Nocturia Time to wake up to the seriousness

Nocturia: Time to wake up to the seriousness of the problem R. ROSEN 1, V. KUPELIAN 1, and T. HOLM-LARSEN 2 1 New England Research Institutes, Watertown, Massachusetts, USA; 2 University of Copenhagen, Denmark and The Right Value Story, Copenhagen, Denmark

Absolutely! Because it is linked with: Is nocturia a serious health issue? Increased mortality and morbidity Increased falls and fractures Reduced productivity Sleep disruption Reduced Qo. L AND It is highly prevalent – in young and old, men and women Qo. L, quality of life

Nocturia and Mortality – U. S. Data NHANES III - Kupelian et al. J Urol 2011; 185: 571– 7

Nocturia and Mortality – Hazard Ratios (HR) NHANES III: Kupelian et al. J Urol 2011; 185: 571– 7 *Adjusted for baseline age, BMI, marital status, education, smoking, CVD, diabetes, hypertension, medications use (diuretics, antihypertensives, lipid lowering, antidepressants) Kupelian et al. J Urol 2011; 185: 571– 7

Similar findings in a recent study in Japan (Nakagawa et al. , 2009) Percentage survival 100. 0 ≤ 1 97. 5 n=788, mean age 75 years Log rank test p<0. 0002 95. 0 ≥ 2 92. 5 90. 0 0 5 10 15 20 25 Months 30 35 40 ≥ 2 voids/night are associated with increased mortality in the elderly, even after adjusting for age, gender, BMI, comorbidities and medications (HR: 2. 68 [1. 12– 6. 43]) BMI, body mass index; HR, hazard ratio Nakagawa et al. J Urol 2009; 181(Suppl): 8

Increased risk of falls in elderly patients with nocturia § 5872 community-dwelling men aged ≥ 65 years § Primary outcome: 1 -year cumulative incidence of falls with moderate/severe vs mild LUTS at baseline § Nocturia was among the LUTS most strongly associated with falls 2– 3 voids/night Relative risk of at least one fall Relative risk of at least two falls 4– 5 voids/night 5% 23% (RR 1. 05, 95% CI, 0. 96– 1. 16) (RR 1. 23, 95% CI 1. 08– 1. 41) 11% 42% (RR 1. 11, 95% CI, 1. 08– 1. 41) (RR 1. 42, 95% CI, 1. 16– 1. 74) LUTS, lower urinary tract symptom; RR, relative risk; CI, confidence interval Parsons et al. BJU Int 2009; 104: 63– 68

Nocturia is a risk factor for hip fractures, regardless of age § 1820 Austrian men aged 40– 80 years completed the IPSS 1 § The IPSS was not correlated with the occurrence of hip fractures § Nocturia (≥ 2 voids/night) was an age-independent risk factor for hip fractures (OR 1. 36; 95% CI 1. 03– 1. 80, p=0. 03) Hip fracture, age and nocturia 1 Nocturia Age (years) Total Hip fracture 0 49± 7 649 6 (0. 92%) 1 54+9 796 8 (1. 01%) ≥ 2 55+10 375 10 (2. 67%) Total 52 ± 9 1820 24 (1. 32%) An overall in-hospital mortality rate of 5. 3% following hip fracture has been reported 2 IPSS, International Prostate Symptom Score; OR, odds ratio 1. Temml et al. Neurourol Urodyn 2009; 28: 949– 952; 2. Alvarez-Nebreda et al. Bone 2008; 42: 278– 285

Nocturia affects daytime activity and work productivity § § Productivity, vitality and Qo. L were assessed in 203 professionally active adults in Sweden with ≥ 1 void/night Compared with controls, nocturia patients had significantly (p<0. 001): – Increased work impairment, due to greater impairment while working (not hours missed; assessed using WPAI) – Increased impairment in non-work activities (WPAI) – Reduced vitality (SF-36) – Reduced overall Qo. L (utility; EQ-5 D) Work impairment increased with nocturia severity (p<0. 05) Vitality decreased with nocturia severity (p<0. 01) WPAI, work productivity and activity impairment questionnaire; SF-36, Short-Form 36; EQ-5 D, Euro. Qol questionnaire Kobelt et al. BJU Int 2003; 91: 190– 195

Reduced Qo. L is specifically associated with nocturia in LUTS patients Percentage of patients with LUTS rating Qo. L as good or very good 1 § Of all IPSS symptoms, nocturia correlates most strongly with HRQo. L at baseline and after treatment 2 § Nocturia is a key factor driving Qo. L in LUTS patients Reducing nocturia to <2 voids/night may reduce Qo. L burden 90. 6 80 Percentage Amongst a sample of 502 Spanish men ≥ 60 years with LUTS, proportion who rate Qo. L as good/very good is more than halved if nocturia is present 1 § 100 § 60 42. 9 40 20 0 Without nocturia With noctura HRQo. L, health-related quality of life 1. Hernández et al. Curr Med Res Opin 2008; 24: 1033– 1038; 2. Van Dijk et al. BJU Int [Epub ahead of print]

Nocturia associated with similar reductions in Qo. L as local advanced prostate cancer Nocturia 1 PCa Utility score of HRQo. L 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0 1 void/ 2 voids/ night 3 voids/ 4 voids/ night Local Terminal advanced PCa, prostate cancer Kobelt et al. BJU Int 2003; 91: 190– 195; Tengs & Wallace. Med Care 2000; 38: 583– 637

Burden of nocturia increases with severity NQo. L score* Qo. L in 663 Taiwanese community-dwelling adults aged 40– 79 years with nocturia 100 90 80 70 60 50 40 30 20 10 0 Voids/night 1 2 3 4+ Sleep/energy subscale *Lower score indicates worse Qo. L NQo. L, nocturia-specific quality of life Yu et al. Urology 2006; 67: 713– 718 Bother/concern subscale NQo. L total

1. 0 No nocturia * ** ** ≥ 3 voids/night ** ** ** n=1888 Finnish women (similar results in males) *p <0. 05; **p <0. 001 (test for trend) Tikkinen et al. Eur Urol 2010; 57: 488– 496 ** Depression Discomfort Mental function ** Usual activities Speech Eating Breathing Hearing Seeing ** Eliminating 0. 7 ** ** Sexual activity ** Sleeping 0. 8 2 voids/night ** Vitality ** 1 void/night Distress 0. 9 Moving 15 D instrument (level value) Nocturia associated with significant decreases in 14/15 dimensions of HRQo. L

What level of severity of nocturia is important? § Results from multiple studies of mortality, fractures and Qo. L 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 to patients may be significantly reduced

Prevalence of nocturia (%) Nocturia affects both sexes equally 80 70 EPIC study: survey of 19, 165 adults in Europe and Canada Males Females 60 50 40 30 20 10 0 ≥ 1 void/night ♀: 54. 5% ♂: 48. 6% ≥ 2 voids/night ♀: 24. 0% ♂: 20. 9% § ≤ 39 years 40– 59 years ≥ 60 years Nocturia usually considered a male condition 1 BUT it is just as prevalent in women 2 § Nocturia increases with age 2 § Over a third of younger people (<40 years of age) are affected – 13– 17% in this age group have ≥ 2 voids/night 2 1. Wein et al. BJU Int 2002; 90(suppl 3): 28– 31; 2. Irwin et al. Eur Urol 2006; 50: 1306– 1314

Could sleep disruption be a prime mediator of subsequent effects of nocturia? Prevalence of poor sleep in 3669 Swedish women aged 40– 64 years according to nocturia severity Percentage (%) 80 60 Age (years) 40– 44 45– 49 50– 54 55– 59 60– 64 40 20 0 None One Two Nocturia episodes/night Asplund & Aberg. Maturitas 1996: 24: 73– 81 Three or more

Nocturia is the leading cause of sleep disturbance in older adults Prevalence (%) of self-reported causes of disturbed sleep How often do the following disturb your sleep? 90 80 70 60 50 40 n=1424; aged 55– 84 years Nocturia Physical pain Caregiving Health concerns Cough Night-time heartburn Headache Money problems Family problems Uncomfortable bed 30 20 10 0 Every night/ Few nights/ almost every week night Bliwise et al. Sleep Med 2009; 10: 540– 548 Few nights/ month Rarely Never

Reduced sleep efficiency associated with increased mortality in the elderly Survival as a function of sleep efficiency 1. 0 Cumulative survival n=185 healthy older adults 0. 8 0. 6 Efficiency ≥ 80% 0. 4 Controlling for age, gender and baseline medical burden, those with sleep efficiency <80% are at 1. 93 times greater risk of mortality (p=0. 014; CI 1. 14– 3. 25) 0. 2 Efficiency <80% 0. 0 0 100 200 300 400 500 600 Weeks Dew et al. Psychosom Med 2003; 65: 67– 73 700 800 900 1000

Sleep efficiency is reduced in nocturia 2 2. 0 *** ≥ 5. 0 *** 1. 4 Score Increasing difficulty 4 Voids per night 1. 8 1. 6 3 1. 2 ** 1. 0 0. 8 * 0. 6 0. 4 0. 2 0. 0 Subjective sleep quality Sleep latency Sleep duration Habitual sleep efficiency Domain Sleep disturbance Sleep medication Daytime dysfunction PSQI domain scores for all patients by increasing voiding frequency *p=0. 0012, **p=0. 0003, ***p<0. 0001 Score range: 0 (no difficulty) to 3 (severe difficulty). PSQI domain scores are standardised versions of areas routinely assessed during clinical interviews of patients with sleep/wake complaints PSQI, Pittsburgh Sleep Quality Index Ancoli-Israel et al. Neurourol Urodyn 2009; 28: 635. Abstract 54; Chartier-Kastler et al. Prog Urol 2009; 19: 333– 340

§ § § Awaking from sleep is associated with increased heart rate and blood pressure (major determinants of cardiac oxygen consumption and vascular stress, endocrine and clotting activation) – Contributes to clustering of cardiovascular events during morning hours Nocturia causes additional awakening during the night and is associated with non-dipping hypertension 1 12 -year survival is 10% lower for CHD patients with nocturia vs without (61% vs 72%, p=0. 02)2 1. Perk et al. Hypertension 2001; 37(2 Part 2): 749– 752; 2. Bursztyn et al. Am J Cardiol 2006; 98: 1311– 1315 Survival distribution function Nocturnal awakening due to nocturia as a cardiovascular stressor No nocturia 1. 0 Nocturia 0. 8 0. 6 0. 4 0. 2 0. 0 0 2 4 6 8 10 12 28 46 24 43 Years of follow-up Nocturia 54 No nocturia 65 50 61 47 57 39 53 33 48 12 -year survival in 70 -year-old subjects with ischaemic heart disease for 54 who reported nocturia versus 65 who did not (p=0. 0206, log-rank test)

Conclusions § Like other asymptomatic conditions (hypertension, type 2 diabetes, hypercholesterolaemia), nocturia is associated with serious consequences for mortality, morbidity and Qo. L – but is most often considered a ‘lifestyle condition’ and ignored, BUT… § Nocturia (≥ 2 voids) is potentially a harbinger of multiple negative outcomes – High risks to patient Qo. L, functioning, health, possibly mortality § Large proportion of men and women are affected by nocturia 1, 2 § Increasing evidence that older and younger people are: 3– 6 – Widely affected by nocturia – Experience major Qo. L and health impact Public health attention to nocturia, its aetiology and treatment is urgently needed 1. Wein et al. BJU Int 2002; 90(Suppl 3): 28– 31; 2. Irwin et al. Eur Urol 2006; 50: 1306– 1314; 3. Asplund & Aberg. Maturitas 1996; 24: 73– 81; 4. Hunskaar. BJU Int 2005; 96(suppl 1): 4– 7; 5. Fitzgerald et al. J Urol 2007; 177: 1385– 1389; 6. Bosch & Weiss. J Urol: in press