J Gastroenterol https://doi.org/10.1007/s00535-021-01769-0 REVIEW Evidence-based clinical practice guidelines for peptic ulcer disease 2020 1,2 2 2 2 Tomoari Kamada • Kiichi Satoh • Toshiyuki Itoh • Masanori Ito • 2 2 2 2 Junichi Iwamoto • Tadayoshi Okimoto • Takeshi Kanno • Mitsushige Sugimoto • 2 2 2 2 Toshimi Chiba • Sachiyo Nomura • Mitsuyo Mieda • Hideyuki Hiraishi • 2 2 2 2 Junji Yoshino • Atsushi Takagi • Sumio Watanabe • Kazuhiko Koike Received: 7 October 2020 / Accepted: 3 February 2021 Ó The Author(s) 2021 Abstract The Japanese Society of Gastroenterology second-line therapy. Patients who do not use NSAIDs and (JSGE) revised the third edition of evidence-based clinical are H. pylori negative are considered to have idiopathic practice guidelines for peptic ulcer disease in 2020 and peptic ulcers. Algorithms for the prevention of NSAID- created an English version. The revised guidelines consist and low-dose aspirin (LDA)-related ulcers are presented in of nine items: epidemiology, hemorrhagic gastric and this guideline. These algorithms differ based on the con- duodenal ulcers, Helicobacter pylori (H. pylori) eradica- comitant use of LDA or NSAIDs and ulcer history or tion therapy, non-eradication therapy, drug-induced ulcers, hemorrhagic ulcer history. In patients with a history of non-H. pylori, and nonsteroidal anti-inflammatory drug ulcers receiving NSAID therapy, PPIs with or without (NSAID) ulcers, remnant gastric ulcers, surgical treatment, celecoxib are recommended and the administration of VPZ and conservative therapy for perforation and stenosis. is suggested for the prevention of ulcer recurrence. In Therapeutic algorithms for the treatment of peptic ulcers patients with a history of ulcers receiving LDA therapy, differ based on ulcer complications. In patients with PPIs or VPZ are recommended and the administration of a NSAID-induced ulcers, NSAIDs are discontinued and anti- histamine 2-receptor antagonist is suggested for the pre- ulcer therapy is administered. If NSAIDs cannot be dis- vention of ulcer recurrence. continued, the ulcer is treated with proton pump inhibitors (PPIs). Vonoprazan (VPZ) with antibiotics is recom- Keywords Peptic ulcer Á Helicobacter pylori eradication Á mended as the first-line treatment for H. pylori eradication, Nonsteroidal anti-inflammatory drug Á Low-dose aspirin Á and PPIs or VPZ with antibiotics is recommended as a Idiopathic ulcer The members of the Guidelines Committee are listed in the Appendix. The original version of this article appeared in Japanese as ‘‘Shokasei Introduction Kaiyo Sinryo Guideline 2020’’ from the Japanese Society of Gastroenterology (JSGE), published by Nankodo, Tokyo, in 2020. In 2009, the Japanese Society of Gastroenterology (JSGE) Please see the article on the standards, methods, and process of developed evidence-based clinical practice guidelines for developing the guidelines. peptic ulcer disease. The guidelines were revised in 2015 and again in 2020. Of the 90 clinical questions (CQs) & Tomoari Kamada included in the previous guidelines, those with a clear [email protected] conclusion were considered background questions (BQs) 1 Department of Health Care Medicine, Kawasaki Medical and those requiring future research were considered future School General Medical Center, 2-6-1, Nakasange, Kita-ku, research questions (FRQs) in this revised guideline. Thus, Okayama 700-8505, Japan the revised guidelines consist of nine items (28 CQs and 2 Guidelines Committee for Creating and Evaluating the one FRQ), including, for the first time, epidemiology and ‘‘Evidence-Based Clinical Practice Guidelines for Peptic remnant gastric ulcer. Both epidemiology and conservative Ulcer,’’ the Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Bldg., 2-6-2 Shimbashi, Minato-ku, therapy for perforation and stenosis included only BQ. The Tokyo 105-0004, Japan prevention of hemorrhagic peptic ulcers in patients taking 123 http://guide.medlive.cn/ J Gastroenterol antithrombotic drugs and the treatment of ischemic duo- • Recommended that aspirin be continued for conditions denal ulcers have been added as a CQ and FRQ, at high risk for thromboembolic events. respectively. Recommendation: strong, 100% agreed, evidence level A literature search of Medline and the Cochrane Library B. was performed for data regarding the CQs published • Suggested to change antiplatelet agents to aspirin in between 1983 and October 2018, and the Igaku Chuo patients with conditions with a high risk of throm- Zasshi databases were searched for data published between boembolic events. 1983 and December 2018. The guidelines were developed Recommendation: weak, 100% agreed, evidence level using the Grading of Recommendations Assessment, D. Development and Evaluation (GRADE) system [1]. The • Suggested to suspend antiplatelet agents, except for in quality of evidence was graded as A (high), B (moderate), patients at high risk for thromboembolic events. C (low), and D (very low). Recommendation strength was Recommendation: weak, 100% agreed, evidence level indicated as either a ‘‘strong recommendation’’ or a ‘‘weak D. recommendation’’ The systematic review (SR) team con- • Recommended to suspend warfarin, if necessary, in ducted meta-analysis (MA) and decided the total strength endoscopic hemostasis patients. If warfarin is discon- of the evidence from A to D. The consensus was previously tinued, we suggest heparin or resuming warfarin as defined as 70% or more votes in agreement. soon as hemostasis is established. In Japan, incidence of cerebral infarction and myocar- Recommendation: strong, 100% agreed, evidence level dial infarction are increasing, and many patients undergo C. antithrombotic therapy including dual antiplatelet therapy • Suggested to resume DOACs early (within 1–2 days) (DAPT). In endoscopic clinical practice, focus has shifted after confirming endoscopic hemostasis. from the risk of gastrointestinal (GI) bleeding to throm- Recommendation: weak, 100% agreed, evidence level boembolism associated with the withdrawal of antithrom- D. botic therapy [2, 3]. In addition, for nearly 50 years, the • In patients receiving both antiplatelet agents and only oral anticoagulants were vitamin K antagonists warfarin, suggested to change antiplatelet agents to (warfarin); however, four non-vitamin K antagonist direct aspirin or cilostazol. Continue warfarin under a suit- oral anticoagulants (DOACs) are currently available. The able prothrombin time-international normalized ratio hemorrhagic gastric and duodenal ulcer section of the (PT-INR) or to change warfarin to heparin. revised guidelines emphasizes methods for the discontin- Recommendation: weak, 100% agreed, evidence level uation of antithrombotic therapy including DOACs and for D. the prevention of hemorrhagic ulcers in patients taking • In patients receiving dual antiplatelet agents, recom- anticoagulant and antiplatelet drugs, such as DAPT. mended that aspirin alone should be continued. Vonoprazan (VPZ) provides potent and long-lasting Recommendation: strong, 100% agreed, evidence level inhibition of gastric acid secretion, and its efficacy is, D. therefore, expected to be superior to that of proton pump Comment: The risk of re-bleeding due to continuing inhibitors (PPIs). Recent reports have shown that triple anticoagulant and/or antiplatelet agents and the risk of therapy including VPZ is as effective as first-line and thromboembolism associated with their withdrawal second-line therapies for the eradication of Helicobacter should be considered. One randomized controlled trial pylori [4]. Several reports have indicated that VPZ effec- (RCT) [8] reported significantly lower mortality in the tively heals peptic ulcers [5] and prevents the recurrence of continuing LDA group compared with the group that nonsteroidal anti-inflammatory drugs (NSAIDs) [6] and did not. However, clinical evidence is currently lacking low-dose aspirin (LDA)-related ulcers [7]. This revised to support the management of patients who receive version also emphasizes the clinical results of VPZ. antiplatelet agents excluding aspirin, warfarin, and DOACs with peptic ulcer bleeding (PUB). We consid- ered that these recommendations are based on expert Hemorrhagic gastric and duodenal ulcers opinions of the guidelines of Japan Gastroenterological Endoscopy, Asia–Pacific working group and European Non-endoscopic hemostatic therapy Society of Gastroenterological Endoscopy. It is neces- sary to collaborate closely with gastroenterologists and CQ-1 cardiologists as patients at high risk of thromboem- bolism with PUB could be unstable. Treatment of with patients with hemorrhagic peptic ulcers if they prescribed anticoagulants and/or antiplatelet agents? 123 http://guide.medlive.cn/ J Gastroenterol CQ-2 Prevention of hemorrhagic peptic ulcer Is interventional radiology (IVR) effective in patients CQ-4 undergoing refractory endoscopic treatment for hemor- rhagic peptic ulcers? What drugs are recommended for the prevention of hem- orrhagic ulcers in antithrombotic users? • In patients undergoing refractory endoscopic treatment for hemorrhagic peptic ulcers, interventional radiology • In DAPT, we recommend the combined use of PPIs to (IVR) is suggested due to its safety and effectiveness. prevent upper gastrointestinal bleeding (UGIB). Recommendation: weak, 100% agreed, evidence level Recommendation: strong, 100% agreed, evidence level C. A. Comment: The effectiveness of IVR with transcatheter • If taking warfarin, we suggest using PPIs to prevent arterial embolization