ORIGINAL ARTICLE. Key words benign prostatic hyperplasia, bother, lower urinary tract symptoms, quality of life, tamsulosin

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1 LUTS (2012) 4, ORIGINAL ARTICLE Correlations among Lower Urinary Tract Symptoms, Bother, and Quality of Life in Patients with Benign Prostatic Hyperplasia and Associated Fluctuations with Tamsulosin Administration Momokazu GOTOH, 1 Yoshihisa MATSUKAWA, 1 Yasuhito FUNAHASHI, 1 Masashi KATO, 1 Yoshiro MASEKI, 2 Harunori NARITA, 3 Osamu KAMIHIRA, 4 and Ryohei HATTORI 1 1 Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan, 2 Department of Urology, Maseki Clinic, Nagoya, Japan, 3 Department of Urology, Narita Clinic, Nagoya, Japan, and 4 Department of Urology, Komaki Municipal Hospital, Komaki, Japan Objectives: To estimate correlations among lower urinary tract symptoms (LUTS), bother, and quality of life (QOL) and assess fluctuations in these parameters after α1-blocker administration in patients with benign prostatic hyperplasia (BPH). Methods: Untreated BPH patients with international prostate symptom scores (IPSS) 8 and IPSS-QOL scores 2 were administered tamsulosin at 0.2 mg/day for 4 weeks in a prospective multicenter study. We subsequently estimated the IPSS, bother score for each IPSS item, BPH impact index (BII), and IPSS-QOL score before and 4 weeks after tamsulosin administration. We also analyzed the LUTS that might strongly influence QOL by using a path analysis model. Results: Analyzable data were obtained from 198 of the 257 patients enrolled. The IPSS were highest for LUTS such as slow stream, followed by increased daytime frequency and nocturia. The bother score was highest for slow stream, followed by nocturia. We observed dissociations between IPSS and bother scores for both urgency and nocturia. After tamsulosin administration, total and individual IPSS, total and individual bother scores, total and individual BII scores, and IPSS-QOL score demonstrated significant improvements. Path analysis showed that physical discomfort and bothersomeness were BII items that strongly influenced QOL. Furthermore, feeling of incomplete, urgency, and slow stream were LUTS that strongly influenced QOL. Conclusion: Tamsulosin administration improved patient QOL by possible mechanisms via improvement in subjective symptoms and bother. The LUTS that strongly influenced QOL comprised feeling of incomplete, urgency, and slow stream. Key words benign prostatic hyperplasia, bother, lower urinary tract symptoms, quality of life, tamsulosin 1. INTRODUCTION Recent epidemiological studies conducted in many countries have demonstrated that a large number of people have lower urinary tract symptoms (LUTS) and that LUTS negatively impact the quality of life (QOL) in a variety of domains of daily life. 1 4 Awareness of the great demand for treating LUTS has promoted active development of various therapeutic modalities, including a variety of new medicines. Bother and QOL assessment of patients with LUTS has recently been suggested as an important factor for selecting an appropriate treatment strategy, in addition to LUTS assessment itself. 5 8 Nonetheless, correlations among three factors, namely, patient LUTS, bother, and QOL, and fluctuations in these factors affected by treatment have not been adequately estimated. This study investigated correlations among LUTS, bother, and QOL, as well as fluctuations in these factors following α1-blocker administration. 2. METHODS The study protocol was evaluated and approved by the ethics committee at Nagoya University Graduate School of Medicine prior to initiation. All patients provided written informed consent prior to their enrollment in the study. This was a prospective, open-labeled, multicenter study. Previously untreated benign prostatic hyperplasia (BPH) patients with international prostate symptom scores (IPSS) 8, IPSS-QOL scores 2, and prostate volume >20 ml Correspondence: Momokazu Gotoh, MD, PhD, Department of Urology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya , Japan. Tel: ; Fax: gotoh@med.nagoya-u.ac.jp Received 26 August 2011; revised 12 October 2011; accepted 24 October DOI: /j x

2 46 Momokazu Gotoh et al. TABLE 1. Changes of the international prostate symptom scores (IPSS), bother score and benign prostatic hyperplasia impact index after tamsulosin treatment Variable Before treatment After treatment P-value IPSS (n = 198) 2.4 ± 1.8 (2: 1 4) 1.6 ± 1.4 (1: 0.8 2) < Daytime frequency 3.0 ± 1.5 (3: 2 4) 1.9 ± 1.4 (2: 1 3) < ± 1.9 (2: 1 4) 1.6 ± 1.5 (1: 0 2.3) < ± 1.7 (1: 0 3) 1.0 ± 1.2 (1: 0 1.3) < ± 1.6 (4: 3 5) 2.2 ± 1.6 (2: 1 3) < ± 1.7 (1.5: 0 3) 1.3 ± 1.4 (1: 0 2) < ± 1.3 (2: 1 3) 1.8 ± 1.1 (2: 1 2) < IPSS total score 17.7 ± 6.3 (16: 12 22) 11.3 ± 6.1 (10: 6 16) < Voiding score 7.9 ± 3.8 (8: 5 11) 5.0 ± 3.7 (4: 2 7) < Storage score 7.4 ± 3.2 (7: 5 10) 4.7 ± 2.5 (4: 3 6) < QOL index 4.7 ± 0.9 (5: 4 6) 3.2 ± 1.5 (3: 2 4) < Bother score (n = 198) 2.5 ± 1.1 (3: 2 3) 1.9 ± 1.1 (2: 1 3) < Daytime frequency 2.6 ± 1.0 (3: 2 3) 2.0 ± 1.1 (2: 1 3) < ± 1.1 (3: 2 3) 1.8 ± 1.1 (2: 1 3) < ± 1.1 (2: 2 3) 1.7 ± 1.1 (1: 1 2) < ± 0.8 (3: 3 4) 2.0 ± 1.0 (2: 1 3) < ± 1.1 (2: 1 3) 1.6 ± 1.0 (2: 1 2) < ± 1.0 (3: 2 4) 2.3 ± 1.1 (2: 1 3) < BII (n = 166) discomfort 1.9 ± 0.9 (2: 1 3) 1.2 ± 0.8 (1: 1 2) < ± 1.0 (2: 1 2) 1.2 ± 0.9 (1: 1 2) < ± 0.9 (2: 1 3) 1.2 ± 0.9 (1: 1 2) < Time kept from usual activities 1.1 ± 1.2 (1: 0 2) 0.6 ± 0.9 (0: 0 1) < BII total 6.8 ± 3.8 (7: 4 9) 4.2 ± 3.2 (4: 2 6) < Data presented as mean ± standard deviation (median: 25 75th percentile) *Wilcoxon s signed-ranks test. BII, benign prostatic hyperplasia impact index; QOL, quality of life. were administered tamsulosin at 0.2 mg/day for 4 weeks, which was the standard dose approved in Japan. Prostate volume was measured by transabdominal ultrasonography. Exclusion criteria were as follows: (i) concomitant other lower urinary tract disorders such as prostate cancer, bladder tumor, bladder calculus, prostatitis, urethral structure, etc.; (ii) active urinary tract infection; (iii) neurogenic bladder; (iv) serious cardiac depression, cardiovascular accident, hepatic dysfunction, or renal dysfunction; (v) hypersensitivity to tamsulosin; and (vi) use of a therapeutic agent that affects lower urinary tract function within 1 week of starting tamsulosin treatment in this study. Concomitant use of the following agents that might affect lower urinary tract function were prohibited: hormonal agents, α- orβ-adrenoceptor antagonists, anticholinergics, cholinergic agonists, and antidepressants. At baseline and after a 4-week administration of tamsulosin, subjective symptoms, patients bother from the symptoms, and impact of symptoms on patients QOL were assessed by self-administered questionnaires. Subjective symptoms were assessed using IPSS, and QOL was evaluated using IPSS-QOL and BPH impact index (BII). 9 Japanese versions of IPSS, IPSS-QOL, and BII had been psychometrically validated. 10 Patients bother was assessed by a face-scale questionnaire based on IPSS; each item of IPSS was rated from 0 to 4 using a face scale (Appendix). The questionnaire was conceived to measure patients bother corresponding to each symptom included in IPSS, although not psychometrically validated. The score data for questionnaires were presented as means (standard deviation [SD]) (median: 25 75th percentile) (Table 1). The changes in scores between baseline and post-administration of tamsulosin were analyzed using a stratified Wilcoxon s signed-rank test. All tests were two-sided, and P-values less than 0.05 were considered statistically significant. In addition to the assessment of subjective symptoms, bother, and QOL, a path analysis was conducted to explore the key symptoms that affect QOL. The outline of the model is illustrated in Figure 1. In the path analysis, after bother and BII scores were determined for each item of IPSS and IPSS-QOL before and after a 4-week treatment with tamsulosin hydrochloride, an analysis was performed using a structural equation model (SEM) 11,12 based on the following assumptions and with adjustment for background factors such as prostate volume (as its objective finding) and medical history: (i) the frequency of each symptom has a direct effect on bother of the corresponding symptom; (ii) bother of each symptom has a direct effect on the four BII items; (iii) the QOL score is directly affected by the four BII items; and (iv) the baseline severity of each symptom has a direct effect on the post-treatment severity of the corresponding subjective symptom. It was assumed that there is error correlation among the four BII items, although the details are omitted. Estimation was made via the maximum likelihood method using Amos 7.0 (IBM Corporation, Armonk, NY, USA). To test model fit, we used goodness-of-fit index, and calculated the appropriate sample size based

3 Correlation among LUTS, Bother, and QOL 47 Before Treatment After Treatment QOL BPH Impact Index Time kept from Usual Activities Bother score IPSS Symptom IPSS Symptom Bother score BPH Impact Index Time kept from Usual Activities QOL Fig. 1 Outline of the model. In the path analysis, an analysis was performed using a structural equation model after bother and benign prostatic hyperplasia (BPH) impact index scores were determined for each item of international prostate symptom scores (IPSS) and IPSS-quality of life (QOL) score before and after treatment. The paths between observed variables were set as follows: boxes represent observed variables; and arrows represent direct effects (correlations among error variables and among explanatory variables are not illustrated in this figure). on this goodness-of-fit index. The sample size to get the appropriate value of RMSA (Root Mean Square Error of Approximation) <0.08 was calculated to be 157 patients. 3. RESULTS Fifty-nine patients were excluded from the initial group of 257, and the remaining 198 patients were included in the analysis. Reasons for exclusion were as follows: 21 patients did not have a second visit after tamsulosin administration; 15 did not satisfy the selection criteria; 6 patients did not satisfy the medication period; 7 patients had prohibited concomitant drugs; 6 discontinued tamsulosin because of adverse events; and 4 patients lacked data on their questionnaires. Mean age of the analyzed patients was 68.3 years (SD: 8.6; median: 70; 25 75th percentile: 63 73), and mean prostate volume was 33.6 ml (SD: 33.6; median: 31.1; 25 75th percentile: ). The scores for each item in IPSS and IPSS bother questionnaire at baseline and after tamsulosin treatment are shown in Table 1. The evaluation of pretreatment IPSS yielded the highest score for slow stream, followed by increased daytime frequency. LUTS with the highest bother score was for slow stream, followed by nocturia. For slow stream, both IPSS and bother scores were highest. Dissociations were observed between IPSS and bother scores in both urgency and nocturia. The score of each item in BII is listed in Table 1. Although high scores were observed in items of physical discomfort and bothersomeness, the score in time kept from usual activities was lower than for other items. After tamsulosin treatment, mean total IPSS significantly decreased from 17.7 to Scores of all items of IPSS and IPSS bother score also demonstrated significant decreases (Table 1). BII total score, IPSS-QOL score, and scores of all items of BII demonstrated significant decreases (Table 1). For 163 patients with all data available, path analysis was performed to determine LUTS that may affect QOL. For all symptoms, the regression coefficient of frequency on the bother score was significant and positive both before and after treatment, indicating a natural tendency that higher frequency of subjective symptoms was associated with greater bother. The goodness-of-fit indices are shown in Table 2. The standardized regression coefficients of bother on QOL are shown in Figure 2. Both before and after treatment, physical discomfort and bothersomeness were TABLE 2. Goodness-of-fit indices CFI RMSEA Chi-squared Degrees of freedom AIC Model The CFI of model are around 0.87, which is just under the desirable value 0.9, but this value is considered to be acceptable because the RMSEAs are under AIC, akaike s information criterion; CFI, comparative fit index; RMSEA, root mean square error of approximation.

4 48 Momokazu Gotoh et al. (a) I- I-PSS Bother score score BII Daytime Frequency * * * * * * ** QOL Index * Time kept from Usual Activities (b) I- I-PSS Bother Bother score score BII BII Daytime Frequency * * * * * * ** * * ** * * ** * * * QOL Index * * * Time kept from Usual Activities Fig. 2 Path diagram. The standardized regression coefficients of bother (international prostate symptom scores [IPSS] bother score) and quality of life (QOL) (benign prostatic hyperplasia impact index [BII], IPSS-QOL index) are shown in the path diagram for (a) pre- and (b) post-treatment. discomfort, bothersomeness and worry about of BII items have a significant effect on QOL index after treatment. According to the standardized regression coefficient of bother on BII, feeling of incomplete, urgency and slow stream significantly affect the BII items. P < 0.05, P < influential on the QOL score. In addition to physical discomfort and bothersomeness, worry about had a significant effect after treatment, showing that the BII items that affected QOL were physical discomfort, worry about, and bothersomeness. The R 2 value was lower at baseline (0.24) than after treatment (0.4). This may have been because subjects were screened with a certain level of IPSS at baseline (cut-off effect). As for the standardized regression coefficient of bother on BII, feeling of incomplete, urgency, and slow stream significantly affected the BII items. In addition, the effect of nocturia on bothersomeness could not be ignored, although not significant at a level of 5% (P = 6%). At baseline, feeling of incomplete significantly affected physical discomfort and bothersomeness, both of which were most influential on IPSS. Consequently, three LUTS, namely, feeling of incomplete

5 Correlation among LUTS, Bother, and QOL 49, urgency, and slow stream, were found to affect QOL. 4. DISCUSSION Assessment of symptom and bother at baseline demonstrated that slow stream was associated with high IPSS and bother scores. In contrast, dissociation between IPSS and bother scores was observed in nocturia and urgency. This is consistent with the report by Yoshida et al. that slow stream and nocturia were frequent symptoms (IPSS), and that dissociation between IPSS and bother scores was observed in nocturia and urgency. 13 For nocturia and urgency associated with the dissociation between IPSS and bother scores, it may be necessary to assess not only the frequency of symptoms (IPSS) but also the degree of distress, such as the bother score, to make an adequate decision in selecting treatment options and evaluating therapeutic efficacy. After treatment with tamsulosin, total and individual IPSS, total and individual bother scores, total and individual BII scores, and IPSS-QOL score were significantly improved (Table 1). Even for nocturia and urgency associated with the dissociation between IPSS and bother scores, both scores were significantly improved, suggesting that tamsulosin improved not only the frequency of symptoms but also the degree of distress, which contributed to improvement in QOL. In the present study, treatment efficacy was measured after a rather short administration period of 4 weeks, which might be open to criticism. However, it has recently been well known that α1-blocker works as quickly as a few days and its efficacy is evident by 4 weeks. The path analysis revealed that three BII items physical discomfort, worry about, and bothersomeness affected QOL after treatment. The remaining BII item, time kept from usual activities, which posed no problem in BPH patients with low scores at baseline, did not significantly affect QOL. BII items like physical discomfort, worry about, and bothersomeness were affected by the bother score for feeling of incomplete, urgency, and slow stream. Although it has been commonly reported that urgency and slow stream negatively affect patients QOL, 14,15 few studies have investigated the impact of feeling of incomplete voiding on QOL. The symptom of feeling of incomplete voiding used to be included in the voiding symptoms; however, this symptom was regarded as a post-micturition symptom, which was newly categorized in the new terminology on lower urinary tract function reported by the International Continence Society in Interestingly, the BII score was closely correlated with post-micturition symptoms, storage symptoms, and voiding symptoms, which are three subgroups of LUTS. These findings suggest that feeling of incomplete voiding, the newly categorized postmicturition symptom, needs to be further investigated for its impact on bother and QOL of patients. In contrast, intermittency was negatively correlated with the BII item of bothersomeness. This may have been because the effect of improvement in other symptoms was greater than that in intermittency, rather than improvement in intermittency reducing the QOL. At baseline, the path analysis showed that QOL was affected by two BII items, namely, physical discomfort and bothersomeness, which in turn were affected by the bother score for feeling of incomplete. The degree of freedom adjusted R 2, which represents the goodness-of-fit indices was lower at baseline than after treatment. This may be explained by the cut-off effect resulting from screening of subjects with an IPSS of 8 and an IPSS-QOL score of 2. In the present study, BII score-based path analysis did not identify nocturia as a factor affecting QOL. However, there have been many reports that nocturia exerts a negative impact on QOL in a variety of domains of daily life. 17,18 BII did not include susceptible domains that were affected by the presence of nocturia; this might be the reason that nocturia did not show a strong correlation to QOL in the present study. -specific questionnaires such as nocturia quality of life, rather than BII, should therefore have been used to evaluate the effect of nocturia on QOL. In conclusion, the BII-score path analysis revealed that the LUTS affecting QOL were feeling of incomplete, urgency, and slow stream, which were typical post-micturition, storage, and voiding symptoms, respectively. Tamsulosin improved the three voiding, storage, and post-micturition symptoms in a balanced manner, thereby leading to improvement in BII and QOL. In the assessment of QOL in patients with diseases such as BPH, it may be important to assess not only the frequency of symptoms but also the degree of distress from a multilateral perspective, that is, to assess the patient-reported outcomes Disclosure There are no financial or commercial interests for the authors of the present paper. REFERENCES 1. Irwin DE, Milsom I, Hunsker S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006; 50: Sexton CC, Coyne KS, Vats V, Kopp ZS, Irwin DE, Wagner TH. Impact of overactive bladder on work productivity in the United States: results from EpiLUTS. Am J Manag Care 2009; 15: S Robert G, Descazeaud A, Azzouzi R et al. Impact of lower urinary tract symptoms on discomfort in men aged between 50and80years. Urol Int 2010; 84: Coyne KS, Wein AJ, Tubaro A et al. 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