Review Article Tamsulosin versus nifedipine to facilitate urinary stone passage: a systematic review and meta-analysis

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1 Int J Clin Exp Med 2018;11(3): /ISSN: /IJCEM Review Article Tamsulosin versus nifedipine to facilitate urinary stone passage: a systematic review and meta-analysis Yongqiang Zhang 1,2*, Dongbo Yuan 1,3,4,5*, Haofu Rao 3,7, Tianfei Cheng 3,8, Boshi Luan 3, Wei Wang 3, Jiaming Su 6, Yuanlin Wang 1,3, Zhaolin Sun 1,3,4,5, Guiping Ouyang 2, Jianguo Zhu 1,3,4,5 1 Guizhou Provincial People s Hospital, The Affiliated Hospital of Guizhou University, Guizhou, , China; 2 School of Pharmaceutical Sciences, Guizhou University, Guizhou, , China; 3 Department of Urology, Guizhou Provincial People s Hospital, The Affiliated Hospital of Guizhou Medical University, Guizhou, , China; 4 Medical College of Guizhou University, Guizhou, , China; 5 College of Life Science, Guizhou University, Guizhou, , China; 6 Zunyi Medical University, Guizhou, , China; 7 The First People s Hospital of Xiushui county, Jiujiang City, Jiangxi, , China; 8 The People s Hospital of Liang Ping District in Chongqing, Chongqing, , China. * Equal contributors. Received September 8, 2017; Accepted January 8, 2018; Epub March 15, 2018; Published March 30, 2018 Abstract: Objectives: To assess the effectiveness of Tamsulosin versus Nifedipine, as an expulsive agent, for both intact ureteral stones and stones after shock wave lithotripsy. Methods: Relevant studies were searched for in MEDLINE, SCOPUS, and the Cochrane database libraries. All randomized controlled trials comparing Tamsulosin to Nifedipine for the treatment of ureteral stones (intact or after shock wave lithotripsy), were included in the study. The primary outcome was the proportion of the patients who passed the stones. Results: Ten randomized trials (RCT), with a total of 4816 patients that underwent medical therapy only, were included in this meta-analysis. Tamsulosin was associated with a higher risk of stone passage rate (SPR) (OR = 2.67, 95% CI , P<0.05), and with a shorter average stone-expulsion time, in tamsulosin groups (WMD: -1.95; 95% CI: ; P = 0.03). There were no statistically significant differences in the side effects between these groups (OR = 0.78, 95% CI , P = 0.07). Three trials comprised of 199 patients who had the expulsive therapy after shock wave lithotripsy. No statistically significant differences were detected in the SPR, between the two groups (OR = 1.56, 95% CI , P = 0.17). Conclusions: This meta-analysis suggested that Tamsulosin was more effective and quicker than Nifedipine as an expulsive agent for the intact ureteral stones. Keywords: Tamsulosin, nifedipine, urinary stone, shock wave, meta-analysis Introduction It is estimated that urinary stone disease affects approximately 5-12% of the world s population. There is a male predominance of about 13%, versus 7% in women. In addition, the recurrence of renal colic in the urolithiasis patients is 50%, within five years of their first episode. These data demonstrate the substantial economic consequences and the significant health care issues resulting from this high prevalence of urolithiasis [1-4]. Several studies have demonstrated that small ( 5 mm) ureteral stones had a spontaneous passage rate of 71-98% [5-7]. However, passage of stones can cause significant morbidity, namely renal or ureteral colic. The colic episode can not only cause severe pain, but often results in hospitalization. Therefore, medical expulsive therapy has been advocated to facilitate stone passage, and to reduce morbidities. This treatment has been used for both intact ureteral stones and for stones after shock wave lithotripsy. Both, calcium-channel blockers and adrenergic α-antagonists, have been used as expulsive agents. Tamsulosin and Nifedipine were the most commonly used drugs [8, 9]. Several randomized trials have been published to compare the effectiveness of Tamsulosin versus Nifedipine, as expulsive agents. They were used for both intact stones and after shock wave lithotripsy. These studies produced substantial conflicting results. Therefore, we embarked on

2 this review and meta-analysis of the published literature, in an attempt to provide a more comprehensive assessment of the efficacy of Tamsulosin, as compared to Nifedipine, as an expulsive agent. Methods Search strategy, eligibility criteria, and exclusion criteria Figure 1. Systematic search and selection strategy. Randomized controlled trials were identified from MEDLINE, SCOPUS, and the Cochrane database libraries. The search terms used for the retrieval of the relevant studies included both Tamsulosin and Nifedipine. There was no restriction by the year of publication, the language, or publication status applied. The reference lists the identified publications, and relevant review articles, that were searched looking for additional studies. Trials that met the follow- uded meta-analysis that was assessed by the Jadad score [10]. The primary endpoint in the studies was the overall stone expulsion rate (cumulative incidence). The secondary endpoint was side-effects incidence and average stone-expulsion time. Randomized controlled trials, with scores greater than or equal to three points were defined as high-quality studies. Whereas, the randomized controlled trials with scores less than three points were defined as lesser quality studies [11]. Statistical analysis ing criteria were eligible for inclusion in this study: (1) randomized controlled trials; (2) studies comparing Tamsulosin with Nifedipine for the treatment of ureteral stones; (3) reporting data of the proportion of patients who passed stones. Exclusion criteria were (1) not containing the two medications; (2) reporting insufficient data. When there was a duplicated publication or data, only the newest eligible data was included. The details of the systematic search and selection strategy are shown in Figure 1. Data extraction and quality assessment The data extraction included authors, year of publication, journal source, sample size, patient characteristics, overall stone expulsion rate, average stone-expulsion time, side-effects, incidence, mean analgesic consumption for renal colic, pain relief therapy, and its route of administration. The quality of the randomized controlled trials incl- The data in the form of means and standard deviations were included in our meta-analysis. The continuous variables, such as the median and the range, were excluded. In this metaanalysis, weighted mean differences (WMDs) were used for the analysis of continuous variables. The odds ratios (ORs) were used for the dichotomous variables. Random-effects mod Int J Clin Exp Med 2018;11(3):

3 Table 1. Characteristics of the 10 selected clinical studies (use drug alone) Study Location Study style Group No. of Patients Age (years) Overall stone expulsion Average stoneexpulsion time Ye et al. (2010) China RCT Tamsulosin (95.9%) hours Nifedipine (73.5%) hours Porpiglia et al. (2004) U.S.A. RCT Tamsulosin (85%) 7.9 days Nifedipine (80%) 9.3 days Dellabella et al. (2005) U.S.A. RCT Tamsulosin (97.1%) 72 hours Nifedipine (77.1%) 120 hours Gandhi et al. (2013) India RCT Tamsulosin (79.7%) 9 days Nifedipine (50%) 23 days Zhang et al. (2009) China RCT Tamsulosin (73.5%) - Nifedipine (68.0%) - Lü et al. (2006) China RCT Tamsulosin (81.7%) 4 days Nifedipine (73.3%) 8 days Balci et al. (2014) Turkey RCT Tamsulosin (76.%) 9 days Nifedipine (64.%) 9.1 days Islam et al. (2010) Bangladesh RCT Tamsulosin (84.4%) 7.9 days Nifedipine (71.0%) 9.3days Liao et al. (2011) China RCT Tamsulosin (19-49) 49 (83.1%) 11 days Nifedipine (19-49) 27 (51.0%) 14 days Pickard et al. (2015) UK RCT Tamsulosin (81.2%) 16.5 days RCT = randomized controlled trial. Nifedipine (80.2%) 16.2 days Table 2. Characteristics of the 3 selected clinical studies (use drug after shock wave lithotripsy) Study Location Study style Group Gender Overall stone Stone location Male Female expulsion Up Mid Low Micali et al. (2007) China. RCT Tamsulosin (82.1%) Nifedipine (85.7%) FabioC. et al. (2011) U.S.A RCT Tamsulosin (60.5%) Nifedipine (48.6%) Choi. et al. (2008) U.S.A RCT Tamsulosin (84.4%) RCT = randomized controlled trial. Nifedipine (67.7%) els were used to identify the heterogeneity among the studies [11]. Heterogeneity was assessed using the chi-square test. The ninetyfive percent confidence intervals (CIs) were calculated. P values 0.05 were considered to be statistically significant. Statistical analyses were performed using Review Manager version 4.2 (Cochrane Collaboration, Copenhagen, Denmark). Results Characteristics of included studies The initial search yielded fifty-three citations, using the medication only. Ten randomized trials [12-21] met the inclusion criteria, and constituted the base of the meta-analysis. It has a total of 4,816 patients (2,414 in the Tamsulosin group and 2,402 in the Nifedipine group). In addition, three RCTs [22-24] used the medications after the shock wave lithotripsy (SWL), with a total of 199 patients (98 in the Tamsulosin group and 101 in the Nifedipine group), that were also considered to be suitable for the meta-analysis. Tables 1 and 2 summarize the main characteristics of the studies included in this meta-analysis. All of the thirteen randomized controlled trials were considered to be of high quality, with scores of no less than 3 points as assessed by the Jadad score (Table 3) Int J Clin Exp Med 2018;11(3):

4 Table 3. Quality assessment of included RCTs Investigator Randomization Doubleblind Use drug alone Improvement of ureteral stone passage Nifedipine versus tamsulosin for the management of ureteral stones: Eight RCTs [12-21] investigated the efficacy of medical expulsive therapy. All of them showed that the Tamsulosin was associated with a higher rate of stone passage than Nifedipine. A random-effects model was used to combine the data, because the heterogeneity was evident (P< ). In the pooled data, the incidence of successful stone passage in the Tamsulosin group was significantly higher than the Nifedipine group (OR = 2.67, 95% CI , P<0.05) (Figure 2). Adjuvant tamsulosin versus nifedipine after SWL for renal stones: All of the studies [22-24] showed improved stone expulsion rate. There were, however, no significant differences between the Tamsulosin group and the Nifedipine group. The fixed effects model was used to combine the data, because the heterogeneity was not significant (P = 0.42). In the pooled data, the Tamsulosin group and the Nifedipine group had similar stone passage rate (OR = 1.56, 95% CI , P = 0.17) (Figure 3). Side-effects profile Withdrawals/ drop outs Score Ye et al Porpiglia et al Dellabella et al Gandhi et al Zhang et al Lü et al Melih et al Islam et al Liao et al Pickard et al Use drug after shock wave lithotripsy Micali et al Fabio C. et al Choi. et al Nifedipine versus tamsulosin for the management of the in situ ureteral stones: There were eight trials [12-17, 20, 21] that included the adverse events. The other two trials [18, 19] did not. Both showed a lack of significant differ- Five studies [16-18, 20, 21], including 498 patients, provided data on the average stone-expulsion time in both groups. The random-effects model was used to combine the data, because the heterogeneity test showed heterogeneity in the average stone-expulsion time of the five clinical studies (P = 0.04). In the pooled data, meta-analysis demonstrated less stone-expulsion time in the Tamsulosin group than in the Nifedipine group (WMD: -1.95; 95% CI: ; P = 0.03) (Figure 5). Mean analgesic consumption for renal colic The presentation of these data was heterogeneous. Since there was also the lack of mean and standard deviation data, a meta-analysis would not be appropriate. Of the included studies, seven trials [12, 13, 15-19] showed that the mean consumption of diclofenac for recurrent renal colic in the Tamsulosin group was less than the Nifedipine group. Whereas, in the other trial, [14] the conclusion was diametric. Therefore, the difference in the consumption of diclofenac between the groups was unclear. Three trials in the SWL did not record any analgesic data. No meta-analysis could be done. Pain relief therapy ence between the Tamsulosin and the Nifedipine group. The fixed effect model was used to combine the data because the heterogeneity was not significant (P = 0.27). In the pooled data, there were no statistically significant differences in the side effect incidences between the groups (OR = 0.78, 95% CI , P = 0.07) (Figure 4). Average stone-expulsion time Only one study [13] provided data regarding pain relief therapy. It showed that the rate of pain relief therapy in the Tamsulosin group (1.53%) was significantly less than that that in the Nifedipine group (4.84%). Again, a metaanalysis would not be appropriate. Assessment of publication bias A funnel plot was performed to assess publication bias in this meta-analysis. The shapes of 1461 Int J Clin Exp Med 2018;11(3):

5 Figure 2. Forest plot showing stone passage between Nifedipine and Tamsulosin groups. Figure 3. Forest plot showing stone passage between Nifedipine and Tamsulosin groups after SWL. Figure 4. Forest plot showing side-effects between Nifedipine and Tamsulosin groups. the funnel plots included the side-effects incidence and overall stone expulsion. The metaanalyses were symmetrical and did not show any obvious evidence of asymmetry (Figure 6). In addition, the P value of the Egger s tests was more than 0.05, thus it provided statistical evidence of the funnel plot symmetry (Figure 6). The result, therefore, suggested that publication bias was not evident in this meta-analysis. Discussion Ureteral stones are a common form of urolithiasis. Ureteral colic is extremely painful and is the 1462 Int J Clin Exp Med 2018;11(3):

6 Figure 5. Forest plot showing average stone-expulsion time between Nifedipine and Tamsulosin groups. most common cause of urolithiasis in patients seeking emergency medical care. Fortunately, most ureteral stones will pass spontaneously. Treatment that can facilitate the stone passage will, undoubtedly, relieve patient suffering and reduce the medical cost. In this context, medical expulsive therapy has gained widespread interest in recent years [25, 26]. The adrenergic α-antagonists and the calcium-channel blockers were found to be the most effective classes of the expulsive agents. Tamsulosin and Nifedipine are two of the more frequently used medications for this purpose. Their efficacy and safety profile have been extensively studied. However, there was inconsistent data regarding which of the two medications is superior in terms of efficacy and safety profile. SWL and ureteroscopy represent the current surgical treatment options for the ureteral stones that have failed to pass spontaneously. SWL is a non-invasive procedure, but it has a lower success rate and a higher re-treatment rate [8, 9, 27-29]. URS, on the other hand, is an invasive procedure, but with the highest success rate. It is also more costly than SWL. Patients who have undergone SWL therapy are routinely placed on expulsive medication to facilitate the passage of stone fragments, and to reduce the risks of post-treatment colic. There were thirteen clinical studies [12-21, 22-24] that compared Tamsulosin with Nifedipine (use alone or SWL) to investigate their value as medical expulsive therapy in the treatment of urinary stone disease. This meta-analysis of ten clinical studies [12-21] showed that the stone passage rate in the Tamsulosin group was 91.1%, while the rate for the Nifedipine group was 73.3%. Therefore, Tamsulosin was a significantly more effective expulsive agent than Nifedipine. The meta-analysis of three clinical studies [22-24] with SWL showed no significant differences between the Tamsulosin group (stone passage rate of 74.5%), and the Nifedipine group (stone passage rate of 67.3%). There are eight trials [12-17, 20, 21] that have included an adverse event and two that did not. The incidence of side-effects in the Tamsulosin group was 4.4%, while the incidence in the Nifedipine group was 5.6%. Our meta-analysis revealed that the side-effect profile was not significantly different between the Tamsulosin group and the Nifedipine group. Whereas, the adverse event between the two groups, after shock wave lithotripsy [22-24] lacks data. Therefore, we can t make a conclusion and we need to do further research in future studies. Our meta-analysis of five clinical studies [16-18, 20, 21] revealed significantly less operative time in the Tamsulosin group than in the Nifedipine group. This may lead to reduced average onset of pain and analgesia for patients. But Balci et al. [16], and Ye, et al. [13] data showed that the common analgesic consumption of the Tamsulosin group and the Nifedipine group was 544 mg/day and 602 mg (P = 0.98) and 0.98 mg and mg, respectively (P<0.01). These biases can be caused by the pain tolerance and the severity of obstruction among patients. There were some limitations to this meta-analysis. First, studies included data on the average stone expulsion time and the mean consumption of diclofenac. Neither included data in the form of mean and standard deviation, to allow proper meta-analysis. However, nine studies [12-18, 20, 21] did show that Tamsulosin had a significantly shorter stone expulsion time than Nifedipine. Seven trials [12, 13, 15-19] showed that the mean consumption of diclofenac, needed for recurrent renal colic, in the 1463 Int J Clin Exp Med 2018;11(3):

7 Figure 6. Funnel plot for the results from all studies comparing stone passage, side-effects in patients between Nifedipine and Tamsulosin groups. Tamsulosin group was less than that in the Nifedipine group. The conclusion of the other trial [14] was diametric. Yet, another study [13] included data on pain relief therapy, demonstrating that Tamsulosin was actually significantly inferior than Nifedipine. These conflicting 1464 Int J Clin Exp Med 2018;11(3):

8 and insufficient data affected the accuracy of this meta-analysis. Second, different studies might have differing defining criteria for the outcomes we were interested in, but might not be reported in the study methodology. Third, there was the limitation of nonpublication and selective reporting bias, which could not be accounted for. This meta-analysis suggested that Tamsulosin was more effective and a more quickly expulsive medication than Nifedipine for the patients with ureteral stones. The study showed that there was no significant difference in efficacy between these two medications when they were used after SWL. Further prospective, randomized, and double-blind RCTs, will be needed to reach a more definitive conclusion. Acknowledgements The study was supported by the Outstanding Youth Science and Technology Talent Cultivating Project of the Guizhou Province in 2013 ( ), The Young Talents Project of Guizhou Province in 2012 ( ), The Science and Technology Project of Guiyang in 2015 ( ), and the National Natural Science Foundation of China ( ). Disclosure of conflict of interest None. Address correspondence to: Dr. Guiping Ouyang, School of Pharmaceutical Sciences, Guizhou University, Guizhou , China. Tel: ; Fax: ; Dr. Jianguo Zhu, Department of Urology, Guizhou Provincial People s Hospital, The Affiliated Hospital of Guizhou Medicine University, Guiyang , Guizhou Province, China. Tel: ; Fax: ; doctorzhujianguo@163.com References [1] Pak CY. Kidney stones. Lancet 1988; 351: [2] Segura JW, Preminger GM, Assimos DG, Dretler SP, Kahn RI, Lingeman JE, Macaluso JN Jr. Ureteral stones clinical guidelines panel summary report on the management of ureteral calculi. J Urol 1997; 158: [3] Miller OF, Kane CJ. Time to stone passage for observed ureteral calculi: a guide for patient education. J Urol 1999; 162: [4] Teichman JM. Clinical practice. Acute renal colic from ureteral calculus. N Engl J Med 2004; 350: [5] Hübner WA, Irby P, Stoller ML. Natural history and current concepts for the treatment of small ureteral calculi. Eur Urol 1993; 24: [6] Ueno A, Kawamura T, Ogawa A, Takayasu H. Relation of spontaneous passage of ureteral calculi to size. Urology 1977; 10: [7] Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to stone size and location as revealed by unenhanced helical CT. AJR Am J Roentgenol 2002; 178: [8] Cervenàkov I, Fillo J, Mardiak J, Kopecný M, Smirala J, Lepies P. Speedy elimination of ureterolithiasis in lower part of ureters with the alpha 1 blockers-tamsulosin. Int J Urol Nephrol 2002; 34: [9] Ukhal M, Malomuzh O, Strashny V. Administration of doxazosine for speedy elimination of stones from lower part of ureter. Eur Urol 1999; 35 Suppl 2: 4-6. [10] Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: [11] Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, Tugwell P, Klassen TP. Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998; 352: [12] Dellabella M, Milanese G, Muzzonigro G. Randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi. J Urol 2005; 174: [13] Ye Z, Yang H, Li H, Zhang X, Deng Y, Zeng G, Chen L, Cheng Y, Yang J, Mi Q, Zhang Y, Chen Z, Guo H, He W, Chen Z. A multicentre, prospective, randomized trial: comparative efficacy of tamsulosin and nifedipine in medical expulsive therapy for distal ureteric stones with renal colic. BJU Int 2011; 108: [14] Porpiglia F, Ghignone G, Fiori C, Fontana D, Scarpa RM. Nifedipine versus tamsulosin for the management of lower ureteral stones. J Urol 2004; 172: [15] Gandhi HR, Agrawal C. The efficacy of tamsulosin vs. nifedipine for the medical expulsive therapy of distal ureteric stones: a randomized clinical trial. Arab Journal of Urology 2013; 11: [16] Balci M, Tuncel A, Aydin O, Aslan Y, Guzel O, Toprak U, Polat F, Atan A. Tamsulosin versus nifedipin in medical expulsive therapy for distal ureteral stones and the predictive value of 1465 Int J Clin Exp Med 2018;11(3):

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