Silodosin versus naftopidil for the treatment of benign prostatic hyperplasia: A multicenter randomized trial

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1 The study protocol was approved by the ethics committee and institutional review board of Nihon University School of Medicine. Written informed consent was obtained from all patients. From December 2007 to November 2010, a total of 109 BPH patients with aged 50 years or more were enrolled into the study. Inclusion criteria included significant LUTS and deteriorated QOL, with IPSS of 8 or more and its QOL score of 3 or more. The patients were randomly assigned to receive silodosin (8 mg/day, n = 58) or naftopidil (75 mg/day, n = 51) using a random number table envelope method. Exclusion criteria included estabbs_bs_banner International Journal of Urology (2013) 20, doi: /iju Short Communication Silodosin versus naftopidil for the treatment of benign prostatic hyperplasia: A multicenter randomized trial Kenya Yamaguchi, 1,2 Yutaka Aoki, 2 Tetsuo Yoshikawa, 2 Takahiko Hachiya, 2 Tadanori Saito 2 and Satoru Takahashi 1,2 1 Department of Urology, Nihon University School of Medicine, Tokyo, and 2 Sakura Clinical Study Group, Tokyo, Japan Abbreviations & Acronyms BPH = benign prostatic hyperplasia IIEF = International Index of Erectile Function IPSS = International Prostate Symptom Score LOCF = last observation carried forward LUTS = lower urinary tract PSA = prostate-specific antigen PVR = postvoid residual Qmax = peak urinary flow QOL = quality of life Correspondence: Satoru Takahashi M.D., Department of Urology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo , Japan. takahashi.satoru@nihon-u.ac.jp Received 8 September 2012; accepted 10 March Online publication 3 June 2013 Abstract: This was a multicenter randomized trial to investigate the clinical efficacy and the impact on sexual function of alpha-1a selective silodosin and alpha-1d selective naftopidil for treatment of benign prostatic hyperplasia. A total of 97 patients with lower urinary tract /benign prostatic hyperplasia who had an International Prostate Symptom Score of 8 or more were randomly assigned to receive silodosin (8 mg/day, n = 53) or naftopidil (75 mg/day, n = 44). Before and 4, 8 and 12 weeks after treatment, International Prostate Symptom Score and its quality of life score were used to assess lower urinary tract. Also, International Index of Erectile Function-5, and an original questionnaire were used to evaluate erectile function and ejaculation for sexually active patients, respectively. The silodosin group showed advantages in terms of voiding and quality of life of International Prostate Symptom Score when compared with the naftopidil group. Both silodosin and naftopidil showed no significant effect on International Index of Erectile Function-5. A total of 23 sexually active patients in the silodosin group experienced more ejaculatory impairment than 21 patients in the naftopidil group, with a decrease of ejaculation volume (87% vs 40%, P = 0.003), prolonged time to ejaculation (56% vs 33%, P = 0.027) and decrease of orgasm (50% vs 39%, P = 0.027). These results suggest that alpha-1a selective blockers are more effective for voiding, whereas alpha-1d selective blockers offer a minor degree of ejaculatory dysfunction. Key words: alpha-1 adrenoreceptor subtypes, alpha-1 blockers, benign prostatic hyperplasia, ejaculation, sexual function. Introduction One of the adverse events in the use of alpha-1 blockers is ejaculatory disorder. Alpha-1 blockers differ in their likelihood of causing abnormal ejaculation. Alpha-1A selective blockers can result in reduced or absent seminal emission through inhibition of smooth muscle contraction. 1 An alpha-1 blocker, silodosin, is 162-fold more selective for alpha-1a than for alpha-1b, and is approximately 55-fold more selective for alpha-1a than for alpha-1d. 2 In contrast, naftopidil is an alpha-1d selective blocker, which has been recently reported to be less likely to induce ejaculatory disorders. 3 To investigate clinical efficacies and impacts on sexual function of these alpha-1 blockers in patients with BPH, we carried out a multicenter randomized trial. Methods The Japanese Urological Association

2 Silodosin vs naftopidil for BPH Table 1 Patient characteristics Silodosin group (n = 53) Naftopidil group (n = 44) P-value Age (years) Prostate volume (ml) PSA value Total IPSS Voiding symptom Storage symptom QOL index Qmax (ml/s) PVR (ml) Sexually active cases (n = 23) Sexually active cases (n = 21) IIEF Total ejaculation score Variables were summarized using the mean and standard deviation. lished prostate cancer, neurogenic bladder and any other complications that affect micturitional status. Patients who underwent prostate surgery, intervention or radiation therapy were also excluded. Out of 109 cases, 12 cases (5 cases of silodosin group and 7 cases of naftopidil group) dropped out of the study. The reasons for dropout were: the patient withdrew by their own decision in 10 and data missing after enrolment in two. Therefore, we analyzed 97 cases (53 cases of silodosin group and 44 cases of naftopidil group). Evaluated parameters included IPSS, QOL, Qmax (ml/s) and PVR (ml). The voiding included feeling of incomplete emptying, intermittency, slow stream and straining of the IPSS, whereas the storage included frequency, urgency and nocturia. For the evaluation of sexual function, we used the IIEF-5 and an original questionnaire of ejaculatory function. We considered patients who experienced at least one time of ejaculation as sexually active. The original questionnaire consisted of four questions, regarding ejaculation volume, time to ejaculation, orgasm and satisfaction (Appendix I). We collected information from questionnaires before treatment, and 4, 8 and 12 weeks after treatment, and measured the Qmax and PVR of each patient before and 12 weeks after treatment. Statistical analysis Some evaluations included cases where the LOCF imputation technique was used; that is, cases with a missing value that was replaced with the most recent valid non-missing value. The Wilcoxon test was used to evaluate changes of the scores and objective parameters between the two points of assessment (before vs 4, 8, 12 weeks) in each group. The Mann Whitney test was carried out to evaluate intergroup differences in changes from the baseline of the scores and parameters. P-values <0.05 were considered statistically significant and analyses were carried out using SPSS version 6 (IBM, Armonk, NY, USA). Results The patient characteristics are summarized in Table 1. Before treatment, 44% (n = 23) of patients taking silodosin and 47% (n = 21) of patients taking naftopidil were sexually active. No parameter showed a significant difference between the silodosin and naftopidil groups in the assessments before treatment. Efficacies of silodosin and naftopidil on LUTS Both silodosin and naftopidil significantly improved total IPSS and QOL at 4, 8 and 12 weeks after treatment (Table 2). At 12 weeks after administration, changes from the baseline of voiding and QOL in the silodosin group were significantly larger than those in the naftopidil group (Fig. 1a; P = 0014 and P = 0.023, respectively). In contrast, changes from the baseline of storage in IPSS of the naftopidil group tended to be larger than those in the silodosin group. However, they did not reach a statistical significance (Fig. 1a). Significant Qmax and PVR improvements were observed 12 weeks after treatment in both groups without intergroup differences (Table 3). Impacts of silodosin and naftopidil on sexual function At 12 weeks, 23 sexually active patients in the silodosin group showed a significant decrease from the baseline in every question of the IIEF-5 except that of confidence (from P > 0.03 to P > 0.001). When defining a decrease of 25% or 2013 The Japanese Urological Association 1235

3 K YAMAGUCHI ET AL. Table 2 Changes of total IPSS and QOL Before 4 Weeks 8 Weeks 12 Weeks P-value P-value P-value Silodosin n = 53 n = 48 n = 41 Naftopidil n = 44 n = 42 n = 38 Total IPSS silodosin naftopidil QOL Silodosin Naftopidil P-values are for the comparison versus before treatment. (a) 0% Total IPSS Voiding Storage QOL Table 3 Changes of total Qmax and PVR Before 12 Weeks P-value 20% 40% 60% P = P = P = 0.36 P = Qmax Silodosin Naftopidil <0.01 PVR Silodosin Naftopidil (b) 20% 0% 20% 40% 60% 80% Volume Time Orgasm Satisfaction P = P = P = P = 0.53 Fig. 1 (a) Changes in total IPSS, voiding, storage and QOL at 12 weeks after treatment (P = 0.014, 0.023). (b) Changes in ejaculation scores at LOCF (P = 0.003, 0.027, 0.027)., Silodosin;, naftopidil. more as deterioration, 4 all of these questions had deteriorated. In the naftopidil group, 21 sexually active patients showed a significant decrease from the baseline in every question of the IIEF-5 except for that of maintenance and completion (from P > 0.03 to P > 0.001). However, all decreases were smaller than 25% of baseline. Intergroup differences were not significant for changes from the baseline of each question (from P = 0.48 to P = 0.55). A significant impairment of ejaculation score was observed during the study period in the silodosin group. Self-assessed ejaculation volume, time to ejaculation, orgasm and satisfaction had all significantly deteriorated at 4, 8 and 12 weeks after treatment in the silodosin group (Table 4). At LOCF, the changes from baseline of volume, time and orgasm had deteriorated more in the silodosin group than in the naftopidil group (Fig. 1b; P = 0.003, 0.027, 0.027). Regarding the loss of ejaculation, 45% of sexually active 23 patients in the silodosin group replied that their ejaculation was lost at LOCF. In contrast, 8% of the 21 patients in the naftopidil group lost ejaculation. Discussion Accumulated knowledge of alpha-adrenoceptor subtypes led to the development of alpha-1 blockers that are more selective to prostatic smooth muscle, such as tamsulosin, which have fewer undesirable effects on the cardiovascular system. 5,6 As for the other adverse events, ejaculatory disorder occurred in 4.5% with tamsulosin, 0.3% with terazosin and 0% with alfuzosin. 7 The etiology has been reported to be retrograde ejaculation. 7 However, Hisasue et al. recently carried out a real-time observation of ejaculation using color Doppler ultrasound, and reported that the ejaculatory disorder induced by alpha-1 blocker is not retrograde ejaculation, but emission failure. 1 The effect of alpha-1 blockers on erectile function is still a controversial issue Demir et al. showed the effectiveness of doxazocin for LUTS patients with erectile dysfunction, and Yokoyama et al. reported an improvement of the The Japanese Urological Association

4 Silodosin vs naftopidil for BPH Table 4 Changes of ejaculation scores Before 4 Weeks 8 Weeks 12 Weeks P-value P-value P-value Silodosin n = 53 n = 48 n = 41 Naftopidil n = 44 n = 42 n = 38 Volume Silodosin Naftopidil Time Silodosin <0.001 <0.001 Naftopidil Orgasm Silodosin Naftopidil Satisfaction Silodosin < Naftopidil Total Silodosin Naftopidil P-values are for the comparison versus before treatment. IIEF-5 in patients receiving naftopidil treatment. 8,9 However, Chen observed no effect of tamsulosin for domains of the IIEF Similarly, we observed no improvement of the IIEF-5 for both naftopidil or silodosin treatment. Although intergroup differences of the two drugs were not evident, each IIEF-5 question, except for that of confidence, had obviously deteriorated in the silodosin group. It is possible that prolonged ejaculation time affected questions in the IIEF-5. There are a few questionnaires for ejaculatory function Shimizu et al. evaluated ejaculatory function by three questions including quality of orgasm, the number of the bulbocavernosus/pelvic muscle contraction and the amount of semen. 13 As their questionnaire is for healthy volunteers, it might not be fit for clinical use. Rosen et al. addressed a validated questionnaire of four questions that are very similar to ours. 12 They consist of volume, force, cum and bother, whereas ours consist of volume, time, orgasm and satisfaction. To date, there are no established questionnaires. Therefore, we should be prudent when using the original questionnaire without validation. As the results we obtained clearly identified a deterioration of ejaculatory function in patients taking silodosin, we should pay attention to this adverse event when prescribing alpha-1 blockers. When prescribing this drug for patients with voiding difficulty, it is necessary to obtain adequate consent for adverse events, especially in relation to ejaculation. Recent reports suggested that the efficacy of silodosin for voiding function is parallel to the degree of ejaculation disorder; that is, better efficacy is associated with worse ejaculation status. 14,15 We observed a similar tendency of each effect at LOCF, unless it did not attain statistical significance (P = 0.06). Further studies are warranted to identify the impacts of various alpha-1 blockers on sexual function. Conclusions The efficacy of the alpha-1a selective blocker, silodosin, on LUTS has advantages in relation to voiding and QOL of IPSS, whereas alpha-1d selective blockers cause a minor degree of ejaculatory dysfunction. Acknowledgments The Sakura Clinical Study Group includes the following institutions: Akiru Municipal Medical Center, Chigasaki Tokusyukai General Hospital, Higashimatsuyama Municipal Hospital, Itabashiku Ishikai Hospital, Kasukabe Municipal Hospital, Kawaguchi Municipal Medical Center, Nichidai Itabashi Hospital, Nichidai Nerima Hikarigaoka 2013 The Japanese Urological Association 1237

5 K YAMAGUCHI ET AL. Hospital, Surugadai Nichidai Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation Toshima Hospital, Tokyo Rinkai Hospital and Yokohama Central Hospital. Conflict of interest None declared. References 1 Hisasue S, Furuya R, Itoh N, Kobayashi K, Furuya S, Tsukamoto T. Ejaculatory disorder caused by alpha-1 adrenoceptor antagonists is not retrograde ejaculation but a loss of seminal emission. Int. J. Urol. 2006; 13: Kaplan SA. Side effects of alpha-blocker use: retrograde ejaculation. Rev. Urol. 2009; 11: S Takei R, Ikegaki I, Shibata K, Tsujimoto G, Asano T. Naftopidil, a novel alpha1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human alpha1-adrenoceptors. Jpn. J. Pharmacol. 1999; 79: Homma Y, Kawabe K, Tsukamoto T et al. Estimate criteria for efficacy of treatment in benign prostatic hyperplasia. Int. J. Urol. 1996; 3: Takenaka T, Fujikura T, Honda K, Asano M, Niigata K. Discovery and development of tamsulosin hydrochloride, a new alpha 1-adrenoceptor antagonist. Yakugaku Zasshi 1995; 115: Furuya S, Kumamoto Y, Yokoyama E, Tsukamoto T, Izumi T, Abiko Y. Alpha-adrenergic activity and urethral pressure in prostatic zone in benign prostatic hypertrophy. J. Urol. 1982; 128: Debruyne FM. Alpha blockers: are all created equal? Urology 2000; 56: Demir O, Ozdemir I, Bozkurt O, Aslan G, Esen AA. The effect of alpha-blocker therapy on erectile functions in patients with lower urinary tract due to benign prostate hyperplasia. Asian J. Androl. 2009; 11: Yokoyama T, Hara R, Fukumoto K et al. Effects of three types of alpha-1 adrenoceptor blocker on lower urinary tract and sexual function in males with benign prostatic hyperplasia. Int. J. Urol. 2011; 18: Chen Y, Wu X, Liu J, Tang W, Zhao T, Zhang J. Effects of a 6-month course of tamsulosin for chronic prostatitis/chronic pelvic pain syndrome: a multicenter, randomized trial. WorldJ.Urol.2011; 29: Ponholzer A, Madersbacher S. Lower urinary tract and erectile dysfunction; links for diagnosis, management and treatment. Int. J. Impot. Res. 2007; 19: Rosen RC, Catania JA, Althof SE et al. Development and validation of four-item version of Male Sexual Health Questionnaire to assess ejaculatory dysfunction. Urology 2007; 69: Shimizu F, Taguri M, Harada Y, Matsuyama Y, Sase K, Fujime M. Impact of dry ejaculation caused by highly selective alpha1a-blocker: randomized, double-blind, placebo-controlled crossover pilot study in healthy volunteer men. J. Sex. Med. 2010; 7: Homma Y, Kawabe K, Takeda M, Yoshida M. Ejaculation disorder is associated with increased efficacy of silodosin for benign prostatic hyperplasia. Urology 2010; 76: Roehrborn CG, Kaplan SA, Lepor H, Volinn W. Symptomatic and urodynamic responses in patients with reduced or no seminal emission during silodosin treatment for LUTS and BPH. Prostate Cancer Prostatic Dis. 2011; 14: Appendix I: Original index of ejaculation Over the past 4 weeks: Question Score How much was the amount Absence of ejaculation Decreased Fairly decreased Same as usual Fairly increased Increased of ejaculation volume? 2. How long was the time to Absence of ejaculation Prolonged Fairly prolonged Same as usual Fairly shortened Shortened ejaculation? 3. How was the orgasm? Absence of orgasm Decreased Fairly decreased Same as usual Fairly increased Increased 4. How satisfied with your ejaculation? Very dissatisfied Dissatisfied Fairly dissatisfied Mixed about equally satisfied and dissatisfied Fairly satisfied Satisfied Very satisfied The original index for evaluation of ejaculation consists of four questions regarding ejaculatory volume, time required for ejaculating, orgasm and satisfaction. The lowest sum is 0 and indicates the poorest status of ejaculation, whereas the highest sum is 21 and indicates the best status of it The Japanese Urological Association