Regarding APAs, several studies have reported on the safety of continued aspirin use after gastric ESD.
11- Igarashi K.
- Takizawa K.
- Kakushima N.
- et al.
Should antithrombotic therapy be stopped in patients undergoing gastric endoscopic submucosal dissection?.
, 12- 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.
, 13- Harada H.
- Suehiro S.
- Murakami D.
- et al.
Feasibility of gastric endoscopic submucosal dissection with continuous low-dose aspirin for patients receiving dual antiplatelet therapy.
, 14- Lim J.H.
- Kim S.G.
- Kim J.W.
- et al.
Do antiplatelets increase the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms?.
However, evidence is limited on the use of thienopyridine and cilostazol to support the validity of the guidelines. Especially for thienopyridine, the American Society for Gastrointestinal Endoscopy guidelines recommend aspirin replacement, and the European Society of Gastrointestinal Endoscopy guidelines recommend drug interruption. However, the Japan Gastroenterological Endoscopy Society (JGES) guideline recommends replacement with aspirin or cilostazol for patients at high risk of antithrombotic events. A 16.6% to 35.4% post-ESD bleeding rate has been reported in patients treated with multiple APAs.
12- 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.
,15- Furuhata T.
- Kaise M.
- Hoteya S.
- et al.
Postoperative bleeding after gastric endoscopic submucosal dissection in patients receiving antithrombotic therapy.
However, these patients are also at high risk of thromboembolism after interruption of treatment and require careful monitoring. Nagami et al
16- Nagami Y.
- Hatta W.
- Tsuji Y.
- et al.
Antithrombotics increase bleeding after endoscopic submucosal dissection for gastric cancer: nationwide propensity score analysis.
reported that antithrombotic drugs increased the incidence of delayed bleeding after gastric ESD, although the risk for each APA administered and the management of each drug were not investigated. Data on APAs other than aspirin are lacking, and it is important to generate new case data to validate the existing guidelines. In the present study, we evaluated the association between the use of each APA, including thienopyridine and cilostazol, and the risk of post-ESD bleeding based on data from a nationwide multicenter study in Japan.
17- Hatta W.
- Tsuji Y.
- Yoshio T.
- et al.
Prediction model of bleeding after endoscopic submucosal dissection for early gastric cancer: BEST-J score.
Discussion
This study investigated the risk of post-ESD bleeding in relation to APA therapy status (continuation, interruption, replacement, or heparin bridging therapy) using nationwide multicenter data. The analysis revealed an association between both continuation and interruption of therapy and the risk of bleeding after ESD in patients treated with thienopyridine, although no association was found with the increased risk of bleeding in the replacement group. In patients treated with cilostazol, there was no significant risk of bleeding after ESD in either group. In patients treated with aspirin, there was a significant association with the increased risk of bleeding after ESD only in the continuation group. The rates of post-ESD bleeding were high in patients treated with DAPT, regardless of APA status.
In 2012, the JGES published guidelines for the management of antithrombotic therapy in patients undergoing endoscopic procedures.
5- Fujimoto K.
- Fujishiro M.
- Kato M.
- et al.
Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment.
Guidelines tend to emphasize the risk of thromboembolism associated with the interruption of antithrombotic drugs in addition to the risk of bleeding associated with the continuation of antithrombotic drugs. When ESD is performed in patients treated with APAs, the guidelines recommend continuing treatment with aspirin alone or interrupting thienopyridine therapy for 5 to 7 days and replacing this with aspirin or cilostazol to prevent thromboembolism.
5- Fujimoto K.
- Fujishiro M.
- Kato M.
- et al.
Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment.
Several reports showed that ESD can be performed safely with aspirin continuation before and after the guideline revision.
11- Igarashi K.
- Takizawa K.
- Kakushima N.
- et al.
Should antithrombotic therapy be stopped in patients undergoing gastric endoscopic submucosal dissection?.
, 12- 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.
, 13- Harada H.
- Suehiro S.
- Murakami D.
- et al.
Feasibility of gastric endoscopic submucosal dissection with continuous low-dose aspirin for patients receiving dual antiplatelet therapy.
, 14- Lim J.H.
- Kim S.G.
- Kim J.W.
- et al.
Do antiplatelets increase the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms?.
However, to date, there are few reports on the safety of ESD in patients treated with cilostazol or thienopyridine.
11- Igarashi K.
- Takizawa K.
- Kakushima N.
- et al.
Should antithrombotic therapy be stopped in patients undergoing gastric endoscopic submucosal dissection?.
,19- Ono S.
- Myojo M.
- Harada H.
- et al.
Is it possible to perform gastric endoscopic submucosal dissection without discontinuation of a single antiplatelet of thienopyridine derivatives?.
,20- Oh S.
- Kim S.G.
- Kim J.
- et al.
Continuous use of thienopyridine may be as safe as low-dose aspirin in endoscopic resection of gastric tumors.
Because most previous reports included a small number of subjects, the safety of ESD for patients with APAs, such as thienopyridine and cilostazol, has not been demonstrated. In particular, the association of aspirin or cilostazol replacement with the rate of bleeding after ESD for patients treated with thienopyridine alone has not been reported. Our study revealed that thrombosis did not occur, and the OR of post-ESD bleeding was lower in patients after replacement of thienopyridine with aspirin or cilostazol compared with the thienopyridine continuation or interruption groups. This result supports the validity of the aspirin or cilostazol replacement policy in patients at high risk of thromboembolism after thienopyridine interruption. In the present study, we could not determine why the interruption groups had a higher bleeding rate than replacement groups (aspirin or cilostazol or heparin bridging) among the thienopyridine users. Ono et al
21- Ono S.
- Fujishiro M.
- Yoshida N.
- et al.
Thienopyridine derivatives as risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study.
reported in their prospective study that among DAPT users, post-ESD bleeding occurred after the resumption of thienopyridine. In our present study, most cases of post-ESD bleeding occurred after thienopyridine resumption. Resuming thienopyridine might cause post-ESD bleeding, but further study is needed to elucidate this hypothesis.
Another issue to be investigated is whether aspirin replacement or cilostazol replacement is better. None of the cases in which thienopyridine was replaced with cilostazol had post-ESD bleeding. However, only 14 cases were replaced with cilostazol, and there is room for further study, including the effect of cilostazol on prevention of thromboembolism.
Regarding the association between cilostazol treatment and the risk of bleeding after ESD, there were no significant associations irrespective of medication status. As in previous reports,
11- Igarashi K.
- Takizawa K.
- Kakushima N.
- et al.
Should antithrombotic therapy be stopped in patients undergoing gastric endoscopic submucosal dissection?.
,22- Kono Y.
- Obayashi Y.
- Baba Y.
- et al.
Postoperative bleeding risk after gastric endoscopic submucosal dissection during antithrombotic drug therapy.
the bleeding rates were 1.8% in the continuation group and 2.1% in the interruption group. Therefore, these data based on a multicenter investigation involving a large number of subjects suggest that continued treatment with cilostazol is acceptable. In patients taking aspirin, multivariate analysis showed that the risk of bleeding after ESD was significant in the continuation group. Thromboembolism has been reported to occur in 1.0% to 7.5% of patients undergoing gastric ESD after interruption of APAs.
14- Lim J.H.
- Kim S.G.
- Kim J.W.
- et al.
Do antiplatelets increase the risk of bleeding after endoscopic submucosal dissection of gastric neoplasms?.
,23- Takeuchi T.
- Ota K.
- Harada S.
- et al.
The postoperative bleeding rate and its risk factors in patients on antithrombotic therapy who undergo gastric endoscopic submucosal dissection.
,24- Sanomura Y.
- Oka S.
- Tanaka S.
- et al.
Continued use of low-dose aspirin does not increase the risk of bleeding during or after endoscopic submucosal dissection for early gastric cancer.
In this study, many patients underwent ESD with continuous aspirin after revision of the JGES guideline in 2012, and no cases of thromboembolic events occurred in the perioperative period.
5- Fujimoto K.
- Fujishiro M.
- Kato M.
- et al.
Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment.
These results suggest the validity of the current guidelines, which recommend continued aspirin treatment only in patients at high risk of thromboembolism such as postcoronary stent placement, recent ischemic stroke or transient ischemic attack, arteriosclerosis obliterans with Fontaine stage, and so on.
Several reports have shown that multiple APAs increase the risk of bleeding after ESD.
12- 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.
,15- Furuhata T.
- Kaise M.
- Hoteya S.
- et al.
Postoperative bleeding after gastric endoscopic submucosal dissection in patients receiving antithrombotic therapy.
,20- Oh S.
- Kim S.G.
- Kim J.
- et al.
Continuous use of thienopyridine may be as safe as low-dose aspirin in endoscopic resection of gastric tumors.
,22- Kono Y.
- Obayashi Y.
- Baba Y.
- et al.
Postoperative bleeding risk after gastric endoscopic submucosal dissection during antithrombotic drug therapy.
APAs are used to prevent and treat cardiovascular diseases such as acute coronary syndrome, and aspirin is essential for the prevention of thromboembolism after coronary stent placement.
25- Meschia J.F.
- Bushnell C.
- Boden-Albala B.
- et al.
Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association.
The risk of coronary stent restenosis is particularly high after coronary intervention with drug-eluting stents, hence the requirement for DAPT for 12 months after intervention and the use of aspirin thereafter.
26- Grines C.L.
- Bonow R.O.
- Casey D.E.
- et al.
Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians.
Therefore, the JGES guidelines recommended the use of aspirin or cilostazol only after interrupting thienopyridine for 5 to 7 days when performing gastric ESD in patients on DAPT.
There have been several reports about gastric ESD in patients on DAPT. Harada et al
13- Harada H.
- Suehiro S.
- Murakami D.
- et al.
Feasibility of gastric endoscopic submucosal dissection with continuous low-dose aspirin for patients receiving dual antiplatelet therapy.
reported a higher rate of bleeding after ESD in patients treated with DAPT (aspirin and clopidogrel in all patients) with continued aspirin (23.1%) than with both drugs interrupted (5%), although this difference was not significant. In a prospective study, Ono et al
19- Ono S.
- Myojo M.
- Harada H.
- et al.
Is it possible to perform gastric endoscopic submucosal dissection without discontinuation of a single antiplatelet of thienopyridine derivatives?.
reported that gastric ESD in patients on DAPT with continuation of only thienopyridine caused bleeding after ESD in 20% of patients (2/10). In another prospective study investigating endoscopic procedures with a high risk of bleeding, Ono et al
21- Ono S.
- Fujishiro M.
- Yoshida N.
- et al.
Thienopyridine derivatives as risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study.
also found that DAPT use was a significant risk factor for bleeding after gastric ESD. This report also showed that all bleeding after ESD occurred after the resumption of thienopyridine. In our study, we also observed a high rate of bleeding after ESD (12.0%-20.0%) in patients on DAPT, even after interruption of 1 or 2 APAs. However, more than half of these patients developed bleeding after restarting the interrupted APAs. These results suggest that careful management of postoperative APA resumption is necessary in patients on DAPT, and further study is required.
There are several limitations to this study. First, although this is a nationwide, multicenter study, the sample size was small for each APA when examining each in detail, and there was the significant likelihood of confounding variables. However, to the best of our knowledge, this is the largest study investigating the association between perioperative APA management and the risk of post-ESD bleeding, and our results provide robust data concerning each APA risk. Second, although many patients in this study were managed with APAs according to the new guidelines, in this retrospective analysis management was at the discretion of the attending physician. It is important to note that in some cases the timing of the interruption of therapy and other factors were not standardized.
In conclusion, when performing gastric ESD in patients at high risk of thromboembolism, thienopyridine continuation is associated with a high risk of post-ESD bleeding, and it is appropriate to replace it with aspirin or cilostazol. Cilostazol continuation has no significant association with the risk of post-ESD bleeding, and aspirin continuation is also an acceptable approach, although the rate of post-ESD bleeding increased. In addition, as previously reported, a multivariate analysis excluding ACs shows that the risk of post-ESD bleeding is high in patients treated with DAPT, and careful attention should be paid to the timing of the resumption of APAs. Further analysis of clinical data on a larger scale is warranted to further standardize the management of APAs in accordance with the guidelines.
Acknowledgments
We thank all collaborators in the Fight-Japan study group for the enrollment of patients and data collection: Sho Shiroma (Cancer Institute Hospital, Japanese Foundation for Cancer Research); Hiroyuki Ono (Shizuoka Cancer Centre); Hiroyuki Odagiri (Toranomon Hospital); Kazuhiro Matsunaga and Shigenori Wakita (Ishikawa Prefectural Central Hospital); Shusei Fukunaga, Masaki Ominami, and Taishi Sakai (Osaka City University Graduate School of Medicine); Minami Hashimoto, Jun Nakamura, and Ko Watanabe (Fukushima Medical University Hospital); Ryusuke Ariyoshi (Kobe University Graduate School of Medicine); Yutaka Okagawa, Takeyoshi Minagawa, and Ryoji Fujii (Tonan Hospital); Takao Maekita and Kazuhiro Fukatsu (Wakayama Medical University); Yoichi Hiasa (Ehime University Graduate School of Medicine); Daisuke Chinda, Hidezumi Kikuchi, and Tetsuya Tatsuta (Hirosaki University Hospital); Atsushi Goto (Yamaguchi University Graduate School of Medicine); Daisuke Maruoka, Kenichiro Okimoto, and Naoki Akizue (Chiba University Graduate School of Medicine); Tomoaki Yamasaki, Takehisa Suekane, and Yu Yasui (Osaka City General Hospital); Tsutomu Nishida and Masashi Yamamoto (Toyonaka Municipal Hospital); Keiichi Hashiguchi and Naoyuki Yamaguchi (Nagasaki University Hospital); Yoichi Akazawa and Hiroyuki Komori (Juntendo University School of Medicine); Yoshiki Tsujii, Hideki Iijima, and Tetsuo Takehara (Osaka University Graduate School of Medicine); Masaki Murata (Shiga University of Medical Science Hospital); Takashi Ohta (Kansai Rosai Hospital); Hidehiko Takabayashi (Saitama Medical Centre); Yoshiyuki Itakura (Kohnodai Hospital, National Centre for Global Health and Medicine); Kazuya Kitamura (Kanazawa University Hospital); Daisuke Akutsu (University of Tsukuba); and Toshio Uraoka (Gunma University Graduate School of Medicine).
Article info
Publication history
Published online: January 10, 2023
Accepted:
December 30,
2022
Received:
October 7,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
DISCLOSURE: The following authors disclosed financial relationships: Y. Tsuji: Research funding from and speaker for Olympus. A. Masamune: Research funding from EA Pharma, Otsuka Pharmaceutical, Gilead Sciences, Asahi Kasei Pharma, Eisai, AbbVie GK, Takeda Pharmaceutical, and Daiichi Sankyo; speaker for EA Pharma, Takeda Pharmaceutical, Daiichi Sankyo, and Lylan.co.jp. M. Fujishiro: Research funding from Olympus and Fujifilm; speaker for Olympus, Fujifilm, and Takeda Pharmaceutical. All other authors disclosed no financial relationships.
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© 2023 by the American Society for Gastrointestinal Endoscopy