MISCELLANEOUS Comparison of Alpha-Blockers and Antimuscarinics in Improving Ureteral Stent-Related Symptoms: A Meta-Analysis Yiyang Gao1,3,#,Hengrui Liang1,2,3,#, Luhao Liu1,4, Alberto Gurioli5, Wenqi Wu1* Purpose: A meta-analysiswas conducted to compare alpha-blocker (AB) and antimuscarinic (AM) monotherapies in releasing US-related symptoms. Methods: A comprehensive literature search was performed on online databases PubMed, Web of Science, Med- line, and Cochrane library. Ureteric Symptom Score Questionnaire (USSQ), International Prostate Symptom Score (IPSS), quality of life (QoL) and visual analogue pain scale (VAPS) were pooled and compared. Results: Nine full-text articles met the inclusion criteria and have been included. The studies were conducted in 9 different centers between 2009 and 2016. All articles were RCT studies and a total of 654 patients were recorded totally, among which 323 were given alpha-blockers while others were given antimuscarinics. Although patients using alpha-blockers presented lower USSQ scores, no statistically significant difference was recorded in urinary symptom(SMD 0.5, 95 % CI -0.2 to 1.20, P = 0.159), pain(SMD 0.33, 95 % CI -0.26 to 0.92, P = 0.280),general health, work performance(SMD-0.34, 95 % CI -0.08 to 0.76, P = 0.115) and sexual performance (all p > 0.05) (SMD 0.12, 95 % CI -0.10 to 0.34, P = 0.280). Meanwhile IPSS (SMD -0.10, 95 % CI -0.32 to 0.11, P = 0.358), QoL(SMD-0.03, 95 % CI -0.23 to 0.18, P = 0.802) and VAPS(SMD 0.08, 95 % CI -0.15 to 0.31, P = 0.447) were similar between the two groups (all P > 0.05). Conclusion: The analysis suggests that AB showed a similar effect with AM. It is necessary to conduct a larger and more detailed cohort study and find the population that potentially might benefit most by AM. Keywords: alpha-Blockers; antimuscarinics; ureteral stent-related symptoms; meta-analysis INTRODUCTION Indwelling ureteral stent (US) is common during en-dourological practice since 1967[1]. However,it has been reported that 38% to 80% patients ever experi- enced stent related symptoms(2,3), which may be caused by the spasm of ureteric smooth musculature around the indwelling foreign object. Alpha-blockers (AB) effica- cy is already proven in releasing stent-related morbidi- ty(4, 5). The potential mechanism may include the reduc- tion of bladder irritation symptoms due to involuntary bladder contraction. Meanwhile, antimuscarinics (AM) have been used to overcome symptoms caused by the involuntary overactive contraction of the bladder due to the distal end of the stent in the urinary bladder, with encouraging results(6).A randomized clinical trial has proved that preoperative administration of oral toltero- 1 Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guang- dong Key Laboratory of Urology, Guangzhou, Guangdong, China 2 Nanshan School, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 511436, China 3 The First Clinical Academy, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guang- zhou 511436, China 4 Department of organ transplantation, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 511436, China 5 Department of Urology, Turin University of Studies, Italy #These authors equally contributed to the paper *Correspondence: Department of Urology, Minimally InvasiveSurgery center, the first affiliated Hospital of Guangzhou medical Uni- versity, Guangdong Key Laboratory of Urology. Kangda Road 1#, Haizhu District, Guangzhou, China, 510230. Telephone: 86-020-34294145. Email: wwqwml@163.com. Received September 2017 & Accepted April 2018 dine could reduce catheter related bladder discomfort after percutaneous nephrolithotomy(7). Several cohort studies and meta-analysis have demon- strated the superiority of either AB or AM to placebo on alleviating US-related symptoms(8,9,10). However, there are still limited studies to compare the therapeutic effect on US-related symptom between AB and AM. To address this issue, we gathered the available pro- spective randomized controlled studies and conducted a meta-analysisto investigate if a statistically significant difference exist between AB and AM monotherapies in releasing US-related symptoms. METHODS Literature search and selection A systematic and comprehensive literature search of on- Miscellaneus 307 Vol 16 No 03 May-June 2019 308 line databases PubMed (National Library of Medicine, Bethesda, MD, US), Web of Science (Thompson Sci- entific, Philadelphia, PA, US), Embase, and Cochrane library was performed to identify randomized con- trolled trials(RCTs) before February 28th,2017. Search strategy was as following:(alpha-blocker OR α-blocker OR tamsulosin) AND (antimuscarinic OR tolterodine OR solifenacin) AND (ureteral stent-related symptoms OR ureteric stent-related discomfort OR SRS).Mean- while,references and related articles of clinical studies and reviews were also manually checked. Language was limited to English. The therapeutic effects of AB and AM on patients with US-related symptoms were examined. We evaluated all search results according to the PRIS- MA (Preferred Reporting Items for Systematic Re- views and Meta-Analyses) statement(11). The selection of original studies was based on the process of viewing titles, abstracts and full papers. The inclusion criteria were as following:(1) studies focused on patients with US insertion;(2) comparative studies examining effect of AB versus AM;(3) RCTs studies;(4) comparative studies that reported at least one outcome of interest. Non-com- parative studies, review articles, abstracts, case reports, editorials, expert opinions, commentary articles, and letters were excluded. Data extraction and quality assessment Data were extracted independently by two investigators (Y.Y. Gao and H.R. Liang) and conflicts were adjudi- cated by a third investigator (W.Q. Wu). Information about all available variables from selected studies was extracted. Ureteric Symptom Score Questionnaire (USSQ)(12)including urinary symptom, pain, general health, work performance and sexual performance, In- ternational Prostate Symptom Score (IPSS), quality of life (QoL)[13] and visual analogue pain scale (VAPS) were used to evaluate the outcomes. Quality assessment was assessed using the JADAD scoring(14). Statistical analysis Standardized mean difference (SMD) with 95% CI was calculated for outcomes. Cochran’s X2 test and I2 were used to examine the heterogeneity among effect estimates. Statistical heterogeneity among studies was defined as I2 statistic greater than 50%. Fixed effects model was preferred to random effects model when there was no statistically significant heterogeneity and vice versa when there was significant heterogeneity(15). Study bias was detected using the methods of Funnel plots and the egger and Begger’s test(16). Statistical sig- nificance was taken as two-sided P < 0.05. The analy- sis was conducted with STATA 12.0 (Stata Corporation College Station, TX, USA) RESULTS Study selection and quality assessment Initially 146 records were screened and 38 additional relevant studies were identified after a hand searching inspection. 153 papers remained after excluding dupli- cates. After an in-depth review, 9 full-text articles met the inclusion criteria and were considered in the analy- sis(6,17-24) (Figure 1). All of the articles were RCT studies with a total of 654 patients. 323 patients were treated with AB monother- apy while 331 were treated with AM monotherapy. All studies gained 6 or 7 score in study quality assessment (Table 1). Ureteric Symptom Score Questionnaire (USSQ) USSQ was presented for evaluating the US-related symptoms including frequency, urgency, pain, dysuria, Comprison of ABs and AMs in improving USSs-Yiyang Gao et.al. Table 1. Characteristics of the included studies in the meta-analysis. Year Design Treatment Outcomes Duration Total N α-blocker N Antimuscarinic N Stent size Jadad score 2016 RCT Tamsulosin 0.4mg QD Oxybutynin 5mg QD USSQ,QoL day 7 34 17 17 24/26cm;6F 3 2016 RCT Tamsulosin 0.4mg QD Solifenacin 5mg QD USSQ day 14 87 44 43 24/26cm;6F 3 2016 RCT Tamsulosin 0.4mg QD Solifenacin 5mg QD USSQ day 21 117 59 58 24/26/28cm;4.7/6/7F 5 2015 RCT Tamsulosin 0.2mg QD Solifenacin 5mg QD USSQ day 14 40 20 20 20/22/24/26/28cm;6F 3 2013 RCT Terazosin 2mg Bid Tolterodine 2mg QD IPSS,VAPS,QoL NG 46 23 23 28cm;4.8F 5 2013 RCT Tamsulosin 0.4mg QD Solifenacin 10mg QD IPSS,VAPS,QoL day 14 160 80 80 NG 5 2012 RCT Doksazosin 4 mgQD Tolterodine 4 mg QD IPSS,QoL NG 42 21 21 26/28cm;4.7F 5 2011 RCT Tamsulosin 0.2mg QD Solifenacin 5mg QD IPSS,VAPS,QoL day 14 88 43 45 24/26cm;6F 3 2009 RCT Alfuzosin 10mg QD Tolterodine 4mg QD USSQ day 42 40 20 20 24-28cm;6F 5 Table2. SummarySWD of Ureteric Symptom Score Questionnaire of Alpha-blockers versus antimuscarinic. Outcomes Study number Heterogeneity I2(%) Statistical Method Summary SWD(%)(95%CI) Urinary symptom 5 88.2 random 0.50 [ -0.2,1.20], P = 0.159 Pain 5 83.9 random 0.33 [-0.26,0.92], P = 0.280 General health 5 68.9 random 0.34 [-0.08,0.76], P = 0.115 Work performance 5 54.9 random 0.29 [-0.05,0.64], P = 0.098 Sexual performance 5 20.8 random 0.12 [-0.10,0.34], P = 0.280 incomplete emptying and hematuria. Random effects model was used in the five groups. Although lower USSQ score was noticed in patients using AB com- pared with AM group in all items, urinary symptom (SMD 0.5, 95 % CI -0.2 to 1.20, P = 0.159), pain (SMD 0.33, 95 % CI -0.26 to 0.92, P = 0.280), general health (SMD-0.34, 95 % CI -0.08 to 0.76, P = 0.115), work performance (SMD 0.29, 95 % CI -0.05 to 0.64, P = 0.098) and sexual performance (SMD 0.12, 95 % CI -0.10 to 0.34, P = 0.280) there is no significant differ- ence (Table 2). International prostate symptom score (IPSS) The IPSS was lower in patients treated with AB mono- therapy than in patients treated with AM monotherapy in fixed model, but no significantly (SMD -0.10, 95 % CI -0.32 to 0.11, P = 0.358), with low heterogeneity (I2 = 9.8%, p = 0.344) (Figure 2). Quality of life (QoL) 6 studies including 370 cases reported QoL. Fixed mod- el was used. No significant difference was found be- tween AB and AM monotherapies (SMD-0.03, 95 % CI -0.23 to 0.18, P = 0.802), with no heterogeneity (I2 = 0, p = 0.425) (Figure 3). Visual Analog Pain Score (VAPS) The present meta-analysis in fixed model indicated that the VAPS was similar between AB or AM (SMD 0.08, 95 % CI -0.15 to 0.31, P = 0.447), with low heterogene- ity (I2 = 21.8, p = 0.279) (Figure 4). Publication bias and sensitivity analysis Visual inspection of funnel plots suggested there was no obviously asymmetric distribution of main outcomes. Begger and Egger’s test confirmed there was no signif- icant publication bias (Table 3). A sensitivity analysis was performed by excluding the studies with the low- est-quality score. This did not influence the results. DISCUSSION To our knowledge, this is the first meta-analysis aimed to evaluate the efficacy of AB and AM monotherapies in relieving US-related symptoms. We did not observed statistically significant superiority of AB in overcoming stent-related symptoms compared to AM. The analysis suggests that both drugs can effectively treat US-related symptoms. Despite a growing number of studies on US-related symptoms, explicit pathophysiology is still matter of debate. Lang et al.(25) proposed that US-related pain and urinary symptoms may be the result of ureteric spasm or trigonal irritation. Pain and lower urinary tract symp- toms (LUTS) caused by stent could be worsened by the increasing pressure transmitted to the renal pelvis dur- ing urination, bladder ischemia and lower ureteric and bladder spasm(26,27). A US may also exacerbate pre-ex- Comprison of ABs and AMs in improving USSs-Yiyang Gao et.al. Outcomes Number of estimates P value for Begg's test P value for Egger's test General health 5 0.806 0.908 Urinary symptom 5 0.462 0.572 Pain score 5 0.806 0.907 Work performance 5 1 0.927 Sexual performance 5 0.462 0.457 IPSS 4 0.308 0.592 QoL 5 0.806 0.588 VAPS 3 0.296 0.297 Table 3.Assessment for publication bias. Figure 1. flow diagram detailing the search strategy and identification of studies used in Meta-analysis Figure 2. . Forest plot of International prostate symptom score (IPSS) of Alpha-blockers versus antimuscarinic Miscellaneus 309 Vol 16 No 03 May-June 2019 310 isting subclinical detrusor over-activity and induce overactive bladder symptoms(28). AB are the first-line treatment for LUTS, while AM are widely used for the treatment of overactive blad- der. Both drugs have been applied to treat US-related symptoms in clinical practice. AB could reduce the US-induced pain during voiding probably determining a relaxation of bladder neck/prostatic smooth muscu- lature and consequently reducing voiding pressure and urinary reflux(29). Flank pain may be the result of ureter spasm in patients with indwelling US, AB may relieve it by decreasing ureteral spasm and vescico-ureteral re- flux(30). Ureteral Stent Symptom Questionnaire(USSQ), Inter- national Prostate Symptom Score (IPPS), Visual Ana- logue Pain Score (VAPS) and Quality of Life (QoL) are measuring tools used in the included studies about ureteral stent-related symptoms. USSQ was designed to characterize urinary symptoms associated with stent including frequency, urgency, pain, dysuria, incomplete emptying and hematuria. IPSS was used as frequently as USSQ for assessing stent-related symptoms, which was divided into the total score, obstructive symptom score, and irritative symptom score. Analogue Pain Scale graded from 1 (minimal or no symptoms) to 10 (symptoms of maximal severity). In endourological clinical practice, AB are much more commonly used than AM to release US-related symp- toms. However, our results suggest that AM were not significantly inferior in improving US-related symp- toms if compared to AB. Thus, AM can be a valid alter- native to AB in this category of patients. This study has some limitations. First, many clinical factors and any underlying ureteral disease would have influenced the outcomes, and different patient char- acteristics also may have a negative influence on the overall results. Second, different types of intra-corpo- real lithotripsy and dose difference of medications to patients were not sub-analyzed in our study because of data limitation. Third, since majority of included studies reported an insufficient follow-up period, consequently, we were unable to evaluate the outcomes varying from time. CONCLUSIONS In conclusion, the analysis suggests that AB showed a similar effect with AM. Although lower USSQ and IPSS score were noticed in patients using AB compared with AM group in all items, but without statistically significant difference, and equally no significant differ- ence were found between AB and AM monotherapies in the way of QoL and VAPS. It is necessary to conduct a larger and more detailed cohort study and find the population that potentially might benefit most by AM. REFERENCES 1. Zimskind PD, Fetter TR, Wilkerson JL. Clinical use of long-term indwelling silicone rubber ureteral splints inserted cystoscopically.J Urol. 1967;97:840-844. 2. Nabi G, Cook J, N'Dow J, et al. Outcomes of stenting after uncomplicated ureteroscopy: systematic review and meta-analysis. BMJ.2007;334:572. 3. Byrne RR, Auge BK, Kourambas J, et al. Routine ureteral stenting is not necessary after ureteroscopy and ureteropyeloscopy: a randomized trial. J Endourol. 2002;16:9-13. 4. Beddingfield R, Pedro RN, Hinck B, et al. Alfuzosin to relieve ureteral stent discomfort: a prospective, randomized, placebo controlled study.J Urol. 2009;181:170-176. 5. Damiano R, Autorino R, De Sio M, et al. Effect of tamsulosin in preventing ureteral stent-related morbidity: a prospective study. J Endourol. 2008;22:651-656. 6. Kuyumcuoglu U, Eryildirim B, Tuncer M, et al. Effectiveness of medical treatment in overcoming the ureteral double-J stent related symptoms. Can Urol Assoc.2012;6:E234-7. 7. Maghsoudi R -, Farhadi-Niaki S, Etemadian M,et al.Comparing the efficacy of tolterodine Comprison of ABs and AMs in improving USSs-Yiyang Gao et.al. Figure 3. Forest plot of Quality of life (QoL) of Alpha-blockers versus antimuscarinic Figure 4. Forest plot of Visual Analog Pain Score (VAPS) of Alpha- blockers versus antimuscarinic and gabapentin versus placebo in catheter related bladder discomfort after percutaneous nephrolithotomy: A randomized clinical trial.J Endourol.2017 Dec 26. doi: 10.1089/ end.2017.0563. [Epub ahead of print]. 8. Zhou L, Cai X, Li H, et al. Effects of alpha- Blockers, Antimuscarinics, or Combination Therapy in Relieving Ureteral Stent-Related Symptoms: A Meta-Analysis.J Endourol. 2015;29:650-656. 9. Yakoubi R, Lemdani M, Monga M, et al. Is there a role for alpha-blockers in ureteral stent related symptoms? A systematic review and meta-analysis.J Urol. 2011;186:928-934. 10. Norris RD, Sur RL, Springhart WP, et al. A prospective, randomized, double-blinded placebo-controlled comparison of extended release oxybutynin versus phenazopyridine for the management of postoperative ureteral stent discomfort. Urology. 2008;71:792-795. 11. Knobloch K, Yoon U, Vogt PM. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and publication bias. J Cranio Maxill Surg. 2011;39:91-92. 12. Joshi HB, Newns N, Stainthorpe A, et al. Ureteral stent symptom questionnaire: development and validation of a multidimensional quality of life measure. J Urol.2003;169:1060-1064. 13. Joshi HB, Stainthorpe A, Keeley FX Jr, et al.Indwelling ureteral stents: Evaluation of quality of life to aid outcome analysis. J Endourol.2001;15:151-154. 14. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12. 15. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-560. 16. Seagroatt V, Stratton I. Bias in meta-analysis detected by a simple, graphical test. Test had 10% false positive rate. BMJ. 1998;316:470; author reply 470-1. 17. Park SC, Jung SW, Lee JW, et al. The effects of tolterodine extended release and alfuzosin for the treatment of double-j stent-related symptoms. J Endourol. 2009;23:1913-1917. 18. Lim KT, Kim YT, Lee TY, et al. Effects of tamsulosin, solifenacin, and combination therapy for the treatment of ureteral stent related discomforts. Korean J Urol. 2011;52:485-488. 19. Shalaby E, Ahmed AF, Maarouf A, et al. Randomized controlled trial to compare the safety and efficacy of tamsulosin, solifenacin, and combination of both in treatment of double-j stent-related lower urinary symptoms. Adv Urol. 2013;2013:752382. 20. Tehranchi A, Rezaei Y, Khalkhali H, et al. Effects of terazosin and tolterodine on ureteral stent related symptoms: a double-blind placebo-controlled randomized clinical trial. Int Braz JUrol. 2013;39:832-840. 21. Park J, Yoo C, Han DH, et al. A critical assessment of the effects of tamsulosin and solifenacin as monotherapies and as a combination therapy for the treatment of ureteral stent-related symptoms: a 2 x 2 factorial randomized trial. World J Urol. 2015;33:1833-1840. 22. Abdelaal AM, Al-Adl AM, Abdelbaki SA, et al. Efficacy and safety of tamsulosin oral- controlled absorption system, solifenacin, and combined therapy for the management of ureteric stent-related symptoms. Arab J Urol. 2016;14:115-122. 23. El-Nahas AR, Tharwat M, Elsaadany M, et al. A randomized controlled trial comparing alpha blocker (tamsulosin) and anticholinergic (solifenacin) in treatment of ureteral stent- related symptoms. World J Urol. 2016;34:963- 968. 24. Maldonado-Avila M, Garduno-Arteaga L, Jungfermann-Guzman R, et al. Efficacy of Tamsulosin, Oxybutynin, and their combination in the control of double-j stent- related lower urinary tract symptoms. Int Braz JUrol.2016;42:487-493. 25. Lang RJ, Davidson ME, Exintaris B. Pyeloureteral motility and ureteral peristalsis: essential role of sensory nerves and endogenous prostaglandins.Exp Physiol. 2002;87:129-146. 26. Siggers JH, Waters S, Wattis J, et al. Flow dynamics in a stented ureter. Math Med Biol. 2009;26:1-24. 27. Camoes J, Coelho A, Castro-Diaz D, et al. Lower Urinary Tract Symptoms and Aging: The Impact of Chronic Bladder Ischemia on Overactive Bladder Syndrome. Urol Int. 2015;95:373-379. 28. Joshi HB, Okeke A, Newns N, et al. Characterization of urinary symptoms in patients with ureteral stents. Urology. 2002;59:511-516. 29. Wang CJ, Huang SW, Chang CH. Effects of specific alpha-1A/1D blocker on lower urinary tract symptoms due to double-J stent: a prospectively randomized study. Urol Res. 2009;37:147-152. 30. Davenport K, Timoney AG, Keeley FX, Jr. Effect of smooth muscle relaxant drugs on proximal human ureteric activity in vivo: a pilot study. Urol Res. 2007;35:207-213. Comprison of ABs and AMs in improving USSs-Yiyang Gao et.al. 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