REVIEW Safety of Surgery in Benign Prostatic Hyperplasia Patients on Antiplatelet or Anticoagulant Therapy: A Systematic Review and Meta-Analysis Xiongfa Liang1,2,*, Weizhou Wu1,2,*, Yapeng Huang1,2, Shike Zhang1,2, Jian Huang1,2, Tao Zeng1,2, Fangling Zhong1,2, Yongchang Lai1,2, Xiaolu Duan1,2, Chao Cai1,2, Alberto Gurioli3, Tuo Deng1,2, Wenqi Wu#1,2 Purpose: The management strategies of anticoagulant (AC) or antiplatelet (AP) therapy in the preoperative period of benign prostatic hyperplasia (BPH) is still controversial. Therefore, a meta-analysis to systematically evaluate the surgical safety for BPH patients on AC or AP therapy was performed. Materials and Methods: The protocol for the review is available on PROSPERO (CRD42018105800). A lit- erature search was performed by using MEDLINE, Web of Science, PubMed, Cochrane library, and Embase. Summarized odds ratios (OR), mean difference (MD) and 95% confidence intervals (CI) were used to assess the difference in outcomes. Results: We identified 13 trials with a total of 3767 patients. An intragroup significant difference was found in bleeding complications and blood transfusions when undergoing transurethral resection of the prostate (TURP). For laser surgery, the intragroup significant difference was found in the result of blood transfusion. Bridging ther- apy would not cause a higher risk of bleeding complications and blood transfusion during the perioperative period. Besides, no difference existed in operation time, catheterization time, hospitalization, and thromboembolic events. Conclusion: Patients with BPH on perioperative AC/AP therapy would have a risk of postoperative hemorrhage after TURP or laser treatments. To reduce the risk of hemorrhage, bridging therapy could be a good choice. Keyword: Transurethral resection of prostate (TURP); Laser treatment; Benign prostatic hyperplasia (BPH); Anticoagulant; Antiplatelet INTRODUCTION Benign prostatic hyperplasia (BPH) is a disease common in men over 50 years of age. Up to 50% of men in their sixth decade suffer from BPH, and the corresponding rate was increased with age(1) The men troubled by lower urinary tract symptoms need drug treatment or surgical intervention. For pharmacological treatment, α1-adrenoceptor antagonists like tamsulosin can effectively improve lower urinary tract symptoms. (2) Nevertheless, α1-adrenoceptor antagonist can- not prevent the occurrence of urinary retention or the need for surgery. Transurethral resection of the pros- tate (TURP) has been the gold standard for the surgi- cal management of BPH in recent decades. However, morbidity followed with TURP is still concerned, es- pecially bleeding requiring blood transfusion and late postoperative bleeding.(3) With an aging population and a high incidence of cardiovascular disease, the number of patients requiring anticoagulant (AC) or antiplatelet (AP) therapy is steadily growing.(4) With an increasing elderly population requiring surgical procedures for BPH treatment and long-term use of anticoagulants, the management strategies of AC/AP therapy in the pre- operative period remain controversial. Some surgeons prefer to discontinue AC/AP therapy and replaced low molecular weight heparin (LMWH) in advance of sur- gery, whereas others continue AC/AP therapy periop- eratively. Recently, a number of laser techniques have emerged as alternatives to TURP including the holmium yttrium aluminum garnet neodymium (Ho:YAG), thulium la- ser, and potassium titanyl phosphate (KTP, also known as the Greenlight), offering new options for patients with BPH. These laser surgeries present the advantage of hemostasis comparing with TURP and have been an effective tool for BPH.(5-8) All types of lasers are con- sidered suitable and safe for patients taking anticoagu- lants in the recommendation of European Association of Urology (EAU) guidelines for the treatment of BPH. Furthermore, EAU guidelines on the surgical treat- ment of BPH nominated that 532-nm laser vaporization should be considered in patients receiving anticoagu- lant medication or for those with a high cardiovascular risk.(9) However, the EAU guidelines did not mention whether preoperative anticoagulant therapy should be Urology Journal/Vol 18 No. 2/ March-April 2021/ pp. 151-158. [DOI: 0.22037/uj.v16i7.5974] 1Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, China. 2Guangdong Key Laboratory of Urology, Guangzhou, Guangdong, China. 3Department of Urology, Turin University of Studies, Italy. *Correspondence: Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou, Guangdong, China. Kangda Road. Haizhu District, Guangzhou, Guangdong, China, 510230. Email: wwqwml@163.com. * These authors contributed equally to this work. Received February 2020 & Accepted July 2020 Vol 18 No 2 March-April 2021 138 withdrawn regardless of whether traditional TURP or advanced laser technology is selected. Similarly, the National Institute for Health and Care Excellence (NICE) guidelines did not specify the perioperative management of patients under AC/AP therapy.(10) Therefore, we performed this meta-analysis based on the current evidence to assess the safety of surgery in BPH patients on AC/AP therapy. Our goal was to de- rive an evidence-based recommendation for clinical practice. MATERIALS AND METHODS Literature search The present meta-analysis was performed in accord- ance with the Preferred Reporting Item for systematic Reviews and Meta-Analysis (PRISMA) guidelines. The protocol for the review was available on PROSPERO (CRD42018105800; https://www.crd.york.ac.uk/pros- pero/). The studies were identified by a literature search of MEDLINE, Web of Science, PubMed, Cochrane library and Embase database articles published up to July 2019. Separate searches were completed using the following search terms: benign prostatic hyperplasia, BPH, transurethral resection of the prostate, TURP, holmium laser enucleation of the prostate, HoLEP, photoselective vaporization of the prostate, PVP, thu- lium vaporesection of the prostate, ThuVARP, laser therapy, anticoagulants, antiplatelet, aspirin, warfarin, Coumadin and clopidogrel. The detailed retrieval strat- egy was listed in S1 file. In addition, a manual search was also performed in the references from the included studies and databases like EMBASE. No temporal, re- gional, publication status, or language restrictions were applied. Inclusion and exclusion criteria Literature searching, study examinations, data extrac- tions, study quality assessment and statistical analyses were conducted by two authors (JH and YH) inde- pendently. Disagreement was resolved through consul- tation with the third author (TZ). Eligibility criteria for the included studies were defined base on the PICOS principles: (1) Participants (P): Patients having a series of symptoms of urinary obstruction, with clinical and laboratory evidence suggesting enlarged prostate and necessitating surgical treatment. (2) Interventions (I) and comparisons (C): Exploring the safety of surgery in BPH patients on AC/AP therapy compared with the patients who do not need AC/AP therapy. (3) Outcomes (O): Including at least one of the predefined outcome measurements. (4) Study design (S): randomized con- trolled trials (RCTs), case-control studies or cohort studies with relative data could be used directly or in- directly. In contrast, studies were excluded if the inclu- sion criteria were not met or the relevant data could not be extracted in the appropriate format and obtaining the data from the authors. Additionally, studies as confer- ence proceedings, reviews, case reports, abstracts, and unpublished studies were excluded from this study. Procedures Patients on AC/AP therapy during the surgery for BPH constituted AC/AP group, and patients who do not need AC/AP therapy formed the control group. The following variables from each study were recorded in- dependently by two reviewers: first author name; pub- lication year; study period; research design type; AC/ AP type; total number of patients enrolled; PSA (pros- tate-specific antigen level); IPSS (international pros- tate symptom score); maximum urinary flow; prostate volume; weight of resected tissue; and age of patients. In addition, the following outcome measures were ex- tracted: operative time, bleeding complications, throm- boembolic events, blood transfusion, length of hospital stay, and catheterization time. Bleeding complication is a combined concept described in the included stud- ies. Several studies directly defined bleeding compli- cation as an extended period of bladder irrigation (3 or more days postoperatively), clot retention or persistent hematuria necessitating recatheterization.(11-13) While two only record incidents of persistent hematuria,(14,15) and the other one record incidents of extended period of bladder irrigation.(16) Thromboembolic events, as included studies described, was defined as pulmonary embolism, deep venous thrombosis, acute coronary syndromes, and cerebrovascular events like stroke.(12, 17- 19) Outcome of bleeding complication and blood trans- fusion, assessing the degree of hemorrhage, were the key parameters evaluating the safety of the surgery for BPH patients with AC/AP therapy. Discrepancies were resolved through consultation with the third author. Safety of BPH surgery under anticoagulants-Liang et al. Table 1. Characteristics and quality evaluation of including studies. Study Country Study period Design No. of patients Age Comparability Study quality AC/AP Control AC/AP Control Ala-Opas et al. 1995 Finland May. 1993 to Feb. 1994 CCT 40 42 69 (53-85) 75 (64-86) ①④⑥ 4 (NOS) Dotan et al. 2002 America Nov. 1997 to Feb. 2001 CCT 20 20 N/A N/A ①③④⑤ 6 (NOS) Nielsen et al. 2000 Denmark 1996 to 1998 RCT 26 27 70 (66-74) 69 (65-76) ①②③④⑤⑥ 3 (Jadad) Descazeaud et al. 2011France Jan. 2007 to Dec. 2008 CCT 55 406 75 ± 14.14 71 ± 14.14 ②③④⑤⑥ 6 (NOS) Taylor et al. 2011 Australia Jan. 2008 to Jun. 2009 CCT 7 91 69 ± 6.37 71 ± 8.56 ①④ 6 (NOS) Ong et al. 2015 Australia Jan. 2011 to Dec. 2013 CCT 32 166 N/A N/A ①④⑤⑥ 6 (NOS) Tyson et al. 2009 England May. 2002 to Sep. 2007 CCT 25 37 69.4 ± 7.2 65.2 ± 8.7 ①③⑤ 5 (NOS) Tayeb et al. 2016 America 1999 to 2014 CCT 30 1558 N/A N/A ②③④⑤ 7 (NOS) Ruszat et al. 2006 Switzerland Sep. 2002 to Jan. 2006 CCT 71 92 72 ± 9 68 ± 9 ②③⑤ 7 (NOS) Knapp et al. 2017 Australia Jul. 2010 to Dec. 2016 CCT 59 272 74.9 ± 10.3 67.6 ± 9 ①②③⑤ 6 (NOS) Piotrowicz et al. 2017 Poland 2009 to 2012 CCT 65 44 68.3 ± 6.63 66.9 ± 6.5 ②③⑤ 6 (NOS) Eken et al. 2018 Turkey Nov. 2012 to Oct. 2016 CCT 59 174 74.8±9.1 69.2±5.5 ① 5 (NOS) Meskawi et al. 2018 Canada 2011 to 2016 CCT 87 274 70±7.48 66±9.62 ①②③④ 7 (NOS) ①bleeding complications ②operation time ③catheterization time ④blood transfusion ⑤hospitalization ⑥Thromboembolic events. RCT: randomized controlled trials, CCT: case control trials, AC: anticoagulant, AP: antiplatelet, N/A: not available, NOS: Newcastle– Ottawa Scale, Jadad: Jadad scale. Values are presented as mean ± standard deviation or mean ( range). Vol 18 No 2 March-April 2021 152 Vol 18 No 1 January-February 2021 Evaluations The quality of the randomized controlled trials (RCT) included in this systematic review was assessed inde- pendently by two reviewers by using the Jadad scale score,(20) which ranges from 0 to 5 points; a higher score indicates a better quality of the research. The Jadad score evaluates studies based upon their randomization, blinding, and descriptions of participant withdrawals and dropouts. A study with a Jadad score of 3 points or more was considered to be a relatively high-quality study. The Newcastle-Ottawa scale (NOS) was used to assess the quality of case-control trials included in this meta-analysis.(21) The review scores range from 0 to 9 points for each trial. Scores between 0 and 4 implied a low-quality study, while those between 5 and 9 im- plied a high-quality study. Discrepancies were resolved through consultation with the third author. Statistical analysis Odds ratios (OR) were used for binary outcomes with 95% confidence intervals (CI), and mean difference (MD) or standardized mean difference was used for continuous variables with 95% CI. Pooled estimates were calculated using a fixed-effects model(22) if no het- erogeneity was presented; otherwise, a random-effects model(23) was used. The overall effect was determined by the Z-effect, and p < .05 was considered to be statis- tically significant. The Cochrane X2-test and Inconsist- ency (I2) were used to assess the heterogeneity among studies.(24,25) P < .1 indicated the presence of heterogene- ity, and I2 < 50% indicated that the level of heterogene- ity was acceptable. Sensitivity analysis was performed using a single item removal method. The funnel plot was used to assess the publication bias. All tests were performed using Review Manager Software (Revman 5.3, Cochrane Collaboration, Oxford, English). RESULTS Study characteristics The search protocol and its results are shown in Figure 1. The initial search identified 383 potentially relevant studies. Additionally, 33 studies were available by man- ual search with references. Then 181 duplicates were detected and excluded by NoteExpress. After screen- ing of studies titles and abstract, 39 potentially rele- vant studies needed further assessment for eligibility. Among them, 9 studies were excluded for no control Study Surgery Prostate Weight of Preoperative Preoperative Preoperative maximum AC/AP Perioperative type volume (ml) resected tissue (g) PSA (ng/ml) IPSS urinary flow (ml/s) type management AC/AP Control AC/AP Control AC/AP Control AC/AP Control AC/AP Control of AC/AP therapy Ala- TURP N/A N/A 30 (7-70) 28 (5-80) N/A N/A N/A N/A 9 (4.2-19) 9.6 (4.6-16.8) AC AC continued Opas et al. 1995 Dotan TURP N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A Type of AC/ AC/AP withdrawal + LMWH et al. 2002 AP was not counted separately Nielsen TURP N/A N/A 37 (27-64) 30 (16-50) N/A N/A N/A N/A N/A N/A AP AP continued et al. 2000 Descaz- TURP 58.5 49 30.5 21.7 3.8 4.6 17.6 20.5 5.8 8.3 AC AC withdrawal + LMWH eaud et al. 2011 Taylor TURP N/A N/A 17 25 N/A N/A N/A N/A N/A N/A AP AP continued et al. 2011 Ong TURP N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A AP AP continued et al. 2015 Tyson HoLEP 50.3 ± 16.7 49.9 ± 20.6 N/A N/A 3.9 (2.2) 4.4 (3.9) 16.5 (8.7) 23.5 (6.7) N/A N/A AC AC continued et al. 2009 Tayeb HoLEP N/A N/A 55.5 68 5.5 5.2 N/A N/A N/A N/A AP AP continued et al. 2016 (1-206) (0.2-532.2) Ruszat PVP 58 ± 31 71 ± 39 N/A N/A 3.4 (2.7) 4.6 (4.2) N/A N/A N/A N/A AP AP continued et al. 2006 Knapp PVP 90.8 ± 58.7 79.1 ± 47 N/A N/A 5.6 (6.2) 6.2 (8.0) 17.8 (6.9) 20(7.1) N/A N/A AC AC continued et al. 2017 Piotro- PVP 66.3 ± 6.63 66.9 ± 6.5 N/A N/A 2.55 (1.25) 2.68 (1.42) 24.7 (4.58) 25.19 (4.11) 9.78 (2.99) 9.42 (2.73) Type of AC/AP withdrawal + LMWH wicz et al. 2017 AC/AP was not counted separately Eken PVP 61.5 ± 20.7 54.8 ± 16.9 N/A N/A 3.3 (2.8) 3 (2.4) 22.5 (7.6) 21.6 (5.3) 7.9 (2.2) 8.3 (3.1) Type of AC/AP withdrawal + LMWH et al. 2018 AC/AP was not counted separately Meska- PVP 71 ± 29.63 76 ± 29.63 N/A N/A 3.8 7.6 N/A N/A N/A N/A AP AP continued wi et al. 2018 AC: anticoagulant, AP: antiplatelet, PSA: prostate-specific antigen level, IPSS: international prostate symptom score, HoLEP: holmium laser enucleation of the prostate, TURP: transurethral resection of the prostate, PVP: photoselective vaporization of the prostate, LMWH: low molecular weight heparin, N/A: not available, Values are presented as mean ± standard deviation or mean ( range). Table 2. Perioperative parameters of each selected studies. Safety of BPH surgery under anticoagulants-Liang et al. Review 12 Review 153 group; 8 studies were excluded for irrelevant topics; 3 studies were excluded for failure to extract the prima- ry data assessing the safety of surgery; and 6 for being reviews. At the end, 13 eligible studies(11-19, 26-29) including 3767 patients (564 on AC/AP and 3203 con- trol) were included in the subsequent meta-analysis ac- cording to our predefined selection criteria. The 13 studies included one RCT and twelve case-con- trol trials. No prospective cohort study that met the in- clusion criteria was found (Table 1). The methodologi- cal quality of the included non-randomized studies was mostly granted a score between 5 and 7, while the RCT got 3 points on the Jadad scale. AC agent reported included coumadin and pradaxa, and AP agent reported included aspirin, clopidogrel, ticlopidine and dipyridamole. Of BPH patients on AC/ AP, seven included studies evaluated the surgical safety of perioperative AP therapy, and three included studies evaluated the surgical safety of perioperative AC thera- py. Three included studies did not record the use of AC and AP agent separately when assessing the safety of surgery. AC/AP therapy was continued during the peri- operative period in nine studies, while AC/AP therapy was withdrawn and replaced with low molecular weight heparin in four studies (Table 2). Preoperative measurement of prostate size and the weight of the resected prostate during operation of each study were summarized in Table 2. Five studies reported weight of resected tissue, and seven studies reported preoperative measurement of prostate volume rather than weight of resected tissue. One study report- ed both preoperative measurement of prostate volume and weight of resected tissue. Preoperative PSA, IPSS, and maximum urinary flow in each study were also de- scribed in Table 2. Bleeding complications Figure 2A presents the comparison of the cases of bleeding complications between the AC/AP group and the control group. As the heterogeneity was low among these studies (P = .17, I2 = 31%), a fixed-effects mod- el was applied for meta-analysis and showed that peri- operative AC/AP therapy would lead to a higher risk of bleeding complications compared with the control group (95% CI: 1.32–4.13, OR = 2.33, P = .004) (Figure 2A). The funnel plot showed no publication bias (Fig- ure S1A). Subgroup analysis was conducted on account of surgical type, AC/AP type, and management of AC/ AP therapy. The subgroup meta-analysis result showed that patients in TURP treatment for BPH would have a higher risk of bleeding complication in AC/AP group (OR = 2.58, P = .005, Table S1). However, for laser surgical treatment for BPH, including holmium laser enucleation of the prostate (HoLEP) and photoselective vaporization of the prostate (PVP), the risk of bleed- ing complications in the AC/AP group was similar to the control group (OR = 1.70, P = .36, Table S1). The subgroup meta-analysis result also showed that periop- erative AP therapy would increase the risk of bleeding complication (OR = 2.65, P =.004, Table S1), while no significant difference between patients on perioperative AC therapy and controls (OR = 0.91, P = .92, Table S1). Besides, the analysis indicated no significance be- tween AC/AP patients bridged with LMWH and con- trols (OR = 2.58, P = 0.24, Table S1). Continuing AC/ AP therapy during surgery could led to increased risk of bleeding complication (OR = 2.29, P = .008, Table S1). Blood transfusion Eight studies were included in the forest plot of blood transfusion. As no heterogeneity existed among these studies (P = .89, I2 = 0%, Figure 2B), a fixed effects model was applied for meta-analysis. The pooled result showed that perioperative AC/AP therapy would lead to a higher risk of blood transfusion compared with the control group (OR = 2.86, 95% CI: 1.50–5.45, P = Figure 1. Meta-analysis flowchart. Safety of BPH surgery under anticoagulants-Liang et al. Vol 18 No 2 March-April 2021 154 .001, Figure 2B). The funnel plot did not show obvious publication bias (Figure S1B). The subgroup analysis showed that both the patients undergoing laser surgical treatment and TURP need more blood transfusions (OR = 2.53, P = .01; OR = 5.47, P = .01, respectively, Table S2). Of AC/AP type, the subgroup analysis presented the transfusion rate of patients under AC therapy was similar to that of the control group (OR = 3.79, P = .13, Table S2), whereas the transfusion rate of patients un- der AP therapy was higher than the control group (OR = 2.76, P = .004, Table S2). Of perioperative adminis- tration of AC/AP therapy, the method that preoperative AC/AP therapy replaced with LMWH would not cause a higher risk of blood transfusion in BPH patients dur- ing the perioperative period (OR = 2.81, P = .12, Table S2). The patients who continued AC/AP therapy during perioperative period had a higher risk of blood transfu- sion compared with the control group (OR = 2.76, P = .004, Table S2). Operation time Seven studies were included in the forest plot of op- eration time. The pooled result showed no significant difference between the AC/AP group and control group (MD = -4.18 min, 95% CI: -10.13–1.76, P = .17, Fig- ure 2C). The random effect model was applied because there was evidence of significant heterogeneity (P = .0001, I2 = 79%). The sensitivity analysis showed that heterogeneity originated from the studies of Tayeb et al(27) and Meskawi et al(29), probably due to the differ- ent size of resected prostate tissue (Table 2). The fun- nel plot showed no publication bias (Figure S1C). The subgroup analysis results based on surgical type, AC/ AP type and management of AC/AP therapy all showed that no significant difference between the AC/AP group and control group, which were consistent with overall outcome (Table S3). Catheterization time Nine studies reported the catheterization time after surgery. Random effect was applied for analysis with significant heterogeneity (P < .00001, I2 = 95%). The pooled results showed that no significant difference between the AC/AP group and control group (MD = 0.26 day, 95% CI: -0.06–0.58, P = .11, Figure 3A). The sensitivity analysis suggested that heterogeneity being mainly from the study of Dotan et al(16). Limited sam- ple size from the study of Dotan et al, causing potential bias, may be the reason of the heterogeneity. After re- moval of study of Dotan et al, the pooled results still showed no significant difference between the AC/AP group and control group with mild heterogeneity (MD = 0.08 day, 95% CI: -0.08–0.25, P = .33, I2 = 35%). The subgroup analysis results account of surgical type, AC/AP type and management of AC/AP therapy was Figure 2. Forest plots and meta-analysis. (A) Bleeding complications, (B) blood transfusion, (C) operation time. Safety of BPH surgery under anticoagulants-Liang et al. Review 155 also conducted. The funnel plot did not show obvious publication bias (Figure S1D). The subgroup analy- sis revealed that patients on perioperative AP therapy would have a longer catheterization time (MD = 0.18 day, 95% CI: 0.11–0.24, P < 0.00001, Table S4), while perioperative AC therapy would not prolong the cath- eterization time (MD = 0.46 day, 95% CI: -0.16–0.24, P < 0.00001, Table 4). Meanwhile, the subgroup anal- ysis of surgical type or management of AC/AP therapy showed that no significant difference between the AC/ AP group and control group, which were consistent with overall outcome (Table S4). Hospitalization Nine studies reported the hospitalization time. The pooled meta-analysis result using a random effects model because of existence of significant heterogeneity among these studies (P < 0.00001, I2 = 97%) showed no significant difference between the AC/AP group and control group (MD = 0.71 day, 95% CI: -0.04–1.45, P = .06, Figure 3B). The sensitivity analysis showed that heterogeneity mainly originated from the study of Dotan et al and Descazeaud et al(16,17). The sample size, study design, geographical area, and individual differ- ences of patients were all likely responsible for the het- erogeneity. The heterogeneity decreased substantially after remove the study of Dotan et al and Descazeaud et al (MD = 0.13 day, 95% CI: -0.07–0.34, P = .20, I2 = 30%). The funnel plot did not show obvious publication bias (Figure S1E). The subgroup analysis results based on the surgical type and AC/AP type showed that no significant difference between the AC/AP group and the control group, which were consistent with the over- all outcome (Table S5). Of perioperative management of AC/AP therapy, our subgroup analysis indicated that the patients who continued AC/AP therapy during perioperative period had longer hospitalization time compared with the control group (MD = 0.25, P = .04, Table S5), whereas the method that preoperative AC/ AP therapy replaced with LMWH would not prolong hospitalization time (MD = 1.60, P = .08, Table S5). Thromboembolic events Four studies were included in the forest plot of throm- boembolic events. All included studies were on TURP treatment group. A fix effects model was applied for analysis as no heterogeneity exist (P = .88, I2 = 0%, Fig- ure 3C). The pooled results revealed that no significant difference between AC/AP group and control (OR = 2.42 , 95% CI: 0.69–8.51, P = .17, Figure 3C). The fun- nel plot did not give any indication of publication bias (Figure S1F). The subgroup results of AC/AP type and management of AC/AP therapy was also conducted. The results both showed that no significant difference Figure 3. Forest plots and meta-analysis. (A) Catheterization time, (B) hospitalization, (C) thromboembolic events. Safety of BPH surgery under anticoagulants-Liang et al. Vol 18 No 2 March-April 2021 156 between the AC/AP group and control group, which were consistent with overall outcome (Table S6). DISCUSSION TURP has been widely used for the treatment of BPH. However, the morbidity of patients after TURP is con- siderably high due to intraoperative and postoperative bleeding and electrolyte disorder. Due to the AC/AP therapy for atrial fibrillation, recurrent thromboembolic disease, or prosthetic heart valves, the risk of bleeding complications associated with surgery is higher in BPH patients;(30) however, discontinuation of AC/AP therapy before surgery may predispose patients to thromboem- bolism caused by the release of tissue thromboplastins. (31) Various laser treatment options have been developed for BPH surgery for these patients on AC/AP therapy in recent years, such as PVP, Ho:YAG. These laser thera- pies seem to minimize bleeding during surgery.(32-35) Particularly in patients receiving AC/AP therapy, these laser treatments seem to have a favorable safety pro- file.(33,35,36) Both EAU guidelines and NICE guidelines recommend that laser treatment can be safely applied in patients who have an increased risk of bleeding. However, regarding the perioperative management of AC/AP therapy, the guidelines did not mention wheth- er there is a need to discontinue or replace to LMWH. (9,10) Consequently, some surgeons discontinued AC/AP therapy and replaced LMWH in advance of surgery, whereas others continued AC/AP therapy periopera- tively. Recently, Zheng and his colleagues conducted a meta-analysis to assess the efficacy and safety of PVP on high-risk patients including patients on anticoagu- lation.(37) However, their analysis did not conduct sub- group analysis for people on AC/AP therapy, and the management of perioperative AC/AP therapy still re- mained unsettled. Therefore, our meta-analysis, which synthesized all available evidence including TURP and other laser surgeries, should offer an objective verdict. A series of subgroup analyses based on surgical type, AC/AP type, and management of AC/AP therapy were conducted. The present meta-analysis studied the safety profile of the surgery for BPH patients with AC/AP therapy. The incidence of bleeding complications and blood transfu- sions can represent a key parameter when evaluating the safety of the surgery for BPH patients with AC/ AP therapy. Our subgroup analysis indicated that AC/ AP therapy would have a higher risk of blood trans- fusion and bleeding complications when receiving TURP treatment for BPH. For the patients receiving laser surgical treatment for BPH, our result presented that continuing perioperative AC/AP therapy would in- crease blood transfusions, but would not have effects on the incidence of bleeding complications. Although the excellent hemostasis of laser surgery,(38,39) the laser treatment might still carry a risk of bleeding on patients receiving AC/AP therapy. Besides, the subgroup meta-analysis result of bleeding complication, blood transfusion, and catheterization time on AC/AP type showed that the patients under pe- rioperative AP therapy had a higher risk of postopera- tive bleeding than those who did not need anticoagulant or antiplatelet agent, which was in line with previous studies.(13,17) However, the subgroup analysis results in- dicated that perioperative AC therapy would not affect postoperative bleeding. The reason is probably because of limited sample size. Notably, AC therapy subgroup analysis showed all postoperative bleeding was related to laser treatment. For perioperative AC/AP manage- ment, the commonly used procedure in current practice included bridging treatment with LMWH and contin- ued therapy. One of the main concerns about bridging treatment is that it might increase the risk of thrombo- embolic events. To settle this dilemma, the subgroup analysis of perioperative AC/AP management was also conducted. According to our result, the patients bridg- ing with LMWH would not increase the incidence of bleeding complications, blood transfusion, and prolong hospitalization time, indicating that bridging treatment could effectively reduce the risk of severe hemorrhage requiring blood transfusion. Furtherly, our meta-anal- ysis proved that the bridging treatment before surgery had no effect on thromboembolic events, which was consistent with the previous researches. Chakravarti et al.(40) managed anticoagulation for 11 patients under- going TURP by stopping warfarin and bridging with heparin preoperatively. They observed only one blood transfusion, but mild bleeding occurred in 27% of the patients. Descazeaud et al.(41) also concluded that re- placement by LMWH preoperatively is preferable for BPH patients under AC/AP therapy. Among the studies for operation time and catheteri- zation time, the synthesis of meta-analysis revealed a same effect between groups. These results suggest that application of AC/AP therapy during perioperative pe- riod would not affect the quality of surgery. There are several limitations to our present study. First, most of the studies were case-control trials except for one RCT, which may cause potential bias in our results. In addition, because the use of anticoagulant and an- tiplatelet drugs in the included studies is not recorded in detail, comparison among antiplatelet drugs or an- ticoagulant drugs failed to be conducted. Comparison of different doses of AC/AP therapy failed to be per- formed, either. All included studies did not mention the threshold of transfusion, and the definition of bleeding complication varied among included studies, posing po- tential bias on the pooled results. In addition, although random-effect model was applied to some parameters with high heterogeneity, there might be some influence on the efficiency of our meta-analysis. CONCLUSIONS This meta-analysis has demonstrated that patients on perioperative AC/AP therapy would have a higher risk of hemorrhage in TURP for the treatment of BPH. Even for laser treatments, perioperative AC/AP therapy also have a risk of postoperative hemorrhage. To reduce the incidence of hemorrhage requiring transfusion, bridg- ing treatment with LMWH could be a good choice. Due to the inherent limitations of the included studies, fur- ther large cohorts prospective, multi-center, and RCTs should be conducted to confirm our findings. APPENDIX https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryFiles/downloadPublic/18 ACKNOWLEDGEMENT This work was supported by The National Natural Sci- Safety of BPH surgery under anticoagulants-Liang et al. Review 157 Vol 18 No 2 March-April 2021 158 ence Foundation of China (No.81402430, 81602541). CONFLICT OF INTEREST No conflict of interest exits in this study. REFERENCES 1. Berry S J, Coffey D S, Walsh P C, Ewing LL. 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