A narrative review of postoperative bleeding in patients with gastric cancer treated with endoscopic submucosal dissection

Introduction

Endoscopic submucosal dissection (ESD) was first reported by Hirao and colleagues in Japan in 1988 (1). ESD is widely used in the treatment of early gastric cancer (EGC) because it preserves the stomach and allows one-piece resection with tumor-free margins, even in cases with large and ulcerative lesions and therefore, reduces the risk of local recurrence (1). ESD also permits accurate histological assessments (2). Compared with endoscopic mucosal resection (EMR), ESD offers a higher complete resection rate, higher en bloc resection rate, and a lower local recurrence rate (3).

Although the incidence of intraoperative bleeding is significantly higher with ESD than that with EMR because of longer operation and more invasive (4), the post-operative bleeding rate is comparable between the two techniques (3-5). ESD is therefore, considered a standard treatment for EGCs (6). However, ESD causes relatively large lesions and lesion-related ulcers, ulcer scars. The long operation time also increases the risk of adverse events such as post-ESD bleeding. The ESD related bleeding includes intraoperative bleeding and post-ESD bleeding. Intraoperative bleeding is treated during the procedure.

The present review concentrated on post-ESD bleeding. We were to summarize the incidence, the risk factors of the delayed bleeding in patients with ESD and the preventive and therapeutic strategies. We present the following article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-466/rc).

Methods

The literature on post-ESD bleeding, including systematic reviews and meta-analyses, randomized controlled trials, retrospective study, cohort studies and case series were extensively reviewed.

Discussion

Definition and incidence

The definition of post-ESD bleeding is not unique. Ojima and coworkers (6) defined as clinical evidence of bleeding that required endoscopic treatment with metal clips and/or electrocoagulation; Mochizuki et al. (7) defined as hemorrhage with clinical symptoms and confirmed by emergency endoscopy from the completion of ESD until postoperative day 28. The clinical symptoms include hematemesis, melena, or a decrease in haemoglobin of >2g/dL since the last laboratory test. Yano et al. (8) defined as one of the followings: hematemesis or melena after ESD and needs blood transfusion or emergency endoscopy; second-look endoscopy confirms the presence of bloody gastric juice; spurting bleeding from the ulcer floor is observed and needs hemostasis; sudden drop of the hemoglobin level by 2 g/dL or more on blood testing. Although there is no universally recognized definition, it is clear that post-ESD bleeding is a serious complication and may be life-threatening.

Another definition is the time of bleeding. Okada et al. (9) categorized post-ESD bleedings into early delayed bleeding (≤4 postoperative days) and late delayed bleeding (≥5 postoperative days). Libanio et al. (10) suggested that bleeding happened within 24 hours after ESD is categorised early bleeding, >24 hours called delayed bleeding. Yano et al. (8) classified post-ESD bleeding as acute post-ESD bleeding (0–5 days after ESD) and delayed post-ESD bleeding (6 or more days after ESD). Shiroma et al. (11) analyzed 10,320 ESD cases, they also defined 0–5 days after ESD as early post-ESD bleeding and found that the median time to post-ESD bleeding was 4 days. We agree to define 0–5 days after ESD as early post-ESD because this definition set an alert for the endoscopists to closely monitor the patients for 5 days after ESD.

The rate of post-ESD bleeding is also various (0–15.6%) (12-15); this rate for patients with antithrombotic agents or anticoagulants is even higher. Takeuchi et al. (16) found that post-ESD bleeding in antithrombotic group was 23.3%, significantly higher than 2.0% in the non-antithrombotic group. Toya and colleagues (17) reported that post-ESD bleeding was significantly more frequent for lesions in patients with anticoagulant therapy than in those without anticoagulant (11.7% vs. 1.5%, respectively; P<0.001). Recently, Shiroma and colleagues (11) analyzed 10,320 ESD cases and found that the post-ESD bleeding rates were 3.2% in not taking any antithrombotic agents; antiplatelet agents increased this rate from 3.2% to 8.7%; anticoagulants increased the bleeding rate to 15.5%; and antiplatelet agents plus anticoagulants escalate the post-ESD bleeding rate to 29.9%. Overall, the post-ESD bleeding rates are diverse because of the different medications. The experiences of the endoscopists also impact the procedure time and the rates of post-ESD bleeding.

Risk factors

ESD location

Lesions are at the lower-third of the stomach. Nam and colleagues (18) found that the lesions in the lower third of the stomach (OR, 2.845; 95% CI: 1.381–5.860; P=0.005) are prone to post-ESD bleedings. Yano et al. (8) found that a lesion in the distal stomach is an independent risk factor (OR, 2.0) of post-ESD bleeding. About 82% of the post-ESD bleedings are in the lower-third of the stomach (18). However, Sato et al. (19) found that the incidence of post-ESD bleeding is the same among upper, middle and lower stomach (4.1%, 5.4%, 5.3%). A systemic review performed by Libanio et al. (10) also found no differences based on location (5.2%, 5.6%, 5.5% respectively). The high frequency of post-ESD bleeding in the lower stomach is because the majority of gastric cancers are located in the lower stomach (upper 17.3%, middle 31.2% and lower 51.5%) (19). A lesion in the lesser curvature is also prone to post-ESD bleeding after ESD (OR, 1.74) (10,20). Because this area has more penetrating vessels and is surrounded with solid fibrotic tissue which makes the incisions and dissections more difficult (21). Univariate and multivariate analyses showed that the lesion in the upper third of the stomach and post-ESD coagulation are independent factors of lower delayed bleeding (2). The lesions in the middle and in the lower thirds of the stomach have similar post-ESD bleeding rates (upper third,1.1 % vs. middle or lower, 7.4%; P<0.005). Although the correlation between ESD location and post-ESD bleeding is inconsistent in the literature, the studies tend to support that ESD at the lower third of the stomach is prone to post-ESD bleeding (Table 1) and therefore, the endoscopists should monitor more closely and pay more attention to the patient whose lesion is at the lower third of the stomach.

ESD size and depth

Theoretically, the larger the lesion size, the risker the post-ESD bleeding. Lesion size is an independent risk factor after procedure (17). Using multivariate analysis, Yano et al. (8) found that specimen diameter ≥40 mm is an independent risk factor of post-ESD bleeding (OR, 2.48, P<0.001). Yamamoto et al. (27) also elucidated that tumor size >40 mm is a risk factor of post-ESD bleeding (OR, 4.25, P<0.01). Multivariate analysis by Tomida et al. (28) showed that age ≥65, receiving multiple antithrombotic agents, resection of multiple lesions and lesion size ≥30 mm were independent risk factors. Furthermore, patients taking antithrombotic agents and having a large resection (≥40 mm) have a high rate of post‐ESD bleeding (21–38%) (29). Another factor is that the larger tumor needs longer time for operation, which is also a significant risk factor for postoperative bleeding (16). Yano et al. (8) demonstrated that procedure time ≥90 min is a risk factor of post‐ESD bleeding. Deeper tumor invasion was associated with a higher risk of post-ESD bleeding (5.3% in mucosal/submucosal layer 1 group vs. 12.5% in submucosal layer 2/muscularis propria group, P<0.001) (30).

Chronic kidney disease (CKD)

CKD is one of the risk factors in post-ESD bleeding (24,31-33). Choi et al. (31) compared 102 CKD patients underwent ESD for gastric neoplasms to 102 non-CKD patients, the propensity score was matched in these two groups. Sixty-one patients were at stage 3, 19 at stage 4 and 22 at stage 5. They found that the post-ESD bleeding rates were 6.6%, 26.3% and 22.7%, respectively, this rate in non-CKD patients was 4.9%. The post-ESD bleeding rates in CKD patients with stage 4 and 5 were significantly higher compared with that in non-CKD patients. Their multivariate analysis showed that stage 4/5 CKD was a significant risk predictor of post-ESD bleeding (HR 4.99; 95% CI: 1.32–18.8; P=0.018). The pathogenesis of bleeding in CKD may be due to the uremic toxins that cause the abnormalities in platelet-platelet and platelet-vessel wall interactions (31). Other factors, such as abnormalities in blood coagulation, medications, and hemodialysis may also play roles (32). Yoshioka and coworkers (32) found that estimated glomerular filtration rate (eGFR) is correlated with post-ESD bleeding. They demonstrated that if the cut-off value of eGFR is set to 27.3 mL/min, the sensitivity and specificity for the prediction of post-ESD bleeding were 87.5% and 70.6%, respectively. Numata et al. (33) analyzed 63 consecutive CKD patients with EGCs and treated by ESD, they found that the post-ESD bleeding rate was 33% in patients with hemodialysis and 9% in those without hemodialysis (P<0.05). They concluded that hemodialysis is a risk factor of post-ESD bleeding. Choi et al. (31) concluded that patients with stage 3 CKD have similar risk for post-ESD bleeding compared with non-CKD patients. However, patients with stage 4 and 5 CKD need to be closely monitored for bleeding events after ESD.

Anticoagulant and antithrombotic agents

In the aging society, patients using antithrombotic agents are increasing to prevent the cardio- and cerebrovascular diseases, which expose the patients with ESD into a vulnerable position of bleeding. Delayed bleeding after gastric ESD in patients with anticoagulants remains unavoidable (28). Continuing using aspirin is a risk factor of delayed bleeding (34). There is a dilemma of whether the anticoagulant/antiplatelet agents should be used in EGC patients undergoing ESD. On one hand, these patients need antithrombotic agents to prevent/treat cardio- and cerebrovascular diseases. Antithrombotic interruption may cause thrombosis. Igarashi et al. (35) reported that only antithrombotic interruption (3–7 days) cause thrombosis (4/245, 1.6%). Jaruvongvanich et al. (36) did a meta-analysis which included 5 studies (included Igarashi’s study) and 700 patients (266 in the aspirin-continued group and 434 in the aspirin-interrupted group). The rate of thrombotic events is 2.1% (9/434) in the aspirin-interrupted group and non thrombotic events in the aspirin-continued group. On the other hand, these agents increase the risk of delayed bleeding after gastric ESD. Toya et al. (17) analyzed 2,553 ESDs for EGC. After propensity score matching, they found that post-ESD bleeding was significantly more frequent in lesions of patients with than without anticoagulant therapy (11.7% vs. 1.5%, P=0.001). A multivariate analysis demonstrated that anticoagulant therapy is an independent risk factor of post-ESD bleeding. Other studies also confirmed that anticoagulant therapies are risk factor for post-ESD bleeding (37,38). Tomida et al. (28) analyzed 728 patients who received anticoagulants and needed to be treated with ESD for gastric neoplasms. Among them, 261 were treated with direct oral anticoagulants (DOACs), and 467 with warfarin. They found that delayed bleeding occurred in 14% of patients treated with DOACs, and 18% of those with warfarin (P>0.05). Some guidelines recommend replacing warfarin or DOACs with heparin (heparin bridge therapy, HBT) to prevent thrombotic events when warfarin is discontinued (39). However, HBT also causes delayed bleeding for gastric ESD (40).

DOACs include the direct thrombin inhibitor, dabigatran, and the direct factor Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban. Yoshio et al. (41) compared these two types of DOACs and found that the delayed bleeding rate is significantly higher in rivaroxaban users compared with those on dabigatran (45% vs. 0%, P<0.05). One reason may be that rivaroxaban is a long-acting agent. Another reason is that dabigatran is given as an inactive prodrug, which is converted to active dabigatran by esterase-catalyzed hydrolysis in the liver, digestive tract, and the plasma (28,42). Dabigatran may not have an anticoagulant effect locally in the stomach. In comparison, rivaroxaban is given as an active drug which directly target coagulation proteins around the lesion in the stomach after ESD. This difference explains the different risk of delayed bleeding (41). Substituting dabigatran for oral anticoagulants in the perioperative period is a reasonable option to reduce the risk of post-ESD bleeding (28).

Whether the patients need to switch the anticoagulant from warfarin to HBT is inconclusive. Nakamura et al. (43) found that replacing antithrombotic agents or anticoagulants by heparin before ESD reduce the risk of cardiovascular events, they did not find the increased delayed bleeding after ESD. In our clinical practice, we treat the patients with anticoagulant/antithrombosis the similar way as Nakamura and colleagues: we replaced anticoagulant/antithrombosis for one week before ESD and one week after ESD, if the patients do not have a sign of post-ESD bleeding, we switch back the original anticoagulant/antithrombosis therapies. We deliver low-molecular heparin with subcutaneous injection, 5,000 IU/day combined with proton pump inhibitor (PPI). We have not found the increased delayed bleeding after ESD nor the thrombosis events. Harada et al. (44) compared the continuing low dose warfarin to HBT, they found that the post-ESD bleeding tends to be higher in HBT group (9.1% vs. 21.7%), although the difference did not reach significance. Kubo et al. (45) evaluated the risk factors for delayed bleeding after therapeutic gastrointestinal endoscopy (including ESD, EMR, polypectomy and cold polypectomy) in patients receiving oral anticoagulants and found that continued anticoagulant therapy (OR 2.29), anticoagulant withdrawal with HBT (OR 2.18), and the combination of anticoagulant with 1 antiplatelet drug (OR 1.72) are independent risk factors for delayed bleeding (45). Yoshio et al. (41) found that HBT significantly increased the post-ESD bleeding (OR, 10.7). Douketis and coworkers (46) did a randomized, double-blind, placebo-controlled trial for the patients with atrial fibrillation who need to interrupt warfarin treatment due to elective invasive procedures, they compared the patients with HBT and those without and showed that HBT does not reduce perioperative arterial thromboembolism but significantly increased bleeding events. Birnie et al. (47) found that continuous warfarin use is better than HBT. More evidence supports that continuous use of warfarin throughout the perioperative period is a better choice for patients on warfarin than HBT. In summary, most studies demonstrated that HBT is an independent risk factor of post-ESD bleeding (19,48-50) (Table 2). We suggest performing ESD without stopping antithrombotic agents because thrombosis is more serious than bleeding (35). Gastric ESD without cessation of antithrombotic agents may be more feasible.

Diagnostic models of post-ESD bleeding

There is no formular to calculate the risk of post-ESD bleeding. Fujishiro group (13) tried to establish a model (called BEST-J score) to stratify the risks of bleeding after ESD. They retrospectively enrolled 8,291 patients who underwent ESD for EGC derivation cohort from 25 institutions. They enrolled 2029 patients from eight institutions in other areas to validate the model. Their prediction model is based on 9 variables. 4 points for the warfarin or direct oral anticoagulants; 3 points for chronic kidney disease with haemodialysis; 2 points each for P2Y12 receptor antagonist and aspirin; 1 point each for cilostazol, a tumour size >30 mm, lower third in tumour location and presence of multiple tumours, −1 point for interruption of each kind of antithrombotic agents. They demonstrated that the patients with 0 to 1 point have low-risk of bleeding after ESD (2.8%), with 2 points have intermediate-risk of bleeding (6.1%), with 3 to 4 points have high-risk (11.4%) and ≥5 points have very high-risk (29.7%) of post-ESD bleeding. Choe et al. (51) analysed 5,080 patients with ESD procedures, multivariate logistic regression showed that ongoing antithrombotic use during the procedure, cancer pathology on biopsy before ESD, and piecemeal resection were independent risk factors of post-ESD bleeding. They created a classification and regression tree (CART) model. Ongoing antithrombotic use, specimen size, and age are the components in this model. The theory of CART model is similar to BEST-J score (13). The number of terminal nodes in the tree decides the risk score, 1–1 and 1–2 were classified as low risk of bleeding, 1–3 and 1–4 as high risk of bleeding. The predictive accuracy of this model is close to 95% (51).

Managements

The physicians need to know the vascular architecture of the stomach before performing ESD. Normally, the vessels vertically penetrate the muscle layer and then flow horizontally along the middle submucosal layer where they form the vascular network. In the high vessel density areas, the perivascular fibrotic tissue and the vascular network form a fasciae-like layer (21). The physicians need to distinguish the penetrating vessels from the vessels in the network. The most important step is to visually identify the vessels before making decisions. The visible vessels need to be coagulated during the ESD procedure to prevent delayed bleeding (2).

Coagulating potential bleeding spots

The common sense is to coagulate potential bleeding spots. Lin et al. (30) used norepinephrine to increase blood pressure to 150 mmHg for 5 min after the specimen was extracted and thus the non-obvious potential hemorrhage spots were exposed and coagulated. Compared with controls, the incidence of post-ESD bleeding in norepinephrine group was lower (1.3%, 2/151 vs. 10.1%, 16/158, P=0.01).

ESD ulcer closure

The lesions after ESD cause bleeding, especially for those with diameter ≥40 mm. There are several methods of lesion closure: endoloop, endoclips, Metal hemoclips and suture. Closing the lesion theoretically prevents the post-ESD bleeding. However, studies on the effect of lesion closure on the post-ESD bleeding are inconsistent. Ego et al. (48) studied the effectiveness of endoscopic closure using an endoloop and endoclips in preventing post-ESD bleeding in EGC patients who were taking antithrombotic therapy. They compared 131 ESDs in 110 patients in the closure group and 269 ESDs in 217 patients in the non-closure group and found that ulcer base closure using endoloop and endoclips did not prevent post-ESD bleeding (11.5% vs. 11.9%, P=0.89). Shiotsuki and coworkers (52) used endoloop to close the lesion after ESD and found that in general, the rate of post-ESD bleeding was lower in closure group. This difference reached significance in those the lesion <40 mm (P=0.03) or with Multiple antithrombotic agents (P=0.02).

The majority of the lesion suture studies are single arm. Akimoto et al. (53) sutured 22 lesions in 20 patients, no post-ESD event occurred. Han et al. (54) sutured 18 lesions in the stomach after ESD, there was no delayed bleeding. They concluded that endoscopic suturing of post-ESD defects in the stomach is feasible, safe, and effective on preventing post-ESD bleeding. Maekawa et al. (55) sutured 11 patients, Kantsevoy et al. (56) sutured 4 lesions in the stomach, there was no immediate or delayed bleedings. Goto et al. (20) concluded that endoscopic hand-suturing (EHS), when successfully completed and sustained, is feasible and safe with favorable outcomes. EHS decreases the post-ESD bleeding even in patients undergoing antithrombotic therapy. Akimoto et al. (57) created 12 mucosal defects in 2 pigs. they compared the open (control) lesions with those sutured with EHS. They found that at post operative day 14, the lesions in EHS group were covered with the epithelium without inversion of the mucosal edge, whereas the ulcer bed in the control group was still exposed. The degree of neovascularity and fibroblasts in the submucosa was smaller in the EHS group compared with those in controls. They concluded that EHS enhances lesion healing after ESD which might be applicable to prevent post-ESD bleeding in clinical practice. In summary, more studies support the application of lesion closure in stomach lesions after ESD (Table 3).

ESD ulcer shielding

Tan and colleagues (60) sprayed porcine fibrin glue (FG) to the ulcer surface after ESD, they assigned 301 patients to non-FG group and 96 to FG group. They revealed that 18/301 patients had delayed bleeding after ESD in non-FG group, no bleeding in all 96 patients in FG group (P<0.05). However, the majority of the ESD physicians combine FG with polyglycolic acid (PGA) sheet.

Takimoto et al. (61) first used the combination of PGA sheet and FG in 2014 after duodenal endoscopic submucosal dissection. Kataoka et al. (62) compared the effect of lesion shielding with those without and found that post-ESD bleeding occurred in 4.5% patients with PGA sheet and 5.7% in the control group. They concluded that the PGA shielding method did not have a significant effect on the prevention of post-ESD bleeding.

Using keywords “polyglycolic acid + post-ESD bleeding + gastric cancer”, there are 4 original articles in PubMed. Only Kataoka group showed that PGA shielding had no significant effect on the prevention of post-ESD bleeding, the other 3 consistently favor the application of PGA (63-65).

Takimoto and coworkers (66) used PGA sheet and fixed in place with fibrin glue, they found that the PGA sheets were still attached to the ulcer at 3 weeks after treatment. Kikuchi et al. (67) combined the autologous FG and PGA sheet to prevent post-ESD bleeding in patients with antithrombotic therapy. They first immersed the lesion size-matched PGA sheet in the autologous fibrinogen, then attached it onto the lesion and fixed it with clip, they finally sprayed the autologous fibrinogen and thrombin to the PGA sheet. They compared the post-ESD bleeding rate between the PGA sheet users and no PGA sheet users and found that PGA sheet significantly decreased the delayed bleeding (1/38 vs. 12/85, P<0.05), blood transfusion (0/38 vs. 8/85, P<0.05) and endoscopic hemostasis (6/38 vs. 35/38, P<0.05). Kawata et al. (63) compared the post-ESD bleeding between the patients with PGA sheet shielding after ESD and those without and found that post-ESD bleeding occurred in 5.8% in covering group and 20.8% in control groups (P<0.05). They concluded that the covering technique using PGA sheets and FG has the potential to decrease post-ESD bleeding in patients with continuing antithrombotic agents. Similar data also demonstrated in Fukuda (68) and Tsuji (65) groups who demonstrated that PGA sheets decreased the delayed bleeding from 22% to 6.7% in high‐risk patients after ESD. In summary, majority of the pertinent studies support this notion that sealing the ulcer lesion with PGA sheet after ESD reduces post-ESD bleeding (Table 4).

Sakagushi and coworkers (69) used envelope to deliver PGA sheets which avoided becoming wet and fold in animal model. Because of the gravity, the median PGA sheet application time was 1.00 (0.68–1.30) min/cm² with conventional method and 0.32 (0.18–0.52) min/cm² with the envelope techniques (P=0.002). The time for conquering the gravity was 1.20 (1.13–1.63) min/cm² with conventional techniques and 0.50 (0.39–0.58) min/cm² (P=0.002) for the envelope method. The endoscopy and histology found that the fixation of the PGA sheets was not sufficient on conventional group. However, the envelope group had sufficient fixation. They concluded that the envelope technique delivers the PGA sheets to the stomach quickly and cover ulcers appropriately in living pigs (69). Glubran 2, a new endoscopic synthetic sealant, may be another material applicable in clinical practice in the future (70).

Acid secretion inhibitors

As it is well known that the gastric bleeding is affected by pH levels. Platelet aggregation, coagulation, and fibrinolysis on gastric hemorrhagic ulcers all strongly depend on intragastric pH levels (71). When pH is below 6.8, platelet aggregation and blood coagulation is abnormal; when pH is <5.4, platelet aggregation and plasma coagulation are virtually obliterated, when pH is <4.0, fibrin clots are dissolved (72). Therefore, it is very important to inhibit acid secretion in and after the procedure. There are currently three type of acid inhibitors, histamine2-receptor antagonists (H₂RAs), PPI and potassium-competitive acid blocker (P-CAB). Tomita et al. (73) compared the effectiveness of famotidine, a H₂RA, and omeprazole, a PPI, on post-ESD bleedings. This prospective randomized controlled trial study found that the delayed bleeding after ESD occurred in 6.5% of subjects with PPI administration and 6.3% in H2RA group. They therefore concluded that PPI is similar to H2RA for the prevention of delayed bleeding after ESD. The advantage of H2RA is that it is faster, H2RAs exert their inhibitory effects within a couple of hours after administration. Abe et al. (74) compared famotidine and omeprazole in 10 healthy, Helicobacter pylori-negative male subjects. They found that in all ten subjects, an intravenous dose of 20 mg famotidine increased intragastric pH more rapidly than intravenous omeprazole 20 mg. The disadvantage is that, compared with PPIs, H2RAs are less potent. Uedo et al. (75) demonstrated that PPI therapy is more effective on preventing delayed bleeding after ESD compared with H2RA treatment.

Jiang and coworkers (71) performed a meta-analysis to compare the effects of PPIs and H2RAs on post-ESD bleeding. They found that PPIs are significantly more efficacious in preventing post-ESD bleeding compared with H2RAs (OR: 1.83; 1.10 to 3.05, P<0.05). PPIs need longer time to reach their full potency. Four weeks application shows similar efficacy between PPIs and H₂Ras. However, PPIs are better than H2RAs in 8 weeks' treatment (OR: 1.91; 1.08 to 3.40, P<0.05). In summary, PPIs are better than H2RAs if the application is long enough. The maximum acid inhibition was achieved at day 5 after PPI administration (72). The physicians should use PPIs early enough to get the full potency to prevent post-ESD bleeding (76).

Another type of acid inhibitor is potassium-competitive acid blocker. Vonoprazan, a first-in-class P-CAB, is approved for clinical application in 2015 (77). these drugs bind reversibly to potassium and block the H⁺, K⁺ ATPase enzyme, thus block acid production. Kakushima et al. (78) compared the delayed bleeding rate in patients who were using antithrombotics. They divided these patients into two groups, one used PPIs (71 patients with 101 lesions) and another used vonoprazan (59 patients with 90 lesions). The delayed bleeding occurred in 18% patients in the PPI group and 31% patients in the vonoprazan group. There was no significant difference in the two groups (78). Another retrospective analysis showed that overall incidence of post-ESD bleeding was not significantly different between patients treated with PPIs and P-CAB (3.0% vs. 2.6%, P=0.77). After propensity score matching (n=153 in each group), the incidence was not significantly different between the two groups (2.6% vs. 2.6%) (79).

Suto and coworkers (80) compared the post-ESD bleeding between patients with PPIs and those with vonoprazan, they found that 15% of the patients with PPIs had post-ESD bleeding, the percentage was 4% for those with P-CAB. They concluded that vonoprazan has better protective effect on post-ESD bleeding than PPIs (P<0.05). Furthermore, they also found that the ulcer healing is better in patients treated with vonoprazan than those with PPIs. The reason why vonoprazan is better than PPIs is that vonoprazan is faster, stronger, and long-lasting inhibition of gastric acid secretion after administration (76) compared with PPIs. Kagami et al. (81) found that in overall genotype group, pH ≥5 holding time ratios with vonoprazan twice a day, vonoprazan daily, esomeprazole twice a day and esomeprazole daily were 99%, 91%, 84% and 54% respectively. Furthermore, the gastric pH tends to be higher for patients with vonoprazan compared with those with PPI (76). If the patients are given vonoprazan the night before ESD, the pH will increase to 6.96 on the day of ESD (80). On the contrary, it takes several days for the gastric pH to reach a high level with conventional PPIs (80). As a new class of acid-suppressing agents, vonoprazan reduces the incidence of delayed bleeding after ESD better than conventional PPIs (71). Moreover, vonoprazan effect is not affected by CYP2C19 polymorphisms (81). In addition, vonoprazan has better effects on mucosal protection than PPIs (71). Upper gastrointestinal endoscopy about 8 weeks after ESD showed that only one vonoprazan user (1/32, 3%) had ulcer scarring. In comparison, 11 PPI users (11/64, 17%) had open ulcers.

Overall, a meta-analysis revealed that vonoprazan is currently the best acid secretion inhibitor, the better one is PPI and H₂RA ranks the third in preventing bleeding after ESD. The effects of the combination of vonoprazan with mucosal protective antiulcer drug may have even better efficacy on the prevention of post-ESD bleeding. Jiang et al. recommended that the patients with a high risk of bleeding, such as long operation time, large resection ulcer, deeper tumor location, and anticoagulant or antithrombotic drugs, need vonoprazan-mucosal protective antiulcer drugs for 8 weeks (71). According to the literature, we suggest vonoprazan the first line agent in clinical practice.

Routine second-look endoscopy (SLE) after gastric ESD remains controversial. The potential advantage is that endoscopists can evaluate the status of post-ESD ulcers and can take additional hemostatic measures if necessary. The study by Guo et al. (82) supports SLE. They reported that the incidence of late delayed bleeding was significantly decreased in the SLE group compared with that in the non-SLE group (4.5 vs. 12%, P=0.028). However, the majority of the pertinent studies denied the necessity of routine SLE. Mochizuki and coworkers (7) ran a multicentre prospective randomised controlled non-inferiority trial and revealed that the incidences of post-ESD bleeding were not significantly different between SLE and non-SLE groups (5.4% vs. 3.8%, P>0.05). Non-inferiority statistics showed that absolute risk difference between the non-SLE group and the SLE group was of −1.6% (P_{non-inferiority} <0.001). the P_{non-inferiority} value is still significant even they set the non-inferiority margin to 4%. Kim et al. (83) did a meta-analysis on the role of SLE after ESD, they included 16 pertinent studies which included Mochizuki’s study. This meta-analysis concluded that SLE has no role in reducing the risk of delayed post-ESD bleeding. On the contrary, delayed post‐ESD bleeding is more common in patients who receive prophylactic hemostasis at SLE than in those who do not. Therefore, SLE is just for the patients with high risk of post-ESD bleeding (Figure 1), routine second-look endoscopy after gastric ESD may not be necessary.

Figure 1 Managements of post- ESD bleeding. ESD, endoscopic submucosal dissection; H2RA, histamine-receptor antagonists; PPI, proton pump inhibitor; P-CAB, potassium-competitive acid blocker; CKD, chronic kidney disease; HBT, heparin bridge therapy; SLE, second-look endoscopy; EHS, endoscopic hand-suturing; PGA, polyglycolic acid; FG, fibrin glue.

Summary

ESD is the standard treatment for EGCs. However, this procedure is time consuming and may have some complications such as post-ESD bleeding. The risk factors include lesion location, ulcer size, CKD, and the usage of anticoagulant/antithrombotic agents. The managements including hemostasis during ESD, ulcer closure, ulcer shielding and antiacid drug administration.

Acknowledgments

Funding: This work was funded by the Beijing-Tianjin-Hebei research cooperation project (No. H2018206450).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-466/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-466/coif). All authors report that this paper was funded by Beijing-Tianjin-Hebei research cooperation project H2018206450. The authors have no other conflicts of interest to declare.

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