Secondary Prevention of Variceal Rebleeding by Endoscopic Ultrasound-guided Therapy Versus Conventional Endoscopic Therapy in Hepatocellular Carcinoma Patients: a Randomized Controlled Trial

Chronic liver diseases and cirrhosis are common health problems in the Asia-Pacific region. In 2015, 54.3% of global deaths due to cirrhosis occurred in the Asia-Pacific region. Acute variceal bleeding is a life-threatening complication of cirrhosis that occurs at a rate of 10 - 15% per year, with a 6-week mortality rate up to 25%. In patients with successful acute bleeding control by endoscopic therapy and vasoactive agents, rebleeding is common in those without subsequent secondary prevention by non-selective beta blocker and/or endoscopic therapy (e.g. variceal band ligation (VBL) for esophageal varices (EV) and glue injection for gastric varices (GV)).

Apart from variceal bleeding, hepatocellular carcinoma (HCC) (liver cancer) is another important complication of cirrhosis. HCC patients with prior variceal bleeding are at high risk of rebleeding due to significant portal hypertension and frequent presence of portal vein thrombosis (PVT). In this difficult-to-manage population, variceal rebleeding rates remain substantial after conventional endoscopic therapies. In a large multicenter study comparing clinical outcomes after EV bleeding in patients with or without HCC, lack of secondary prevention for rebleeding was found to be frequent in HCC patients and was associated with a higher rate of rebleeding and mortality. In HCC patients with EV bleeding, secondary prevention failure by conventional endoscopic therapy was significantly higher (50% vs 31%, P = 0.001) when compared with patients without HCC. However, the optimal endoscopic approach for secondary prevention in HCC patients has not been well defined. Whether commonly used endoscopic techniques such as VBL for EV and cyanoacrylate glue injection for GV being performed at intervals of 3 - 4 weeks for secondary prevention can achieve durable variceal control in HCC patients remains unclear.

Direct endoscopic ultrasound (EUS)-guided variceal interventions by cyanoacrylate glue injection, coiling, or a combination of both using a therapeutic curvilinear echoendoscope is a novel endoscopic technique that have attracted clinical attention due to its high efficacy in variceal control. In recent studies by others and our group on direct EUS-guided therapy for varices in cirrhotic patients, high technical success (90 - 100%), low post-treatment rebleeding rate (3 - 11%) and low adverse event rate (~3%) have been reported for GV treatment by cyanoacrylate glue injection, coiling or a combination of both, and for cyanoacrylate glue injection or coiling of EV refractory to VBL.

In a retrospective study published by our group in 2020, we compared outcomes in 27 HCC patients with variceal bleeding who underwent secondary prevention by EUS-guided glue injection every 12 weeks and 33 HCC patients without secondary prevention after control of acute variceal bleeding. The technical success of EUS-guided therapy was 100%. The overall procedure-related adverse event rate was low (3.7%) and no radiographic evidence of glue-lipiodol embolization was observed. The EUS-guided therapy group was found to have a significantly lower 90-day death-adjusted cumulative incidence of rebleeding and a significantly higher variceal bleeding-free survival at 3 and 6 months. As such, it would be clinically important to conduct a prospective randomized controlled study to confirm the benefits of EUS-guided therapy for secondary prevention in HCC patients.