Non-variceal upper gastrointestinal bleeding: advances and future directions in management

Waku Hatta; Yohei Ogata; Takashi Chiba; Naotaro Tanno; Makoto Kawabe; Kimiko Kayada; Yutaka Hatayama; Masahiro Saito; Akira Imatani; Tomoyuki Koike; Atsushi Masamune

doi:10.5946/ce.2025.202

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Review Non-variceal upper gastrointestinal bleeding: advances and future directions in management: Waku Hatta^1,*, Yohei Ogata^1,*, Takashi Chiba², Naotaro Tanno¹, Makoto Kawabe¹, Kimiko Kayada¹, Yutaka Hatayama¹, Masahiro Saito¹, Akira Imatani¹, Tomoyuki Koike¹, Atsushi Masamune¹; Clinical Endoscopy 2026;59(4):510-522.
DOI: https://doi.org/10.5946/ce.2025.202
Published online: December 17, 2025

¹Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan

²Cancer Detection Center, Miyagi Cancer Society, Sendai, Japan

Correspondence: Waku Hatta Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 9808574, Japan E-mail: waku-style@festa.ocn.ne.jp

*Waku Hatta and Yohei Ogata contributed equally as co-first authors.

• Received: June 26, 2025 • Revised: September 19, 2025 • Accepted: September 21, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
INTRODUCTION
PRE-ENDOSCOPIC MANAGEMENT
ENDOSCOPIC TREATMENT
POST-ENDOSCOPIC MANAGEMENT
IDENTIFICATION AND MANAGEMENT OF REFRACTORY BLEEDING
CONCLUSIONS
NOTES
REFERENCES

Abstract

Numerous clinical guidelines have been developed for the management of non-variceal upper gastrointestinal bleeding (NVUGIB), yet significant variations exist among the recommendations. This review summarizes the most recent evidence on NVUGIB management, structured across four key stages: pre-endoscopic management, endoscopic treatment, post-endoscopic care, and the identification and management of refractory bleeding. In the pre-endoscopic phase, several risk-scoring systems have been developed to predict mortality. A restrictive transfusion strategy, with a threshold of 7 to 8 g/dL, is now recommended for most patients. Pre-endoscopic administration of intravenous erythromycin also improves visualization during endoscopy. A wide array of endoscopic hemostasis techniques is available, with the choice of method depending on the underlying cause of bleeding. When endoscopic hemostasis fails, transcatheter arterial embolization (TAE) is generally preferred over surgery as the second-line intervention. Once hemostasis is achieved, high-dose acid suppression is essential, and the risk of rebleeding should be assessed. For patients who experience rebleeding, repeat endoscopic therapy is recommended as the first-line approach. However, determining the optimal timing for TAE remains a challenge. Because of the heterogeneity of clinical presentations, NVUGIB management should be personalized. Further research is needed to establish evidence-based, individualized treatment strategies.
Keywords: Endoscopy; Hemorrhage; Mortality

INTRODUCTION

Non-variceal upper gastrointestinal bleeding (NVUGIB) is a common medical emergency worldwide, defined as bleeding originating from the esophagus, stomach, or duodenum, excluding variceal bleeding. Although the incidence of NVUGIB declined until approximately a decade ago, recent data indicate a resurgence of cases in the United States (US).¹ In contrast, the incidence has continued to decline in Japan.² Despite advances in diagnostic and therapeutic approaches, the mortality associated with NVUGIB remains substantial, ranging from 2% to 15%.³^,⁴ Notably, bleeding-related causes account for only 13.8% to 20.9% of overall mortality among patients with NVUGIB,⁵ highlighting the need for comprehensive management that addresses both hemorrhagic and non-hemorrhagic complications.

Multiple guidelines have been developed for the management of NVUGIB, but substantial variations exist among them.²^,⁶^-¹⁰ NVUGIB encompasses a broad spectrum of etiologies, including peptic ulcer bleeding (PUB), gastrointestinal (GI) tumors, Mallory-Weiss tears, and vascular abnormalities. Patient characteristics and comorbidities also vary widely. Consequently, optimal management must be tailored to both the underlying cause and the individual patient’s clinical condition.

The management of NVUGIB can be broadly categorized into four stages: pre-endoscopic management, endoscopic treatment, post-endoscopic care, and identification and management of refractory bleeding. This review summarizes the latest evidence across all stages of NVUGIB management and explores emerging directions for individualized care.

PRE-ENDOSCOPIC MANAGEMENT

Risk stratification

Numerous risk-scoring systems have been developed to predict clinical outcomes in patients with NVUGIB, including mortality, rebleeding, and the need for endoscopic or other therapeutic interventions. Internationally validated pre-endoscopic risk scores include the Glasgow-Blatchford score (GBS),¹¹ albumin, international normalized ratio, mental status, systolic blood pressure, and age >65 years (AIMS65),¹² Canada-United Kingdom-Adelaide (CANUKA),¹³ age, blood tests and comorbidities (ABC),¹⁴ and The Charlson comorbidity Index ≥ 2, in-Hospital onset, Albumin <2.5 g/dL, altered Mental status, Eastern Cooperative Oncology Group Performance status ≥2, Steroid use (CHAMPS).⁵ In contrast, post-endoscopic risk scores include the Rockall score¹⁵ and the Progetto Nazionale Emorragia Digestiva (PNED).¹⁶ These scoring systems are summarized in Table 1.

Accurate identification of very low-risk patients who may be safely discharged early with outpatient follow-up has become increasingly important, as it can significantly reduce healthcare costs while maintaining patient safety.⁹^,¹⁷ An international multicenter prospective study demonstrated that the GBS outperformed the Rockall score, PNED, and AIMS65 in predicting the need for hospital-based intervention or death.¹⁸ A GBS threshold of ≤1 showed an acceptable false negative rate (≤1%) and is now widely adopted in guidelines for identifying candidates for outpatient management.⁷^-¹⁰

Equally important is identifying patients at high risk of mortality. Recently, two novel scores—the ABC and CHAMPS—have shown promising results. In external validation cohorts, the ABC score outperformed AIMS65 in predicting 30-day mortality, stratifying patients into low-risk (≤3 points, 1.0% mortality), medium-risk (4–7 points, 7.0%), and high-risk (≥8 points, 25.0%) groups. The CHAMPS score, a simpler model, outperformed the GBS, Rockall, AIMS65, and ABC in predicting in-hospital mortality, with respective mortality rates of 0.2%, 2.3%, and 26.5% across the low (0 points), intermediate (1–2 points), and high-risk (≥3 points) groups. While these scoring systems have been validated in both prospective and retrospective studies,¹⁹^,²⁰ larger multicenter prospective studies are needed to confirm their generalizability.

Despite the development of multiple risk-scoring systems, clinical use remains limited, largely due to their inherent complexity. Moreover, these systems are typically applied only at presentation and are not designed for repeated use, even though patients’ condition may change rapidly, thereby altering the risk profile. Recently, a machine-learning model was developed to identify patients with upper GI bleeding (UGIB) who reached a composite endpoint of hospital-based intervention or death within 30 days. This model demonstrated superior performance compared with the GBS, Rockall score, and AIMS65.²¹ Because machine-learning models can be integrated into electronic health records, they hold promise for more widespread clinical use in the future. Furthermore, a novel ingestible bleeding sensor has also been developed, which may facilitate effective risk stratification of patients with suspected UGIB, minimizing unnecessary hospital admissions and urgent endoscopies.²²^,²³

Blood transfusion

Two randomized controlled trials (RCTs) have compared restrictive versus liberal transfusion strategies.²⁴^,²⁵ Villanueva et al.²⁴ reported that a restrictive strategy with a hemoglobin threshold of 7 g/dL resulted in significantly better outcomes compared with a 9 g/dL threshold, including lower 6-week mortality (5% vs. 9%), less further bleeding (10% vs. 16%), fewer transfusion reactions (3% vs. 9%), and fewer cardiac complications (11% vs. 16%). Conversely, Jairath et al.²⁵ found no significant differences between thresholds of 8 and 10 g/dL for 28-day mortality (5% vs. 7%), further bleeding (5% vs. 9%), or thromboembolic/ischemic events (4% vs. 7%).

A meta-analysis of 31 RCTs further showed no significant difference in 30-day mortality between restrictive (7–8 g/dL) and liberal (9–10 g/dL) transfusion thresholds (risk ratio [RR], 0.99; 95% confidence interval [CI], 0.86–1.15).²⁶ Based on this evidence, a restrictive transfusion strategy with a threshold of 7 to 8 g/dL—rather than a fixed single threshold—is generally recommended for most patients with NVUGIB (Fig. 1), although guideline recommendations vary.²^,⁶^-¹⁰

Certain patient subgroups, particularly those with cardiovascular disease, may benefit from a more liberal transfusion approach. A meta-analysis of 11 RCTs found that restrictive transfusion was associated with a higher risk of acute coronary syndrome in patients with cardiovascular disease (RR, 1.78; 95% CI, 1.18–2.70), although 30-day mortality did not differ significantly.²⁷ Additionally, a large RCT of 3,504 patients with acute myocardial infarction and anemia showed that a liberal transfusion strategy with a threshold of 10 g/dL did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days compared with a restrictive strategy using thresholds of 7 or 8 g/dL (RR for restrictive vs. liberal, 1.15; 95% CI, 0.99–1.34).²⁸ However, point estimates consistently favored liberal transfusion, suggesting potential harm from overly restrictive thresholds. Therefore, in patients with myocardial infarction and UGIB, a more liberal transfusion threshold may be warranted (Fig. 1), though data specific to GI bleeding populations remain limited.

Pre-endoscopic medication

1) Prokinetics

The use of prokinetic agents before endoscopy aims to clear the stomach of blood and clots, thereby improving mucosal visualization.⁹ Erythromycin, a motilin receptor agonist, accelerates gastric emptying and has been widely studied. A recent network meta-analysis of eight RCTs demonstrated that erythromycin improves endoscopic visualization, reduces the need for blood transfusion and repeat endoscopy, and shortens hospital stay.²⁹ Accordingly, the US guidelines recommend an intravenous infusion of erythromycin 250 mg given 20 to 90 minutes before endoscopy in patients with UGIB (Fig. 1).⁹ European guidelines also support pre-endoscopic administration of intravenous erythromycin in selected patients with clinically severe or ongoing active UGIB.¹⁰

A recent RCT evaluated the efficacy of intravenous metoclopramide (10 mg administered 30–120 minutes before endoscopy) in patients with active UGIB.³⁰ While no improvement was observed in overall endoscopic visualization, a post hoc subgroup analysis revealed enhanced visualization in patients with gastric lesions, particularly in the fundus. Although further studies are warranted, metoclopramide may have potential utility in select cases.

2) Acid-suppressive therapy

Proton pump inhibitors (PPIs) promote hemostasis by elevating intragastric pH, thereby enhancing platelet aggregation and stabilizing blood clots.³¹ A meta-analysis of six RCTs found that pre-endoscopic PPI administration significantly reduced the need for endoscopic hemostasis at index endoscopy (odds ratio [OR], 0.68; 95% CI, 0.50–0.93).³² However, there is insufficient evidence to determine whether pre-endoscopic PPI therapy improves, worsens, or has no effect on other outcomes, including mortality, rebleeding, and the need for surgery.³² Although guideline recommendations differ,⁶^,⁷^,⁹^,¹⁰ pre-endoscopic PPI therapy may be appropriate, particularly when endoscopy is delayed or unavailable within 24 hours of presentation (Fig. 1).¹⁷

ENDOSCOPIC TREATMENT

Timing of endoscopy

Although no RCTs have directly compared endoscopy within 24 hours versus after 24 hours of NVUGIB presentation, guidelines recommend performing endoscopy within 24 hours.⁷ A recent RCT found that in high-risk patients with UGIB (defined as GBS ≥12), urgent endoscopy performed within 6 hours did not reduce 30-day mortality or rebleeding compared with endoscopy performed 6 to 24 hours after consultation (30-day mortality, 8.9% vs. 6.6%; rebleeding, 10.9% vs. 7.8%).³³ Accordingly, guidelines published after this RCT recommend endoscopy within 24 hours for patients with NVUGIB (Fig. 2).²^,⁹^,¹⁰ It is important to note, however, that this RCT excluded patients with persistent hypotensive shock despite resuscitation. For such patients, urgent diagnostic and therapeutic intervention remains necessary (Fig. 2).

Selection of endoscopic treatment methods based on NVUGIB causes

The causes of NVUGIB include PUB, GI tumor bleeding, Mallory-Weiss tears, and vascular abnormalities. Available endoscopic treatment methods include contact thermal therapy, through-the-scope clip (TTSC), over-the-scope clip (OTSC), sclerosant injection, argon plasma coagulation (APC), epinephrine injection, and topical hemostatic therapy (e.g., hemostatic powders and gels). The optimal method depends on the etiology of bleeding (Fig. 2).

1) PUB

Peptic ulcers are classified using the Forrest classification: Ia, spurting bleeding; Ib, oozing bleeding; IIa, non-bleeding visible vessel; IIb, adherent clot; IIc, flat pigmented spot; and III, clean ulcer base.³⁴ A 2009 meta-analysis of RCTs showed that endoscopic therapy significantly reduced rebleeding in patients with active bleeding (Forrest Ia and Ib; RR, 0.29) and in those with non-bleeding visible vessels (Forrest IIa; RR, 0.49).³⁵ Consequently, guidelines consistently recommend endoscopic therapy in these cases (Fig. 2).²^,⁶^,⁹^,¹⁰

Endoscopic therapy for adherent clots (Forrest IIb) remains controversial. Two small RCTs reported significant reductions in rebleeding with clot removal.³⁶^,³⁷ Japanese guidelines recommend removing adherent clots to evaluate for underlying exposed vessels.²

2) Contact thermal therapy

Contact thermal therapies (Fig. 3A) include bipolar electrocoagulation, heater probe, and monopolar soft coagulation. A meta-analysis of 19 RCTs demonstrated that bipolar electrocoagulation or heater probe significantly reduced rebleeding (RR, 0.44) and mortality (RR, 0.58) compared with no endoscopic therapy.³⁵

Monopolar soft coagulation, which uses a peak voltage <200 V, is now widely adopted.² An RCT comparing this method with TTSC after initial epinephrine injection in Forrest Ia and Ib ulcers showed higher initial hemostasis (98.2% vs. 80.4%), lower rebleeding rates (3.6% vs. 17.7%), and shorter procedure times and hospital stays.³⁸ A meta-analysis of four RCTs indicated a lower risk of persistent bleeding compared with TTSC and heater probe (RR, 0.35; 95% CI, 0.12–1.03).⁹ Although more evidence is needed, monopolar soft coagulation appears effective for PUB. Thus, contact thermal therapy is recommended.

3) TTSC

Although TTSC (Fig. 3B) has long been used, evidence supporting its efficacy is limited. No RCTs have compared TTSC with no treatment. A meta-analysis of two RCTs comparing TTSC with epinephrine injection showed higher definitive hemostasis with TTSC (86.5% vs. 75.4%).³⁹ Another small RCT comparing TTSC with absolute ethanol injection found no significant difference in rebleeding (9.5% vs. 14.3%).⁴⁰

TTSC causes less tissue damage than thermal therapy or ethanol injection, making it suitable for deeply excavated duodenal ulcers or refractory bleeding. However, it may be less effective in tangential or highly fibrotic ulcers.² Overall, TTSC is recommended for PUB, with consideration of its limitations.

4) Absolute ethanol injection

A meta-analysis of three RCTs showed that absolute ethanol injection (Fig. 3C) significantly reduced rebleeding (RR, 0.56) and mortality (RR, 0.18) compared with no endoscopic therapy.³⁵ However, another meta-analysis of five RCTs suggested that contact thermal therapy may be more effective (RR, 0.69; 95% CI, 0.47–1.01).³⁵ To minimize ethanol-induced tissue damage, the injection volume should be limited.⁴⁰^,⁴¹ Most guidelines recommend absolute ethanol injection as an option for PUB based on moderate-quality evidence.⁷^,⁹^,¹⁰ Japanese guidelines caution, however, that ethanol injection alone may be insufficient for active bleeding because of volume limitations.²

5) Epinephrine injection

A meta-analysis of four RCTs found that epinephrine monotherapy is less effective than standard monotherapies such as TTSC or contact thermal therapy (RR for rebleeding, 2.20).⁹ In contrast, a meta-analysis of seven RCTs showed that combining epinephrine with another modality significantly reduced rebleeding compared with epinephrine alone (RR, 0.34).³⁵ Therefore, epinephrine should always be combined with another method.²^,⁹^,¹⁰

6) APC

Evidence for APC is limited. In a small RCT, APC reduced rebleeding compared with distilled water injection (3.6% vs. 16%) but showed no mortality difference (3.4% vs. 3.4%).⁴² A meta-analysis of three RCTs found no significant differences in rebleeding or mortality between APC (with/without epinephrine) and other modalities⁹ and is particularly useful for superficial, diffuse bleeding rather than spurting bleeding.²

7) OTSC

OTSC, developed in 2008,⁴³ enables full-thickness capture and suturing of tissue.⁴⁴ A meta-analysis of five RCTs comparing OTSC with conventional therapies as first-line treatment for NVUGIB showed lower 30-day rebleeding (RR, 0.43) and higher clinical success (RR, 1.19).⁴⁵ However, high cost limits its routine use.⁴⁶ Most guidelines currently available predate the accumulating evidence supporting OTSC as first-line therapy. The 2025 Japanese guidelines recommend OTSC when conventional therapy fails or in cases of rebleeding, though widespread use remains limited in Japan.²

8) Topical hemostatic therapy

Several hemostatic powders—TC-325, polysaccharide-based agents, UI-EWD, and CEGP-003—have been evaluated. Among these, TC-325 (a bentonite-based powder forming a mechanical barrier) is the most studied. An RCT found TC-325 non-inferior to standard therapy for UGIB (rebleeding, 9.9% vs. 18.6%) and PUB (11.7% vs. 16.2%), with comparable 30-day rebleeding rate (8.1% vs. 8.66%).⁴⁷

In PUB, a polysaccharide powder plus epinephrine was non-inferior to conventional therapy for initial hemostasis and rebleeding.⁴⁸ By contrast, CEGP-003 was associated with higher rebleeding (14.4% vs. 2.9%) despite higher initial hemostasis (96.3% vs. 91.8%).⁴⁹ A recent RCT showed that UI-EWD (Fig. 3D) following standard therapy reduced both 3-day and 30-day rebleeding compared with standard therapy alone (2.9% vs. 11.3% and 7.0% vs. 18.8%, respectively).⁵⁰ These findings indicate variable efficacy among agents. Further studies are needed to determine whether combination therapy or monotherapy is optimal.

Hemostatic gel (TDM-621) has also been developed, but no RCTs have evaluated it in UGIB. Additional trials are needed to assess its effectiveness.

9) Tumor bleeding

Benign and malignant tumor bleeding accounts for approximately 5% of all NVUGIB cases.¹⁷ Although endoscopic therapy is often employed, its efficacy varies widely, with primary hemostasis rates ranging from 31%–86% and rebleeding rates from 28%–80%.⁵¹^-⁵⁵ No guidelines have yet established a standard endoscopic treatment for tumor bleeding. Among available therapies, hemostatic powders—particularly TC-325—show promise. An RCT comparing TC-325 with conventional endoscopic therapy for malignant tumor bleeding demonstrated significantly lower 30-day rebleeding (2.1% vs. 21.3%) and higher immediate hemostasis (100% vs. 68.6%).⁵⁶ A recent individual patient data meta-analysis of RCTs also reported higher immediate hemostasis (OR, 46.6), lower 30-day rebleeding (OR, 0.28), and lower overall rebleeding (OR, 0.11) with TC-325 compared with standard therapy.⁵⁷ Although no RCTs have evaluated other hemostatic powders, their ability to cover large bleeding surfaces suggests potential as standard options for tumor bleeding (Fig. 2).

10) Bleeding from Mallory-Weiss tears

Mallory-Weiss tears account for 3%–11% of UGIB cases.² While spontaneous hemostasis occurs in most patients and rebleeding is rare (<10%), endoscopic hemostasis is recommended for active bleeding.¹⁷ The Japanese guidelines advocate mechanical hemostasis,² whereas Korean guidelines and other literature do not specify an optimal modality.⁶^,¹⁷^,⁵⁸ Two small RCTs found that epinephrine injection was comparable in efficacy and safety to mechanical approaches such as endoscopic band ligation (EBL) and TTSC for Mallory-Weiss tears.⁵⁹^,⁶⁰ However, large-scale RCTs are lacking. According to the Japanese guidelines, mechanical methods are preferred, particularly when the bleeding vessel is located on the esophageal side, because of the thinner muscle layer and increased risk of perforation with epinephrine injection or contact thermal therapy.² Nonetheless, this recommendation is based on limited evidence, highlighting the need for further research to determine the optimal treatment for this condition.

11) Bleeding from vascular abnormalities

Vascular abnormalities include gastric antral vascular ectasia (GAVE), portal hypertensive gastropathy, radiation gastritis, and other forms of angioectasia.²^,⁶¹ GI angioectasia in patients with severe aortic stenosis (Heyde’s syndrome) has gained increasing attention, with bleeding shown to improve after transcatheter aortic valve replacement.⁶² GAVE is responsible for 2%–4% of NVUGIB cases⁶³ and is associated with conditions such as chronic kidney disease, cirrhosis, scleroderma, ischemic heart disease, acute myeloid leukemia, and hypertension.⁶⁴ Several endoscopic modalities have been employed for the management of GAVE and other vascular lesions, including APC (Fig. 3E), EBL (Fig. 3F), laser therapy, radiofrequency ablation (RFA), and other thermal techniques.¹⁷^,⁶¹ Of these, APC, EBL, and RFA are the most studied. Japanese guidelines currently recommend APC as first-line treatment, partly because EBL and RFA are not covered by health insurance in Japan.² However, a meta-analysis of 10 observational studies comparing EBL and APC showed superior eradication rates (88.6% vs. 57.9%) and lower rebleeding rates (6.6% vs. 39.7%) for EBL.⁶⁵ Another meta-analysis of 12 studies found no significant differences between APC and RFA in clinical outcomes, including bleeding control.⁶⁶ Although high-quality RCTs are needed, EBL may be considered the preferred first-line therapy for GAVE (Fig. 2). The mean number of bands deployed during EBL ranged from 5.3 to 19.3 across studies, and the pooled mean number of sessions required was 2.31 (95% CI, 1.99–2.63).⁶⁵ Another meta-analysis reported that repeat endoscopy was typically scheduled at 1–6-week intervals until improvement was achieved.⁶⁷

Next-step management after unsuccessful endoscopic hemostasis

Endoscopic therapy achieves initial hemostasis in >90% of PUB cases.⁶⁸ Failures, however, may occur due to persistent bleeding, poor endoscopic visibility (e.g., food residue or clots), or hemodynamic instability. In such cases, transcatheter arterial embolization (TAE) or surgery is considered as secondary intervention. Although no RCTs have directly compared TAE and surgery, a population-based cohort study found no significant difference in 30-day mortality between the two (hazard ratio [HR], 0.70; 95% CI, 0.37–1.35).⁶⁹ TAE was associated with a higher risk of rebleeding (HR, 2.48; 95% CI, 1.33–4.62) but fewer complications (8.3% vs. 32.2%) and a shorter hospital stay (median, 8 vs. 16 days). Similar results were reported in a meta-analysis of 13 observational studies on NVUGIB.⁷⁰ Accordingly, most guidelines recommend TAE over surgery as the preferred next step in management after failed endoscopic hemostasis (Fig. 2).²^,⁶^,⁹^,¹⁰ Nevertheless, the decision between TAE and surgery should be individualized based on factors such as the availability of interventional radiology and the patient’s overall clinical condition and comorbidities.

POST-ENDOSCOPIC MANAGEMENT

Second-look endoscopy

Second-look endoscopy is typically performed within 24–48 hours after initial endoscopic hemostasis. An RCT demonstrated the non-inferiority of a single endoscopy compared with second-look endoscopy in terms of 30-day rebleeding rates for PUB (5.6% vs. 10.1%).⁷¹ A meta-analysis of nine RCTs further supported these findings, showing no significant benefit of routine second-look endoscopy in reducing rebleeding (RR, 0.79; 95% CI, 0.51–1.23), need for surgery (RR, 0.58; 95% CI, 0.29–1.15), or mortality (RR, 0.69; 95% CI, 0.33–1.45).⁷² Accordingly, most guidelines do not recommend routine second-look endoscopy in NVUGIB management (Fig. 4).⁶^-⁸^,¹⁰ However, the Japanese guidelines weakly recommend second-look endoscopy in patients at high risk of rebleeding, such as those with unsatisfactory initial hemostasis (Fig. 4),² although robust supporting evidence is lacking.

Acid-suppressive therapy after endoscopic therapy

1) PPI

Acid suppression in NVUGIB aims to stabilize blood clots by reducing intragastric acidity.³¹ A meta-analysis of 12 and 10 RCTs comparing PPIs with placebo or histamine-2 receptor antagonists demonstrated lower rebleeding (6.9% vs. 13.2%) and mortality (2.0% vs. 3.5%), respectively, with PPI use.⁷ In Western countries, high-dose PPI therapy, defined as ≥80 mg daily for ≥3 days, is widely available. A meta-analysis of 15–17 RCTs comparing high-dose versus non–high-dose PPI regimens found no significant differences in rebleeding (10.7% vs. 9.0%) or mortality (2.7% vs. 2.6%).⁷ Nonetheless, non–high-dose PPI therapy was superior to no PPI therapy in reducing rebleeding but not mortality. As a result, several guidelines recommend high-dose PPI therapy following successful endoscopic hemostasis (Fig. 4), although the optimal dosing regimen—oral versus intravenous and continuous versus intermittent—remains uncertain.⁷^,⁹^,¹⁰

2) Potassium-competitive acid blocker

Potassium-competitive acid blockers (P-CABs), such as vonoprazan and tegoprazan, provide rapid onset and sustained acid inhibition, representing a novel approach to acid suppression.⁷³ In NVUGIB, only one RCT has compared vonoprazan with high-dose PPI for PUB, demonstrating non-inferiority in 30-day rebleeding (7.1% vs. 10.4%).⁷⁴ A large retrospective database study using propensity score matching found no significant differences between vonoprazan and oral PPI (both groups received prior intravenous PPI) in terms of rebleeding (6.4% vs. 6.1%), in-hospital mortality (1.4% vs. 1.5%), or post-rebleeding mortality (0.3% vs. 0.2%).⁷⁵ Vonoprazan may be a viable alternative to high-dose PPIs, especially in countries such as Japan, where high-dose PPI use is limited (Fig. 4). Additional evidence is needed.

IDENTIFICATION AND MANAGEMENT OF REFRACTORY BLEEDING

Risk factors for rebleeding

A 2011 meta-analysis of 14 studies identified hemodynamic instability (OR, 3.30), low hemoglobin (OR, 1.73), transfusion (OR not calculable), active bleeding (OR, 1.70), large ulcer size (OR, 2.81), posterior duodenal ulcer location (OR, 3.83), and high lesser gastric curvature ulcer location (OR, 2.86) as predictors of rebleeding in PUB.⁷⁶ High-dose steroid use was also a significant risk factor, with a dose-dependent effect.⁷⁷ A recent large cohort study further identified endoscopic high-risk stigmata (OR, 2.12), duodenal ulcer bleeding (OR, 1.87), and hemodynamic instability (OR, 1.55) as key predictors.⁷⁸ Among duodenal ulcer cases, post-bulbar location was associated with higher rebleeding rates than bulbar location (29.2% vs. 10.2%), particularly when serum albumin was <2.5 g/dL (51.4%).⁷⁹ An international multicenter prospective study found that the PNED score, which incorporates rebleeding as a variable, outperformed the GBS, Rockall score, and AIMS65 in predicting rebleeding.¹⁸

Management of rebleeding

An RCT comparing endoscopic therapy with surgery for rebleeding after initial successful hemostasis found that while endoscopic therapy had a higher rate of further bleeding (23% vs. 7%), it resulted in fewer complications (15% vs. 36%) and no significant difference in mortality (10% vs. 18%).⁸⁰ Because endoscopic therapy avoided surgery in 73% of cases, several guidelines favor repeat endoscopic therapy over TAE or surgery for PUB-related rebleeding.²^,⁷^,⁹^,¹⁰

If endoscopic therapy fails, TAE is generally preferred over surgery in Korean and Western guidelines,⁶^,⁹^,¹⁰ whereas Japanese guidelines recommend either TAE or surgery.² Given the advantages of TAE over surgery in initial failures, it may also be preferable in rebleeding cases with failed endoscopic hemostasis (Fig. 4).

Some studies have explored optimal modalities for recurrent PUB. An RCT showed that OTSC was superior to standard endoscopic therapy in preventing further bleeding (15.2% vs. 57.6%).⁸¹ Consequently, the European guidelines suggest using OTSC or topical hemostatic therapy when conventional methods fail (Fig. 4).¹⁰

The timing of TAE or surgery in repeated rebleeding remains challenging. One RCT evaluated additional TAE after endoscopic hemostasis in high-risk PUB patients and found no overall benefit.⁸² However, in ulcers ≥15 mm, additional TAE reduced the risk of rebleeding nearly fivefold (23.1% vs. 4.5%). Thus, selected high-risk patients with recurrent bleeding or poor general health may be appropriate candidates for TAE (Fig. 3).

CONCLUSIONS

Future perspective

Over the past two decades, numerous RCTs have been conducted to evaluate NVUGIB management, leading to the establishment of standard treatment protocols. However, further research is needed to enable personalized strategies.

For instance, the role of second-look endoscopy in specific subgroups remains uncertain. If beneficial, the populations most likely to gain from this approach have yet to be defined. Rebleeding remains a critical clinical concern, but most existing risk scores show suboptimal predictive power.¹⁸ Although the PNED score demonstrates relatively high accuracy,¹⁸ its inclusion of rebleeding as a variable16 may partly explain this, limiting its independent utility. Rebleeding and repeated bleeding are significant burdens for both clinicians and patients, underscoring the need to develop novel risk scores specifically for these outcomes. In addition, the optimal timing of TAE or surgery in rebleeding remains unclear and warrants further investigation. Emerging hemostatic agents—including powders, gels, and P-CABs—also require robust evaluation. Comparative studies will be essential to determine the most effective powder for achieving hemostasis and preventing rebleeding.

Given the multifactorial nature of NVUGIB, optimal management is likely to vary with patient characteristics and clinical setting. Further high-quality evidence is therefore essential to advance personalized treatment approaches.

Conflicts of Interest

The authors have no potential conflicts of interest.

Funding

None.

Author Contributions

Conceptualization: WH; Data curation: WH, YO, TC; Formal analysis: WH, YO; Investigation: WH, YO; Methodology: WH, YO; Project administration: WH; Supervision: MA; Validation: all authors; Visualization: WH; Writing–original draft: WH; Writing–review & editing: all authors.

Fig. 1.

Pre-endoscopic management of non-variceal upper gastrointestinal bleeding (NVUGIB). GBS, Glasgow-Blatchford score; RBC, red blood cell; Hb, hemoglobin; PPI, proton pump inhibitor.

Fig. 2.

Endoscopic management of non-variceal upper gastrointestinal bleeding (NVUGIB). PUB, peptic ulcer bleeding; TTSC, through-the-scope-clip; OTSC, over-the-scope clip; EBL, endoscopic band ligation; APC, argon plasma coagulation; RFA, radiofrequency ablation; TAE, transcatheter arterial embolization. ^a)Endoscopic therapy for Forrest IIa lesions remains controversial; however, removal of adherent clots at the ulcer base is generally recommended.

Fig. 3.

Endoscopic treatment methods for non-variceal upper gastrointestinal bleeding (NVUGIB). (A) Contact thermal therapy for peptic ulcer bleeding (PUB). (B) Through-the-scope-clip for PUB. (C) Absolute ethanol injection for PUB. (D) Hemostatic powder (UI-EWD) for PUB. (E) Argon plasma coagulation for bleeding from gastric antral vascular ectasia (GAVE). (F) Endoscopic band ligation for bleeding from GAVE.

Fig. 4.

Post-endoscopic management following successful initial hemostasis and strategies for managing refractory bleeding. NVUGIB, non-variceal upper gastrointestinal bleeding; PPI, proton pump inhibitor; P-CAB, potassium-competitive acid blocker; TTSC, through-the-scope-clip; OTSC, over-the-scope clip; TAE, transcatheter arterial embolization.

Table 1.

Internationally validated risk-scoring systems in NVUGIB

	Timing of evaluation	Components	Range of score
Rockall score, 1996	Post-endoscopy	5 Variables (age, shock index, comorbidities, cause of NVUGIB, stigmata of recent hemorrhage)	0–11
Glasgow-Blatchford score, 2000	Pre-endoscopy	7 Variables (heart rate, systolic blood pressure, BUN, Hb, melena, syncope, comorbidities [hepatic disease, cardiac failure])	0–23
PNED, 2010	Post-endoscopy	7 Variables (age, time to admission, Hb, comorbidities [renal failure, neoplasm, liver cirrhosis], ASA classification, rebleeding, failure of endoscopic treatment)	0–23
AIMS65, 2011	Pre-endoscopy	5 Variables (albumin, INR, mental status, systolic blood pressure, age)	0–5
CANUKA, 2019	Pre-endoscopy	9 Variables (age, melena, hematemesis, syncope, comorbidities [liver disease, malignancy], heart rate, systolic blood pressure, Hb, BUN)	0–20
ABC score, 2021	Pre-endoscopy	6 Variables (age, BUN, albumin, creatinine, altered mental status, comorbidities [liver cirrhosis, disseminated malignancy, ASA classification])	0–17
CHAMPS score, 2021	Pre-endoscopy	6 Variables (in-hospital onset, altered mental status, steroid, albumin, ECOG-PS, CCI)	0–6

NVUGIB, non-variceal upper gastrointestinal bleeding; BUN, blood urea nitrogen; Hb, hemoglobin; PNED, progetto nazionale emorragia digestive; ASA, American Society of Anesthesiology; AIMS65, albumin, international normalized ratio, mental status, systolic blood pressure, and age >65 years; INR, international normalized ratio; CANUKA, Canada-United Kingdom-Adelaide; ABC, age, blood tests and comorbidities; CHAMPS, The Charlson comorbidity index ≥2, in-Hospital onset, Albumin <2.5 g/dL, altered Mental status, Eastern Cooperative Oncology Group Performance status ≥2, Steroid use; ECOG-PS, Eastern Cooperative Oncology Group performance status; CCI, Charlson comorbidity index.

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Management of upper gastrointestinal haemorrhage: an updated narrative review
Thomas Arkle, Abdelrahman Abdelaal, Leo Alexandre, Bhaskar Kumar, Nicholas Penney
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Non-variceal upper gastrointestinal bleeding: advances and future directions in management

Clin Endosc. 2026;59(4):510-522. Published online December 17, 2025

DOI: https://doi.org/10.5946/ce.2025.202

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Non-variceal upper gastrointestinal bleeding: advances and future directions in management

Fig. 1. Pre-endoscopic management of non-variceal upper gastrointestinal bleeding (NVUGIB). GBS, Glasgow-Blatchford score; RBC, red blood cell; Hb, hemoglobin; PPI, proton pump inhibitor.

Fig. 2. Endoscopic management of non-variceal upper gastrointestinal bleeding (NVUGIB). PUB, peptic ulcer bleeding; TTSC, through-the-scope-clip; OTSC, over-the-scope clip; EBL, endoscopic band ligation; APC, argon plasma coagulation; RFA, radiofrequency ablation; TAE, transcatheter arterial embolization. a)Endoscopic therapy for Forrest IIa lesions remains controversial; however, removal of adherent clots at the ulcer base is generally recommended.

Fig. 3. Endoscopic treatment methods for non-variceal upper gastrointestinal bleeding (NVUGIB). (A) Contact thermal therapy for peptic ulcer bleeding (PUB). (B) Through-the-scope-clip for PUB. (C) Absolute ethanol injection for PUB. (D) Hemostatic powder (UI-EWD) for PUB. (E) Argon plasma coagulation for bleeding from gastric antral vascular ectasia (GAVE). (F) Endoscopic band ligation for bleeding from GAVE.

Fig. 4. Post-endoscopic management following successful initial hemostasis and strategies for managing refractory bleeding. NVUGIB, non-variceal upper gastrointestinal bleeding; PPI, proton pump inhibitor; P-CAB, potassium-competitive acid blocker; TTSC, through-the-scope-clip; OTSC, over-the-scope clip; TAE, transcatheter arterial embolization.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Non-variceal upper gastrointestinal bleeding: advances and future directions in management

	Timing of evaluation	Components	Range of score
Rockall score, 1996	Post-endoscopy	5 Variables (age, shock index, comorbidities, cause of NVUGIB, stigmata of recent hemorrhage)	0–11
Glasgow-Blatchford score, 2000	Pre-endoscopy	7 Variables (heart rate, systolic blood pressure, BUN, Hb, melena, syncope, comorbidities [hepatic disease, cardiac failure])	0–23
PNED, 2010	Post-endoscopy	7 Variables (age, time to admission, Hb, comorbidities [renal failure, neoplasm, liver cirrhosis], ASA classification, rebleeding, failure of endoscopic treatment)	0–23
AIMS65, 2011	Pre-endoscopy	5 Variables (albumin, INR, mental status, systolic blood pressure, age)	0–5
CANUKA, 2019	Pre-endoscopy	9 Variables (age, melena, hematemesis, syncope, comorbidities [liver disease, malignancy], heart rate, systolic blood pressure, Hb, BUN)	0–20
ABC score, 2021	Pre-endoscopy	6 Variables (age, BUN, albumin, creatinine, altered mental status, comorbidities [liver cirrhosis, disseminated malignancy, ASA classification])	0–17
CHAMPS score, 2021	Pre-endoscopy	6 Variables (in-hospital onset, altered mental status, steroid, albumin, ECOG-PS, CCI)	0–6

Table 1. Internationally validated risk-scoring systems in NVUGIB