Characteristics and risk factors for postoperative bleeding following endoscopic resection of esophageal squamous neoplasms

Characteristics and risk factors for postoperative bleeding following endoscopic resection of esophageal squamous neoplasms | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Characteristics and risk factors for postoperative bleeding following endoscopic resection of esophageal squamous neoplasms Daiki Kitagawa, Takashi Kanesaka, Ryu Ishihara, Yasuhiro Tani, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5339326/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Dec, 2024 Read the published version in Digestive Diseases and Sciences → Version 1 posted 9 You are reading this latest preprint version Abstract Background Reports on postoperative bleeding after esophageal endoscopic resection are limited. Aims This study aimed to identify the clinical characteristics and risk factors for postoperative bleeding following endoscopic resection of esophageal neoplasms. Methods This single-center, retrospective study included consecutive patients who underwent endoscopic resection for esophageal squamous cell carcinoma or squamous intraepithelial neoplasm between January 2018 and December 2022. We investigated the incidence, timing, severity, and risk factors for postoperative bleeding. Results Among the 1,288 patients, postoperative bleeding occurred in seven (0.5%) patients (95% confidence interval [CI] 0.2–1.1%; median postoperative day 8 [range, 4–17 days]). In these seven patients, hemoglobin concentration decreased by a median of 3.0 g/dL (range, 1.6–6.8 g/dL). Direct oral anticoagulants (DOACs) were identified as the most significant risk factor for postoperative bleeding (odds ratio [OR] 41.9, 95% CI 6.8–294.6; P < 0.001) and were significantly associated with postoperative bleeding even after propensity score matching (3/39 [8%] vs. 0/78 [0%], P = 0.035). Among 43 patients who received DOACs, postoperative bleeding occurred in four (9%) patients (95% CI 2.6–22.1%). Conclusions The overall bleeding rate following esophageal endoscopic resection was 0.5%, with a delayed onset, leading to anemia. DOACs emerged as the most significant risk factor for postoperative bleeding. Esophageal Neoplasms Esophageal Squamous Cell Carcinoma Endoscopy Endoscopic Mucosal Resection and Gastrointestinal Hemorrhage Figures Figure 1 Figure 2 Figure 3 Introduction Endoscopic resection, such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), which are minimally invasive treatments for esophageal cancer, are performed worldwide, including in Japan and other Asian and Western countries [ 1 , 2 ]. The characteristics of postoperative bleeding, which is a major adverse event in endoscopic resection, have been extensively investigated in relation to gastric and colorectal endoscopic resection [ 3 – 14 ]. However, reports investigating postoperative bleeding characteristics in relation to esophageal endoscopic resection are limited [ 15 ]. This study aimed to identify the characteristics and risk factors associated with postoperative bleeding in esophageal endoscopic resection. Methods Study design and patients This retrospective study included consecutive patients who had undergone endoscopic resection for esophageal squamous cell carcinoma or squamous intraepithelial neoplasm at the Osaka International Cancer Institute between January 2018 and December 2022. Patients who underwent endoscopic resection of other organs on the same day and those with a history of esophagectomy were excluded. The study protocol was approved by the Institutional Review Board of Osaka International Cancer Institute on June 8, 2023 (Approval No. 23041). Endoscopic procedure The indications for endoscopic resection were determined in accordance with the Japan Gastroenterological Endoscopy Society guidelines: (i) non-circumferential cT1a-EP/LPM (epithelium/lamina propria mucosa) or cT1a-MM/T1b-SM1 (muscularis mucosa/superficial submucosa ≤ 200 µm) squamous cell carcinoma (or squamous intraepithelial neoplasms), (ii) whole-circumferential cT1a-EP/LPM esophageal squamous cell carcinoma (or squamous intraepithelial neoplasms) ≤ 5 cm, and (iii) no lymph node and distant metastases [ 1 ]. EMR and ESD procedures were selected at the endoscopist’s discretion based on lesion size. For EMR, an endoscope with a large-diameter plastic cap (D-206-04; Olympus Corporation, Tokyo, Japan) was used. After injecting saline solution into the submucosa, a small-diameter snare (SD-7P; Olympus Corporation) was opened within the plastic cap. The lesion was aspirated into the plastic cap and resected using a snare in forced coagulation mode or endo-cut mode with an electrosurgical generator (VIO 300D or VIO 3, ERBE, Tübingen, Germany). In ESD, an electrosurgical knife (FlushKnife BT-S 1.5 mm, DK 2620JI; FUJIFILM Medical Co., Ltd., Tokyo, Japan, or HookKnife J, KD-625; Olympus Corporation) was used with an electrosurgical generator (VIO 300D or VIO 3, ERBE). After injecting 10% glycerin solution or hyaluronic acid into the submucosa, mucosal incision and submucosal dissection were performed. After resection, the thick vessels exposed on the resection wound were cauterized using hemostatic forceps (Coagrasper, FD-410LR; Olympus Corporation) in soft coagulation mode. Steroids were injected into the submucosa if the wound covered more than three-quarters of the esophageal circumference. If no perforation occurred during the procedure, it was completed without closing the resection wound. Clinical pathway of esophageal endoscopic resection Endoscopic resection was performed during hospitalization. Drinking water was administered after the patient was awakened from sedation on postoperative day (POD) 0. The patient underwent blood tests on POD 1 to evaluate hemoglobin concentration, white blood cell counts, and biochemistry. If the patient remained symptom-free, food intake was initiated on POD 2. The patient was discharged on POD 4. Proton pump inhibitors and hemostatic agents were not administered perioperatively. Perioperative management of antithrombotic agents The management of antithrombotic agents, including withdrawal or replacement with other drugs, was mainly based on Japan Gastroenterological Endoscopy Society guidelines [ 16 , 17 ]. Aspirin monotherapy was maintained in patients at high risk of thromboembolism and withdrawn after 3–5 days in those at low risk of thromboembolism. Thienopyridine derivatives were replaced with aspirin or cilostazol in patients at high risk of thromboembolism and withdrawn after 5–7 days in those at low risk of thromboembolism. The procedure was performed with aspirin or cilostazol monotherapy in patients already receiving aspirin in combination with other antiplatelet agents. Warfarin was continued if the prothrombin time-international normalized ratio fell within the therapeutic range or temporarily switched to direct oral anticoagulants (DOACs) for patients with non-valvular atrial fibrillation. Heparin replacement was administered at the attending physician’s discretion following consultation with the prescribing doctor. DOACs were continued until the day before the procedure and withdrawn on the morning of the procedure. In patients receiving a combination of antiplatelet agents and DOACs, antiplatelet agents other than aspirin or cilostazol were replaced with aspirin or cilostazol monotherapy, and DOACs were withdrawn on the morning of the procedure. Patients resumed their original antiplatelet therapy and DOACs on the morning of POD 1 after confirming no symptoms of postoperative bleeding, such as hematemesis or melena. Definition of postoperative bleeding Postoperative bleeding was defined as an episode of hematemesis or melena within 28 days of esophageal endoscopic resection that required hemostasis. The esophageal hemorrhage grade was assessed following the Common Toxicity Criteria for Adverse Events v5.0. For example, Grade 3 indicated the need for transfusion and invasive intervention leading to hospitalization; Grade 4 indicated life-threatening consequences requiring urgent intervention; and Grade 5 indicated death. Histopathological evaluation The resected specimens were cut into 2 mm slices. The histological type of tumor, invasion depth, size, lymphovascular involvement, and resection margins were first assessed by one pathologist and then again by a second pathologist. Statistical analysis Among patients with multiple lesions, only the lesion with the largest specimen size was included in the analysis. If multiple lesions were removed together (en bloc), they were analyzed as a single specimen. To identify the risk factors for postoperative bleeding, the characteristics of patients with and without postoperative bleeding were compared. Chi-square or Fisher’s exact tests were used to compare clinical variables, and the Mann–Whitney U test was used for continuous variables. P -values < 0.05 were considered statistically significant. For the resection wound circumference, Youden’s J index was calculated to distinguish between patients with and without postoperative bleeding. Receiver operating characteristic (ROC) curves were constructed to determine the optimal cut-off value for distinguishing between patients with and without postoperative bleeding. The optimal cut-off value was defined as the point on the ROC curve closest to 1 minus a specificity of 0 and a sensitivity of 1.0. Propensity scores were estimated by fitting a logistic regression model adjusted for certain clinical variables. One-to-two pair matching between patients who received DOACs and those who did not was performed using a caliper width equal to 0.2 of the standard deviation of the logit of the propensity score. All analyses were conducted using R software, version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria; http://cran.r-project.org/ ) and the EZR software package, v. 1.55 (Saitama Medical Center, Jichi Medical University, Tochigi, Japan). Results Patient characteristics Of the 1,378 patients who underwent esophageal endoscopic resection between January 2018 and December 2022, 90 were excluded and 1,288 were eligible for analysis (Fig. 1 ). The median age of the patients was 69 years (interquartile range, 62–75 years), and 1,004 (78%) patients were male. Regarding the type of endoscopic resection, 1,062 (82%) patients underwent ESD, and the remaining 226 (18%) patients underwent EMR. Postoperative bleeding occurred in seven (0.5%) patients (95% confidence interval [CI] 0.2–1.1%) at a median time of POD 8 (range, 4–17 days). Hemoglobin concentration in these patients decreased by a median of 3.0 g/dL (range, 1.6–6.8 g/dL). Of the 43 patients who received DOACs, postoperative bleeding occurred in four (9%) patients (95% CI 2.6–22.1%). Hospitalization was required for all seven patients, blood transfusion was indicated in four patients, and Grade 3 esophageal hemorrhage was noted in all seven patients. The postoperative bleeding details are presented in Table 1 . Table 1 Clinical findings concerning the seven patients with postoperative bleeding Clinical findings Postoperative onset time, day 8 (4–17) Symptoms Hematemesis 4 (57) Melena 3 (43) Type of bleeding Spurting bleeding 1 (14) Oozing bleeding 6 (86) Hemostasis technique Cauterization 6 (86) Clipping 1 (14) Decrease in hemoglobin concentration, g/dL 3.0 (1.6–6.8) Transfusion 4 (57) Hospitalization, day 5 (3–7) Grade of esophageal hemorrhage† Grade 3 7 (100) Grade 4 0 (0) Grade 5 0 (0) Data are presented as the median (range) or n (%) †Grade 3: Transfusion indicated, invasive intervention indicated, hospitalization; Grade 4: Life-threatening consequences, urgent intervention indicated; Grade 5: Death Risk factors for postoperative bleeding Clinical characteristics were compared between patients with and without postoperative bleeding (Table 2 ). Postoperative bleeding occurred only in ESD cases, with no significant difference in bleeding rates between EMR and ESD (0%, 95% CI 0–1.6% vs. 0.7%, 95% CI 0.3–1.4%; P = 0.613). Antithrombotic agent use, resection wound circumference, and specimen size were significantly associated with postoperative bleeding ( P < 0.001, P = 0.002, and P = 0.024, respectively). Table 3 shows the association between each antithrombotic agent and postoperative bleeding. Anticoagulants, warfarin, and DOACs were significantly associated with postoperative bleeding ( P = 0.048 and P < 0.001, respectively). In contrast, antiplatelet agents, aspirin, and thienopyridine were not significantly associated with postoperative bleeding. When the resection wound circumference exceeded three-quarters, Youden’s J index was 0.57, representing the maximal value in the postoperative bleeding group. The cut-off value for specimen size was determined to be 39 mm using ROC curve analysis (Supplementary Fig. 1). Consequently, warfarin (odds ratio [OR] 26.4, 95% CI 0.5–259.0; P = 0.048), DOAC (OR 41.9, 95% CI 6.8–294.6; P < 0.001), more than three-quarter circumferential resection of the wound (OR 15.3, 95% CI 2.5–162.1; P < 0.001), and specimen size ≥ 40 mm (OR 6.5, 95% CI 1.1–69.0; P = 0.021) were identified as significant risk factors for postoperative bleeding (Table 4 ). DOACs were significantly associated with postoperative bleeding, even after adjusting for background clinicopathological characteristics using propensity score matching (Tables 5 and 6 ). Postoperative bleeding occurred in four (9%, 95% CI 2.6–22.1%) of 43 patients who received DOACs and in five (3%, 95% CI 1.1–7.5%) of 153 patients with more than three-quarter circumferential resection of the wound and a specimen size ≥ 40 mm. Table 2 A comparison of the characteristics of patients with and without postoperative bleeding Characteristics Patients with postoperative bleeding (n = 7) Patients with no postoperative bleeding (n = 1,281) P -value Age, years 75 (68–76) 69 (62–75) 0.279 Sex 0.359 Male 7 (100) 997 (78) Female 0 (0) 284 (22) Antithrombotic agent use < 0.001 Yes 6 (86) 193 (14) No 1 (14) 1,088 (86) Tumor location 0.656 Cervical esophagus 0 (0) 41 (3) Upper thoracic esophagus 1 (14) 215 (17) Middle thoracic esophagus 3 (43) 693 (54) Lower thoracic esophagus 3 (43) 311 (24) Abdominal esophagus 0 (0) 21 (2) Macroscopic type 0.824 0-I 0 (0) 21 (2) 0-IIa 0 (0) 83 (7) 0-IIb 1 (14) 317 (25) 0-IIc 6 (86) 860 (67) Endoscopic procedure 0.613 EMR 0 (0) 226 (18) ESD 7 (100) 1,055 (82) Resection wound circumference 0.002 < 1/2 2 (29) 802 (63) ≥ 1/2, < 3/4 0 (0) 300 (23) ≥ 3/4 5 (71) 179 (14) Steroid injection 4 (57) 493 (39) 0.44 Specimen size, mm† 45 (34–58) 30 (22–40) 0.024 Pathological tumor invasion depth‡ 0.432 Intraepithelial neoplasm/No malignancy 0 (0) 62 (5) EP/LPM 5 (71) 1,019 (80) MM/SM1 1 (14) 131 (10) SM2 1 (14) 66 (5) Data are presented as the median (interquartile range) or n (%) †‡Three patients were excluded from those without postoperative bleeding as their histological evaluations were insufficient owing to degeneration of the resected specimens and intraoperative perforation EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection, EP, epithelium; LPM, lamina propria; MM, muscularis mucosa; SM1, submucosa ≤ 200 µm; SM2, submucosa > 200 µm Table 3 The association between each antithrombotic agent and postoperative bleeding Antithrombotic agent use Patients with postoperative bleeding (n = 7) Patients with no postoperative bleeding (n = 1,281) P -value Single antithrombotic therapy Aspirin 1 (14) 104 (8) 0.449 Thienopyridine 0 (0) 37 (3) 1 Warfarin 1 (14) 8 (0.6) 0.048 DOAC 3 (43) 35 (3) < 0.001 Dual antithrombotic therapy Aspirin + thienopyridine 0 (0) 5 (0.4) 1 Aspirin + DOAC 0 (0) 2 (0.2) 1 Thienopyridine + DOAC 1 (14) 2 (0.2) 0.016 DOAC (not limited to single use) 4† (57) 39‡ (3) < 0.001 Apixaban 3§ (43) 9¶ (0.7) < 0.001 Rivaroxaban 1 (14) 12|| (0.9) 0.069 Edoxaban 0 16⁑ (1.2) 1 Dabigatran 0 2†† (0.2) 1 Data are presented as n (%) †One patient used DOAC in combination with thienopyridine ‡Four patients used DOACs in combination with aspirin or thienopyridine §One patient used apixaban in combination with thienopyridine ¶One patient used apixaban in combination with aspirin ||One patient used rivaroxaban in combination with thienopyridine ⁑One patient used edoxaban in combination with aspirin ††One patient used dabigatran in combination with thienopyridine DOAC, direct oral anticoagulant Table 4 Risk factors for postoperative bleeding Clinical characteristics Odds ratio (95% CI) P -value Warfarin 26.4 (0.5–259.0) 0.048 DOAC (not limited to single use†) 41.9 (6.8–294.6) < 0.001 Apixaban (not limited to single use‡) 101.7 (13.1–692.6) < 0.001 Resection wound circumference ≥ 3/4 15.3 (2.5–162.1) < 0.001 Specimen size ≥ 40 mm 6.5 (1.1–69.0) 0.021 †Five of 43 patients used aspirin or thienopyridine in combination with DOACs ‡Two of 12 patients used aspirin or thienopyridine in combination with apixaban CI, confidence interval; DOAC, direct oral anticoagulant Table 5 Characteristics of the patients who received or did not receive DOACs in the propensity-matched cohort Clinical characteristics Patients who received DOACs (n = 39) Patients who did not receive DOACs (n = 78) P -value Standardized difference Age, years 77 (72–80) 76 (72–80) 0.77 0.034 Sex 1 0.055 Male 37 (95) 73 (94) Female 2 (5) 5 (6) Tumor location 1 0.103 Cervical esophagus 2 (5) 4 (5) Upper thoracic esophagus 6 (15) 13 (17) Middle thoracic esophagus 19 (49) 37 (47) Lower thoracic esophagus 11 (28) 23 (30) Abdominal esophagus 1 (3) 1 (1) Macroscopic type 1 0.029 0-Ⅰ 0 (0) 0 (0) 0-Ⅱa 3 (8) 6 (8) 0-Ⅱb 11 (28) 23 (30) 0-Ⅱc 25 (64) 49 (63) Endoscopic procedure 0.603 0.134 EMR 8 (21) 12 (15) ESD 31 (80) 66 (85) Resection wound circumference 0.899 0.103 < 1/2 22 (56) 40 (51) ≥ 1/2, < 3/4 9 (23) 20 (26) ≥ 3/4 8 (21) 18 (23) Steroid injection 0.33 0.206 Yes 18 (46) 44 (56) No 21 (54) 34 (44) Specimen size, mm 31 (24–40) 30 (23–44) 0.766 0.083 Pathological depth of invasion 0.767 0.247 Intraepithelial neoplasm/No malignancy 2 (5) 5 (6) EP/LPM 31 (80) 56 (72) MM/SM1 4 (10) 8 (10) SM2 2 (5) 9 (12) Data are presented as the median (interquartile range) or n (%). Standardized difference < 0.1 represents adequate variable balance between the two groups. DOAC, direct oral anticoagulant; EMR, endoscopic mucosal resection; EP, epithelium; ESD, endoscopic submucosal dissection; LPM, lamina propria; MM, muscularis mucosa; SM1, submucosa ≤ 200 µm; SM2, submucosa > 200 µm Table 6 Incidence of postoperative bleeding of the patients who received or did not receive DOACs in the propensity-matched cohort Patients who received DOACs (n = 39) Patients who did not receive DOACs (n = 78) P -value Postoperative bleeding 0.035 Yes 3 (8) 0 (0) No 36 (92) 78 (100) Data are presented as the median (interquartile range) or n (%). DOAC, direct oral anticoagulant. Representative cases Case 1 A 77-year-old male who received apixaban for atrial fibrillation underwent ESD for esophageal squamous cell carcinoma of the upper esophagus (Fig. 2 a). The resected wound constituted three-quarters of the circumference, and the size of the resected specimen was 60 mm (Fig. 2 b). The patient was discharged without any adverse events on POD 4 but was re-admitted owing to hematemesis on POD 7. Emergency endoscopy revealed oozing bleeding from the resection wound (Fig. 2 c), and hemostasis was achieved by clipping (Fig. 2 d). The patient was discharged three days after endoscopic hemostasis. Case 2 A 60-year-old male, who had not received antithrombotic agents, underwent ESD for esophageal squamous cell carcinoma of the middle esophagus (Fig. 3 a). The resection wound constituted three-quarters of the circumference, and the size of the resected specimen was measured at 80 mm (Fig. 3 b). The patient was discharged without any adverse events on POD 4 but was re-admitted owing to hematemesis on POD 17. Tachycardia and anemia (hemoglobin concentration decreased from 13.9 g/dL to 8.1 g/dL) were noted, necessitating blood transfusion. Emergency endoscopy revealed oozing bleeding from the resection wound (Fig. 3 c), and hemostasis was achieved via cauterization using hemostatic forceps (Coagrasper, FD-410LR; Olympus Corporation) (Fig. 3 d). The patient was discharged 6 days after endoscopic hemostasis. Discussion This study found that postoperative bleeding occurred in 0.5% of patients after esophageal endoscopic resection, with a median onset at postoperative day 8. Owing to its low frequency and delayed onset, implementing effective preventive measures for postoperative bleeding after esophageal endoscopic resection is challenging. However, postoperative bleeding often leads to anemia and may require blood transfusion, which is a significant issue that must be addressed. Anticoagulant use (particularly DOAC and warfarin), wide resection (more than three-quarters of the circumference of the resection wound), and specimen size (≥ 40 mm) were identified as significant risk factors for postoperative bleeding. Iizuka et al. reported that postoperative bleeding after esophageal endoscopic resection was 0.6% (4 out of 664 patients) [ 18 ], whereas Horie et al. reported it as 0.7% (7 out of 957 patients) [ 15 ]. In these studies, patients with hematemesis or melena who required no hemostasis might have also been included in the postoperative bleeding cases. However, in our study, only patients who required hemostasis were defined as postoperative bleeding cases for accurate extraction from the database. Despite certain differences in definition, our data were generally consistent with these reports, with lower rates for gastric ESD (4.4%) and colorectal ESD (1.5–2.8%) [ 6 , 9 ]. Horie et al. suggested that lack of irritation to the resection wound from gastric acid or hard stool, or relatively low blood flow may contribute to the low incidence of postoperative bleeding in esophageal endoscopic resection [ 15 ]. The present study showed that anticoagulant use, especially DOACs, was the greatest risk factor for bleeding after endoscopic esophageal resection. In particular, 3 (25%) of the 12 patients who received apixaban developed bleeding, which was significantly associated with postoperative bleeding (Table 4 ). In contrast, patients who received edoxaban ( n = 16) or dabigatran ( n = 2) did not develop bleeding. Tomida et al. reported the following bleeding rates after gastric ESD in patients who received DOACs: apixaban, 27% (12 out of 45 patients); rivaroxaban, 15% (15 out of 103 patients); edoxaban, 10% (2 out of 21 patients), and dabigatran, 8% (7 out of 92 patients) [ 11 ]. Even after gastric ESD, the bleeding rate was higher with apixaban and lower with dabigatran, although the overall rate tended to be high. Apixaban, rivaroxaban, and edoxaban are factor Xa inhibitors, whereas dabigatran is a thrombin inhibitor. In colorectal ESD, Yoshida et al. found that postoperative bleeding was significantly higher with dabigatran (18.26%) compared to other DOACs: apixaban (10.08%, P = 0.029), edoxaban (7.73%, P = 0.001), and rivaroxaban (7.21%, P < 0.001) [ 19 ]. Dabigatran is a prodrug that is degraded and absorbed by the elastase enzyme of intestinal bacteria. This suggests that DOACs might directly impact resection wounds. Furthermore, differences in the administration interval may also have influenced this result: rivaroxaban and edoxaban were administered once a day, whereas apixaban was administered twice a day. Murata et al. reported that plasma concentrations of each DOAC (apixaban, rivaroxaban, and edoxaban) were similar in patients with and without post-ESD bleeding [ 20 ]. Moreover, in that prospective study, there were no significant differences in factor Xa activity between patients with and without post-ESD bleeding [ 20 ]. Specimen size and circumference of the resection wound were likely risk factors for postoperative bleeding. Although these and other factors potentially represent confounding factors in this study, we could not perform a multivariate analysis owing to the limited sample size of postoperative bleeding cases. To address the potential confounding effects of DOACs, propensity score matching was performed to adjust for background factors and reassess the risk of bleeding. The use of DOACs was found significantly associated with postoperative bleeding (Table 5 ). The delayed onset of bleeding (median, POD 8) following esophageal endoscopic resection was noteworthy. Shiroma et al. reported a median time to postoperative bleeding of POD 4 in gastric ESD, with a main peak on POD 1 and a second peak from POD 7 to POD 9 [ 10 ]. They also identified DOAC use as the primary risk factor for postoperative bleeding occurring on POD 5. Yoshio et al. reported the median time to POD 10 for postoperative bleeding in patients on DOACs who underwent gastric ESD [ 21 ]. In our study, 4 of the 7 patients with postoperative bleeding (57%) were on DOACs, which might have contributed to the delayed timing of the bleeding. Additionally, 4 of the 7 patients with postoperative bleeding (57%) required blood transfusions. Prevention of postoperative bleeding in all esophageal ESD cases is challenging because of the low frequency and late onset of postoperative bleeding. However, intervention may be required for patients taking DOACs. Although there is limited evidence, switching from apixaban to another DOAC, such as dabigatran, may be an option. The strengths of our study include a larger sample size than that of similar previous studies, in addition to a clear definition of postoperative bleeding and grading according to the Common Adverse Events Toxicity Criteria v5.0. However, our study had several limitations. This was a single-center retrospective study with a risk of selection bias. To mitigate this potential bias, we extracted consecutive cases from the electronic records of patients who underwent endoscopic resection and emergency endoscopy. The sample size for postoperative bleeding was small owing to its infrequent occurrence, precluding multivariate analysis. To account for potential confounding factors related to DOAC use, propensity score matching was employed to adjust for background factors and reassess the risk of bleeding. The perioperative management of antithrombotic agents in Japanese guidelines differs from that in Western guidelines, e.g., DOACs are resumed from two to three after the procedure [ 22 ]. Furthermore, the length of hospitalization might be longer than that in Western countries. The differences in these conditions may have influenced our findings. In conclusion, in this study, the overall bleeding rate following esophageal endoscopic resection was 0.5%, with a delayed onset leading to anemia. DOAC use has emerged as the most significant risk factor for postoperative bleeding. Declarations Ethics Approval: This retrospective study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study protocol was approved by the Institutional Review Board of Osaka International Cancer Institute on June 8, 2023 (Approval No. 23041). Data availability statement : The data that support the findings of this study are available from the corresponding author, T.K, upon reasonable request. Patient consent: We used the opt-out method to obtain informed consent for this study. Author Contributions: T.K; Patient management and data collection: D.K, T.K, R.I, Y.T, Y.O, Y.A, T.U, A.K, T.N, Y.A, G.T, Y.F, H.M, M.K, S.Y, S.S, S.Y, K.H, N.U, and T.M; Analysis and interpretation of the data: D.K and T.K; Drafting of the article: D.K; Critical revision of the article for crucial intellectual content: T.K and Y.F; Final approval of the article: All authors. Acknowledgments: We would like to thank Editage (www.editage.jp) for English language editing. Funding information: None. Conflict of Interest: T.K has received honoraria for lectures from Olympus Corporation, AstraZeneca, and AI Medical Service, Inc. R.I has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., Daiichi Sankyo Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., AI Medical Service, Inc., AstraZeneca, MSD, Ono Pharmaceutical Co., Ltd., and KYORIN Pharmaceutical Co., Ltd. S.S has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., EA Pharma Co., Ltd., AstraZeneca, AI Medical Service Inc., and Janssen Pharmaceutical K.K. S.Y has received honoraria for lectures from MSD and Ono Pharmaceutical Co., Ltd. N.U has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., Boston Scientific Japan K.K., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., AstraZeneca, Miyarisan Pharmaceutical Co., Ltd., and AI Medical Service Inc. Y.F has received honoraria for lectures from Takeda Pharmaceutical Co., Ltd., AstraZeneca, Astellas pharma Inc., EA Pharma Co., Ltd., Daiichi Sankyo Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. The other authors declare no financial relationships. References Ishihara R, Arima M, Iizuka T, Oyama T, Katada C, Kato M, et al . 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Surg Endosc. 2021;35:6583–90. https://doi.org/10.1007/s00464-020-08156-5 Ono H, Yao K, Fujishiro M , Oda I, Uedo N, Nimura S, et al . Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer. 2nd ed. Dig Endosc 2021;33:4–20 Shiroma S, Hatta W, Tsuji Y, Yoshio T, Yabuuchi Y, Hoteya S, et al . Timing of bleeding and thromboembolism associated with endoscopic submucosal dissection for gastric cancer in japan. J Gastroenterol Hepatol. 2021;36:2769–77. https://doi.org/10.1111/jgh.15536 Tomida H, Yoshio T, Igarashi K, Morita Y, Oda I, Inoue T, et al . Influence of anticoagulants on the risk of delayed bleeding after gastric endoscopic submucosal dissection: A multicenter retrospective study. Gastric Cancer. 2021;24:179–89. https://doi.org/10.1007/s10120-020-01105-0 Lau LH, Guo CL, Yip TC, Mak JW, Wong SH, Lam KL, et al . Risks of post-colonoscopic polypectomy bleeding and thromboembolism with warfarin and direct oral anticoagulants: A population-based analysis. Gut. 2022;71:100–10. https://doi.org/10.1136/gutjnl-2020-323600 Tani Y, Kanesaka T, Takeuchi Y, Okubo Y, Kawakami Y, Sakurai H, et al . Indication of emergency colonoscopy after colorectal endoscopic submucosal dissection: A proposal of hematochezia scale. J Gastroenterol Hepatol. 2022;37:1998–2003. https://doi.org/10.1111/jgh.15925 Sugimoto M, Murata M, Kawai T. Assessment of delayed bleeding after endoscopic submucosal dissection of early-stage gastrointestinal tumors in patients receiving direct oral anticoagulants. World J Gastroenterol. 2023;29:2916–31. https://doi.org/10.3748/wjg.v29.i19.2916 Horie Y, Horiuchi Y, Ishiyama A, Tsuchida T, Yoshimizu S, Hirasawa T, et al . The effect of antithrombotic drug use on delayed bleeding with esophageal endoscopic resection. J Gastroenterol Hepatol. 2022;37:1792–800. https://doi.org/10.1111/jgh.15944 Fujimoto K, Fujishiro M, Kato M, Higuchi K, Iwakiri R, Sakamoto C, et al . Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig Endosc. 2014;26:1–14. https://doi.org/10.1111/den.12183 Kato M, Uedo N, Hokimoto S, Ieko M, Higuchi K, Murakami K, et al . Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment: 2017 appendix on anticoagulants including direct oral anticoagulants. Dig Endosc. 2018;30:433–40. https://doi.org/10.1111/den.13184 Iizuka T, Kikuchi D, Hoteya S. Outcomes of endoscopic submucosal dissection for superficial esophageal cancer in an elderly population: A retrospective single center cohort study. Endosc Int Open. 2019;7:E355–60. https://doi.org/10.1055/a-0832-8257 Yoshida N, Hayashi Y, Togo D, Oka S, Takada K, Fukunaga S, et al . An analysis of delayed bleeding in cases of colorectal endoscopic submucosal dissection due to types of direct oral anticoagulants in japan. Clin Gastroenterol Hepatol. 2024;22:271–282.e3. https://doi.org/10.1016/j.cgh.2023.09.012 Murata M, Sugimoto M, Ueshima S, Nagami Y, Ominami M, Sawaya M, et al . Association of direct oral anticoagulant and delayed bleeding with pharmacokinetics after endoscopic submucosal dissection. Gastrointest Endosc. 2024;99:721–731.e4. https://doi.org/10.1016/j.gie.2023.11.048 Yoshio T, Tomida H, Iwasaki R, Horiuchi Y, Omae M, Ishiyama A, et al . Effect of direct oral anticoagulants on the risk of delayed bleeding after gastric endoscopic submucosal dissection. Dig Endosc. 2017;29:686–94. https://doi.org/10.1111/den.12859 Veitch AM, Radaelli F, Alikhan R, Dumonceau JM, Eaton D, Jerrome J, 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;53:947–69. https://doi.org/10.1055/a-1547-2282 Additional Declarations Competing interest reported. T.K has received honoraria for lectures from Olympus Corporation, AstraZeneca, and AI Medical Service, Inc. R.I has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., Daiichi Sankyo Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., AI Medical Service, Inc., AstraZeneca, MSD, Ono Pharmaceutical Co., Ltd., and KYORIN Pharmaceutical Co., Ltd. S.S has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., EA Pharma Co., Ltd., AstraZeneca, AI Medical Service Inc., and Janssen Pharmaceutical K.K. S.Y has received honoraria for lectures from MSD and Ono Pharmaceutical Co., Ltd. N.U has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., Boston Scientific Japan K.K., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., AstraZeneca, Miyarisan Pharmaceutical Co., Ltd., and AI Medical Service Inc. Y.F has received honoraria for lectures from Takeda Pharmaceutical Co., Ltd., AstraZeneca, Astellas pharma Inc., EA Pharma Co., Ltd., Daiichi Sankyo Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. The other authors declare no financial relationships. Supplementary Files Fig1s.tiff Supportinginformationlegends.docx Cite Share Download PDF Status: Published Journal Publication published 04 Dec, 2024 Read the published version in Digestive Diseases and Sciences → Version 1 posted Editorial decision: Revision requested 03 Nov, 2024 Reviews received at journal 03 Nov, 2024 Reviews received at journal 02 Nov, 2024 Reviewers agreed at journal 02 Nov, 2024 Reviewers agreed at journal 30 Oct, 2024 Reviewers invited by journal 30 Oct, 2024 Editor assigned by journal 30 Oct, 2024 Submission checks completed at journal 29 Oct, 2024 First submitted to journal 26 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5339326","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":373533792,"identity":"f47fe617-e227-4784-a77d-2fc416601977","order_by":0,"name":"Daiki Kitagawa","email":"","orcid":"","institution":"Osaka International Cancer Institute","correspondingAuthor":false,"prefix":"","firstName":"Daiki","middleName":"","lastName":"Kitagawa","suffix":""},{"id":373533796,"identity":"34946732-4237-43f6-ac21-88b6034cf339","order_by":1,"name":"Takashi Kanesaka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYFACNgYGxgYJAwjnAIMcAzOI4sGtgQddizGxWhjgWhIbCDnLnv1Y4sefOyyM+Wc3H/7w44xdej8788MDDDJ3cNvCk3ZYmveMhJnEnWNpkj03knNnNrMZAB32DI/D0hukGdskbBhu5Jgx8Hxgzt1wmAfkl8O4tfA/b/75E6hF/kb+549/PtSnGxDUIpF2TIK3TcLM4EYOgzTPjcMJhLXceJZmDdRibHgjzUxa5sxxQ7BfEvD4hb0/zfjmz7Y6w3k3kh9/fHOsWp6f//DjDx97cIcYDpDYc4BULQw/SNcyCkbBKBgFwxYAAMe1WJpxx4qQAAAAAElFTkSuQmCC","orcid":"","institution":"Osaka International Cancer Institute","correspondingAuthor":true,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Kanesaka","suffix":""},{"id":373533798,"identity":"23743ea6-a7ed-432a-a5f9-5bd982f72fc1","order_by":2,"name":"Ryu Ishihara","email":"","orcid":"","institution":"Osaka International Cancer 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University","correspondingAuthor":false,"prefix":"","firstName":"Yasuhiro","middleName":"","lastName":"Fujiwara","suffix":""}],"badges":[],"createdAt":"2024-10-27 01:38:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5339326/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5339326/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10620-024-08776-0","type":"published","date":"2024-12-04T15:57:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69356320,"identity":"06cfc6fa-4efe-4679-8223-6dd400ae8407","added_by":"auto","created_at":"2024-11-19 13:48:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":369451,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-5339326/v1/bf31978a94af7044e20a9ab9.png"},{"id":69358139,"identity":"8324284b-5dcb-4c03-8c84-9c00ba84c0f7","added_by":"auto","created_at":"2024-11-19 13:56:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3181638,"visible":true,"origin":"","legend":"\u003cp\u003eEndoscopic images from Case 1 (\u003cstrong\u003ea)\u003c/strong\u003e A 50-mm superficial squamous cell carcinoma in the upper esophagus. (\u003cstrong\u003eb)\u003c/strong\u003e The resection wound after endoscopic submucosal dissection covers more than three-quarters of the esophageal circumference. (\u003cstrong\u003ec)\u003c/strong\u003eOozing bleeding at the resection wound on postoperative day 7. (\u003cstrong\u003ed)\u003c/strong\u003eHemostasis is achieved with clipping.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-5339326/v1/d99d220bfa44979cea33518c.png"},{"id":69356324,"identity":"e3cc81d3-f9a4-4961-8836-a0b985ae4f4e","added_by":"auto","created_at":"2024-11-19 13:48:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3317826,"visible":true,"origin":"","legend":"\u003cp\u003eEndoscopic images from Case 2 (\u003cstrong\u003ea)\u003c/strong\u003e A 70-mm superficial squamous cell carcinoma in the middle of the esophagus. (\u003cstrong\u003eb)\u003c/strong\u003e The resection wound after endoscopic submucosal dissection covers more than three-quarters of the esophageal circumference. (\u003cstrong\u003ec)\u003c/strong\u003e Oozing bleeding at the resection wound on postoperative day 17. (\u003cstrong\u003ed)\u003c/strong\u003e Hemostasis was achieved by cauterization using hemostatic forceps.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-5339326/v1/1b41324771e9557bcf210238.png"},{"id":70965347,"identity":"26b607f5-b46b-402d-a46f-7b0bfce3aaad","added_by":"auto","created_at":"2024-12-09 16:19:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":12542334,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5339326/v1/c32f71a3-c4be-4f4d-b85e-d2133972e74c.pdf"},{"id":69356322,"identity":"939f8bfc-891f-4a7e-8a2a-852d727786d6","added_by":"auto","created_at":"2024-11-19 13:48:55","extension":"tiff","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":6083614,"visible":true,"origin":"","legend":"","description":"","filename":"Fig1s.tiff","url":"https://assets-eu.researchsquare.com/files/rs-5339326/v1/76b5a8e686d4fb62fbde9fa0.tiff"},{"id":69358138,"identity":"6a45a7fa-2372-4e31-9c76-b886d848d9c0","added_by":"auto","created_at":"2024-11-19 13:56:55","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":14454,"visible":true,"origin":"","legend":"","description":"","filename":"Supportinginformationlegends.docx","url":"https://assets-eu.researchsquare.com/files/rs-5339326/v1/6b96bda35607f72157d5703b.docx"}],"financialInterests":"Competing interest reported. T.K has received honoraria for lectures from Olympus Corporation, AstraZeneca, and AI Medical Service, Inc. R.I has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., Daiichi Sankyo Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., AI Medical Service, Inc., AstraZeneca, MSD, Ono Pharmaceutical Co., Ltd., and KYORIN Pharmaceutical Co., Ltd. S.S has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., EA Pharma Co., Ltd., AstraZeneca, AI Medical Service Inc., and Janssen Pharmaceutical K.K. S.Y has received honoraria for lectures from MSD and Ono Pharmaceutical Co., Ltd. N.U has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., Boston Scientific Japan K.K., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., AstraZeneca, Miyarisan Pharmaceutical Co., Ltd., and AI Medical Service Inc. Y.F has received honoraria for lectures from Takeda Pharmaceutical Co., Ltd., AstraZeneca, Astellas pharma Inc., EA Pharma Co., Ltd., Daiichi Sankyo Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. The other authors declare no financial relationships.","formattedTitle":"Characteristics and risk factors for postoperative bleeding following endoscopic resection of esophageal squamous neoplasms","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndoscopic resection, such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), which are minimally invasive treatments for esophageal cancer, are performed worldwide, including in Japan and other Asian and Western countries [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The characteristics of postoperative bleeding, which is a major adverse event in endoscopic resection, have been extensively investigated in relation to gastric and colorectal endoscopic resection [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, reports investigating postoperative bleeding characteristics in relation to esophageal endoscopic resection are limited [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. This study aimed to identify the characteristics and risk factors associated with postoperative bleeding in esophageal endoscopic resection.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eThis retrospective study included consecutive patients who had undergone endoscopic resection for esophageal squamous cell carcinoma or squamous intraepithelial neoplasm at the Osaka International Cancer Institute between January 2018 and December 2022. Patients who underwent endoscopic resection of other organs on the same day and those with a history of esophagectomy were excluded. The study protocol was approved by the Institutional Review Board of Osaka International Cancer Institute on June 8, 2023 (Approval No. 23041).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEndoscopic procedure\u003c/h3\u003e\n\u003cp\u003eThe indications for endoscopic resection were determined in accordance with the Japan Gastroenterological Endoscopy Society guidelines: (i) non-circumferential cT1a-EP/LPM (epithelium/lamina propria mucosa) or cT1a-MM/T1b-SM1 (muscularis mucosa/superficial submucosa\u0026thinsp;\u0026le;\u0026thinsp;200 \u0026micro;m) squamous cell carcinoma (or squamous intraepithelial neoplasms), (ii) whole-circumferential cT1a-EP/LPM esophageal squamous cell carcinoma (or squamous intraepithelial neoplasms)\u0026thinsp;\u0026le;\u0026thinsp;5 cm, and (iii) no lymph node and distant metastases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. EMR and ESD procedures were selected at the endoscopist\u0026rsquo;s discretion based on lesion size. For EMR, an endoscope with a large-diameter plastic cap (D-206-04; Olympus Corporation, Tokyo, Japan) was used. After injecting saline solution into the submucosa, a small-diameter snare (SD-7P; Olympus Corporation) was opened within the plastic cap. The lesion was aspirated into the plastic cap and resected using a snare in forced coagulation mode or endo-cut mode with an electrosurgical generator (VIO 300D or VIO 3, ERBE, T\u0026uuml;bingen, Germany). In ESD, an electrosurgical knife (FlushKnife BT-S 1.5 mm, DK 2620JI; FUJIFILM Medical Co., Ltd., Tokyo, Japan, or HookKnife J, KD-625; Olympus Corporation) was used with an electrosurgical generator (VIO 300D or VIO 3, ERBE). After injecting 10% glycerin solution or hyaluronic acid into the submucosa, mucosal incision and submucosal dissection were performed. After resection, the thick vessels exposed on the resection wound were cauterized using hemostatic forceps (Coagrasper, FD-410LR; Olympus Corporation) in soft coagulation mode. Steroids were injected into the submucosa if the wound covered more than three-quarters of the esophageal circumference. If no perforation occurred during the procedure, it was completed without closing the resection wound.\u003c/p\u003e\n\u003ch3\u003eClinical pathway of esophageal endoscopic resection\u003c/h3\u003e\n\u003cp\u003eEndoscopic resection was performed during hospitalization. Drinking water was administered after the patient was awakened from sedation on postoperative day (POD) 0. The patient underwent blood tests on POD 1 to evaluate hemoglobin concentration, white blood cell counts, and biochemistry. If the patient remained symptom-free, food intake was initiated on POD 2. The patient was discharged on POD 4. Proton pump inhibitors and hemostatic agents were not administered perioperatively.\u003c/p\u003e\n\u003ch3\u003ePerioperative management of antithrombotic agents\u003c/h3\u003e\n\u003cp\u003eThe management of antithrombotic agents, including withdrawal or replacement with other drugs, was mainly based on Japan Gastroenterological Endoscopy Society guidelines [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Aspirin monotherapy was maintained in patients at high risk of thromboembolism and withdrawn after 3\u0026ndash;5 days in those at low risk of thromboembolism. Thienopyridine derivatives were replaced with aspirin or cilostazol in patients at high risk of thromboembolism and withdrawn after 5\u0026ndash;7 days in those at low risk of thromboembolism. The procedure was performed with aspirin or cilostazol monotherapy in patients already receiving aspirin in combination with other antiplatelet agents. Warfarin was continued if the prothrombin time-international normalized ratio fell within the therapeutic range or temporarily switched to direct oral anticoagulants (DOACs) for patients with non-valvular atrial fibrillation. Heparin replacement was administered at the attending physician\u0026rsquo;s discretion following consultation with the prescribing doctor. DOACs were continued until the day before the procedure and withdrawn on the morning of the procedure. In patients receiving a combination of antiplatelet agents and DOACs, antiplatelet agents other than aspirin or cilostazol were replaced with aspirin or cilostazol monotherapy, and DOACs were withdrawn on the morning of the procedure. Patients resumed their original antiplatelet therapy and DOACs on the morning of POD 1 after confirming no symptoms of postoperative bleeding, such as hematemesis or melena.\u003c/p\u003e\n\u003ch3\u003eDefinition of postoperative bleeding\u003c/h3\u003e\n\u003cp\u003ePostoperative bleeding was defined as an episode of hematemesis or melena within 28 days of esophageal endoscopic resection that required hemostasis. The esophageal hemorrhage grade was assessed following the Common Toxicity Criteria for Adverse Events v5.0. For example, Grade 3 indicated the need for transfusion and invasive intervention leading to hospitalization; Grade 4 indicated life-threatening consequences requiring urgent intervention; and Grade 5 indicated death.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eHistopathological evaluation\u003c/h2\u003e \u003cp\u003eThe resected specimens were cut into 2 mm slices. The histological type of tumor, invasion depth, size, lymphovascular involvement, and resection margins were first assessed by one pathologist and then again by a second pathologist.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAmong patients with multiple lesions, only the lesion with the largest specimen size was included in the analysis. If multiple lesions were removed together (en bloc), they were analyzed as a single specimen. To identify the risk factors for postoperative bleeding, the characteristics of patients with and without postoperative bleeding were compared. Chi-square or Fisher\u0026rsquo;s exact tests were used to compare clinical variables, and the Mann\u0026ndash;Whitney U test was used for continuous variables. \u003cem\u003eP\u003c/em\u003e-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. For the resection wound circumference, Youden\u0026rsquo;s J index was calculated to distinguish between patients with and without postoperative bleeding. Receiver operating characteristic (ROC) curves were constructed to determine the optimal cut-off value for distinguishing between patients with and without postoperative bleeding. The optimal cut-off value was defined as the point on the ROC curve closest to 1 minus a specificity of 0 and a sensitivity of 1.0. Propensity scores were estimated by fitting a logistic regression model adjusted for certain clinical variables. One-to-two pair matching between patients who received DOACs and those who did not was performed using a caliper width equal to 0.2 of the standard deviation of the logit of the propensity score. All analyses were conducted using R software, version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://cran.r-project.org/\u003c/span\u003e\u003cspan address=\"http://cran.r-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and the EZR software package, v. 1.55 (Saitama Medical Center, Jichi Medical University, Tochigi, Japan).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eOf the 1,378 patients who underwent esophageal endoscopic resection between January 2018 and December 2022, 90 were excluded and 1,288 were eligible for analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median age of the patients was 69 years (interquartile range, 62\u0026ndash;75 years), and 1,004 (78%) patients were male. Regarding the type of endoscopic resection, 1,062 (82%) patients underwent ESD, and the remaining 226 (18%) patients underwent EMR. Postoperative bleeding occurred in seven (0.5%) patients (95% confidence interval [CI] 0.2\u0026ndash;1.1%) at a median time of POD 8 (range, 4\u0026ndash;17 days). Hemoglobin concentration in these patients decreased by a median of 3.0 g/dL (range, 1.6\u0026ndash;6.8 g/dL). Of the 43 patients who received DOACs, postoperative bleeding occurred in four (9%) patients (95% CI 2.6\u0026ndash;22.1%). Hospitalization was required for all seven patients, blood transfusion was indicated in four patients, and Grade 3 esophageal hemorrhage was noted in all seven patients. The postoperative bleeding details are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical findings concerning the seven patients with postoperative bleeding\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical findings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative onset time, day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (4\u0026ndash;17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematemesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMelena\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpurting bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOozing bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemostasis technique\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCauterization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClipping\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecrease in hemoglobin concentration, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.0 (1.6\u0026ndash;6.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransfusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization, day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (3\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade of esophageal hemorrhage\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eData are presented as the median (range) or \u003cem\u003en\u003c/em\u003e (%)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u0026dagger;Grade 3: Transfusion indicated, invasive intervention indicated, hospitalization; Grade 4: Life-threatening consequences, urgent intervention indicated; Grade 5: Death\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eRisk factors for postoperative bleeding\u003c/h2\u003e \u003cp\u003eClinical characteristics were compared between patients with and without postoperative bleeding (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Postoperative bleeding occurred only in ESD cases, with no significant difference in bleeding rates between EMR and ESD (0%, 95% CI 0\u0026ndash;1.6% vs. 0.7%, 95% CI 0.3\u0026ndash;1.4%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.613). Antithrombotic agent use, resection wound circumference, and specimen size were significantly associated with postoperative bleeding (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002, and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024, respectively). Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the association between each antithrombotic agent and postoperative bleeding. Anticoagulants, warfarin, and DOACs were significantly associated with postoperative bleeding (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). In contrast, antiplatelet agents, aspirin, and thienopyridine were not significantly associated with postoperative bleeding. When the resection wound circumference exceeded three-quarters, Youden\u0026rsquo;s J index was 0.57, representing the maximal value in the postoperative bleeding group. The cut-off value for specimen size was determined to be 39 mm using ROC curve analysis (Supplementary Fig.\u0026nbsp;1). Consequently, warfarin (odds ratio [OR] 26.4, 95% CI 0.5\u0026ndash;259.0; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048), DOAC (OR 41.9, 95% CI 6.8\u0026ndash;294.6; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), more than three-quarter circumferential resection of the wound (OR 15.3, 95% CI 2.5\u0026ndash;162.1; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and specimen size\u0026thinsp;\u0026ge;\u0026thinsp;40 mm (OR 6.5, 95% CI 1.1\u0026ndash;69.0; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021) were identified as significant risk factors for postoperative bleeding (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). DOACs were significantly associated with postoperative bleeding, even after adjusting for background clinicopathological characteristics using propensity score matching (Tables\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and \u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Postoperative bleeding occurred in four (9%, 95% CI 2.6\u0026ndash;22.1%) of 43 patients who received DOACs and in five (3%, 95% CI 1.1\u0026ndash;7.5%) of 153 patients with more than three-quarter circumferential resection of the wound and a specimen size\u0026thinsp;\u0026ge;\u0026thinsp;40 mm.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eA comparison of the characteristics of patients with and without postoperative bleeding\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients with postoperative bleeding\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients with no postoperative bleeding\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1,281)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75 (68\u0026ndash;76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (62\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.279\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.359\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e997 (78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e284 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntithrombotic agent use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e193 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,088 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.656\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCervical esophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpper thoracic esophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e215 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiddle thoracic esophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e693 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLower thoracic esophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e311 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal esophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacroscopic type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.824\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0-I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0-IIa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0-IIb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e317 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0-IIc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e860 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndoscopic procedure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.613\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEMR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e226 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,055 (82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResection wound circumference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e802 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1/2, \u0026lt;\u0026thinsp;3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e300 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e179 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSteroid injection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e493 (39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpecimen size, mm\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (34\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (22\u0026ndash;40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological tumor invasion depth\u0026Dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.432\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntraepithelial neoplasm/No malignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEP/LPM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,019 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMM/SM1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e131 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSM2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as the median (interquartile range) or \u003cem\u003en\u003c/em\u003e (%)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u0026dagger;\u0026Dagger;Three patients were excluded from those without postoperative bleeding as their histological evaluations were insufficient owing to degeneration of the resected specimens and intraoperative perforation\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eEMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection, EP, epithelium; LPM, lamina propria; MM, muscularis mucosa; SM1, submucosa\u0026thinsp;\u0026le;\u0026thinsp;200 \u0026micro;m; SM2, submucosa\u0026thinsp;\u0026gt;\u0026thinsp;200 \u0026micro;m\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe association between each antithrombotic agent and postoperative bleeding\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntithrombotic agent use\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients with postoperative bleeding\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients with no postoperative bleeding\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1,281)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle antithrombotic therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspirin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e104 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.449\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThienopyridine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWarfarin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDOAC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDual antithrombotic therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspirin\u0026thinsp;+\u0026thinsp;thienopyridine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspirin\u0026thinsp;+\u0026thinsp;DOAC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThienopyridine\u0026thinsp;+\u0026thinsp;DOAC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDOAC (not limited to single use)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u0026dagger; (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39\u0026Dagger; (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApixaban\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u0026sect; (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u0026para; (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRivaroxaban\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12|| (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEdoxaban\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16⁑ (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDabigatran\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u0026dagger;\u0026dagger; (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as \u003cem\u003en\u003c/em\u003e (%)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u0026dagger;One patient used DOAC in combination with thienopyridine\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u0026Dagger;Four patients used DOACs in combination with aspirin or thienopyridine\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u0026sect;One patient used apixaban in combination with thienopyridine\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u0026para;One patient used apixaban in combination with aspirin\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e||One patient used rivaroxaban in combination with thienopyridine\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e⁑One patient used edoxaban in combination with aspirin\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u0026dagger;\u0026dagger;One patient used dabigatran in combination with thienopyridine\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eDOAC, direct oral anticoagulant\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factors for postoperative bleeding\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOdds ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWarfarin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26.4 (0.5\u0026ndash;259.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDOAC (not limited to single use\u0026dagger;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41.9 (6.8\u0026ndash;294.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApixaban (not limited to single use\u0026Dagger;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e101.7 (13.1\u0026ndash;692.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResection wound circumference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15.3 (2.5\u0026ndash;162.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpecimen size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;40 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.5 (1.1\u0026ndash;69.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u0026dagger;Five of 43 patients used aspirin or thienopyridine in combination with DOACs\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u0026Dagger;Two of 12 patients used aspirin or thienopyridine in combination with apixaban\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eCI, confidence interval; DOAC, direct oral anticoagulant\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the patients who received or did not receive DOACs in the propensity-matched cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients who received DOACs\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients who did not receive DOACs\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;78)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eStandardized difference\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77 (72\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (72\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73 (94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCervical esophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpper thoracic esophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiddle thoracic esophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLower thoracic esophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal esophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacroscopic type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0-Ⅰ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0-Ⅱa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0-Ⅱb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0-Ⅱc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndoscopic procedure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.603\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.134\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEMR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResection wound circumference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.899\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1/2, \u0026lt;\u0026thinsp;3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSteroid injection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.206\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpecimen size, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (24\u0026ndash;40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (23\u0026ndash;44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.766\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological depth of invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.767\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.247\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntraepithelial neoplasm/No malignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEP/LPM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMM/SM1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSM2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are presented as the median (interquartile range) or \u003cem\u003en\u003c/em\u003e (%). Standardized difference\u0026thinsp;\u0026lt;\u0026thinsp;0.1 represents adequate variable balance between the two groups.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eDOAC, direct oral anticoagulant; EMR, endoscopic mucosal resection; EP, epithelium; ESD, endoscopic submucosal dissection; LPM, lamina propria; MM, muscularis mucosa; SM1, submucosa\u0026thinsp;\u0026le;\u0026thinsp;200 \u0026micro;m; SM2, submucosa\u0026thinsp;\u0026gt;\u0026thinsp;200 \u0026micro;m\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncidence of postoperative bleeding of the patients who received or did not receive DOACs in the propensity-matched cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients who received DOACs\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients who did not receive DOACs\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;78)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as the median (interquartile range) or \u003cem\u003en\u003c/em\u003e (%).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eDOAC, direct oral anticoagulant.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eRepresentative cases\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003eCase 1\u003c/h2\u003e \u003cp\u003eA 77-year-old male who received apixaban for atrial fibrillation underwent ESD for esophageal squamous cell carcinoma of the upper esophagus (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The resected wound constituted three-quarters of the circumference, and the size of the resected specimen was 60 mm (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). The patient was discharged without any adverse events on POD 4 but was re-admitted owing to hematemesis on POD 7. Emergency endoscopy revealed oozing bleeding from the resection wound (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec), and hemostasis was achieved by clipping (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). The patient was discharged three days after endoscopic hemostasis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eCase 2\u003c/h2\u003e \u003cp\u003eA 60-year-old male, who had not received antithrombotic agents, underwent ESD for esophageal squamous cell carcinoma of the middle esophagus (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). The resection wound constituted three-quarters of the circumference, and the size of the resected specimen was measured at 80 mm (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). The patient was discharged without any adverse events on POD 4 but was re-admitted owing to hematemesis on POD 17. Tachycardia and anemia (hemoglobin concentration decreased from 13.9 g/dL to 8.1 g/dL) were noted, necessitating blood transfusion. Emergency endoscopy revealed oozing bleeding from the resection wound (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec), and hemostasis was achieved via cauterization using hemostatic forceps (Coagrasper, FD-410LR; Olympus Corporation) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed). The patient was discharged 6 days after endoscopic hemostasis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study found that postoperative bleeding occurred in 0.5% of patients after esophageal endoscopic resection, with a median onset at postoperative day 8. Owing to its low frequency and delayed onset, implementing effective preventive measures for postoperative bleeding after esophageal endoscopic resection is challenging. However, postoperative bleeding often leads to anemia and may require blood transfusion, which is a significant issue that must be addressed. Anticoagulant use (particularly DOAC and warfarin), wide resection (more than three-quarters of the circumference of the resection wound), and specimen size (\u0026ge;\u0026thinsp;40 mm) were identified as significant risk factors for postoperative bleeding.\u003c/p\u003e \u003cp\u003eIizuka et al. reported that postoperative bleeding after esophageal endoscopic resection was 0.6% (4 out of 664 patients) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], whereas Horie et al. reported it as 0.7% (7 out of 957 patients) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In these studies, patients with hematemesis or melena who required no hemostasis might have also been included in the postoperative bleeding cases. However, in our study, only patients who required hemostasis were defined as postoperative bleeding cases for accurate extraction from the database. Despite certain differences in definition, our data were generally consistent with these reports, with lower rates for gastric ESD (4.4%) and colorectal ESD (1.5\u0026ndash;2.8%) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Horie et al. suggested that lack of irritation to the resection wound from gastric acid or hard stool, or relatively low blood flow may contribute to the low incidence of postoperative bleeding in esophageal endoscopic resection [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe present study showed that anticoagulant use, especially DOACs, was the greatest risk factor for bleeding after endoscopic esophageal resection. In particular, 3 (25%) of the 12 patients who received apixaban developed bleeding, which was significantly associated with postoperative bleeding (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). In contrast, patients who received edoxaban (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16) or dabigatran (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2) did not develop bleeding. Tomida et al. reported the following bleeding rates after gastric ESD in patients who received DOACs: apixaban, 27% (12 out of 45 patients); rivaroxaban, 15% (15 out of 103 patients); edoxaban, 10% (2 out of 21 patients), and dabigatran, 8% (7 out of 92 patients) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Even after gastric ESD, the bleeding rate was higher with apixaban and lower with dabigatran, although the overall rate tended to be high. Apixaban, rivaroxaban, and edoxaban are factor Xa inhibitors, whereas dabigatran is a thrombin inhibitor.\u003c/p\u003e \u003cp\u003eIn colorectal ESD, Yoshida et al. found that postoperative bleeding was significantly higher with dabigatran (18.26%) compared to other DOACs: apixaban (10.08%, P\u0026thinsp;=\u0026thinsp;0.029), edoxaban (7.73%, P\u0026thinsp;=\u0026thinsp;0.001), and rivaroxaban (7.21%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Dabigatran is a prodrug that is degraded and absorbed by the elastase enzyme of intestinal bacteria. This suggests that DOACs might directly impact resection wounds. Furthermore, differences in the administration interval may also have influenced this result: rivaroxaban and edoxaban were administered once a day, whereas apixaban was administered twice a day. Murata et al. reported that plasma concentrations of each DOAC (apixaban, rivaroxaban, and edoxaban) were similar in patients with and without post-ESD bleeding [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Moreover, in that prospective study, there were no significant differences in factor Xa activity between patients with and without post-ESD bleeding [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSpecimen size and circumference of the resection wound were likely risk factors for postoperative bleeding. Although these and other factors potentially represent confounding factors in this study, we could not perform a multivariate analysis owing to the limited sample size of postoperative bleeding cases. To address the potential confounding effects of DOACs, propensity score matching was performed to adjust for background factors and reassess the risk of bleeding. The use of DOACs was found significantly associated with postoperative bleeding (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe delayed onset of bleeding (median, POD 8) following esophageal endoscopic resection was noteworthy. Shiroma et al. reported a median time to postoperative bleeding of POD 4 in gastric ESD, with a main peak on POD 1 and a second peak from POD 7 to POD 9 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. They also identified DOAC use as the primary risk factor for postoperative bleeding occurring on POD 5. Yoshio et al. reported the median time to POD 10 for postoperative bleeding in patients on DOACs who underwent gastric ESD [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In our study, 4 of the 7 patients with postoperative bleeding (57%) were on DOACs, which might have contributed to the delayed timing of the bleeding. Additionally, 4 of the 7 patients with postoperative bleeding (57%) required blood transfusions.\u003c/p\u003e \u003cp\u003ePrevention of postoperative bleeding in all esophageal ESD cases is challenging because of the low frequency and late onset of postoperative bleeding. However, intervention may be required for patients taking DOACs. Although there is limited evidence, switching from apixaban to another DOAC, such as dabigatran, may be an option.\u003c/p\u003e \u003cp\u003eThe strengths of our study include a larger sample size than that of similar previous studies, in addition to a clear definition of postoperative bleeding and grading according to the Common Adverse Events Toxicity Criteria v5.0. However, our study had several limitations. This was a single-center retrospective study with a risk of selection bias. To mitigate this potential bias, we extracted consecutive cases from the electronic records of patients who underwent endoscopic resection and emergency endoscopy. The sample size for postoperative bleeding was small owing to its infrequent occurrence, precluding multivariate analysis. To account for potential confounding factors related to DOAC use, propensity score matching was employed to adjust for background factors and reassess the risk of bleeding. The perioperative management of antithrombotic agents in Japanese guidelines differs from that in Western guidelines, e.g., DOACs are resumed from two to three after the procedure [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Furthermore, the length of hospitalization might be longer than that in Western countries. The differences in these conditions may have influenced our findings.\u003c/p\u003e \u003cp\u003eIn conclusion, in this study, the overall bleeding rate following esophageal endoscopic resection was 0.5%, with a delayed onset leading to anemia. DOAC use has emerged as the most significant risk factor for postoperative bleeding.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval:\u003c/strong\u003e This retrospective study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study protocol was approved by the Institutional Review Board of Osaka International Cancer Institute on June 8, 2023 (Approval No. 23041).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e: The data that support the findings of this study are available from the corresponding author, T.K, upon reasonable request.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePatient consent:\u0026nbsp;\u003c/strong\u003eWe used the opt-out method to obtain informed consent for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eT.K; Patient management and data collection: D.K, T.K, R.I, Y.T, Y.O, Y.A, T.U, A.K, T.N, Y.A, G.T, Y.F, H.M, M.K, S.Y, S.S, S.Y, K.H, N.U, and T.M; Analysis and interpretation of the data: D.K and T.K; Drafting of the article: D.K; Critical revision of the article for crucial intellectual content: T.K and Y.F; Final approval of the article: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eWe would like to thank Editage (www.editage.jp) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information:\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eT.K has received honoraria for lectures from Olympus Corporation, AstraZeneca, and AI Medical Service, Inc. R.I has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., Daiichi Sankyo Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., AI Medical Service, Inc., AstraZeneca, MSD, Ono Pharmaceutical Co., Ltd., and KYORIN Pharmaceutical Co., Ltd. S.S has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., EA Pharma Co., Ltd., AstraZeneca, AI Medical Service Inc., and Janssen Pharmaceutical K.K. S.Y has received honoraria for lectures from MSD and Ono Pharmaceutical Co., Ltd. N.U has received honoraria for lectures from Olympus Corporation, FUJIFILM Medical Co., Ltd., Boston Scientific Japan K.K., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., AstraZeneca, Miyarisan Pharmaceutical Co., Ltd., and AI Medical Service Inc. Y.F has received honoraria for lectures from Takeda Pharmaceutical Co., Ltd., AstraZeneca, Astellas pharma Inc., EA Pharma Co., Ltd., Daiichi Sankyo Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. The other authors declare no financial relationships.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eIshihara R, Arima M, Iizuka T, Oyama T, Katada C, Kato M,\u003cem\u003e\u0026nbsp;\u003c/em\u003eet al\u003cem\u003e.\u003c/em\u003e Endoscopic submucosal dissection/endoscopic mucosal resection guidelines for esophageal cancer. Dig Endosc. 2020;32:452\u0026ndash;93. https://doi.org/10.1111/den.13654\u003c/li\u003e\n \u003cli\u003ePimentel-Nunes P, Lib\u0026acirc;nio D, Bastiaansen BAJ, Bhandari P, Bisschops R, Bourke MJ, et al\u003cem\u003e.\u003c/em\u003e Endoscopic submucosal dissection for superficial gastrointestinal lesions: European society of gastrointestinal endoscopy (esge) guideline - Update 2022. 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Surg Endosc. 2021;35:6583\u0026ndash;90. https://doi.org/10.1007/s00464-020-08156-5\u003c/li\u003e\n \u003cli\u003eOno H, Yao K, Fujishiro M\u003cem\u003e,\u0026nbsp;\u003c/em\u003eOda I, Uedo N, Nimura S,\u003cem\u003e\u0026nbsp;\u003c/em\u003eet al\u003cem\u003e.\u003c/em\u003e Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer. 2nd ed. \u003cem\u003eDig Endosc\u003c/em\u003e 2021;33:4\u0026ndash;20\u003c/li\u003e\n \u003cli\u003eShiroma S, Hatta W, Tsuji Y, Yoshio T, Yabuuchi Y, Hoteya S, et al\u003cem\u003e.\u003c/em\u003e Timing of bleeding and thromboembolism associated with endoscopic submucosal dissection for gastric cancer in japan. J Gastroenterol Hepatol. 2021;36:2769\u0026ndash;77. https://doi.org/10.1111/jgh.15536\u003c/li\u003e\n \u003cli\u003eTomida H, Yoshio T, Igarashi K, Morita Y, Oda I, Inoue T, et al\u003cem\u003e.\u003c/em\u003e Influence of anticoagulants on the risk of delayed bleeding after gastric endoscopic submucosal dissection: A multicenter retrospective study. Gastric Cancer. 2021;24:179\u0026ndash;89. https://doi.org/10.1007/s10120-020-01105-0\u003c/li\u003e\n \u003cli\u003eLau LH, Guo CL, Yip TC, Mak JW, Wong SH, Lam KL,\u003cem\u003e\u0026nbsp;\u003c/em\u003eet al\u003cem\u003e.\u003c/em\u003e Risks of post-colonoscopic polypectomy bleeding and thromboembolism with warfarin and direct oral anticoagulants: A population-based analysis. Gut. 2022;71:100\u0026ndash;10. https://doi.org/10.1136/gutjnl-2020-323600\u003c/li\u003e\n \u003cli\u003eTani Y, Kanesaka T, Takeuchi Y, Okubo Y, Kawakami Y, Sakurai H, et al\u003cem\u003e.\u003c/em\u003e Indication of emergency colonoscopy after colorectal endoscopic submucosal dissection: A proposal of hematochezia scale. J Gastroenterol Hepatol. 2022;37:1998\u0026ndash;2003. https://doi.org/10.1111/jgh.15925\u003c/li\u003e\n \u003cli\u003eSugimoto M, Murata M, Kawai T. Assessment of delayed bleeding after endoscopic submucosal dissection of early-stage gastrointestinal tumors in patients receiving direct oral anticoagulants. World J Gastroenterol. 2023;29:2916\u0026ndash;31. https://doi.org/10.3748/wjg.v29.i19.2916\u003c/li\u003e\n \u003cli\u003eHorie Y, Horiuchi Y, Ishiyama A, Tsuchida T, Yoshimizu S, Hirasawa T, et al\u003cem\u003e.\u003c/em\u003e The effect of antithrombotic drug use on delayed bleeding with esophageal endoscopic resection. J Gastroenterol Hepatol. 2022;37:1792\u0026ndash;800. https://doi.org/10.1111/jgh.15944\u003c/li\u003e\n \u003cli\u003eFujimoto K, Fujishiro M, Kato M, Higuchi K, Iwakiri R, Sakamoto C,\u003cem\u003e\u0026nbsp;\u003c/em\u003eet al\u003cem\u003e.\u003c/em\u003e Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig Endosc. 2014;26:1\u0026ndash;14. https://doi.org/10.1111/den.12183\u003c/li\u003e\n \u003cli\u003eKato M, Uedo N, Hokimoto S, Ieko M, Higuchi K, Murakami K,\u003cem\u003e\u0026nbsp;\u003c/em\u003eet al\u003cem\u003e.\u003c/em\u003e Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment: 2017 appendix on anticoagulants including direct oral anticoagulants. Dig Endosc. 2018;30:433\u0026ndash;40. https://doi.org/10.1111/den.13184\u003c/li\u003e\n \u003cli\u003eIizuka T, Kikuchi D, Hoteya S. Outcomes of endoscopic submucosal dissection for superficial esophageal cancer in an elderly population: A retrospective single center cohort study. Endosc Int Open. 2019;7:E355\u0026ndash;60. https://doi.org/10.1055/a-0832-8257\u003c/li\u003e\n \u003cli\u003eYoshida N, Hayashi Y, Togo D, Oka S, Takada K, Fukunaga S, et al\u003cem\u003e.\u003c/em\u003e An analysis of delayed bleeding in cases of colorectal endoscopic submucosal dissection due to types of direct oral anticoagulants in japan. Clin Gastroenterol Hepatol. 2024;22:271\u0026ndash;282.e3. https://doi.org/10.1016/j.cgh.2023.09.012\u003c/li\u003e\n \u003cli\u003eMurata M, Sugimoto M, Ueshima S, Nagami Y, Ominami M, Sawaya M, et al\u003cem\u003e.\u003c/em\u003e Association of direct oral anticoagulant and delayed bleeding with pharmacokinetics after endoscopic submucosal dissection. Gastrointest Endosc. 2024;99:721\u0026ndash;731.e4. https://doi.org/10.1016/j.gie.2023.11.048\u003c/li\u003e\n \u003cli\u003eYoshio T, Tomida H, Iwasaki R, Horiuchi Y, Omae M, Ishiyama A, et al\u003cem\u003e.\u003c/em\u003e Effect of direct oral anticoagulants on the risk of delayed bleeding after gastric endoscopic submucosal dissection. Dig Endosc. 2017;29:686\u0026ndash;94. https://doi.org/10.1111/den.12859\u003c/li\u003e\n \u003cli\u003eVeitch AM, Radaelli F, Alikhan R, Dumonceau JM, Eaton D, Jerrome J,\u003cem\u003e\u0026nbsp;\u003c/em\u003eet al\u003cem\u003e.\u003c/em\u003e 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\u0026ndash;69. https://doi.org/10.1055/a-1547-2282\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Esophageal Neoplasms, Esophageal Squamous Cell Carcinoma, Endoscopy, Endoscopic Mucosal Resection, and Gastrointestinal Hemorrhage","lastPublishedDoi":"10.21203/rs.3.rs-5339326/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5339326/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eReports on postoperative bleeding after esophageal endoscopic resection are limited.\u003c/p\u003e\u003ch2\u003eAims\u003c/h2\u003e \u003cp\u003eThis study aimed to identify the clinical characteristics and risk factors for postoperative bleeding following endoscopic resection of esophageal neoplasms.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis single-center, retrospective study included consecutive patients who underwent endoscopic resection for esophageal squamous cell carcinoma or squamous intraepithelial neoplasm between January 2018 and December 2022. We investigated the incidence, timing, severity, and risk factors for postoperative bleeding.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the 1,288 patients, postoperative bleeding occurred in seven (0.5%) patients (95% confidence interval [CI] 0.2\u0026ndash;1.1%; median postoperative day 8 [range, 4\u0026ndash;17 days]). In these seven patients, hemoglobin concentration decreased by a median of 3.0 g/dL (range, 1.6\u0026ndash;6.8 g/dL). Direct oral anticoagulants (DOACs) were identified as the most significant risk factor for postoperative bleeding (odds ratio [OR] 41.9, 95% CI 6.8\u0026ndash;294.6; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and were significantly associated with postoperative bleeding even after propensity score matching (3/39 [8%] vs. 0/78 [0%], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035). Among 43 patients who received DOACs, postoperative bleeding occurred in four (9%) patients (95% CI 2.6\u0026ndash;22.1%).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe overall bleeding rate following esophageal endoscopic resection was 0.5%, with a delayed onset, leading to anemia. DOACs emerged as the most significant risk factor for postoperative bleeding.\u003c/p\u003e","manuscriptTitle":"Characteristics and risk factors for postoperative bleeding following endoscopic resection of esophageal squamous neoplasms","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-19 13:48:50","doi":"10.21203/rs.3.rs-5339326/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-03T22:45:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-03T16:15:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-02T20:04:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"138936755386585526986866814131752838085","date":"2024-11-02T19:09:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"136981591793306668631143621247131996807","date":"2024-10-31T01:50:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-31T01:47:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-31T00:58:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-29T04:53:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Digestive Diseases and Sciences","date":"2024-10-27T01:31:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3151732c-5504-4bcd-ae1d-be4f9bee639f","owner":[],"postedDate":"November 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-09T16:13:06+00:00","versionOfRecord":{"articleIdentity":"rs-5339326","link":"https://doi.org/10.1007/s10620-024-08776-0","journal":{"identity":"digestive-diseases-and-sciences","isVorOnly":false,"title":"Digestive Diseases and Sciences"},"publishedOn":"2024-12-04 15:57:07","publishedOnDateReadable":"December 4th, 2024"},"versionCreatedAt":"2024-11-19 13:48:50","video":"","vorDoi":"10.1007/s10620-024-08776-0","vorDoiUrl":"https://doi.org/10.1007/s10620-024-08776-0","workflowStages":[]},"version":"v1","identity":"rs-5339326","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5339326","identity":"rs-5339326","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}