Turn over the new leaf of the treatment in peptic ulcer bleeding: a review of the literature

Abstract

Peptic ulcer bleeding is the most common cause of upper gastrointestinal bleeding, which has a high mortality risk. The standard therapy for acute peptic ulcer bleeding combines medication administration and endoscopic therapies. Both pharmacologic and endoscopic therapies have developed continuously in the past few decades. Proton pump inhibitors (PPIs) already reached a high efficacy in ulcer healing and have been widely used in the past few decades. Endoscopic hemostasis, which includes local epinephrine injection, heater probe coagulation, use of hemostatic clips, and/or band ligation, is highly effective with an overall hemostatic success rate of 85%–90%. However, 10%–20% of patients could not be cured by the current standard combination treatment. Recurrent ulcer bleeding, despite an initial successful hemostasis, is also a big problem for longer hospitalization stays, higher mortality, and higher complication rates, especially for malignant ulcer bleeding. How to manage all types of peptic ulcer bleeding and how to prevent early recurrent peptic ulcer bleeding remain unresolved clinical problems. Recently, several novel medications and endoscopic methods have been developed. Potassium competitive acid blockers have shown a stronger and longer acid suppression than PPI. Hemostatic powder spray and hemostatic gel emulsion are novel hemostatic weapons with emerging evidence, which are potential missing pieces of the puzzle. This literature review will go through the development of endoscopic hemostasis to the prospects of novel endoscopic treatments.

Keywords

endoscopic hemostasis hemostatic gel emulsion hemostatic powder spray P-CAB peptic ulcer bleeding

Introduction

A peptic ulcer is a mucosal break with a size over 5 mm that forms in the lining of the stomach or the duodenum. Many kinds of etiologies can result in peptic ulcer disease. Helicobacter pylori (Hp) infection and non-steroidal anti-inflammatory drugs (NSAIDs) are the two major causes of peptic ulcers.¹ Other uncommon etiologies for peptic ulcers are named Hp-negative, NSAID-negative ulcers, including gastrinoma (Zollinger–Ellison syndrome), gastric malignancy (adenocarcinoma and lymphoma), Crohn disease, eosinophilic gastroenteritis, viral infections, Behcet disease, acute stress, and mucosal ischemia.²

Gastric acid, bicarbonate, and digestive enzymes compose the gastric environment with a dynamic pH value between 1.5 and 3. In normal conditions, protective mechanisms of the stomach can protect and repair the gastric mucosa. When an imbalance between gastric acid and mucosal protection occurs, such as gastric acid hypersecretion and impaired duodenal bicarbonate secretion, it may result in peptic ulcer disease. Hp infection can disrupt the protective mucous layer, causing gastritis and impair the mucosa healing.³ Hp-induced antral inflammation can also increase basal and stimulated gastric acid secretion.⁴ NSAIDs inhibit mucosal prostaglandin synthesis, which can reduce the mucosa blood flow, the integrity of the mucosal barrier, and the amount of bicarbonate.⁵

Common symptoms of peptic ulcers include epigastric pain, bloating, nausea, vomiting, and in severe cases, bleeding or perforation of the stomach or duodenum.^1,6 The most common complication of peptic ulcers in emergency departments is bleeding, approximately 100–170 per 100,000 worldwide. Peptic ulcer bleeding is a serious medical condition causing hematemesis, melena (tarry stool), or hematochezia. Patients without timely treatment can progress into anemia, hypovolemic shock, multiorgan failure, or even death. The mortality rate of peptic ulcer bleeding is approximately 5%–12%.^7,8 Therefore, clinicians have been dedicated to developing the most effective treatment for peptic ulcer bleeding for decades.

Current treatment for peptic ulcer bleeding

A standardized assessment and timely treatment are necessary for patients with bleeding peptic ulcers (Figure 1). The initial step is stabilizing the patient’s hemodynamic status and airway patency. The treatment goal of fluid resuscitation is to keep systolic blood pressure over 100 mmHg and pulse lower than 100/min by intravenous crystalloid fluid resuscitation. Packed RBC, platelets, and fresh frozen plasma transfusion are needed to keep the hemoglobin level higher than 7 g/dL, platelet counts over 50,000/mm³, and prothrombin time international normalized ratio (PT-INR) less than 15 s.

Figure 1.

Management flowchart for peptic ulcer bleeding.

Several risk score assessments have been designed to assist with the risk stratification for peptic ulcer bleeding patients (Figure 2). Glasgow–Blatchford bleeding score aimed to identify the urgency of endoscopic therapy by using the patient’s blood test, blood pressure, past history, and clinical presentations.⁹ A score >0 is in need of medication and endoscopic intervention, while a score over 8 points is indicated for ICU admission. The AIMS65 scale has been proven to predict in-hospital mortality and length of hospitalization by using the patient’s blood test, blood pressure, and clinical presentations.¹⁰ On the other hand, the pre-endoscopic Rockall score is a useful prognostic indicator to identify mortality risk by using vital signs and past history.¹¹

Figure 2.

Risk assessment score interpretation for peptic ulcer before endoscopy.

After risk assessments, patients with bleeding peptic ulcers should receive pharmacologic treatment and endoscopic examination within 24 h. The current guideline suggests intravenous proton pump inhibitor (PPI) as the first choice for gastric acid suppression, and the dose and duration depend on the endoscopic findings. The endoscopic finding of bleeding peptic ulcers can be classified by Forrest classification (Figure 3), which can identify high or low risk for rebleeding and mortality.^12,13 Forrest IA (spurting vessel), IB (active oozing), IIA (non-bleeding visible vessel), and IIB (adherent clots) are defined as major stigmata of recent hemorrhage (SRH), indicating a higher rebleeding and mortality risk in need of appropriate endoscopic treatment.¹² Forrest IIC (flat red spot) is defined as minor SRH with a lower risk, and Forrest III (clean base) is without recent SRH.¹⁴ In combination with the clinical presentation and endoscopic findings, the complete Rockall score predicts the rebleeding and mortality risk.^15,16 A complete Rockall score of 0–1 was low risk, 2–4 was intermediate risk, and ⩾5 was defined as a high risk.¹⁶

Figure 3.

Forrest classification of peptic ulcer.

Pharmacologic treatment

Peptic ulcer healing is a reconstruction process of mucosa through the formation of granulation tissue.¹⁷ Granulation tissue formation takes place approximately 72 h through the formation of the ulcer base, blood vessel, and re-establishment of glandular architecture after the ulcer occurs.¹⁸ To ensure the appropriate environment for ulcer healing, pharmacologic treatment of peptic ulcers includes three aspects—acid suppression, mucosa protection, and Hp eradication.¹⁹

PPI and histamine (H2) receptor antagonists

Gastric acid impairs clot formation, induces platelet disaggregation, and facilitates clot lysis.^20,21 Acid suppression to keep intragastric pH > 3 over 20 h is the mainstay of a peptic ulcer treatment.²² PPIs can inhibit gastric acid secretion by blocking the H+/K+ ATPase enzyme activity by covalently binding to its sulfhydryl group of parietal cells in the stomach.²³ PPIs are prodrugs requiring gastric acid secretion to be converted to the active form.²⁴ After the conversion into active sulfenamide or sulfenic acid, PPIs can maintain intragastric pH > 4 for approximately 20 h per day.²⁵ In contrast, H2 receptor antagonists can only maintain intragastric pH > 4 for 8 h, and tachyphylaxis may occur within 3–5 days of regular use.²⁶

In 2015, United States Food and Drug Administration (FDA) approved six types of PPIs—omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole. For peptic ulcer-related active bleeding, intravenous esomeprazole and pantoprazole are suggested.²⁷ Before endoscopic evaluation, administration of intravenous PPI can reduce the proportion of participants with SRH and the requirement for endoscopic therapy.²⁸ After standard endoscopic treatment, bolus (80 mg) with continuous infusion of high-dose (8 mg/hr) esomeprazole or pantoprazole for 72 h is suggested for patients with major SRH to reduce the rate of rebleeding, in need of surgery, and mortality.^29,30 For patients with a minor SRH peptic ulcer or a clean-based ulcer, a standard dose of oral PPI is sufficient for ulcer healing.³¹

Potassium-competitive acid blocker

Potassium-competitive acid blocker (P-CAB) inhibits H+/K+ ATPase in gastric parietal cells.³² Different from oral-form PPIs, P-CABs are not degraded by gastric acid, so P-CABs do not require enteric coating before absorption. Besides, P-CABs are active drugs, not prodrugs as PPIs. In this situation, P-CABs can reach a near-maximum inhibitory effect from the first dose and remain effective for 24 h, while oral-form PPIs require 3–5 days for maximal acid inhibition.^33,34 P-CABs have potential superior effects over oral PPIs due to stronger acid suppression, stability in acidic environments, faster drug onset, and longer half-life.³⁵

Vonoprazan, one of the P-CABs, has been proven to be non-inferior to oral PPIs in erosive esophagitis,³⁶ Hp eradication,³⁷ recurrent peptic ulcer prevention,^38,39 and ulcer treatment.⁴⁰ Due to stronger acid suppression and faster drug onset, P-CABs have potential benefits in bleeding peptic ulcers.³⁵ For bleeding peptic ulcers, a recent multicenter randomized clinical trial revealed a non-inferior effect of oral-form vonoprazan to intravenous high-dose PPI in preventing 30-day rebleeding after a successful endoscopic hemostasis.⁴¹ It can be expected that P-CABs will play more important roles in the treatment of peptic ulcer bleeding in the future.

Tranexamic acid

Tranexamic acid (TXA) is an antifibrinolytic medication that functions by inhibiting fibrin degradation through binding to tissue plasminogen, thus impeding blood clot breakdown and diminishing bleeding.⁴² Numerous studies have demonstrated its efficacy in reducing blood loss and transfusion requirements in surgical bleeding scenarios.^43–45

However, its application in gastrointestinal (GI) bleeding remains controversial. TXA may be effective in reducing GI-bleeding-related mortality, but its hemostatic ability is inconsistent.⁴⁶ A multicenter study—Hemorrhage Alleviation with Tranexamic Acid–Intestinal System (HALT-IT) trial—concluded that intravenous TXA failed to prevent GI-bleeding-related deaths among 12,009 patients.⁴⁷

The antifibrinolytic properties of TXA are at the bleeding site.^48,49 In contrast to systemic application, local administration is anticipated to yield superior efficacy. A recent clinical trial demonstrated a lower treatment failure rate and longer freedom from 28-day rebleeding spraying topical TXA after endoscopic hemostasis on a bleeding peptic ulcer.⁵⁰

Sucralfate

Sucralfate, a basic aluminum salt of sucrose octasulfate, can increase mucus secretion, mucosal blood flow, and local prostaglandin production.^51,52 In the presence of acid, the sucralfate tablet dissolves into an aluminum salt and sucrose sulfate to bind to exposed proteins on damaged cells and create a protective layer to shield the GI mucosa.⁵³ Sucralfate also binds to growth factors and thus promotes angiogenesis and mucosal healing.⁵⁴ Therefore, sucralfate has been used in the treatment of GI ulcers.^55,56

For preventing peptic ulcer bleeding, sucralfate can prevent stress ulcers in critical patients in ICU.⁵⁷ Applying sucralfate to the stomach through a nasogastric tube (2 g every 8 h) can reduce the formation of peptic ulcers.⁵⁸ In vitro, sucralfate can protect the blood clot from gastric acid lysis.⁵⁹ However, for active peptic ulcer bleeding, sucralfate has shown no impact on hemostasis.⁶⁰ This may be because sucralfate cannot alter gastric acid secretion or buffer acid, and it only has a local effect to protect the blood clot and the ulcer by direct contact.⁶¹ Oral intake of the tablet does not guarantee the contact duration between sucralfate and the peptic ulcer, so the effect on the bleeding peptic ulcer is not evident. Otherwise, if sucralfate can be applied precisely to the bleeding ulcer site through endoscopic assistance, the hemostatic effect of this drug may be re-evaluated.

Misoprostol

Misoprostol, a synthetic prostaglandin E1 (PGE1), can directly stimulate PGE1 receptors on parietal cells in the stomach to inhibit gastric acid.^62,63 It can also induce mucus and bicarbonate secretion to improve blood flow and enhance mucosal healing.^64,65 Misoprostol has a similar effect with PPIs for NSAID-related ulcers.⁶⁶ FDA has approved misoprostol for the prevention and treatment of NSAID-induced peptic ulcers.⁶⁴ However, abdominal pain and diarrhea appear to be a prominent adverse effect of misoprostol, so the tolerance was inferior to PPIs.⁶⁶

For GI bleeding, clinical trials demonstrated that misoprostol can reduce blood loss and promote the healing of bleeding small bowel ulcers among aspirin users.^67,68 For hemostasis, misoprostol can promote the constriction of blood vessels and reduce blood loss in surgery and labor.^69,70 However, due to the higher adverse effect frequency, no large-scale study has evaluated the hemostatic effect of misoprostol on peptic ulcer bleeding against PPIs.⁷¹ Current guidelines for peptic ulcer bleeding do not identify the role of misoprostol. However, based on acid-suppression and mucosa-protection effect, it is believed to be beneficial during combination therapy for refractory peptic ulcers.⁷²

Endoscopic treatment

Endoscopic hemostasis is the primary treatment to stop bleeding for bleeding peptic ulcers. Without adequate endoscopic treatment, peptic ulcers with a spurting vessel (Forrest IA, 100%), active oozing (Forrest IB, 30%), non-bleeding visible vessel (Forrest IIA, 50%), and adherent clots (Forrest IIB, 30%) are generally with high risk (>30%) for recurrent bleeding.⁷³ After adequate combination therapy with PPI and endoscopic hemostasis, the recurrent bleeding rates can be reduced to 5%–20%.⁷⁴ On the other hand, ulcers with a clean base (Forrest III) or a flat pigmented spot (Forrest IIC) are at low risk of recurrent bleeding (<10%), and endoscopic hemostasis is not required. Endoscopic hemostatic therapy includes injection therapy (epinephrine, ethanol, and histoacryl), thermal coagulation, argon plasma coagulation (APC), hemostatic clips, and combination therapy, chosen based on the bleeding lesion’s characteristics and the operator’s judgment.

Injection therapy

The main method of injection therapy is diluted epinephrine, typically mixed with normal saline at ratios of 1:10,000 or 1:20,000 and injected in amounts ranging from 0.5 to 2.0 mL in four quadrants within 3 mm of the bleeding site. This mixture is chosen for its ability to induce local tamponade and vasoconstriction effects. Epinephrine injection is advantageous because it effectively slows down bleeding temporarily, especially during active hemorrhage in endoscopic procedures. This temporary slowdown helps improve visibility, facilitating the easier performance of afterward endoscopic interventions. Injection therapy alone has a higher risk of recurrent bleeding than other standard treatments, such as thermal coagulation and hemostatic clips.⁷⁵ Therefore, injection therapy alone is not an adequate endoscopic treatment. Combination therapy with epinephrine injection and another endoscopic therapy reduces the risk of recurrent bleeding after the initial treatment, which is the current standard endoscopic treatment.^75,76

Pure ethanol is another effective injection therapy to control bleeding from peptic ulcers. Pure ethanol injection causes blood vessel constriction, sclerosis, and local thrombosis, promoting blood clot formation and hemostasis.⁷⁷ Ethanol injection revealed a prominent hemostatic effect as thermal therapy and hemostatic clips.^77–79 Aliquots of 0.1–0.2 mL of absolute ethanol were repeatedly injected, with at least two injections per quadrant, 1–3 mm from the bleeding point of the vessel. However, pure ethanol can lead to local dehydration, sclerosis, tissue necrosis, and even perforation.^80,81 The appropriate volume of ethanol is not easy to handle; less than 1 mL may avoid ulcer perforation,⁸² while 1–2 mL may be needed to stop a spurting bleeder.⁸³ Animal experiments have shown that injecting more than 2 mL can cause severe tissue injury.⁸⁴ Therefore, the total volume per session should be limited to 2 mL for safety. Due to possible severe adverse effects, pure ethanol injection is not often applied in current endoscopic treatment.

N-butyl-2-cyanoacrylate (Histoacryl) is a liquid tissue adhesive agent, which turns into a solid material when it touches blood.⁸⁵ Cyanoacrylates quickly block bleeding vessels and have been the standard therapy for variceal bleeding. For peptic ulcer bleeding, Histoacryl injection showed a similar effect to hypertonic saline–epinephrine injection in stopping bleeding, and with an even lower rebleeding rate for active arterial bleeding.⁸⁵ However, it can cause serious issues like thromboembolism, tissue damage, or perforation.^86,87 Because of these rare but severe risks, it is recommended to use Histoacryl as a last resort before considering surgery for peptic ulcer bleeding treatment.⁸⁵

In current endoscopic practice guidelines, the role of injection therapy is more likely a bridging therapy, especially for bleeding ulcers with spurting vessels.⁷⁵ With the rapid but short effect of tamponade by injection, the bleeding can be stopped temporarily and the endoscopic view can be clearer for the application of more reliable and endurable therapies, such as thermal and mechanical therapies.

Thermal therapy

Thermal coagulation was the first endoscopic treatment. When the temperature reaches 60°C, the protein coagulates and thus causes thermal contraction of the bleeding vessels and tissue.⁸⁸ Thermal therapies are divided into contact and non-contact modalities.⁸⁹

Contact devices like heater probes, bipolar electrocoagulation, and soft monopolar electrocoagulation use pressure from the probe tip directly on the bleeding site, along with heat or electricity, to stop bleeding.⁸⁹ Thermal contact devices can effectively reduce recurrent bleeding and mortality rates.^29,90 Besides, combined thermal therapy with injection therapy is superior to thermal coagulation alone in reducing rebleeding risk.⁹¹ However, tissue vaporizes when the temperature reaches 100°C, so a higher temperature may result in extensive tissue destruction, deeper ulceration, and even perforation.⁸⁸ For patients with deep and huge ulcers, applying high temperatures to vessel walls may lead to perforation.⁸⁸ Hence, the current guideline suggests to use of the large 3.2-mm probe with firm pressure for 8–10 s.⁷⁵

Monopolar hemostatic forceps with soft coagulation (MHFSC), a relatively new contact thermal device, has been widely used in the treatment of bleeding vessels during endoscopic submucosal dissection (ESD).⁹² MHFSC works at a lower voltage (maximum of 200 V), so it is associated with a lower risk of perforation because of the reduced coagulation effect at the deep tissue level.⁹³ MHFSC has been proven to be effective for initial hemostasis and preventing rebleeding.^92–94

APC is a non-contact thermal device that delivers a jet of ionized gas to the bleeding lesion.⁹⁵ Argon gas is emitted and then ionized by an electrical current that results in the coagulation of the lesion, which stops the bleeding.⁹⁶ It is commonly used for superficial vascular issues like angiodysplasia and gastric antral vascular ectasia.⁹⁷ APC application after water injection is better at preventing rebleeding from peptic ulcers than water injection alone.⁹⁶ However, while the absence of direct contact is beneficial for small superficial vessels, this method might not work as well for larger vessels.^97,98 In this situation, APC is only conditionally recommended for peptic ulcer bleeding in current guidelines.⁷⁵

Mechanical therapies

Mechanical therapies include band ligation and clipping, providing a simple and direct local tamponade of bleeding ulcers and vessels to achieve hemostasis. Band ligation is a principle where pliable tissue is drawn into a cylindrical chamber attached to the end of an endoscope, followed by the release of an elastic band to constrict both the tissue and the vessel beneath it.⁹⁹ This method is commonly employed for variceal bleeding. Additionally, for patients with non-variceal upper GI bleeding, band ligation offers a safe and effective means of achieving hemostasis.^100,101 It has proven to be an effective and safe treatment for peptic ulcer bleeding and can serve as a salvage therapy for difficult cases unresponsive to injection therapy.^102,103 Combining band ligation with epinephrine injection has also shown superior hemostatic efficacy over epinephrine injection alone for bleeding peptic ulcers.¹⁰⁴ However, its efficacy is limited in cases of large ulcers with hard, fibrotic bases, which are difficult to suction into the endoscopic device before applying the elastic band.¹⁰⁵ Therefore, endoscopic band ligation presents itself as an alternative treatment option for small peptic ulcer bleeding.

Clipping method includes through-the-scope clip (TTSC) and over-the-scope clip (OTSC). TTSCs are metal clips that can pass through the working channel of endoscopy without the need for endoscopy withdrawal. TTSCs have been widely used for hemostasis, perforation closure, and endoscopic marking since the 1990s.^106,107 Novel TTSCs have emerged in recent years with different rotatability, open angles, tensile strength, and closure strength.¹⁰⁶

For bleeding peptic ulcers, single-use of TTSC has shown a lower recurrent bleeding rate than injection therapy alone.¹⁰⁸ Similarly, combining TTSC with injection therapy has a lower rebleeding rate than injection therapy alone.^104,109 These results indicate that a longer and stabler direct tamponade at the bleeding vessel is the mainstay of hemostasis.¹⁰⁸ Although the combination therapy of TTSC and injection showed similar hemostatic efficacy to TTSC alone, the endoscopic view may be clearer after the bleeding stops by injection.⁹¹ The hemostatic efficacy was also similar between TTSC and thermal therapy.⁹¹ However, TTSC requires accuracy and experience, and it can be challenging to apply in specific areas (e.g. proximal lesser curvature of the stomach, posterior wall, and junction of the first and second portion of the duodenum) and with fibrotic ulcers.¹¹⁰ Thermal therapy can be more accessible among those specific areas.

Different from TTSCs, endoscopy withdrawal is needed for the OTSC installation. The OTSC is shaped like a “bear claw,” and the sizes (11, 12, and 14 mm) and depths (3 and 6 mm) are larger than traditional TTSCs.¹¹¹ In this situation, OTSC has a greater area captured and greater compression force than TTSCs.¹¹² OTSC was originally designed for the closure of GI perforations or leaks, owing to its capability to grasp a larger volume of tissue with increased compression force.¹¹³ The strong grasp of OTSC expanded its application to hemostasis among GI bleeding.¹¹⁴ For patients with recurrent peptic ulcer bleeding, OTSC has a lower rebleeding rate than combination therapy of TTSC and injection.¹¹⁵ For refractory peptic ulcer bleeding, OTSC is an effective and safe rescue therapy with a rescue rate of approximately 80%.^112,116 A recent clinical trial even proved a superior initial hemostatic rate and a lower rebleeding rate of OTSC over TTSC among first-line therapy for bleeding peptic ulcers.¹¹⁷ However, another clinical trial with large peptic ulcers (size ⩾ 1.5 cm) showed routine employing OTSCs as the primary hemostatic measure did not demonstrate a significant decrease in 30-day rebleeding compared to standard endoscopic therapy.¹¹⁸ Additionally, OTSC migrated into the gastric wall, and leaking out to the third space can happen.¹¹⁹ Based on current evidence, OTSC is recommended as a rescue therapy for recurrent and refractory peptic ulcer bleeding.

Challenging ulcer bleeding and salvage treatments

Despite advancements in endoscopic and pharmacological therapies, still a minority of patients (8%–15%) experience refractory peptic ulcer bleeding.¹²⁰ Predictors of rebleeding include initial hemodynamic instability, low hemoglobin levels upon presentation, greater blood transfusion requirements, high-risk endoscopic stigmata, large ulcer size, and specific ulcer locations like posterior duodenal or high lesser gastric curvature ulcers.^121,122 For patients with peptic ulcers who experience recurrent bleeding despite initial endoscopic treatment, a second-look endoscopy has shown long-term bleeding control with reduced complications, no increased mortality risk, and lower costs compared to surgery.¹²³ Therefore, guidelines recommend a second-look endoscopy in such cases.^75,124

Malignancy-related ulcer bleeding is another challenge to manage. Due to local vessel invasion and friable neovascularization of tumors, malignant ulcers can rebleed even after initial hemostasis was achieved.¹²⁵ Although surgery and endoscopic resection can remove the tumor, not all patients are appropriate candidates. Standard combination therapy with injection and thermal or mechanical treatment can reach 80%–90% initial hemostasis.¹²⁶ However, the overall rebleeding rate of malignant ulcers is 40%, and the rebleeding rate within 30 days is 30%.¹²⁶ Until now, there is no strongly recommended therapy for malignant bleeding in treatment guidelines.⁷⁵

If bleeding cannot be controlled through endoscopy, options such as transcatheter arterial embolization (TAE) or surgical intervention should be considered. Although TAE has higher rebleeding rates compared with surgery, it is associated with significantly lower complication risks, shorter hospital stays, and no difference in mortality.^127,128 Hence, TAE is the preferred salvage therapy for patients with failed endoscopic therapy, while surgery is considered when TAE is unavailable locally or after failed TAE attempts.^75,124

Novel endoscopic therapy—hemostatic powder spray

Hemostatic powder spray is a novel technique developed since 2013, offering a valuable solution for managing active peptic ulcer bleeding. Through air supply by the spraying system, the hemostatic powder can directly attach to bleeding surfaces under the endoscopy view.¹²⁹ Through the absorption of water molecules of the oozing blood, it becomes a physical barrier and concentrates clotting factors at the site of bleeding.¹³⁰ This non-touch technique can avoid heat coagulation thermal injury and sclerosis therapy-related mucosal damage.¹³¹ Additionally, the hemostatic powder spray is easy to use, which can reduce the operational difficulty among endoscopy trainees.

TC-325 (Hemospray) and EndoClot are commonly used hemostatic powder spraying systems. Hemospray is the first and the most widely used hemostatic powder in the world. Hemospray is comprised of bentonite, a mineral powder that rapidly absorbs water in the blood, creating an adhesive physical barrier for mechanical tamponade.¹³² After the bleeding stops, the powder falls off from the mucosa within 72 h without causing obstruction in the GI tract.¹³² Hemospray was approved in 2018 for use in facilitating endoscopic hemostasis and reducing recurrent bleeding.¹³³ Hemospray monotherapy demonstrated high successful procedure rate (>95%) and high hemostatic rate (>90%) in bleeding peptic ulcers, even in Forrest IA lesions.^133–135 It can also serve as a rescue therapy when conventional standard endoscopic hemostasis fails, especially in malignant ulcer bleeding.^136,137 However, early fall-off of the Hemospray barrier increases the rebleeding risk within 72 h. Besides, Forrest IA peptic ulcers are reported to be associated with a higher risk of rebleeding after Hemospray monotherapy.¹³⁸

EndoClot consists of absorbable modified polymers sourced from plant starch. When in contact with blood, these polymers rapidly absorb water to create a protective gel matrix and concentrate coagulation factors at the bleeding ulcer.¹³⁹ Additionally, EndoClot has demonstrated the ability to stimulate fibroblasts and growth factors, thereby aiding in wound healing.¹⁴⁰ Similar to Hemospray, the adhesive material of EndoClot falls off within 24 h, causing a risk of early rebleeding after endoscopic treatment.¹³⁹ Hemospray and EndoClot share a similar successful hemostasis rate (>90%) and rebleeding rate (<20%) within 30 days.^141,142 Air blow injury is the major concern among the use of hemostatic powder spray. Numerous instances of visceral perforation have been observed after the administration of hemostatic powder.^143,144

Several new hemostatic powder devices have emerged in the last decades, for example, UI-EWD (NexPowder, Nextbiomedical, Incheon, South Korea), and Ankaferd Blood Stopper (ABS, Ankaferd Health Products Ltd, Turkey). However, several concerns do not suggest this treatment modality to be used as a first-line therapy. The powders can block the endoscopic view and the bleeder, making subsequent rescue therapies difficult.¹³⁶ Furthermore, technical issues of catheter occlusion may occur before and during the spray, especially when the working channel is moist.¹³⁶ Therefore, hemostatic powder spray is commonly used as the last step during the endoscopic treatment. The 2019 consensus guidelines recommend the utilization of hemostatic powder sprays as a temporary solution to control bleeding when conventional endoscopic treatments are ineffective or inaccessible.¹⁴⁵ This strategy is especially advantageous in instances of malignant ulcers and difficult-to-contact bleeders (proximal lesser curvature of the stomach, posterior wall, and junction of the first and second portion of the duodenum).¹⁴⁵

Future prospectives

Hemostatic gel emulsion may become another rescue solution for uncontrollable peptic ulcer bleeding. PuraStat, a novel transparent gel with self-assembling peptides, has been invented for treating hemorrhages from small vessels in the GI tract.¹⁴⁶ PuraStat gel includes three types of amino acids, which can be activated after contact with bodily fluid as a change in pH and salt concentration.¹⁴⁶ After activation, PuraStat transforms into matrix fibers to stick to and seal the blood vessel as a mechanical barrier.¹⁴⁶ PuraStat was first been applied to reduce delayed bleeding and improve wound healing after endoscopic resection in the GI tract, such as ESD.¹⁴⁷ For acute GI bleeding, the hemostatic gel also demonstrated a high hemostatic rate (90%) as a rescue therapy after conventional therapy.^148,149 The advantage of PuraStat over hemostatic powders is the transparency, which improved visualization and a chance for subsequent endoscopic interventions.¹⁵⁰ Further clinical trials using hemostatic gels are warranted to evaluate the efficacy of being the first-line therapy for peptic ulcer bleeding.

The combination of the powder spray system and hemostatic drugs is another possible solution for challenging bleeding ulcers. With the air supply from the spray system, medication powders with a local hemostatic effect can be directly brought to the bleeding site. TXA is an antifibrinolytic medication that inhibits fibrin degradation with a local effect, and the delivery of TXA powder has been proven to improve hemostasis and reduce the recurrent bleeding rate in peptic ulcers.⁵⁰ Based on our review, sucralfate can create a protective layer and promote mucosal healing with a local effect, which makes it a potential drug powder for a bleeding ulcer.⁵⁴ Through the precise drug powder spray, the drug dosage can be minimized to avoid possible adverse events. However, this idea about drug powder delivery in bleeding ulcers needs more studies for validation.

Conclusion

With the development of medications and endoscopic therapies, the successful rate of immediate hemostasis of peptic ulcers has been improved to over 90%, and the 30-day rebleeding rate has been reduced to nearly 10%. Gastroenterologists are still working on the perfect solution for challenging peptic ulcer bleeding. Hemostatic powder spray and hemostatic gel emulsion are potentially the final parts of the puzzle. How to avoid powder obstruction and maintain a clear endoscopic view are unsolved problems after hemostatic powder spray. Extending the powder/gel residence time on the ulcer can potentially reduce the rebleeding rate. Among novel pharmacologic treatments, P-CABs have shown non-inferior efficacy to high-dose intravenous PPIs, which may also be beneficial before endoscopic treatment and after endoscopic treatment fails. A combination of conventional and novel treatment, including drugs and endoscopy, may become the mainstream approach for individual therapy. Clinical trials and real-world evidence are needed in the last mile toward the perfect solution for peptic ulcer bleeding.

Footnotes

Appendix

Acknowledgements

None.

Declarations

ORCID iD

Hsueh-Chien Chiang

References

Malfertheiner

Chan

McColl

. Peptic ulcer disease. Lancet 2009; 374(9699): 1449–1461.

Chiang

Chuang

. Case report: gastric ischemia, a fatal disease of gastric pneumatosis. BMC Gastroenterol 2021; 21(1): 368.

Partipilo

Woster

. The role of Helicobacter pylori in peptic ulcer disease. Pharmacotherapy 1993; 13(4): 330–339.

Olbe

Fandriks

Hamlet

, et al. Mechanisms involved in Helicobacter pylori induced duodenal ulcer disease: an overview. World J Gastroenterol 2000; 6(5): 619–623.

Tai

FWD

McAlindon

. Non-steroidal anti-inflammatory drugs and the gastrointestinal tract. Clin Med (Lond) 2021; 21(2): 131–134.

Kavitt

Lipowska

Anyane-Yeboa

, et al. Diagnosis and treatment of peptic ulcer disease. Am J Med 2019; 132(4): 447–456.

Kyaw

Lau

JYW

. High rate of mortality more than 30 days after upper gastrointestinal bleeding. Clin Gastroenterol Hepatol 2017; 15(12): 1858–1859.

Sung

JJY

Lau

JYW

Ching

JYL

, et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med 2010; 152(1): 1–9.

Chatten

Purssell

Banerjee

, et al. Glasgow Blatchford Score and risk stratifications in acute upper gastrointestinal bleed: can we extend this to 2 for urgent outpatient management? Clin Med (Lond) 2018; 18(2): 118–122.

10.

Park

Song

Tak

, et al. The AIMS65 score is a useful predictor of mortality in patients with nonvariceal upper gastrointestinal bleeding: urgent endoscopy in patients with high AIMS65 scores. Clin Endosc 2015; 48(6): 522–527.

11.

Tham

James

Kelly

. Predicting outcome of acute non-variceal upper gastrointestinal haemorrhage without endoscopy using the clinical Rockall Score. Postgrad Med J 2006; 82(973): 757–759.

12.

Bleau

Gostout

Sherman

, et al. Recurrent bleeding from peptic ulcer associated with adherent clot: a randomized study comparing endoscopic treatment with medical therapy. Gastrointest Endosc 2002; 56(1): 1–6.

13.

de Groot

van Oijen

MGH

Kessels

, et al. Reassessment of the predictive value of the Forrest classification for peptic ulcer rebleeding and mortality: can classification be simplified? Endoscopy 2014; 46(1): 46–52.

14.

Yen

H-H

P-Y

T-L

, et al. Forrest classification for bleeding peptic ulcer: a new look at the old endoscopic classification. Diagnostics (Basel) 2022; 12(5): 1066.

15.

Cieniawski

Kuźniar

Winiarski

, et al. Prognostic value of the Rockall score in patients with acute nonvariceal bleeding from the upper gastrointestinal tract. Przegl Lek 2013; 70(1): 1–5.

16.

Bozkurt

Peker

Unsal

, et al. The importance of Rockall Scoring System for upper gastrointestinal bleeding in long-term follow-up. Indian J Surg 2017; 79(3): 188–191.

17.

Tarnawski

. Cellular and molecular mechanisms of gastrointestinal ulcer healing. Dig Dis Sci 2005; 50(Suppl. 1): S24–S33.

18.

Syam

Sadikin

Wanandi

, et al. Molecular mechanism on healing process of peptic ulcer. Acta Med Indones 2009; 41(2): 95–98.

19.

Manu

Rogozea

Sandor

, et al. Pharmacological management of peptic ulcer: a century of expert opinions in Cecil Textbook of Medicine. Am J Ther 2021; 28(5): e552–e559.

20.

Patchett

Enright

Afdhal

, et al. Clot lysis by gastric juice: an in vitro study. Gut 1989; 30(12): 1704–1707.

21.

Green

Jr Kaplan

Curtis

, et al. Effect of acid and pepsin on blood coagulation and platelet aggregation. A possible contributor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978; 74(1): 38–43.

22.

Hunt

Cederberg

Dent

, et al. Optimizing acid suppression for treatment of acid-related diseases. Dig Dis Sci 1995; 40(Suppl): 24S–49S.

23.

Sachs

Shin

Howden

. Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther 2006; 23(Suppl. 2): 2–8.

24.

Shin

Sachs

. Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep 2008; 10(6): 528–534.

25.

Wolfe

Sachs

. Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology 2000; 118(Suppl. 1): S9–S31.

26.

Wilder-Smith

Ernst

Gennoni

, et al. Tolerance to oral H2-receptor antagonists. Dig Dis Sci 1990; 35(8): 976–983.

27.

Laine

Jensen

. Management of patients with ulcer bleeding. Am J Gastroenterol 2012; 107(3): 345–360; quiz 361.

28.

Sreedharan

, et al. Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database Syst Rev 2010; 2010(7): CD005415.

29.

Laine

McQuaid

. Endoscopic therapy for bleeding ulcers: an evidence-based approach based on meta-analyses of randomized controlled trials. Clin Gastroenterol Hepatol 2009; 7(1): 33–47; quiz 1–2.

30.

Strand

Kim

Peura

. 25 years of proton pump inhibitors: a comprehensive review. Gut Liver 2017; 11(1): 27–37.

31.

Laine

Peterson

. Bleeding peptic ulcer. N Engl J Med 1994; 331(11): 717–727.

32.

Hori

Imanishi

Matsukawa

, et al. 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases. J Pharmacol Exp Ther 2010; 335(1): 231–238.

33.

Andersson

Carlsson

. Potassium-competitive acid blockade: a new therapeutic strategy in acid-related diseases. Pharmacol Ther 2005; 108(3): 294–307.

34.

Sakurai

Mori

Okamoto

, et al. Acid-inhibitory effects of vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects—a randomised open-label cross-over study. Aliment Pharmacol Ther 2015; 42(6): 719–730.

35.

Abdel-Aziz

Metz

Howden

. Review article: potassium-competitive acid blockers for the treatment of acid-related disorders. Aliment Pharmacol Ther 2021; 53(7): 794–809.

36.

Ashida

Sakurai

Nishimura

, et al. Randomised clinical trial: a dose-ranging study of vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the treatment of erosive oesophagitis. Aliment Pharmacol Ther 2015; 42(6): 685–695.

37.

Yang

Zhang

, et al. Meta-analysis of Helicobacter pylori eradication therapy using vonoprazan as an acid suppressor compared with bismuth quadruple therapy. Helicobacter 2024; 29(2): e13059.

38.

Kawai

Oda

Funao

, et al. Vonoprazan prevents low-dose aspirin-associated ulcer recurrence: randomised phase 3 study. Gut 2018; 67(6): 1033–1041.

39.

Mizokami

Oda

Funao

, et al. Vonoprazan prevents ulcer recurrence during long-term NSAID therapy: randomised, lansoprazole-controlled non-inferiority and single-blind extension study. Gut 2018; 67(6): 1042–1051.

40.

Ichida

Ueyama

Eto

, et al. Randomized controlled trial comparing the effects of vonoprazan plus rebamipide and esomeprazole plus rebamipide on gastric ulcer healing induced by endoscopic submucosal dissection. Intern Med 2019; 58(2): 159–166.

41.

Geeratragool

Kaosombatwattana

Boonchote

, et al. Comparison of vonoprazan versus intravenous proton pump inhibitor for prevention of high-risk peptic ulcers rebleeding after successful endoscopic hemostasis: a multicenter randomized noninferiority trial. Gastroenterology 2024; 167: 778–787.e3.

42.

Picetti

Shakur-Still

Medcalf

, et al. What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies. Blood Coagul Fibrinolysis 2019; 30(1): 1–10.

43.

Hunt

. The current place of tranexamic acid in the management of bleeding. Anaesthesia 2015; 70(Suppl. 1): 50–53, e18.

44.

Farzanegan

Ahmadpour

Khoshmohabbat

, et al. The effect of topical tranexamic acid on intraoperative blood loss in patients undergoing posterior lumbar laminectomy and discectomy: a randomized, double-blind, controlled trial study. Asian Spine J 2022; 16(6): 857–864.

45.

Husain

Ramos

Karaf

JHA

, et al. Efficacy of topical tranexamic acid to reduce bleeding in endoscopic sinus surgery for chronic rhinosinusitis with polyposis. Eur Arch Otorhinolaryngol 2023; 280(2): 737–741.

46.

Bennett

Klingenberg

Langholz

, et al. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev 2014; 2014(11): CD006640.

47.

HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet 2020; 395(10241): 1927–1936.

48.

Arun-Kumar

Naresh-Babu

. Is there a role for preoperative local infiltration of tranexamic acid in elective spine surgery? A prospective randomized controlled trial analyzing the efficacy of intravenous, local infiltration, and topical administration of tranexamic acid. Global Spine J 2021; 11(1): 21–27.

49.

Engelen

Schutgens

Mauser-Bunschoten

, et al. Antifibrinolytic therapy for preventing oral bleeding in people on anticoagulants undergoing minor oral surgery or dental extractions. Cochrane Database Syst Rev 2018; 7(7): CD012293.

50.

Chiang

H-C

Chen

P-J

Yang

E-H

, et al. Precise application of topical tranexamic acid to enhance endoscopic hemostasis for peptic ulcer bleeding: a randomized controlled study (with video). Gastrointest Endosc 2023; 98(5): 755–764.

51.

Yoshida

Terao

Nagashima

. Sucralfate, a basic aluminum salt of sucrose sulfate. IV. Interaction with enzyme pepsin. Arzneimittelforschung 1980; 30(1): 78–80.

52.

Nagashima

. Development and characteristics of sucralfate. J Clin Gastroenterol 1981; 3(Suppl. 2): 103–110.

53.

Nicaeus

Tolentino

Adamis

, et al. Sucralfate and basic fibroblast growth factor promote endothelial cell proliferation around porous alloplastic implants in vitro. Ophthalmic Plast Reconstr Surg 1996; 12(4): 235–239.

54.

Masuelli

Tumino

Turriziani

, et al. Topical use of sucralfate in epithelial wound healing: clinical evidences and molecular mechanisms of action. Recent Pat Inflamm Allergy Drug Discov 2010; 4(1): 25–36.

55.

Drugs for GERD and peptic ulcer disease. Med Lett Drugs Ther 2022; 64(1647): 49–56.

56.

Blaser

Lytvyn

, et al. Gastrointestinal bleeding prophylaxis for critically ill patients: a clinical practice guideline. BMJ 2020; 368: l6722.

57.

Toews

George

Peter

, et al. Interventions for preventing upper gastrointestinal bleeding in people admitted to intensive care units. Cochrane Database Syst Rev 2018; 6(6): CD008687.

58.

Eddleston

Pearson

Holland

, et al. Prospective endoscopic study of stress erosions and ulcers in critically ill adult patients treated with either sucralfate or placebo. Crit Care Med 1994; 22(12): 1949–1954.

59.

Nysaeter

Berstad

. Sucralfate protects blood clots from peptic digestion by gastric juice in vitro. Digestion 2006; 73(2–3): 198–203.

60.

Wang

, et al. Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: an updated systematic review and network meta-analysis of randomized trials. Intensive Care Med 2020; 46(11): 1987–2000.

61.

Fohl

Regal

. Proton pump inhibitor-associated pneumonia: not a breath of fresh air after all? World J Gastrointest Pharmacol Ther 2011; 2(3): 17–26.

62.

Watkinson

Akbar

. Misoprostol in peptic ulcer disease. Prostaglandins 1987; 33(Suppl): 78–92.

63.

Wilson

. Antisecretory and mucosal protective actions of misoprostol. Potential role in the treatment of peptic ulcer disease. Am J Med 1987; 83(1A): 2–8.

64.

Turner

Agatonovic-Kustrn

Ward

. Off-label use of misoprostol in gynaecology. Facts Views Vis Obgyn 2015; 7(4): 261–264.

65.

Kim

. [NSAID-induced gastroenteropathy]. Korean J Gastroenterol 2008; 52(3): 134–141.

66.

Hawkey

Karrasch

Szczepañski

, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998; 338(11): 727–734.

67.

Kyaw

Otani

Ching

JYL

, et al. Misoprostol heals small bowel ulcers in aspirin users with small bowel bleeding. Gastroenterology 2018; 155(4): 1090–1097.e1.

68.

Taha

McCloskey

McSkimming

, et al. Misoprostol for small bowel ulcers in patients with obscure bleeding taking aspirin and non-steroidal anti-inflammatory drugs (MASTERS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2018; 3(7): 469–476.

69.

Protopapas

Kathopoulis

Chatzipapas

, et al. Misoprostol vs vasopressin as a single hemostatic agent in laparoscopic myomectomy: comparable, or just better than nothing? J Obstet Gynaecol Res 2020; 46(11): 2356–2365.

70.

Sambo

Ijaiya

Nwachukwu

, et al. Randomized controlled study comparing oral misoprostol with intramuscular oxytocin in active management of third stage of labour. Obstet Gynecol Sci 2024; 67: 279–285.

71.

Kim

Hong

, et al. Effectiveness of acid suppressants and other mucoprotective agents in reducing the risk of occult gastrointestinal bleeding in nonsteroidal anti-inflammatory drug users. Sci Rep 2019; 9: 11696.

72.

Kamada

Satoh

Itoh

, et al. Evidence-based clinical practice guidelines for peptic ulcer disease 2020. J Gastroenterol 2021; 56(4): 303–322.

73.

Colle

Wilmer

Le Moine

, et al. Upper gastrointestinal tract bleeding management: Belgian guidelines for adults and children. Acta Gastroenterol Belg 2011; 74(1): 45–66.

74.

Bitar

Moussa

. The risk factors for the recurrent upper gastrointestinal hemorrhage among acute peptic ulcer disease patients in Syria: a prospective cohort study. Ann Med Surg (Lond) 2022; 74: 103252.

75.

Laine

Barkun

Saltzman

, et al. ACG clinical guideline: upper gastrointestinal and ulcer bleeding. Am J Gastroenterol 2021; 116(5): 899–917.

76.

Vergara

Bennett

Calvet

, et al. Epinephrine injection versus epinephrine injection and a second endoscopic method in high-risk bleeding ulcers. Cochrane Database Syst Rev 2014; 2014(10): CD005584.

77.

Waring

Sanowski

Sawyer

, et al. A randomized comparison of multipolar electrocoagulation and injection sclerosis for the treatment of bleeding peptic ulcer. Gastrointest Endosc 1991; 37(3): 295–298.

78.

Shimoda

Iwakiri

Sakata

, et al. Evaluation of endoscopic hemostasis with metallic hemoclips for bleeding gastric ulcer: comparison with endoscopic injection of absolute ethanol in a prospective, randomized study. Am J Gastroenterol 2003; 98(10): 2198–2202.

79.

Koyama

Fujimoto

Iwakiri

, et al. Prevention of recurrent bleeding from gastric ulcer with a nonbleeding visible vessel by endoscopic injection of absolute ethanol: a prospective, controlled trial. Gastrointest Endosc 1995; 42(2): 128–131.

80.

Lee

Lieberman

. Complications related to endoscopic hemostasis techniques. Gastrointest Endosc Clin N Am 1996; 6(2): 305–321.

81.

Loperfido

Patelli

La Torre

. Extensive necrosis of gastric mucosa following injection therapy of bleeding peptic ulcer. Endoscopy 1990; 22(6): 285–286.

82.

Sugawa

Fujita

Ikeda

, et al. Endoscopic hemostasis of bleeding of the upper gastrointestinal tract by local injection of ninety-eight per cent dehydrated ethanol. Surg Gynecol Obstet 1986; 162(2): 159–163.

83.

Lin

Lee

Kang

, et al. Heat probe thermocoagulation and pure alcohol injection in massive peptic ulcer haemorrhage: a prospective, randomised controlled trial. Gut 1990; 31(7): 753–757.

84.

Randall

Jensen

Hirabayashi

, et al. Controlled study of different sclerosing agents for coagulation of canine gut arteries. Gastroenterology 1989; 96(Pt 1): 1274–1281.

85.

Lee

Kim

Hahm

, et al. Randomized trial of N-butyl-2-cyanoacrylate compared with injection of hypertonic saline-epinephrine in the endoscopic treatment of bleeding peptic ulcers. Endoscopy 2000; 32(7): 505–511.

86.

Lee

Kim

Lee

, et al. Life-threatening intraabdominal arterial embolization after histoacryl injection for bleeding gastric ulcer. Endoscopy 2000; 32(5): 422–424.

87.

Kobilica

Flis

Sojar

. Major complication after histoacryl injection for endoscopic treatment of bleeding peptic ulcer. Endoscopy 2012; 44(Suppl. 2): E204–E205.

88.

Kumar

Fleischer

. Thermal therapy for gastrointestinal bleeding. Gastrointest Endosc Clin N Am 1997; 7(4): 593–609.

89.

Jang

. Recent developments in the endoscopic treatment of patients with peptic ulcer bleeding. Clin Endosc 2016; 49(5): 417–420.

90.

Barkun

Martel

Toubouti

, et al. Endoscopic hemostasis in peptic ulcer bleeding for patients with high-risk lesions: a series of meta-analyses. Gastrointest Endosc 2009; 69(4): 786–799.

91.

Baracat

Moura

Bernardo

, et al. Endoscopic hemostasis for peptic ulcer bleeding: systematic review and meta-analyses of randomized controlled trials. Surg Endosc 2016; 30(6): 2155–2168.

92.

Tang

RSY

Lau

JYW

. Monopolar hemostatic forceps with soft coagulation: earning a place in the endoscopic hemostasis repertoire for peptic ulcer bleeding. Gastrointest Endosc 2019; 89(4): 803–805.

93.

Kamal

Khan

Tariq

, et al. Systematic review and meta-analysis: monopolar hemostatic forceps with soft coagulation in the treatment of peptic ulcer bleeding. Eur J Gastroenterol Hepatol 2020; 32(6): 678–685.

94.

Toka

Eminler

Karacaer

, et al. Comparison of monopolar hemostatic forceps with soft coagulation versus hemoclip for peptic ulcer bleeding: a randomized trial (with video). Gastrointest Endosc 2019; 89(4): 792–802.

95.

Chau

Siu

Law

BKB

, et al. Randomized controlled trial comparing epinephrine injection plus heat probe coagulation versus epinephrine injection plus argon plasma coagulation for bleeding peptic ulcers. Gastrointest Endosc 2003; 57(4): 455–461.

96.

Wang

H-M

Tsai

W-L

H-C

, et al. Improvement of short-term outcomes for high-risk bleeding peptic ulcers with addition of argon plasma coagulation following endoscopic injection therapy: a randomized controlled trial. Medicine (Baltimore) 2015; 94(32): e1343.

97.

Zenker

. Argon plasma coagulation. GMS Krankenhhyg Interdiszip 2008; 3(1): Doc15.

98.

Chauhan

Mathews

Rostami

. Argon plasma coagulation is not effective in every vascular lesion. Gastroenterol Hepatol Bed Bench 2016; 9(3): 232–236.

99.

Hepworth

Swain

. Mechanical endoscopic methods of haemostasis for bleeding peptic ulcers: a review. Baillieres Best Pract Res Clin Gastroenterol 2000; 14(3): 467–476.

100.

Matsui

Kamisako

Kudo

, et al. Endoscopic band ligation for control of nonvariceal upper GI hemorrhage: comparison with bipolar electrocoagulation. Gastrointest Endosc 2002; 55(2): 214–218.

101.

Krishnan

Velayutham

Satyanesan

, et al. Role of endoscopic band ligation in management of non-variceal upper gastrointestinal bleeding. Trop Gastroenterol 2013; 34(2): 91–94.

102.

Park

Lee

Joo

, et al. Endoscopic band ligation for control of acute peptic ulcer bleeding. Endoscopy 2004; 36(1): 79–82.

103.

Misra

Dwivedi

Misra

, et al. Endoscopic band ligation as salvage therapy in patients with bleeding peptic ulcers not responding to injection therapy. Endoscopy 2005; 37(7): 626–629.

104.

Park

C-H

Joo

Y-E

Kim

H-S

, et al. A prospective, randomized trial comparing mechanical methods of hemostasis plus epinephrine injection to epinephrine injection alone for bleeding peptic ulcer. Gastrointest Endosc 2004; 60(2): 173–179.

105.

Banerjee

Trivedi

Swied

. Endoscopic band ligation for gastric ulcer bleeding. Surg Laparosc Endosc Percutan Tech 2000; 10(4): 246–248.

106.

Wang

Aihara

Thompson

, et al. Choosing the right through-the-scope clip: a rigorous comparison of rotatability, whip, open/close precision, and closure strength (with videos). Gastrointest Endosc 2019; 89(1): 77–86.e1.

107.

Binmoeller

Thonke

Soehendra

. Endoscopic hemoclip treatment for gastrointestinal bleeding. Endoscopy 1993; 25(2): 167–170.

108.

Ljubicic

Budimir

Biscanin

, et al. Endoclips vs large or small-volume epinephrine in peptic ulcer recurrent bleeding. World J Gastroenterol 2012; 18(18): 2219–2224.

109.

C-C

Hsu

P-I

G-H

, et al. Comparison of hemostatic efficacy for epinephrine injection alone and injection combined with hemoclip therapy in treating high-risk bleeding ulcers. Gastrointest Endosc 2006; 63(6): 767–773.

110.

Galloro

Zullo

Luglio

, et al. Endoscopic clipping in non-variceal upper gastrointestinal bleeding treatment. Clin Endosc 2022; 55(3): 339–346.

111.

Mennigen

Senninger

Laukoetter

. Novel treatment options for perforations of the upper gastrointestinal tract: endoscopic vacuum therapy and over-the-scope clips. World J Gastroenterol 2014; 20(24): 7767–7776.

112.

Wei

Ahn

Friedland

. Over-the-scope clip in the treatment of gastrointestinal leaks and perforations. Clin Endosc 2021; 54(6): 798–804.

113.

Verlaan

Voermans

van Berge Henegouwen

, et al. Endoscopic closure of acute perforations of the GI tract: a systematic review of the literature. Gastrointest Endosc 2015; 82(4): 618–628.e5.

114.

Manno

Mangiafico

Caruso

, et al. First-line endoscopic treatment with OTSC in patients with high-risk non-variceal upper gastrointestinal bleeding: preliminary experience in 40 cases. Surg Endosc 2016; 30(5): 2026–2029.

115.

Schmidt

Gölder

Goetz

, et al. Over-the-scope clips are more effective than standard endoscopic therapy for patients with recurrent bleeding of peptic ulcers. Gastroenterology 2018; 155(3): 674–686.e6.

116.

Villaescusa Arenas

de Santiago

Gandía

MÁR

, et al. Over-the-scope-clip (OTSC^®) as a rescue treatment for gastrointestinal bleeding secondary to peptic ulcer disease. Rev Esp Enferm Dig 2023; 115(2): 70–74.

117.

Soriani

, et al. Over-the-scope clip as first-line treatment of peptic ulcer bleeding: a multicentre randomized controlled trial (TOP Study). Endoscopy. Epub ahead of print May 2024. DOI: 10.1055/a-2303-4824.

118.

Chan

Pittayanon

Wang

H-P

, et al. Use of over-the-scope clip (OTSC) versus standard therapy for the prevention of rebleeding in large peptic ulcers (size ⩾1.5 cm): an open-labelled, multicentre international randomised controlled trial. Gut 2023; 72(4): 638–643.

119.

Bonura

Soriani

Biancheri

, et al. Extramural extension of a buried over-the-scope clip in the stomach: an unusual adverse event. Endoscopy 2022; 54(9): E486–E487.

120.

Lau

JYW

Barkun

Fan

D-m

, et al. Challenges in the management of acute peptic ulcer bleeding. Lancet 2013; 381(9882): 2033–2043.

121.

García-Iglesias

Villoria

Suarez

, et al. Meta-analysis: predictors of rebleeding after endoscopic treatment for bleeding peptic ulcer. Aliment Pharmacol Ther 2011; 34(8): 888–900.

122.

Laursen

Stanley

Laine

, et al. Rebleeding in peptic ulcer bleeding—a nationwide cohort study of 19,537 patients. Scand J Gastroenterol 2022; 57(12): 1423–1429.

123.

Lau

Sung

Lam

, et al. Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med 1999; 340(10): 751–756.

124.

Gralnek

Stanley

Morris

, et al. Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline—update 2021. Endoscopy 2021; 53(3): 300–332.

125.

Sheibani

Kim

Chen

, et al. Natural history of acute upper GI bleeding due to tumours: short-term success and long-term recurrence with or without endoscopic therapy. Aliment Pharmacol Ther 2013; 38(2): 144–150.

126.

Kim

Y-I

Choi

Cho

S-J

, et al. Outcome of endoscopic therapy for cancer bleeding in patients with unresectable gastric cancer. J Gastroenterol Hepatol 2013; 28(9): 1489–1495.

127.

Sverdén

Mattsson

Lindström

, et al. Transcatheter arterial embolization compared with surgery for uncontrolled peptic ulcer bleeding: a population-based cohort study. Ann Surg 2019; 269(2): 304–309.

128.

Tarasconi

Baiocchi

Pattonieri

, et al. Transcatheter arterial embolization versus surgery for refractory non-variceal upper gastrointestinal bleeding: a meta-analysis. World J Emerg Surg 2019; 14: 3.

129.

Babiuc

Purcarea

Sadagurschi

, et al. Use of hemospray in the treatment of patients with acute UGIB—short review. J Med Life 2013; 6(2): 117–119.

130.

Barkun

Moosavi

Martel

. Topical hemostatic agents: a systematic review with particular emphasis on endoscopic application in GI bleeding. Gastrointest Endosc 2013; 77(5): 692–700.

131.

Changela

Papafragkakis

Ofori

, et al. Hemostatic powder spray: a new method for managing gastrointestinal bleeding. Therap Adv Gastroenterol 2015; 8(3): 125–135.

132.

Sung

JJY

Luo

JCY

, et al. Early clinical experience of the safety and effectiveness of Hemospray in achieving hemostasis in patients with acute peptic ulcer bleeding. Endoscopy 2011; 43(4): 291–295.

133.

Aziz

Weissman

Mehta

, et al. Efficacy of hemospray in non-variceal upper gastrointestinal bleeding: a systematic review with meta-analysis. Ann Gastroenterol 2020; 33(2): 145–154.

134.

Sung

JJY

Moreea

Dhaliwal

, et al. Use of topical mineral powder as monotherapy for treatment of active peptic ulcer bleeding. Gastrointest Endosc 2022; 96(1): 28–35.e1.

135.

Deliwala

Chandan

Mohan

, et al. Hemostatic spray (TC-325) vs. standard endoscopic therapy for non-variceal gastrointestinal bleeding: a meta-analysis of randomized controlled trials. Endosc Int Open 2023; 11(3): E288–E295.

136.

Paoluzi

Cardamone

Aucello

, et al. Efficacy of hemostatic powders as monotherapy or rescue therapy in gastrointestinal bleeding related to neoplastic or non-neoplastic lesions. Scand J Gastroenterol 2021; 56(12): 1506–1513.

137.

Pittayanon

Khongka

Linlawan

, et al. Hemostatic powder vs standard endoscopic treatment for gastrointestinal tumor bleeding: a multicenter randomized trial. Gastroenterology 2023; 165(3): 762–772.e2.

138.

Haddara

Jacques

Lecleire

, et al. A novel hemostatic powder for upper gastrointestinal bleeding: a multicenter study (the “GRAPHE” registry). Endoscopy 2016; 48(12): 1084–1095.

139.

Beg

Al-Bakir

Bhuva

, et al. Early clinical experience of the safety and efficacy of EndoClot in the management of non-variceal upper gastrointestinal bleeding. Endosc Int Open 2015; 3(6): E605–E609.

140.

Wang

Dong

, et al. Effects of PerClot^® on the healing of full-thickness skin wounds in rats. Acta Histochem 2012; 114(4): 311–317.

141.

Hagel

Raithel

Hempen

, et al. Multicenter analysis of endoclot as hemostatic powder in different endoscopic settings of the upper gastrointestinal tract. J Physiol Pharmacol 2020; 71(5): 657–664.

142.

Kim

Park

Kim

, et al. Hemostatic powder application for control of acute upper gastrointestinal bleeding in patients with gastric malignancy. Endosc Int Open 2018; 6(6): E700–E705.

143.

Vitali

Naegel

Atreya

, et al. Comparison of hemospray^® and endoclot™ for the treatment of gastrointestinal bleeding. World J Gastroenterol 2019; 25(13): 1592–1602.

144.

Becq

Houdeville

Minh

M-LT

, et al. Experience with the use of a hemostatic powder in 152 patients undergoing urgent endoscopy for gastrointestinal bleeding. Clin Res Hepatol Gastroenterol 2021; 45(5): 101558.

145.

Saltzman

. Hemostatic spray for the management of gastrointestinal bleeding. Gastroenterol Hepatol (NY) 2019; 15(1): 40–43.

146.

Subramaniam

Kandiah

Thayalasekaran

, et al. Haemostasis and prevention of bleeding related to ER: the role of a novel self-assembling peptide. United European Gastroenterol J 2019; 7(1): 155–162.

147.

Subramaniam

Kandiah

Chedgy

, et al. A novel self-assembling peptide for hemostasis during endoscopic submucosal dissection: a randomized controlled trial. Endoscopy 2021; 53(1): 27–35.

148.

de Nucci

Reati

Arena

, et al. Efficacy of a novel self-assembling peptide hemostatic gel as rescue therapy for refractory acute gastrointestinal bleeding. Endoscopy 2020; 52(9): 773–779.

149.

Branchi

Klingenberg-Noftz

Friedrich

, et al. PuraStat in gastrointestinal bleeding: results of a prospective multicentre observational pilot study. Surg Endosc 2022; 36(5): 2954–2961.

150.

Dhindsa

Tun

Scholten

, et al. New alternative? Self-assembling peptide in gastrointestinal bleeding: a systematic review and meta-analysis. Dig Dis Sci 2023; 68(9): 3694–3701.