Surgical Endoscopy (2019) 33:1271–1283 and Other Interventional Techniques https://doi.org/10.1007/s00464-018-6409-4 Comparative efficacy of various anti-ulcer medications after gastric endoscopic submucosal dissection: a systematic review and network meta-analysis Eun Hye Kim1 · Se Woo Park2 · Eunwoo Nam3 · Jae Gon Lee4 · Chan Hyuk Park4 Received: 4 May 2018 / Accepted: 24 August 2018 / Published online: 30 August 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Background The comparative efficacy of various anti-ulcer medications after gastric endoscopic submucosal dissection (ESD) has not been fully evaluated. Recently, vonoprazan, a novel potassium-competitive acid blocker, has also been used in ulcer treatment after ESD. Methods We searched for all relevant randomized controlled trials examining the efficacy of anti-ulcer medications after gastric ESD, published through October 2017. Healing of iatrogenic ulcers was investigated at 4–8 weeks after ESD. A network meta-analysis was performed to calculate the network estimates. Results Twenty-one studies with 2005 patients were included. Concerning the comparative efficacy for ulcer healing at 4 weeks after ESD, no network inconsistency was identified (Cochran’s Q-test, df = 10, P = 0.13; I2 = 34%). A combination therapy of proton-pump inhibitor (PPI) and muco-protective agent was superior to PPI alone [risk ratio (RR) (95% confi- dence interval, CI) 1.69 (1.20–2.39)]. The combination therapy of PPI and muco-protective agents tended to be superior to vonoprazan [RR (95% CI) 1.98 (0.99–3.94)]. There was no difference of ulcer healing effect between PPI and vonoprazan [RR (95% CI) PPI vs. vonoprazan, 1.17 (0.64–2.12)]. Concerning the ulcer healing rate at 8 weeks after ESD, however, vonoprazan was superior to PPI [RR (95% CI) 1.27 (1.03–1.56)]. Additionally, vonoprazan tended to be superior to the combination therapy of PPI and muco-protective agent [RR (95% CI) 1.20 (0.96–1.51)]. Conclusions A combination therapy of PPI and muco-protective agent was superior to PPI alone for ulcer healing at 4 weeks after ESD. In the ulcer healing effect at 8 weeks after ESD, vonoprazan was superior to PPI. Keywords Endoscopic submucosal dissection · Anti-ulcer medication · Proton-pump inhibitor · Vonoprazan Gastric endoscopic submucosal dissection (ESD) has been the most common adverse event after the procedure and can widely used for the treatment of early gastric cancer and be life threatening [2, 3]. To prevent iatrogenic ulcer bleed- gastric adenoma [1]. Despite the minimal invasiveness of ing, endoscopists may perform second-look endoscopy after ESD, iatrogenic ulcer bleeding is a concern because it is ESD [4]. Unfortunately, however, many studies reported that second-look endoscopy cannot reduce the risk of post-ESD bleeding [5]. Electronic supplementary material The online version of this Currently, the best way to reduce iatrogenic ulcer bleed- article (https ://doi.org/10.1007/s0046 4-018-6409-4) contains ing is to administer anti-ulcer drugs, including proton-pump supplementary material, which is available to authorized users. * Chan Hyuk Park Hospital, Hallym University College of Medicine, Hwasung, [email protected] Republic of Korea 3 Biostatistical Consulting and Research Lab, Medical 1 Division of Gastroenterology, Department of Internal Research Coordinating Center, Hanyang University, Seoul, Medicine, Severance Hospital, Institute of Gastroenterology, Republic of Korea Yonsei University College of Medicine, Seoul, Republic of Korea 4 Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, 2 Division of Gastroenterology, Department of Internal Republic of Korea Medicine, Hallym University Dongtan Sacred Heart Vol.:(0123456789)1 3 1272 Surgical Endoscopy (2019) 33:1271–1283 inhibitors (PPIs) [3]. Several studies reported that PPIs were anti-ulcer medications after gastric endoscopic resection, superior to histamine-2-receptor antagonists (H2RAs) in by using the MEDLINE, Embase, and Cochrane Library terms of avoiding bleeding [3, 6]. In addition, it has been databases. The following search string was used: ((ESD) suggested that a combination therapy of PPI and muco- OR (endoscopic submucosal dissection) OR (EMR) OR protective agents including rebamipide may be effective for (endoscopic mucosal resection) OR (iatrogenic) OR (arti- iatrogenic ulcer healing [6]. ficial)) AND (ulcer*) AND ((vonoprazan) OR (TAK-438) Recently, vonoprazan (VPZ), a novel potassium-compet- OR (revaprazan) OR (YH1885) OR ((potassium) AND itive acid blocker, has been used for gastric acid inhibition (competitive)) OR (potassium-competitive) OR (PPI) OR [7]. Similar to PPIs, VPZ inhibits gastric H +/K+-adenosine (proton pump inhibitor*) OR (dexlansoprazole) OR (esome- triphosphatase [8]. However, it has a more rapid and potent prazole) OR (ilaprazole) OR (lansoprazole) OR (omepra- acid-inhibitory effect than PPIs [7]. The efficacy of VPZ has zole) OR (pantoprazole) OR (rabeprazole) OR (((histamine) been proven in various gastrointestinal diseases, including OR (histamine2) OR (histamine-2) OR (h2) OR (h-2)) AND erosive esophagitis, peptic ulcers, and Helicobacter pylori ((antagonist*) OR (blocker*))) OR (h2ra) OR (famotidine) infection [9–11]. In addition, one prospective study with OR (cimetidine) OR (ranitidine) OR (nizatidine) OR (lafu- a historical comparison showed that the risk of post-ESD tidine) OR (misoprostol) OR (rebamipide) OR (ecabet) OR bleeding can be reduced through the administration of VPZ (irsogladine) OR (polaprezinc) OR (muco-protective) OR after ESD [12]. VPZ may be a promising drug that facilitates (mucoprotective)). The detailed search strategies for each iatrogenic ulcer healing. database are shown in “Appendix”. In order to identify To date, two pairwise meta-analyses have compared iatro- additional studies, we also examined the references of the genic ulcer healing between PPI and H2RA, or between PPI screened articles. The latest date for updating our search was alone and PPI with a muco-protective agent [6, 13]. How- October 31, 2017. ever, comprehensive comparisons among the various drug regimens for iatrogenic ulcers have yet to be conducted. In Study selection addition, there are other studies comparing iatrogenic ulcer healing between PPI and muco-protective agents, H2RA In the first stage of the study selection, the titles and abstracts and muco-protective agents, or PPI and VPZ [14–18]. In of papers identified by our search were examined to exclude this situation, all relevant evidence, both direct and indi- irrelevant articles. Next, the full texts of all selected studies rect, should be considered in order to fully analyze each were screened according to inclusion and exclusion criteria. pairwise comparison [19]. Unlike the traditional pairwise The inclusion criteria were as follows: (a) patients: patients meta-analysis, a network meta-analysis can synthesize direct who underwent gastric ESD; (b) intervention: anti-ulcer and indirect estimates of multiple drug regimens [20]. In medication after the procedure; (c) comparator: another this study, therefore, we conducted a network meta-analysis regimen of anti-ulcer medication; and (d) outcome: ulcer of randomized controlled trials (RCTs) in order to identify healing rate. The exclusion criteria were (a) non-RCTs, (b) the efficacy of various drug regimens for iatrogenic ulcer non-human studies, and (c) publications in a language other healing after ESD. than English. Two investigators (E.H.K. and C.H.P.) independently evaluated the studies for eligibility and resolved any disa- Methods greements through discussion and consensus. If no agree- ment could be reached, a third investigator (S.W.P.) deter- This systematic review and network meta-analysis was mined eligibility. The Cochrane Risk of Bias assessment conducted according to the PRISMA (Preferred Reporting tool was used for assessing the risk of bias in individual Items for Systematic Reviews and Meta-Analyses) state- studies [23]. ment [21] and the report of the International Society for Pharmacoeconomics and Outcomes Research Task Force on Data extraction Indirect Treatment Comparisons Good Research Practices [22]. Approval of Institutional Review Board was not needed Using a data extraction form developed in advance, two in this study because the meta-analysis only analyzed data reviewers (E.H.K. and C.H.P.) independently extracted derived from published articles or abstract proceedings. the following information from each chosen study: first author, year of publication, study design, country, enroll- Search strategy ment period, drug name and dosage of anti-ulcer medica- tions, assessment timing of ulcer healing, and ulcer healing We searched for all relevant studies published between Janu- rate according to the drug regimens. The assessment timing ary 1970 and October 2017 that examined the efficacy of of ulcer healing was categorized into two groups (4 weeks 1 3 Surgical Endoscopy (2019) 33:1271–1283 1273 after ESD vs. 8 weeks after ESD), by using a cutoff value the mixed estimates [27]. In addition, we calculated P-scores, of 6 weeks because most studies reported the ulcer healing which measured the extent of certainty that one treatment rate at 4 or 8 weeks after endoscopic resection whereas a few was better than another treatment, averaged over all com- studies assessed iatrogenic ulcer at 4–6 weeks after ESD. peting treatments [28]. To assess the robustness of