Vol 19 No 1 January-February 2022 138 Supine is Superior to Prone Position in Treating the Distal Ureteral Calculi During Extracorporeal Shockwave Lithotripsy: An Updated Meta-Analysis Haiyan Lu,1 Jun Wang,1* Peixuan Han,2 Weizhen Xu3 Purpose: Although extracorporeal shockwave lithotripsy (SWL) has been confirmed to be effective in treating ureteral stone, a definitive conclusion on which patient’s position is the optimal option during SWL treatment remains unclear. We, therefore, performed this updated meta-analysis to further clarify it. Materials and Methods: PubMed, Embase, and Cochrane library were performed to capture all potentially eli- gible studies from their inception to October 2020. After screening eligible studies, extracting essential data, and assessing the risk of bias, we used STATA 14.0 to complete all statistical analyses. Results: We included 7 studies involving 8 cohorts in the final analysis. Our meta-analysis suggested that the prone position was inferior to the supine position in terms of stone fragmentation and stone clearance rate after completing the first treatment (95% CI: 0.30-0.63; OR = 0.44;), however, subgroup analysis indicated that the difference between supine and prone positions for stone fragmentation and the stone clearance rate was only get- ting statistical significance for distal ureteral stone (95% CI: 0.23-0.53; OR = 0.35). Moreover, subgroup analysis of two eligible randomized controlled trials suggested that the mean number of sessions per patient in the supine group was less than that in the prone group (95% CI: 0.11-0.48; WMD = 0.294). No major and severe complication was detected to be done with the association with positions. Conclusion: SWL of the supine position may be the preferred option because this strategy can increase the distal ureteral stone-free rate compared to the prone position. Keywords: lithotripsy; meta-analysis; prone position; shockwave lithotripsy; supine position; ureteral stone INTRODUCTION There is no optimal strategy for the management of ureteral stone, especially distal ureteral stone so far.(1) Although extracorporeal shockwave lithotripsy (SWL) and ureteroscopy are all considered as accept- able treatments for ureteral stones, SWL is considered the first-line therapeutic option and has been extensive- ly used to treat ureteral stones, especially distal ureteral stones(2,3) because it has several advantages, compared to ureteroscopy, such as characteristics of noninvasive management, ambulatory procedure, and lack of severe undesirable side effects.(4) However, the clinical value of SWL is associated with several aspects such as ba- sic characteristics of stones including size, location and specified composition and the type of the lithotripter used.(1) For the purpose of improving the treatment effects of SWL, several regimes including sedation, a slow shock wave firing rate, ramping up the voltage, sufficient transmission media for optimal coupling, a wider focal zone, the application of a belt, and adequate pain relief have been developed and introduced.(5) Un- fortunately, the optimal strategy of ureteral stone espe- cially distal location has not yet been obtained. 1Department of Urology, The First People's Hospital of Lanzhou City, Lanzhou City, Gansu Province, China. 2Winona State University, Winona City, Minnsota State, The United States. 3Maternal and Child Health Care Hospital, Lanzhou City, Gansu Province, China. *Correspondence: Department of Urology, The First People's Hospital of Lanzhou City, Lanzhou City, Gansu Province, China. Tel: 86-13993169748. E-mail: wyr3514828@163.com. #These authors contributed equally to this work. Received August 2021 & Accepted December 2021 Evidence suggested that the position of patients during SWL will directly affect the treatment effects of SWL because the bony structure of the pelvis will interfere with the effective transmission of the shock waves to the target stone.(6,7) Although the pronee position has been widely used for the treatment of distal ureteral stone in order to reduce the negative effect of the pelvis,(8) several drawbacks such as large skin-to-stone distance limits the application of prone position.(9) Therefore, modifications to patient positioning during SWL have been proposed in order to improve the efficacy of the treatment.(10) As an alternative option, supine position has been introduced previously into clinical practice to address the issues faced by conventional prone position during SWL because it can effectively avoid the nega- tive impact of pelvic bone through passing the greater sciatic foramen along the gluteus maximus muscle to deliver the shock waves.(11) To date, several clinical trials have been performed to investigate the comparative efficacy and safety of con- ventional prone position and modified supine position during SWL for the treatment of ureteral calculi and found that SWL via the supine position is more effective and safer than that via the prone position. Moreover, a REVIEW Urology Journal/Vol 19 No. 1/ January-February 2022/ pp. 9-16. [DOI: 10.22037/uj.v19i.6946] previous meta-analysis(12) also suggested that supine SWL is more effective than prone SWL for achieving a stone-free status. However, there are limited studies providing a high level of evidence. So, a definitive conclusion about the optimal position during SWL remains conflicting. Moreover, previous meta-analy- sis simultaneously incorporated studies with different designs into individual analysis which will cause to estimate biased results because of bias resulting from studies with different designs can not be eliminated, Supine versus prone position for UC-Lu et al. Study, Year Country Design Location of Stone Sizea, Mm; Sample Size Age, Year; Ureteral Stone Mean ± SD (Range) Mean ± SD (Range) Prone Supine Prone Supine Prone Supine Choo, 2018 Korea RCT Distal 6.73 ± 1.67 6.40 ± 1.54 75 73 44.95 ± 11.5 44.5 ± 12.2 Göktaş, 2000 Turkey RCT Proximal 7.85 ± 0.94 8.10 ± 0.83 48 48 NA NA Kamel, 2015 Egypt RCT Distal 8.4 ± 0.65 8.6 ± 0.5 49 49 47.6 ± 3.5 44.3 ± 4.3 Hara, 2006a Japan RSC Both 7.3 (3-11) 9.1 (3-28) 110 248 NA NA Hara, 2006b Japan RSC Both 7.7 (3-18) 9.1 (3-24) 98 156 NA NA Istanbulluoglu, 2011 Turkey RSC Distal 61.32 (16-204)a 59.04 (10-238)a 194 148 41.12 (2-81) 50.16 (10-84) Phipps, 2013 UK RSC Distal 7.9 ± 0.4 7.6 ± 0.3 38 72 48.3 ± 2.2 51.3 ± 1.8 Zomorrodi, 2007 Iran RSC Proximal 13.6 12.8 35 33 43.6 46 Table 1. Basic characteristics of 7 included studies Abbreviations: RCT, randomized controlled trial; RSC, retrospective cohort; athe unit of number is mm2; NA, not available. Figure 1. Flow diagram of identification and screening of eligible studies. Other sources are defined as reference lists of included studies. Review 10 Vol 19 No 1 January-February 2022 138 which greatly comprises the robustness and reliability of findings. We, therefore, performed this updated sys- tematic review and meta-analysis to further determine the comparative efficacy of SWL for treating ureteral stone including distal and proximal location performed in the supine related to the prone position. MATERIALS AND METHODS We developed the framework of the current systematic review and meta-analysis according to the recommen- dations issued by the Cochrane Collaboration(13) for the purpose of ensuring the methodological quality because we did not register formal protocol. Moreover, all re- sults were reported based on the framework recom- mended by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement.(14) We did not impose ethical approval and patients’ informed consent because all essential data in the current system- atic review and meta-analysis was extracted from pub- lished studies. Eligibility criteria We mainly designed our selection criteria according to the previous meta-analysis.(12) The inclusion crite- ria were as follows: (a) adult patients who underwent lithotripsy for ureteral stone; (b) trials investigating the comparative efficacy and safety of supine SWL with prone SWL for treating ureteral stone; and (c) studies that discuss at least one of the following outcomes in- cluding stone-free rate after the first and the final SWL session and the mean number of SWL sessions per pa- tient. Studies were excluded if they met the following criteria: (a) a preliminary study group and another up- dated study with comprehensive information has been reported by the same study, (b) studies without suffi- cient information, and (c) reviews, editorials, letters, case reports, conference abstracts, and cell and animal studies. No ethical consent was required because this study was prepared on the basis of previous data. Information sources and search strategy According to the recommendation proposed by the Study, Year Type of Sedation Rate of Shocks Mean No. of Shock Wavesa Mean Powera, % Prone Supine Prone Supine Choo, 2018 general or regional anesthesia 90 pulses/min, with a maximum NA NA NA NA of 4000 shock waves/session Göktaş, 2000 no analgesics or anesthetics NA 4863.54 ± 2114.85 3704.16 ± 1726.75 NA NA Kamel, 2015 sedoanalgesia maximum of 4000 shocks/session 3667±187 3634 ± 156 78.7 ± 3.1 75.6 ± 2.9 Hara, 2006a diclofenac sodium or intramuscular pentazocine 3000 waves shocks/session NA NA NA NA Hara, 2006b NA NA NA NA Istanbulluoglu, 2011 midazolam and fentanyl NA 3960 (1940-7000) 2953 (1250-5500) NA NA Phipps, 2013 oral/rectal diclofenac NA 3997.9 ± 225 5043.2 ± 154.7 71.4 ± 1.9 70.7 ± 1.6 Zomorrodi, 2007 NA NA 3148.5 ± 621.0 3066.1 ± 346.3 NA NA Table 2. Parameters of ESWL aData are presented as mean ± SD (range). ESWL, extracorporeal shock wave lithotripsy; NA, not applicable. Figure 2. Forest plot of stone-free rate after the first session. OR, odds ratio. The black horizontal line and diamond presents 95% confi- dence interval (CI) of individual study respectively, and grey square represents weight of each study. Moreover, the blue diamond refers to pooled estimate. Supine versus prone position for UC-Lu et al. Vol 19 No 1 January-February 2022 11 Cochrane handbook, a systematic search was conduct- ed in three electronic databases including PubMed, Embase and the Cochrane library in order to identify relevant studies. The time of search was limited from their inception until to October 2020. We used medi- cal subject heading (MeSH) of ‘Lithotripsy’, ‘Ureter- al’, ‘Prone position’ and ‘Supine position’ as well as relevant keywords to develop the search strategy, and modification was made according to the unique require- ments of each database. We only considered studies Figure 3. Subgroup analysis of stone-free rate after the first session. OR, odds ratio; RCT, randomized controlled trial. The black hori- zontal line and diamond presents 95% confidence interval (CI) of individual study respectively, and grey square represents weight of each study. Moreover, the blue diamond refers to pooled estimate. Figure 4. Forest plot of the number of sessions. OR, odds ratio. The black horizontal line and diamond presents 95% confidence interval (CI) of individual study respectively, and grey square represents weight of each study. Moreover, the blue diamond refers to pooled estimate. Supine versus prone position for UC-Lu et al. Review 12 Vol 19 No 1 January-February 2022 138 published in the English language for inclusion because no translator who has expertise in other languages was enrolled. Meanwhile, we also manually the references list of all included studies and topic-related reviews to help identify any potential studies. Any disagreements about identification of studies were resolved by discus- sion or consulting a third senior reviewer. Study selection Two independent investigators selected eligible studies according to our selection criteria. We firstly removed duplicate studies based on literature management soft- ware. Then, we excluded ineligible studies through screening titles and abstracts of unique studies. Finally, we retrieved the full-texts of the remaining studies to check their eligibility for inclusion. Data collection Two investigators independently extracted the follow- ing items using the pre-designed data extraction sheet: basic characteristics of the study including first author, publication year, and country, patients’ characteristics including sample size, the number and age of the pa- tients, location of the ureteral stone, and stone size, and clinical characteristics of study including outcomes, and sources of risk of bias. Stone-free rate after the first SWL treatment session was included as the primary outcome, and the mean number of SWL sessions per patient was regarded as the secondary outcome. Stone- free status was defined as having either no or only clin- ically insignificant residual stone fragments (< 3 mm), evaluated by kidney-ureter-bladder radiography or ul- trasonography performed at the third month or longer after the last SWL session.(12) If an included study was designed to have more than two groups, then the meth- ods recommended by the Cochrane Handbook for Sys- tematic Reviews of Interventions were used to divide the individual study into two unique RCTs or combine groups to create a single pair-wise comparison.(15) If es- sential information was missed from the original study, then the leading author was contacted for additional in- formation. Any inconsistencies in data extraction were solved based on the consensus principle. Quality of the evidence At the end of our research, a total of 8 cohorts of patients from 7 studies entered our analysis. Level of evidence of all articles was assessed independently by two au- thors according to the Cochrane Handbook(16) and mod- ified the Newcastle-Ottawa Quality Assessment Scale. (17) In Cochrane risk of bias assessment tool, the quality of all eligible studies was assessed from the following six domains: random sequence, allocation concealment, blinding, incomplete data, selective reporting, and oth- er sources. In the modified Newcastle-Ottawa Scale, a score of 1-9 stars were assigned to all controlled studies. Discrepancy in the assessment were resolved through discussion until a consensus was achieved. Statistical analysis All of the analyses were performed using STATA SE 14.0 software (StataCorp, College Station, Texas, USA). The number of stone-free patients after the first session and the average number of treatment sessions under each position was extracted. Dichotomous data and continuous data were expressed as odds ratio (OR) and weighted mean difference (WMD) with 95% confi- dence interval (CI), respectively. Statistical heterogene- ity among these studies was qualitatively assessed using Cochran’s Q and estimated quantitatively using I2 sta- tistic (> 50%, and P < .1, high heterogeneity).(18) Con- sidered the potential heterogeneity from variabilities of study region and patients, we adopted random-ef- fect model in all of the combined effects to avoid the overestimation of the pooled results.(19) Moreover, we also performed subgroup analysis of stone-free after Figure 5. Subgroup analysis of the number of sessions. OR, odds ratio; RCT, randomized controlled trial. The black horizontal line and diamond presents 95% confidence interval (CI) of individual study respectively, and grey square represents weight of each study. More- over, the blue diamond refers to pooled estimate. Supine versus prone position for UC-Lu et al. Vol 19 No 1 January-February 2022 13 the first session and number of sessions based on lo- cation of ureteral stone and type of study design. We didn’t assess possible publication bias by funnel plots and Egger’s test due to the number of studies included in each quantitative analysis was less than 10, in which case the funnel plots and Egger’s test could yield mis- leading results.(20,21) RESULTS Search results A total of 114 studies were identified at the initial search stage for PubMed, Embase, and Cochrane Library. We excluded 13 duplicate studies with the EndNote soft- ware. A total of 32 studies were retained after excluding 69 ineligible studies through verifying the title and ab- stract. We included 7 eligible studies for the final analy- sis after excluding 25 ineligible studies as the following reasons through full-text check: ineligible aim or study design (n = 4), ineligible participants (n = 2), ineligible intervention regime (n = 8), not accessible (n = 2), and ineligible language (n = 9). The process of searching and screening literature was shown in Figure 1. Basic characteristics of all included studies A total of 7 eligible studies involving 8 cohorts were enrolled finally. Of 7 studies, three were randomized controlled trial(9,22,23) and four were retrospective co- hort.(6,8,24,25) These studies were undertaken in Korea,(22) Turkey,(23,24) Egypt,(9) Japan,(6) UK,(8) and Iran,(25) re- spectively. The publication year of all included studies were between 2006 and 2018. The sample size of indi- vidual eligible study was between 68 and 358, with the total sample size of 1474. Of these 7 eligible studies, one study(6) was divided into two unique cohorts. Four studies(8,9,22,24) focused on distal ureteral stone, two(23,25) focused on proximal ureteral stone, and one(6) focused on both ureteral stone. We documented the basic char- acteristics of all 7 studies were in Table 1. Meanwhile, parameters of ESWL and characteristics of stone were summarized in Table 2. Quality of all included studies Among the three randomized controlled trials, only one study(22) was grated as low risk of bias in random se- quence generation and allocation concealment, all were high risk of bias in blinding of participants and person- nel and low risk of bias in incomplete outcome data, se- lective reporting, and other bias. Among four retrospec- tive cohorts,(6,8,24,25) the total quality score of individual study was all more than 7. We summarized the results of appraising quality of all included studies in Table S1. Stone-free rate after the first session Seven studies(6,8,9,22-25) involving 8 cohorts reported stone-free rate for SWL in the supine and prone po- sitions after the first SWL session. Heterogeneity in pooled analysis was not significant (P = .21; I2 = 27%). Based on a meta-analysis of data from these 8 cohorts, the stone-free rate in the prone group was significant- ly lower than that in the supine group (95% CI: 0.30- 0.63; OR = 0.44; Figure 2), and the sensitivity analysis through omitting individual study with one by one fur- ther confirmed the robustness of pooled result (Figure S1). Subgroup analysis based on location of stone in- dicated that the difference between supine and prone positions was only statistical significance in distal ureteral stone (95% CI: 0.23-0.53; OR = 0.35; Figure 3A). Subgroup analysis based on study design includ- ing randomized controlled trial (95% CI: 0.25-0.71; OR = 0.42; Figure 3B) and retrospective cohort (95% CI: 0.26-0.81; OR = 0.46; Figure 3B) further confirmed the difference between supine and prone positions. Number of sessions per patient Among 7 eligible studies, four(22-25) reported the num- ber of sessions per patient. Meta-analysis suggested no statistical difference (95% CI: -0.03-0.31; WMD = 0.14; Figure 4) between prone and supine positions during SWL, which was further confirmed by sensitiv- ity analysis through omitting individual study with one by one (Figure S2). Subgroup analysis depending on the location of the stone (Figure 5A) obtained consist- ent pooled results with overall pooled result. However, subgroup analysis based on study design found that the mean number of sessions per patient in the supine group was lower than that in the prone group when calculated pooled estimates bwas ased on two eligible randomized controlled trials (95% CI: 0.11-0.48; WMD = 0.294; Figure 5B). Complications during treatment Of seven included studies, five studies reported com- plications during SWL treatment. Istanbulluoglu and colleagues reported that patients experienced petechiae with various degrees and early hematuria.(24) Göktas and colleagues reported that patients in the prone position experienced discomfort on inspiration and expiration and pain localized to the lumbar vertebrae.(23) Howev- er, no serious complications were reported by Phipps et al.,(8) Kamel et al. ,(9) and Choo et al.(22) We could not quantitatively estimate the pooled effects about compli- cations because data were not suitable for meta-anal- ysis. However, most importantly, available evidence suggested that no major or severe complications were observed in any of these trials. DISCUSSION To date, the optimal strategy of ureteral stone is not still unclear, especially for distal ureteral stone.(26) Whereas, SWL and ureteroscopy were considered as the accept- able therapeutic methods for distal ureteral stones by both the American Urological Association (AUA) and European Association of Urology (EAU) guidelines. (27,28) However, compared to ureteroscopy, extracorpor- eal shockwave lithotripsy has been extensively used to treat distal ureteral stones as first-line treatment due to several advantages such as minimal invasion and lack of major or severe undesirable side effects.(4) To date, however, the optimal strategy of SWL has not yet been obtained despite several advances in technology.(29) Considering the fact that the efficiency of transmission of shockwave during SWL is deeply associated with bony structure of pelvis, modifications of patient’s po- sition during SWL treatment was introduced, and then several studies have also investigated the impact of var- ious patient’s positions on the efficiency of SWL.(6,8,23- 25) Meanwhile, one meta-analysis has also further in- vestigated the comparative efficacy and safety between supine and prone positions during SWL, and initially suggested that supine SWL is more effective than prone SWL for achieving a stone-free status.(12) Nevertheless, a definitive conclusion has not yet been generated. After completing the current updated systematic review and meta-analysis, we found that the supine position was made in association with increased the stone-free Distal ureter in NU-Morriss et al.Supine versus prone position for UC-Lu et al. Review 14 Vol 19 No 1 January-February 2022 15 rate compared to prone position, which was also con- firmed by sensitivity analysis and subgroup analysis based on study design. Moreover, subgroup analysis based on location of ureteral stone further suggested that supine position during SWL significantly increased the distal ureteral stone-free rate. Although we did not find significant difference between supine and prone positions in terms of the number of sessions per patient when we incorporated all studies with various designs into individual analysis, subgroup results based on two randomized controlled trials indicated that supine position may be associated with decreased number of sessions compared to prone position during SWL treat- ment. However, urologists must firstly identify whether SWL should be adopted through comprehensively eval- uating several factors such as stone size, stone location, patient medical status, patient age, and body mass in- dex. To date, only one meta-analysis(12) focused on compar- ative efficacy and safety between supine and prone po- sitions during SWL has been published, and concluded a superior comparison of supine position compared to prone position from the stone-free rate after treatment. It must be pointed out that, however, the conclusion was generated from pooled estimate based on 4 clinical studies, of which 3 studies were retrospective design. Moreover, the previous meta-analysis only focused on patients with distal ureteral stone although our present study found that the supine position only associated with increased distal ureteral stone-free rate after per- forming subgroup analysis. Compared to the previous meta-analysis, our meta-analysis obtained more reliable and robust pooled results because our study has major two advantages including more eligible studies and de- tailed clarification of ureteral stone. We also must acknowledge some limitations in our sys- tematic review and meta-analysis. Firstly, we included the observational study in our analysis simultaneously owing to the paucity number of RCTs in the specific topic. However, we performed subgroup analysis being dependent on the study design to further test the robust- ness of all pooled results. Secondly, we failed to quanti- tatively obtain the pooled estimate of the safety profile of each position since only one study has reported nu- merical data.(22) Thirdly, the stone free rate in the in- cluded studies was evaluated by the plain x-ray of kid- ney, ureter, and bladder (KUB) and/or ultrasonography (US), however those both are inefficient for detection of ureteral stones. Fourthly, we did not perform subgroup analysis to further explore the impact of several impor- tant features including stone composition and density and radiographic characteristics on pooled results due to limited data. Fifthly, another one limitation with the present systematic review was the language restriction and that only three major databases were searched and therefore, relevant studies may have been missed. CONCLUSIONS Our study further confirmed the supine approach is su- perior in stone fragmentation and clearance than prone approach. Stone-free rate of the supine position after the first treatment session is significantly higher compared to prone position for patients who underwent SWL. However, research that compared the safety profile of each position is still destitute. Future research can focus on the long-term benefit and patients report outcomes regarding the safety of supine and prone position. 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