The Safety of Continuing Low-Dose Aspirin Therapy Perioperatively in Percutaneous Nephrolithotomy: A Systematic Review and Meta-analysis Yang Pan1, Mingming Xu1, Jiaqi Kang1, Shangren Wang1, Xiaoqiang Liu1* Purpose: Aspirin is often stopped prior to percutaneous nephrolithotomy (PCNL) due to surgical bleeding risk. However, this practice is mainly based on expert opinion, and mounting evidence suggests holding aspirin periop- eratively might not be more harmful than once thought. In this systematic review and meta-analysis, we aimed to discuss the safety of continuing low-dose aspirin perioperatively in PCNL. Materials and Method: We performed a comprehensive literature search in PubMed, EMBASE, Web of Science, and Cochrane Library to identify relevant studies up to December 31st, 2021. The ROBINS-I (Risk of Bias in Non-randomized Studies of Interventions) tool was used to evaluate the quality of the included studies. The safety was assessed by all kinds of perioperative complications and bleeding complications mainly. Egger's test estimated publication bias. The statistical analyses were performed using Rev-Man 5.3 and STATA 15.1 software. Results: Overall, four eligible studies with a total of 1054 patients were included in our study. The meta-analy- sis results revealed that operative time (95%CI: -14.20 - 4.50, MD = -4.85, P = .31), hospital durations (95%CI: -1.80 - 0.50, MD = -0.65, P = .26), stone size (95%CI: -2.90 - 0.67, MD = -1.11, P = .22), and estimated blood loss (95%CI: -17.15 - 0.47, MD = -8.34, P = .06) were not significantly different between the continuing low-dose as- pirin group and the control group. Moreover, there were no significant differences in total complication rate (25% vs 27.9%, 95%CI: -0.07 - 0.08, RD = 0.00, P = .94) and serious complication rate (6.0% vs 3.0%, 95%CI: -0.08 - 0.06, RD = -0.01, P = .84) between the two groups. Similarly, no significant differences were observed in terms of bleeding complication rate (8.3% vs 14.0%, 95%CI: -0.04 - 0.06, RD = 0.01, P = .75), transfusion rate (5.4% vs 10.8%, 95%CI: -0.04 - 0.04, RD = -0.00, P = .98), and postoperative thrombotic events rate (0.6% vs 0.2%, 95%CI: -0.03 - 0.02, RD = -0.00, P = .85). Sensitivity analysis suggested that our results were convincing and no publication bias was observed with the Egger’s test (P = .112). Conclusion: It appears that continuing low-dose aspirin therapy perioperatively in PCNL might be relatively safe. However, further well-designed prospective studies with a large sample size are needed to confirm and validate our findings. Keywords: aspirin; percutaneous nephrolithotomy; safety; systematic review; meta-analysis INTRODUCTION Nephrolithiasis is a common disease affecting the general population. For stones larger than 2 cm or stones in the lower pole of the kidney, percutaneous nephrolithotomy (PCNL) is commonly used and recom- mended by the guidelines for its efficacy and safety(1). In some suitable cases, technological advances in retro- grade intrarenal surgery (RIRS) have also permitted us to approach those stones of ≥ 2 cm(2,3). Renal hemor- rhage is one of the more frequent and worrisome com- plications of PCNL(4). Blood transfusion, embolization, and even nephrectomy have been reported to manage severe bleeding(5). Due to these complications and risks, aspirin, as an antiplatelet agent, was traditionally dis- continued perioperatively to prevent bleeding. Moreo- ver, PCNL is categorized as a high-risk procedure for bleeding and the recommendations of the European As- sociation of Urology (EAU) include the suspension of aspirin before proceeding with this kind of procedure(1). However, what interested us was that some reports de- scribed that PCNL could be safely performed despite continued aspirin therapy(6-8). In addition, when consid- ering aspirin cessation before surgery, there was an in- creased risk of cardiovascular events(9,10), which may be associated with aspirin withdrawal syndrome(11). There- fore, we conducted this systematic review and me- ta-analysis of available literature to evaluate the safety of continuing low-dose aspirin therapy perioperatively in the patients who had undergone PCNL. MATERIALS AND METHODS This meta-analysis was performed based on the guide- lines outlined in the Preferred Reporting Items for Sys- tematic Reviews and Meta-analysis (PRISMA) state- ment(12). Search strategy We performed a systematic literature search of elec- tronic databases, including Cochrane Library, PubMed, EMBASE, Web of Science, and China National Knowl- edge Infrastructure. The time range of articles search was set from database building to December 31st, 2021. The search strategy was as follows: (“Nephrolithotomy, Percutaneous” OR “Nephrolithotomies, Percutaneous” OR “Percutaneous Nephrolithotomies” OR “Percu- 1Department of Urology, Tianjin Medical University General hospital, Tianjin, China. *Correspondence: Department of Urology, Tianjin Medical University General Hospital, Tianjin 30052, China. Tel: +86 13820915038, Fax: +86-22-60814889, E-mail: xiaoqiangliu1@163.com Received January 2022 & Accepted June 2022 Urology Journal/Vol 19 No. 4/ July-August 2022/ pp. 253-261. [DOI: 10.22037/uj.v18i.7170] REVIEW taneous Nephrolithotomy” OR “PCNL” OR “PNL”) AND (“Aspirin” OR “Acetylsalicylic Acid” OR “Acid, Acetylsalicylic” OR “2-(Acetyloxy)benzoic Acid” OR “ASA” OR “Acylpyrin” OR “Aloxiprimum” OR “Col- farit” OR “Dispril” OR “Easprin” OR “Ecotrin” OR “Endosprin” OR “Magnecyl” OR “Micristin” OR “Pol- opirin” OR “Polopiryna” OR “Solprin” OR “Solupsan” OR “Zorprin” OR “Acetysal”). All identified studies were then reviewed for eligibility. The reference lists and citations from key studies were also reviewed for additional eligible studies associated with our topic. Inclusion and exclusion criteria The studies were included in the meta-analysis if the following inclusion criteria were met: 1) study types: randomized controlled trials (RCTs) or retrospective case-control design; 2) included urolithiasis patients who had undergone PCNL; 3) evaluated the safety of continuing low-dose aspirin therapy perioperatively; 4) conducted the safety comparison between the con- tinuing low-dose aspirin therapy group and the control group; 5) provided sufficient data to calculate and ana- lyze. Besides, the exclusion criteria were as follows: 1) con- ference abstract; 2) guidelines; 3) review; 4) case report; 5) editorial comment; 6) animal studies; 7) non-com- parative studies; 8) repeated publication. Data extraction and outcome measurement All eligible articles and available data from the enrolled studies were extracted, respectively, by two independ- ent reviewers and then checked by each other. If any disagreement appeared, a third reviewer would join in and discuss it with them to reach a consensus. Data were extracted from each paper separately and outcome measures were set as follows: first author, publication year, country, study design, study period, techniques used for percutaneous renal access, tract size, number of the surgeon(s), and surgical experience of the sur- geon(s), sample size, age, body mass index (BMI), gender ratio, stone size, operative time, and hospital durations. The safety was assessed by all kinds of intra- or post- operative complications. Serious complications were defined as Clavien-Dindo grade IIIa or higher based on the modified Clavien-Dindo system. The major compli- cations which occurred with aspirin during PCNL were bleeding. Postoperative thrombotic events were also an important concern, especially for patients without continuing aspirin therapy. Therefore, our study also focused on these major complications and analyzed the relevant results. Besides, hemoglobin drop and estimat- Endourology and Stones diseases 180 Table 1. Characteristics and quality evaluation of included studies Author Year Country Study Study Technique for Tract No. Surgical CQC Design Period Renal Access Size (Fr) surgeon Experience Scores a Leavitt et al. 2014 American Case–control Jul. 2012 to Mar. 2014 Balloon/Amplatz dilators 30Fr 3 Experienced 8 Otto et al. 2017 American Case–control Feb. 2012 to Dec. 2015 Balloon/Amplatz dilators 30Fr 1 Experienced 8 Wang et al. 2019 China Case–control Jul. 2014 to Jul. 2017 Amplatz dilators 18Fr 1 Experienced 7 Falahatkar et al. 2021 Iran Cross-sectional Mar. 2012 to Dec. 2018 Amplatz dilators 28/30 Fr 1 Experienced 8 Abbreviations: CQC, Cambridge Quality Checklists Figure 1. Flow diagram of identification and screening of eligible studies (PRISMA flow diagram). Safety of continuing aspirin during PCNL-Pan et al. Vol 19 No 4 July-August 2022 254 ed blood loss were compared and analyzed. Hemoglo- bin drop meant that the postoperative hemoglobin level decrease compared with that of pre-operative evalua- tion. Quality assessment of included studies The quality of the included studies was assessed by two independent reviewers. The most precise tool to assess the quality of included articles is the risk of bias scales. If the articles were randomized, the Cochrane risk of bias tool (RoB2) was used(13). For papers reporting on non-randomized controlled studies, the ROBINS-I (Risk of Bias in Non-randomized Studies of Interven- tions) tool was applied to assess the risk of bias(14). The ROBINS-I was used to assess the methodological quality of non-randomized studies on seven domains: confounding factors, selection of participants into the study, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported results. Each domain was classified as having low, moderate, serious, critical, or no information available for risk of bias. The overall risk of bias for the studies was determined by combining the levels of bias in each domain. Moreover, we also appraised study quality by using the Cambridge Quality Checklists(15), which could assess the quality of correlational evidence for risk and pro- tective factors (on the basis of sampling, participation rates, sample size, and measurement reliability), tem- poral evidence (whether data are cross-sectional, retro- spective, or prospective), and causal evidence (whether there is variation in the risk or protective factor, change in outcomes is analyzed, and confounding is accounted for). Abbreviations: BMI, body mass index; M, male; F, female; NA, not available. Data was presented as “the continuing low-dose aspirin group / the control group”. a Median. Table 2. Demographic and clinical characteristics of included patients Study Sample Age BMI Gender Stone Operative Hemoglobin Estimated Blood Hospital Size (n) (years) (kg/m2) (M: F) Size (mm) Time (mins) Drop (g/dL) Loss (mL) Duration (days) Leavitt et al. 2014 15 69 a 31.1 a 11:4 21 ± 11 74 a 1.9 a 150 a 2.0 a 38 62 a 32.9 a 19:19 23 ± 14 77 a 2.3 a 125 a 2.0 a Otto et al. 2017 67 66 ± 10 32.1 ± 9 37:30 37 ± 16 163 ± 62 0.99 ± 1.1 44 ± 45 3.2 ± 2.7 207 52 ± 15 30.3 ± 9 100:107 40 ± 19 190 ± 67 0.94 ± 0.96 54 ± 48 3.2 ± 3.8 Wang et al. 2019 44 58.74 ± 10.06 NA NA 20.60 ± 5.21 28.27 ± 7.08 NA 44.94 ± 21.24 NA 40 50.40 ±12.49 21.33 ± 5.00 27.02 ± 5.12 51.70 ± 34.22 Falahatkar et al. 2021 40 60.08 ± 9.45 28.59 ± 4.91 16:24 32.85 ± 16.37 43.20 ± 21.37 1.02 ± 1.31 NA 1.25 ± 0.98 603 48.66 ± 12.32 27.85 ± 4.89 331:272 33.27 ± 13.22 44.83 ± 16.84 1.43 ± 1.44 2.43 ± 1.27 Safety of continuing aspirin during PCNL-Pan et al. Figure 2. Results of the risk of bias assessment using ROBINS-I scale. Review 255 Endourology and Stones diseases 182 Statistical analysis The mean difference (MD) and the risk difference (RD) were used to compare continuous and dichotomous var- iables, respectively. The relevant results were shown in the forest plot. The quantity of heterogeneity among these articles was tested by Cochrane Q test and Hig- gins I2 value. The fixed-effects model was used if heter- ogeneity was thought to be acceptable (I2 < 50%); oth- erwise, a random-effects model was used. P values of dichotomous and continuous variables were calculated by Mantel–Haenszel (MH) test and Inverse-Variance (IV) weighting, respectively. The Z test determined all the pooled effects. The sensitivity analysis was per- formed to explain the high heterogeneity using an arti- cle-by-article culling method. The publication bias was estimated by Egger's test. The statistical analysis was performed using Manager 5.4 (Cochrane Collaboration, Oxford, UK) and STATA 15.1 (College Station, Tex- as, USA). Results of the risk of bias assessment using ROBINS-I were analyzed and visualized using the R software (version 4.1.2, “robvis” package). For all sta- tistical analyses, a two-sided p < .05 was considered statistically significant. RESULTS Literature search and study characteristics A PRISMA flow chart of screening and selection re- sults was shown in Figure 1. After searching databas- es systematically, we identified 68 potentially relevant articles. No additional records were identified through other sources. There were 53 different articles after re- moving duplicates. According to the inclusion and ex- clusion criteria, 43 articles were excluded after review- ing their titles or abstracts. The remaining 10 studies were assessed for eligibility by reading full texts. Af- ter a full-text review, four eligible studies with a total sample size of 1054 patients were included in the me- ta-analysis finally(16-19). Table 3. Intra- or postoperative complications of the included patients Study No. (%) of No. (%) of No. (%) of No. (%) of No. (%) of postoperatives total complications serious complications* bleeding complication needing transfusion thrombotic event Leavitt et al. 2014 5 (29%) a 1 (6%) a 3 (18%) a 3 (18%) a 0 14 (33%) a 7 (16%) a 8 (19%) a 6 (14%) a 0 Otto et al. 2017 23 (34.4%) 7 (10.4%) 2 (3.0%) 1 (1.5%) 1 (1.5%) 55 (26.6%) 12 (5.8%) 6 (2.9%) 2 (1.0%) 0 Wang et al. 2019 1 (2.3%) 0 0 0 0 3 (7.5%) 3 (7.5%) 1 (2.5%) 0 2 (5%) Falahatkar et al. 2021 13 (32.5%) 2 (5.0%) 9 (22.5%) 5 (12.5%) 0 177 (29.4%) 5 (0.8%) 110 (18.2%) 88 (14.6%) 0 Data was presented as “the continuing low-dose aspirin group / the control group”. * Clavien IIIa or greater. a Total number of PCNL procedures as denominator. Figure 3. Forest plot of clinical characteristics including stone size, hospital duration, estimated blood loss, and operative time between the continuing low-dose aspirin group (Group A) and the control group (Group B). Safety of continuing aspirin during PCNL-Pan et al. Vol 19 No 4 July-August 2022 256 The characteristics and quality evaluation of eligible studies are reported in Table 1. Overall, the quality of retrospective case-control studies was relatively high. Only one study was considered as a serious risk of bias based on the ROBINS-I assessment. The whole results of the risk of bias assessment using ROBINS-I were shown in Figure 2. In addition, the majority of studies reported the demographic and clinical characteristics such as patients’ average age, BMI, sex ratio, and stone size. The demographic and clinical characteristics of Figure 5. Forest plot of bleeding complication rate, needing transfusion rate, and postoperative thrombotic events rate between the con- tinuing low-dose aspirin group (Group A) and the control group (Group B). Figure 4. Forest plot of total complication rate and serious complication rate between the continuing low-dose aspirin group (Group A) and the control group (Group B). Safety of continuing aspirin during PCNL-Pan et al. Review 257 enrolled patients were summarized in Table 2. Perioperative and clinical characteristics The meta-analysis results revealed that operative time (95%CI: -14.20 - 4.50, MD = -4.85, P = .31; Figure 3) and hospital durations (95%CI: -1.80 - 0.50, MD = -0.65, P = .26; Figure 3) were both not significant- ly different between the continuing low-dose aspirin group and the control group. However, significant het- erogeneity was reported (P = .006, I² = 80%; and P = .009, I² = 85%, respectively, Figure 3). Similarly, no significant differences were observed in terms of stone size (95%CI: -2.90 - 0.67, MD = -1.11, P = .22; Figure 3) and estimated blood loss (95%CI: -17.15 - 0.47, MD = -8.34, P = .06; Figure 3). The heterogeneity was low (P = .83, I2 = 0%; and P = .72, I2 = 0%; respectively). In addition, three studies reported that there was no differ- ence in the change of hemoglobin, hematocrit, or serum creatinine between the two groups. Total complications and serious complications The results of complications were summarized and list- ed in Table 3. All eligible studies reported total compli- cation rate. The total complication rate was presented in Figure 4. There was no statistically significant differ- ence in the total complication rate between two groups (25% vs 27.9%, 95%CI: -0.07 - 0.08, RD = 0.00, P = .94; Figure 4). The heterogeneity was also relatively low (P = .29, I2 = 20%; Figure 4). Serious complica- tions were defined as Clavien-Dindo grade IIIa or high- er based on the modified Clavien-Dindo system. Simi- larly, no statistically significant difference was reported in the serious complication rate between two groups (6.0% vs 3.0%, 95%CI: -0.08 - 0.06, RD = -0.01, P = .84; Figure 4), however, relatively high heterogeneity was reported (P = .07, I² = 57%; Figure 4). Major complications The meta-analysis results revealed that no significant differences were observed in terms of bleeding com- plication rate (8.3% vs 14.0%, 95%CI: -0.04 - 0.06, RD = 0.01, P = .75; Figure 5), needing transfusion rate (5.4% vs 10.8%, 95%CI: -0.04 - 0.04; RD = -0.00, P = .98; Figure 5), and postoperative thrombotic events rate (0.6% vs 0.2%, 95%CI: -0.03 - 0.02; RD = -0.00, P = .85; Figure 5). Moreover, there was no significant heterogeneity (P = .71, I² = 0%; P = .94, I² = 0%; and P = .51, I² = 0%; respectively; Figure 5). Sensitivity analysis and Publication Bias After the research by Otto et al. was excluded, the I2 value in operative time changed from 80% to 0%. The analysis suggested that this study might be the major cause of the heterogeneity for operative time. The het- erogeneities for other results were relatively low and still stable, when we got rid of one or two studies every time from the meta-analysis. Therefore, the sensitivity analysis suggested that our results were convincing. In addition, no publication bias in the primary outcome (total complications) was observed with the Egger’s test (P = .112, Figure 6). DISCUSSION Many urologic surgeries including prostate biopsies, renal biopsies, robot-assisted radical prostatectomy, and kidney transplants have been reported to have no significant increase in the risk of major bleeding com- plications and transfusion rate with a continuation of perioperative aspirin(20-26). Based on our systematic re- view and meta-analysis, we further find that there might be no significantly higher risk of bleeding during PCNL for patients continuing low-dose aspirin therapy. The risk factors for bleeding after PCNL are complex. Figure 6. Egger’s plot for total complications rate. Safety of continuing aspirin during PCNL-Pan et al. Vol 19 No 4 July-August 2022 258 Some studies show that upper caliceal puncture, soli- tary kidney, staghorn stone, multiple punctures, surgeon experience, and the presence of diabetes mellitus are factors associated with increased risk for bleeding dur- ing PCNL(27,28). The other important factors relevant to bleeding during PCNL include larger tract size, longer surgical duration, greater stone burden, the workload of the surgical surgeon, and so on(29). Different PCNL techniques could also influence bleed- ing and complications. All kinds of techniques associ- ated with reducing bleeding during PCNL have been reported, and one predominant technique is to decrease the size of percutaneous renal access because renal ac- cess has a potential impact on renal tissue and blood loss. A smaller tract could prevent the parenchymal and infundibular trauma, thereby resulting in less hemor- rhage and lower PCNL-associated complication rates. The most notable ones are mini PCNL where sheaths from 15 Fr to 20 Fr are deployed, and ultra-mini PCNL where sheath sizes range from 11 Fr to 14 Fr(30). Com- pared to standard PCNL, the hemoglobin drop, reported pain, need for transfusion, and duration of hospitaliza- tion were all lesser in patients who had undergone mi- ni-PCNL and ultra mini PCNL(31). There is no certainty as to whether aspirin was the re- sponsible factor for bleeding disparities in some small studies(32,33). Furthermore, the EAU guidelines recom- mended that temporary discontinuation or bridging of antithrombotic therapy in high-risk patients should be decided in consultation with the patient’s internist(1). Those patients who reported in the included studies used aspirin mainly for primary or secondary cardio- vascular prevention such as prior myocardial infarction, transient ischemic attack or stroke, coronary artery dis- ease or stent, peripheral artery disease or stent. They were considered relatively high risk. The surgical team did not play a decisive role in initiating or ending aspi- rin use. The continued and uninterrupted aspirin thera- py perioperatively was based on mutual decision mak- ing between the patient, cardiologist and or neurologist, anesthesiologist, and urologist. Moreover, the included studies showed that there was no significant difference in other variables, which can affect bleeding such as stone size and operative time, between the two groups; therefore, the main factor that can affect bleeding in the two groups might be whether to continue low-dose as- pirin therapy perioperatively. The included studies reported the rate of need for trans- fusion ranging from 0 to 18% in the continuing low- dose aspirin group and from 0 to 14.6% in the control group, with no significant difference. No deaths or ad- mission to intensive care centers were reported. Our systematic review of these studies shows the safety of continuing low-dose aspirin therapy during PCNL. The 81-100mg dose aspirin was applied in most patients and this suggested that continuing 81-100mg dose aspirin therapy might not increase the risk of bleeding in the perioperative period of PCNL. What should be emphasized is that preventing cardio- vascular and cerebrovascular events might be more crit- ical than prevention of perioperative bleeding. Aspirin is an important drug for those at high risk of life-threat- ening cardio-vascular diseases and the main reason for its use. In addition, these high-risk patients are those in whom cessation of aspirin poses the greatest risk (34). Routinely, aspirin will be discontinued 7 days before the surgery and the aspirin withdrawal syndrome may significantly increase the risk of cardiovascular and cerebrovascular events(11). This syndrome peaks around the time of the surgical operation(35). The only rand- omized controlled study and a meta-analysis concluded that continuation of perioperative aspirin was associat- ed with one third lower risk of major adverse cardiac events(35,36). In conjunction with our analysis in bleeding complications, aspirin played an important role in re- ducing the risk and severity of thromboembolic compli- cations when compared to those that discontinued as- pirin. In two studies included in our systematic review, we found one postoperative thrombotic event occurred in continuing low-dose aspirin group(18); furthermore, two patients in the discontinuing group did need an- gioembolization for bleeding(17). This information indi- cates that postoperative thrombotic events may also oc- cur in the continuing aspirin group, and severe bleeding may also occur in the discontinuing group. As a result, it seems that there might be no obvious corresponding relationship about the continuation of low-dose aspirin perioperatively and occurring cardiovascular events in patients who need PCNL(18). In the present study, major complications were made up of bleeding complications and postoperative thrombot- ic events. There was no significant difference found in major complications in these studies, as well as length of stay, frequency of readmission, and changes in he- moglobin, hematocrit and serum creatinine levels. The continuation of aspirin seems not to influence renal function or the incidence of other complications, con- cluding that continuing low-dose aspirin might be rela- tively safe in the PCNL surgery. We recognize certain limitations of this study. First, this systematic review and meta-analysis had the limit- ed number of studies involved and the relatively small sample size. Second, these included studies were almost single-center and retrospective. Third, the small patient cohort and short follow-up make the evidence level of our study relatively weak. It is possible that some bleed- ing events or thromboembolic events could have been missed during the short period. Thus, the generaliza- bility of our outcomes might be limited. Further ran- domized, multi-center trials will contribute objective evidence to these aspects. Despite these limitations, this systematic review and meta-analysis provides valuable evidence and reference for continuing low-dose aspirin therapy perioperatively during PCNL. Even though our findings all preferred that it was safe to perform PCNL in patients with continuing low-dose aspirin therapy (81-100mg), it was still hard for us to draw such definitive conclusions due to given limited available evidence. Patients who have been receiving aspirin therapy should be informed of the risks in detail before making decisions to continue the aspirin thera- py during PCNL or not. Therefore, larger prospective studies or randomized controlled trials (RCT) should be done to confirm and validate our findings. CONCLUSIONS It appears that continuing low-dose aspirin therapy peri- operatively in the patients had undergone PCNL might be relatively safe. Considering the number of studies involved and the relatively lack of evidence, larger and prospective randomized controlled studies should be done to confirm and validate our findings. Safety of continuing aspirin during PCNL-Pan et al. Review 259 ACKNOWLEDGEMENT Our project was supported by National Natural Science Foundation of China (No. 82171594). The role of the funders was in the design and writing the study. CONFLICT ON INTEREST The authors declare that they have no competing inter- ests. REFERENCES 1. Türk C, Petřík A, Sarica K, Seitz C, Skolarikos A, Straub M, et al. EAU Guidelines on Interventional Treatment for Urolithiasis. Eur Urol. 2016;69:475-82. 2. Barone B, Crocetto F, Vitale R, Di Domenico D, Caputo V, Romano F, et al. Retrograde intra renal surgery versus percutaneous nephrolithotomy for renal stones >2 cm. A systematic review and meta-analysis. Minerva Urol Nefrol. 2020;72:441-50. 3. Lai D, He Y, Li X, Chen M, Zeng X. 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