Re-bleeding from esophageal and gastric varices in cirrhosis is a common and severe complication with a high mortality rate. This article reviews the latest advances in the treatment of this condition, with a focus on emerging technologies and clinical research hotspots. Esophageal and gastric variceal bleeding (EGVB) is one of the primary complications of portal hypertension, particularly in patients with cirrhosis, where it is associated with poor prognosis and a high rate of rebleeding after treatment. Data indicate that for untreated EVB patients, the rebleeding rate within 1 - 2 years can reach up to 60% [1] , and the 6-week mortality rate can reach up to 20% [2] . Therefore, early implementation of active and effective intervention measures is of significant clinical importance for controlling rebleeding and reducing mortality rates.

Re-bleeding is defined as hematemesis, melena, or black stools accompanied by changes in laboratory findings (hemoglobin level decreasing to >2 g/dl within 24 hours) or vital signs (systolic blood pressure decreasing to <90 mmHg or heart rate increasing to >100 beats per minute), and must be confirmed by endoscopic examination [3] . Clinical observations indicate that approximately 25% of patients may experience uncontrollable bleeding or early recurrence within 6 weeks of the first bleeding episode. Notably, the risk of rebleeding is most significant within the first 5 days, accounting for approximately 40% of rebleeding cases. As time progresses, the risk gradually decreases, and by the 6^th week, the patient’s risk of rebleeding has largely returned to the baseline level prior to bleeding [4] . High risk of rebleeding and poor prognosis are important causes of mortality in patients with cirrhosis. Recurrent bleeding from gastric varices is a major challenge in the management of cirrhosis.

Portal hypertension is one of the most severe non-neoplastic complications of cirrhosis. As the primary driver of variceal development and variceal bleeding, it can lead to life-threatening consequences, including esophageal variceal rupture and bleeding, refractory ascites, and hepatic encephalopathy. Its pathogenesis primarily stems from significant increases in portal venous blood flow resistance due to vascular structural changes caused by cirrhosis. On this basis, secondary visceral arterial vasodilation triggers a systemic hyperkinetic circulatory state (characterized by increased cardiac output and reduced peripheral vascular resistance). The combined effects of these two factors further exacerbate portal venous pressure [5] .

New advances in drug treatment for bleeding esophageal varices in cirrhosis show that non-selective beta-blockers can effectively reduce portal pressure, and terlipressin is more effective than traditional drugs in stopping bleeding. It is worth noting that a Cochrane review incorporating 12 RCTs indicated that the prophylactic use of antibiotics (such as ceftriaxone or norfloxacin) has become a standard care measure for acute bleeding, significantly reducing the risk of bacterial infection (RR 0.35) and short-term mortality (RR 0.79) [6] ; The latest clinical evidence shows that combined endoscopic treatment can reduce the risk of rebleeding by 50%, highlighting the comprehensive advantages of multimodal treatment.

NSBBs are the cornerstone of drug therapy for portal hypertension, with a multifaceted mechanism of action: they reduce cardiac output by blocking beta-1 receptors, while simultaneously inducing a visceral vascular alpha-receptor dominance effect through beta-2 receptor blockade, resulting in a significant reduction in portal vein pressure [7] . In clinical practice, traditional NSBBs (propranolol, nadolol) and the newer drug carvedilol each have distinct characteristics: the latter, which blocks both β and α₁ receptors, not only achieves more pronounced portal pressure-lowering effects but also exhibits multifunctional pharmacological properties such as antioxidant and anti-inflammatory effects [8] . Extensive clinical evidence confirms that these drugs effectively reduce the risk of rebleeding in both primary and secondary prevention of variceal bleeding [9] , providing an important treatment option for patients with cirrhosis. It is important to note that drug selection requires individualized assessment to balance efficacy with potential adverse effects.

The pharmacological treatment of acute variceal bleeding (AVB) primarily involves two classes of drugs: vasopressin analogues (e.g., terlipressin) and somatostatin analogues (e.g., octreotide) [10] . Terlipressin, a synthetic analog of vasopressin, exerts an immediate systemic vasoconstrictive effect by slowly converting into its active component. It selectively targets V1 receptors in the visceral circulation, causing constriction of the superior mesenteric artery and abdominal trunk vascular bed, thereby significantly reducing portal vein pressure. Additionally, it enhances esophageal smooth muscle tone to directly compress varicose veins [10] . A Cochrane meta-analysis (including seven placebo-controlled trials) confirmed that terlipressin effectively controls variceal bleeding and improves survival rates [11] . Compared with octreotide, terlipressin has a more sustained portal vein pressure-lowering effect [12] ; clinical studies show that it is superior to other vasoactive drugs in controlling bleeding [13] .

A recent RCT study by Wu et al. (2025) [14] provided evidence for the use of NSBBs in combination with endoscopic therapy. The study showed that adding NSBB (propranolol/carvedilol) to endoscopic variceal treatment (obliteration and ligation) reduced the 1-year rebleeding rate in GOV1/GOV2 patients from 32.6% to 15.2%, with good safety, significantly reducing recurrent variceal bleeding in cirrhotic patients. This benefit may be related to NSBB’s ability to lower portal vein pressure (HVPG), inhibit early inflammatory portal hypertension, and promote long-term vascular remodeling.

The most commonly used agents are polyethylene glycol and ethylene glycol, which have similar chemical properties. In China, the most commonly used agent is domestically produced polyethylene glycol [15] . The mechanism of polyethylene glycol and ethylene glycol in treating varicose veins involves injecting the sclerosant into the varicose veins, which damages the vascular endothelium, causing aseptic chemical inflammation in the varicose veins, followed by thrombosis and fibrosis, ultimately leading to the closure and disappearance of the lumen [16] . This method is suitable for bleeding esophageal varices [17] , but may cause complications such as ulcers and strictures [18] .

Endoscopic variceal ligation (EVL) remains the primary method for controlling active bleeding. During multiple treatments, rubber bands are placed around the varices until they are eliminated. By ligating the varices, blood flow is blocked, reducing the risk of rebleeding [18] . Studies have shown that EVL is highly effective in preventing rebleeding [19] . However, this technique also carries certain risks of complications, the most common of which is post-ligation ulceration. Other possible complications include temporary difficulty swallowing and postoperative bleeding.

Mainly used for bleeding from gastric varices, its core principle is to use rapidly curing tissue adhesives (such as cyanoacrylate) to occlude varices through injection, achieving immediate hemostasis and long-term prevention of rebleeding [19] . Studies have shown that tissue glue injection is effective in controlling bleeding from gastric varices, but the risk of embolism should be noted [20] .

TIPS involves artificially creating a connection between the main branches of the hepatic vein and portal vein within the liver to reduce portal vein pressure, thereby achieving hemostasis and preventing rebleeding [21] . TIPS is highly effective in controlling acute bleeding and preventing rebleeding, but it may increase the risk of hepatic encephalopathy [22] .

This procedure involves blocking the gastric-renal venous shunt and injecting a sclerosing agent to occlude varicose veins. It is performed by inserting a balloon catheter via deep vein puncture, advancing it retrograde through the circulatory system to the distal end of the gastric varices (GV), inflating the balloon to block GV blood flow, and injecting an embolization agent to occlude the GV and shunt. BRTO demonstrates significant efficacy in treating gastric variceal bleeding. Experimental studies by Nakazawa et al. [23] and Ishikawa et al. [24] indicate that it does not increase the risk of hepatic encephalopathy. Additionally, research by Li Yuting et al. [25] highlights that BRTO effectively prevents and controls gastric variceal bleeding and offers notable advantages in improving liver function [26] .

Endoscopic tissue injection (ECI) combined with BRTO or TIPS can significantly reduce gastric variceal bleeding, gastric variceal rebleeding, and rebleeding-related mortality [27] .

Through risk assessment and stratification, based on Child-Pugh classification combined with Hepatic venous pressure gradient (HVPG, obtained by measuring the difference between hepatic venous wedge pressure and free pressure via catheter), and integrating portal shunt anatomy as shown by CT/MR, the risk of rebleeding can be accurately stratified into four levels:

Low risk: Child-Pugh A/B and HVPG < 12 mmHg—only endoscopic EVL combined with non-selective beta-blockers (NSBB) is required [28] .

Moderate risk: Child-Pugh A/B but HVPG ≥ 12 mmHg or GOV2 with splenic-renal shunt—prioritize BRTO; the 2025 Chinese Expert Consensus explicitly states that for patients with spontaneous splenic-renal shunt, BRTO should be prioritized, as it can control variceal bleeding while reducing the incidence of hepatic encephalopathy [29] .

High-risk: Child-Pugh C or HVPG ≥ 20 mmHg—early TIPS within 72 hours; The Baveno VII Consensus states that patients with Child-Pugh C grade or HVPG ≥ 20 mmHg, or Child-Pugh B grade with a score > 7 points, and active bleeding at the first endoscopy should aim to undergo early TIPS within 72 hours of bleeding to significantly reduce the risk of rebleeding and mortality [30] .

Very high risk: High risk combined with PVT or previous endoscopic failure. The 2023 AASLD guidelines further note that if portal vein thrombosis is present, anticoagulation can be administered concurrently with TIPS to further improve patency and hemostasis [31] .

1) EUS-guided tissue glue plus coil embolization (PCSS): A multicenter RCT (n = 120) published in March 2024 was the first to compare PCSS with traditional endoscopic treatment in patients with cirrhosis-related GOV. Preliminary results suggest that PCSS significantly reduces the 6-month rebleeding rate (3.3% vs. 18.3%, P = 0.013), but 1-year follow-up and sample size remain insufficient [32] .

2) Next-generation small-diameter covered stents - TIPS technology

a) Controllable expansion PTFE covered stents (Viatorr CX)

b) Small-diameter (6 - 8 mm) intrahepatic coated stents

The treatment of variceal bleeding in cirrhosis with portal hypertension has evolved into a multidisciplinary comprehensive treatment model. The current combination of drug therapy and endoscopic treatment has significantly reduced the rate of rebleeding, while interventional techniques such as TIPS offer new options for high-risk patients. The application of technologies such as EUS-guided precise embolization and novel covered stents shows promising prospects. Future efforts should focus on addressing key issues such as balancing treatment risks and benefits, and optimizing individualized treatment plans. By developing artificial intelligence prediction models (for predicting the risk of rebleeding and patient response to specific treatments), targeted drug research and development, and improving multidisciplinary collaboration standards, patient outcomes will be further improved, and the goal of comprehensive management will be achieved. Developments in this field provide an important opportunity to improve the quality of life of patients with cirrhosis.

*Corresponding author.