Meta-Analysis Open Access
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Meta-Anal. Oct 28, 2020; 8(5): 411-434
Published online Oct 28, 2020. doi: 10.13105/wjma.v8.i5.411
Effects of antithrombotic agents on post-operative bleeding after endoscopic resection of gastrointestinal neoplasms and polyps: A systematic review and meta-analysis
Bing-Jie Xiang, Yu-Hong Huang, Min Jiang, Cong Dai, Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
ORCID number: Bing-Jie Xiang (0000-0001-6231-3086); Yu-Hong Huang (0000-0001-6228-3022); Min Jiang (0000-0003-0533-7000); Cong Dai (0000-0003-1317-183X).
Author contributions: Xiang BJ had the original idea for the paper, formulated the protocol; Xiang BJ and Huang YH carried out the literature search, selection, validity assessment, data abstraction and data analysis; Xiang BJ and Dai C wrote the paper and incorporated the comments from other authors; and all authors reviewed and approved the final draft of the paper. 
Supported by Liaoning Science and Technology Foundation, No. 20170541052.
Conflict-of-interest statement: No conflict of interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Cong Dai, PhD, Assistant Professor, Department of Gastroenterology, First Affiliated Hospital, China Medical University, No. 92 Beier Road, Heping District, Shenyang 110001, Liaoning Province, China. congdai2006@sohu.com
Received: September 17, 2020
Peer-review started: September 18, 2020
First decision: September 29, 2020
Revised: October 7, 2020
Accepted: October 27, 2020
Article in press: October 27, 2020
Published online: October 28, 2020

Abstract
BACKGROUND

There are some studies investigating the relationship between antithrombotic medication and postoperative bleeding after endoscopic resection (ER) with controversial results. 

AIM

To perform a meta-analysis evaluating the effects of antithrombotic therapy on postoperative bleeding after ER.

METHODS

A systematic search was conducted on PubMed, Web of Science, Cochrane Library. The Newcastle-Ottawa scale was used to evaluate the quality of studies. Stata 12.0 was used for statistical analysis. The odds ratio (OR) and 95%CI were calculated and heterogeneity was quantified using Cochran’s Q test and I2.

RESULTS

Total 66 studies were included in the meta-analysis. Pooled data suggested that antithrombotic therapy was significantly associated with postoperative bleeding (OR = 2.302, 95%CI: 2.057-2.577, P = 0.000) after ER. The risk of postoperative bleeding after endoscopic submucosal dissection, endoscopic mucosal resection and polypectomy in the antithrombotic group was higher than the non-antithrombotic group (OR = 2.439, 95%CI: 1.916-3.105; OR = 2.688, 95%CI: 1.098-6.582; OR = 2.112, 95%CI: 1.434-3.112). 

CONCLUSION

The risk of postoperative bleeding after ER correlated with the types and management of antithrombotic agents by our meta-analysis.

Key Words: Endoscopic resection, Antithrombotic, Anticoagulants, Postoperative bleeding, Endoscopic mucosal resection, Endoscopic submucosal dissection

Core Tip: In recent years, more and more people suffering from cardiovascular disease and/or cerebrovascular disease receive antithrombotic therapy which change patients’ coagulation status and may lead to high risk of postoperative bleeding after endoscopic resection (ER). The relationship between the postoperative bleeding after ER and antithrombotic agents is still uncertain. With this reason, a systematic review and meta-analysis was carried out to identify whether the use of antithrombotic drugs increases the risk of the postoperative bleeding after ER.
INTRODUCTION

Endoscopic resection (ER) is deemed as an effective method for gastrointestinal neoplasia and polyp. ER is an acceptable technique to enable en bloc resection of gastric adenomas, early oesophageal, gastric and colorectal cancer and incidence and its related mortality of colorectal cancer[1-3]. This includes polypectomy, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). For example, patients with oesophageal neoplasia receiving ER can maintain the integrity of oesophageal structure and function, whereas the quality of life can be affected by oesophagectomy[4].

Although the therapeutic effect of ER has been greatly affirmed, Postoperative bleeding as a major complication is still a problem to be solved. Postoperative bleeding after ER is defined as bleeding within 30 d from a mucosal defect shown by massive melena, a decrease in blood hemoglobin level of more than 2 g/dL, or requirement of endoscopic hemostasis or transfusion[1,5,6]. A study has shown that the incidence rate of postoperative bleeding after esophageal or colorectal ESD ranged from 0.0% to 4.6%[7]. And the incidence rate of postoperative bleeding after ESD due to gastric neoplasm ranged from 1.8% to 15.6%[7]. A study that included 3788 cases of poly-pectomy by Choung found that postoperative bleeding occurred in 42 cases (1.1%)[8]. Another study with 30881 cases of polypectomy by Rutter also reported that the postoperative bleeding developed in 291 cases (0.94%)[9]. Preventive strategies such as acid secretion inhibitors and prophylactic clipping have been developed to reduce the postoperative bleeding risk after ER, but postoperative bleeding cannot be completely avoided. Some factors such as the size of polyp and a patient’s coagulation status have been reported to be associated with the risk of postoperative bleeding after ER.

In recent years, more and more people suffering from cardiovascular disease and/or cerebrovascular disease receive antithrombotic therapy which change patients’ coagulation status and may lead to high risk of postoperative bleeding after ER. The relationship between the postoperative bleeding after ER and antithrombotic agents is still uncertain. With this reason, a systematic review and meta-analysis was carried out to identify whether the use of antithrombotic drugs increases the risk of the postoperative bleeding after ER.

MATERIALS AND METHODS

We carried out a systematic review and meta-analysis of the hemorrhagic data of different antithrombotic users after ER from published studies. The review and analysis was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines[10].

Search method

We used PubMed, Web of Science and Cochrane Library to search for articles published in English from inception to February 2019. The search queries were: (1) ( ( (antithrombotic OR anticoagulant OR antiplatelet OR heparin OR warfarin OR aspirin)) AND (endoscopic submucosal dissection OR ESD)) AND (bleeding OR hemorrhage); (2) ( ( (antithrombotic OR anticoagulant OR antiplatelet OR heparin OR warfarin OR aspirin)) AND (EMR OR endoscopic mucosal resection)) AND (bleeding OR hemorrhage); (3) ( ( (antithrombotic OR anticoagulant OR antiplatelet OR heparin OR warfarin OR aspirin)) AND (endoscopic polypectomy)) AND (bleeding OR hemorrhage); and (4) ( ( (antithrombotic OR anticoagulant OR antiplatelet OR heparin OR warfarin OR aspirin)) AND (APC OR argon plasma coagulation)) AND (bleeding OR hemorrhage).

Study selection

The studies that met the following inclusion criteria were included: (1) Polypectomy, EMR, ESD, polypectomy incorporated argon plasma coagulation and the hot and cold snare; (2) Randomized controlled trials, retrospective studies or cohort studies were performed to investigate the risk of postoperative bleeding after ER in patients with gastrointestinal neoplasm receiving antithrombotic medication; (3) The incidence rate of postoperative bleeding can be extracted in the antithrombotic medication group and the non-antithrombotic medication group; and (4) Anticoagulants and antiplatelet drugs were incorporated in antithrombotic agents.

The studies were excluded if: (1) The postoperative bleeding rate or antithrombotic therapy information could not be extracted; (2) Antithrombotic drugs and NSAIDS were recorded together; (3) Endoscopic treatment such as biopsy, sphincterotomy or ampullectomy was carried out; (4) Reviews, case reports, guidelines, or animal studies were screened out; (5) The articles were not written in English; and (6) The full text could not be obtained.

Methodological quality assessment

The Newcastle-Ottawa scale was used to evaluate the quality of the included studies. And the Newcastle-Ottawa scale includes three aspects: Selection, comparability, exposure (retrospective studies) or outcome (cohort studies)[11].

Data extraction

Two authors worked together to extract the basic information about the first author, publication year, country, research method (retrospective/cohort), ER method (ESD/EMR/polypectomy), number, age and gender. Moreover, the odds ratio (OR) and 95%CI of the postoperative bleeding rate were calculated in the antithrombotic group (continued/discontinued) and the non-antithrombotic group. 

Statistical analysis

Statistical analysis was performed by Stata 12.0. The Cochran’s Q test and I2 (P < 0.10 was considered significant) were used to identify heterogeneity. The value I2 of 0-25% indicated insignificant heterogeneity; 26%-50%, low heterogeneity; 51%-75%, moderate heterogeneity; and greater than 75%, high heterogeneity[12]. If there was no significant heterogeneity, the OR and 95%CI were calculated in a fixed-effect model. Otherwise, a random-effect model was used. The funnel plot was used to assess publication bias.

RESULTS
Assessment of the studies

The initial literature yielded 1258 articles (454 articles from PubMed, 679 articles from Web of Science, 125 articles from Cochrane Library). After the exclusion of 929 articles due to duplicates and lack of relevance, 329 articles were retrieved for full text evaluation. 263 articles were excluded after reviewing the full text (Figure 1). Ultimately, 66 studies were included in the meta-analysis (Fifty-nine retrospective studies, seven prospective observational studies). The characteristics of included studies were described in the Table 1. The included studies were carried out from different countries (Fifty from Japan, six from Korean, five from USA, two from Italy, one from UK, one from Australia, one from Holland). The mean age was older than 60 years old in most studies.

Figure 1
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Figure 1 A flow diagram of articles retrieved and inclusion progress through the stage of meta-analysis.
Table 1 Characteristics of included studies and participants.
Ref.
Country
Research method
Location
Age (yr)
Gender male, %
So et al[49], 2019South KoreaRetrospective studyGastric lesion68.8/68.5954, 79.7%
Kishida et al[45], 2019JapanRetrospective studyColorectal lesion64/6855, 41.66%
Inoue et al[65], 2019JapanProspective observational studyGastrointestinal lesion67.4 ± 8.3201, 58.6%
Harada et al[56], 2019JapanRetrospective studyGastric lesion72.3 ± 8.82414, 69.3%
Arimoto et al[54], 2018JapanRetrospective studyColorectal lesion68.5492, 58.3%
Azumi et al[39], 2018JapanRetrospective studyGastric lesion73 (41-94)284, 64.8%
Fujita et al[67], 2018JapanRetrospective studyColorectal lesion72.2 ± 7.4/72.9 ± 8.363, 73.8%
Horikawa et al[58], 2018JapanRetrospective studyGastric lesion78 (56-89)77, 77%
Izumikawa et al[40], 2018JapanRetrospective studyGastric lesion-255, 75.25%
Kono et al[41], 2018JapanRetrospective studyGastric lesion72 (66-78)652, 74.77%
Oh et al[60], 2018South KoreaRetrospective studyGastric lesion70 (49-85)173, 80.47%
Park et al[63], 2018South KoreaProspective observationalstudyColorectal lesion55.8 ± 11.9/52.4 ± 12.32661, 68.46%
Sanomura et al[59], 2018JapanRetrospective studyGastric lesion69.8 ± 9.2719, 70%
Seo et al[55], 2018South KoreaRetrospective studyColorectal lesion63 (55-69.5)723, 60.8%
Sakai et al[64], 2018JapanRetrospective studyColorectal lesion n72.6 ± 7.2/69.1 ± 10.9669, 66.63%
Yamashita et al[36], 2018JapanRetrospective studyColorectal lesion66.6 ± 10.6373, 57.4%
Yanagisawa et al[35], 2018JapanRetrospective studyGastrointestinal lesion-314, 72.02%
Matsumoto et al[46], 2018JapanRetrospective studyColorectal lesion70/65551, 65.44%
Harada et al[61], 2017JapanProspective observational studyGastric lesion76.8 ± 6.0/72.7 ± 7.940, 88.88%
Yano et al[33], 2017JapanRetrospective studyGastric lesion72 (33-94)1319, 74.65%
Ueki et al[14], 2017JapanRetrospective cohort studyGastric lesion71.2 ± 8.4264, 72.5%
Yoshio et al[78], 2017JapanRetrospective studyGastric lesion75/7690, 90.91%
Gotoda et al[15], 2017JapanRetrospective studyGastric lesion75, 68.8-81.0410, 77.5%
Furuhata et al[17], 2017JapanRetrospective studyGastric lesion691377, 77.3%
Shibuya et al[1], 2017JapanRetrospective studyColonic lesion-Unclear
Bronsgeest et al[42], 2017HollandRetrospective studyColorectal lesion67.4 ± 8.3201, 58.6%
Ishigami et al[34], 2017JapanRetrospective studyLower gastrointestinal lesion64.9 ± 11.1526, 68%
Pigò et al[3], 2017ItalyRetrospective studyColorectal lesion65.4385, 63.2%
Kono et al[76], 2017JapanProspective observationalstudyUpper gastrointestinal lesion74 ± 8.344, 89.8%
Lin et al[75], 2017United StatesRetrospective studyColorectal lesion-Unclear
Sato et al[38], 2017JapanRetrospective studyGastric lesion71.11786, 75.1%
Igarashi et al[27], 2017JapanRetrospective studyGastric lesion72.4758, 77.7%
Amato et al[31], 2016ItalyProspective observational studyGastrointestinal lesion59 ± 12.154.3%
Kubo et al[32], 2016JapanRetrospective studyGastrointestinal lesion63.9467,59.3%
Shindo et al[25], 2016JapanRetrospective studyGastric lesion71 ± 8, 32-87190, 72.5%
Yoshida et al[52], 2016JapanRetrospective studyColorectal lesion68.2 ± 10.3Unclear
Ninomiya et al[53], 2015JapanRetrospective studyColorectal lesion67 ± 11.1410, 70.4%
Al-Mammari et al[4], 2015United KingdomProspective observational studyOesophageal lesion71, 65-7885, 72.6%
Odagiri et al[16], 2015JapanRetrospective cohort studyColorectal lesion-4495, 59.4%
Namasivayam et al[5], 2014United StatesRetrospective studyGastrointestinal lesion69Unclear
Terasaki et al[21], 2014JapanRetrospective studyColorectal lesion66.9 ± 11.2233, 64.2%
Tounou et al[50], 2014JapanRetrospective studyGastric lesion71.8, 36-92257, 73.4%
Suzuki et al[18], 2014JapanRetrospective studyColorectal lesion65.5, 29-86183, 57.7%
Matsumura et al[23], 2014JapanRetrospective studyGastric lesion72.1 ± 8.6302, 71.1%
Beppu et al[74], 2014JapanRetrospective studyColorectal lesion59.5 ± 11.6176, 84.6%
Inoue et al[77], 2014JapanRetrospective studyColorectal lesion69.295, 81.2%
Sanomura et al[66], 2014JapanRetrospective studyGastric lesion73.7 ± 8.964, 82.1%
Yoshio et al[47], 2013JapanRetrospective studyGastric lesion70951, 76.1%
Takeuchi et al[29], 2013JapanRetrospective studyGastric lesion5.2477, 57.2%
Koh et al[37], 2013JapanRetrospective studyGastric lesion70.3 ± 8.6817, 74%
Mukai et al[6], 2012JapanRetrospective studyGastric lesion72.4 ± 8.8116, 72%
Lim et al[51], 2012South KoreaRetrospective studyGastric lesion62.61143, 71.8%
Miyahara et al[48], 2012JapanRetrospective studyGastric lesion71.7 ± 8.9, 36-92763, 70.5%
Cho et al[57], 2012South KoreaRetrospective studyColorectal lesion62.2385, 74.9%
Toyokawa T et al[24], 2011JapanRetrospective studyGastric lesion26-95811, 72.2%
Higashiyama et al[19], 2011JapanRetrospective studyGastric lesion69, 29-91702, 76%
Metz et al[2], 2011AustraliaProspective observational studyColonic lesion68, 26-93Unclear
Tokioka et al[30], 2011JapanRetrospective studyGastric lesion69.4378, 73.4%
Okada K et al[22], 2011JapanRetrospective studyGastric lesion68.4, 33-94425, 73%
Mannen et al[20], 2010JapanRetrospective studyGastric lesion71.6 ± 8.6, 36-91323, 74.1%
Goto et al[13], 2010JapanRetrospective studyGastric lesion68.3347, 76.4%
Witt et al[44], 2009United StatesRetrospective cohort studyColorectal lesion69.6691, 56.4%
Ono et al[28], 2019JapanRetrospective studyGastric lesion67Unclear
Takizawa et al[26], 2008JapanRetrospective studyGastric lesion66 ± 10, 29-93779, 80.5%
Sawhney et al[62], 2007United StatesRetrospective studyColorectal lesion65.1169, 97.7%
Yousfi et al[43], 2004United StatesRetrospective studyGastrointestinal lesion70.5, 45-91100, 61.7%
Effect analysis

A total of 48691 cases after ER were enrolled, of which 8918 cases were receiving antithrombotic medication and 39773 cases were not taking any antithrombotic drugs[1,2,4,6,13-33]. The average postoperative bleeding rate in the antithrombotic group was 8.44%, while it was 5.28% in the non-antithrombotic group. With the random-effects model, the risk of postoperative bleeding in the antithrombotic group was higher than the non-antithrombotic group (OR = 2.421, 95%CI: 1.831-3.200, P = 0.000, I2 = 82.5%). In addition, a more homogeneous analysis (I2 = 36.0%) was carried out after six articles[3,5,29,34-36] were screened out in the sensitivity analysis and the results remained unchanged (OR = 2.302, 95%CI: 2.057-2.577, P = 0.000) (Figure 2). Besides this, the results were not changed when data from retrospective and prospective studies were separately analyzed.

Figure 2
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Figure 2 Forest plot of antithrombotic group vs non-antithrombotic group in endoscopic resection.

A total of 27014 cases after ESD were enrolled in this meta-analysis (3624 cases were receiving antithrombotic medication and 23390 cases were not taking antithrombotic drugs[1,6,13-30,33,37-41]). The average postoperative bleeding rate after ESD in the antithrombotic group was 13.91%, while it was 7.77% in the non-antithrombotic group. With the random-effects model, the risk of postoperative bleeding after ESD in the antithrombotic group was higher than the non-antithrombotic group (OR = 2.439, 95%CI: 1.916-3.105, P = 0.000, I2 = 63.5%). Moreover, a more homogeneous analysis (I2 = 0.0%) was carried out after six articles[6,20,24,26,29,36] were screened out in the sensitivity analysis and the results remained unchanged (OR = 2.507, 95%CI: 2.185-2.875, P = 0.000, Figure 3). The risk of postoperative bleeding after gastric ESD in the antithrombotic group was higher than the non-antithrombotic group (OR = 2.295, 95%CI: 1.757-2.998, P = 0.000, I2 = 64.1%)[6,13-15,17,19,20,22-29,33]. Meanwhile, the risk of postoperative bleeding after colorectal ESD in the antithrombotic group was higher than the non-antithrombotic group (OR = 3.305, 95%CI: 1.561-6.998, P = 0.002, I2 = 65.0%)[1,15,18,21,36].

Figure 3
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Figure 3 Forest plot of antithrombotic group vs non-antithrombotic group in endoscopic submucosal dissection.

A total of 5514 cases after EMR were enrolled in this meta-analysis (1475 cases were receiving antithrombotic medication and 4039 cases were not taking any antithrombotic drugs[1,2,4,5,42]). The average postoperative bleeding rate after EMR in the antithrombotic group was 2.85%, while it was 1.29% in the non-antithrombotic group. With the random-effects model, the risk of postoperative bleeding after EMR in the antithrombotic group was higher than the non-antithrombotic group (OR = 2.688, 95%CI: 1.098-6.582, P = 0.030. I2 = 72.7%). Furthermore, a more homogeneous analysis (I2 = 5.3%) was carried out after one article[5] was screened out in the sensitivity analysis and the results remained unchanged (OR = 3.765, 95%CI: 2.380-5.954, P = 0.000, Figure 4). The risk of postoperative bleeding after colorectal EMR in the antithrombotic group was higher than the non-antithrombotic group (OR = 3.711, 95%CI: 2.332-5.904, P = 0.005, I2 = 32.9%). But the analysis on the risk of postoperative bleeding after gastric EMR could not be carried out due to insufficient data.

Figure 4
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Figure 4 Forest plot of antithrombotic group vs non-antithrombotic group in endoscopic mucosal resection.

A total of 10709 cases of polypectomy were enrolled in this meta-analysis (2554 cases were receiving antithrombotic medication and 8155 cases were not taking any antithrombotic drugs[1,3,35,43-46]). The average postoperative bleeding rate in the antithrombotic group was 4.89%, while it was 1.69% in the non-antithrombotic group. With the random-effects model, there was no significant difference (OR = 2.338, 95%CI: 0.610-8.954, P = 0.215, I2 = 93.6%) in the postoperative bleeding rate between the two groups. Another more homogeneous analysis (I2 = 44.4%) was carried out after two articles[3,35] were screened out in the sensitivity analysis and the results were found to have changed (OR = 2.112, 95%CI: 1.434-3.112, P = 0.006, Figure 5). The risk of postoperative bleeding after colorectal polypectomy in the antithrombotic group was higher than the non-antithrombotic group (OR = 2.921, 95%CI: 1.821-4.687, P = 0.000, I2 = 31.9%). Table 2 shows the number of cases with or without antithrombotic agents and hemorrhagic outcome.

Figure 5
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Figure 5 Forest plot of antithrombotic group vs non-antithrombotic group in polypectomy.
Table 2 Number of cases with or without antithrombotic agents and hemorrhagic outcome.
Ref.
Resection method
Total
Drug
Post-bleeding
No bleeding
So et al[48], 2019ER1197Antithrombotic agent (+/-)40/50359/748
Continued antithrombotic agent (+/-)11/769/138
Discontinued antithrombotic agent (+/-)29/43330/657
HR (+)59
Kishida et al[45],2019Polypectomy6382Antithrombotic agent (+/-)15/40986/5341
Single APT (+)4683
Single anticoagulants (+)285
Multiple APT (+)3163
Multiple antithrombotic agents (+)239
Single antithrombotic agent (+)13947
HR (+)416
Inoue et al[65], 2019EMR102VKA (+)1273
Discontinued VKA (+)04
Continued VKA (+)02
HR (+)1598
DOAC (+)314
Discontinued DOAC (+)03
Inoue et al[65], 2019ESD54VKA (+)1431
Discontinued VKA (+)12
Continued VKA (+)01
HR (+)1331
DOAC (+)27
Discontinued DOAC (+)24
Harada et al[56], 2019ESD597Antithrombotic agent (-)21422
Single-LDA (+)1085
DAPT (+)1049
Continued LDA (+)1580
Discontinued APT (+)554
Arimoto et al[54], 2018ESD919Antithrombotic agent (-)26757
APT (+)5131
Discontinued APT (+)5105
Continued APT (+)026
Azumi et al[39], 2018ESD438Antithrombotic agent (+/-)6/1572/345
Fujita et al[67], 2018EMR84Discontinued anticoagulants (+)142
HR (+)437
Horikawa et al[58], 2018ESD100Antithrombotic agent (-)149
Continued LDA149
Izumikawa et al[40], 2018ESD273Antithrombotic agent (+/-)15/1166/207
Kono et al[41], 2018ESD872Antithrombotic agent (+/-)23/38159/652
Single antithrombotic agent12130
Multiple antithrombotic agents (+)1129
Discontinued antithrombotic agent (+)8120
Discontinued
Single APT (+)388
Multiple APT (+)316
Single anticoagulants (+)113
Continued
Single APT (+)116
Multiple APT (+)42
Single anticoagulants (+)713
HR (+)1021
Oh et al[60], 2018ESD215Single APT (+)14147
Multiple APT (+)1539
LDA (+)1282
Thienopyridine (+)254
Continued APT (+)23130
Discontinued APT (+)656
Park et al[63], 2018Polypectomy3887APT (+)12339
Anticoagulants (+)015
Sanomura et al[58], 2018ESD1243Antithrombotic agent (-)401127
Anticoagulants (+)1165
Warfarin (+)532
DOAC (+)414
Seo et al[55], 2018ESD1189Antithrombotic agent (-)26945
APT (+)7175
Aspirin (+)2139
Warfarin (+)010
DOAC (+)12
Single antithrombotic agent (+)10326
Multiple antithrombotic agents (+)023
Discontinued antithrombotic agent (+)7206
Continued antithrombotic agent (+)05
Sakai et al[64], 2018Polypectomy1004Discontinued anticoagulants (+)120
HR (+)870
Warfarin (+)755
DOAC (+)115
Yamashita et al[36], 2018ESD650Antithrombotic agent (+/-)7/1821/652
Warfarin (+)514
DOAC27
Yanagisawa et al[35], 2018Polypectomy436Antithrombotic agent (+/-)30/2188/216
Discontinued anticoagulants (+)023
Continued anticoagulants (+)1083
HR (+)2082
Continued warfarin (+)241
Continued DOAC (+)842
Warfarin (+)20125
DOAC (+)1063
Matsumoto et al[46], 2018Polypectomy1003Antithrombotic agent (+/-)2/2184/815
Harada et al[61], 2017ESD45Continued warfarin (+)220
HR518
Yano et al[33], 2017ESD144Antithrombotic agent (+/-)47/103287/1330
Ueki et al[14], 2017ESD364Antithrombotic agent (+/-)7/1767/273
Discontinued antithrombotic agent (-)767
Discontinued single APT (+)457
Discontinued single anticoagulants (+/-)24
Aspirin (+)443
Thienopyrindine (+)07
Yoshio et al[78], 2017ESD97Warfarin (+)1855
DOAC519
Gotoda et al[15], 2017ESD529Antithrombotic agent (+/-)12/1496/407
APT (+)880
Single antithrombotic agent (+)680
Multiple antithrombotic agents (+)717
Single APT (+)369
Multiple APT (+)511
Warfarin (+)311
Aspirin (+)233
Thienopyridine (+)010
Furuhata et al[17], 2017ESD1781Antithrombotic agent (+/-)33/68220/1460
Single antithrombotic agent (+)11139
Multiple antithrombotic agents (+)630
Continued single APT (+)114
HR (+)1537
Shibuya et al[1], 2017ESD259Antithrombotic agent (+/-)4/632/217
Shibuya et al[1], 2017EMR3018Antithrombotic agent (+/-)16/15510/2477
Shibuya et al[1], 2017Polypectomy892Antithrombotic agent (+/-)3/5163/721
Bronsgeest et al[42], 2017EMRAntithrombotic agent (+/-)13/15107/277
APT (+)453
Anticoagulants (+)443
Ishigami et al[34], 2017ER773Antithrombotic agent (+/-)10/1435/714
HR (+)1035
Pigò et al[3], 2017Polypectomy609Antithrombotic agent (+/-)38/3272/467
Single APT1457
Multiple APT38
HR (+)217
Aspirin (+)1032
Thienopyridine425
Kono et al[76], 2017ESD/EMR49Single antithrombotic agent (+)424
Multiple antithrombotic agents (+)714
Discontinued antithrombotic agent (+)520
Continued antithrombotic agent (+)618
HR (+)412
Lin et al[75], 2017Polypectomy4923Aspirin (+)363897
Thienopyridine (+)5590
Sato et al[38], 2017ESD2378Antithrombotic agent (+/-)46/76401/1855
APT (+)35270
Anticoagulants (+)233
HR (+)633
Aspirin (+)12199
Thienopyridine (+)019
Warfarin (+)116
DOAC (+)117
Igarashi et al[27], 2017ESD976Antithrombotic agent (+/-)35/30332/692
Discontinued antithrombotic agent (+)26250
Continued antithrombotic agent (+)549
HR433
Multiple antithrombotic agents (+) 970
Single antithrombotic agent (+)26262
Continued aspirin (+)429
Discontinue aspirin (+)19152
Continued thienopyridine (+)117
Discontinued thienopyridine (+)963
Continued anticoagulants (+)111
Discontinued anticoagulants (+)327
Amato et al[31], 2016ER2692Antithrombotic agent (+/-)16/16595/2069
APT (+)11461
Anticoagulants (+)5134
Kubo et al[32], 2016ER788Antithrombotic agent (+/-)16/13194/565
APT (+)8146
Anticoagulants (+)1172
HR (+)1063
Shindo et al[25], 2016ESD262Antithrombotic agent (+/-)10/1338/201
Discontinued antithrombotic agent (+)025
Continued APT (+)28
HR (+)85
Yoshida et al[52], 2016ESD678Antithrombotic agent (-)10585
APT (+)360
Anticoagulants (+)317
Ninomiya et al[53], 2015ESD609Antithrombotic agent (-)28537
Discontinued APT (+)211
Continued APT (+)526
Al-Mammari et al[4], 2015EMR117Antithrombotic agent (+/-)1/114/101
Odagiri et al[16], 2015ESD7567Antithrombotic agent (+/-)49/282440/6796
Namasivayam et al[5],2014EMR1712Antithrombotic agent (+/-)4/10772/912
APT (+)3521
Anticoagulants (+)089
Single antithrombotic agent (+)1617
Multiple antithrombotic agents (+)3111
Thienopyridine (+/-)0/1017/912
Terasaki et al[21], 2014ESD363Antithrombotic agent (+/-)4/2036/303
Tounou et al[50], 2014ESD350Antithrombotic agent (-)16245
Discontinued single APT (+)737
Continued single APT (+)212
Dual APT (+)1120
Aspirin (+)944
Thienopyridine (+)05
Suzuki et al[18], 2014ESD317Antithrombotic agent (+/-)1/1327/276
HR06
Matsumura et al[23], 2014ESD425Antithrombotic agent (+/-)10/1077/328
Discontinued antithrombotic agent (+)239
Continued antithrombotic agent (+), HR (-)322
HR (+)516
Beppu et al[74], 2014ER208APT (+)918
Anticoagulants (+)129
Aspirin (+)611
Thienopyridine (+)37
Inoue et al[77], 2014Polypectomy117Discontinued antithrombotic agent (+)171
HR (+)936
Sanomura et al[66], 2014ESD78Continued LDA (+) 127
Discontinued LDA (+)363
Yoshio et al[47], 2013ESD1250Antithrombotic agent (-)45972
Discontinued antithrombotic agent (-)12197
HR (+)915
Takeuchi et al[29], 2013ESD833Antithrombotic agent (+/-)21/1569/728
Koh et al[37], 2013ESD1166Antithrombotic agent (+/-)17/45158/946
Mukai et al[6], 2012 ESD161Antithrombotic agent (+/-)4/1729/111
Lim et al[51], 2012ESD1591Antithrombotic agent (-)681249
Discontinued APT (+)696
Continued APT (+)20152
Miyahara et al[48], 2012ESD1082Antithrombotic agent (-)68883
Discontinued antithrombotic agent (+)7124
Cho et al[57], 2012ESD514Antithrombotic agent (-)15424
Discontinued APT (+)254
Continued APT (+)415
Toyokawa et al[24], 2011ESD1123Antithrombotic agent (+/-)8/48175/892
Higashiyama et al[19], 2011ESD924Antithrombotic agent (+/-)123/7733/25
Metz et al[2], 2011EMR269Antithrombotic agent (+/-)8/1130/220
APT (+)618
Anticoagulants (+)110
HR (+)12
Aspirin (+)512
Thienopyridine (+)16
Tokioka et al[30], 2011ESD515Antithrombotic agent (+/-)3/2337/452
Okada et al[22], 2011ESD582Antithrombotic agent (+/-)4/2470/484
Mannen et al[20], 2010ESD436Antithrombotic agent (+/-)1/3832/365
Goto et al[13],2010ESD454Antithrombotic agent (+/-)5/2152/376
Witt et al[44], 2009Polypectomy1225Antithrombotic agent (+/-)11/2414/798
Ono et al[28], 2019ESD444Antithrombotic agent (+/-)6/2050/368
Takizawa et al[26], 2008ESD968Antithrombotic agent (+/-)3/6074/831
Sawhney et al[62], 2007Polypectomy173APT (+)1751
Anticoagulants (+)1412
Yousfi et al[43], 2004Polypectomy162Antithrombotic agent (+/-)32/4927/54
APT (+)3227
ER: Endoscopic resection; ESD: Endoscopic submucosal dissection; EMR: Endoscopic mucosal resection; APT: Antiplatelet; LDA: Low dose of aspirin; HR: Heparin replacement; DOAC: Direct oral anticoagulant; Thienopyridine: Thienopyridine derivatives.
Quality assessment and publication bias

The Newcastle-Ottawa scale was used to assess the quality of the included studies in this meta-analysis. Thirteen articles had 6 stars, twenty-three articles had 7 stars, twenty-eight articles had 8 stars, and the others had 9 stars (Table 3). At the same time, the funnel plot did not show any features associated with publication bias (Figure 6).

Figure 6
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Figure 6 Funnel plot of antithrombotic group vs non-antithrombotic group in endoscopic resection.
Table 3 The quality assessment of included studies.
Ref.Selection
ComparabilityOutcome/exposure
Stars
1
2
3
4
1
2
3
So et al[49], 2019*********9
Kishida et al[45], 2019******6
Inoue et al[65], 2019********8
Harada et al[56], 2019********8
Arimoto et al[54], 2018********8
Azumi et al[39], 2018********8
Fujita et al[67], 2018********8
Horikawa et al[58], 2018********8
Izumikawa et al[40], 2018******6
Kono et al[41], 2018*******7
Oh et al[60], 2018******6
Park et al[63], 2018********8
Sanomura et al[59], 2018*******7
Seo et al[55], 2018********8
Sakai et al[64], 2018*******7
Yamashita et al[36], 2018*******7
Yanagisawa et al[35], 2018********8
Matsumoto et al[46], 2018******6
Harada et al[61], 2017*******7
Yano et al[33], 2017*******7
Ueki et al[14], 2017*******7
Yoshio et al[78], 2017********8
Gotoda et al[15], 2017******6
Furuhata et al[17], 2017********8
Shibuya et al[1], 2017********8
Bronsgeest et al[42], 2017********8
Ishigami et al[34], 2017*******7
Pigò et al[3], 2017*******7
Kono et al[76], 2017********8
Lin et al[75], 2017*******7
Sato et al[38], 2017********8
Igarashi et al[27], 2017*******7
Amato et al[31], 2016*******7
Kubo et al[32], 2016*******7
Shindo et al[25], 2016******6
Yoshida et al[52], 2016******6
Ninomiya et al[53], 2015******6
Al-Mammari et al[4], 2015*******7
Odagiri et al[16], 2015*******7
Namasivayam et al[5], 2014******6
Terasaki et al[21], 2014*******7
Tounou et al[50], 2014*******7
Suzuki et al[18], 2014*******7
Matsumura et al[23], 2014******6
Beppu et al[74], 2014********8
Inoue et al[77], 2014********8
Sanomura et al[66], 2014********8
Yoshio et al[47], 2013*******7
Takeuchi et al[29], 2013********8
Koh et al[37], 2013********8
Mukai et al[6], 2012******6
Lim et al[51], 2012********8
Miyahara et al[48], 2012********8
Cho et al[57], 2012********8
Toyokawa T et al[24], 2011*******7
Higashiyama et al[19], 2011*******7
Metz et al[2], 2011********8
Tokioka et al[30], 2011********8
Okada K et al[22], 2011******6
Mannen et al[20], 2010******6
Goto et al[13], 2010********8
Witt et al[44], 2009*******7
Ono et al[28], 2019*******7
Takizawa et al[26], 2008********8
Sawhney et al[62], 2007********8
Yousfi et al[43], 2004*********9
Subgroup analyses

Among the ESD group, we performed several subgroup analyses to independently evaluate the effects of different types of antithrombotic agents in postoperative bleeding: (1) In gastric ESD retrospective comparison studies of single antithrombotic user (No. bleeding/total = 43/524) vs non-antithrombotic agent user (No. bleeding/total = 112/2671)[15,17,27]: The risk of postoperative bleeding in single antithrombotic agent group was significantly higher than the non-antithrombotic agent group [OR = 2.061, 95%CI: 1.405-3.024, P = 0.000 (I2 = 0.0%)]; (2) In gastric ESD retrospective comparison studies of multiple antithrombotic user (No. bleeding/total = 33/179) vs non-antithrombotic agent user (No. bleeding/total = 150/3361)[15,17,27,41]: The risk of postoperative bleeding in multiple antithrombotic agents group was significantly higher than the non-antithrombotic agent group [OR = 4.985, 95%CI: 3.251-7.561, P = 0.000 (I2 = 40.6%)]; (3) In gastric ESD retrospective comparison studies of multiple antithrombotic (No. bleeding/total = 33/179) user vs single antithrombotic user (No. bleeding/total = 55/666)[15,17,27,41]: The risk of postoperative bleeding in multiple antithrombotic agents group was higher than the single antithrombotic agent group [OR = 2.492, 95%CI: 1.563-3.974, P = 0.000 (I2 = 43.9%)]; (4) In gastric ESD retrospective comparison studies of discon-tinued antithrombotic user vs (No. bleeding/total = 81/1074) non-antithrombotic agent user (No. bleeding/total = 216/3894)[14,25,27,47-49]: The risk of postoperative bleeding in discontinued antithrombotic agent group was slightly higher than the non-antithrombotic agent group [OR = 1.405, 95%CI: 1.069-1.848, P = 0.015 (I2 = 34.4%)]; (5) In gastric ESD retrospective comparison studies of continuous antithrombotic user (No. bleeding/total = 18/144) vs non-antithrombotic user (No. bleeding/total = 50/1081)[25,27,49]: The risk of postoperative bleeding in continuous antithrombotic agent group was higher than the non-antithrombotic agent group [OR = 2.886, 95%CI: 1.513-5.504, P = 0.001 (I2 = 0.0%)]; (6) In gastric ESD retrospective comparison studies of continuous antithrombotic user (No. bleeding/total = 18/144) vs dis-continued antithrombotic user (No. bleeding/total = 55/660)[25,27,49]: There was no significant difference in the risk of postoperative bleeding between the two groups [OR = 1.615, 95%CI: 0.919-2.837, P = 0.096 (I2 = 32.9%)]; (7) In gastric ESD retrospective comparison studies of antiplatelet (APT) (No. bleeding/total = 100/891) user vs non-antithrombotic user (No. bleeding/total = 212/4620)[15,38,41,50,51]: The risk of postoperative bleeding in the APT agent group was higher than the non-antithrombotic agent group [OR = 2.545, 95%CI: 1.979-3.273, P = 0.000 (I2 = 38.8%)]. In colorectal ESD retrospective comparison studies of APT user (No. bleeding/total = 22/425) vs non-antithrombotic user (No. bleeding/total = 90/2914)[52-55]: The risk of postoperative bleeding in the APT agent group was higher than the non-antithrombotic agent group [OR = 1.821, 95%CI: 1.127-2.944, P = 0.014 (I2 = 25.8%)]; (8) In gastric ESD retrospective comparison studies of discontinued APT user (No. bleeding/total = 17/271) vs non-antithrombotic user (No. bleeding/total = 127/2450)[41,51,56]: There was no significant difference in the risk of postoperative bleeding risk between the two groups [OR = 1.218, 95%CI: 0.721-2.060, P = 0.461 (I2 = 0.0%)]. In colorectal ESD retrospective comparison studies of discontinued APT user (No. bleeding/total = 9/179) vs non-antithrombotic user (No. bleeding/total = 69/1787)[53,54,57]: There was no significant difference in the risk of postoperative bleeding between the two groups [OR = 1.494, 95%CI: 0.725-3.081, P = 0.277 (I2 = 0.0%)]; (9) In gastric ESD retrospective comparison studies of continuous APT user (No. bleeding/total = 43/350) vs non-antithrombotic user (No. bleeding/total = 141/2710)[25,41,51,56,58]: The risk of postoperative bleeding in continuous APT agent group was higher than the non-antithrombotic agent group [OR = 2.955, 95%CI: 2.026-4.310, P = 0.000 (I2 = 0.0%)]. In colorectal ESD retrospective comparison studies of continuous APT user (No. bleeding/total = 9/75) vs non-antithrombotic user (No. bleeding/total = 69/1787)[53,54,57]: The risk of postoperative bleeding risk in continuous APT agent group was higher than the non-antithrombotic agent group [OR = 3.409, 95%CI: 1.652-7.036, P = 0.001 (I2 = 43.9%)]; (10) In gastric ESD retrospective comparison studies of continuous APT user (No. bleeding/total = 44/299) vs discontinued APT user (No. bleeding/total = 20/297)[41,56,59,60]: The risk of postoperative bleeding in continuous APT agent group was higher than the discontinued APT agent group [OR = 2.004, 95%CI: 1.095-3.668, P = 0.024 (I2 = 0.0%)]. In colorectal ESD retrospective comparison studies of continuous APT user (No. bleeding/total = 9/75) vs discontinued APT user (No. bleeding/total = 9/179)[53,54,57]: There was no significant difference in the risk of postoperative bleeding between the two groups [OR = 1.740, 95%CI: 0.616-4.910, P = 0.296 (I2 = 50.6%)]; (11) In gastric ESD retrospective comparison studies of multiple APT user (No. bleeding/total = 33/131) vs non-antithrombotic user (No. bleeding/total = 89/1815)[15,41,50,56]: The risk of postoperative bleeding in multiple APT agent group was higher than the non-antithrombotic agent group [OR = 6.437, 95%CI: 4.048-10.237, P = 0.000 (I2 = 7.3%)]; (12) In gastric ESD retrospective comparison studies of multiple APT user (No. bleeding/total = 48/185) vs single APT user (No. bleeding/total = 40/494)[15,41,50,56,60]: The risk of postoperative bleeding in multiple APT agent group was higher than the single APT agent group [OR = 3.606, 95%CI: 2.270-5.726, P = 0.000 (I2 = 39.4%)]; (13) In gastric ESD retrospective comparison studies of continuous single APT user (No. bleeding/total = 5/96) vs non-antithrombotic user (No. bleeding/total = 71/1262)[17,41,50,58]: There was no significant difference in the risk of postoperative bleeding between the two groups [OR = 1.427, 95%CI: 0.524-3.886, P = 0.486 (I2 = 0.0%)]; (14) In gastric ESD retrospective comparison studies of aspirin user (No. bleeding/total = 38/491) vs non-antithrombotic user (No. bleeding/total = 145/3396): The risk of postoperative bleeding in aspirin agent group was higher than the non-antithrombotic agent group [OR = 1.889, 95%CI: 1.293-2.759, P = 0.000 (I2 = 47.0%)]; (15) In gastric ESD retrospective comparison studies of continuous aspirin user (No. bleeding/total = 36/320) vs discontinued aspirin user (No. bleeding/total = 34/391): There was no significant difference in the postoperative bleeding risk between the two groups [OR = 1.430, 95%CI: 0.786-2.603, P = 0.241 (I2 = 0.0%)]; (16) In gastric ESD retrospective comparison studies of discontinued aspirin user (No. bleeding/total = 31/325) vs non-antithrombotic user (No. bleeding/total = 147/3047)[27,51,53,56]: The risk of postoperative bleeding in discontinued aspirin agent group was higher than the non-antithrombotic agent group [OR = 2.093, 95%CI: 1.349-3.246, P = 0.001 (I2 = 33.1%)]; (17) In gastric ESD retrospective compatison studies of thienopyridine derivatives user (No. bleeding/total = 0/41) vs non-antithrombotic user (No. bleeding/total = 123/2903)[14,15,38,50]: There was no significant difference in the risk of postoperative bleeding between the two groups [OR = 0.983, 95%CI: 0.234-4.132, P = 0.981 (I2 = 0.0%)]; (18) In gastric ESD retrospective comparison studies of aspirin user (No. bleeding/total = 39/440) vs thieno-pyridine derivatives user (No. bleeding/total = 78/2009)[14,15,38,50,60]: The risk of postoperative bleeding in the aspirin agent group was higher than the thienopyridine derivatives agent group [OR = 1.806, 95%CI: 1.062-3.037, P = 0.029 (I2 = 47.0%)]; (19) In gastric ESD comparison studies (two retrospective studies and one prospective study) of anticoagulant user (No. bleeding/total = 21/145) vs non-antithrombotic user (No. bleeding/total = 154/3788)[38,41,59]: The risk of postoperative bleeding [OR = 4.029, 95%CI: 2.442-6.646, P = 0.000 (I2 = 18.1%)] in the anticoagulant agent group was significantly higher than the non-antithrombotic agent group; (20) In gastric ESD comparison studies (three retrospective studies and one prospective study) of warfarin user (No. bleeding/total = 24/127) vs direct oral anticoagulants (DOAC) user (No. bleeding/total = 10/60)[38,47,59]: There was no significant difference in the risk of postoperative bleeding between the two groups [OR = 0.940, 95%CI: 0.407-2.171, P = 0.885 (I2 = 0.0%)]; (21) In gastrointestinal ESD retrospective comparison studies of anticoagulant user (No. bleeding/total = 13/89) vs APT user (No. bleeding/total = 49/501)[38,41,52]: There was no significant difference in the risk of postoperative bleeding between the two groups [OR = 1.677, 95%CI: 0.852-3.302, P = 0.135 (I2 = 64.1%)]; (22) In gastric ESD retrospective comparison studies of heparin replacement (HR) (No. bleeding/total = 25/128) user vs non-antithrombotic user (No. bleeding/total = 154/3681)[23,27,38,41]: The risk of postoperative bleeding [OR = 5.547, 95%CI: 3.457-8.900, P = 0.000 (I2 = 16.9%)] in HR agent group was significantly higher than the non-antithrombotic agent group; (23) In gastric ESD retrospective comparison studies of HR user (No. bleeding/total = 32/125) vs continuous antithrombotic user (No. bleeding/total = 10/101)[17,25,27,61]: The risk of postoperative bleeding in the HR agent group was significantly higher than the continuous antith-rombotic agent group [OR = 2.859, 95%CI: 1.257-6.503, P = 0.012 (I2 = 0.0%)]; and (24) In gastric ESD retrospective comparison studies of HR user (No. bleeding/total = 29/120) vs continuous single APT user (No. bleeding/total = 7/83)[17,27,41]: The risk of postoperative bleeding in HR agent group was significantly higher than the continuous single APT agent group (OR = 2.988, 95%CI: 1.173-7.761, P = 0.000 (I2 = 3.1%)].

Among the EMR group, we performed several subgroup analyses to evaluate the effects of different types of antithrombotic agents on postoperative bleeding: (1) APT (No. bleeding/total = 13/605) user vs non-antithrombotic user (No. bleeding/total = 36/1445)[2,5,42]: OR = 1.744, 95%CI: 0.398-7.643, P = 0.461 (I2 = 78.8%). There were two retrospective studies and one prospective study in the subgroup analysis. There were two studies about colorectal EMR and one study about gastric EMR in the subgroup analysis; (2) Anticoagulant user (No. bleeding/total = 44/567) vs non-antithrombotic user (No. bleeding/total = 218/8131)[2,5,42]: There was no significant difference in the risk of postoperative bleeding risk between the two groups [OR = 1.409, 95%CI: 0.552-3.597, P = 0.474 (I2 = 0.0%)]. There were two retrospective studies and one prospective study in the subgroup analysis. There were two studies about colorectal EMR and one study about gastric EMR in the subgroup analysis; and (3) Anticoagulant user (No. bleeding/total = 5/147) vs APT user (No. bleeding/total = 13/605)[2,5,42]: There was no significant difference in the risk of postoperative bleeding between the two groups [OR = 0.768, 95%CI: 0.261-2.261, P = 0.631 (I2 = 0.0%)]. There were two retrospective studies and one prospective study in the subgroup analysis. There were two studies about colorectal EMR and one study about gastric EMR in the subgroup analysis.

Among the polypectomy group, we also performed several subgroup analyses to evaluate the effects of different types of antithrombotic agents on postoperative bleeding: (1) APT (No. bleeding/total = 56/994) user vs non-antithrombotic user (No. bleeding/total = 121/5983)[3,43,45]: OR = 1.766, 95%CI: 1.192-2.616, P = 0.005 (I2 = 73.9%) (retrospective studies). There were two studies about colorectal polypectomy and one study about gastric polypectomy in the subgroup analysis; (2) Anticoagulant user (No. bleeding/total = 16/128) vs APT user (No. bleeding/total = 33/1106)[45,62,63]: The risk of postoperative bleeding after colorectal polypectomy in the anticoagulant agent group was significantly higher than the APT agent group [OR = 3.132, 95%CI: 1.442-6.803, P = 0.004 (I2 = 9.0%)] (retrospective studies); and (3) Warfarin user (No. bleeding/total = 32/226) vs DOAC (No. bleeding/total = 13/98)[35,36,64]: There was no significant difference in the risk of postoperative bleeding between the two groups [OR = 1.126, 95%CI: 0.557-2.275, P = 0.741 (I2 = 0.0%)] (retrospective studies). There were two studies about colorectal polypectomy and one study about gastric polypectomy in the subgroup analysis. 

A subgroup analysis was planned to assess the risk of postoperative bleeding according to the difference in the size of the lesion, dosage and cessation period of antithrombotic agent, but we failed to perform the analysis because of insufficient data.

Thromboembolic event

Thromboembolic event is defined as arterial thromboembolism. This includes stroke, transient ischemic attack and infarction perioperative period. These thromboembolic events in included studies were available in nineteen articles (one event in the heparin therapy group[17], five events in the antithrombotic group[5,27], three events in the HR group[35,47,64], one event in the discontinued anticoagulant therapy group[30], one event in the discontinued antithrombotic therapy group[32], two events in the withdrawal period of antiplatelet therapy group[2,51], one event in the anticoagulant therapy group[44], one event in the withdrawal period of anti-vitamin K antagonisis therapy group[65], four events in the low dose aspirin interrupted group[66]). No thromboembolic events occurred in seven studies[36,41,49,58,59,67].

DISCUSSION

Despite several practice guidelines about the cessation or continuation of antithrombotic drugs before ER made by the British Society of Gastroenterology[68], the European Society of Gastrointestinal Endoscopy[68], the American Society for Gastrointestinal Endoscopy[69] and the Japan Gastroenterological Endoscopy Society[70], the effect of antithrombotic drugs on the risk of postoperative bleeding was still controversial in some studies[4,6,13,14,16,19-22,24,26,27,31,37,48,57]. Our study found that antithrombotic agents confer a higher risk for postoperative bleeding after ESD and EMR. But the risk of postoperative bleeding after polypectomy was not significantly elevated in the patients with antithrombotic drugs from our study, which was in consistent with the results of a study by Matsumoto et al[46]. Nevertheless, there was significant heterogeneity in the analysis of antithrombotic group vs non-antithrombotic group. To explain the heterogeneity (I2 = 82.5%) of our meta-analysis, we got the following findings: (1) Different methods were used to prevent postoperative bleeding; (2) Different definitions on postoperative bleeding[2,19]; (3) Different types and doses of antithrombotic agents; and (4) Different follow-up time, ranging 24 h to 3 mo. In order to reduce the heterogeneity, we have done the subgroup analyses to assess the effect of different types of antithrombotic agents in the risk of postoperative bleeding.

Some studies found that APT did not correlate with the risk of postoperative bleeding[32,52]. At the same time, the risk of delayed postoperative bleeding after ESD was not increased in a single APT agent (continued or discontinued)[17]. In contrast, it has been demonstrated that APT (especially dual APT) increases the risk of postoperative bleeding[50]. A retrospective study by Singh et al[71] showed that clopidogrel alone was not an independent risk factor for postoperative bleeding, but a randomized trial by Chan et al[72] showed that continued clopidogrel use results in a higher risk of postoperative bleeding compared to the discontinued clopidigrel use group. Our study found that continued single APT agent use did not increase the risk of postoperative bleeding, but multiple APT agents increased the risk of postoperative bleeding after ER.

Some studies found that low dose aspirin and continued use of aspirin didn’t induce a higher risk of postoperative bleeding after polypectomy and gastric ESD[23,43,50]. However, Ninomiya et al[53] found that continued use of aspirin increased the risk of postoperative bleeding after colorectal ESD. A study by Metz et al[2] demonstrated that the use of aspirin within 7 d of the operation was an independent risk factor for postoperative bleeding after colonic EMR. In a meta-analysis by Shalman et al[73], the risk of immediate bleeding in patients with aspirin was not increased, but the risk of delayed bleeding in patients with aspirin or thienopyridine derivatives was increased. Our study found that the use of aspirin significantly increased the risk of postoperative bleeding, but thienopyridine derivatives did not increase the risk of postoperative bleeding after ER. Nevertheless, the guidelines recommend continuing aspirin and withdrawing thienopyridine derivatives in the endoscopic resection[68-70]. Therefore, more prospective or randomized controlled trials are needed to determine the effects of aspirin and thienopyridine on the risk of postoperative bleeding after ER.

 Several guidelines about gastroenterological endoscopy recommend that anticoagulant agent should be discontinued with HR[68-70]. APT plus HR (meaning that anticoagulants were substituted by heparin before polypectomy) were not correlated with postoperative bleeding, but anticoagulant or anticoagulant plus HR were risk factors for postoperative bleeding[32]. Besides, HR alone was related to postoperative bleeding in univariate analysis but was not in multivariate analysis[32]. And our study has reached the same conclusion. Cessation of antithrombotic therapy could result in thromboembolic events such as cerebral infarction and hemorrhagic shock. But the risk of the thromboembolic events in the included studies is relatively low.

There were several drawbacks in this meta-analysis. First of all, the results of our meta-analysis were derived from retrospective studies. Retrospective studies may underestimate the risk of postoperative bleeding. Further prospective studies are needed to confirm our results. Secondly, the surveillance periods of included studies were not exactly the same. Finally, different types and doses of antithrombotic agents were used in the included studies, which may lead to bias.

CONCLUSION

In conclusion, the risk of postoperative bleeding after ER (polypectomy, EMR and ESD) correlated with the types and management of the antithrombotic agents according to our meta-analysis. Interrupting or switching antithrombotic therapy might result in the increased risk of serious thromboembolic events. Therefore, it is important to comprehensively assess the risk of postoperative bleeding and thromboembolic events in the patients with antithrombotic drugs after ER.

ARTICLE HIGHLIGHTS
Research background

Endoscopic resection (ER) is deemed as an effective method for gastrointestinal neoplasia, polyp, gastric adenomas, early oesophageal, gastric and colorectal cancer. More and more people suffering from cardiovascular disease and/or cerebrovascular disease receive antithrombotic therapy which change patients’ coagulation status and may lead to high risk of postoperative bleeding after ER. The relationship between the postoperative bleeding after ER and antithrombotic agents is still uncertain.

Research motivation

This study explored the relationship between the postoperative bleeding after ER and antithrombotic agents.

Research objectives

The aim of this study is to identify whether the use of antithrombotic drugs increases the risk of the postoperative bleeding after ER by a systematic review and meta-analysis.

Research methods

A systematic search was conducted on PubMed, Web of Science, Cochrane library. The Newcastle-Ottawa scale was used to evaluate the quality of studies. Stata 12.0 was used for statistical analysis. The odds ratio and 95%CI were calculated and heterogeneity was quantified using Cochran’s Q test and I2.

Research results

Total 66 studies were included in the meta-analysis. Pooled data suggested that antithrombotic therapy was significantly associated with postoperative bleeding after ER. The risk of postoperative bleeding after endoscopic submucosal dissection, endoscopic mucosal resection and polypectomy in the antithrombotic group was higher than the non-antithrombotic group.

Research conclusions

The risk of postoperative bleeding after ER correlated with the types and management of antithrombotic agents by our meta-analysis.

Research perspectives

Our results can guide the use of antithrombotic drugs before ER and evaluate the risk of postoperative bleeding.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: China

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): E

P-Reviewer: Hosoe N, Komeda Y, Rege S S-Editor: Wang JL L-Editor: A P-Editor: Ma YJ

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