TIPS prevents further decompensation and improves survival in patients with cirrhosis and portal hypertension in an individual patient data meta-analysis.

BACKGROUND & AIMS: Further decompensation represents a prognostic stage of cirrhosis associated with higher mortality compared with first decompensation. A transjugular intrahepatic portosystemic shunt (TIPS) is indicated to prevent variceal rebleeding and for refractory ascites, but its overall efficacy to prevent further decompensations is unknown. This study assessed the incidence of further decompensation and mortality after TIPS vs. standard of care (SOC). METHODS: Controlled studies assessing covered TIPS compared with SOC for the indication of refractory ascites and prevention of variceal rebleeding published from 2004 to 2020 were considered. We collected individual patient data (IPD) to perform an IPD meta-analysis and to compare the treatment effect in a propensity score (PS)-matched population. Primary outcome was the incidence of further decompensation and the secondary outcome was overall survival. RESULTS: In total, 3,949 individual patient data sets were extracted from 12 controlled studies and, after PS matching, 2,338 patients with similar characteristics (SOC = 1,749; TIPS = 589) were analysed. The 2-year cumulative incidence function of further decompensation in the PS-matched population was 0.48 (95% CI 0.43-0.52) in the TIPS group vs. 0.63 (95% CI 0.61-0.65) in the SOC group (stratified Gray's test, p <0.0001), considering mortality and liver transplantation as competing events. The lower further decompensation rate with TIPS was confirmed by adjusted IPD meta-analysis (hazard ratio 0.44; 95% CI 0.37-0.54) and was consistent across TIPS indication subgroups. The 2-year cumulative survival probability was higher with TIPS than with SOC (0.71 vs. 0.63; p = 0.0001). CONCLUSIONS: The use of TIPS for refractory ascites and for prevention of variceal rebleeding reduces the incidence of a further decompensation event compared with SOC and increases survival in highly selected patients. IMPACT AND IMPLICATIONS: A further decompensation (new or worsening ascites, variceal bleeding or rebleeding, hepatic encephalopathy, jaundice, hepatorenal syndrome-acute kidney injury and spontaneous bacterial peritonitis) in patients with cirrhosis is associated with a poor prognosis. Besides the known role of TIPS in portal hypertension-related complications, this study shows that TIPS is also able to decrease the overall risk of a further decompensation and increase survival compared with standard of care. These results further support the role of TIPS in the management of patients with cirrhosis and portal hypertension-related complications.

Acute kidney injury in patients with cirrhosis: Prospective longitudinal study in 405 patients.

BACKGROUND: Acute kidney injury (AKI) is common in patients with cirrhosis. In 2015, the International Club of Ascites (ICA) proposed new definitions of AKI in order to improve the prediction of outcomes. Our aim was to assess the prevalence and prognostic value of ICA 2015 - AKI criteria in hospitalised patients with cirrhosis. METHODS: We prospectively collected data from 405 consecutive cirrhotic patients admitted to the hospital between November 2016 and November 2017. AKI was diagnosed at inclusion according to ICA 2015 criteria, and was assessed to predict 30-day and 90-day in-hospital mortality. RESULTS: AKI was diagnosed in 78 (19.3%) patients. AKI was independently associated with 90-day death (HR 7.61; 95% CI 4.75-12.19; p < 0.001). In hospital, 30-day and 90-day survival was lower in the group of patients with AKI compared to the group with no AKI (72% vs. 98%, p < 0.001; 64% vs. 96%, p < 0.001; and 49% vs. 81%, p < 0.001, respectively). Patients with stage 1a AKI had a lower 30-day and 90-day survival compared to the group of patients who did not develop AKI (71% vs. 96%, p < 0.001, and 71% vs. 91%, p < 0.01, respectively) and better survival than patients with more severe AKI (71% vs. 40%, p < 0.01). CONCLUSIONS: AKI was independently associated with mortality in patients with cirrhosis, even at the very early 1a stage. Response to treatment improved survival, and was inversely proportional to the stage of AKI, which suggests that treatment should be started at the earliest stage of AKI.

Management of Severe and Refractory Ascites.

Considering the poor prognosis, severe and refractory ascites is a milestone in cirrhotic patients. Liver transplantation must be considered first. In the case of contraindication to liver transplantation or when the waiting period is estimated to be more than 6 months, transjugular intrahepatic portosystemic shunt should be discussed in eligible patients. Regardless of the type of treatment, a careful selection of patients is crucial to avoid further decompensation and specific complications of each treatment.

The Use of Rifaximin in the Prevention of Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt : A Randomized Controlled Trial.

BACKGROUND: The efficacy of rifaximin in the secondary prevention of overt hepatic encephalopathy (HE) is well documented, but its effectiveness in preventing a first episode in patients after transjugular intrahepatic portosystemic shunt (TIPS) has not been established. OBJECTIVE: To determine whether rifaximin prevents overt HE after TIPS compared with placebo. DESIGN: Randomized, double-blind, multicenter, placebo-controlled trial. (ClinicalTrials.gov: NCT02016196). PARTICIPANTS: 197 patients with cirrhosis undergoing TIPS for intractable ascites or prevention of variceal rebleeding. INTERVENTION: Patients were randomly assigned to receive rifaximin (600 mg twice daily) or placebo, beginning 14 days before TIPS and continuing for 168 days after the procedure. MEASUREMENTS: The primary efficacy end point was incidence of overt HE within 168 days after the TIPS procedure. RESULTS: An episode of overt HE occurred in 34% (95% CI, 25% to 44%) of patients in the rifaximin group (n = 93) and 53% (CI, 43% to 63%) in the placebo group (n = 93) during the postprocedure period (odds ratio, 0.48 [CI, 0.27 to 0.87]). Neither the incidence of adverse events nor transplant-free survival was significantly different between the 2 groups. LIMITATIONS: The study's conclusion applies mainly to patients with alcoholic cirrhosis, who made up the study population. The potential benefit of rifaximin 6 months after TIPS and beyond remains to be investigated. CONCLUSION: In patients with cirrhosis treated with TIPS, rifaximin was well tolerated and reduced the risk for overt HE. Rifaximin should therefore be considered for prophylaxis of post-TIPS HE. PRIMARY FUNDING SOURCE: French Public Health Ministry.

A Prospective Study Identifying Predictive Factors of Cardiac Decompensation After Transjugular Intrahepatic Portosystemic Shunt: The Toulouse Algorithm.

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is now a standard for the treatment of portal hypertension-related complications. After the TIPS procedure, incidence and risk factors of cardiac decompensation are poorly known. The main objectives were to measure the incidence of the onset of cardiac decompensation after TIPS and identify the predictive factors. APPROACH AND RESULTS: All patients with cirrhosis treated with TIPS between May 2011 and June 2016 were considered for inclusion. They received a cardiac assessment by standard biological parameters, transthoracic echocardiography, and right heart catheterization. Patients were followed for 1 year after TIPS insertion. The main endpoint was the incidence of cardiac decompensation requiring hospitalization. One hundred seventy-four patients were treated by TIPS during the period. One hundred patients who underwent a complete cardiac evaluation were included. A cardiac decompensation occurred in 20% of the patients. The parameters associated with the occurrence of severe cardiac decompensation were a prolonged QT interval corrected (462 vs. 443 ms; P = 0.05), an elevated pre-TIPS brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) level, an elevated E/A ratio (1.5 vs. 1.0; P = 0.001) and E/e' ratio (11 vs. 7; P < 0.001), and a left atrial dilatation (40 vs. 29 mL/m2 ; P = 0.011). The presence of aortic stenosis was also associated with cardiac decompensation. A level of BNP <40 pg/mL and NT-proBNP <125 pg/mL allowed identifying patients without risk of cardiac decompensation. Additionally, absence of diastolic dysfunction criteria at echocardiography ruled out the risk of further cardiac decompensation. CONCLUSIONS: Hospitalization for cardiac decompensation is observed in 20% of patients in the year after TIPS insertion. Combining BNP or NT-proBNP levels and echocardiographic parameters should help improve patient selection.

Bleeding risk of variceal band ligation in extrahepatic portal vein obstruction is not increased by oral anticoagulation.

BACKGROUND AND OBJECTIVES: Noncirrhotic nontumoral extrahepatic portal vein obstruction (EHPVO) is the second leading cause of portal hypertension (PHT) and is mainly related to prothrombotic disorders. Patients with EHPVO often require prolonged oral anticoagulation therapy (OAT) together with variceal band ligation (VBL) to prevent thrombosis recurrence and PHT-related bleeding, respectively. The benefit-risk balance of VBL in this context remains unknown. We aimed to assess upper gastrointestinal bleeding (UGB) risk and variceal eradication efficacy in EHPVO patients undergoing a VBL program without stopping OAT. PATIENTS AND METHODS: All patients with EHPVO treated (group A) or not (group B) with OAT and undergoing the VBL program were included between 2001 and 2010 in two tertiary French liver centers. We compared the incidence, source, and severity of UGB and variceal eradication efficacy. All EHPVO patients were then matched 1 : 1 with compensated cirrhotic patients with PHT not receiving OAT (group C) to compare UGB incidence and VBL efficacy. RESULTS: Forty-three EHPVO patients (30 with and 13 without OAT) and 43 cirrhotic patients were included for a total of 471 VBL sessions. The incidence of UGB was similar between group A (nine episodes/121 sessions) and group B (6/130), and tended to be higher in EHPVO patients (group A and B) than in cirrhotic patients (2/220). There was no difference between groups when considering bleeding source or severity and variceal eradication efficacy (84%). CONCLUSION: VBL can be performed safely and efficiently without stopping anticoagulation therapy in EHPVO patients.

Transjugular intrahepatic portosystemic shunt placement before abdominal intervention in cirrhotic patients with portal hypertension: lessons from a pilot study.

BACKGROUND: Abdominal interventions are usually contraindicated in patients with cirrhosis and portal hypertension because of increased morbidity and mortality. Decreasing portal pressure with transjugular intrahepatic portosystemic shunt (TIPS) may improve patient outcomes. We report our experience with patients treated by neoadjuvant TIPS to identify those who would most benefit from this two-step procedure. PATIENTS AND METHODS: All patients treated by dedicated neoadjuvant TIPS between 2005 and March 2013 in two tertiary referral hospitals were included. The primary endpoint was the rate of failure, defined by the inability to proceed to the planned intervention after TIPS placement or persistent liver decompensation 3 months after intervention. The secondary endpoints were the rate of complications, parameters associated with failure, and 1-year survival. RESULTS: Twenty-eight consecutive patients were included, with a mean age of 61.2±6.6 years, mean Child-Pugh score of 6.6±1.5, and mean model for end-stage liver disease score of 10.4±3.3. Procedures were digestive (43%) or liver (25%) resections, abdominal wall surgery (21%), or interventional gastrointestinal endoscopies (11%). The scheduled procedure was performed in 24 (86%) patients within a median of 25 days after TIPS. Procedure failures occurred in six (21%) patients: four did not undergo surgery and two experienced persistent liver decompensation. Seven (25%) patients had postoperative complications, mainly local. Viral origin of cirrhosis, history of encephalopathy, and hepatic surgery were found to be associated with failure. One-year survival in the whole cohort was 70%. CONCLUSION: In selected patients, extrahepatic surgery or interventional endoscopies can be safely performed after portal hypertension has been controlled by TIPS.

Transjugular Intrahepatic Portosystemic Shunts With Covered Stents Increase Transplant-Free Survival of Patients With Cirrhosis and Recurrent Ascites.

BACKGROUND & AIMS: There is controversy over the ability of transjugular intrahepatic portosystemic shunts (TIPS) to increase survival times of patients with cirrhosis and refractory ascites. The high rate of shunt dysfunction with the use of uncovered stents counteracts the benefits of TIPS. We performed a randomized controlled trial to determine the effects of TIPS with stents covered with polytetrafluoroethylene in these patients. METHODS: We performed a prospective study of 62 patients with cirrhosis and at least 2 large-volume paracenteses within a period of at least 3 weeks; the study was performed at 4 tertiary care centers in France from August 2005 through December 2012. Patients were randomly assigned to groups that received covered TIPS (n = 29) or large-volume paracenteses and albumin as necessary (LVP+A, n = 33). All patients maintained a low-salt diet and were examined at 1 month after the procedure then every 3 months until 1 year. At each visit, liver disease-related complications, treatment modifications, and clinical and biochemical variables needed to calculate Child-Pugh and Model for End-Stage Liver Disease scores were recorded. Doppler ultrasonography was performed at the start of the study and then at 6 and 12 months after the procedure. The primary study end point was survival without a liver transplant for 1 year after the procedure. RESULTS: A higher proportion of patients in the TIPS group (93%) met the primary end point than in the LVP+A group (52%) (P = .003). The total number of paracenteses was 32 in the TIPS group vs 320 in the LVP+A group. Higher proportions of patients in the LVP+A group had portal hypertension-related bleeding (18% vs 0%; P = .01) or hernia-related complications (18% vs 0%; P = .01) than in the TIPS group. Patients in LVP+A group had twice as many days of hospitalization (35 days) as the TIPS group (17 days) (P = .04). The 1-year probability of remaining free of encephalopathy was 65% for each group. CONCLUSIONS: In a randomized trial, we found covered stents for TIPS to increase the proportion of patients with cirrhosis and recurrent ascites who survive transplantation-free for 1 year, compared with patients given repeated LVP+A. These findings support TIPS as the first-line intervention in such patients. ClinicalTrials.gov ID: NCT00222014.

Clinical characteristics and outcome of cirrhotic patients with high protein concentrations in ascites: a prospective study.

BACKGROUND: The protein concentration in ascites is usually low in cirrhosis because capillarization and defenestration of the sinusoids limit diffusion of large proteins from plasma to the space of Disse. However, some cirrhotic patients have high-protein ascites (HPA). AIM: The aim of this study was to describe and compare the characteristics and prognosis between cirrhotic patients with HPA (>20 g/l) and patients with low-protein ascites (LPA). PATIENTS AND METHODS: In this longitudinal observational prospective cohort study, all consecutive cirrhotic patients with ascites hospitalized in our tertiary liver center were included and followed for up to 2 years, provided that they had no other cause of HPA. HPA was defined as protein concentrations of more than 20 g/l. RESULTS: Among 107 patients included, 19 (17.8%) had HPA. HPA patients had more refractory ascites (63 vs. 34%), better liver functions, and a higher 1-year transplant-free survival rate compared with LPA patients (P<0.05). Portal hypertension parameters were not different. During follow-up, 47% of HPA patients were treated by transjugular intrahepatic portosystemic shunts versus 18% of LPA patients, whereas 15 LPA patients required liver transplantation for end-stage liver disease versus only one HPA patient. We observed higher protein filtration and less pericellular, centrilobular, and sinusoidal fibrosis in cirrhotic HPA livers compared with LPA livers. CONCLUSION: Almost 20% of cirrhotic patients with ascites have HPA (>20 g/l). These patients have better liver functions and a higher 1-year survival than those with LPA, even though ascites are more often refractory.

Central obesity is associated with non-cirrhotic portal vein thrombosis.

BACKGROUND & AIMS: 30-40% of portal vein thrombosis (PVT) remains of unknown origin. An association between metabolic syndrome (MetS) and peripheral vein thrombosis has been reported but not with PVT, to date. The aim of this study was to investigate the association between MetS and PVT. METHODS: Between 2003 and 2014, all consecutive patients with non-cirrhotic PVT were prospectively included. Patient's characteristics and risks factors were recorded at the time of inclusion. Controls were selected by random in the general population and were matched 1/1 according to age and sex. RESULTS: Seventy-nine patients with PVT were included: 40 present with at least one risk factor for PVT (SPVT) and 39 were found to be idiopathic (IPVT). The prevalence of MetS was 25.6% in SPVT group vs. 47.4% in IPVT group and 17.9% in controls from the general population (C-IPVT: p=0.01). The waist circumference and body mass index were higher in the IPVT group than in the SPVT group (105 vs. 93cm, p=0.004 and 29.4 vs. 25.0kg/m(2), p=0.004) and in the C-IPVT group (105 vs. 92cm, p=0.001 and 29.4 vs. 25.8kg/m(2), p=0.003). Overweight was observed in 82.0% of patients in the IPVT group vs. 44% in the SPVT group (p=0.002) and 51% in the C-IPVT group (p=0.01). The mean visceral fat area was higher in IPVT than in SPVT (18,223mm(2)vs. 12,690mm(2), p=0.02). In multivariate analyses, an increase in waist circumference was the strongest parameter associated with idiopathic PVT. CONCLUSION: Central obesity is associated with PVT and could become one of the main risk factors for digestive thromboses.

Treatment of autochthonous acute hepatitis E with short-term ribavirin: a multicenter retrospective study.

BACKGROUND & AIMS: Hepatitis E virus (HEV) genotypes 3 and 4 cause sporadic cases of infection in developed countries. Being elderly and having an underlying liver disease are the main risk factors for death in this population. Chronic infection has been described in immunocompromised patients. Ribavirin is now the antiviral treatment of choice in solid-organ-transplant recipients with chronic HEV infection. We hypothesized that early short-term treatment of acute HEV infection may be useful for patients with risk factors or undergoing chemotherapy. METHODS: Between July 2010 and January 2014, 21 patients diagnosed with acute HEV infection were treated with ribavirin, at 600-800 mg/day for up to 3 months. All serum samples were positive for HEV RNA. RESULTS: Nine patients were treated for severe hepatitis. Six patients were aged >70 years. Four patients were receiving an immunosuppressive therapy for an autoimmune disease and two patients were undergoing chemotherapy for a malignancy. Two patients received a fixed-dose regimen. For all other patients, ribavirin was stopped when HEV became undetectable in the serum. The median duration of ribavirin treatment was 26 days. Two patients developed severe anaemia. Two patients with encephalopathy died. One patient relapsed transiently. All patients were cleared of HEV and regained normalized liver-enzyme levels. Immunosuppressive treatment and chemotherapy could be resumed. CONCLUSIONS: Treatment of acute HEV infection using ribavirin seems safe and effective. Short-term treatment tailored to viraemia may be the best regimen for this indication.

Serum tests, liver stiffness and artificial neural networks for diagnosing cirrhosis and portal hypertension.

BACKGROUND: The diagnostic performance of biochemical scores and artificial neural network models for portal hypertension and cirrhosis is not well established. AIMS: To assess diagnostic accuracy of six serum scores, artificial neural networks and liver stiffness measured by transient elastography, for diagnosing cirrhosis, clinically significant portal hypertension and oesophageal varices. METHODS: 202 consecutive compensated patients requiring liver biopsy and hepatic venous pressure gradient measurement were included. Several serum tests (alone and combined into scores) and liver stiffness were measured. Artificial neural networks containing or not liver stiffness as input variable were also created. RESULTS: The best non-invasive method for diagnosing cirrhosis, portal hypertension and oesophageal varices was liver stiffness (C-statistics=0.93, 0.94, and 0.90, respectively). Among serum tests/scores the best for diagnosing cirrhosis and portal hypertension and oesophageal varices were, respectively, Fibrosis-4, and Lok score. Artificial neural networks including liver stiffness had high diagnostic performance for cirrhosis, portal hypertension and oesophageal varices (accuracy>80%), but were not statistically superior to liver stiffness alone. CONCLUSIONS: Liver stiffness was the best non-invasive method to assess the presence of cirrhosis, portal hypertension and oesophageal varices. The use of artificial neural networks integrating different non-invasive tests did not increase the diagnostic accuracy of liver stiffness alone.

Screening of esophageal varices by esophageal capsule endoscopy: results of a French multicenter prospective study.

BACKGROUND AND STUDY AIM: Esophageal video capsule endoscopy (ECE) is a new technique that allows examination of the esophagus using a noninvasive approach. The aim of this study was to compare ECE with esophagogastroduodenoscopy (EGD) for the diagnosis of esophageal varices in patients with cirrhosis. PATIENTS AND METHODS: A total of 330 patients with cirrhosis and with no known esophageal varices were prospectively enrolled. Patients underwent ECE first, followed by EGD (gold standard). The endoscopists who performed EGD were blind to the ECE result. Patient satisfaction was assessed using a visual analog scale (maximum score 100). RESULTS: A total of 30 patients were excluded from the analysis because they did not undergo any endoscopic examinations. Patients (mean age 56 years; 216 male) had mainly alcoholic (45 %) or viral (27 %) cirrhosis. The diagnostic indices of ECE to diagnose and correctly stage esophageal varices were: sensitivity 76 % and 64 %, specificity 91 % and 93 %, positive predictive value 88 % and 88 %, and negative predictive value 81 % and 78 %, respectively. ECE patient satisfaction scored significantly higher than EGD (87 ±â€Š22 vs. 58 ±â€Š35; P < 0.0001). CONCLUSIONS: ECE was well tolerated and safe in patients with liver cirrhosis and suspicion of portal hypertension. The sensitivity of ECE is not currently sufficient to replace EGD as a first exploration in these patients. However, due to its excellent specificity and positive predictive value, ECE may have a role in cases of refusal or contraindication to EGD. ECE might also improve compliance to endoscopic follow-up and aid important therapeutic decision making in the prophylaxis of bleeding. TRIAL REGISTRATION: EudraCT (ID RCB 2009-A00532-55) and ClinicalTrials.gov (NCT00941421).

Pre-transjugular intrahepatic portosystemic shunts (TIPS) prediction of post-TIPS overt hepatic encephalopathy: the critical flicker frequency is more accurate than psychometric tests.

UNLABELLED: Transjugular intrahepatic portosystemic shunts (TIPS) is a second-line treatment because of an increased incidence of overt hepatic encephalopathy (OHE). A better selection of patients to decrease this risk is needed and one promising approach could be the detection of minimal hepatic encephalopathy (MHE). The aim of the present prospective study was to determine whether pre-TIPS minimal hepatic encephalopathy was predictive of post-TIPS OHE and to compare Psychometric Hepatic Encephalopathy Sum Score(PHES) and the Critical Flicker Frequency (CFF) in this setting. From May 2008 to January 2011, 54 consecutive patients treated with TIPS were included. PHES and CFF were performed 1 to 7 days before and after TIPS at months 1, 3, 6, 9, and 12 or until liver transplantation or death. Before TIPS, MHE was detected by PHES and CFF in 33% and 39% of patients, respectively. After the TIPS procedure, 19 patients (35%) experienced a total of 64 episodes of OHE. OHE developed significantly more often inpatients for whom an indication for TIPS had been refractory ascites, with a history of OHE or of renal failure, lower hemoglobin level, or MHE as diagnosed by CFF. Post-TIPS OHE was more accurately predicted by CFF than by PHES. Absence of MHE at CFF had a good negative predictive value (91%) for the risk of post-TIPS recurrent OHE, defined as the occurrence of three or more episodes of OHE or of one episode which lasted more than 15 days. The absence of pre-TIPS history of OHE and a CFF value equal to or greater than 39 Hz had a 100% negative predictive value for post-TIPS recurrent OHE. CONCLUSION: Aiming to decrease the rate of post-TIPS HE, the use of CFF could help selecting patients for TIPS.

Use of early-TIPS for high-risk variceal bleeding: results of a post-RCT surveillance study.

BACKGROUND & AIMS: In a recent randomized international clinical trial (RCT) in high-risk cirrhotic patients with acute variceal bleeding, the early use of transjugular intrahepatic portosystemic shunt (TIPS) was associated with marked and significant reductions in both treatment failure and mortality. The aim of this study was to confirm these results in clinical practice in the same centers of the RCT study. METHODS: We retrospectively reviewed patients admitted for acute variceal bleeding and high risk of treatment failure (Child C <14 or Child B plus active bleeding), treated with early-TIPS (n=45) or drugs+endoscopic therapy (ET) (n=30). RESULTS: Patients treated with early-TIPS had a much lower incidence of failure to control bleeding or rebleeding than patients receiving drug+ET (3 vs. 15; p <0.001). The 1-year actuarial probability of remaining free of this composite end point was 93% vs. 53% (p <0.001). The same was observed in mortality (1-year actuarial survival was 86% vs. 70% respectively; p=0.056). Actuarial curves of failure to control bleeding+rebleeding and of survival were well within the confidence intervals of those observed in the RCT. CONCLUSIONS: This study supports the early use of TIPS in patients with cirrhosis and a high-risk variceal bleeding.