Tadalafil 5 mg Once Daily Improves Lower Urinary Tract Symptoms and Erectile Dysfunction: A Systematic Review and Meta-analysis

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1 LUTS (2018) 10, ORIGINAL ARTICLE Tadalafil 5 mg Once Daily Improves Lower Urinary Tract Symptoms and Erectile Dysfunction: A Systematic Review and Meta-analysis Yilin WANG, 1 Yiping BAO, 2, Jie LIU, 1 Lijun DUAN, 1 and Yuanshan CUI 2, 1 Biochip Laboratory, Yantai Yuhuangding Hospital Affiliated to Medical College of Qingdao University, Yantai, China and 2 Department of Urology, Yantai Yuhuangding Hospital Affiliated to Medical College of Qingdao University, Yantai, China Objectives: We carried out a systematic review and meta-analysis to assess tadalafil 5 mg once-daily for the treatment of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). Methods: A literature review was performed to identify all published randomized double-blind, placebo-controlled trials of tadalafil 5 mg once-daily for the treatment of LUTS and ED. The search included the following databases: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. Results: Thirteen publications involving a total of 3973 patients were used in the analysis, including 13 RCTs that compared tadalafil 5 mg once-daily with placebo. We found that tadalafil 5 mg once-daily was effective in improving LUTS suggestive of BPH and treating ED over 12 weeks in our meta-analysis. Total International Prostate Symptom Score (IPSS) (SMD = 2.02, 95% CI = 2.52 to 1.53, P < ); Benign Prostatic Hyperplasia Impact Index (BPH-II) (SMD = 0.58, 95% CI = 0.84 to 0.33, P < ); International Index of Erectile Function-erectile function (IIEF) domain (standardized mean difference [SMD] = 5.18, 95% confidence interval [CI] = , P < ) indicated that tadalafil 5 mg once-daily was more effective than the placebo. Safety assessments included discontinuations due to adverse event (odds ratio (OR) = 1.79, 95% CI = , P = 0.01) indicated that tadalafil 5 mg once-daily was well tolerated. Conclusions: This meta-analysis indicates that tadalafil 5 mg once-daily to be an effective treatment for LUTS and ED with a low occurrence of side effects. Key words erectile dysfunction, lower urinary tract symptoms, meta-analysis, randomized controlled trial, tadalafil 1. INTRODUCTION Medical management of erectile dysfunction (ED) changed with the observation in 1992 that the nitric oxide-cyclic GMP pathway plays a critical role in erectile function (EF) and defects in this pathway may cause some forms of ED. 1 This observation motivated the development of oral inhibitors of phosphodiesterase type 5 (PDE5) for this indication: sildenafil, tadalafil and vardenafil. 2 4 For all three PDE5 inhibitors, men must take medication on demand before sexual activity. 5 7 While, tadalafil is rapidly absorbed after oral administration and has a longer half-life (17.5 h) than sildenafil and vardenafil. 8,9 Therefore, a once-a-day dosing regimen was developed for the treatment of ED, providing an alternative therapeutic option of continuous efficacy as opposed to as-needed dosing. 10,11 Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH), are increasingly common in aging men, including voiding symptoms, storage symptoms, and postmicturition symptoms. 15 Medical therapy for men with moderate to severe LUTS suggestive of BPH includes alpha-1 adrenergic blockers (a-blockers), or 5-alpha reductase inhibitors (5-ARIs) in men with an enlarged prostate. 16 Both drug classes are effective, but may produce unwanted side effects, including sexual dysfunction. Several clinical studies have shown that PDE5 inhibitors, including tadalafil, may improve BPH-LUTS and that adverse events are few and mostly mild to moderate in severity. 17 The goal of the present study was to perform a metaanalysis to evaluate the efficacy and safety of tadalafil 5 mg once-daily in men with LUTS and ED suggestive of BPH, which may resolve some of the current controversies over use of the drug. Correspondence: Yuanshan Cui, MD, Yuhuangding Hospital, 20 East Yuhuangding Rd., Zhifu Dist., Yantai , Shandong, P.R. China. doctorcuiys@163.com Co-first author. Received 21 January 2016; revised 10 April 2016; accepted 9 May 2016 DOI: /luts.12144

2 Tadalafil for LUTS and ED METHODS 2.1. Search strategy In order to identify randomized controlled trials (RCTs) that with respect to the impact of tadalafil 5 mg once-daily on treating LUTS suggestive of BPH and ED, we searched Medline (1966 April 2014), Cochrane Controlled Trials Register databases, Embase (1974 April 2014), as well as reference lists of the retrieved studies. Tadalafil once-daily, ED, LUTS, Randomized controlled trial were applied as the multiple search terms Inclusion criteria and trial selection Randomized controlled trials that fulfilled the following criteria were included in our study: (i) The study design included treatment with tadalafil once-daily; (ii) full text of the selected study was accessible; and (iii) a study should provide accurate data so that it could be analyzed, including the total number of subjects and the values of each given index. If an identical study was published in distinct journals or during different periods, the most recently published one was used for our meta-analysis. In addition, when the same group of researchers investigated a certain subject group with various experiments, each study was included. As shown in Figure 1, a flow diagram was drawn to illustrate the study selection process Quality assessment The quality of the retrieved RCTs was evaluated by using the Jadad scale, as previously described. 18 All the identified RCTs were included in our meta-analysis regardless of the quality score. The methodological quality for each study was evaluated based on how patients were allocated to the arms of the study, the concealment of allocation procedures, blinding, and data loss resulting from attrition. The studies were therefore classified qualitatively, following the guidelines introduced in the Cochrane Handbook for Systematic Reviews of Interventions v In the light of the quality assessment criteria, every individual study was rated and then assigned to one of the three quality categories as follows: (i) once all quality criteria were adequately fulfilled, the study was considered to carry a low risk of bias; (ii) when one or more quality criteria was merely partially met or ambiguous, the study was perceived to harbor a moderate risk of bias; or (iii) if one or more of the criteria was barely met or not included, the study was a delineation of high risk of bias. Differences were resolved by discussion among the authors Data extraction The following information should be collected for each study: (i) the regimen patients received; (ii) the study design and specimen size; (iii) the RCT name; (iv) the region where the study was conducted; and (v) data including the total International Prostate Symptom Score (IPSS), the IPSS voiding subscore (IPSS-V), the IPSS storage subscore (IPSS-S), the IPSS quality of life (QoL), the Fig. 1 A flow diagram of the study selection process. RCT, randomized controlled trial. Benign Prostatic Hyperplasia Impact Index (BPH-II), the International Index of Erectile Function-erectile function (IIEF) domain, the sexual encounter profile (SEP) question 2 (SEP2) and question 3 (SEP3), and discontinuations due to adverse event Statistical analysis and meta-analysis The meta-analysis of comparable data was performed using REVMAN V (Cochrane Collaboration, Oxford, UK). 19 Changes in the IIEF domain, the SEP2 and SEP3, the total IPSS, the IPSS-V, the IPSS-S, the IPSS QoL, the BPH-II and discontinuations due to adverse event were determined as differences between baseline (study entry) and study completion. The DerSimonian and Laird random-effects model was applied to estimate the relative risk for dichotomous outcomes and the standardized mean difference (SMD) for continuous outcomes pooled across studies, 20 and a 95% confidence interval (CI) was adopted. The studies were deemed as homogeneous if the analytic result exhibited P > 0.05, and then a fixedeffect model was used for meta-analysis. Otherwise, a random-effect model was chosen. We also quantified the inconsistency through the I 2 statistic, with which we generally describe the proportion of heterogeneity across studies that cannot be accounted for by chance, thereby illustrating the degree of true inconsistency in results across trials. 21 I 2 < 25% indicates a low extent of inconsistency whereas I 2 > 50% reflects a substantial inconsistency. 3. RESULTS 3.1. Characteristics of the individual studies The database search found 356 articles that could have been included in our meta-analysis. Based on the inclusion and exclusion criteria, 323 articles were excluded after reading the titles and abstracts of the articles. Twenty articles lacked useful data. In all, 13 articles, reporting data from a total of 13 RCTs that compared

3 86 Yilin Wang et al. TABLE 1. Study and patient characteristics Study Therapy in Therapy in Sample size experimental control group group Country Experimental Control Inclusion criteria Exclusion criteria Age Administration (median) method Porst H 2006 T P Argentina, Brazil, France, Germany, and the UK Hatzichristou D 2007 T P North America, Europe and Australia Men with at least ED caused by other 3-month history of ED. sexual or endocrine disorders Men with at least a 3-month history of Type 1 or Type 2 diabetes and ED. Rajfer J 2007 T P USA Men with a minimum 3-month history of ED. Porst H 2009 T P Ten countries including UK Rubio-Aurioles E 2009 T P Austria, France, Germany, Mexico, and the US Montorsi F 2011 T P Italy, Spain, Greece, Germany and US Giuliano F 2013 T P Australia, Austria, Belgium, France, Germany, Greece, Italy, Mexico, Netherlands, and Poland Roehrborn CG Men at least 45 years old with a history of LUTS of 6 months or longer Men with at least a 3-month history of ED Men with at least a 3-month history of ED Men at least 45 years old who had had LUTS/BPH for >6 month. T P 10 countries Men at least 45 years old with a history of LUTS of 6 months or longer. Porst H 2011 T P Argentina, Germany, Italy, Mexico, and the US Egerdie RB 2012 T P Fifty-four urology sites in nine countries Oelke M 2012 T P Australia, Austria, Belgium, France, Germany, Greece, Italy, Mexico, The Netherlands, and Poland Yokoyama O 2013 T P Japanese, Korean, and Taiwan Men at least 45 years old who had had LUTS/BPH for >6 month Men at least 45 years old who had BPH-LUTS for >6 months Men at least 45 years old who had had LUTS/BPH for >6 month Men at least 45 years old who had had LUTS/BPH. Takeda M 2014 T P Japan and Korea Asian men at least 45 years old who had had LUTS/BPH. ED caused by pelvic surgery history. ED caused by untreated endocrine disease. ED caused by pelvic surgery history. ED caused by other primary sexual disorders or pelvic surgery history. ED caused by other sexual or endocrine disorders or pelvic surgery history. PSA >10.0 ng/ml or a PVR 300 ml at screening. Who received finasteride or dutasteride within 3 and 12 months. PSA >10.0 ng/ml or a PVR 300 ml at screening. Histological confirmation of BPH. PSA >10.0 ng/ml or a PVR 300 ml at screening. PSA >10.0 ng/ml and PVR 300 ml. PSA >10.0 ng/ml and PVR 300 ml mg once-daily 57 5 mg once-daily mg once-daily mg once-daily mg once-daily 52 5 mg once-daily 63 5 mg once-daily mg once-daily mg once-daily mg once-daily mg once-daily 63 5 mg once-daily mg once-daily BPH, benign prostatic hyperplasia; ED, erectile dysfunction; LUTS, Lower Urinary Tract Symptoms; P, placebo; PSA, prostate-specific antigen; PVR, postvoid residual volume; T, tadalafil. tadalafil 5 mg once-daily with placebo, were included in the analysis (Fig. 1). The baseline characteristics of the studies included in our meta-analysis are listed in Table Quality of the individual studies All 13 RCTs were double blinded, and all described the randomization processes that they had used. All included a power calculation to determine the optimal sample size (Table 2). The level of quality for the individual identified study was A (Table 2). The funnel plot provided a qualitative estimation of publication bias of the studies, and no evidence of bias was found (Fig. 2) Efficacy The total IPSS Seven of the RCTs included the total IPSS improvement data representing a cohort of 2651 participants (1330 in the tadalafil 5 mg once-daily group and 1321 in the control group) (Fig. 3). The fixed-effects estimate of the SMD was 2.02, and the 95% CI was 2.52 to 1.53 (P < ). This result suggests that tadalafil

4 Tadalafil for LUTS and ED 87 TABLE 2. Quality assessment of individual study Study Allocation sequence generation Allocation concealment Blinding Loss to follow-up Calculation of sample size Statistical analysis intention-to-treat analysis Level of quality Porst H 2006 A A A 1 YES Analysis of covariance YES A Hatzichristou D 2007 A A A 7 YES Analysis of covariance NO A Rajfer J 2007 A A A 0 YES Analysis of covariance YES A Porst H 2009 A A A 3 YES Analysis of covariance YES A Rubio-Aurioles E 2009 A A A 0 YES Analysis of covariance YES A Montorsi F 2011 A A A 1 YES Analysis of covariance YES A Giuliano F 2013 A A A 3 YES Analysis of covariance NO A Roehrborn CG 2008 A A A 5 YES Analysis of covariance YES A Porst H 2011 A A A 3 YES Fed-sequence test NO A Egerdie RB 2012 A A A 4 YES Analysis of covariance YES A Oelke M 2012 A A A 3 YES Analysis of covariance YES A Yokoyama O 2013 A A A 2 YES Analysis of covariance YES A Takeda M 2014 A A A 3 YES Two-sided t-test NO A A, all quality criteria met (adequate): low risk of bias; B, one or more of the quality criteria only partly met (unclear): moderate risk of bias; C, one or more criteria not met (inadequate or not used): high risk of bias; ITT, intention-to-treat analysis. Fig. 2 Funnel plot of the studies represented in our meta-analysis. Although 13 articles are included in our study, the most articles that reported one of the indexes at the same time is 12. So 12 symbols are reported in the graph. OR, odds ratio; SE, standard error. [Colour figure can be viewed at wileyonlinelibrary.com]. 5 mg once-daily had significantly greater improvement in the total IPSS The IPSS-V Five of the RCTs included the IPPS-V improvement data representing a cohort of 2011 participants (1005 in the tadalafil 5 mg once-daily group and 1006 in the control group) (Fig. 3). The fixed-effects estimate of the SMD was 1.20, and the 95% CI was 1.57 to 0.83 (P < ). This result suggests that tadalafil 5 mg once-daily showed statistically significant improvement in the IPPS-V The IPSS-S Five of the RCTs included the IPPS-S improvement data representing a cohort of 2011 participants (1005 in the tadalafil 5 mg once-daily group and 1006 in the control group) (Fig. 3). The fixed-effects estimate of the SMD was 0.72, and the 95% CI was 0.98 to 0.47 (P < ). This result suggests that tadalafil 5 mg once-daily showed statistically significant improvement in the IPPS-S The IPSS QoL Five of the RCTs included the IPPS QoL improvement data representing a cohort of 2011 participants (1005 in the tadalafil 5 mg once-daily group and 1006 in the control group) (Fig. 3). The fixed-effects estimate of the SMD was 0.29, and the 95% CI was 0.43 to 0.16 (P < ). This result suggests that tadalafil 5 mg oncedaily showed statistically significant improvement in the IPPS QoL compared with placebo The BPH-II Five of the RCTs included the BPH-II improvement data representing a cohort of 1809 participants (907 in

5 88 Yilin Wang et al. Fig. 3 Forest plots showing changes in (a) the total IPSS, (b) the IPSS-V, (c) the IPSS-S, (d) the IPSS QoL and (e) the BPH-II in the treatment studies. BPH-II, Benign Prostatic Hyperplasia Impact Index; CI, confidence interval; IPSS, International Prostate Symptom Score; IPSS QoL, IPSS quality of life; IPSS-S, IPSS storage subscore; IPSS-V, IPSS voiding subscore; IV, inverse variance; SD, standard deviation. [Colour figure can be viewed at wileyonlinelibrary.com].

6 Tadalafil for LUTS and ED 89 Fig. 4 Forest plots showing changes in (a) the IIEF domain, (b) the SEP2 and (c) the SEP3 in the treatment studies. CI, confidence interval; IIEF, International Index of Erectile Function-erectile function; IV, inverse variance; MH, mantel haenszel; SD, standard deviation; SEP2, sexual encounter profile (SEP) question 2; SEP3, SEP question 3. [Colour figure can be viewed at wileyonlinelibrary.com]. the tadalafil 5 mg once-daily group and 902 in the control group) (Fig. 3). The fixed-effects estimate of the SMD was 0.58, and the 95% CI was 0.84 to 0.33 (P < ). This result suggests that tadalafil 5 mg once-daily showed statistically significant improvement in the BPH-II The IIEF domain Ten RCTs, representing 2711 participants (1519 in the tadalafil 5 mg once-daily group and 1192 in the control group) (Fig. 4). The heterogeneity test showed P = 0.003, so we adopted the random-effects model. Based on our

7 90 Yilin Wang et al. Fig. 5 Forest plots showing changes in discontinuation due to adverse events in the treatment studies. CI, confidence interval; MH, mantel haenszel. [Colour figure can be viewed at wileyonlinelibrary.com]. analysis, the pooled estimate of SMD was 5.18, and the 95% CI was (P < ). This result suggests that tadalafil 5 mg once-daily showed statistically significant improvement in the IIEF domain compared with placebo The SEP2 Five RCTs, representing 1111 participants (715 in the tadalafil 5 mg once-daily group and 396 in the control group) (Fig. 4). According to our analysis, no heterogeneity was found among the trials (Fig. 4), and a fixed-effects model was thus chosen for the analysis. Based on our analysis, the pooled estimate of odds ratio (OR) was 5.46, and the 95% CI was (P < ). This result suggests that tadalafil 5 mg once-daily showed statistically significantly greater improvement in the SEP 2 compared with placebo The SEP3 Six RCTs, representing 1519 participants (923 in the tadalafil 5 mg once-daily group and 596 in the control group) (Fig. 4). The heterogeneity test showed P = 0.29, so we adopted the fixed-effects model. The pooled estimate of the OR was 4.14, and the 95% CI was (P < ). This result suggests that tadalafil 5 mg once-daily showed statistically significant improvement in the SEP 3 compared with placebo Safety Discontinuations due to adverse event Thirteen RCTs, representing 3973 participants (2151 in the tadalafil 5 mg once-daily group and 1822 in the control group), included the discontinuations due to adverse event data (Fig. 5). Fixed-effects model was adopted. The pooled estimate of OR was 1.79, and the 95% CI was , P = The result suggests that tadalafil 5 mg once-daily was well tolerated. 4. DISCUSSION Erectile dysfunction and LUTS suggestive of BPH are bothersome and commonly coexist in aging men. 35 Pathophysiological links between ED and LUTS suggestive of BPH have been identified in the Multinational Survey of the Aging Male 35 and several other studies. 36,37 Gacci et al. had demonstrated a strong and consistent association between LUTS and ED, suggesting that elderly men with LUTS should be evaluated for sexual dysfunction and vice versa. Pathophysiologic hypotheses regarding common basics of LUTS and sexual dysfunction as discussed in the literature are (i) alteration of the nitric oxide (NO)-cyclic guanosine monophosphate (cgmp) pathway, (ii) enhancement of RhoA-Rho-kinase (ROCK) contractile signaling, (iii) autonomic adrenergic hyperactivity, and (iv) pelvic atherosclerosis. 38 Recently, proof-ofconcept studies have demonstrated that treatment with PDE5 inhibitors, including tadalafil, significantly improved LUTS suggestive of BPH. A recent review also suggested the use of a single daily dose of tadalafil is an effective treatment option for both LUTS and ED. 43 Given the common co-occurrence of ED and LUTS suggestive of BPH, assessing tadalafil once daily for the treatment of ED and LUTS suggestive of BPH is of clinical interest. The current study suggests that tadalafil 5 mg oncedaily is efficacious in the treatment of LUTS suggestive of BPH patients over 12 weeks who took tadalafil 5 mg once-daily showed statistically significant improvement in the total IPSS, IPSS-V, IPSS-S, IPSS QoL and BPH- II. The mean total IPSS score decreased from 4.2 to 6.3 points. Increasing evidence suggests that tadalafil mediates relief of LUTS by inhibiting PDE5 isoenzymes in pelvic tissues. 36,44 Specifically, inhibition of PDE5 in these

8 Tadalafil for LUTS and ED 91 tissues results in increased nitric oxide availability, leading to smooth muscle and vascular relaxation in the bladder neck, prostate and urethra, and consequent increases in blood perfusion and oxygenation. Afferent nerve activity in the bladder is also modulated. 36,44 Our study also reveals daily administration of tadalafil 5 mg is efficacious and well tolerated in the treatment of ED patients over 12 weeks who took tadalafil 5 mg once-daily had significant EF improvement compared with placebo as assessed by IIEF domain, SEP 2 and SEP 3. In the current study, the mean IIEF domain score increased from 4.5 to 9.7 points. Because daily dosing with tadalafil was efficacious, this regimen may provide a novel approach to ED therapy in which sexual activity need not be tied to drug administration. As reported by Hanson et al., the five measures considered most important to patients in defining success were cure, pleasure, partner satisfaction, reproduction, and naturalness. 45 Thus, taking a long-acting drug once a day may be the best way for some patients to forget their ED and be ready for spontaneous sexual activity. The safety findings from our study are consistent with those from previous tadalafil and no unexpected treatment-emergent adverse events were observed. Few participants discontinued because of adverse events (OR = 1.79, 95% CI was , P = 0.01), showing that tadalafil was generally well tolerated. The meta-analysis on the use of PDE5 inhibitors for LUTS which written by Gacci et al. 42 suggests that PDE5 inhibitors can significantly improve LUTS and erectile function in men with BPH. PDE5 inhibitors seem to be a promising treatment option for patients with LUTS secondary to BPH with or without ED for the first time. And the author highlighted several limitations of the evidence including small numbers of patients. A recent review written by Gacci et al. 43 shows that the remarkable improvement of both LUTS/BPH and ED with tadalafil 5 mg once daily suggests a leading role for this PDE5 inhibitors treatment for men with comorbid BPH and ED. As a result of the wide uptake of PDE5 inhibitors, recent worldwide trends suggest that the greatest increases in expenditures for ED will be for outpatient evaluation and treatment. Cost analyses suggested that tadalafil would higher direct costs compared with sildenafil in Martin et al. s systematic review. 46 LUTS is a non-life threatening and non-painful condition, so patients willingness to pay for treatment may represent the appropriate way to demonstrate value for tadalafil. So the health economics on tadalafil 5 mg once daily for the LUTS is a potential problem, which deserves more in-depth discussion. Studies that are all findings from randomized doubleblind, placebo-controlled trials were included in this meta-analysis. Based on the quality-assessment scale we developed, the quality for each study in the metaanalysis was conformed. The results of this analysis were obtained considerably from a scientific standpoint, but also in the routine clinical practice. Moreover, there were a myriad of studies included in our meta-analysis. However, the longer term safety, efficacy, and persistence of tadalafil once-daily cannot be extrapolated from this article. Besides, the analysis excluded the data in unpublished studies. These factors may be responsible for a bias. More high-quality trials with longer duration specimens, considering the effectiveness and safety of the therapy on ED and LUTS suggestive of BPH, are expected to be further conducted. 5. CONCLUSION This meta-analysis indicates that tadalafil 5 mg oncedaily to be an effective treatment for ED and LUTS suggestive of BPH with a low occurrence of side-effects. Disclosure The authors declare no conflict of interest. REFERENCES 1. Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. NEnglJMed1992; 326: Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. NEnglJMed1998; 338: Padma-Nathan H, McMurray JG, Pullman WE. Ondemand IC351 (Cialis(trademark)) enhances erectile function in patients with erectile dysfunction. IntJImpotRes 2001; 13: Porst H, Rosen R, Padma-Nathan H. Vardenafil. A new highly selective PDE5 inhibitor, improves erectile function irrespective of the baseline severity and aetiology of ED or age of patient. Eur Urol 2001; 39: Viagra (sildenafil citrate) label. [Cited 9 Jan 2006.] Available from URL: 1s15s18lbl.pdf New York, Pfi-zer Inc Levitra (vardenafil HCl) label. [Cited 9 Jan 2006.] Available from URL: 004lbl.pdf Cialis (tadalafil) label. [Cited 9 Jan 2006.] Available from URL: bl.pdf Coward RM, Carson CC. Tadalafil in the treatment of erectile dysfunction. Ther Clin Risk Manag 2008; 4: Francis SH, Corbin JD. Molecular mechanisms and pharmacokinetics of phosphodiesterase-5 antagonists. Curr Urol Rep 2003; 4: McMahon C. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously unresponsive to ondemand tadalafil. JSexMed2004; 1: McMahon C. Comparison of efficacy, safety, and tolerability of on-demand tadalafil and daily dosed tadalafil for the treatment of erectile dysfunction. JSexMed2005; 2: Jacobsen SJ, Girman CJ, Guess HA et al. Natural history of prostatism: factors associated with discordance between frequency and bother of urinary symptoms. Urology 1993; 42: Norman RW, Nickel JC, Fish D. Prostate-related symptoms in Canadian men 50 years of age or older: prevalence and relationships among symptoms. Br J Urol 1994; 74: Sagnier PP, MacFarlane G, Teillac P, Botto H, Richard F, Boyle P. Impact of symptoms of prostatism on level of bother and quality of life of men in the French community. JUrol1995; 153 (3, Pt 1): Abrams P, Cardozo L, Fall M, Standardisation Sub- Committee of the International Continence Society. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003; 61:

9 92 Yilin Wang et al. 16. Guideline on the Management of Benign Prostatic Hyperplasia (BPH). American Urological Association Web site. [Cited July 2011.] Available from URL: guidelines-and-quality-care/clinical-guidelines/mainreports/bph-management/chap_1_guidelinemanagementof (BPH).pdf. Updated McVary KT, Roehrborn CG, Kaminetsky JC et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. JUrol2007; 177: Jadad AR. Randomised Controlled Trials. London: BMJ Publishing Group, Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions, v.5.1 [updated March 2011]. Cochrane Collaboration Web site. Cochrane Collaboration. Available from URL: DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: Porst H, Giuliano F, Glina S et al. Evaluation of the efficacy and safety of once-a-day dosing of tadalafil 5 mg and 10 mg in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol 2006; 50: Hatzichristou D, Gambla M, Rubio-Aurioles E et al. Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction. Diabet Med 2008; 25: Rajfer J, Aliotta PJ, Steidle CP, Fitch WR, Zhao Y, Yu A. Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US. IntJImpotRes2007; 19: Porst H, McVary KT, Montorsi F et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol 2009; 56: Rubio-Aurioles E, Kim ED, Rosen RC et al. Impact on erectile function and sexual quality of life of couples: a double-blind, randomized, placebo-controlled trial of tadalafil taken once daily. JSexMed2009; 6: Montorsi F, Aversa A, Moncada I et al. A randomized, double-blind, placebo-controlled, parallel study to assess the efficacy and safety of once-a-day tadalafil in men with erectile dysfunction who are naive to PDE5 inhibitors. JSexMed 2011; 8: Giuliano F, Oelke M, Jungwirth A et al. Tadalafil once daily improves ejaculatory function, erectile function, and sexual satisfaction in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia and erectile dysfunction: results from a randomized, placebo- and tamsulosin-controlled, 12-week double-blind study. JSex Med 2013; 10: Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. JUrol2008; 180: Porst H, Kim ED, Casabe AR et al. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol 2011; 60: Egerdie RB, Auerbach S, Roehrborn CG. Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study. JSexMed2012; 9: Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol 2012; 61: Yokoyama O, Yoshida M, Kim SC et al. Tadalafil once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a randomized placebo- and tamsulosincontrolled 12-week study in Asian men. Int J Urol 2013; 20: Takeda M, Yokoyama O, Lee SW. Tadalafil 5 mg oncedaily therapy for men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results from a randomized, double-blind, placebo-controlled trial carried out in Japan and Korea. Int J Urol 2014; 21(7): Rosen R, Altwein J, Boyle P et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol 2003; 44: Andersson KE, de Groat WC, McVary KT et al. Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: Pathophysiology and mechanism(s) of action. Neurourol Urodyn 2011; 30: McVary KT, McKenna KE. The relationship between erectile dysfunction and lower urinary tract symptoms: epidemiologi-cal, clinical, and basic science evidence. Curr Urol Rep 2004; 5: Gacci M, Eardley I, Giuliano F et al. Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 2011; 60: McVary KT, Monnig W, Camps JL Jr, Young JM, Tseng LJ, van den Ende G. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol 2007; 177: Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 2008; 53: Tamimi NA, Mincik I, Haughie S, Lamb J, Crossland A, Ellis P. A placebo-controlled study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia. BJU Int 2010; 106: Gacci M, Corona G, Salvi M et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 2012; 61: Gacci M, Salvi M, Sebastianelli A et al. The use of a single daily dose of tadalafil to treat signs and symptoms of benign prostatic hyperplasia and erectile dysfunction. Res Rep Urol 2013; 5: Giuliano F, Uckert S, Maggi M, Birder L, Kissel J, Viktrup L. The mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. Eur Urol 2013; 63: Hanson-Divers C, Jackson SE, Lue TF, Crawford SY, Rosen RC. Health outcomes variables important to patients in the treatment of erectile dysfunction. JUrol1998; 159: Martin AL, Huelin R, Wilson D, Foster TS, Mould JF. A systematic review assessing the economic impact of sildenafil citrate (Viagra) in the treatment of erectile dysfunction. JSex Med 2013; 10: