Early Use of TIPSS in Patients With Cirrhosis and Variceal Bleeding
Condition: Liver Cirrhosis; Variceal Haemorrhage
MeSH terms: Liver Cirrhosis; Hemorrhage; Fibrosis
Study type: Interventional

Summary: 
      Gastro-oesophageal varices (swollen veins in the gullet and stomach) are present in 50% of
      patients with liver cirrhosis and are its most serious complication as their rupture results
      in potentially life threatening bleeding. Bleeding from these veins occurs in up to one third
      of patients with varices. This is associated with 20% mortality at 6 weeks.

      In the event of bleeding from these veins the current UK guidelines recommend certain drugs
      followed by early endoscopic treatment with variceal band ligation (rubber bands placed over
      the veins to stop them bleeding). The use of a shunt inside the liver ("TIPSS" transjugular
      intrahepatic portosystemic shunt) is largely reserved for cases of uncontrolled bleeding from
      these swollen veins. A recent randomised multicenter study carried out by Garcia Pagan and
      colleagues reported improved survival with early TIPSS in patients with bleeding from these
      swollen veins in advanced liver disease. From these guideline international guidelines now
      recommend consideration of early TIPSS for all high-risk patients presenting with variceal
      bleeding. This practice clearly has significant cost implications. To validate the findings a
      further randomised control trial is needed.

      This is a multi-center parallel-group randomized controlled trial. Both hospitals taking part
      in the trial will have a TIPSS service. Patients who consent to enter the trial will be
      randomized to either: (1) Endoscopic treatment (standard care) or (2) early TIPSS.

      Potential participants will be all patients with a diagnosis of liver cirrhosis presenting
      with an acute variceal bleed to a participating hospital who do not fulfill an exclusion
      criteria. All causes of cirrhosis will be included.

      Participants will be reviewed during their regular hepatology clinic appointments at their
      respective hospitals on 3 occasions over a one-year period.
    

Detailed description: 
      Background and Rationale for the Study

      Gastro-oesophageal varices are present in 50% of patients with cirrhosis [2] and are the most
      serious complication of portal hypertension as their rupture results in potentially life
      threatening variceal haemorrhage with overall mortality rates historically reported as 30-50%
      [3]. Although mortality can be up to 40% at 6 weeks, it can be up to 70% at one year [2].
      With the generally improved management of critically ill cirrhotic patients, together with
      vasoactive therapy and new endoscopic techniques for managing variceal haemorrhage, overall
      mortality has reduced, with one centre in Europe showing a reduction from 42% in 1980 to 14%
      in 2000 [4]. 60-80% of patients who bleed from varices will re-bleed if not treated [5-8],
      and the risk of re-bleeding is greatest in the first 10 days [1,9], during which 50% of those
      who are going to re-bleed, do so. The risk of re-bleeding gradually falls over the first
      month when an additional 10% re-bleed [7, 8]; the risk after the first six weeks then
      plateaus out.

      Despite the advent of endoscopic therapies and early pharmacological therapies, re-bleeding
      rates are still higher early on, with factors predictive of early re-bleeding /treatment
      failure at 5 days including: active bleeding at index endoscopy; severity of liver disease
      (Child-Pugh class); severity of bleed; and severity of portal hypertension [1, 10]. Hepatic
      Venous Pressure Gradient (HVPG) is one of the best predictors of identifying those who will
      re-bleed. After an index variceal bleed, a reduction of HVPG to less than 12mmHg or by at
      least 20%, reduces the risk of re-bleeding from 46-65% to 0.13% [11]. HVPG measurement is
      usually limited to specialist centres.

      The early use of TIPSS has been explored in two studies [1,12]. The first [12] categorised
      patients presenting with a variceal bleed to be either high or low risk of re-bleeding
      determined by their HVPG. Those with an HVPG greater or equal to 20mmHg went on to receive an
      early TIPSS and had an improved outcome compared with those treated medically. However, the
      results must be interpreted with caution, as the medical management was not current standard
      of care.

      A further study investigating the use of early TIPSS for variceal haemorrhage was carried out
      by Garcia-Pagan and colleagues [1]. This landmark study selected patients for early TIPSS
      (within 3 days) determined by Child-Pugh score. Participants, who had Child's B or C
      cirrhosis and on-going bleeding, progressed to early use of TIPSS (with an e-PFTE-covered
      stent). The results of this trial demonstrated a significant reduction in the failure to
      control bleeding and re-bleeding with no increase in the risk of hepatic encephalopathy. The
      study also demonstrated a significant survival benefit with early TIPSS at all time points.
      There were, however, several features of this study that raised concern.

      Firstly recruitment was prolonged (3 years) to recruit 63 patients via 9 centres, with a high
      exclusion rate (296 patients excluded). The second concern featured the inclusion of patients
      with ongoing bleeding following index endoscopy. This might arguably be termed a rescue TIPSS
      and although no studies have been done in this area it is intuitive to suggest that survival
      would be improved if haemostasis has not been achieved. Thirdly, survival at 1 year with
      early TIPSS was extremely high (86% vs. 61% in the medical management group). For patients
      with Child's C cirrhosis presenting with variceal bleeding this survival rate is remarkable.

      These two studies [1, 12] of the early use of TIPSS for variceal haemorrhage are the first in
      portal hypertension to show a mortality benefit. As such these demand action. Either the
      management of variceal bleeding in patients with advanced cirrhosis must change or, given the
      concerns regarding the study design and the significant cost implications, these results need
      to be further validated.

      STUDY DESIGN This is a multi-centre, open-label, parallel-group, randomised control trial.
      Both hospitals taking part in the trial will have a 24-hour TIPSS service. Potential
      participants will be all patients with a diagnosis of liver cirrhosis presenting with
      variceal haemorrhage to a participating hospital who do not fulfil an exclusion criteria.
      Potential participants will be identified by the gastroenterology team responsible for the
      patient care. Patients and their relatives will be approached by a nominated registrar, or
      consultant, identified in the ethics application or delegation log. Patients will be followed
      up for one year and will be reviewed on three occasions. Patients who consent to enter the
      trial will be randomized to either: (1) EVBL ("standard care") arm or (2) early TIPSS arm.

      FOLLOW UP During their regular Hepatology follow-ups, patients will be reviewed at 6 weeks, 6
      months, and 12 months, which is the end of the study. TIPSS patency will be checked at 6
      months and 1 year as per current standard protocol. All patients will be followed up until
      death or the end of the study, whichever is first.

      IDENTIFYING PARTICIPANTS Potential participants will be all patients with a diagnosis of
      liver cirrhosis presenting with an acute variceal haemorrhage to a participating hospital who
      do not fulfil an exclusion criteria. All aetiologies of cirrhosis (including cryptogenic and
      where the aetiology is yet to be established) will be included. Potential participants will
      be identified by the gastroenterology team responsible for the patient. The consultant
      responsible for the care of each patient will determine whether the identified patients are
      suitable and may be approached.

      OBTAINING CONSENT If patients are alert and able to give informed consent then they will be
      issued with a patient information sheet and consent sought from the patient. Patients and
      their next of kin will have sufficient time usually 3 hours or more, from the index endoscopy
      to consent to inclusion in the study.

      Patients with liver disease may have fluctuating conscious level and may lack capacity due to
      hepatic encephalopathy. Potential participants who lack capacity will be included in the
      study. Here capacity will be assessed by the consenting clinician at the time of taking
      consent. A further consent will be sought from those patients who regain capacity.

      RANDOMISATION This study will involve simple 1:1 randomisation. Randomisation will be done
      using a web-based randomisation programme that will be available 24 hours a day to both study
      centres.

      STUDY ASSESSMENT Participants will attend the gastroenterology/hepatology clinics at their
      respective hospital on three occasions over a one-year period. If participants are in
      hospital at the time of a scheduled visit then they will either be assessed whilst inpatient
      or at the programmed visit as an outpatient. The programme visits are: 6 Weeks, 6 Months and
      1 year.

      SAMPLE SIZE CALCULATION Given that we are validating results of the Garcia Pagan study, we
      have powered the study using the results that they observed. We wish to find a difference in
      survival between the two trial arms. Garcia Pagan observed 14% and 39% deaths in the two
      trial arms. We calculate that we would need 48 patients per group. This is from a 2-sided
      log-rank test, with alpha=0.05, and a power of 80%, allowing 4 extra patients per group to
      allow for drop out and non-compliance.
    

Intervention name(s): Endoscopic Variceal Band Ligation; Transjugular Intrahepatic Porto-Systemic Stent Shunt
Intervention type(s): Procedure; Procedure
Intervention description(s): Standard care: Endoscopic application of rubber bands to varices (swollen veins) in the oesophagus this is repeated on 4-5 occasions until the varices are eradicated.; Within 72 hours of the initial endoscopy to apply bands to the bleeding varices the patient undergoes a Transjugular Intrahepatic Porto-Systemic Stent Shunt (TIPSS) procedure. Under x-ray guidance a shunt is created in the liver between the hepatic vein and portal vein via a catheter introduced via the jugular vein. It may require a check once or twice per year to ensure it remains patent.
Other intervention name(s): Endosopic banding,; Banding; TIPSS; TIPS
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Oesophageal Variceal Bleed; TIPSS; Endoscopic Variceal Band Ligation; Decompensated Liver Disease