Economic Impact of European Liver and Intestine Transplantation Association (ELITA) Recommendations for Hepatitis B Prophylaxis After Liver Transplantation.

The European Liver and Intestine Transplant Association, ELITA, promoted a Consensus Conference involving 20 experts across the world which generated updated guidelines on HBV prophylaxis in liver transplant candidates and recipients. This study explores the economic impact associated with the implementation of the new ELITA guidelines. To this aim, a condition-specific cohort simulation model has been developed to compare new and historical prophylaxis, including only pharmaceutical cost and using the European perspective. The target population simulated in the model included both prevalent and incident cases, and consisted of 6,133 patients after the first year, that increased to 7,442 and 8,743 patents after 5 and 10 years from its implementation. The ELITA protocols allowed a cost saving of around € 235.65 million after 5 years and € 540.73 million after 10 years; which was mainly due to early HIBG withdrawal either after the first 4 weeks or after the first year post Liver Transplantation (LT) depending on the virological risk at transplantation. Results were confirmed by sensitivity analyses. The money saved by the implementation of the ELITA guidelines would allow healthcare decision makers and budget holders to understand where costs could be reduced and resources re-allocated to different needs.

Protective Role of Tacrolimus, Deleterious Role of Age and Comorbidities in Liver Transplant Recipients With Covid-19: Results From the ELITA/ELTR Multi-center European Study.

BACKGROUND AND AIMS: Despite concerns that liver transplant (LT) recipients may be at increased risk of unfavorable outcomes from COVID-19 due the high prevalence of co-morbidities, immunosuppression and ageing, a detailed analysis of their effects in large studies is lacking. METHODS: Data from adult LT recipients with laboratory confirmed SARS-CoV2 infection were collected across Europe. All consecutive patients with symptoms were included in the analysis. RESULTS: Between March 1 and June 27, 2020, data from 243 adult symptomatic cases from 36 centers and 9 countries were collected. Thirty-nine (16%) were managed as outpatients while 204 (84%) required hospitalization including admission to the ICU (39 of 204, 19.1%). Forty-nine (20.2%) patients died after a median of 13.5 (10-23) days, respiratory failure was the major cause. After multivariable Cox regression analysis, age >70 (HR, 4.16; 95% CI, 1.78-9.73) had a negative effect and tacrolimus (TAC) use (HR, 0.55; 95% CI, 0.31-0.99) had a positive independent effect on survival. The role of co-morbidities was strongly influenced by the dominant effect of age where comorbidities increased with the increasing age of the recipients. In a second model excluding age, both diabetes (HR, 1.95; 95% CI, 1.06-3.58) and chronic kidney disease (HR, 1.97; 95% CI, 1.05-3.67) emerged as associated with death CONCLUSIONS: Twenty-five percent of patients requiring hospitalization for COVID-19 died, the risk being higher in patients older than 70 and with medical co-morbidities, such as impaired renal function and diabetes. Conversely, the use of TAC was associated with a better survival thus encouraging clinicians to keep TAC at the usual dose.

Location and allocation: Inequity of access to liver transplantation for patients with severe acute-on-chronic liver failure in Europe.

There is growing evidence that liver transplantation (LT) is the most effective treatment for acute-on-chronic liver failure grade-3 (ACLF-3). This study examines whether and how this evidence translates into practice by analyzing the variability in intensive care unit (ICU) admissions, listing strategies, and LT activity for patients with ACLF-3 across transplantation centers in Europe. Consecutive patients who were admitted to the ICU with ACLF-3, whether or not they were listed and/or transplanted with ACLF-3, between 2018 and 2019 were included across 20 transplantation centers. A total of 351 patients with ACLF-3 were included: 33 had been listed prior to developing ACLF-3 and 318 had not been listed at the time of admission to the ICU. There was no correlation between the number of unlisted patients with ACLF-3 admitted to the ICU and the number listed or transplanted while in ACLF-3 across centers. By contrast, there was a correlation between the number of patients listed and the number transplanted while in ACLF-3. About 21% of patients who were listed while in ACLF-3 died on the waiting list or were delisted. The percentage of LT for patients with ACLF-3 varied from 0% to 29% for those transplanted with decompensated cirrhosis across centers (average = 8%), with an I2 index of 68% (95% confidence interval, 49%-80%), showing substantial heterogeneity among centers. The 1-year survival for all patients with ACLF-3 was significantly higher in centers that listed and transplanted more patients with ACLF-3 (>10 patients) than in centers that listed and transplanted fewer: 36% versus 20%, respectively (p = 0.012). Patients with ACLF-3 face inequity of access to LT across Europe. Waitlisting strategies for patients with ACLF-3 influence their access to LT and, ultimately, their survival.

COVID-19 in liver transplant candidates: pretransplant and post-transplant outcomes - an ELITA/ELTR multicentre cohort study.

OBJECTIVE: Explore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course. DESIGN: Data from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed. RESULTS: From 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10-30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15-19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44-102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31-170). CONCLUSIONS: Increased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%).

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

BACKGROUND & AIMS: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. METHODS: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. RESULTS: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. CONCLUSIONS: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. LAY SUMMARY: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: Results of the ELITA/EF-CLIF collaborative study (ECLIS).

BACKGROUND & AIMS: Liver transplantation (LT) has been proposed as an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to assess the current clinical practice and outcomes of patients with ACLF who are wait-listed for LT in Europe. METHODS: This was a retrospective study including 308 consecutive patients with ACLF, listed in 20 centres across 8 European countries, from January 2018 to June 2019. RESULTS: A total of 2,677 patients received a LT: 1,216 (45.4%) for decompensated cirrhosis. Of these, 234 (19.2%) had ACLF at LT: 58 (4.8%) had ACLF-1, 78 (6.4%) had ACLF-2, and 98 (8.1%) had ACLF-3. Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and the Netherlands had medium rates (9-15%); and the United Kingdom and Spain had low rates (3-5%) (p <0.0001). The 1-year probability of survival after LT for patients with ACLF was 81% (95% CI 74-87). Pre-LT arterial lactate levels >4 mmol/L (hazard ratio [HR] 3.14; 95% CI 1.37-7.19), recent infection from multidrug resistant organisms (HR 3.67; 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74; 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the waiting list. In an intention-to-treat analysis, 1-year survival of patients with ACLF on the LT waiting list was 73% for ACLF-1 or -2 and 50% for ACLF-3. CONCLUSION: The results reveal wide variations in the listing of patients with ACLF in Europe despite favourable post-LT survival. Risk factors for mortality were identified, enabling a more precise prognostic assessment of patients with ACLF. LAY SUMMARY: Acute-on-chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation is an effective therapeutic option. This study has demonstrated that in Europe, referral and access to liver transplantation (LT) for patients with ACLF needs to be harmonised to avoid inequities. Post-LT survival for patients with ACLF was >80% after 1 year and some factors have been identified to help select patients with favourable outcomes.

High rates of 30-day mortality in patients with cirrhosis and COVID-19.

BACKGROUND & AIMS: Coronavirus disease 2019 (COVID-19) poses a major health threat to healthy individuals and those with comorbidities, but its impact on patients with cirrhosis is currently unknown. Herein, we aimed to evaluate the impact of COVID-19 on the clinical outcome of patients with cirrhosis. METHODS: In this multicentre retrospective study, patients with cirrhosis and a confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection were enrolled between 1st and 31th March 2020. Clinical and biochemical data at diagnosis of COVID-19 and at the last outpatient visit were obtained through review of medical records. RESULTS: Fifty patients with cirrhosis and confirmed SARS-CoV-2 infection were enrolled (age 67 years, 70% men, 38% virus-related, 52% previously compensated cirrhosis). At diagnosis, 64% of patients presented fever, 42% shortness of breath/polypnea, 22% encephalopathy, 96% needed hospitalization or a prolonged stay if already in hospital. Respiratory support was necessary in 71%, 52% received antivirals, 80% heparin. Serum albumin significantly decreased, while bilirubin, creatinine and prothrombin time significantly increased at COVID-19 diagnosis compared to last available data. The proportion of patients with a model for end-stage liver disease (MELD) score ≥15 increased from 13% to 26% (p = 0.037), acute-on-chronic liver failure and de novo acute liver injury occurred in 14 (28%) and 10 patients, respectively. Seventeen patients died after a median of 10 (4-13) days from COVID-19 diagnosis, with a 30-day-mortality rate of 34%. The severity of lung and liver (according to CLIF-C, CLIF-OF and MELD scores) diseases independently predicted mortality. In patients with cirrhosis, mortality was significantly higher in those with COVID-19 than in those hospitalized for bacterial infections. CONCLUSION: COVID-19 is associated with liver function deterioration and elevated mortality in patients with cirrhosis. LAY SUMMARY: Coronavirus disease 2019 (COVID-19) poses a major health threat to healthy individuals and those with comorbidities. Herein, we assessed its impact on patients with cirrhosis. Infection with COVID-19 was associated with liver function deterioration and elevated mortality in patients with cirrhosis.

Longterm Outcomes of Patients Undergoing Liver Transplantation for Acute-on-Chronic Liver Failure.

Recent data have demonstrated >80% 1-year survival probability after liver transplantation (LT) for patients with severe acute-on-chronic liver failure (ACLF). However, longterm outcomes and complications are still unknown for this population. Our aim was to compare longterm patient and graft survival among patients transplanted across all grades of ACLF. We analyzed the United Network for Organ Sharing database for the years 2004-2017. Patients with ACLF were identified using the European Association for the Study of the Liver-Chronic Liver Failure criteria. Kaplan-Meier and Cox regression methods were used to determine patient and graft survival and associated predictors of mortality in adjusted models. A total of 56,801 patients underwent transplantation of which 31,024 (54.6%) had no ACLF, 8757 (15.4%) had ACLF grade 1, 9039 (15.9%) had ACLF grade 2, and 7891 (14.1%) had ACLF grade 3. The 5-year patient survival after LT was lower in the ACLF grade 3 patients compared with the other groups (67.7%; P < 0.001), although after year 1, the percentage decrease in survival was similar among all groups. Infection was the primary cause of death among all patient groups in the first year. Infection was the primary cause of death among all patient groups in the first year. After the first year, infection was the main cause of death in patients transplanted with ACLF grade 1 (32.1%), ACLF grade 2 (33.9%), and ACLF grade 3 (37.6%), whereas malignancy was the predominant cause of death in those transplanted with no ACLF (28.5%). In conclusion, patients transplanted with ACLF grade 3 had lower 5-year survival as compared with patients with ACLF grades 0-2, but mortality rates were not significantly different after the first year following LT. Graft survival was excellent across all ACLF groups.

Outcomes of Liver Transplant for Adults With Wilson's Disease.

Wilson's disease (WD) is a rare genetic disorder with protean manifestations. Even if liver transplantation (LT) could represent an effective therapeutic option for patients with end-stage liver disease, it has remained controversial in the presence of neuropsychiatric involvement. This study aimed to examine the frequency of adult LT for WD in Italy, focusing on the disease phenotype at the time of LT. A retrospective, observational, multicenter study was conducted across Italy exploring the frequency and characteristics of adults transplanted for WD between 2006 and 2016. A total of 29 adult WD patients underwent LT during the study period at 11 Italian LT centers (accounting for 0.4% of all LTs performed), and 27 of them were considered in this analysis (male/female, n = 9/18; age at LT, 29 years [19-60 years]; median Model for End-Stage Liver Disease score at LT, 27 [6-49]). Isolated hepatic phenotype was the indication for LT in 17 (63%) patients, whereas 2 (7%) patients underwent LT for neurological impairment on compensated liver disease. Overall 1- and 5-year patient survival was excellent (88% and 83%, respectively). Neuropsychiatric symptoms early after LT completely recovered in only a few patients. In conclusion, WD remains an uncommon, unusual indication for LT in Italy, displaying good post-LT graft and patient survival. Because isolated neuropsychiatric involvement represents a rare indication to LT, more data are needed to properly assess the value of LT for WD in this subset of patients.

Clinical outcome indicators in chronic hepatitis B and C: A primer for value-based medicine in hepatology.

BACKGROUND & AIMS: Chronic liver diseases (CLDs) are major health problems that require complex and costly treatments. Liver-specific clinical outcome indicators (COIs) able to assist both clinicians and administrators in improving the value of care are presently lacking. The Value-Based Medicine in Hepatology (VBMH) study aims to fill this gap, devising and testing a set of COIs for CLD, that could be easily collected during clinical practice. Here we report the COIs generated and recorded for patients with HBV or HCV infection at different stages of the disease. METHODS/RESULTS: In the first phase of VBMH study, COIs were identified, based on current international guidelines and literature, using a modified Delphi method and a RAND 9-point appropriateness scale. In the second phase, COIs were tested in an observational, longitudinal, prospective, multicentre study based in Lombardy, Italy. Eighteen COIs were identified for HBV and HCV patients. Patients with CLD secondary to HBV (547) or HCV (1391) were enrolled over an 18-month period and followed for a median of 4 years. The estimation of the proposed COIs was feasible in the real-word clinical practice and COI values compared well with literature data. Further, the COIs were able to capture the impact of new effective treatments like direct-acting antivirals (DAAs) in the clinical practice. CONCLUSIONS: The COIs efficiently measured clinical outcomes at different stages of CLDs. While specific clinical practice settings and related healthcare systems may modify their implementation, these indicators will represent an important component of the tools for a value-based approach in hepatology and will positively affect care delivery.

Portosystemic shunts versus endoscopic intervention with or without medical treatment for prevention of rebleeding in people with cirrhosis.

BACKGROUND: People with liver cirrhosis who have had one episode of variceal bleeding are at risk for repeated episodes of bleeding. Endoscopic intervention and portosystemic shunts are used to prevent further bleeding, but there is no consensus as to which approach is preferable. OBJECTIVES: To compare the benefits and harms of shunts (surgical shunts (total shunt (TS), distal splenorenal shunt (DSRS), or transjugular intrahepatic portosystemic shunt (TIPS)) versus endoscopic intervention (endoscopic sclerotherapy or banding, or both) with or without medical treatment (non-selective beta blockers or nitrates, or both) for prevention of variceal rebleeding in people with liver cirrhosis. SEARCH METHODS: We searched the CHBG Controlled Trials Register; CENTRAL, in the Cochrane Library; MEDLINE Ovid; Embase Ovid; LILACS (Bireme); Science Citation Index - Expanded (Web of Science); and Conference Proceedings Citation Index - Science (Web of Science); as well as conference proceedings and the references of trials identified until 22 June 2020. We contacted study investigators and industry researchers. SELECTION CRITERIA: Randomised clinical trials comparing shunts versus endoscopic interventions with or without medical treatment in people with cirrhosis who had recovered from a variceal haemorrhage. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. When possible, we collected data to allow intention-to-treat analysis. For each outcome, we estimated a meta-analysed estimate of treatment effect across trials (risk ratio for binary outcomes). We used random-effects model meta-analysis as our main analysis and as a means of presenting results. We reported differences in means for continuous outcomes without a meta-analytic estimate due to high variability in their assessment among all trials. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We identified 27 randomised trials with 1828 participants. Three trials assessed TSs, five assessed DSRSs, and 19 trials assessed TIPSs. The endoscopic intervention was sclerotherapy in 16 trials, band ligation in eight trials, and a combination of band ligation and either sclerotherapy or glue injection in three trials. In eight trials, endoscopy was combined with beta blockers (in one trial plus isosorbide mononitrate). We judged all trials to be at high risk of bias. We assessed the certainty of evidence for all the outcome review results as very low (i.e. the true effects of the results are likely to be substantially different from the results of estimated effects). The very low evidence grading is due to the overall high risk of bias for all trials, and to imprecision and publication bias for some outcomes. Therefore, we are very uncertain whether portosystemic shunts versus endoscopy interventions with or without medical treatment have effects on all-cause mortality (RR 0.99, 95% CI 0.86 to 1.13; 1828 participants; 27 trials), on rebleeding (RR 0.40, 95% CI 0.33 to 0.50; 1769 participants; 26 trials), on mortality due to rebleeding (RR 0.51, 95% CI 0.34 to 0.76; 1779 participants; 26 trials), and on occurrence of hepatic encephalopathy, both acute (RR 1.60, 95% CI 1.33 to 1.92; 1649 participants; 24 trials) and chronic (RR 2.51, 95% CI 1.38 to 4.55; 956 participants; 13 trials). No data were available regarding health-related quality of life. Analysing each modality of portosystemic shunts individually (i.e. TS, DSRS, and TIPS) versus endoscopic interventions with or without medical treatment, we are very uncertain if each type of shunt has effect on all-cause mortality: TS, RR 0.46, 95% CI 0.19 to 1.13; 164 participants; 3 trials; DSRS, RR 0.93, 95% CI 0.65 to 1.33; 352 participants; 4 trials; and TIPS, RR 1.10, 95% CI 0.92 to 1.31; 1312 participants; 19 trial; on rebleeding: TS, RR 0.28, 95% CI 0.14 to 0.56; 127 participants; 2 trials; DSRS, RR 0.26, 95% CI 0.11 to 0.65; 330 participants; 5 trials; and TIPS, RR 0.44, 95% CI 0.36 to 0.55; 1312 participants; 19 trials; on mortality due to rebleeding: TS, RR 0.25, 95% CI 0.06 to 0.96; 164 participants; 3 trials; DSRS, RR 0.31, 95% CI 0.13 to 0.74; 352 participants; 5 trials; and TIPS, RR 0.65, 95% CI 0.40 to 1.04; 1263 participants; 18 trials; on acute hepatic encephalopathy: TS, RR 1.66, 95% CI 0.70 to 3.92; 115 participants; 2 trials; DSRS, RR 1.70, 95% CI 0.94 to 3.08; 287 participants; 4 trials, TIPS, RR 1.61, 95% CI 1.29 to 1.99; 1247 participants; 18 trials; and chronic hepatic encephalopathy: TS, Fisher's exact test P = 0.11; 69 participants; 1 trial; DSRS, RR 4.87, 95% CI 1.46 to 16.23; 170 participants; 2 trials; and TIPS, RR 1.88, 95% CI 0.93 to 3.80; 717 participants; 10 trials. The proportion of participants with shunt occlusion or dysfunction was overall 37% (95% CI 33% to 40%). It was 3% (95% CI 0.8% to 10%) following TS, 7% (95% CI 3% to 13%) following DSRS, and 47.1% (95% CI 43% to 51%) following TIPS. Shunt dysfunction in trials utilising polytetrafluoroethylene-covered stents was 17% (95% CI 11% to 24%). Length of inpatient hospital stay and cost were not comparable across trials. Funding was unclear in 16 trials; 11 trials were funded by government, local hospitals, or universities. AUTHORS' CONCLUSIONS: Evidence on whether portosystemic shunts versus endoscopy interventions with or without medical treatment in people with cirrhosis and previous hypertensive portal bleeding have little or no effect on all-cause mortality is very uncertain. Evidence on whether portosystemic shunts may reduce bleeding and mortality due to bleeding while increasing hepatic encephalopathy is also very uncertain. We need properly conducted trials to assess effects of these interventions not only on assessed outcomes, but also on quality of life, costs, and length of hospital stay.

Development and Validation of a Scoring System That Includes Corrected QT Interval for Risk Analysis of Patients With Cirrhosis and Gastrointestinal Bleeding.

BACKGROUND & AIMS: The electrocardiographic QT interval frequently is prolonged in patients with cirrhosis. Acute gastrointestinal bleeding further prolongs corrected QT (QTc) in patients with cirrhosis, which has been associated with an increased risk of death within 6 weeks. We aimed to confirm these findings and develop a mortality risk index that incorporates QTc. METHODS: We collected data from 274 patients with cirrhosis and acute gastrointestinal bleeding from any cause admitted to a hospital in Bologna, Italy, from January 2001 through December 2012 (training set). We used logistic regression analysis to identify patient factors associated with death within 6 weeks (6-week mortality). We validated our findings by using data from 200 patients with cirrhosis and gastrointestinal bleeding treated at 2 separate hospitals in Italy, from 2001 through 2016 and 2007 through 2012. Our primary aim was to confirm the prognostic effects of prolonged QTc in a large population of patients and develop a 6-week mortality risk score for acute gastrointestinal bleeding from any cause that incorporates the QTc interval. RESULTS: In the training set, QTc greater than 456 ms, the model for end-stage liver disease-sodium (MELD-Na) score, previous bleeding, and serum albumin concentration were associated independently with 6-week mortality. We combined these parameters to create a risk scoring system that we named MELD-Na acute gastrointestinal bleeding (MELDNa-AGIB). In the validation set, the MELDNa-AGIB identified patients who died within 6 weeks with an area under the receiver operating characteristic curve (AUROC) of 0.888; this value was higher than that of the MELD score (AUROC, 0.838; P = .031), MELD score with updated calibration (AUROC, 0.837; P = .029), Child-Turcotte-Pugh score (AUROC, 0.789; P = .004), D'Amico score (AUROC, 0.761; P = .003), and Augustin score (AUROC, 0.792; P = .001), with a net reclassification improvement better than the MELD-Na score (0.266; P = .045). In calibration, the MELDNa-AGIB produced a high score in the Hosmer-Lemeshow test (P = .947), which was superior to that of MELD-Na (P = .146). In the training set, only 6.3% of patients with MELDNa-AGIB scores of 4 or less died within 6 weeks. Among patients with a scores of 9, 16, and 25 or higher, 15.5%, 41.5%, and 81% or more patients died within 6 weeks, respectively. The probability of survival progressively and significantly decreased with increasing scores in the training and validation sets. CONCLUSIONS: We confirmed QTc as an independent predictor of 6-week mortality in a large population of patients with cirrhosis and acute gastrointestinal bleeding. The combination of QTc, MELD-Na, previous bleeding, and serum albumin (the MELDNa-AGIB score) accurately determines the risk of 6-week mortality, providing timely identification of patients at very high risk of death.

Plasma expanders for people with cirrhosis and large ascites treated with abdominal paracentesis.

BACKGROUND: Plasma volume expanders are used in connection to paracentesis in people with cirrhosis to prevent reduction of effective plasma volume, which may trigger deleterious effect on haemodynamic balance, and increase morbidity and mortality. Albumin is considered the standard product against which no plasma expansion or other plasma expanders, e.g. other colloids (polygeline , dextrans, hydroxyethyl starch solutions, fresh frozen plasma), intravenous infusion of ascitic fluid, crystalloids, or mannitol have been compared. However, the benefits and harms of these plasma expanders are not fully clear. OBJECTIVES: To assess the benefits and harms of any plasma volume expanders such as albumin, other colloids (polygeline, dextrans, hydroxyethyl starch solutions, fresh frozen plasma), intravenous infusion of ascitic fluid, crystalloids, or mannitol versus no plasma volume expander or versus another plasma volume expander for paracentesis in people with cirrhosis and large ascites. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, CNKI, VIP, Wanfang, Science Citation Index Expanded, and Conference Proceedings Citation Index until January 2019. Furthermore, we searched FDA, EMA, WHO (last search January 2019), www.clinicaltrials.gov/, and www.controlled-trials.com/ for ongoing trials. SELECTION CRITERIA: Randomised clinical trials, no matter their design or year of publication, publication status, and language, assessing the use of any type of plasma expander versus placebo, no intervention, or a different plasma expander in connection with paracentesis for ascites in people with cirrhosis. We considered quasi-randomised, retrieved with the searches for randomised clinical trials only, for reports on harms. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We calculated the risk ratio (RR) or mean difference (MD) using the fixed-effect model and the random-effects model meta-analyses, based on the intention-to-treat principle, whenever possible. If the fixed-effect and random-effects models showed different results, then we made our conclusions based on the analysis with the highest P value (the more conservative result). We assessed risks of bias of the individual trials using predefined bias risk domains. We assessed the certainty of the evidence at an outcome level, using GRADE, and constructed 'Summary of Findings' tables for seven of our review outcomes. MAIN RESULTS: We identified 27 randomised clinical trials for inclusion in this review (24 published as full-text articles and 3 as abstracts). Five of the trials, with 271 participants, assessed plasma expanders (albumin in four trials and ascitic fluid in one trial) versus no plasma expander. The remaining 22 trials, with 1321 participants, assessed one type of plasma expander, i.e. dextran, hydroxyethyl starch, polygeline, intravenous infusion of ascitic fluid, crystalloids, or mannitol versus another type of plasma expander, i.e. albumin in 20 of these trials and polygeline in one trial. Twenty-five trials provided data for quantitative meta-analysis. According to the Child-Pugh classification, most participants were at an intermediate to advanced stage of liver disease in the absence of hepatocellular carcinoma, recent gastrointestinal bleeding, infections, and hepatic encephalopathy. All trials were assessed as at overall high risk of bias. Ten trials seemed not to have been funded by industry; twelve trials were considered unclear about funding; and five trials were considered funded by industry or a for-profit institution.We found no evidence of a difference in effect between plasma expansion versus no plasma expansion on mortality (RR 0.52, 95% CI 0.06 to 4.83; 248 participants; 4 trials; very low certainty); renal impairment (RR 0.32, 95% CI 0.02 to 5.88; 181 participants; 4 trials; very low certainty); other liver-related complications (RR 1.61, 95% CI 0.79 to 3.27; 248 participants; 4 trials; very low certainty); and non-serious adverse events (RR 1.04, 95% CI 0.32 to 3.40; 158 participants; 3 trials; very low certainty). Two of the trials stated that no serious adverse events occurred while the remaining trials did not report on this outcome. No trial reported data on health-related quality of life.We found no evidence of a difference in effect between experimental plasma expanders versus albumin on mortality (RR 1.03, 95% CI 0.82 to 1.30; 1014 participants; 14 trials; very low certainty); serious adverse events (RR 0.89, 95% CI 0.10 to 8.30; 118 participants; 2 trials; very low certainty); renal impairment (RR 1.17, 95% CI 0.71 to 1.91; 1107 participants; 17 trials; very low certainty); other liver-related complications (RR 1.10, 95% CI 0.82 to 1.48; 1083 participants; 16 trials; very low certainty); and non-serious adverse events (RR 1.37, 95% CI 0.66 to 2.85; 977 participants; 14 trials; very low certainty). We found no data on heath-related quality of life and refractory ascites. AUTHORS' CONCLUSIONS: Our systematic review and meta-analysis did not find any benefits or harms of plasma expanders versus no plasma expander or of one plasma expander such as polygeline, dextrans, hydroxyethyl starch, intravenous infusion of ascitic fluid, crystalloids, or mannitol versus albumin on primary or secondary outcomes. The data originated from few, small, mostly short-term trials at high risks of systematic errors (bias) and high risks of random errors (play of chance). GRADE assessments concluded that the evidence was of very low certainty. Therefore, we can neither demonstrate or discard any benefit of plasma expansion versus no plasma expansion, and differences between one plasma expander versus another plasma expander.Larger trials at low risks of bias are needed to assess the role of plasma expanders in connection with paracentesis. Such trials should be conducted according to the SPIRIT guidelines and reported according to the CONSORT guidelines.

Impact of DAAs on liver transplantation: Major effects on the evolution of indications and results. An ELITA study based on the ELTR registry.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) have dramatically improved the outcome of patients with hepatitis C virus (HCV) infection including those with decompensated cirrhosis (DC). We analyzed the evolution of indications and results of liver transplantation (LT) in the past 10 years in Europe, focusing on the changes induced by the advent of DAAs. METHODS: This is a cohort study based on data from the European Liver Transplant Registry (ELTR). Data of adult LTs performed between January 2007 to June 2017 for HCV, hepatitis B virus (HBV), alcohol (EtOH) and non-alcoholic steatohepatitis (NASH) were analyzed. The period was divided into different eras: interferon (IFN/RBV; 2007-2010), protease inhibitor (PI; 2011-2013) and second generation DAA (DAA; 2014-June 2017). RESULTS: Out of a total number of 60,527 LTs, 36,382 were performed in patients with HCV, HBV, EtOH and NASH. The percentage of LTs due to HCV-related liver disease varied significantly over time (p <0.0001), decreasing from 22.8% in the IFN/RBV era to 17.4% in the DAA era, while those performed for NASH increased significantly (p <0.0001). In the DAA era, the percentage of LTs for HCV decreased significantly (p <0.0001) from 21.1% (first semester 2014) to 10.6% (first semester 2017). This decline was more evident in patients with DC (HCV-DC, -58.0%) than in those with hepatocellular carcinoma (HCC) associated with HCV (HCV-HCC, -41.2%). Conversely, three-year survival of LT recipients with HCV-related liver disease improved from 65.1% in the IFN/RBV era to 76.9% in the DAA era, and is now comparable to the survival of recipients with HBV infection (p = 0.3807). CONCLUSIONS: In Europe, the number of LTs due to HCV infection is rapidly declining for both HCV-DC and HCV-HCC indications and post-LT survival has dramatically improved over the last three years. This is the first comprehensive study of the overall impact of DAA treatment for HCV on liver transplantation in Europe. LAY SUMMARY: After the advent of direct-acting antivirals in 2014, a dramatic decline was observed in the number of liver transplants performed both in patients with decompensated cirrhosis due to hepatitis C virus (HCV), minus 60%, and in those with hepatocellular carcinoma associated with HCV, minus 41%. Furthermore, this is the first large-scale study demonstrating that the survival of liver transplant recipients with HCV-related liver disease has dramatically improved over the last three years and is now comparable to the survival of recipients with hepatitis B virus infection. The reduction in HCV-related indications for LT means that there is a greater availability of livers, at least 600 every year, which can be allocated to patients with indications other than HCV.

Delisting HCV-infected liver transplant candidates who improved after viral eradication: Outcome 2 years after delisting.

BACKGROUNDS & AIMS: Treating patients with decompensated cirrhosis with direct-acting antiviral (DAA) therapy while on the waiting list for liver transplantation results in substantial improvement of liver function allowing 1 in 4 patients to be removed from the waiting list or delisted, as reported in a previous study promoted by the European Liver and Intestine Transplant Association (ELITA). The aim of this study was to report on clinical outcomes of delisted patients, including mortality risk, hepatocellular carcinoma development and clinical decompensation requiring relisting. METHODS: One hundred and forty-two HCV-positive patients on the liver transplant waiting list for decompensated cirrhosis, negative for hepatocellular carcinoma, between February 2014 and June 2015 were treated with DAA therapy and were prospectively followed up. RESULTS: Forty-four patients (30.9%) were delisted following clinical improvement. This percentage was higher than in the original study because of a number of patients being delisted long after starting DAAs. The median Child-Pugh and MELD score of delisted patients was 5.5 and 9 respectively. Four patients were relisted, because of HCC diagnosis in 1 case and 3 patients developed ascites. One further patient died (2.4%) because of rapidly progressing hepatocellular carcinoma twenty-two months after delisting. Of the 70 patients who received a liver graft, 9 died (13%). CONCLUSIONS: Antiviral therapy allows for a long-term improvement of liver function and the delisting of one-third of treated patients with risk of liver-related complications after delisting being very low.

Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study.

BACKGROUND & AIMS: All oral direct acting antivirals (DAA) have been shown to improve the liver function of patients with decompensated cirrhosis but it is presently unknown whether this clinical improvement may lead to the delisting of some patients. The aim of this study was to assess if and which patients can be first inactivated due to clinically improvement and subsequently delisted in a real life setting. METHODS: 103 consecutive listed patients without hepatocellular carcinoma were treated with different DAA combinations in 11 European centres between February 2014 and February 2015. RESULTS: The cumulative incidence of inactivated and delisted patients by competing risk analysis was 15.5% and 0% at 24weeks, 27.6% and 10.3% at 48weeks, 33.3% and 19.2% at 60weeks. The 34 patients who were inactivated showed a median improvement of 3.4 points for MELD (delta MELD, p<0.0001) and 2 points for Child-Pugh (CP) (delta-CP, p<0.0001). Three variables emerged from the most parsimonious multivariate competing risk model as predictors of inactivation for clinical improvement, namely, baseline MELD classes (MELD 16-20: HR=0.120; p=0.0005, MELD >20:HR=0.042; p<0.0001), delta MELD (HR=1.349; p<0.0001) and delta albumin (HR=0.307; p=0.0069) both assessed after 12weeks of DAA therapy. CONCLUSIONS: This study showed that all oral DAAs were able to reverse liver dysfunction and favoured the inactivation and delisting of about one patient out-of-three and one patient out-of-five in 60weeks, respectively. Patients with lower MELD scores had higher chances to be delisted. The longer term benefits of therapy need to be ascertained. LAY SUMMARY: The excellent efficacy and safety profile of the new drugs against Hepatitis C virus, "direct acting antivirals" or DAAs, have made antiviral therapy possible also for patients with advanced liver disease and for those on the waiting list for liver transplantation (LT). This study shows for the first time that the DAAs may lead to a remarkable clinical improvement allowing the delisting of one patient out of 5.