Prevalence, Severity, and Symptom Bother of Lower Urinary Tract Symptoms among Men in the EPIC Study: Impact of Overactive Bladder

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1 EUROPEAN UROLOGY 56 (2009) available at journal homepage: Platinum Priority Voiding Dysfunction Editorial by Christopher R. Chapple on pp of this issue Prevalence, Severity, and Symptom Bother of Lower Urinary Tract Symptoms among Men in the EPIC Study: Impact of Overactive Bladder Debra E. Irwin a, *, Ian Milsom b, Zoe Kopp c, Paul Abrams d, Walter Artibani e, Sender Herschorn f a Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA b Department of Obstetrics and Gynecology, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden c Pfizer Inc, New York, NY, USA d Bristol Urological Institute, Southmead Hospital, Bristol, UK e Urology Unit, University of Padova, Padova, Italy f Sunnybrook Health Science Centre, University of Toronto, Toronto, ON, Canada Article info Article history: Accepted February 18, 2009 Published online ahead of print on March 3, 2009 Keywords: Urination disorders Overactive bladder Prevalence Severity Men Abstract Background: Lower urinary tract symptoms (LUTS) are prevalent among men. Objective: To describe the prevalence, severity, and symptom bother of LUTS in all men and men with overactive bladder (OAB) symptoms in the EPIC study. Design, setting, and participants: A secondary analysis of data from EPIC, a multinational population-based survey of adults, was performed. Current International Continence Society definitions were used for individual LUTS and OAB; OAB cases were defined as men reporting urgency. Measurements: Participants were asked about the presence of individual LUTS and associated symptom bother. LUTS severity was measured using the International Prostate Symptom Score (IPSS). Results and limitations: There was substantial overlap of storage, voiding, and postmicturition symptoms among all men (n = 7210) and in men with OAB symptoms (n = 502); men with OAB symptoms were more likely to experience multiple LUTS subtypes. Among both populations, nocturia was the most commonly reported symptom, except for urgency (the hallmark symptom) among men with OAB symptoms; terminal dribble and sensation of incomplete emptying were the most common voiding and postmicturition symptoms. The prevalence of all LUTS increased with age among the general population; only storage LUTS increased with age among men with OAB symptoms. Number of LUTS and mean IPSS increased with age in both populations but were higher among men with OAB symptoms at all ages; the proportion reporting moderate severe LUTS was higher than the general population (30% vs 6%). The proportion of men with OAB symptoms reporting symptom bother increased with urgency severity and severity and number of LUTS. LUTS severity may have been underestimated by the IPSS, which does not assess incontinence. Conclusions: Men with LUTS commonly experience coexisting storage, voiding, and postmicturition symptoms, emphasizing the need for comprehensive urologic assessments. Men with OAB symptoms reported more LUTS and greater severity than the general population. Symptom bother was related to number of LUTS and urgency severity. # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Epidemiology, University of North Carolina, CB#7435 McGavran Greenberg Bldg., Chapel Hill, NC 27599, USA. Tel ; Fax: address: dirwin@ .unc.edu (D.E. Irwin) /$ see back matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 56 (2009) Introduction Lower urinary tract symptoms (LUTS) experienced by patients with various disorders, such as bladder outlet obstruction (BOO) and overactive bladder (OAB) [1], are divided into three categories: storage, voiding, and postmicturition symptoms. Storage symptoms include increased micturition frequency, nocturia, urinary urgency, and urinary incontinence [1]. Common voiding symptoms include slow or weak stream, hesitancy, and terminal dribble. Postmicturition symptoms include the sensation of incomplete emptying and postmicturition dribble [1]. OAB is a syndrome of storage symptoms defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia [1,2], and it is often associated with detrusor overactivity (DO) [1]. Storage symptoms may be more bothersome in men than voiding or postmicturition symptoms [3]. Although OAB symptoms and DO in men may develop secondary to BOO, they may also occur independently [4,5]. However, LUTS in men are often treated with therapies targeting the prostate [4,5]. Estimates of the prevalence of LUTS in community and clinic populations differ depending on the questions asked [6,7]. Some studies report overall prevalence using the International Prostate Symptom Score (IPSS) [8] instead of individual symptom prevalence [9,10]. To date, only one large population-based study, the EPIC study [7], has evaluated the prevalence of all LUTS using current International Continence Society (ICS) definitions [1]. In EPIC, 62.5% of 7210 men in the five countries surveyed reported one or more LUTS; the prevalence of individual LUTS in men increased with age. A greater percentage of men reported storage symptoms (51.3%) than voiding (25.7%) or postmicturition (16.9%) symptoms. Nocturia, defined by the ICS as waking one or more times to urinate during the night, was the most commonly reported symptom (48.6% of men); terminal dribble (14.2% of men) and sensation of incomplete emptying (13.5% of men) were the most commonly reported voiding and postmicturition symptoms, respectively. The hallmark symptom of OAB, urgency, was reported by 10.8% of men [7]. There was considerable overlap between storage, voiding, and postmicturition symptoms, among the general population of men [7] and among men with OAB [11]. Among men and women with OAB, those who reported symptom bother, particularly those with urinary incontinence, were significantly more likely to seek health care or to use coping techniques [12]. Among respondents with OAB aged 50 yr, men were more likely than women (82.7% vs 64.8%) to seek health care. The aim of this analysis was to use data from the EPIC study [7] to provide additional information on the overall prevalence of LUTS, LUTS severity, and age-related changes among men in general and among men with OAB, using current ICS definitions. Additionally, we assessed symptom bother associated with LUTS among men with OAB symptoms. 2. Methods The EPIC study was a population-based, cross-sectional telephone survey of adults aged 18 yr in five countries (Canada, Germany, Italy, Sweden, and the United Kingdom) performed between April and December 2005 [7]. All respondents were asked about demographics, the presence of urinary tract infection (UTI), the presence of individual LUTS using current ICS definitions, and symptom items from the IPSS [8]. IPSS scores were used to assess LUTS severity: 0, none; 1 7, mild; 8 19, moderate; 20 35, severe. This analysis included men in the general population survey and men with symptoms consistent with the ICS definition of OAB. The presence of OAB symptoms was determined by a response of yes to either of the following questions: (1) Do you experience a sudden compelling desire to urinate which is difficult to put off? What I mean is a sudden intense feeling of urgency where you feel you must urinate immediately ; and (2) Do you leak urine with a sudden compelling desire to urinate? By that I mean in connection with a sudden intense feeling of urgency. Respondents who reported UTI were excluded from this cohort. A longer questionnaire was administered to men with OAB symptoms and included condition-specific questions about symptom bother using the Overactive Bladder-Validated 8 (OAB- V8) [13], Patient Perception of Bladder Condition (PPBC) [14], and the IPSS Quality of Life (QoL) item [8]. Men who met either of the following criteria were classified as having symptom bother: PPBC-positive responses (their bladder condition caused them minor, moderate, severe, or many severe problems); or OAB-V8 score >15. Men also rated the severity of their urgency on a scale of 1 10 with responses grouped as: 1 4, mild; 5 7, moderate; and 8 10, severe. To account for the underlying sampling frame and to provide representative population prevalence estimates, the sample population was weighted by age (5-yr groups), household size (one person, two people, three people, four people, and five or more people), and country size. Prevalence data are presented as percentages, weighted by age, household size, and country size. Chi-square analyses were performed to test for significant differences between the proportions from categorical variables. Mean differences in continuous variables for IPSS categories were compared using student t tests. All statistical analyses were performed using SPSS v.14.0 (SPSS Inc, Chicago, IL, USA). 3. Results 3.1. Prevalence of lower urinary tract symptoms Among men in the general population sample (n = 7210), 62.5% reported experiencing one or more LUTS; 37.7% (ie, 60% of all men reporting any LUTS) reported experiencing only one LUTS subtype, whereas 24.8% (ie, 40% of all men reporting any LUTS) reported experiencing one or more LUTS subtype (Fig. 1a). The most commonly reported clusters of LUTS subtypes were storage plus voiding LUTS (8.9% of the general population sample or 14% of all men reporting any LUTS) and all three LUTS subtypes, which were reported for 8.8% of the general population sample (14% of all men reporting any LUTS) (Fig. 1a). By definition, all men with OAB symptoms (n = 502) reported urgency; 29.3% reported only storage symptoms. Men with OAB symptoms reported a greater prevalence of multiple LUTS subtypes than men in the general population ( p < 0.05). All three LUTS subtypes were reported by 37.3% of men with OAB symptoms, 21.3% reported voiding plus

3 16 EUROPEAN UROLOGY 56 (2009) were the most frequently reported voiding and postmicturition symptoms (Fig. 2c and d). The prevalence of individual LUTS among men in the general population increased with age (Fig. 2a and C; p < 0.05). Among men with OAB symptoms, the prevalence of storage LUTS increased with age ( p < 0.05), but the prevalence of voiding and postmicturition LUTS were variable (Fig. 2d). The number of individual LUTS reported by each respondent increased with age ( p < 0.05), particularly among men with OAB symptoms (Fig. 3a and b). The overall prevalence of any LUTS increased with age in the general population, from 51.3% for men <40 yr to 80.7% for men >60 yr ( p < 0.05). Only 9.8% of men in the general population reported four or more LUTS (Fig. 3a), whereas 53.8% of men with OAB symptoms reported four or more LUTS (Fig. 3b). The proportion of men with OAB symptoms who reported six or more LUTS increased with age, whereas the proportion with one or two LUTS decreased ( p < 0.05; Fig. 3b) Symptom severity and bother Fig. 1 Distribution* (%) of lower urinary tract symptoms (LUTS) by type among (a) all men in the general population (n = 7210) and (b) men in the overactive bladder (OAB) population (n = 502). For all men in the general population (a), the total distribution for individual LUTS is indicated with overlapping or nonoverlapping symptoms indicated as the percent in each section. Storage LUTS include the following symptoms: micturition frequency, nocturia, urinary urgency, and urinary incontinence. Voiding LUTS include slow or weak stream, hesitancy, and terminal dribble. Postmicturition LUTS include sensation of incomplete emptying and postmicturition dribble. *Weighted by age, household size, and country size. storage symptoms, and 12.2% reported postmicturition plus storage symptoms (Fig. 1b). The most common storage symptom was nocturia (one or more episodes per night) among men in the general population (48.6%; Fig. 2a). Nocturia was the second most common storage symptom among men with OAB symptoms (75.3%; Fig. 2b) after urgency (100%), the defining symptom of OAB. Terminal dribble (general population, 14.2%; OAB cases, 36.9%) and the sensation of incomplete emptying (general population, 13.5%; OAB cases, 36.9%) More than 6% of men in the general population (Fig. 4a) reported moderate (5.4%) or severe (0.7%) LUTS, as scored by the IPSS. By contrast, almost 30% of men with OAB symptoms (Fig. 4b) reported moderate (25.5%) or severe (4.4%) LUTS. For both populations, the proportional increase in men reporting any LUTS (mild, moderate, or severe) with age was significant ( p < 0.05). Overall, mean IPSS was nearly three times higher among men with OAB symptoms versus the general population sample (mean SE: vs , respectively; p < 0.05). In the general population, men 60 yr of age reported a higher mean IPSS than men <40 yr (mean SE: vs , respectively; p < 0.05); larger age-related increases were observed among men with OAB symptoms (60 yr, ; <40 yr, ) (Fig. 4a and b). Men with OAB symptoms rated the severity of their urgency as follows: mild urgency, 26.3%; moderate urgency, 44.8%; severe urgency, 21.3%; and unsure, 7.6%. The proportion reporting symptom bother increased with urgency severity (mild, 33.3%; moderate, 57.3%; and severe, 72.0%; p < 0.05). The proportion of men with OAB symptoms who reported symptom bother significantly increased with the number of LUTS reported ( p < 0.05; Table 1). The largest increase occurred among those who reported two and three LUTS. With increasing number of LUTS, the proportion of men with OAB symptoms who reported they would be delighted or pleased to spend the rest of their life with their current urinary conditions (IPSS QoL question) decreased substantially ( p < 0.05; Table 1). 4. Discussion The EPIC study is the largest population-based study to date of LUTS in adults using current ICS definitions. Previous reports from EPIC showed that overall prevalence of any

4 EUROPEAN UROLOGY 56 (2009) Fig. 2 Distribution (%) of storage lower urinary tract symptoms (LUTS) by age group among (a) men in the general population (n = 7210) and (b) men in the overactive bladder (OAB) population (n = 502); distribution (%) of voiding and postmicturition LUTS by age group among (c) men in the general population (n = 7210) and (d) men in the OAB population (n = 502). UI = urinary incontinence. LUTS among men 18 yr is high (62.5%); that the prevalence of LUTS among men increases with age; that the prevalence of urgency (the defining symptom of OAB) is similar in men (10.8%) and women (12.8%); and that there is significant Table 1 Symptom bother and International Prostate Symptom Score (IPSS) quality of life (QoL) score among men in the overactive bladder (OAB) population No. of LUTS (n) Reported symptom bother * IPSS QoL y n (%) n (%) 1 (50) 7 (14) 31 (72) 2 (104) 29 (28) 66 (70) 3 (116) 61 (53) 45 (48) 4 (92) 57 (62) 39 (41) 5 (59) 43 (73) 22 (37) 6 (81) 71 (74) 22 (19) Total (502) 271 (54) 225 (45) LUTS = lower urinary tract symptoms; OAB-V8 = Overactive Bladder Validated 8; PPBC = Patient Perception of Bladder Condition. * Number (percentage) of participants with PPBC-positive responses, indicating that their bladder condition caused them minor, moderate, severe, or many severe problems, or with OAB-V8 score >15. y Number (percentage) of participants who responded that they were delighted or pleased to spend the rest of their lives with their current urinary conditions. overlap of storage, voiding, and postmicturition symptoms among men in the general population [7] and those with OAB symptoms [11]. In the current analysis, men with OAB symptoms, who by definition have storage symptoms, were more likely to experience multiple LUTS subtypes compared with men in the general population. Storage plus voiding symptoms and storage plus voiding plus postmicturition symptoms clustered at similar rates in men in the general population; however, storage plus voiding plus postmicturition symptoms was the most common cluster in men with OAB symptoms. Age-related changes in LUTS prevalence also differed between the two populations. Among men in the general population sample, the prevalence of all individual LUTS increased linearly with age. In contrast, this was only true for storage symptoms among men with OAB symptoms. Age-related changes in voiding and postmicturition symptoms were variable. Men with OAB symptoms also reported more individual LUTS and greater LUTS severity than men in the general population. The number of LUTS reported by individuals increased with age among both populations, but the rate of this increase was greater for men with OAB symptoms. Men with OAB symptoms were more likely to report high

5 18 EUROPEAN UROLOGY 56 (2009) Fig. 3 Distribution (%) of number of lower urinary tract symptoms (LUTS) by age group among (a) men in the general population (n = 7210) and (b) men in the overactive bladder (OAB) population (n = 502). Fig. 4 Distribution (%) of International Prostate Symptom Score (IPSS) by age group among (a) men in the general population (n = 7210) and (b) men in the overactive bladder (OAB) population (n = 502). The mean IPSS for each category is provided. numbers of individual LUTS (eg, four or more) compared with men from the general population. Mean IPSS scores also increased with age in both populations but were higher for men with OAB symptoms at all ages. The total prevalence of moderate to severe LUTS as determined by IPSS scores was about 6% in the general population versus 30% in men with OAB symptoms. Symptom bother (measured by OAB-V8) among men with OAB symptoms increased with the number of LUTS reported and severity of urgency. A previous analysis of data from the EPIC study using these same men with OAB symptoms found that 54% reported symptom bother; those who were bothered were significantly more likely to seek health care for their urinary symptoms than those who reported no bother (55% vs 18%, p 0.05) [12]. Duration of OAB symptoms; age; presence of urinary frequency, incontinence, or nocturia; and presence of comorbidities were also significantly associated with seeking of health care [12]. The high prevalence of LUTS among men observed in the EPIC study is primarily attributable to the high proportion reporting storage symptoms (51.3%), specifically nocturia (48.6%), which is defined by the ICS as waking one or more times to urinate during the night [1]. This definition is relatively broad, and the clinical relevance of one episode per night has yet to be fully determined. A subanalysis of data from the EPIC study, however, showed that 19% of men who reported one episode of nocturia per night were bothered by it; not surprisingly, the percentage of men reporting bother increased with greater numbers of episodes per night [11]. Similarly, another study found that one episode of nocturia causes significant symptom bother and has a significant impact on health-related QoL [15]. These findings support the current ICS definition of nocturia. In another analysis of data from the EPIC study, the prevalence of storage LUTS and nocturia was assessed with a definition of waking two or more times per night; using this definition, the prevalence of storage LUTS was 26.9% and the prevalence of nocturia was 20.9% in the general male population [7]. These prevalence estimates correspond with recent population-based surveys reporting the prevalence of one or more LUTS to be between 43% and 91% and the prevalence of moderate to severe LUTS to be between 3% and 31% [6,9,10,16 18]. Similarly, the findings that the total number of LUTS reported and the overall prevalence of LUTS increase dramatically with age are consistent with an increase in prevalence of OAB with age among men that has been observed in earlier population-based studies in the United States and Europe [19,20] that were conducted before publication of current ICS definitions. Similarly, a sharp increase in OAB prevalence was found among Finnish men >60 yr of age, although the overall prevalence of OAB was lower than in other epidemiologic studies [21]. The variation in prevalence rates across studies may be due to case definition differences and/or methodologic dissimilarity (eg, telephone vs postal surveys) or differences in the

6 EUROPEAN UROLOGY 56 (2009) proportions of younger subjects (18 40 yr) that were included. The IPSS assesses three categories of LUTS but not incontinence and, therefore, likely underestimates the overall prevalence and severity of storage LUTS. The International Consultation on Incontinence Modular Questionnaire Male LUTS (ICIQ-MLUTS) [22] asks about all OAB symptoms and associated bother and may have been a better instrument for this study. Another possible limitation is that respondents may have had difficulty differentiating terminal dribble from postmicturition dribble, which may confound voiding and postmicturition prevalence estimates. Finally, LUTS and OAB were assessed from a subjective questionnaire-based approach; consequently, these prevalence rates may not reflect clinical evaluation. Some respondents who rated their urgency as mild, for example, may not be diagnosed with OAB in the clinic. Additionally, ICS guidelines suggest that use of the term overactive bladder is appropriate in the absence of infection or other obvious pathology [1]. Although respondents who reported UTI were excluded from the OAB cohort, it is possible that some men were inappropriately included. Men with OAB symptoms reported more severe symptoms (as measured by IPSS) and a higher total number of LUTS compared with their general population counterparts. While the IPSS for men with OAB symptoms might be expected to be higher due to the presence of urgency in all subjects, this does not account for the significant difference in IPSS scores. Symptom bother (measured by OAB-V8) among men with OAB symptoms increased with the number of LUTS reported and with the severity of urgency. There was a greater overlap of LUTS subtypes among men with OAB symptoms than men in the general population. Evidence suggests that DO and/or OAB symptoms may develop secondary to BOO in men; the high rate of coexisting storage and voiding symptoms in OAB cases may reflect this to some extent. DO and/or OAB symptoms, however, often coexist independently with BOO and may persist after therapeutic intervention for BOO [23]. It is unclear from this analysis whether the presence of other urinary disorders also increases the likelihood of coexisting LUTS subtypes. These data have important implications for clinical practice and emphasize a need for comprehensive urologic assessments in men with LUTS. This statement is supported by findings that men with symptoms suggestive of both OAB and benign prostatic hyperplasia gained more benefit from treatment with an antimuscarinic and an a-receptor antagonist than either therapy alone [24 28]. 5. Conclusions This study shows that all LUTS subtypes are common in men, who often experience coexisting subtypes. Generally, men with OAB symptoms were found to have a greater number of LUTS and greater LUTS severity, and their urinary symptom bother was related to the total number of LUTS. Further research should use consistent case definitions, such as those standardized by the ICS, and should assess all LUTS in men. The IPSS does not assess incontinence and, thus, may underestimate LUTS severity in men with storage symptoms; an alternative or new instrument to characterize all LUTS in men should be used in the future. To encourage accurate diagnosis and to improve the quality of care for these widespread symptoms, clinicians should assess all LUTS when evaluating men with LUTS. Author contributions: Debra Irwin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Irwin, Milsom, Kopp, Abrams, Artibani, Herschorn. Acquisition of data: Irwin, Milsom, Abrams, Artibani, Herschorn. Analysis and interpretation of data: Irwin, Milsom, Kopp, Abrams, Artibani, Herschorn. Drafting of the manuscript: Irwin, Milsom, Kopp, Abrams, Artibani, Herschorn. Critical revision of the manuscript for important intellectual content: Irwin, Milsom, Kopp, Abrams, Artibani, Herschorn. Statistical analysis: Irwin. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: None. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Debra Irwin is an investigator for Pfizer. Ian Milsom is a consultant and lecturer for Pfizer, Astellas, and Novartis; he is an investigator for Pfizer and Astellas. Zoe Kopp is an employee of Pfizer, Inc. Paul Abrams is a consultant for Bayer, Ferring, Novarits, Pfizer, Plethora; he is a lecturer for Astellas, Novartis, Ferring, and Pfizer; he is an investogator for Pfizer, Plethora, and Schwarz-Pharma. Walter Artibani is an advisory board member and lecturer for Astellas, Pfizer, Lilly (Boehringer) and Pierre Fabre. Sender Herschorn is a consultant for Pfizer, Astellas, Paladin, and Triton; he is a lecturer for Pfizer, Astellas, Triton, and Oryx; he is an investigator for Pfizer and Astellas. Funding/support and role of the sponsor: Pfixer, Inc. played a role in and provided support for the study in the following ways: design and conduct of the study; collection of the data; management of the data; analysis and interpretation of the data; preparation, review, and approval of the manuscript. Pfizer also funded editorial support. Acknowledgment statement: The authors would like to acknowledge the invaluable expertise in statistical programming by Christer Eksvärd. Editorial support was provided by Donald G. Buerk, PhD, from Complete Healthcare Communications, Inc. The authors also gratefully acknowledge the EPIC Study Group: Karin Coyne, Center for Health Outcomes Research, United BioSource Corporation, Bethesda, MD, USA; Christian Hampel, Urologische Klinik und Polyklinik, Johannes Gutenberg-Universität, Mainz, Germany; Steinar Hunskaar, Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway; Con Kelleher, St. Thomas Hospital, London, UK; Kate Reilly, Pfizer Inc, New York, NY, USA. References [1] Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:

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