meeting Hong Kong Continence Society 8th October 2016 Dr. Wong Kwok Keung William Associate Consultant Department of M&G/KWH No Disclaimer

2 Myths about Nocturia in the past decades TAMUS study ( ) Population based study in Finland (FINNO) (2003 / 2004) NERI analysis of nocturia and mortality (2010 / 2011) based on NHANES III ICS standardization of terminology (2002) Japan mortality study ( ) EpiLUTS study (2009) A disease of elderly which is attributed as a part of ageing Secondary to other underlying conditions including overactive bladder and benign prostatic hypertrophy A disease of the urinary bladder No effective specific treatment

3 ICS Definition in 2002 The complaint that the individual has to wake at night, one or more times to void & Each void must be preceded and followed by sleep Van Kerrebroeck P, Abrams P, Chalkin D et al The standardisation of terminology in nocturia: Report from the standardisation subcommittee of the International Continence Society Neurourol Urodynam :

4 Threshold triggering poor Outcomes 2 voids/night Poor Outcomes Mortality Fall Hip fracture Reduced QoL Sleep disturbance

5 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):

6 Effects of poor sleep Poor sleep associated with deficits in daily functioning: 1,2 Mood disturbance Cognitive and memory impairment Reduced performance at work Poor sleep associated with reduced health: 1 4 Morbidity and mortality Risk of falling, traffic and occupational accidents Risk of cardiovascular disease and diabetes 3 Risk of depression 4 Healthcare costs Immune response 1. Carskadon. Med Clin North Am 2004;88: ; 2. Dinges et al. Sleep 1997;20: Newman et al. J Am Geriatr Soc 2000;48: ; 4. Buysse. Geriatrics 2004;59:47 52

7 Prevalence (%) of self-reported causes of disturbed sleep Nocturia is the leading cause of sleep disturbance in older adults How often do the following disturb your sleep? n=1424; aged Nocturia Headache Physical pain Money problems Care-giving Family problems Health concerns Uncomfortable bed Cough Night-time heartburn 0 Every night/almost every night Few nights/ week Few nights/ month Rarely Never National Sleep Foundation. Annual Sleep in America Poll (2003); Bliwise et al. Sleep Med 2009;10:7 8

8 Survival Probability Nocturia and Mortality U.S. Data NHANES III 1 Men 1 Women Nocturia <2 Nocturia Months.5 Nocturia <2 Nocturia Months Hazard Ratios (HR) Men Women (1.49) (1.32) Kupelian et al. J Urol 2011;185:571 7

9 Percentage survival Nocturia and Mortality Japan Data Nakagawa et al., n=788, mean age 75 years Log rank test p< Months 2 voids/night are associated with increased mortality in the elderly, even after adjusting for age, gender, BMI, comorbidities and medications (HR: 2.68 [ ]) BMI, body mass index; HR, hazard ratio Nakagawa et al. J Urol 2009;181(Suppl):8

10 Nocturia and Falls Parsons et al. 2009: Nocturia is the LUTS most associated with falls and the risk increases with number of voids/night 1. Parsons et al. BJU Int 2009;104:

11 Nocturia and 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) HR for fall-related fractures was 2.20 ( ) with nocturia ( 2 voids/night) 1. Temml et al. Neurourol Urodyn 2009;28: Nakagawa et al. J Urol 2010;184:

12 Nocturia and QoL Reduced QoL (based on HR-QoL) is specifically associated with nocturia in LUTS patients 1,2 Burden of nocturia increases with severity (based on N-QoL 3 ) Nocturia is associated with significant decreases in 14/15 dimensions of HR-QoL 4 (all except eating) Nocturia s impact on sleep and QoL is more pronounced in younger compared with older patients5, 6, 7 1. Hernández et al. Curr Med Res Opin 2008;24: Asplund & Aberg. Maturitas 1996;24: Van Dijk et al. BJU Int 2010;105: Hunskaar. BJU Int 2005;96(suppl 1): Yu et al. Urology 2006;67: Irwin et al. Eur Urol 2006;50: Tikkinen et al. Eur Urol 2010;57: Daneshgari et al. Abstract 212 at ICS/IUGA

13 But How to start with? Nocturnal polyuria Nocturia Psychological sleep problems Benign prostatic obstruction Primary polydipsia Detrusor overactivity Reduced bladder capacity Uncompensated heart disease Oestrogen deficiency Untreated diabetes mellitus or insipidus Nocturia is a multifactorial condition 13

14 Approach Good medical history Drug history Social history Caffeine, Alcohol, etc Functional state Physical examination Frequency Volume Chart Analysis

15 Classification by Frequency Volume Chart (FVC) Nocturnal Polyuria Reduced bladder capacity FVC Mixed Global polyuria Nocturnal Polyuria: NUV >33% by ICS Guideline Criterion Global Polyuria: 24-hour output >40 ml/kg

16 Possible etiology of nocturia Urological evaluation reveals: Nocturnal polyuria Reduced nocturnal bladder capacity Global polyuria Definition: Nocturnal urine volume >33% 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):

17 FVC Analysis of Nocturia NUV (Noctural Urine Volume) Include 1 st morning void MVV (Maximum Voided Volume) 24hr urine volume/body Weight NPi (Nocturnal Polyuria Index) = NUV/24hr urine volume Ni (Nocturia Index) = NUV/MVV ANV (Actual Nightly Voids) PNV (Predicted Nightly Voids) = Ni - 1 NBCi (Nocturnal Bladder Capacity Index) = ANV-PNV The higher is the NBCi, the lower would be the nocturnal bladder capacity (NBC) compared with the functional bladder capacity (FBC)

18 Interpretation of parameters NPi (Nocturnal Polyuria Index) >33% suggest nocturnal polyuria 24 hour urine volume >40 ml/kg/day suggest global polyuria NBCi (Nocturnal Bladder Capacity Index) > 0 suggest reduced nocturnal bladder capacity > 2 strongly suggestive

19 Case (1) Patient complained of nocturia 4 times/night Body weight 55kg Bladder diary Fluid Intake 3000ml 24 hour voided volume 2800ml Nocturnal Urinary Volume (NUV) 800ml Maximum Voided Volume (MVV) 350ml

20 Calculations NUV = 800ml MVV = 350ml 24hr VV/Body Weight = 51ml/kg (<40ml/kg) NPi = NUV/24hr VV= 800/2800 = 0.28 (<0.33) Ni = NUV/MVV = 800/350 = 2.28 ANV = 4 PNV = Ni 1 = = 1.28 NBCi = = 2.72

21 Global Polyuria (51ml/kg) Reduced nocturnal bladder capacity (NCBi 2.72) Urological evaluation reveals: Nocturnal polyuria Reduced nocturnal bladder capacity Global polyuria Definition: Nocturnal urine volume >33% 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):

22 Case (2) Patient complained of nocturia 7 times/night Body weight 55kg Bladder diary Fluid Intake 1600ml 24 hour voided volume 1500ml Nocturnal Urinary Volume (NUV) 750ml Maximum Voided Volume (MVV) 150ml

23 Calculations NUV = 750ml MVV = 150ml 24hr VV/Body Weight = 27ml/kg (<40ml/kg) NPi = NUV/24hr VV = 750/1500 = 0.5 (<0.33) Ni = NUV/MVV = 750/150 = 5 ANV = 7 PNV = Ni 1 = 5-1 = 4 NBCi = ANV PNV = 7 4 = 3

24 Nocturnal Polyuria (NPi 0.5) Reduced nocturnal bladder capacity (NBCi 3) Urological evaluation reveals: Nocturnal polyuria Reduced nocturnal bladder capacity Global polyuria Definition: Nocturnal urine volume >33% 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 Anything we can do? Non pharmacological measures Dietary modification Caffeine, Alcohol Lifestyle modification Drinking habits (Time, Fluid restriction..) Empty bladder before going to bed Leg elevation, Compressive stocking. Pharmacological measures Medication modification (Anti-HT, NSAIDs, Diuretics..) Drugs for OAB and BOO Diuretics Anti-Diuretic

26 Drugs causing nocturia Increase urine output CNS/Insomnia Lithium Diuretics Calcium channel blockers Corticosteroids NSAID Psychotropic (MAOIs and SSRIs) Antiepileptics Dopaminergic agonists AB, BB, Methyldopa Albuterol, Theophylline

27 Real life Medication modification is always difficult especially in medical patients

28 Real life Timed Diuretics based therapy Problematic hypokalaemia and dehydration Fluid restriction Patient discomfort, dehydration. Drugs for OAB Tolerability. Effectiveness for nocturia? Drugs for BOO Effectiveness for nocturia?

29 Medical therapies for OAB/BPH have limited effect on nocturia BPH/OAB therapy Net advantage vs. placebo (reduction in number of voids) BPH OAB Terazosin 1 Tamsulosin OCAS 2 Doxazosin + Finasteride 3 Solifenacin 4 Solifenacin 5 Tolterodine ER voids 0.3 voids ~0.2 voids 0.16 voids 0.08 voids (NP) 0.18 voids (No NP) ~0.75 voids/week 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: ; 2. Djavan et al. Eur Urol Suppl 2005;4:61 68; 3. Johnson et al. J Urol 2007;178: ; 4. Yamaguchi et al. BJU Int 2007;100: ; 5. Brubaker & FitzGerald. Int Urogynecol J Pelvic Floor Dysfunct 2007;18: ; 6. Nitti et al. BJU Int 2006;97: ; 7. Rackley et al. J Urol 2006;67: ; 8. Kaplan et al. JAMA 2006;296:

30 Effects of TURP on Nocturia 138 patients who underwent TURP 118 had nocturia before treatment Three months after treatment 91 reported still having nocturia The rate of improvement in nocturia was less than 20% Nocturia was the LUTS least improved after TURP Rates of improvement in other LUTS ranged from 37% (for urgency) to 63% (for a weak stream) The authors commented that the association between BPH and nocturia is controversial Yoshimura K, Ohara H, Ichioka K, et al. Nocturia and benign prostatic hyperplasia. Urology. 2003;61(4):

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

32 Anything we can do? Non pharmacological measures Dietary modification Caffeine, Alcohol Lifestyle modification Drinking habits (Time, Fluid restriction..) Empty bladder before going to bed Leg elevation, Pressure stocking. Pharmacological measures Medication modification (Anti-HT, NSAIDs, Diuretics..) Drugs for OAB and BOO Diuretics Anti-Diuretics Desmopressin

33 ADH stimulation and effects hyperosmolality, hypovolemia, angiotensin II + baroreceptors, natriuretic peptides ADH V1a Receptors V2 Receptors vasoconstriction renal H 2 O reabsorption

34 Nocturic patient impaired nocturnal rise in ADH Hvistendahl GM et al, J Urol 2007, 178,

35 Desmopressin Selective V 2 -receptor agonist Retains the antidiuretic properties of vasopressin 1 Lacks the unwanted pressor activity of vasopressin Bound to V 2 -receptors in the kidney Increases tubular water permeability Enhances water reabsorption Extracellular fluid becomes more dilute Urine becomes more concentrated 2 1. Vilhardt H. Drug Investigation 1990; 2(Suppl. 5):2 8; 2. Hammer M & Vilhardt H. J Pharmacol Exp Ther 1985; 234:

36 History 1972: Introduced for the treatment of central diabetes insipidus Intra-nasal : 2001: Approved for primary nocturnal enuresis (PNE) in children Grade A, Level 1 recommendation (ICI) Intra-nasal and Oral Approved for nocturia associated with nocturnal polyuria in adult Grade A, Level 1 recommendation (ICI) Oral

37 Desmopressin: Key recommendations International Consultation on Incontinence (ICI) Grade A (level 1) 1,2 European Association of Urology (EAU) Grade A (level 1b) 3,4,5. American Urological Association BPH guideline 1. In Abrams et al. (eds) Incontinence; 4th International Consultation on Incontinence. Paris: Health Publication Ltd, Available at: p:// 2. Abrams et al. Neurourol Urodyn 2010 ; 29 : Schröder et al. Guidelines on Urinary Incontinence. European Association of Urology Available at: 4. 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: 37

38 Formulations approved for nocturia associated with nocturnal polyuria Oral Tablet Dosage: 100mcg-400mcg at bedtime Orally Disintegrating Tablet (ODT Melt) Sublingual 60mcg, 120mcg, 240mcg melt tablets

39 Is Desmopressin effective? SWEET trials (Nasal Spray) In children with primary nocturnal enuresis (PNE) NOCTUPUS trials (Oral tablets) : Higher dose oral tablets NOCDURNA trials (Oral Disintegrating Tablet) Lower dose oral disintegration tablets Men 50mcg, 75mcg and Women 25mcg End-points: Nocturnal volume, Number of voids, QoL, Sleep quality, First Uninterrupted Sleep Period (FUSP)

40 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 treatment 1 5 Desmopressin is well tolerated in the short- and long-term; cessation causes nocturia severity to revert to baseline at 1 year 1 5 Both patient QoL and productivity at work improve with desmopressin treatment 4,6 1. Lose et al. Am J Obstet Gynecol 2003;189: ; 2. Mattiasson et al. BJU Int 2002;89: ; 3. Lose et al. J Urol 2004;172: ; 4. van Kerrebroeck et al. Eur Urol 2007;52: ; 5. Weiss et al. Abstract 198/ ICS Daneshgari et al. Abstract 212/ ICS

41 Adverse reaction of desmopressin High dose Tablet Dizziness and vertigo Headache Nausea and vomiting Hyponatraemia Heart failure Chest pain Hypertension >50% reported adverse reaction but usually mild NOCTUPUS Trial 2A, 3A, 4

42 High-Dose Tablet: Overall Safety Hyponatraemia appears to be the only significant AE of desmopressin therapy in patients with nocturia A well-known undesired effect of desmopressin, when water intake is not 5% of all patients develop hyponatreamia (Serum sodium <130 mmol/l) The minimum level ranged from 129 to 116 mmol/l Half were symptomatic No new cases occurred on extended treatment Characteristics of subjects with hyponatraemia Female Older (All aged > 65) Lower body weight More severe nocturnal polyuria Lower basal serum sodium level Lower creatinine clearance rate

43 Gender/Age difference on Hyponatraemia Age difference Elderly are more prone to develop hyponatraemia Impaired thirst sensation Reduced extra-cellular volume Impaired ability to conserve sodium by kidney Gender difference Women are more sensitive to desmopressin Relative sensitivity 2-3:1(Juul K V et al. Am J Physiol Renal Physiol 2011;300:F1116) Use lower dose in elderly and women

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45 Trial of Desmopressin MELT Serum Sodium Levels <130 mmol/l 1 Serum Sodium n = 4 (all 65 yr) n = 4 (2 65 yr) Serum sodium <130 mmol/l but 125 mmol/l (considered a clinically relevant cutoff) Was dose related 50 µg Was age related (28/34 were 65 years) Serum sodium <125 mmol/l not observed at 25-µg dose 1. Weiss JP et al. Neurourol Urodyn. 2012;31(4):

46 Safe use of desmopressin Cautious Precaution Age > 65 Low basal serum Na CrCl < 60ml/min Heart failure Concomitant use of diuretics Polydipsia Fluid restriction 1hr before and 8 hrs after Withhold if acute illness Monitor Na levels 1 week 4 weeks

47 Demystifying Nocturia A common condition in both men/women and adult/elderly More impact on younger patient A distinct medical condition, rather than as a symptom of BPH, OAB or other diseases Frequency Volume Chart (FVC) analysis can help to identify the underlying etiology Nocturnal polyuria is a common finding in all nocturic patients Sleep disruption may be the culprit of poor outcomes associated with nocturia More evidence on ineffectiveness of some treatments like antimuscarinic and alpha blocker Hyponatraemia is less problematic than thought before especially with lower dose formulations Elderly and Female are more porn to develop hyponatraemia 47

48 Thank you!