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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
Reprint requests: Yosuke Tsuji, MD, PhD, Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Affiliations
Department of Gastroenterology, The University of Tokyo, Bunkyo-ku, Japan
Department of Gastroenterology, Kobe University International Clinical Cancer Research Center, Kobe, JapanDepartment of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Japan
Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, JapanDepartment of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Shinjuku-ku, JapanDivision of Digestive Endoscopy, Shiga University of Medical Science Hospital, Shiga, Japan
Department of Gastroenterology and Hepatology, Saitama Medical Center, Kawagoe, JapanGastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan
Department of Gastroenterology, National Hospital Organization Hakodate National Hospital, Hakodate, JapanJunpukai Health Maintenance Center Kurashiki, Kurashiki, Japan
Data are lacking regarding post–endoscopic submucosal dissection (ESD) bleeding in patients with early gastric cancer (EGC) who take antiplatelet agents (APAs), particularly in those taking thienopyridine and cilostazol. We aimed to clarify the association between the status of APA medication and post-ESD bleeding risk.
Methods
This study is a secondary analysis using data from a recently conducted nationwide multicenter study in Japan. We retrospectively reviewed patients treated with APAs or on no antithrombotic therapy recruited from 33 institutions who underwent ESD for EGC between November 2013 and October 2016. The primary outcome of this study was the relationship between the rate of post-ESD bleeding and the status of each APA medication.
Results
A total of 9736 patients were included in the analysis. Among 665 aspirin users, the continuation group was significantly associated with post-ESD bleeding (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.77-4.37). Among 227 thienopyridine users, the aspirin or cilostazol replacement group was not significantly associated with post-ESD bleeding (OR, 1.85; 95% CI, .72-4.78). Among 158 cilostazol users, there was no significant association with post-ESD bleeding, irrespective of medication status. The rate of post-ESD bleeding was approximately 10% to 20% irrespective of the status of APA administration among dual-antiplatelet therapy users. No patients experienced thromboembolic events in this study.
Conclusions
Replacement of thienopyridine with aspirin or cilostazol may be acceptable for minimizing both the risk of post-ESD bleeding and thromboembolism in patients with EGC. In patients on cilostazol monotherapy undergoing ESD, continuation of therapy may be acceptable.
Endoscopic submucosal dissection (ESD) is widely performed as an effective treatment for early gastric cancer (EGC). However, post-ESD bleeding is one of the most frequent adverse events, occurring in approximately 5% of patients undergoing gastric ESD.
With the rapid increase in the elderly population worldwide, the number of patients taking antithrombotic drugs is expected to grow. Therefore, the perioperative management of antithrombotic drugs when performing gastric ESD is a matter of great concern.
Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines.
Antithrombotic drugs are classified as antiplatelet agents (APAs) and anticoagulants (ACs). Previous studies on ACs reported a post-ESD bleeding rate of 9.1% with continued warfarin therapy
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.
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.
We retrospectively reviewed patients recruited from 33 institutions who underwent ESD for EGC between November 2013 and October 2016. Exclusion criteria were failure to complete ESD, less than 28 days of follow-up after ESD, a closed or covered ulcer base with polyglycolic acid sheets and fibrin glue after ESD, patient refusal to give consent to the use of their clinical data, photodynamic therapy after ESD, pathologically confirmed invasion of the muscularis propria or a deeper layer, and ESD performed on the remnant stomach. To avoid the effect of ACs on bleeding, patients undergoing AC treatment were excluded in this study. Patients treated with a combination of 3 APAs were also excluded.
This study was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by the review board of each participating institution before patient recruitment. Written informed consent for ESD was obtained from all patients before surgery. The need for obtaining informed consent from each patient to participate in this study was waived because an opt-out approach was provided. The opt-out option was available on the website of each participating institution.
ESD procedure and follow-up
The ESD procedure was performed in all institutions as previously reported.
Most patients fasted on the day of ESD, on the next day started a liquid diet followed by a soft diet for the next 3 days, and then were discharged. A scheduled second-look endoscopy was performed according to the policy of each participating institution. During the ESD perioperative period, proton pump inhibitors, potassium-competitive acid blockers, or H2 receptor antagonists were administered to all patients. In patients treated with antithrombotic drugs, the decision to continue, interrupt, or replace drugs before ESD, including the timing of drug administration, was mainly based on Japanese guidelines,
although the final decision remained at the discretion of the attending physician.
Data analysis
Post-ESD bleeding was defined as clinical symptoms (hematemesis or melena not due to intraoperative bleeding or a decrease in hemoglobin levels >2 g/dL) and bleeding confirmed by endoscopy within 28 days after ESD. Blood retention or minor bleeding from a post-ESD ulcer observed during second-look endoscopy was not interpreted as bleeding after gastric ESD unless the above-mentioned clinical symptoms were present. Cases in which prophylactic hemostasis was performed during second-look endoscopy were not classified as post-ESD bleeding.
Outcome measurements
The primary outcome of this study was the relationship between the rate of post-ESD bleeding and the status of each APA medication categorized as continuation, interruption, aspirin or cilostazol replacement, and heparin bridging therapy. “Interruption” was defined as discontinuation of any APA for more than 1 day. In addition to the primary outcome, the occurrence of thromboembolic events was also evaluated.
Statistical analysis
Categorical variables were compared using the Fisher exact test or χ2 test. Multivariate logistic regression analysis was subsequently performed on variables (age, sex, ischemic heart disease, chronic kidney disease with hemodialysis, number of tumors, tumor size, tumor location, and ESD procedure time) that showed significant differences in univariate analysis of the original study.
All analyses were performed using JMP software (SAS Institute Inc, Cary, NC, USA). A P < .05 was considered as statistically significant.
Results
Baseline characteristics
Among 11,452 patients who underwent ESD for EGC, 10,320 patients were initially enrolled for this study after excluding those who met the exclusion criteria. After further excluding 579 treated with ACs and 5 treated with triple APA therapy, 9736 patients were included in the final analysis (Fig. 1). Single-APA therapy was used in 1050 patients, whereas dual-APA therapy (DAPT) was used in 226 patients. Baseline characteristics of patients and lesions are summarized in Table 1. There were differences in sex, presence of ischemic heart disease or chronic kidney disease with hemodialysis, and lesion specimen ≥30 mm in diameter between the groups.
Figure 1Flowchart of the patient enrollment and rate of bleeding after ESD. ESD, Endoscopic submucosal dissection; EGC, early gastric cancer; PGA, polyglycolic acid; APA, antiplatelet agent.
The rate of post-ESD bleeding among the study participants was 3.9% (375/9736). In patients treated with APAs, the rate of post-ESD bleeding was 8.5% (108/1276), which was significantly higher than in those without APAs (3.2% [267/8460], P < .001). Detailed data regarding the post-ESD bleeding rate stratified for each APA are shown in Figure 1.
Association between single-APA therapy status and post-ESD bleeding risk
The post-ESD bleeding rate for each status of single-APA therapy is shown in Figure 2. Overall, the bleeding rate of patients treated with just thienopyridine medication alone was the highest and that of patients treated with cilostazol medication alone was the lowest. A multivariate analysis of the post-ESD bleeding risk was performed (Table 2). Among patients treated with aspirin medication alone, the continuation group had a significant risk of post-ESD bleeding (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.77-4.37), whereas no significant risk was observed in the interruption group (OR, 1.53; 95% CI, .90-2.60). Among patients treated with thienopyridine medication, the continuation (OR, 5.13; 95% CI, 1.62-16.22) and interruption (OR, 4.44; 95% CI, 2.57-7.54) groups had a significant risk of the bleeding. In contrast, no significant association with post-ESD bleeding was observed in the aspirin or cilostazol replacement group (OR, 1.85; 95% CI, .72-4.78). Among patients treated with cilostazol medication alone, no significant association with post-ESD bleeding was observed in either the continuation or the interruption group, with low ORs (.52 and .66, respectively).
Figure 2Rate of bleeding after endoscopic submucosal dissection according to the status for single-antiplatelet therapy. HBT, Heparin bridging therapy.
Association between dual-APA medication status and post-ESD bleeding risk
The post-ESD bleeding rate for each status of both aspirin and thienopyridine medication is shown in Figure 3. The 2 continuation groups had the highest bleeding rate (25.0%), whereas the aspirin continuation and the 2 interruption groups had a lower bleeding rate (12.0% and 9.4%, respectively). Multivariate analysis revealed a significant risk of post-ESD bleeding for all 3 medication statuses. It was difficult to appropriately evaluate the risk of the thienopyridine continuation group because of the small number of cases involved.
Figure 3Rate of bleeding after endoscopic submucosal dissection according to the status of each antiplatelet agent in patients taking dual-antiplatelet therapy. HBT, Heparin bridging therapy.
Association between the duration of APA interruption and post-ESD bleeding risk
We examined the post-ESD bleeding rate according to different definitions of APA interruption based on the duration of drug cessation. The JGES guidelines classify ESD as a procedure with a high risk of bleeding and recommend the following treatment regimens when ESD is performed: 3 to 5 days of aspirin interruption therapy, 5 to 7 days of thienopyridine interruption therapy, and 1 day of interruption for other APAs. There was no clear difference in the post-ESD bleeding rate between the continuation and interruption groups even when the definition of interruption was varied in each group (Fig. 4A and B).
Figure 4A, Rate of bleeding after endoscopic submucosal dissection (ESD) according to the period of aspirin interruption in patients receiving aspirin monotherapy. A, Drug interruption of at least 1 day was defined as a drug interruption group; B, drug interruption of at least 3 days was defined as a drug interruption group; C, drug interruption of at least 5 days was defined as a drug interruption group. B, Rate of bleeding after ESD according to the period of thienopyridine interruption in patients receiving thienopyridine monotherapy. A, Drug interruption of at least 1 day was defined as a drug interruption group; B, drug interruption of at least 5 days was defined as a drug interruption group; C, drug interruption of at least 7 days was defined as a drug interruption group.
No patient experienced thromboembolic events irrespective of the APA therapy status.
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.
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.
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
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,
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.
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.
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.
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.
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.
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
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
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
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).
References
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Costa M.N.
Pimentel-Nunes P.
et al.
Risk factors for bleeding after gastric endoscopic submucosal dissection: a systematic review and meta-analysis.
Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines.
Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association.
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.
DISCLOSURE: The following authors disclosed financial relationships: Y. Tsuji: Research funding from and speaker for Olympus. A. Masamune: Researchfundingfrom 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: Researchfundingfrom Olympus and Fujifilm; speaker for Olympus, Fujifilm, and Takeda Pharmaceutical. All other authors disclosed no financial relationships.
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