Evidence-based clinical practice guidelines for peptic ulcer disease 2026

Abstract

In 2026, the fourth edition of the evidence-based clinical practice guidelines for peptic ulcer disease by the Japanese Society of Gastroenterology (JSGE) was revised. These revised guidelines cover epidemiology, hemorrhagic peptic ulcers, Helicobacter pylori eradication therapy, non-eradication therapy, drug-induced ulcers, non-H. pylori, and nonsteroidal anti-inflammatory drug (NSAID) ulcers, remnant gastric ulcers, surgical treatment, and conservative therapy for perforation and stenosis. Although H. pylori infection and NSAIDs use remain two major causes of peptic ulcers, the prevalence and mortality rates of peptic ulcer have been declining due to the widespread use of eradication therapy and development of potent acid-inhibitory drugs in recent years. However, an increasing trend in idiopathic ulcers and ulcers caused by non-H. pylori Helicobacter (NHPH) infection has attracted attention. In this revised edition, therapeutic algorithms for the treatment of peptic ulcers based on H. pylori infection, low-dose aspirin (LDA) or NSAID use, ulcer history, and ulcer complications (e.g., hemorrhage) remain largely unchanged. This edition shows options for H. pylori eradication in various situations compared with the previous edition, and recommends the most effective regimens, regardless of Japanese insurance coverage. In addition, a new flowchart outlining the eradication treatment process has been presented. Compared with the previous version, the main changes in pharmacological treatment have been made: due to its acid-inhibitory characteristics compared with proton pump inhibitors and increased evidence of its efficacy and safety, vonoprazan has now been selected as the first-line treatment for peptic ulcers and NSAID- and LDA-induced ulcers.

Introduction

In Japan, the number of patients with peptic ulcers has been declining annually. By 2023, the number of patients with gastric ulcers had fallen to 194,000 per year, and the number of patients with duodenal ulcers had fallen to 20,000 per year—a tenfold and twentyfold decrease, respectively, compared with the number of patients 40 years ago (https://www.mhlw.go.jp/toukei/saikin/hw/kanja/23/index.html). This downward trend can be attributed to the expanded indications under the national health insurance system for H. pylori eradication therapy, introduction of vonoprazan (VPZ), and wider primary and secondary prevention for drug-induced peptic ulcer [1].

Since the Japanese Society of Gastroenterology (JSGE) developed evidence-based clinical practice guidelines for peptic ulcer disease in 2009, the guidelines have been revised three times, with this version being the fourth edition [2]. These guidelines consist of clinical questions (CQs), background questions (BQs), and future research questions (FRQs) that are organized into nine categories. The guidelines, which were revised in the Japanese version as the fourth edition, include 25 CQs, 15 BQs, and 7 FRQs, whereas the English version includes 25 CQs and 4 FRQs (all CQs and selected 4 FRQs).

A literature search of the MEDLINE, the Cochrane Library, and Igaku Chuo Zasshi databases was performed to identify studies related to the CQs published between 1983 and January 2025. Evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [3]. The quality of evidence was graded as A (high), B (moderate), C (low), and D (very low). Recommendation strength was classified as either ‘‘strong recommendation’’ or ‘‘weak recommendation.’’ The systematic review (SR) team conducted meta-analysis by mainly using randomized controlled trials (RCTs) and determined the overall strength of the evidence from A to D. A recommendation was classified as “strong recommendation” when ≥70% of votes supported a strong recommendation and as “weak recommendation” when ≥70% supported either a strong or weak recommendation.

Hemorrhagic gastric and duodenal ulcers

Endoscopic hemostatic therapy

CQ-1

What acid-suppressive agents are useful after endoscopic hemostasis for hemorrhagic peptic ulcers?

• Proton-pump inhibitors (PPIs) are recommended after endoscopic hemostasis for hemorrhagic peptic ulcers.

Recommendation: strong (100% agreed for strong recommendation), evidence level: A.

• VPZ is suggested after endoscopic hemostasis for hemorrhagic peptic ulcers.

Recommendation: weak (16.7% agreed for strong, 83.3% agreed for weak recommendation), evidence level: A.

Comments: As stated in the 2020 guidelines [2], PPI administration after endoscopic hemostasis reduces rebleeding rates, transfusion requirements, the duration of hospitalization, and need for surgery.

Previous meta-analyses showed similar efficacy across PPI doses and administration routes [4–6].

Two RCTs comparing VPZ 40 mg with high-dose continuous PPI (pantoprazole) infusion—an 80 mg bolus followed by continuous infusion at 8 mg/hour for 72 h—have been reported [7, 8]. No differences were observed in rebleeding rates or outcomes such as mortality, need for additional treatment, or hospital stay. VPZ may prevent rebleeding similarly to PPI therapy, but these findings require caution because both drugs were used at high doses.

Helicobacter pylori eradication therapy

When H. pylori infection is treated with eradication therapy, the regimen should maximize eradication and minimize adverse events. The prevalence of drug-resistant strains varies by region and treatment period [9].

A meta-analysis has reported that pretreatment with acid-inhibitory drugs does not affect the success of eradication therapy [10]. Therefore, although acid-inhibitory drugs are recommended after endoscopic hemostasis for hemorrhagic peptic ulcers, it is appropriate to perform H. pylori eradication therapy early following endoscopic hemostasis, irrespective of during PPI administration.

First-line eradication therapy

CQ-2

Does VPZ improve eradication rates compared with PPIs?

• Since a triple regimen containing VPZ achieves a higher eradication rate than regimens using PPIs in the first-line eradication therapy, the use of VPZ is recommended.

Recommendation: strong (100% agreed for strong recommendation), evidence level: A.

• Since the eradication rates and incidence of adverse events are comparable between the VPZ–amoxicillin (AMPC)–metronidazole (MNZ) regimen and the PPI–AMPC–MNZ regimen during second-line eradication therapy, either a PPI or VPZ is recommended when using AMPC-MNZ.

Recommendation: weak (66.7% agreed for strong, 33.3% agreed for weak recommendation), evidence level: B.

Comment: Potent acid inhibition is important for successful eradication [11]. VPZ inhibits acid secretion more rapidly and potently than PPIs [12]. A meta-analysis of seven RCTs [13, 14] found that VPZ therapy achieved a higher eradication rate than PPI therapy, particularly in patients infected with clarithromycin (CAM)-resistant strains (Fig. 1). For second-line eradication therapy [15], eradication rates were comparable between the VPZ–AMPC–MNZ and PPI–AMPC–MNZ regimens.

Fig. 1.

Comparison of eradication rates in the ITT analysis between VPZ-containing and PPI-containing triple regimens in first-line eradication therapy using RCTs. CI confidence interval, DL DerSimonian–Laird, ITT intention-to-treat, M-H Mantel–Haenszel, PPI proton pump inhibitor, RCTs randomized controlled trials, VPZ vonoprazan

Recommended regimens:

• First-line eradication therapy: VPZ-containing eradication regimen.

• Second-line eradication therapy: PPI (standard dose) or VPZ (20 mg) + AMPC (750 mg) + MNZ (250 mg) twice daily (bid) for 1 week.

CQ-3

Is CAM susceptibility testing recommended before first-line eradication therapy?

• If possible, CAM susceptibility testing should be performed before first-line eradication therapy, and the regimen expected to achieve the highest eradication rate should be selected.

Recommendation: strong (100% agreed for strong recommendation), evidence level: A.

Comments: CAM resistance is a critical factor influencing the outcomes of H. pylori eradication therapy. In Japan, the CAM-resistance rate remains high at 35.5% [16]. A meta-analysis by Ma et al. [17] confirmed that susceptibility-guided individualized regimens achieve significantly higher eradication rates than empirical regimens. Nucleic acid amplification tests can detect 23S rRNA mutations from gastric fluid rapidly and accurately, enabling rapid tailored therapy [18].

CQ-4

Which regimen is recommended when CAM susceptibility testing has been performed?

• For CAM-susceptible strains, VPZ–AMPC–CAM therapy is recommended.

• Recommendation: strong (100% agreed for strong recommendation), evidence level: A.

• For CAM-resistant strains, PPI- or VPZ-based therapy with AMPC and MNZ is recommended.

• Recommendation: strong (91.7% agreed for strong recommendation); evidence level: A.

Comments: In Japan, the standard first-line H. pylori eradication regimen consisting of VPZ–AMPC–CAM achieves an eradication rate exceeding 90%; however, its efficacy is significantly reduced in patients infected with CAM-resistant strains [13]. A meta-analysis of RCTs demonstrated that CAM susceptibility-guided therapy significantly improved eradication rates [19]. Therefore, VPZ–AMPC–CAM regimen is recommended when CAM susceptibility is confirmed.

In the same meta-analysis [19], PPI–AMPC–MNZ, high-dose PPI–AMPC, and PPI–AMPC–levofloxacin (LVFX) were evaluated as susceptibility-guided treatment regimens for patients with CAM-resistant strains in randomized controlled trials. PPI–AMPC–MNZ is recommended based on consistent evidence of efficacy from multiple RCTs [20–23].

Recommended regimens:

• CAM-susceptible strains: VPZ (20 mg) + AMPC (750 mg) + CAM (200 mg) bid for 1 week.

• CAM-resistant strains: PPI (standard dose) or VPZ (20 mg) + AMPC (750 mg) + MNZ (250 mg) bid for 1 week.

CQ-5

Which regimen is recommended if CAM susceptibility testing is unavailable for first-line therapy?

• When CAM susceptibility testing is unavailable for first-line therapy, either VPZ–AMPC–CAM or PPI–AMPC–MNZ is recommended.

Recommendation: strong (100% agreed for strong recommendation), evidence level: A.

Comments: In the meta-analysis by Liu et al. [24], the VPZ–AMPC–CAM regimen demonstrated a higher eradication rate than the PPI–AMPC–CAM regimen. In areas with low MNZ and high CAM resistance, such as Japan, the PPI–AMPC–MNZ regimen was superior to the PPI–AMPC–CAM regimen [25]. However, evidence regarding the efficacy of the VPZ–AMPC–MNZ regimen remains insufficient. Therefore, VPZ–AMPC–CAM is recommended and is covered by Japanese health insurance.

Recommended regimens:

• VPZ (20 mg) + AMPC (750 mg) + CAM (200 mg) bid for 1 week.

• PPI (standard dose) + AMPC (750 mg) + MNZ (250 mg) bid for 1 week.

CQ-6

Should dual therapy with VPZ and AMPC be recommended?

• Since the VPZ-AMPC regimen has a lower eradication rate than the VPZ–AMPC–CAM regimen as first-line therapy, we recommend against selecting the dual regimen as the first-line therapy.

Recommendation: weak (33.3% agreed for strong, 66.7% agreed for weak recommendation), evidence level: A.

Comment: The prevalence of CAM-resistant strains in Japan has reached 35–40% [16]. Recently, international guidelines recommend VPZ–AMPC dual therapy as a candidate regimen [9]. A meta-analysis of seven RCTs [26, 27] found that VPZ–AMPC dual regimen had a significantly lower rate than the triple regimen (Fig. 2). There are no reports of RCTs evaluating the efficacy and safety of VPZ–AMPC therapy as second-line or third-line treatment. When dual therapy is selected, AMPC dosing frequency should be increased to maintain therapeutic plasma concentrations [28].

Fig. 2.

Comparison of eradication rates in the ITT analysis between VPZ–AMPC therapy and VPZ–AMPC–CAM therapy in first-line eradication therapy using RCTs. AMPC amoxicillin, CAM clarithromycin, CI confidence interval, DL DerSimonian–Laird, ITT intention-to-treat, M-H, Mantel–Haenszel, RCTs randomized controlled trials, VA VPZ plus AMPC, VAC VPZ plus AMPC and CAM, VPZ vonoprazan

Recommended regimens:

• First-line eradication therapy: VPZ (20 mg) + AMPC (750 mg) + CAM (200 mg) bid for 1 week.

Second-line eradication therapy

CQ-7

Which regimen is recommended for second-line H. pylori eradication therapy after use of CAM in first-line therapy?

• Triple therapy with a PPI or VPZ–AMPC–MNZ for 7 days is recommended.

Recommendation: strong (91.7% agreed for strong, 8.3% agreed for weak recommendation), evidence level: B.

Comment: According to the only small-scale RCT, 7-day VPZ–AMPC–MNZ showed eradication rates comparable to rabeprazole-based therapy [15]. A meta-analysis of 16 observational studies reported that the VPZ group had a higher eradication rate than the PPI group (odds ratio [OR]: 1.51, 95% CI: 1.27–1.81, p < 0.001) [29]. Regarding safety, no clear difference was observed between VPZ and PPI in RCTs [15]. Overall, VPZ-based second-line therapy showed similar efficacy and safety to standard PPI therapy, but evidence for clear superiority remains limited.

Recommended regimens:

• PPI (standard dose) or VPZ (20 mg) + AMPC (750 mg) + MNZ (250 mg) bid for 1 week.

Third-line eradication therapy

CQ-8

Which regimen is recommended after the failure of MNZ-based second-line eradication therapy?

• Triple therapy with a PPI or VPZ–AMPC–sitafloxacin (STFX) is suggested (not covered by the Japanese insurance system).

Recommendation: weak (33.3% agreed for strong, 66.7% agreed for weak recommendation), evidence level: B.

Comments: We conducted a network meta-analysis using RCTs evaluating five regimens [30–34] that met our inclusion criteria: (1) PPI–AMPC–STFX, (2) VPZ–AMPC–STFX, (3) PPI–MNZ–STFX, (4) PPI–AMPC, and (5) PPI–AMPC–LVFX. Compared with PPI–AMPC–STFX, VPZ–AMPC–STFX showed the largest effect size, although the difference was not statistically significant.

Although there has been an increase in antimicrobial agent-resistant H. pylori strain in clinical practice, the introduction of VPZ and selection of appropriate drugs has led to a decrease in the number of patients where eradication is not achieved by the second-line eradication therapy. Among patients with failed second-line eradication, when assessed using the urea breath test (UBT), false-positive results may occur due to the influence of urease-producing non-H. pylori bacteria, particularly in conditions such as autoimmune gastritis with severe atrophy. Therefore, careful consideration for needs of additional therapy is required before initiating third-line or subsequent rescue salvage therapies.

Recommended regimens:

• VPZ (20 mg) or PPI (standard dose) + AMPC (750 mg) + STFXZ (100 mg) bid for 1 week.

FRQ-1

What is “endless eradication”? Are there any precautions in these cases?

“Endless eradication” refers to the medical practice of adding unnecessary eradication treatments despite successful eradication therapy due to false-positive results on the UBT. This is often seen in cases of autoimmune gastritis and requires careful attention.

Comment: The term “endless eradication” is a concept reported by Furuta et al. [35]. After successful eradication, reduced gastric acid secretion may allow urease-producing non-H. pylori bacteria to colonize the stomach, causing weakly positive ¹³C-UBT results and unnecessary repeated treatment. In cases of autoimmune gastritis, gastric acid secretion remains reduced even after successful eradication, increasing the risk of getting endless eradication. Furuta et al. reported that 18% of cases in which eradication therapy was unsuccessful two or more times were autoimmune gastritis [35].

Others

CQ-9

Which regimen is recommended for patients with penicillin allergy?

• A regimen combining VPZ or PPI–MNZ–STFX, or VPZ–MNZ–CAM, is suggested.

Recommendation: weak (16.7% agreed for strong, 83.3% agreed for weak recommendation), evidence level: D.

Comments: For patients with penicillin allergy, RCTs using tetracycline or bismuth have been reported overseas. Evidence in Japan is limited to small observational studies; however, 7-day VPZ-based regimens (VPZ–MNZ–STFX and VPZ–MNZ–CAM) showed high eradication rates [36–38]. A 7-day PPI–MNZ–STFX regimen was also effective, whereas PPI–MNZ–CAM showed poor efficacy [39, 40].

Recommended regimens:

• VPZ (20 mg) or PPI (standard dose) + MNZ (250 mg) + STFX (100 mg) bid for 1 week.

• VPZ (20 mg) + MNZ (250 mg) + CAM (200 mg) bid for 1 week.

CQ-10

Which regimen is recommended for patients with liver dysfunction?

• For first-line eradication, a regimen combining PPI–AMPC–CAM or MNZ is suggested. For second-line eradication, a regimen combining PPI–AMPC–MNZ is suggested.

Recommendation: weak (25.0% agreed for strong, 75.0% agreed for weak recommendation), evidence level: C.

Comments: No clinical trials have directly compared eradication regimens in patients with liver dysfunction. However, a meta-analysis of three observational studies comparing patients with hepatic impairment to healthy individuals demonstrated that eradication rates were not significantly lower in the former group [41–43]. Adverse-event rates also did not increase significantly. Although evidence is limited, standard first- and second-line regimens may be used with careful monitoring of hepatic function and drug metabolism.

Recommended regimens:

• First-line eradication therapy: PPI (standard dose) + AMPC (750 mg) + CAM (200 mg) or MNZ (250 mg) bid for 1 week.

• Second-line eradication therapy: PPI (standard dose) + AMPC (750 mg) + MNZ (250 mg) bid for 1 week.

CQ-11

Which regimen is recommended for patients with renal dysfunction or those on hemodialysis?

• For non-dialysis patients with renal impairment, an AMPC-free regimen, such as a combination of a PPI–CAM–MNZ, is suggested when the benefits of eradication are considered significant.

Recommendation: weak (16.7% agreed for strong, 83.3% agreed for weak recommendation), evidence level: C.

• For patients on hemodialysis, we suggest dose-reduced regimens such as a PPI–AMPC–MNZ or PPI–AMPC–CAM. Precise dosage adjustments should be determined in consultation with renal specialists.

Recommendation: weak (33.0% agreed for strong, 66.7% agreed for weak recommendation), evidence level: C.

Comments: In non-dialysis patients with renal impairment, one randomized controlled trial demonstrated that a regimen of lansoprazole–CAM–MNZ was more effective and safer than AMPC-based triple therapy [44]. For patients on hemodialysis, a meta-analysis of observational studies confirmed that dose-reduced regimens achieve eradication rates equivalent to those observed in healthy individuals (Fig. 3) [45–48], while minimizing minor adverse events, including dysgeusia or abdominal distension.

Fig. 3.

Eradication rates in healthy participants receiving standard doses and hemodialysis patients receiving reduced-dose regimens in observational studies. CI confidence interval, HD hemodialysis, HKSJ Hartung–Knapp–Sidik–Jonkman, IV inverse variance, REML restricted maximum likelihood

Recommended regimens:

• Non-hemodialysis patients: PPI + CAM + MNZ or non-AMPC regimen.

• Hemodialysis patients: PPI + AMPC (reduced) + CAM or MNZ.

  • AMPC dose: 250–375 mg per dose, bid.
  • Hemodialysis in the morning: post-hemodialysis and evening time, bid.
  • Hemodialysis in the evening: morning time and post-hemodialysis, bid or post-hemodialysis (500 mg) once daily (oid).

CQ-12

What is the upper age limit for eradication therapy in older patients with peptic ulcer disease?

• Eradication therapy is suggested for older patients with peptic ulcer disease regardless of age because it may help prevent ulcer recurrence in the short term.

Recommendation: weak (33.3% agreed for strong, 66.7% agreed for weak recommendation), evidence level: D.

Comments: In an observational study, among patients aged ≥65 years who underwent eradication therapy for peptic ulcer disease, successful eradication reduced 1-year ulcer recurrence [49]. Several studies reported no difference in eradication rates between older and younger patients [50]. Although age ≥80 years was reported as an independent factor for eradication failure, this difference disappeared after second-line therapy [51]. Adverse events did not significantly increase, suggesting good tolerability in considerably older patients [52]. Therefore, eradication therapy in older patients is suggested for preventing ulcer recurrence, with careful consideration of comorbidities.

FRQ-2

How does H. pylori eradication therapy affect gut microbiota?

• Eradication therapy temporarily reduces the diversity of the gut microbiota, but it gradually recovers over time. However, the time it takes for diversity to recover varies depending on factors such as the dosages and duration of the combined acid suppressants and antibiotics.

Comments: Eradication therapy temporarily reduces gut microbiota diversity, but recovery typically occurs over time. A meta-analysis by Ye et al. [53] indicated a short-term decrease in α-diversity, though long-term data remained inconclusive due to variables such as antibiotic types, dosages, and treatment duration. In Japan, Horii et al. [54] found that VPZ–AMPC–CAM significantly reduced α-diversity at 1 and 8 weeks, whereas VPZ–AMPC showed no significant change.

General findings from multiple RCTs [55, 56] suggest that diversity decreases within 2 weeks, trends toward recovery between 8 and 12 weeks, and is largely restored by 1 year. Furthermore, Bai et al. [57] highlighted that probiotic supplementation helps prevent dysbiosis and mitigates gastrointestinal side effects. Further research is needed to clarify the long-term effects of eradication therapy on the gut microbiota.

Drug-induced ulcers

Nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer

Prevention

CQ-13

Is preventive therapy for NSAID-induced ulcers necessary in patients with no history of ulcers?

• PPIs are recommended for the prevention of NSAID-induced ulcers, even in patients without a history of peptic ulcers.

Recommendation: strong (100% agreed for strong, recommendation), evidence: level A.

(PPIs are not covered by Japanese health insurance for primary prevention of ulcers in patients taking NSAIDs)

Comment: In patients receiving NSAID therapy for more than 3 months, prostaglandin (PG) analogs [58], PPIs [59], and high-dose H₂RAs [60] have shown preventive efficacy. Scally et al. [61] showed that PPIs had greater protective effects than H₂RAs or PG analogs against peptic ulcers and further bleeding; therefore, PPIs are suggested as a first-line therapy.

CQ-14

What measures should be taken to prevent ulcer recurrence in patients with a history of peptic ulcers or bleeding ulcers who require NSAID therapy?

• VPZ or PPIs are recommended and VPZ is suggested for the prevention of ulcers in patients with a history of ulcers.

Recommendation: strong (100% agreed for strong recommendation), evidence: level B.

• Concomitant administration of a selective cyclooxygenase (COX)− 2 inhibitor with a VPZ or PPI is recommended for preventing recurrence of bleeding NSAID-induced ulcers in patients with a history of bleeding ulcers.

Recommendation: weak (33.3% agreed for strong, 66.7% agreed for weak recommendation), evidence level: B.

Comment: Although PG analogs [62] are effective in high-risk patients with a history of peptic ulcers, patient dropout owing to diarrhea is common.

Studies have shown that PPIs were superior to placebo in reducing ulcer recurrence during long-term NSAID therapy [63, 64]. Therefore, PPIs are recommended as first-line therapy (Fig. 4).

Fig. 4.

Meta-analysis of the preventive effect of secondary prevention of NSAIDs-induced ulcers. CI confidence interval, Esome esomeprazole, Lanso lansoprazole, M-H Mantel–Haenszel, NSAID nonsteroidal anti-inflammatory drug, PPI proton pump inhibitor

Chan et al. suggested that combination therapy with a selective COX-2 inhibitor and PPI was more effective than a selective COX-2 inhibitor alone for preventing ulcer bleeding in high-risk patients [65].

Mizokami et al. [66] reported that VPZ was not inferior to PPIs, indicating that VPZ can be recommended for the secondary prevention of NSAID-induced peptic ulcer similar to PPIs. Prospective real-world data also support VPZ efficacy and safety during long-term NSAIDs therapy [67].

CQ-15

How should NSAID-induced ulcers be prevented in patients receiving concomitant NSAIDs and antithrombotic agents and/or glucocorticoids, and in those with severe comorbidities?

• In patients receiving NSAIDs in combination with glucocorticoids and/or antithrombotic drugs, the use of a COX-2 inhibitor is recommended for ulcer prevention.

Recommendation: strong (91.7% agreed for strong recommendation), evidence: level B.

• In patients with severe comorbidities, the use of VPZ or PPIs is recommended for the prevention of NSAID-induced ulcers.

Recommendation: strong (83.3% agreed for strong recommendation), evidence: level B.

Comment: Concomitant use of nonselective NSAIDs or low-dose aspirin (LDA), but not selective COX-2 inhibitors, with corticosteroids or anticoagulants increases the risk of upper gastrointestinal bleeding (UGIB), suggesting that selective COX-2 inhibitors may be associated with a lower risk of UGIB [68]. In high-risk patients with comorbidities, PPIs reduced a risk of serious NSAID-related ulcer complications [69]. VPZ is also effective in preventing ulcer recurrence during long-term NSAID therapy in patients with comorbidities [67].

LDA-induced ulcer

Treatment

CQ-16

How should LDA-related peptic ulcer be treated?

• Concomitant use of a PPI with continuous LDA therapy is recommended for LDA-related peptic ulcer.

Recommendation: strong (100% agreed for strong recommendation); evidence: level A.

Comment: For patients with a history of LDA-related peptic ulcer bleeding, continuous LDA therapy with a PPI after endoscopic hemostasis reduced cardiovascular mortality without increasing recurrent bleeding [70]. The peptic ulcer healing rate was comparable between a PPI alone and LDA combined with a PPI [71].

Prevention

CQ-17

In patients without a history of peptic ulcer or peptic ulcer bleeding, is the prevention of LDA-related peptic ulcer necessary?

• It is necessary to prevent the development of ulcers because peptic ulcer bleeding in patients taking LDA affects their prognosis.

• A PPI is recommended for the primary prevention of LDA-related peptic ulcer in patients without a history of peptic ulcer or peptic ulcer bleeding.

Recommendation: strong (100% agreed for strong recommendation), evidence level: A.

• In patients receiving dual-antiplatelet drug therapy (DAPT), a PPI or VPZ is recommended for the primary prevention of UGIB in those without a history of peptic ulcer or peptic ulcer bleeding. (Not covered by Japanese insurance except for cases with a history of ulcers)

Recommendation: strong (91.7% agreed for strong recommendation), evidence level: A.

(PPI and VPZ are not covered by Japanese insurance for primary prevention of ulcers in patients taking LDA)

Comment: A meta-analysis of the efficacy of PPIs in LDA-treated patients showed that a PPI reduced the risk of peptic ulcer occurrence compared with placebo [72–74] (Fig. 5A).

Fig. 5.

Efficacy of a PPI in LDA-related peptic ulcer without a history of peptic ulcer or peptic ulcer bleeding (A). A PPI showed a reduction in the risk of peptic ulcer development compared with placebo. Analysis of UGIB in patients receiving DAPT (B). A PPI significantly prevented the incidence of UGIB compared with an H₂RA. CI confidence interval, DAPT dual-antiplatelet therapy, H2RA histamine H2-receptor antagonist, LDA low-dose aspirin, M-H Mantel–Haenszel, PPI proton pump inhibitor, UGIB upper gastrointestinal bleeding

In DAPT, a meta-analysis of three studies [75–77] with 95%–100% of patients without a history of peptic ulcer showed that PPI significantly prevented UGIB compared with H₂RA (RR: 0.21, 95% CI 0.08–0.54, p = 0.001) (Fig. 5B).

UGIB incidence did not differ significantly between VPZ and PPI in patients receiving LDA and thienopyridine antiplatelet agents [78].

CQ-18

How to prevent recurrence of LDA-related peptic ulcer in patients with a history of peptic ulcers?

• A PPI or VPZ is recommended for reducing the recurrence rate of LDA-related peptic ulcer.

Recommendation: strong (100% agreed for strong recommendation), evidence: level A.

Comment: A meta-analysis of four RCTs investigating the efficacy of PPIs in reducing the rate of LDA-related peptic ulcer recurrence showed that a PPI reduced the rate of peptic ulcer recurrence compared with placebo or gefarnate [79–82] (Fig. 6A).

Fig. 6.

Peptic ulcer recurrence rate in patients continuing LDA with a history of peptic ulcers (A). A PPI reduced the rate of peptic ulcer recurrence compared with placebo or gefarnate. Peptic ulcer recurrence rate in patients continuing LDA with a history of peptic ulcers (B). A PPI significantly reduced peptic ulcer recurrence compared with an H₂RA. CI confidence interval, H₂RA histamine H2-receptor antagonist, LDA low-dose aspirin, M-H Mantel–Haenszel, PPI proton pump inhibitor

In a meta-analysis of three studies comparing PPIs and H₂RAs [83–85], a PPI reduced ulcer recurrence compared with an H₂RA (Fig. 6B).

When LDA-induced peptic ulcer recurrence was compared between VPZ and lansoprazole, VPZ 10 mg significantly inhibited recurrence compared with lansoprazole [86].

CQ-19

How to prevent rebleeding in patients taking LDA with a history of UGIB?

• A PPI is recommended to prevent recurrent UGIB in patients receiving LDA. In H. pylori-positive patients, a PPI is recommended after H. pylori eradication.

Recommendation: strong (100% agreed for strong recommendation), evidence: level B.

(PPI is not covered by Japanese insurance for secondary prevention of peptic ulcer bleeding in patients taking LDA)

Comment: The frequency of recurrence of LDA-related peptic ulcer bleeding was decreased by lansoprazole after H. pylori eradication [87]. In patients after H. pylori eradication or in H. pylori-negative patients with a history of peptic ulcer bleeding, a PPI in addition to continuous LDA treatment prevented UGIB compared with an H₂RA [83]. Therefore, a PPI is recommended to prevent UGIB in patients taking LDA who are at risk of cardiovascular events.

CQ-20

What medications are useful in preventing ulcer recurrence when NSAIDs are used in patients taking LDA?

• Celecoxib with concomitant use of a PPI is recommended for the prevention of recurrence of peptic ulcers during NSAID treatment in patients taking LDA.

Recommendation: strong (91.7% agreed for strong recommendation), evidence: level A.

Comment: In patients with a history of peptic ulcer who are receiving combinations of NSAIDs and LDA, concomitant use of a PPI reduced the risk of gastric ulcer recurrence [88, 89]. Furthermore, patients receiving a COX-2 inhibitor plus LDA had fewer gastrointestinal events than those receiving a nonselective NSAID plus LDA [90, 91].

Anticoagulants

CQ-21

What strategies are recommended to prevent UGIB in patients receiving anticoagulant therapy?

• In patients taking anticoagulants who are at high risk of bleeding, concomitant use of a PPI is suggested to prevent peptic ulcer bleeding.

Recommendation: weak (25.0% agreed for strong, 75.0% agreed for weak recommendation), evidence level: C.

Comments: In patients receiving anticoagulant therapy, concomitant use of PPIs significantly reduces the risk of UGIB. In particular, among patients with a history of UGIB, PPI co-therapy significantly reduced the risk of rebleeding [92].

Regarding individual anticoagulants, reduced UGIB risk with PPI co-therapy has been reported for warfarin and edoxaban [74, 93].

European guidelines also recommend PPI co-therapy for high-risk patients with a history of UGIB who require continued anticoagulant therapy [94].

PPI/P-CAB-related adverse events

FRQ-3

Does long-term use of PPIs or VPZ lead to the development of gastric neoplasms or other mucosal lesions?

• Long-term use of PPIs or VPZ may be associated with the development of various gastric mucosal lesions; therefore, prolonged use should be undertaken with caution.

Comments: Long-term use of PPIs and VPZ may be associated with various gastric mucosal lesions, including benign and malignant tumors, and other mucosal changes. Proposed mechanisms include hypergastrinemia, gastric microbiota alterations, and direct drug effects. Meta-analyses [95] and prospective studies [96] have demonstrated an increased risk of fundic gland polyps associated with long-term PPI use, with similar findings reported for VPZ [97]. PPI/VPZ-associated gastric neuroendocrine tumors appear rare, with evidence limited mainly to case reports. Regarding gastric cancer, observational studies report inconsistent results [98, 99]; confounding factors and reverse causality remain major concerns. Thus, causality has not been established. Nevertheless, long-term PPI/VPZ therapy should be prescribed cautiously, and periodic endoscopy should be considered during prolonged therapy.

Non-H. pylori, non-NSAIDs ulcer

CQ-22

How should initial treatment for non-H. pylori, non-NSAID peptic ulcers be provided?

• We suggest VPZ or a PPI for the initial treatment of non-H. pylori, non-NSAID peptic ulcers.

Recommendation: weak (58.3% agreed for strong, 41.7% agreed for weak recommendation), evidence level: C.

Comments: Non-H. pylori, non-NSAID peptic ulcers comprise a heterogeneous group of conditions, including Crohn’s disease, gastrin-producing tumors, specific viral or bacterial infections, eosinophilic gastroenteritis, severe physical or psychological stress, and cancer immunotherapy-associated gastritis. Most cases are idiopathic and have a multifactorial pathogenesis in which gastric acid delays mucosal healing [100]. Consequently, potent acid suppression with either VPZ or a PPI is suggested as first-line therapy, although direct head-to-head RCTs are currently lacking. VPZ and PPIs differ in their mechanisms of acid suppression [101]. PPIs require acid-dependent activation and irreversibly inhibit activated H+/K+-ATPase, whereas VPZ is a potassium-competitive acid blocker that rapidly inhibits H+/K+-ATPase without requiring acid activation [101, 102]. VPZ provides more rapid, potent, and sustained acid suppression and is less affected by CYP2C19 polymorphisms than conventional PPIs [12]. However, whether these pharmacological advantages translate into superior healing or recurrence prevention in non-H. pylori, non-NSAID peptic ulcers remains unproven. Observational studies have reported healing rates of approximately 70–90% [103–105], with variability likely related to dose and treatment duration [104]. Idiopathic ulcers have lower healing rates than H. pylori-associated ulcers, indicating their refractory nature [103, 105].

CQ-23

How should the prevention of recurrence be managed after healing of non-H. pylori, non-NSAID peptic ulcers?

• We suggest a PPI or an H₂RA for the prevention of recurrence after the healing of non-H. pylori, non-NSAID peptic ulcers.

Recommendation: weak (8.3% agreed for strong, 91.7% agreed for weak recommendation), evidence level: C.

Comments: Longitudinal data indicate that untreated non-H. pylori, non-NSAID peptic ulcers carry a remarkably high risk of relapse compared with H. pylori ulcers [106–108]. Specifically, cumulative recurrence rates without maintenance therapy reach 13.4% at 12 months [106], 13.9% at 18 months in Japan [103], and 16.0–42.3% over long-term follow-up of 5–7 years [107, 108]. Furthermore, non-H. pylori, non-NSAID peptic ulcers show significantly higher recurrence rates than with H. pylori ulcers after successful eradication [103, 107]. A single double-blind RCT demonstrated that a PPI and a H₂RA effectively reduced recurrent hemorrhage over 24 months, with no statistically significant difference in efficacy [109]. Moreover, clinical data on potassium-competitive acid blockers, including VPZ, are currently unavailable.

CQ-24

How should the treatment of post-bulbar or descending duodenal ulcers be managed?

• As conservative therapy, we suggest VPZ, a PPI, or misoprostol. In refractory cases, we also suggest strategies to reduce mucosal exposure to bile or pancreatic secretions.

Recommendation: weak (91.7% agreed for weak recommendation), evidence level: D.

Comments: Post-bulbar duodenal ulcers are rare lesions for which underlying ischemia or malperfusion has been suggested as a major pathological factor [110, 111]. Retrospective cohort studies demonstrated that patients with post-bulbar ulcers have significantly higher rates of severe comorbidities, including advanced age and maintenance dialysis, compared with those with bulbar ulcers [112, 113]. Conservative management generally consists of acid suppression or misoprostol for mucosal protection [113]. In refractory cases, endoscopic biliary or pancreatic duct drainage has been reported to facilitate healing [114]. Because this condition may be associated with a poor prognosis, underlying vascular disorders, such as thrombosis or severe arterial stenosis, should be thoroughly investigated. Interventional radiology or surgery should be considered if clinical exacerbation occurs despite conservative therapy.

FRQ-4

What is the frequency of peptic ulcers associated with non-H. pylori Helicobacter infection (NHPH)?

• NHPH infection has been detected in some patients with H. pylori-negative peptic ulcers, but its frequency remains uncertain.

Comments: Studies from Japan, Belgium, and Iran have reported NHPH infection in a subset of patients with peptic ulcer [115–117]. In a Japanese study of H. pylori-negative gastroduodenal diseases, NHPH infection was identified in 20.8% of patients, including several with peptic ulcers [115]. However, the true frequency remains unclear because general-population prevalence and optimal diagnostic methods remain uncertain [118]. A multicenter prospective study in Japan reported an NHPH prevalence of 3.0% among health checkup participants [119]. Further development of reliable diagnostic methods [120] is needed to better define the frequency of NHPH-associated peptic ulcers.

Remnant gastric ulcers

CQ-25

How should remnant gastric ulcers be treated?

• PPIs are recommended for the treatment of remnant gastric ulcers.

Recommendation: strong (75.0% agreed for strong recommendation), evidence level: C.

Comments: Medical therapy is the first-line treatment for remnant gastric ulcers. In an open-label comparative study, omeprazole showed superior early healing compared with cimetidine, sucralfate, colloidal bismuth, and misoprostol, although differences were no longer significant by 6 weeks. No evidence has shown that VPZ is superior to PPIs; thus, PPIs are recommended, and VPZ may also be considered because of its potent acid-suppressive effect [121].

No RCTs have demonstrated the efficacy of H. pylori eradication therapy for remnant gastric ulcers, and observational studies have shown no clear correlation [122–125].

Therapeutic algorithm

There are no major changes for therapeutic algorithms in the treatment of peptic ulcers compared with the previous version (Fig. 7A). If complications (e.g., perforation, stenosis, and hemorrhage) are present, they are addressed prior to treatment of the ulcer by surgical and endoscopic treatments and interventional radiology (IVR). When no complications are present, medical therapy is provided immediately.

Fig. 7.

Algorithm for the treatment of peptic ulcer disease. Complicated ulcers are managed first: perforation or stenosis by surgery or conservative therapy, and hemorrhagic ulcers by endoscopic hemostasis, followed by surgery or IVR if hemostasis fails. Uncomplicated ulcers receive immediate medical therapy (A). NSAIDs are discontinued, and anti-ulcer therapy is provided for the treatment of NSAID-induced ulcers. If NSAIDs cannot be discontinued, the ulcer should be treated with VPZ or a PPI. LDA-related ulcers should be treated with a PPI without discontinuing LDA whenever possible. Patients with peptic ulcers who do not use NSAIDs or LDA should be tested for H. pylori. Eradication therapy is recommended for patients who are H. pylori positive. A remnant gastric ulcer is treated with a PPI, and an idiopathic ulcer is treated with a VPZ or a PPI followed by maintenance therapy with a PPI or an H₂RA (B). 1 Discontinuation of LDA should be avoided as much as possible. 2 Contraindications. Administration should be considered only when discontinuation is not possible. 3 Consider the possibility of an idiopathic ulcer. CQ clinical question, H₂RA histamine H2-receptor antagonist, H. pylori Helicobacter pylori, IPU idiopathic peptic ulcer, IVR interventional radiology, LDA low-dose aspirin, NSAID nonsteroidal anti-inflammatory drug, PPI proton pump inhibitor, VPZ vonoprazan

NSAIDs are discontinued, and a PPI or VPZ is provided for NSAID-induced ulcers. If NSAIDs cannot be discontinued, the ulcer should be treated with a PPI or VPZ. Eradication therapy is recommended for patients with H. pylori infection. For patients without an indication for eradication, non-eradication therapy is provided followed by maintenance therapy to prevent ulcer recurrence. A remnant ulcer is treated with a PPI, and an idiopathic ulcer is treated with a PPI or VPZ (Fig. 7B).

Regardless of age, individuals with H. pylori infection are candidates for eradication therapy, and it is recommended that susceptibility testing for antimicrobial agents be performed prior to treatment (Fig. 8). Regardless of Japanese insurance coverage, Fig. 8 outlines the recommended regimens based on evidence-based medicine (EBM) for various clinical settings, such as first-line, second-line, and third-line therapies, and specific situations (penicillin allergy, and liver and renal dysfunctions).

Fig. 8.

Algorithm for eradication therapy for H. pylori infection. Eradication therapy is recommended for all H. pylori-positive individuals, regardless of age. If possible, CAM susceptibility testing should be performed before first-line therapy. If first-line therapy fails, second-line therapy is indicated. Specialist consultation is essential for third-line therapy and special clinical situations. MNZ-based first-line regimens are not covered by Japanese health insurance and should be used cautiously because of resistance and safety concerns. Regimens are not covered by the Japanese health insurance system. AMPC amoxicillin, CAM clarithromycin, CQ clinical question, FRQ future research question, H. pylori Helicobacter pylori, MNZ metronidazole, PPI proton pump inhibitor, STFX sitafloxacin, VPZ vonoprazan

In the algorithm for preventing NSAID-induced ulcers, prevention varies depending on whether LDA is being used concomitantly, whether there is a history of ulcers, and whether there is a history of bleeding ulcers (Fig. 9). For ulcer prevention, a PPI or VPZ should be selected appropriately, and NSAIDs should be switched to celecoxib when indicated. In this section, there are some parts where evidence-based data for VPZ are lacking.

Fig. 9.

Algorithm for the prevention of NSAID-induced ulcers. Prevention depends on concomitant LDA use, ulcer history, and bleeding history. PPIs are recommended for primary prevention in patients without ulcer history, eradication is recommended for NSAID-naive H. pylori-positive patients, and VPZ or a PPI is recommended for recurrence prevention. CXB is recommended in selected high-risk patients and with a PPI when NSAIDs and LDA are combined. Regimens are not covered by Japanese health insurance. CQ clinical question, CXB celecoxib, H. pylori Helicobacter pylori, LDA low-dose aspirin, NSAID nonsteroidal anti-inflammatory drug, PPI proton pump inhibitor, VPZ vonoprazan

In the algorithm for preventing LDA-induced ulcers, prevention varies depending on whether NSAIDs are being used concomitantly, whether P2Y12 receptor antagonists are being used concomitantly, and whether there is a history of ulcers or hemorrhage (Fig. 10). In addition to administering eradication therapy to H. pylori-positive patients, a PPI or VPZ should be selected appropriately for the prevention of LDA-induced ulcers, and NSAIDs should be switched to celecoxib when they are used concomitantly.

Fig. 10.

Algorithm for the prevention of LDA-related ulcers. Prevention depends on ulcer/bleeding history and concomitant antiplatelet or NSAID therapy. A PPI is recommended for LDA users without ulcer history, a PPI or VPZ for DAPT users or LDA users with ulcer history, and a PPI for those with hemorrhagic-ulcer history. H. pylori-positive patients should receive eradication therapy, and CXB with a PPI is recommended when LDA and NSAIDs are combined. Not covered by Japanese health insurance. CQ clinical question, CXB celecoxib, DAPT dual-antiplatelet therapy, H. pylori Helicobacter pylori, LDA low-dose aspirin, NSAID nonsteroidal anti-inflammatory drug, PPI proton pump inhibitor, VPZ vonoprazan

Abbreviations

AMPC

Amoxicillin

BQs

Background questions

CAM

Clarithromycin

CI

Confidence interval

CQs

Clinical questions

COX

Cyclooxygenase

DAPT

Dual-antiplatelet therapy

FRQs

Future research questions

H₂RAs

Histamine H2-receptor antagonists

H. pylori

Helicobacter pylori

ITT

Intention-to-treat

JSGE

Japanese Society of Gastroenterology

LDA

Low-dose aspirin

LVFX

Levofloxacin

MNZ

Metronidazole

NHPH

Non-H. pylori Helicobacter

NSAIDs

Nonsteroidal anti-inflammatory drugs

OR

Odds ratio

PP

Per-protocol analysis

PPI

Proton pump inhibitor

RCTs

Randomized controlled trials

SR

Systematic review

STFX

Sitafloxacin

UBT

Urea breath test

UGIB

Upper gastrointestinal bleeding

VPZ

Vonoprazan

Appendix

Members of the Guidelines Committee who created and evaluated the JSGE ‘‘Evidence-based clinical practice guidelines for peptic ulcer disease 2026″ are listed below.

Creation committee

Chair: Tomoari Kamada (Department of Health Care Medicine, Kawasaki Medical School). Vice-Chair: Mitsushige Sugimoto (Division of Genome-Wide Infectious Microbiology, Research Center for GLOBAL and LOCAL Infectious Disease, Oita University). Members: Masanori Ito (Department of General Internal Medicine, Hiroshima University Hospital), Junichi Iwamoto (Department of Gastroenterology, Tokyo Medical University Ibaraki Medical Center), Tadayoshi Okimoto (Department of Gastroenterology, Oita Prefectural Hospital), Shoko Ono (Division of Endoscopy, Hokkaido University Hospital), Takeshi Kanno (Division of Gastroenterology, Tohoku University Graduate School of Medicine/R&D Division of Career Education for Medical Professionals, Medical Education Center, Jichi Medical University), Toshimi Chiba (Division of Internal Medicine, Department of Oral Medicine, Iwate Medical University), Kengo Tokunaga (Department of Preventive Medicine, Kyorin University School of Medicine), Sachiyo Nomura (Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo), Takahisa Murao (Department of Health Care Medicine, Kawasaki Medical School), and Toshio Watanabe (Department of Premier Preventive Medicine, Osaka Metropolitan University Graduate School of Medicine).

SR collaborators

Daisuke Asaoka (Department of Gastroenterology, Juntendo Tokyo Koto Geriatric Medical Center), Eri Iwata (Center for Health Surveillance & Preventive Medicine, Tokyo Medical University Hospital), Ting Wang (Division of Internal Medicine, Department of Oral Medicine, Iwate Medical University), Hideki Ono (Department of Gastroenterology, Oita Prefectural Hospital), Ryo Katsumata (Department of Health Care Medicine, Kawasaki Medical School), Satoshi Kikuchi (Department of Gastroenterology, Sanai Hospital), Naoki Konishi (Department of Gastroenterology, Tokyo Medical University Ibaraki Medical Center), Satoshi Sato (Department of Medicine, Division of Gastroenterology, Jichi Medical University), Aya Sunago (Department of Health Care Medicine, Kawasaki Medical School), Hiromi Sekiguchi (Department of Medicine, Division of Gastroenterology, Jichi Medical University), Hourin Cho (Center for Health Surveillance & Preventive Medicine, Tokyo Medical University Hospital), Daisuke Chinda (Division of Endoscopy, Hirosaki University Hospital), Osamu Dohi (Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine), Akinobu Nakata (Department of Gastroenterology, Osaka Metropolitan University Hospital), Akira Higashimori (Department of Gastroenterology, Naniwaikuno Hospital), Yuka Hirashita (Department of Gastroenterology, Faculty of Medicine, Oita University), Keigo Misawa (Department of Medicine, Division of Gastroenterology, Jichi Medical University), Kazuhiro Mizukami (Department of Gastroenterology, Faculty of Medicine, Oita University), Daisuke Miyamori (Department of General Internal Medicine, Hiroshima University Hospital), Junko Mukohyama (Department of Surgery, The Institute of Medical Science, The University of Tokyo), Hideki Mori (Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine), Shuhei Yoshida (Department of General Internal Medicine, Hiroshima University Hospital), and Jun Watanabe (Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University).

Evaluation committee

Chair: Kiichi Sato (Tochigi Medical Examination Plaza). Vice-Chair: Yuji Mizokami (Department of Gastroenterology, New Tokyo Hospital). Member: Atsushi Takagi (Department of Internal Medicine, Kameda Morinosato Hospital).

The Japanese Society of Gastroenterology

Director General: Satoshi Mochida (Saitama Medical University Hospital); Vice Director General: Susumu Eguchi (Nagasaki University Hospital); Past Vice Director General: Yoshifumi Takeyama (Osaka Gyoumeikan Hospital); Director of the Guidelines Editorial Committee: Takao Itoi (Tokyo Medical University Hospital); Vice Director of the Guidelines Editorial Committee: Hajime Isomoto (Tottori University Hospital); Chairperson of the Guidelines Editorial Committee: Sumio Watanabe (Juntendo University Hospital).

Cooperative societies

The Japanese Gastroenterological Association, the Japan Gastroenterological Endoscopy Society, and the Japanese Society for Helicobacter Research.

Declarations

Conflict of interest

Any financial relationship with enterprises, businesses, or academic institutions in the subject matter or materials discussed in the manuscript is listed as follows: (1) personal remuneration (honoraria, consulting fees, advisory roles, etc.) AbbVie Inc.; AstraZeneca K.K.; ASKA Pharmaceutical Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; EA Pharma; Eisai Co., Ltd.; Gilead Sciences Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; Toray Industries Inc,. (2) institutional research funding or other support (commercial/academic cooperation). Nobel pharma Co., Ltd.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.