Role of early transjugular intrahepatic portosystemic stent-shunt in acute variceal bleeding: An update of the evidence and future directions

Table 1 Early transjugular intrahepatic portosystemic stent-shunt in acute variceal bleeding: Key studies

Ref.	Main inclusion criteria	Primary and secondary outcomes	Results	Comments
Randomised controlled trials
Monescillo et al[12], 2004 (Italy)	HVPG > 20 mmHg within 24 h of admission.	(1) Primary: Sensitivity and specificity of HVPG cut-off value (20 mmHg) in predicting transplant-free survival (TFS), and assessment of TFS as well as short- and long-term survival; and (2) Secondary: Transfusional needs, ICU stay, complications during the first week of treatment, and causes of death.	6-wk mortality = 17% in e-TIPSS vs 38% in control (P ≤ 0.05). 1-yr mortality = 31% in e-TIPSS vs 65% in control (P ≤ 0.05). Treatment failure = 12% in e-TIPSS vs 50% in control (P = 0.001).	46% of study population had Child C and 40% had Child B cirrhosis. mean Child score = 9.2. SOC does not reflect current management and only bare metal stents were used.
García-Pagán et al[39], 2010 (Europe)	Child- B with active bleeding or Child C < 14 points.	(1) Composite Primary: Failure to control bleeding and failure to prevent clinically significant VB within 1 yr; and (2) Secondary: Mortality at 6 wk and at 1 yr, failure to control acute bleeding, early rebleeding, rate of rebleeding between 6 wk and 1 yr, other complications of PHTN, number of days in ICU, days spent in the hospital, use of alternative treatments.	6-wk survival = 97% in e-TIPSS vs 67% in control (NNT = 3.3). 1-yr survival = 86% in e-TIPSS vs 61% in control (P < 0.001). 1-yr re-bleeding = 3% in e-TIPSS vs 50% in control (P < 0.001, NNT = 2.1).	mean Child score = 9.4. mean MELD score = 16.2. About 50% of study participants had Child C cirrhosis. Majority had ALD. NSBB (propranolol or nadolol) was administered with EBL in 25 patients.
Lv et al[44], 2019 (China)	Child B and C < 14 points, regardless of active bleeding.	(1) Primary: Transplant-free survival; and (2) Secondary: Failure to control bleeding or rebleeding, new or worsening ascites, overt HE, and other complications of portal hypertension and adverse events.	6-wk TFS = 99% in e-TIPSS vs 84% in SOC (P = 0.02). 1-yr TFS = 86% in e-TIPSS vs 73% in SOC (P = 0.046; NNT = 8). 1-yr re-bleeding/uncontrolled bleeding = 11% in e-TIPSS vs 34% in SOC (P < 0.0001).	mean Child Score = 8.0. mean MELD score = 13.8. More than 55% patients had Child-Pugh B without active bleeding. 75% of patients had Hepatitis B and had Child B cirrhosis. No significant difference in the incidence of HE was observed between two groups.
Dunne et al[46], 2020 (United Kingdom)	Child B and C, 8-13 points (regardless of active bleeding at the endoscopy).	(1) Primary: 1-yr survival; and (2) Secondary: Survival at 6 wk, early rebleeding (within 6 wk) and late rebleeding (between 6 wk and 1 yr), and the development of HE.	1-yr survival = 79.3% in e-TIPSS vs 75.9% in SOC (P = 0.79). e-TIPSS group showed a trend to reduced variceal re-bleeding (P = 0.09).	Median Child score = 9.8. Median MELD score = 17. More than 90% of participants had ALD. More than 55% had Child-C disease. 23/29 received TIPSS, 13 within 72 h. 18/29 (62%) in SOC group had carvedilol, 3 had cardio-selective beta- blocker and 2 had rescue- TIPSS for early re-bleeding. Incidence of HE was higher in e-TIPSS group (P < 0.05).
Observational studies
Garcia-Pagán et al[49], 2013 (Europe)	Child-B with active bleeding or Child-C < 14 points.	(1) Composite primary: Failure to control acute bleeding or to prevent clinically significant variceal rebleeding; and (2) Secondary: mortality, development of other complications related to portal hypertension and the percentage of follow-up days spent in hospital.	1-yr survival = 86 % in e-TIPSS vs 70% in SOC (P = 0.056); e-TIPSS had lower incidence of failure to control bleeding or rebleeding than patients receiving SOC (3 vs 15, P <0.001).	mean Child score = 10. mean MELD score= 17. No significant difference in incidence of HE. Incidence of development of new or worsening ascites was low in e-TIPSS group (P < 0.01).
Rudler et al[52], 2014 (France)	Child-C 10–13 cirrhosis or Child-B with active bleeding	(1) Primary: prevention of rebleeding at 1 yr; and (2) Secondary: 3 and 6-mo survival, liver transplantation, control of bleeding, rate of rebleeding at 6 wk, between 6 wk and 1 yr, and the occurrence of adverse events (HE, acute cardiac failure, sepsis).	1-yr survival = 71% in e-TIPSS vs 74% in control (P = 0.77). 1-yr free of rebleeding = 97% in e-TIPSS vs 51% in control (P < 0.001).	mean Child score = 11.2. mean MELD score = 21.5. 77% had ALD and 77% had Child-C cirrhosis. Patients with previous history of variceal bleeding or with PVT were also included.
Thabut et al[50], 2017 (France)	Child-C (< 14) or Child-B with active bleeding	Survival at 5-d, 6-wk and 1-yr.	1-yr survival = 85% in e-TIPSS vs 59% in control (P = 0.04).	67% had ALD. 52% undergoing TIPSS had Child C cirrhosis. 35% were eligible for e-TIPSS. Severity of liver disease was the only parameter that influenced survival.
Hernández-Gea et al[51], 2018 (Europe and Canada)	Child-C score (< 14 points) or Child-B plus active bleeding	(1) Primary: Survival at 6 weeks and 1 year; and (2) Secondary: (a) The composite end-point of failure to control acute bleeding (up to day 5), early rebleeding (from day 5 to day 42), and late rebleeding (from day 42); (b) onset or worsening of ascites; and (c) development of HE.	6-wk survival = 92% in p-TIPSS vs 77% in control. Overall, 1-yr survival = 78% in p-TIPPS vs 62% in control (P = 0.014). 1-yr survival in Child C patients = 78% in e-TIPSS vs 53% in control (P = 0.002). 1-yr survival in Child-B + AB = 77% in p-TIPSS vs 75% in control (P = 0.935).	Median MELD score= 15.5. Median Child Score= 10. More than 75% of patients had ALD. Development of de novo or worsening of previous ascites was significantly less in p-TIPSS group (P < 0.001). No difference in incidence of HE was observed in two groups.
Lv et al[45], 2018 (China)	Any grade of cirrhosis (with Child score < 14) and AVB.	(1) Primary: All-cause mortality; and (2) Secondary: Failure to control acute bleeding or rebleeding, new or worsening ascites and development of overt HE.	Overall 6-wk mortality = 3.6% in e-TIPSS vs 10.6 % in SOC (P = 0.002). Overall 1-yr mortality = 14.1% in e-TIPSS vs 17.3% in SOC (P = 0.218). e-TIPSS group had significantly lower mortality in MELD ≥ 19 category.	Patients with Child A cirrhosis were also included. Only small number (< 20%) had Child C cirrhosis. Survival benefit was not seen in Child B patients without active bleeding. Incidence of HE was not significantly different between two groups.
Trebicka et al[22], 2020 (Multicentre)	Child-C, Child- B with active bleeding.	(1) Primary: All-cause mortality or liver transplantation at 6 wk and 1 yr; and (2) Secondary: Rebleeding.	6-wk mortality = 13.6 % in e-TIPSS vs 51% in SOC group of patients with ACLF (P = 0.002). 1-yr mortality = 22.7% in e-TIPSS vs 56.5% in SOC group with ACLF (P = 0.002).	Patients with ACLF had a higher rate of rebleeding compared to patients without ACLF (42-d: P < 0.001; 1-yr: 22.9% vs 17.7%, P = 0.024).

e-TIPSS: Early transjugular intrahepatic portosystemic stent-shunt; RCT: Randomised controlled trial; HVPG: Hepatic venous pressure gradient; HCC: Hepatocellular carcinoma; PHTN: Portal hypertension; PVT: Portal vein thrombosis; TFS: Transplant-free survival; HIV: Human immunodeficiency virus; ICU: Intensive care unit; NSBB: Non-selective beta-blockers; EBL: Endoscopic band ligation; IGV: Isolated gastric varices; MELD: Model for end-stage liver disease; ALD: Alcohol-related liver disease; NNT: Number needed to treat; HE: Hepatic encephalopathy; SOC: Standard of care; ACLF: Acute on chronic liver failure.

Table 2 Summary of current Guidelines regarding early transjugular intrahepatic portosystemic stent-shunt

Ref.	Guidelines	e-TIPSS recommendations
[40]	Baveno VI Consensus Workshop (2015)	An early TIPSS (p-TIPSS) with PTFE-covered stents within 72 h (ideally < 24 h) must be considered in patients bleeding from EV, GOV1 and GOV2 at high risk of treatment failure [e.g., Child-Pugh class C < 14 points or Child-Pugh class B with active bleeding) after initial pharmacological and endoscopic therapy (1b; A)]. Criteria for high-risk patients should be refined.
[41]	American Association for the Study of Liver Diseases (2017)	In patients at high risk of failure or rebleeding (CTP class C cirrhosis or CTP class B with active bleeding on endoscopy) who have no contraindications for TIPSS, an “early” (pre-emptive) TIPSS within 72 h from EGD/EVL may benefit selected patients.
[42]	The European Association for the Study of the Liver (2018)	Early pre-emptive covered TIPSS (placed within 24–72 h) can be suggested in selected high-risk patients, such as those with Child class C with score < 14 (I; 2). However, the criteria for high-risk patients, particularly Child B with active bleeding, remains debatable and needs further study. Up to 10%–15% of patients have persistent bleeding or early rebleeding despite treatment with vasoactive drugs plus variceal ligation, and prophylactic antibiotics. TIPSS should be used as the rescue therapy of choice in such cases (I; 1).
[43]	British Society of Gastroenterology (2020)	In patients who have Child’s C disease (C10-13) or MELD ≥ 19, and bleeding from oesophageal varices or GOV1 and GOV2 gastric varices and are hemodynamically stable, early or pre-emptive TIPSS can be considered within 72 h of a variceal bleed where local resources allow (weak recommendation, moderate quality of evidence). However, large multi-centre randomised controlled trials are necessary to determine whether patients with Child’s B disease and active bleeding or with MELD 12-18 benefit from early pre-emptive TIPSS.

PTFE: Polytetrafluoroethylene; p-TIPSS: Pre-emptive transjugular intrahepatic portosystemic shunt; EV: Oesophageal varices, GOV: Gastro-oesophageal varices; CTP: Child-Turcotte-Pugh; EGD: Oesophago-gastro-duodenoscopy; EVL: Endoscopic variceal ligation; MELD: Model for end-stage liver disease.

Table 3 Early transjugular intrahepatic portosystemic stent-shunt in acute variceal bleeding: Key meta-analyses

Ref.	Design	Results	Comments
Deltenre et al[43]	4 studies (2 RCTs[12,39] and 2 Observational[49,52] ) included.	e-TIPSS was associated with fewer deaths [odds ratio (OR) = 0.38, P = 0.02], and with lower rates of bleeding (OR = 0.08, 95%CI: 0.04–0.17, P < 0.001) within 1 year when compared to SOC, without increase in incidence of encephalopathy (OR = 0.84, 95% CI: 0.50–1.42, P = 0.5).	There was moderate heterogeneity between studies. No significant difference in mortality was observed between Child–Pugh B and C patients. This could be explained by inclusion of sicker patients (C-P score < 14) in Rudler et al[52] study.
Nicoară-Farcău et al[47]	Individual data meta-analysis from 7 studies (3 RCTs[12,39,44] and 4 observational studies[45,49,51,52]), comprising 1327 patients (310 received e-TIPSS, 1017 received SOC (drugs + endoscopic treatment).	Overall, e- TIPSS significantly increased 1- year survival compared with SOC [hazard ratio (HR) 0.443; P < 0.001]. e-TIPSS significantly reduced the risk of failure to control bleeding/preventing variceal rebleeding (HR = 0.338; P < 0.001) and ascites without increasing risk of HE, compared with SOC.	Only individual data of those patients fulfilling the high-risk criteria (Child-Pugh B with active bleeding and Child-Pugh C < 14 points) from included studies were included. On multivariate analysis patients with Child-Pugh score > 7 points had a significantly worse survival than those with Child-Pugh score ≤ 7. Both prospective and observational studies were included and latest UK RCT[46] and the multicentre French audit[50] were not included.
Tripathi et al[54]	3 RCTs[39,44,46] comparing e-TIPSS (with covered stent) with SOC, comprising 152 patients.	e-TIPSS significantly reduced incidence of re-bleeding (RR = 0.20; P ≤ 0.001). Improvement in overall survival at 1 and 2 yr was not statistically significant between two groups (RR = 0.62; P = 0.16 and RR = 0.62; P = 0.19 respectively).	There was no significant difference in incidence of HE. RCTs are underpowered to reach firm conclusion about the survival benefit of e-TIPSS.

e-TIPSS: Early transjugular intrahepatic portosystemic stent-shunt; RCT: Randomised controlled trial; SOC: Standard of care; HE: Hepatic encephalopathy.