Research Paper. Academia Journal of Biotechnology 4(9): , September 2016 DOI: /ajb ISSN Academia Publishing

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1 Academia Journal of Biotechnology (9): 07-5, September 206 DOI: 0.5/ajb ISSN Academia Publishing Research Paper Ejaculatory Dysfunction Caused by Alpha Blockers for the Treatment of Lower Urinary Tract Symptoms in Men with Benign Prostatic Hyperplasia: A Systematic Review and Network Meta-analysis Accepted 8 th July, 206 ABSTRACT Shuangjian Jiang, Chengqiang Mo, Wei Sun 2, Zeting Qiu 2, Haiyi Long 2, Wulin Tan, Shaopeng Qiu and Xiaopeng Mao * Department of Urology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. 2 Department of Clinic Medicine, Sun Yat- Sen University Guangzhou, Guangdong, China. Department of Anesthesiology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. *Corresponding author. E- mail:60869@qq.com. Tel: (+86) ; Fax: ( ) To provide a systematic review and network meta-analysis of randomized clinical trials focus on ejaculatory dysfunction (ED) rate of alpha blockers (ABs) for treatment of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH), a systematic literature search was performed to identify all available published randomized controlled trial (RCTs) as regards ABs for the treatment in BPH patients. A systematic review and network meta-analysis was performed using ADDIS RCTs involving 2259 participants were included, comparing 2 selective ABs (silodosin and tamsulosin) and 2 unselective ABs (terazosin and doxazosin) with placebo. For the ejaculatory dysfunction rate, silodosin was higher than placebo (OR=70., 95% CI: 7.70 to 58.8), doxazosin (OR=52.82, 95% CI: 5. to 8.) and terazosin (OR=0., 95% CI: 2.7 to 62.98). And so was tamsulosin compared with placebo (OR=8.70, 95% CI: 2.6 to 59.6), doxazosin (OR=6.5, 95% CI: 0.8 to 8.) and terazosin (OR=.95, 95% CI: 0.5 to 6.75). No statistical differences were observed among doxazosin, terazosin and placebo (OR ). As such, the ranks of ejaculatory dysfunction rate were silodosin > tamsulosin > terazosin doxazosin placebo. The selective ABs were associated with higher risk of ejaculatory dysfunction while the unselective ABs have the same risk as placebo. When focusing on better sexual life, the unselective ABs like doxazosin and terazosin are better. Key words: Lower urinary tract symptom, Benign prostatic hyperplasia, Alpha()- adrenoceptor, Silodosin, Tamsulosin, Terazosin, Doxazosin, Ejaculatory dysfunction. INTRODUCTION Benign prostatic hyperplasia is a common disease in adult men that often causes lower urinary tract symptoms including storage and voiding problems (Armstrong et al., 2009). The goals of therapy for BPH are to relieve the bothering symptoms, improve the quality of life and to prevent disease progression (Bechis et al., 20). Alphablockers (ABs), 5a-reductase inhibitors (5-ARIs) and their combination therapy are widely accepted as the main medical treatment for the patients with BPH (Gratzke et al., 205) and ABs are commonly used as the first-line drugs for the medical treatment of LUTS resulting from BPH (Roehrborn and Schwinn, 200). Ejaculatory dysfunction contains premature or delayed, or an and painful (Lepor, 998). The adverse effects on sexual function for patients with BPH are getting more attention (Tuhkanen et al., 200),particularly in the ejaculatory function associated with the use of ABs (van

2 Academia Journal of Biotechnology; Jiang et al. 08 Dijk et al., 2006). Some trials and studies indicated the relationship between LUTS and sexual dysfunction (SD) through several pathogenic mechanisms, such as chronic inflammation and sex steroid ratio imbalance (Gacci et al., 20). However, a multinational survey declared that, the increasing severity of ED was with the increasing severity of LUTS. It is widely attributed to the fact that ABs are commonly used in the treatment of male LUTS and hypertension, which may lead to SD (Rosen et al., 200). Although, some RCTs generally analyzed the effect of ABs for BPH on erectile function (Jo et al., 20), there were few reports assessing the effect of those on ejaculatory function systematically. This study aims to provide a systematic review and network meta-analysis of randomized clinical trials reporting the ED rate of different ABs for the treatment of LUTS in men with BPH. MATERIALS AND METHODS Systematic Literature Search A literature search was performed in September, 205 using the PubMed, Embase, Medline, Scopus, Web of Science and Cochrane databases. The PubMed search included both free-text and MeSH protocols. Medical treatments for LUTS were identified by free-text searches with terms of prostatic hyperplasia, lower urinary tract symptoms, doxazosin, tamsulosin, terazosin and silodosin and by Mesh searches with terms of Prostatic Hyperplasia, Adrenergic alpha-antagonists, doxazosin, terazosin and tamsulosin. Free-text and MeSH searches were pooled using the OR bolean operator. ED was identified by free-text searches with terms of,, an and ejaculatory dysfunction. Free-text and MeSH searches were pooled using the OR bolean operator. Eventually, both search results were pooled using the AND bolean operator to identify papers concerning medical therapy for LUTS and ED. No limitations were used. The same free-text and Mesh search protocol was applied to the searches of Embase, Medline, Scopus, Web of Science and Cochrane databases without other limits. Recall ratio was preferred to rather than precision ratio in literature search so as to obtain targeted clinical trials systematically. Study selection Studies included in the systematic review were selected by the following inclusion criteria: (i) RCTs with duration of at least weeks; (ii) the subjects were treated by ABs for LUTS and BPH; (iii) the occurrence of ED was indicated detailedly; (iv) the full text of the study could be accessed. Only the study with the exact odds ratios (ORs), median (MD) and relative 95% confidence interval (CI) was included in this analysis. We assessed the study quality by the 5-point Jadad score and only the study with a score could be included. Data extraction The full texts were reviewed by two authors separately to select the studies relevant to the reviewed topic and discrepancies solved by open discussion. Finally, other relevant studies cited in the reference lists were evaluated, as well as, further studies published after the systematic search. Data were independently extracted from each study applying a standardized form by two reviewers and then cross-checked. The quality of the RCTs was assessed using the Jadad score (Table ). Quality assessment The Cochrane Collaboration s risk of bias assessment tool in RevMan 5. software ( was used to summarize the risk of bias containing selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias associated with the evidence for the different interventions. Each bias in each study was classified to one of the three following quality categories: (i) low risk of bias, (ii) unclear risk of bias which signifies moderate risk of bias and (iii) high risk of bias. Thereafter, sensitivity analyses were performed. On occurrence of differences, discussion was adopted by authors. Statistical analysis All calculations were performed using ADDIS.6.5 software (van Valkenhoef et al., 20). The data were analyzed with the intention-to-treat analyses if possible in order to reduce the heterogeneity between the trials. For comparisons between two interventions with both direct and indirect evidence, the inconsistency between these types of evidence were verified by the node-split analysis provided in the ADDIS software. If there was no significant inconsistency, the relative effects of the interventions were analyzed using a consistency model based on a randomeffects Bayesian model provided by the ADDIS software. The results of the analysis are presented as odds ratios or median with associated 95% confidence intervals and estimated probabilities for the interventions to be the worst or second worst, etc. RESULTS Literature search Figure shows the flow diagram of the systematic review and network meta-analysi. The primary database search

3 Academia Journal of Biotechnology; Jiang et al. 09 Table : Characteristics of the included studies. ID Author Year Roehrborn Lepor 996 Lepor 998 Narayan McConnell Kirby Nordling Kawabe Pompeo Marks 2009 Treatments (daily) Number of patients Treatment duration (week) Age Baseline IPSS Baseline Qmax Jadad score Ejaculatory dysfunctio n Number of ejaculatory dysfunction Terazosin 0 mg ± ± ± 0. 5 Placebo ± ± ± 0. 2 Terazosin 0 mg 05 65±6 6.2 ± ± 2.6 ejaculatory 52 Placebo 05 65±7 5.8 ± ± 2.6 ity Tamsulosin 0. mg 25 >5 9.8 ± ± Tamsulosin 0.8 mg 28 >5 9.9 ± ± 2.5 Placebo 25 >5 9.6 ± ± Tamsulosin 0. mg 28 5 N/A N/A 27 Tamsulosin 0.8 mg 2 5 N/A N/A 5 Placebo 29 5 N/A N/A Doxazosin 8 mg ± ± ± Placebo ± ± ± Doxazosin 8 mg 250 6±7 7. ±.2 0. ± Placebo 25 6±7 7.2 ± ± 2.5 Tamsulosin 0. mg 58 6 (50 82) 7. ± Placebo 5 6 (50 82) 7.7 ± disorder 0 Silodosin 8 mg ± ± ± Tamsulosin 0.2 mg ± ± ± 2.79 Placebo ± ± ± Tamsulosin.6 mg 8 6.7± ± ± 6.5 Doxazosin 6 mg ± ± ± 5.6 Silodosin 8 mg ±8. 2. ± ± Placebo ±8. 2. ± ± 2.8 Chapple 20 Silodosin 8 mg ± ±.2 Tamsulosin 0. mg ± ±.7 Placebo ± ± ± ± ± Hong-Jeng Yu 20 Tamsulosin 0. mg ± ± ± 2.8 Silodosin 8 mg ±9. 9. ±.5 0. ± 2.8 0

4 Academia Journal of Biotechnology; Jiang et al. 0 Table Contd: Characteristics of the included studies. ID Author Year Treatments (daily) Number of patients Treatment duration (week) Age Baseline IPSS Baseline Qmax Jadad score Ejaculatory dysfunctio n Number of ejaculatory dysfunction Oelke, M 20 Pande 20 5 Novara 205 Tamsulosin 0. mg (5.5 8.) 6.8 ± ±2.7 placebo ( ) 7. ± ±.6 0 tamsulosin 0. mg ± ±.9 N/A 0 5 silodosin 8 mg 26 6.± ±.2 N/A silodosin 8 mg ±8 20.±.9 9.0± placebo ± ±.8 9.7±.6 8 Figure : The flow diagram of the study selection.

5 Academia Journal of Biotechnology; Jiang et al. Figure 2: Risk of bias graph. got 7 records identified in PubMed, Embase, Medline, Scopus, Web of Science and Cochrane databases. 9 records were identified after removing duplications. Thereafter, the records were screened, leading to 22 studies excluded by title or abstract evaluation and 6 duplicate publications, 25 studies unrelated to RCT, 2 review papers, 5 studies with duration of less than weeks and 7 studies without a full text were excluded. The remaining 6 papers in full text were evaluated. At last, after excluding 5 cross-over studies and 6 studies without detailed records about ED, there were 5 RCTs (Chapple et al., 20; Kawabe et al., 2006; Kirby et al., 200; Lepor, 998; Lepor et al., 996; Marks et al., 2009; McConnell et al., 200; Narayan and Tewari, 998; Nordling, 2005; Novara et al., 205; Oelke et al., 20; Pande et al., 20; Pompeo et al., 2006; Roehrborn et al., 996; Yu et al., 20) containing 22,59 participants included in this systematic review: RCTs compared tamsulosin with placebo, 2 RCTs compared Terazosin with placebo, 2 RCTs compared doxazosin with placebo, 2 RCTs compared silodosin with tamsulosin and placebo, 2 RCTs compared tamsulosin with silodosin, 2 RCTs compared silodosin with placebo and RCTs compared tamsulosin with doxazosin. Study characteristics Table summarizes for 5 included studies, the basic characteristics of ID, article, year, treatments, number of patients, treatment duration, age, baseline IPSS, baseline Qmax, jadad score and types of ejaculatory dysfunction and number of ejaculatory dysfunction. Quality assessment All included studies were randomized, double-blind, parallel and controlled clinical trials. The methodological qualities of included studies by the Cochrane Handbook version 5..0 and CONSORT statement were assessed. Of the 5 included studies, 5 studies reported the randomization method, studies described the detailed blinding method and all studies reported the follow-up or drop-out information. As Figure 2 showed, each risk of bias item was presented as percentages across all included studies. Figure shows each risk of bias item described for each included study. In conclusion, the included studies had a relative low risk of bias. Ejaculatory dysfunction rate Figure shows the evidence network. According to the node-split analyses shown in Table 2, there were no statistical differences (P>0.05) observed between the direct and indirect evidence. Likewise, in line with the network inconsistency model, the inconsistency factors of both cycles of placebo, silodosin, tamsulosin (MD=-0.87, 95% CI: -.0,.0) and doxazosin, placebo, silodosin, tamsulosin (MD=0., 95% CI: -2.,.82) showed that inconsistency had no statistical significance. As such, the network consistency model was adopted for the ORs and the associated CIs for pairs of interventions (Table ). The convergence diagnostics of node-split analyses, network inconsistency model and network inconsistency model were performed and all the Potential Scale Reduction Factor (PSRF) were close to.00, which indicated approximate convergence was reached. Ejaculatory dysfunction was reported in all studies. Table showed that silodosin was statistical significantly superior to placebo (OR=70., 95% CI: 7.70 to 58.8), doxazosin (OR=52.82, 95% CI: 5. to 8.), terazosin (OR=0., 95% CI: 2.7 to 62.98) and tamsulosin (OR=8.0, 95% CI:.70 to 0.70). Tamsulosin was

6 Academia Journal of Biotechnology; Jiang et al. Figure : Risk of bias summary. Figure : The network of included studies. statistically significantly superior to placebo (OR=8.70, 95% CI: 2.6 to 59.6), doxazosin (OR=6.5, 95% CI: 0.8 to 8.) and terazosin (OR=.95, 95% CI: 0.5 to 6.75). However, no statistical differences were observed among doxazosin, terazosin and placebo (OR ), which showed that doxazosin and terazosin were associated with a low risk of ejaculatory dysfunction. Consistent with these observations and based on the calculated probabilities as shown in Table and Figure 5, the ranks of ejaculatory dysfunction rate were ranked as followed: silodosin > tamsulosin > terazosin doxazosin placebo. DISCUSSION Since there were only a few trials comparing effects of overlapping alpha blockers for LUTS in men with BPH on ejaculatory function, a systematic review and network meta-analysis is necessary since it combines direct and indirect evidence from randomized controlled trials (Dias et al., 200). This analysis mainly indicates that the treatment of silodosin and tamsulosin is significantly associated with higher risk of ejaculatory dysfunction than doxazosin, terazosin and placebo, while doxazosin and

7 Academia Journal of Biotechnology; Jiang et al. Table 2: Node-splitting analysis of inconsistency. Name Direct effect Indirect effect Overall P-value Doxazosin, Placebo 0.6 (-2.0,.09) -2.8 (-6.57,.55) (-2.0,.7) 0.2 Doxazosin, Tamsulosin 0. (-.8,.09) 2.96 (0.26, 6.7).86 (-0.2,.2) 0.2 Placebo, Silodosin.89 (2.02, 5.97) 6.0 (2.56,.).25 (2.87, 6.29) 0.27 Placebo, Tamsulosin 2.87 (., 5.8) 0.28 (-2.9, 2.95) 2.6 (0.86,.09) 0.07 Silodosin, Tamsulosin -2.7 (-.86, -.0) -0. (-2.89, 2.77) (-.7, -0.5) 0. Table : Network meta-analysis of ED rates by consistency model. Variables Silodosin Tamsulosin Terazosin Doxazosin Tamsulosin 8.0 (.70, 0.70) Terazosin 0. (2.7, 62.98).95 (0.5, 6.75) - - Doxazosin (5., 8.) 6.5 (0.8, 8.).0 (0.0, 0.0) - Placebo 70. (7.70, 58.8) 8.70 (2.6, 59.6).75 (0., 20.05). (0.8,.06) Table : Rank probability values of 5 treatments. Drug Rank Rank 2 Rank Rank Rank 5 Silodosin Tamsulosin Terazosin Doxazosin Placebo Rank refers to the agent with highest ejaculatory dysfunction rate. Figure 5: Rank probabilities of 5 treatments where rank is the worst and rank 5, the best.

8 Academia Journal of Biotechnology; Jiang et al. terazosinis is associated with the same risk of ejaculatory dysfunction as placebo. It is in accordance with the previous studies that the non-selective ABs were associated with lower risk of ED (Kaplan, 2009) but higher risk of vascular-related adverse events (Nickel et al., 2008). The prior findings demonstrated that silodosin, the highest selective AB drug, significantly improved the LUTS, produced maximum urinary flow rate and placebo-like cardiovascular adverse event at a high risk of ED (Novara et al. 20) applied to the other selective AB drugs such as tamsulosin similarly (Masumori et al., 2009). It means that the improvement of LUTS is at the risk of ED in the aspect of AB drugs. In other words, the more effective ABs are, the more risky the ED will become. Nevertheless, the high risk of ejaculatory dysfunction did not cause the retreat of the selective ABs, due to the high risk of vascular-related adverse events in the unselective Abs (Novara et al., 20). With regard to the mechanism, the aa-ar is more abundant than the ab-adrenoceptor (ab-ar) in the male bladder outflow tract and silodosin has extremely high aato-b binding ratio, suggesting a marked power of relaxing smooth muscle in the lower urinary tract including bladder neck, urethra, prostate, seminal vesicles and vas deferens (Tatemichi et al., 2006). Several clinical trials proved the clinical efficacy of silodosin and tamsulosin for LUTS in men with BPH (Choi et al., 205; Marks et al., 2009). However, side effects were magnified as well as, clinical efficacy for the selective ABs. In a recent clinical trial, 27 of 0 sexually active patients experienced ejaculatory dysfunction after silodosin treatment, which was possibly caused by loss of seminal emission and accumulation of seminal vesicle secretion (Bozkurt et al., 205). Classical statistics offers traditional statistical methods to compare different groups in a series of indexes, but larger sample size is essential as group count increases especially when incidence rates of events are low. It troubles Clinical Trials Center because number of objects could not be infinitely increased; whereas, network meta-analysis exhibits advantages in comparing a range of groups at the same time by combining direct and indirect evidence from plenty of high quality clinical trials (Dias et al., 200). This paper is a high quality systematic review and network meta-analysis of the literature performed in agreement with the PRISMA statement (Moher et al., 2009). However, shortcomings still exist. Firstly, ED can be classified into several sub-types such as premature or delayed, or an and painful, but we only analyzed the total number and incidence rate of ED because the sub-types occur with a low incidence rate and many studies did not report the sub-types of ED. Secondly, there are differences in some characteristic in the participants of the included studies (for example, ages). The older participants are, the weaker sexual capacity they get. As a result the ED occurs more frequently, which influences the result. As such, a subgroup analysis of age is necessary immediately more trials are included. Similarly, the treatment duration and treatment dose impact the result, therefore, a sub-group analysis of duration and dose is needed when more studies involving sub-group of potential factor are available. Thirdly, there is a limit when it comes to head-to-head comparisons in included trials due to no control of placebo. Fourthly, there were only 5 studies and 22,59 participants included in this network meta-analysis, which indicates lack of evidence due to the low incidence rates of ejaculatory dysfunction. Hence, more clinical trials will confirm this study with strong evidence. Despite limitations eralier mentioned, this study is the first systematic review and network meta-analysis aiming at ejaculatory dysfunction rate of alpha blockers for the treatment of LUTS in Men with BPH and we found that selective ABs resulted in higher risk of ED for treatment of LUTS with BPH than the unselective ABs. The latest information in this area was provided based on our knowledge. Conclusion In this systematic review and network meta-analysis reporting the ejaculatory dysfunction rate of alpha blockers for treatment of LUTS in men with BPH, we demonstrated that selective ABs like silodosin and tamsulosin were significantly associated with higher risk of ED than unselective ABs like doxazosin and terazosin. 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