A Network Meta-Analysis of Pharmacological Treatments for Gastric Mucosal Protection in Artificial Ulcers following Endoscopic Submucosal Dissection of the Stomach

Proton pump inhibitor (PPI) was the main prescription for gastric ulcer after endoscopic submucosal dissection (ESD). Some randomized controlled trials showed that a combination of rebamipide and PPI appears to be more efficient than PPI alone for the treatment of ESD-induced gastric ulcer. However, the sample sizes in these trials were limited and the conclusions were underpowered.This meta-analysis was conducted with 5 randomized controlled trials using the combination of rebamipide and PPI for healing ESD-induced ulcer compared with PPI monotherapy. Relevant studies were searched via MEDLINE, PubMed, Embase, and Cochrane Library databases by using terms such as "rebamipide," "proton pump inhibitor," "endoscopic submucosal dissection," "drug therapy," and "gastric ulcer or artificial ulcer."Five studies were included in this meta-analysis. The number of total patients was 626, with 317 patients in the combination group and 309 patients in the PPI alone group. The heterogeneity among these 5 studies was low (I = 22%, P = 0.28). All 5 studies considered scarring stage 1 rate as a primary endpoint, and the scarring stage 1 rate in combination group (115/317) was higher than that in PPI alone group (63/309) (odds ratio 2.61, 95% confidence interval [CI] 1.76-3.88). The mean difference of initial ulcer size between 2 groups was -4.46 (95% CI -266.61 to -257.69, P = 0.97), but it enlarged to 68.38 (95% CI 35.72-101.05, P < 0.00001) in the 4th week.This meta-analysis demonstrates that combination therapy is more efficient than PPI monotherapy in healing ESD-induced gastric ulcer.

Purpose: Proton Pump Inhibitor (PPI) is a common treatment for the ulcer after the endoscopic submucosal dissection (ESD) for gastric lesions. However, the artificial ulcer is sometimes huge and the thermal denaturation has also been added by high frequency electrical effect. Therefore, a more powerful ulcer treatment is required. We compared the PPI monotherapy to the combination of PPI and Rebamipide for artificial ulcer after the ESD based on the Historical Cohort Study method. We examined the effectiveness of the combination of PPI and Rebamipide for the treatment period of the ulcer after the ESD. Methods: We switched from the PPI monotherapy to the combination of the PPI and Rebamipide in order to further improve the treatment for the ulcer after the ESD from November 2009. By following a certain clinical pathway, the management of before and after the surgery was performed. Nothing was changed other than the medicine. Group A (PPI alone): the ESD was implemented for the 58 resections (gastric cancer: 55 cases; adenomas: 3 cases) for four months from July 2009 until October 2009. Group B (Combination of PPI and Rebamipide): 78 resections (gastric cancer: 66 cases; adenomas: 10 cases; carcinoid: 2 cases) for four months from November 2009 until February 2010. We implemented Esophagogastroduodenoscopy (EGD) during the period of 1-3 months and 3-6 months after the ESD.The treatment was determined at the time when the ulcer closure in the EGD was confirmed. Rabeprazole 20 mg was taken orally for PPI for 8 weeks first; subsequently, Rabeprazole 10 mg was taken in each group. In Group B, Rebamipide 300 mg was added. Results: We compared Group A and Group B in terms of their age, sex, lesion site, resection size, the invasion depth, the presence or absence of the ulcer disease, heart disease as an underlying disease, dialysis, liver cirrhosis, aspirin as a concomitant drug, non-aspirin NSAID, non-anticoagulant therapy, experience of the doctors who had performed the surgery (they were divided into two groups: one group had performed more than 100 surgeries and the other group had performed less than 100 surgeries) and surgery duration. No significant bias was observed. The median (50%) and the 80% of the treatment period until the ulcer treatment confirmed by EGD were 68th day and 134th day respectively in Group A. In contrast, they were 46th day and 63th day in Group B respectively. The significant shortening of the treatment period in Group B was confirmed by Kaplan-Meier's Logrank test (p=0.0003). Conclusion: The period until the healing of the artificial ulcer after the ESD was significantly shortened at a high rate by the combination of PPI and Rabeprazole, comparing with the PPI monotherapy.

BackgroundAt present, eradication regimens for non-Helicobacter pylori Helicobacter (NHPH) have not been established yet. We investigated effectiveness of the standard triple-drug combination therapy for Helicobacter pylori eradication and of a proton pump inhibitor (PPI) monotherapy in eradication of NHPH.MethodsSubjects were the patients who were diagnosed with NHPH-infected gastritis based on microscopic findings, helical-shaped organisms obviously larger than Helicobacter pylori, in the gastric mucosal specimens using Giemsa staining at Kenwakai Hospital between November 2010 and September 2021, whose NHPH species were identified by polymerase chain reaction (PCR) analysis of urease genes in endoscopically-biopsied samples, and who consented to NHPH eradication with either the triple-drug combination therapy for one week or a PPI monotherapy for six months. Six months after the completion of eradication, its result was determined with esophagogastroduodenoscopy, microscopic examination, and PCR analysis. In cases of unsuccessful eradication, a second eradication with the other therapy was suggested to the patient.ResultsPCR analysis detected NHPH in 38 patients: 36 as Helicobacter suis and two as Helicobacter heilmannii/Helicobacter ailurogastricus. Fourteen Helicobacter suis-infected and one Helicobacter heilmannii/Helicobacter ailurogastricus-infected patients requested eradication therapy. The triple-drug combination therapy succeeded in four of five patients, while the PPI monotherapy succeeded in five of 10 patients. Three of five patients who had been unsuccessful with the latter therapy requested the triple-drug combination therapy as the second eradication and all three were successful. In total, the triple-drug combination therapy succeeded in seven out of eight (87.5%) attempted cases, while the PPI monotherapy in five out of 10 (50%) attempted cases.ConclusionsIn NHPH eradication, the triple-drug combination therapy was considered to be effective to some extent and to become the first-line therapy. While, although less successful, PPI monotherapy appeared to be a potentially promising option particularly for patients with allergy or resistance to antibiotics. Effectiveness of PPI monotherapy may be attributed to hyperacid environment preference of Helicobacter suis and PPI’s acid-suppressive effect. Additionally, male predominance in NHPH-infected gastritis patients may be explained by gender difference in gastric acid secretory capacity. However, further evidence needs to be accumulated.Study registrationThis study was approved by the Research Ethics Committee of Kenwakai Hospital (No. 2,017,024).

Helicobacter pylori (HP) eradication therapy is a useful treatment for idiopathic thrombocytopenic purpura (ITP). Some investigators have also reported the effects of proton pump inhibitor (PPI) monotherapy on ITP. We performed a randomized study of HP eradication therapy and PPI monotherapy on ITP. Four of nine patients achieved complete remission (CR), two of nine achieved partial remission (PR) in HP eradication therapy, three of eight achieved CR, and two of eight achieved PR in PPI monotherapy. No significant differences were observed in the CR + PR of these patients between HP eradication therapy and PPI monotherapy. As for cost comparisons, HP eradication therapy is cheaper than PPI monotherapy, but it is less effective.

Helicobacter pylori (HP) eradication therapy is a useful treatment for idiopathic thrombocytopenic purpura (ITP). Some investigators have also reported the effects of proton pump inhibitor (PPI) monotherapy on ITP. We performed a randomized study of HP eradication therapy and PPI monotherapy on ITP. Four of nine patients achieved complete remission (CR), two of nine achieved partial remission (PR) in HP eradication therapy, three of eight achieved CR, and two of eight achieved PR in PPI monotherapy. No significant differences were observed in the CR + PR of these patients between HP eradication therapy and PPI monotherapy. As for cost comparisons, HP eradication therapy is cheaper than PPI monotherapy, but it is less effective.

Background/AimsThe ability of endoscopic submucosal dissection (ESD) to resect large early gastric cancers (EGCs) results in the need to treat large artificial gastric ulcers. This study assessed whether the combination therapy of rebamipide plus a proton pump inhibitor (PPI) offered benefits over PPI monotherapy.MethodsIn this prospective, randomized, multicenter, open-label, and comparative study, patients who had undergone ESD for EGC or gastric adenoma were randomized into groups receiving either rabeprazole monotherapy (10 mg/day, n=64) or a combination of rabeprazole plus rebamipide (300 mg/day, n=66). The Scar stage (S stage) ratio after treatment was compared, and factors independently associated with ulcer healing were identified by using multivariate analyses.ResultsThe S stage rates at 4 and 8 weeks were similar in the two groups, even in the subgroups of patients with large amounts of tissue resected and regardless of CYP2C19 genotype. Independent factors for ulcer healing were circumferential location of the tumor and resected tissue size; the type of treatment did not affect ulcer healing.ConclusionsCombination therapy with rebamipide and PPI had limited benefits compared with PPI monotherapy in the treatment of post-ESD gastric ulcer (UMIN Clinical Trials Registry, UMIN000007435).

In our previous study, the healing effect of proton pump inhibitor plus rebamipide for endoscopic submucosal dissection-related artificial ulcer smaller than 40 mm showed statistical significance. However, such effect of the combination was not yet clear for ulcers with dissected diameter more than 40 mm. The aim of this present study was to resolve this problem under sufficient statistical power, with adequate sample size. We conducted a randomized controlled study. Either the proton pump inhibitor mono-therapy or the combination therapy was prescribed for 28 days after endoscopic submucosal dissection. Eighty-seven patients were eligible for outcome evaluation. Combination therapy was significantly superior to mono-therapy, 27.8% vs 0% reached healing stage (scar stage) in cases with ulcers of dissection diameter more than 40 mm. In conclusion, the combination therapy with rebamipide was favorable regimen in patients with larger artificial ulcer after endoscopic submucosal dissection.

Can rebamipide and proton pump inhibitor combination therapy promote the healing of endoscopic submucosal dissection–induced ulcers? A randomized, prospective, multicenter study

Toward further prevention of bleeding after gastric endoscopic submucosal dissection.

Proton pump inhibitor (PPI) monotherapy cannot cure all cases of gastroesophageal reflux disease (GERD), and combination therapy with prokinetics and PPI achieves symptomatic improvement for some GERD patients. Few studies have been performed to predict the need for prokinetics. Subjects were 163 patients (64 male, mean age 53.1 +/- 16.6 years) with GERD symptoms. They were evaluated using the frequency scale for the symptoms of GERD (FSSG), a GERD-specific questionnaire developed in Japan(1) and endoscopy. They were administered with rabeprazole 10 mg daily. At 12 and 24 weeks of treatment, subjects were offered a choice of four treatment regimens according to their degree of satisfaction (1, no need for further treatment; 2, opt for continued PPI treatment; 3, step-down to H2RA; 4, dissatisfied with present treatment, so opt for combination treatment with prokinetics, mosapride 5 mg tid). The choice of treatment after 12 weeks of treatment placed 79.1% of subjects in the satisfied group (1, 21; 2, 98; 3, 10). After 24 weeks, 98.2% of subjects were in the satisfied group. Pretreatment FSSG scores were significantly higher in the dissatisfied group (4, 17.4 +/- 1.4) than in the satisfied group (1, 12.3 +/- 1.3; 2, 12.8 +/- 0.8; 3, 10.2 +/- 1.8) (P < 0.05). The satisfaction rate with these treatment regimens was 98.2% at 24 weeks, suggesting that combination therapy with prokinetics was effective for patients dissatisfied with PPI monotherapy. The FSSG is a useful predictor of the necessity for combination therapy.

Background/AimsProkinetics can be used for treating patients with gastroesophageal reflux disease (GERD), who exhibit suboptimal response to proton pump inhibitor (PPI) treatment. We conducted a systematic review to assess the potential benefits of combination treatment with PPI plus prokinetics in GERD.MethodsWe searched PubMed, the Cochrane Library, and EMBASE for publications regarding randomized controlled trials comparing combination treatment of PPI plus prokinetics to PPI monotherapy with respect to global symptom improvement in GERD (until February 2020). The primary outcome was an absence or global symptom improvement in GERD. Adverse events and quality of life (QoL) scores were evaluated as secondary outcomes using a random effects model. Quality of evidence was rated using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE).ResultsThis meta-analysis included 16 studies involving 1446 participants (719 in the PPI plus prokinetics group and 727 in the PPI monotherapy group). The PPI plus prokinetics treatment resulted in a significant reduction in global symptoms of GERD regardless of the prokinetic type, refractoriness, and ethnicity. Additionally, treatment with PPI plus prokinetics for at least 4 weeks was found to be more beneficial than PPI monotherapy with respect to global symptom improvement. However, the QoL scores were not improved with PPI plus prokinetics treatment. Adverse events observed in response to PPI plus prokinetics treatment did not differ from those observed with PPI monotherapy.ConclusionsCombination of prokinetics with PPI treatment is more effective than PPI alone in GERD patients. Further high-quality trials with large sample sizes are needed to verify the effects based on prokinetic type.

BackgroundGastrointestinal (GI) complications are a major cause of morbidity and mortality in systemic sclerosis (SSc) [1]. Proton pump inhibitors (PPIs) are widely used to treat gastroesophageal reflux disease in SSc....

BackgroundBoth vonoprazan and proton pump inhibitors (PPIs) are currently used to treat artificial ulcers after gastric endoscopic submucosal dissection. However, evidence-based medicine proving the efficacy of vonoprazan is still lacking. Therefore, this meta-analysis aimed to compare the efficacy of vonoprazan and PPIs for the treatment of artificial ulcers after gastric endoscopic submucosal dissection.MethodsThe PubMed, EMBASE and Cochrane Library databases were searched up to September 2023 for related randomized controlled trials (RCTs). RCTs that compared the efficacy of vonoprazan and PPIs in treating artificial gastric ulcers after gastric endoscopic submucosal dissection were included. Two independent reviewers screened the included studies, extracted the data and assessed the risk of bias. The following outcomes were extracted for comparison: ulcer healing rate, ulcer shrinkage rate, delayed postoperative bleeding rate, and ulcer perforation rate.ResultsNine randomized controlled trials involving 926 patients were included. The pooled results showed that vonoprazan had a significantly lower rate of delayed postoperative bleeding than did PPIs (RR = 0.46; 95% CI = 0.23–0.91; P = 0.03). No significant differences were found in terms of ulcer healing, shrinkage rates, or ulcer perforation rates between vonoprazan and PPIs.ConclusionsCompared with PPIs, vonoprazan is superior at reducing delayed postoperative bleeding after endoscopic submucosal dissection. However, further studies are needed to prove the efficacy of vonoprazan.Systematic Review RegistrationIdentifier CRD42024509227.

Proton pump inhibitors (PPI) are effective at healing artificial ulcers after endoscopic submucosal dissection (ESD) for gastric neoplasms; however, the efficacy of vonoprazan is not completely understood. The aim of the present study was to determine the healing effect of vonoprazan on artificial ulcers post-gastric ESD relative to PPI. Thirty-five patients who underwent gastric ESD between April and November 2015 were treated with vonoprazan 20mg/day for 4weeks and subsequently underwent endoscopy for evaluation of ulcer size (V group). Ulcer contraction rate was determined by the following formula: ([ESD specimen size]-[ulcer size at 4weeks after ESD])/(ESD specimen size)×100%. We compared the results with those of a historical control group treated with esomeprazole 20mg/day for 4weeks after gastric ESD and subsequently measured their ulcer size (33 patients, E group) by propensity score-matching methods. Sixty-two subjects were enrolled after propensity score-matching. Ulcer contraction rate at 4weeks after ESD in the V group was significantly higher than that of the E group (97.7±3.2% vs 94.5±6.7%, respectively, P=0.025). Number of subjects with a scar-stage ulcer (100% contraction rate) tended to be higher in the V group relative to the E group (32% [10 of 31] vs 13% [4 of 31], respectively, P=0.070, McNemar's chi-squared test). Vonoprazan has a faster post-gastric ESD artificial ulcer contraction rate than esomeprazole. Vonoprazan may supersede PPI in treating post-ESD artificial ulcers of the stomach.

The aims of gastroesophageal reflux disease (GERD) treatment are symptom relief and healing of oesophagitis. Besides proton pump inhibitors (PPIs), prokinetic agents are also commonly prescribed to treat GERD. Domperidone, a well-known antiemetic, is an example of a prokinetic agent. It is a dopaminergic blocker that increases lower oesophagus sphincter pressure and activates gastric motility. We carried out a systematic review and meta-analysis to explore the benefits of domperidone in addition to PPI therapy for GERD. We searched for publications comparing PPI plus domperidone to PPI monotherapy in terms of symptom improvement in GERD (until 21 April 2022) on PubMed, Scopus, Google Scholar, Web of Science, Cochrane Library, WHO’s International Clinical Studies Registry Platform, and ClinicalTrials.gov without restricting date, language, or study design. The protocol was registered in PROSPERO (CRD42021242076). This meta-analysis incorporated 11 studies with a total of 841 participants (419 in the PPI plus domperidone group and 422 in the PPI monotherapy group). The combination of a PPI and domperidone resulted in a significant reduction in global GERD symptoms. Adverse events associated with PPI plus domperidone treatment were similar to those associated with PPI monotherapy. In conclusion, the combination of domperidone and a PPI is generally safe and effective in treating GERD as compared with that of PPI alone.