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Article

A Prospective Observational Study on Gastric Endoscopic Submucosal Dissection under Continuous Administration of Antithrombotic Agents

1
Department of Gastroenterology, Tsuyama Chuo Hospital, Tsuyama 708-0841, Japan
2
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-0082, Japan
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2024, 13(7), 1886; https://doi.org/10.3390/jcm13071886
Submission received: 21 February 2024 / Revised: 19 March 2024 / Accepted: 20 March 2024 / Published: 25 March 2024
(This article belongs to the Special Issue Gastric Cancer: Diagnosis, Treatment and Prevention)

Abstract

:
Background: This study aimed to assess the completion rate and postoperative bleeding incidence of endoscopic submucosal dissection (ESD) for gastric tumors under continuous antithrombotic therapy. Methods: A prospective observational study was conducted including 88 patients with 100 gastric lesions who underwent gastric endoscopic submucosal dissection (ESD) and received continuous antithrombotic therapy. Additionally, retrospective data on gastric ESD in 479 patients with 534 lesions who did not receive antithrombotic therapy were collected for comparison. Results: The en bloc resection rates (100% in the continuous antithrombotic therapy group vs. 100% in the non-antithrombotic therapy group) and complete resection rates (97.0% vs. 96.3%, respectively) were high and comparable between the groups. No significant differences were found in the specimen size or procedure time. Perforation rates were low (0% vs. 2.3%, respectively) and were not significantly different between the groups. However, postoperative bleeding occurred significantly more frequently in the continuous antithrombotic therapy group (10.2% vs. 4.2%, respectively) than in the non-antithrombotic therapy group. The subgroup analysis revealed a higher incidence of postoperative bleeding in patients receiving thienopyridine derivatives. Conclusions: Continuous administration of antithrombotic agents, especially thienopyridines, increased the risk of postprocedural hemorrhage following gastric ESD. These findings support the need for careful consideration of pharamcological management before ESD, aligning with the current guidelines.

1. Introduction

Gastric adenocarcinoma, a malignancy originating from the stomach’s epithelial lining, ranks as the third most prevalent cause of cancer-related mortality worldwide [1,2]. Traditionally, surgical interventions are reserved for cases presenting with an increased likelihood of lymph node metastasis or those diagnosed with submucosal invasive gastric cancer. In contrast, endoscopic submucosal dissection (ESD), an advanced endoscopic technique, has emerged as a preferred curative strategy for early-stage gastric cancers devoid of these ominous prognostic indicators. ESD entails the meticulous removal of the mucosal and submucosal tissues utilizing specialized endoscopic equipment, offering a minimally invasive alternative to conventional surgical approaches. This innovative procedure boasts high rates of efficacy and safety, making it an increasingly favored option in the management of early gastric malignancies. In Japan, early gastric cancer represents a significant proportion, ranging from 15% to 57%, of all gastric cancer cases [3,4]. This notable prevalence underscores the critical need for effective treatment strategies, with endoscopic resection established as a cornerstone in the management of these lesions [5,6]. Among various endoscopic resection techniques, ESD distinguishes itself by demonstrating superior performance metrics, including higher rates of en bloc resection and lower incidences of local recurrence compared to conventional endoscopic mucosal resection [7,8,9]. However, it is essential to acknowledge that despite these advantages, ESD carries inherent risks, with serious adverse events such as postoperative bleeding among the potential complications. Multiple reports have indicated that antiplatelet agents and anticoagulants increase the incidence of postoperative bleeding [10,11], and the discontinuation of these agents poses a risk of thromboembolism. In addition, a previous report suggested that the continuous administration of antiplatelet agents is not independently and significantly correlated with postoperative bleeding. Currently, insufficient data exist concerning the safety of the continuous use of antithrombotic agents during gastric ESD. Thus, we conducted a prospective observational study to evaluate the impact of the continuous administration of antithrombotic agents, focusing on the completion rate and incidence of postoperative bleeding following ESD for gastric tumors. Furthermore, to investigate whether the continuous oral administration of antithrombotic agents increases postoperative bleeding, we retrospectively collected and compared data on gastric ESD performed during the same period in patients who did not receive antithrombotic therapy.

2. Materials and Methods

2.1. Prospective Observational Study on Gastric ESD in Patients Undergoing Continuous Antithrombotic Therapy

A prospective observational study was conducted at a single hospital in Japan from November 2013 to March 2019, focusing on patients aged ≥20 years diagnosed with or suspected to have early gastric cancer and presenting a negligible risk for lymph-node metastasis. This study included individuals receiving antithrombotic agents, including antiplatelet agents (e.g., aspirin, thienopyridine derivatives, or cilostazol) and antithrombotic agents (e.g., warfarin or direct oral anticoagulants). ESD was indicated for (i) differentiated mucosal cancer lesions without ulcers, regardless of size, (ii) differentiated mucosal cancer lesions ≤3 cm with ulcers, (iii) undifferentiated mucosal cancer lesions ≤2 cm without ulcers, and (iv) adenoma suspected of containing a mucosal cancer component. For all lesions, lymph-node metastasis-free and distant metastasis-free conditions were confirmed using preoperative computed tomography.
The study was approved by the institutional review board of our hospital on 6 February 2013 (number 153) and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients. This study was registered with the University Hospital Medical Network Clinical Trials Registry (trial number: UMIN000012079). All authors had full access to the study data, and the final manuscript was reviewed and approved by all authors.

2.2. Retrospective Observational Study on Gastric ESD in Patients without Antithrombotic Therapy

To investigate whether continuous oral administration of antithrombotic agents increases postoperative bleeding, we retrospectively reviewed patients who did not receive antithrombotic agents and underwent gastric ESD between November 2013 and March 2019. The retrospective study protocol was approved by the institutional review board of our hospital (number 626) and conducted in accordance with the Declaration of Helsinki. The requirement for written informed consent was waived due to the retrospective and anonymous nature of the data.

2.3. ESD Procedure

ESD was performed using a high-frequency generator (VIO 300D; Erbe Elektromedizin GmbH, Tubingen, Germany). Hemostatic forceps (FD-410LR; Olympus Co. or HDB2418W; Hoya Co., Tokyo, Japan) were used in soft coagulation mode at effect 6 and 70 W output. Prophylactic coagulation was performed on the visible vessels; however, ESD ulcer closure was not performed. Administration of an intravenous proton pump inhibitor (PPI) (lansoprazole, 30 mg, twice daily) was initiated on the day of the ESD and replaced with oral PPI (lansoprazole, 30 mg, once daily) the following day. After April 2015, vonoprazan (20 mg, once daily) was used as a substitute for PPI in patients receiving continuous antithrombotic agents. The patients were discharged 7 days after the ESD, and they underwent follow-up endoscopy 8 weeks after the procedure.
In our study, postoperative bleeding, regarded as a critical endpoint, was precisely defined as the occurrence of clinically evident bleeding necessitating immediate intervention, such as emergency endoscopic hemostasis and/or blood transfusion, coupled with a decrease in hemoglobin levels exceeding 2 g/dL.

2.4. Statistical Analysis

Differences between the two groups were determined using the chi-squared test or Fisher’s exact test for discontinuous variables and the Mann–Whitney U test for continuous variables. Statistical analyses were performed using the JMP software package (version 13; SAS Institute, Cary, NC, USA). Statistical significance was set at values of p < 0.05.

3. Results

Between November 2013 and March 2019, 88 patients with 100 gastric lesions, who received antithrombotic drugs, were enrolled in this prospective study (Figure 1). In terms of diagnostic clues for gastric lesions among 88 cases, two patients presented with anemia, and two patients tested positive for fecal occult blood. Among the two patients with anemia, one (Case No. 1) exhibited mild, normocytic normochromic anemia and revealed no lesions causing bleeding during esophagogastroduodenoscopy. No evidence of bleeding was observed from gastric cancer as well. In another patient (Case No. 2), oozing was observed from the surface of a gastric cancer, consistent with the etiology of anemia. One patient with fecal occult blood (Case No. 3) displayed bleeding gastric ulcers unrelated to gastric cancers, necessitating hemostatic intervention via esophagogastroduodenoscopy. The remaining case (Case No. 4) showed no lesions indicative of fecal occult blood on esophagogastroduodenoscopy and CT scans. Bleeding from gastric cancer was also absent.
ESD was performed in all patients, and no perforations occurred during ESD. Antiplatelet agents were administered in 72% of patients. Aspirin was administered to 35 patients, whereas cilostazole and thienopyridine derivatives were administered to 17. Only six patients received dual antiplatelet therapy. During the same period, gastric ESD was performed in 479 patients with 534 lesions who were not receiving antithrombotic agents. We retrospectively collected and analyzed data from these patients.
The clinical characteristics of the patients are summarized in Table 1. No significant difference in sex distribution was observed between the two groups (male: 70% vs. 73% in the continuous antithrombotic therapy and non-antithrombotic therapy groups, respectively). However, the age of patients was higher in the continuous antithrombotic therapy group than in the non-antithrombotic therapy group (median, 79 years vs. 74 years, respectively; p < 0.001). The prevalence of comorbidities associated with antithrombotic therapy including hypertension (68% vs. 56%, p = 0.033), cerebrovascular disease (53% vs. 3%, p < 0.001), ischemic heart disease (25% vs. 4%, p < 0.001), and atrial fibrillation (27% vs. 0.2%, p < 0.001) was higher in the continuous antithrombotic therapy group than in the non-antithrombotic therapy group. Although not statistically significant, alcohol intake was less frequent in the continuous antithrombotic agent group than in the non-antithrombotic agent group (28% vs. 38%, respectively; p = 0.074). Lansoprazole was administered to all patients in the non-antithrombotic agent group as an acid-suppressive agent following gastric ESD, whereas in the continuous antithrombotic agent group, 30% of the patients received lansoprazole and 70% received vonoprazan (p < 0.001).
The technical and pathological results of ESD are shown in Table 2. En bloc resection was performed in all patients, with a complete resection rate of 97.0% in the continuous antithrombotic agent group and 96.3% in the non-antithrombotic agent group, showing no statistical difference. No significant differences in specimen size (median, 35.5 mm vs. 35.0 mm) or procedure time (median, 71.5 min vs. 75.0 min) was observed between the continuous antithrombotic therapy and non-antithrombotic therapy groups, respectively. No patients in the continuous antithrombotic agent group had perforation during or after ESD, whereas 2.3% of patients in the non-antithrombotic agent group had perforations (p = 0.151). Postoperative bleeding was noted in 10.2% of patients in the continuous antithrombotic agent group, which was significantly more frequent than that of patients in the non-antithrombotic agent group (p = 0.018). None of the patients developed cardiocerebrovascular disease during the study period.
Table 3 shows the incidence of postoperative bleeding for each antiplatelet agent. Among antiplatelet agents, post-ESD bleeding was most frequent in patients taking thienopyridine derivatives (29.4%), followed by aspirin (8.6%) and cilostazol (5.9%). We further conducted a sub-analysis comparing groups with and without postoperative bleeding among patients receiving antithrombotic agents. In the postoperative bleeding group, 56% of the patients were receiving thienopyridine derivatives, which was a significantly higher proportion compared with that in the no-bleeding group (15%, p = 0.012) (Table 4). No statistically significant differences were observed between the two groups for any other variables.

4. Discussion

In the present study, en bloc resection was performed in all patients, exhibiting a complete resection rate of 97.0% observed in the continuous antithrombotic therapy group. Additionally, postprocedural bleeding following gastric ESD occurred in 10.2% of patients with continued use of antithrombotic agents. To our knowledge, this is the first prospective observational investigation of gastric ESD performed while continuing antithrombotic agent therapy. Furthermore, it highlights an elevated risk of post-ESD bleeding associated with thienopyridine use among all antithrombotic agents. Although data for the non-antithrombotic agent group were retrospectively collected, the incidence of post-ESD bleeding was higher in the continuous antithrombotic therapy group than in the non-antithrombotic therapy group. These findings emphasize the need for caution regarding the increased risk of postoperative bleeding when continuing antithrombotic agents, particularly in patients receiving thienopyridine therapy, suggesting the need for alternative agents or temporary discontinuation of antithrombotic therapy in this subset of patients.
Several studies have highlighted the increased risk of postoperative bleeding in patients undergoing gastric ESD while receiving antithrombotic therapy. Gotoda et al. found that dual antiplatelet therapy and heparin replacement are associated with this risk [12]. Matsumura et al. identified a large specimen size, heparin replacement, and chronic kidney disease requiring hemodialysis as risk factors for early and delayed postoperative bleeding [13]. Sato et al. further emphasized the risk of postoperative bleeding in patients receiving antithrombotic therapy, particularly in those receiving heparin bridging therapy and dual antiplatelet therapy [14]. Ueki et al. found that interrupted antithrombotic therapy and prolonged ESD procedure times are associated with early and delayed postoperative bleeding, respectively [15].
A number of retrospective studies have suggested that continued use of antiplatelet agents may increase the risk of post-ESD bleeding. Lim et al. investigated a cohort of 1591 subjects, 274 of whom were taking antiplatelets, with 102 discontinuing them for 7 days or more before gastric ESD [16]. Although continuous administration of antiplatelets was not independently associated with a significant increase in bleeding after ESD, the incidence of post-ESD bleeding was higher among those who continued to use antiplatelets (11.6%) compared to those who discontinued them (5.9%) or those who were not taking antiplatelets (5.2%). Igarashi et al. reported a similar incidence of 9.3% in the group continuing antithrombotic therapy, compared to 4.2% in the group not receiving antithrombotic therapy [17]. They further noted that the incidence of post-gastric ESD bleeding was comparable in patients on antithrombotic therapy with heparin bridge therapy (replaced with heparin, 10.8%) and those who ceased antithrombotic therapy (9.4%). Oh et al. examined 215 patients who underwent gastric ESD [18]. Among these, 161 patients received single-agent antiplatelet therapy (94 on aspirin, 56 on thienopyridine, and 11 on alternative agents), while 51 were administered dual therapy, and 3 were subjected to triple antiplatelet regimens. The incidence of bleeding was 15.4% in the continuous aspirin group, 11.8% in the aspirin cessation group, 7.1% in the continuous thienopyridine group, and 0% in the thienopyridine cessation group. Harada et al. reported that the post-gastric ESD bleeding rate was 15.8% in patients receiving continuous administration of antiplatelets, compared to 8.5% in patients who discontinued antiplatelet therapy [19]. According to a recent nationwide, multicenter retrospective study conducted in Japan involving a total of 9736 patients, the post-gastric ESD bleeding rates were 9.3% for the continuous administration of aspirin, 5.3% for discontinued aspirin therapy, 19.0% for continuous thienopyridine therapy, and 14.1% for discontinued thienopyridine therapy [20]. These findings underscore the need for careful monitoring and management of bleeding risk in patients undergoing gastric ESD while receiving antithrombotic therapy.
In Japan and Western countries, guidelines have been published that describe both the risk of gastrointestinal bleeding associated with continuing antithrombotic drugs and the risk of thromboembolism with the temporary discontinuation of this therapy [21,22,23]. According to these guidelines, endoscopic biopsy and endoscopic procedures with a low risk of bleeding, such as balloon endoscopy, marking clip, tattooing, pancreatic duct, and bile duct stenting, and endoscopic papillary balloon dilation, can be performed without discontinuing the antithrombotic drug. However, temporary cessation of antithrombotic drugs is still recommended for endoscopic treatments with a high risk of bleeding, such as polypectomy, ESD, and endoscopic papillotomy. Currently, data supporting the efficacy of these tentative guidelines are insufficient. Hence, evaluating whether the continuous administration of antithrombotic agents influences the efficacy of ESD and increases the risk of post-ESD bleeding is important. In this prospective cohort study, ESD was performed without the cessation of antithrombotic agents, and the complete resection rate for ESD was 97.0%, and post-ESD bleeding occurred in 10.2% of the patients.
The incidence of post-ESD bleeding has been retrospectively reported to be 1.8–15.6% [10,11,13,17,24,25,26,27,28,29,30,31,32,33]. Risk factors for post-ESD bleeding include age [29], hemodialysis [13,30], longer operation time [29,31,33], tumor size [28], resection size [11,13,17,24,31,32], tumor location [10,27,28,31], scar lesion [31], recurrent lesion [28], macroscopic type [28], and administration of antithrombotic agents [11,33]. In this prospective cohort study, only the continuous administration of thienopyridine derivatives showed a significant association with the occurrence of postoperative bleeding, while under continuous administration of antithrombotic agents. Ono et al. reported a significantly higher incidence of postoperative bleeding in patients receiving continuous thienopyridine derivatives and multiple antithrombotic agents than in those not receiving any medication [34]. In a study involving patients who underwent gastric ESD with aspirin withdrawal and continued thienopyridine administration after coronary artery stent placement, the postoperative bleeding rate was reported to be 20% [35]. Tounou et al. reported a postoperative bleeding rate of 35.5% in the aspirin and thienopyridine-derivative administration group [36]. A recent nationwide, multicenter retrospective study conducted in Japan also unveiled that among patients undergoing gastric ESD, the incidence of post-procedural bleeding was notably elevated in those receiving continuous thienopyridine therapy (19.0%), as opposed to individuals with discontinued thienopyridine therapy (14.1%), continuous aspirin administration (9.3%), discontinued aspirin therapy (5.3%), cessation of cilostazol (2.1%), and continuous cilostazol use (1.8%) [20]. The results of the present study, together with those of the existing literature, suggest that thienopyridine is associated with a higher risk of bleeding than other antiplatelet agents. As described in the Japanese guidelines [37], switching thienopyridine to another antiplatelet agent (e.g., aspirin or cilostazol) is considered appropriate for preventing postoperative bleeding.
Our study underscores several significant limitations that necessitate thorough consideration. First, this investigation was carried out exclusively at a singular medical center, which inherently restricts the broader applicability of our findings due to the relatively confined sample size involved in our study cohort. Additionally, within the subset of patients receiving continuous antithrombotic agents, there was a notable transition observed in oral acid-suppressive therapy, shifting from lansoprazole to vonoprazan in the study period. While the incidence rates of postoperative bleeding remained relatively consistent, it is plausible that this alteration may have introduced variability in clinical outcomes. Moreover, data pertaining to patients not receiving antithrombotic medications were retrospectively acquired, potentially introducing inherent biases into our analyses. Nevertheless, notwithstanding these acknowledged limitations, our study leverages prospective observational data garnered from patients undergoing gastric ESD while adhering to antithrombotic drug regimens. We posit that these insights offer valuable real-world perspectives into the clinical management of individuals navigating such therapeutic regimens.

5. Conclusions

In conclusion, our prospective investigation revealed that achieving outstanding en bloc resection (100%) and complete resection (97.0%) rates is feasible with the continuous administration of antithrombotic agents. Postprocedural hemorrhage following gastric ESD manifested in 10.2% of the patients in whom antithrombotic agents were consistently administered. Notably, the heightened risk of bleeding observed in patients receiving thienopyridine underscores the imperative need for medication cessation or modification prior to the procedure. This outcome aligns with the current guidelines, thereby substantiating the necessity for such interventions.

Author Contributions

Conceptualization, D.K. and R.T.; formal analysis, D.K., M.I. and R.T.; investigation, M.I. and R.T.; data collection, D.K., R.T., T.O., T.Y., S.H., K.M., K.T., H.T. and S.F.; writing—original draft preparation, D.K. and R.T.; writing—review and editing, M.I.; supervision, R.T. and S.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Tsuyama Chuo Hospital (protocol number 153 on 6 February 2013 and 626 on 9 February 2023).

Informed Consent Statement

Written informed consent was obtained from all participants involved in the prospective study. Patient consent was waived in the retrospective study due to the retrospective and anonymous nature of the data.

Data Availability Statement

The datasets generated and analyzed in the current study are available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 2015, 136, E359–E386. [Google Scholar] [CrossRef]
  2. Plummer, M.; de Martel, C.; Vignat, J.; Ferlay, J.; Bray, F.; Franceschi, S. Global burden of cancers attributable to infections in 2012: A synthetic analysis. Lancet Glob. Health 2016, 4, e609–e616. [Google Scholar] [CrossRef] [PubMed]
  3. Shimizu, S.; Tada, M.; Kawai, K. Early gastric cancer: Its surveillance and natural course. Endoscopy 1995, 27, 27–31. [Google Scholar] [CrossRef]
  4. Noguchi, Y.; Yoshikawa, T.; Tsuburaya, A.; Motohashi, H.; Karpeh, M.S.; Brennan, M.F. Is gastric carcinoma different between Japan and the United States? Cancer 2000, 89, 2237–2246. [Google Scholar] [CrossRef]
  5. Gotoda, T.; Yanagisawa, A.; Sasako, M.; Ono, H.; Nakanishi, Y.; Shimoda, T.; Kato, Y. Incidence of lymph node metastasis from early gastric cancer: Estimation with a large number of cases at two large centers. Gastric Cancer 2000, 3, 219–225. [Google Scholar] [CrossRef]
  6. Hirasawa, T.; Gotoda, T.; Miyata, S.; Kato, Y.; Shimoda, T.; Taniguchi, H.; Fujisaki, J.; Sano, T.; Yamaguchi, T. Incidence of lymph node metastasis and the feasibility of endoscopic resection for undifferentiated-type early gastric cancer. Gastric Cancer 2009, 12, 148–152. [Google Scholar] [CrossRef]
  7. Oka, S.; Tanaka, S.; Kaneko, I.; Mouri, R.; Hirata, M.; Kawamura, T.; Yoshihara, M.; Chayama, K. Advantage of endoscopic submucosal dissection compared with EMR for early gastric cancer. Gastrointest. Endosc. 2006, 64, 877–883. [Google Scholar] [CrossRef] [PubMed]
  8. Watanabe, K.; Ogata, S.; Kawazoe, S.; Watanabe, K.; Koyama, T.; Kajiwara, T.; Shimoda, Y.; Takase, Y.; Irie, K.; Mizuguchi, M.; et al. Clinical outcomes of EMR for gastric tumors: Historical pilot evaluation between endoscopic submucosal dissection and conventional mucosal resection. Gastrointest. Endosc. 2006, 63, 776–782. [Google Scholar] [CrossRef] [PubMed]
  9. Park, Y.M.; Cho, E.; Kang, H.Y.; Kim, J.M. The effectiveness and safety of endoscopic submucosal dissection compared with endoscopic mucosal resection for early gastric cancer: A systematic review and meta-analysis. Surg. Endosc. 2011, 25, 2666–2677. [Google Scholar] [CrossRef]
  10. Tsuji, Y.; Ohata, K.; Ito, T.; Chiba, H.; Ohya, T.; Gunji, T.; Matsuhashi, N. Risk factors for bleeding after endoscopic submucosal dissection for gastric lesions. World J. Gastroenterol. 2010, 16, 2913–2917. [Google Scholar] [CrossRef]
  11. Koh, R.; Hirasawa, K.; Yahara, S.; Oka, H.; Sugimori, K.; Morimoto, M.; Numata, K.; Kokawa, A.; Sasaki, T.; Nozawa, A.; et al. Antithrombotic drugs are risk factors for delayed postoperative bleeding after endoscopic submucosal dissection for gastric neoplasms. Gastrointest. Endosc. 2013, 78, 476–483. [Google Scholar] [CrossRef]
  12. Gotoda, T.; Hori, K.; Iwamuro, M.; Kono, Y.; Miura, K.; Kanzaki, H.; Kawano, S.; Kawahara, Y.; Okada, H. Evaluation of the bleeding risk with various antithrombotic therapies after gastric endoscopic submucosal dissection. Endosc. Int. Open 2017, 5, E653–E662. [Google Scholar] [CrossRef]
  13. Matsumura, T.; Arai, M.; Maruoka, D.; Okimoto, K.; Minemura, S.; Ishigami, H.; Saito, K.; Nakagawa, T.; Katsuno, T.; Yokosuka, O. Risk factors for early and delayed post-operative bleeding after endoscopic submucosal dissection of gastric neoplasms, including patients with continued use of antithrombotic agents. BMC Gastroenterol. 2014, 14, 172. [Google Scholar] [CrossRef]
  14. Sato, C.; Hirasawa, K.; Koh, R.; Ikeda, R.; Fukuchi, T.; Kobayashi, R.; Kaneko, H.; Makazu, M.; Maeda, S. Postoperative bleeding in patients on antithrombotic therapy after gastric endoscopic submucosal dissection. World J. Gastroenterol. 2017, 23, 5557–5566. [Google Scholar] [CrossRef]
  15. Ueki, N.; Futagami, S.; Akimoto, T.; Maruki, Y.; Yamawaki, H.; Kodaka, Y.; Nagoya, H.; Shindo, T.; Kusunoki, M.; Kawagoe, T.; et al. Effect of antithrombotic therapy and long endoscopic submucosal dissection procedure time on early and delayed postoperative bleeding. Digestion 2017, 96, 21–28. [Google Scholar] [CrossRef]
  16. Lim, J.H.; Kim, S.G.; Kim, J.W.; Choi, Y.J.; Kwon, J.; Kim, J.Y.; Lee, Y.B.; Choi, J.; Im, J.P.; Kim, J.S.; et al. Do antiplatelets increase the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms? Gastrointest. Endosc. 2012, 75, 719–727. [Google Scholar] [CrossRef] [PubMed]
  17. Igarashi, K.; Takizawa, K.; Kakushima, N.; Tanaka, M.; Kawata, N.; Yoshida, M.; Ito, S.; Imai, K.; Hotta, K.; Ishiwatari, H.; et al. Should antithrombotic therapy be stopped in patients undergoing gastric endoscopic submucosal dissection? Surg. Endosc. 2017, 31, 1746–1753. [Google Scholar] [CrossRef] [PubMed]
  18. Oh, S.; Kim, S.G.; Kim, J.; Choi, J.M.; Lim, J.H.; Yang, H.J.; Park, J.Y.; Han, S.J.; Kim, J.L.; Chung, H.; et al. Continuous Use of Thienopyridine May Be as Safe as Low-Dose Aspirin in Endoscopic Resection of Gastric Tumors. Gut Liver 2018, 12, 393–401. [Google Scholar] [CrossRef] [PubMed]
  19. Harada, H.; Suehiro, S.; Murakami, D.; Nakahara, R.; Nagasaka, T.; Ujihara, T.; Sagami, R.; Katsuyama, Y.; Hayasaka, K.; Amano, Y. Feasibility of gastric endoscopic submucosal dissection with continuous low-dose aspirin for patients receiving dual antiplatelet therapy. World J. Gastroenterol. 2019, 25, 457–468. [Google Scholar] [CrossRef]
  20. Miura, Y.; Tsuji, Y.; Yoshio, T.; Hatta, W.; Yabuuchi, Y.; Hoteya, S.; Kikuchi, D.; Tsuji, S.; Nagami, Y.; Hikichi, T.; et al. Association between perioperative management of antiplatelet agents and risk of post-endoscopic submucosal dissection bleeding in early gastric cancer: Analysis of a nationwide multicenter study. Gastrointest. Endosc. 2023, 97, 889–897. [Google Scholar] [CrossRef] [PubMed]
  21. Fujimoto, K.; Fujishiro, M.; Kato, M.; Higuchi, K.; Iwakiri, R.; Sakamoto, C.; Uchiyama, S.; Kashiwagi, A.; Ogawa, H.; Murakami, K.; et al. Japan Gastroenterological Endoscopy Society. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig. Endosc. 2014, 26, 1–14. [Google Scholar] [CrossRef]
  22. Veitch, A.M.; Radaelli, F.; Alikhan, R.; Dumonceau, J.M.; Eaton, D.; Jerrome, J.; Lester, W.; Nylander, D.; Thoufeeq, M.; Vanbiervliet, G.; et al. Endoscopy in patients on antiplatelet or anticoagulant therapy: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guideline update. Endoscopy 2021, 53, 947–969. [Google Scholar]
  23. ASGE Standards of Practice Committee; Acosta, R.; Abraham, N.S.; Chandrasekhara, V.; Chathadi, K.V.; Early, D.S.; Eloubeidi, M.A.; Evans, J.A.; Faulx, A.L.; Fisher, D.A.; et al. Management of antithrombotic agents in patients undergoing GI endoscopy. Gastrointest. Endosc. 2016, 83, 3–16. [Google Scholar]
  24. Mannen, K.; Tsunada, S.; Hara, M.; Yamaguchi, K.; Sakata, Y.; Fujise, T.; Noda, T.; Shimoda, R.; Sakata, H.; Ogata, S.; et al. Risk factors for complications of endoscopic submucosal dissection in gastric tumors: Analysis of 478 lesions. J. Gastroenterol. 2010, 45, 30–36. [Google Scholar] [CrossRef]
  25. Fujishiro, M.; Chiu, P.W.; Wang, H.P. Role of antisecretory agents for gastric endoscopic submucosal dissection. Dig. Endosc. 2013, 25, 86–93. [Google Scholar] [CrossRef]
  26. Isomoto, H.; Shikuwa, S.; Yamaguchi, N.; Fukuda, E.; Ikeda, K.; Nishiyama, H.; Ohnita, K.; Mizuta, Y.; Shiozawa, J.; Kohno, S. Endoscopic submucosal dissection for early gastric cancer: A large-scale feasibility study. Gut 2009, 58, 331–336. [Google Scholar] [CrossRef]
  27. Takizawa, K.; Oda, I.; Gotoda, T.; Yokoi, C.; Matsuda, T.; Saito, Y.; Saito, D.; Ono, H. Routine coagulation of visible vessels may prevent delayed bleeding after endoscopic submucosal dissection--an analysis of risk factors. Endoscopy 2008, 40, 179–183. [Google Scholar] [CrossRef] [PubMed]
  28. Chung, I.K.; Lee, J.H.; Lee, S.H.; Kim, S.J.; Cho, J.Y.; Cho, W.Y.; Hwangbo, Y.; Keum, B.R.; Park, J.J.; Chun, H.J.; et al. Therapeutic outcomes in 1000 cases of endoscopic submucosal dissection for early gastric neoplasms: Korean ESD Study Group multicenter study. Gastrointest. Endosc. 2009, 69, 1228–1235. [Google Scholar] [CrossRef] [PubMed]
  29. Toyokawa, T.; Inaba, T.; Omote, S.; Okamoto, A.; Miyasaka, R.; Watanabe, K.; Izumikawa, K.; Horii, J.; Fujita, I.; Ishikawa, S.; et al. Risk factors for perforation and delayed bleeding associated with endoscopic submucosal dissection for early gastric neoplasms: Analysis of 1123 lesions. J. Gastroenterol. Hepatol. 2012, 27, 907–912. [Google Scholar] [CrossRef]
  30. Higashiyama, M.; Oka, S.; Tanaka, S.; Sanomura, Y.; Imagawa, H.; Shishido, T.; Yoshida, S.; Chayama, K. Risk factors for bleeding after endoscopic submucosal dissection of gastric epithelial neoplasm. Dig. Endosc. 2011, 23, 290–295. [Google Scholar] [CrossRef]
  31. Miyahara, K.; Iwakiri, R.; Shimoda, R.; Sakata, Y.; Fujise, T.; Shiraishi, R.; Yamaguchi, K.; Watanabe, A.; Yamaguchi, D.; Higuchi, T.; et al. Perforation and postoperative bleeding of endoscopic submucosal dissection in gastric tumors: Analysis of 1190 lesions in low- and high-volume centers in Saga, Japan. Digestion 2012, 86, 273–280. [Google Scholar] [CrossRef] [PubMed]
  32. Okada, K.; Yamamoto, Y.; Kasuga, A.; Omae, M.; Kubota, M.; Hirasawa, T.; Ishiyama, A.; Chino, A.; Tsuchida, T.; Fujisaki, J.; et al. Risk factors for delayed bleeding after endoscopic submucosal dissection for gastric neoplasm. Surg. Endosc. 2011, 25, 98–107. [Google Scholar] [CrossRef] [PubMed]
  33. Takeuchi, T.; Ota, K.; Harada, S.; Edogawa, S.; Kojima, Y.; Tokioka, S.; Umegaki, E.; Higuchi, K. The postoperative bleeding rate and its risk factors in patients on antithrombotic therapy who undergo gastric endoscopic submucosal dissection. BMC Gastroenterol. 2013, 13, 136. [Google Scholar] [CrossRef] [PubMed]
  34. Ono, S.; Fujishiro, M.; Yoshida, N.; Doyama, H.; Kamoshida, T.; Hirai, S.; Kishihara, T.; Yamamoto, Y.; Sakae, H.; Imagawa, A.; et al. Thienopyridine derivatives as risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study. Endoscopy 2015, 47, 632–637. [Google Scholar] [CrossRef]
  35. Ono, S.; Myojo, M.; Harada, H.; Tsuji, K.; Murakami, D.; Suehiro, S.; Doyama, H.; Ando, J.; Saito, I.; Fujishiro, M.; et al. Is it possible to perform gastric endoscopic submucosal dissection without discontinuation of a single antiplatelet of thienopyridine derivatives? Endosc. Int. Open 2017, 5, E943–E949. [Google Scholar] [CrossRef]
  36. Tounou, S.; Morita, Y.; Hosono, T. Continuous aspirin use does not increase post-endoscopic dissection bleeding risk for gastric neoplasms in patients on antiplatelet therapy. Endosc. Int. Open. 2015, 3, E31–E38. [Google Scholar] [CrossRef]
  37. Ono, H.; Yao, K.; Fujishiro, M.; Oda, I.; Uedo, N.; Nimura, S.; Yahagi, N.; Iishi, H.; Oka, M.; Ajioka, Y.; et al. Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer (second edition). Dig. Endosc. 2021, 33, 4–20. [Google Scholar] [CrossRef]
Figure 1. Study flowchart. ESD, endoscopic submucosal dissection.
Figure 1. Study flowchart. ESD, endoscopic submucosal dissection.
Jcm 13 01886 g001
Table 1. Clinical characteristics of the patients.
Table 1. Clinical characteristics of the patients.
Continuous Antithrombotic Agent Group
88 Patients, 100 Lesions
Non-Antithrombotic Agent Group
479 Patients, 534 Lesions
p-Value
Age (years), median (range)79(60–92)74(33–94)<0.001
Sex, male, n (%)62(70)349(73)0.642
Habit
  Smoking, n (%)14(16)91(19)0.493
Alcohol consumption, n (%)25(28)184(38)0.074
Comorbidities
Hypertension, n (%)60(68)268(56)0.033
Diabetes mellitus, n (%)25(28)113(24)0.333
Cerebrovascular disease, n (%)47(53)15(3)<0.001
Ischemic heart disease, n (%)22(25)16(4)<0.001
Atrial fibrillation, n (%)24(27)1(0.2)<0.001
Antithrombotic agent
Antiplatelet agents, n (%)63(72)
Aspirin, n (%)35(40)
Cilostazol, n (%)17(19)
Thienopyridine derivatives, n (%)17(19)
Anticoagulant agent27(31)
Warfarin, n (%)11(13)
Apixaban, n (%)9(10)
Rivaroxaban, n (%)4(5)
Dabigatran, n (%)3(3)
Number of antithrombotic agents
Single, n (%)80(91)
Multiple, n (%)8(9)
 Dual antiplatelet agents6(7)
 Aintiplatelet plus anticoagulant2(2)
Lesion size (mm), median (range)12(2–140)12(1–64)0.343
Number of lesions 0.731
Single, n (%)76(86)420(88)
Multiple, n (%)12(14)59(12)
Acid-suppressive agent <0.001
Lansoprazole26(30)479(100)
Vonoprazan62(70)00
Table 2. Technical and pathological results of endoscopic submucosal dissection.
Table 2. Technical and pathological results of endoscopic submucosal dissection.
Continuous Antithrombotic Agent Group
88 Patients, 100 Lesions
Non-Antithrombotic Agent Group
479 Patients, 534 Lesions
p-Value
En bloc resection, n (%)100(100)534(100)1.000
R0 resection, n (%)97(97.0)514(96.3)0.715
Specimen size (mm), median (range)35.5(22–150)35.0(17–96)0.205
Procedure time (min), median (range)71.5(23–273)75.0(22–445)0.876
Adverse event
  Perforation, n (%)0(0)11(2.3)0.151
  Postoperative bleeding, n (%)9(10.2)20(4.2) 0.018
Table 3. The incidence of postoperative bleeding for each antiplatelet agent.
Table 3. The incidence of postoperative bleeding for each antiplatelet agent.
Incidence of Postoperative Bleeding (%)
Antithrombotic agents, overall9/88 (10.2)
Antiplatelet agents7/63 (11.1)
  Aspirin3/35 (8.6)
  Cilostazol1/17 (5.9)
  Thienopyridine derivatives5/17 (29.4)
Anticoagulant agents2/27 (7.4)
  Warfarin0/11 (0)
  Apixaban1/9 (11.1)
  Dabigatran0/3 (0)
  Rivaroxaban1/4 (25.0)
Number of antithrombotic agent
  Multiple2/8 (25.0)
  Dual antiplatelet agents2/6 (33.3)
  Antiplatelet + anticoagulant0/2 (0)
Table 4. Factors associated with postoperative bleeding in patients receiving antithrombotic agents.
Table 4. Factors associated with postoperative bleeding in patients receiving antithrombotic agents.
Postoperative Bleeding
n = 9
No Postoperative Bleeding
n = 79
p-Value
Age (years), median (range)77(69–89)79(60–92)0.634
  Sex, male, n (%)7(78)55(70)1.000
Habit
  Smoking, n (%)0(0)14(18)0.344
  Alcohol consumption, n (%)1(11)24(30)0.436
Helicobacter pylori infection status
  Positive, n (%)3(33)25(32)1.000
Comorbidity
  Hypertension, n (%)6(67)54(68)1.000
  Diabetes mellitus, n (%)2(22)23(29)1.000
  Cerebrovascular disease, n (%)6(67)41(52)0.494
  Ischemic heart disease, n (%)0(0)22(28)0.105
  Atrial fibrillation, n (%)2(22)22(28)1.000
Antithrombotic agent
  Antiplatelet agent7(78)56(71)1.000
   Aspirin, n (%)3(33)32(41)1.000
   Cilostazol, n (%)1(11)16(20)1.000
   Thienopyridine derivatives, n (%)5(56)12(15)0.012
  Anticoagulant agents2(22)25(32)0.716
   Warfarin, n (%)0(0)11(14)0.595
   Apixaban, n (%)1(11)8(10)1.000
   Dabigatran, n (%)0(0)3(4)1.000
   Rivaroxaban, n (%)1(11)3(4)0.356
Number of antithrombotic agent
  Multiple, n (%)2(22)6(8)0.188
   Dual antiplatelet agents2(22)4(5)0.113
   Antiplatelet + anticoagulant0(0)2(3)1.000
Location of lesion (n = 100)
  Upper third, n (%)2(20)10(11)0.644
  Middle third, n (%)5(50)43(48)
  Lower third, n (%)3(30)37(41)
Lesion size (mm), median (range)16(12–40)13(4–140)0.119
Number of lesions
  Multiple, n (%)1(11)11(14)1.000
Acid-suppressive agent
  Vonoprazan6(67)56(71)1.000
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MDPI and ACS Style

Kawai, D.; Iwamuro, M.; Takenaka, R.; Obata, T.; Yamamoto, T.; Hirata, S.; Miura, K.; Takemoto, K.; Tsugeno, H.; Fujiki, S. A Prospective Observational Study on Gastric Endoscopic Submucosal Dissection under Continuous Administration of Antithrombotic Agents. J. Clin. Med. 2024, 13, 1886. https://doi.org/10.3390/jcm13071886

AMA Style

Kawai D, Iwamuro M, Takenaka R, Obata T, Yamamoto T, Hirata S, Miura K, Takemoto K, Tsugeno H, Fujiki S. A Prospective Observational Study on Gastric Endoscopic Submucosal Dissection under Continuous Administration of Antithrombotic Agents. Journal of Clinical Medicine. 2024; 13(7):1886. https://doi.org/10.3390/jcm13071886

Chicago/Turabian Style

Kawai, Daisuke, Masaya Iwamuro, Ryuta Takenaka, Taisuke Obata, Takashi Yamamoto, Shoichiro Hirata, Ko Miura, Koji Takemoto, Hirofumi Tsugeno, and Shigeatsu Fujiki. 2024. "A Prospective Observational Study on Gastric Endoscopic Submucosal Dissection under Continuous Administration of Antithrombotic Agents" Journal of Clinical Medicine 13, no. 7: 1886. https://doi.org/10.3390/jcm13071886

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