Further decompensation in cirrhosis: Results of a large multicenter cohort study supporting Baveno VII statements.

BACKGROUND AND AIMS: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis. APPROACH AND RESULTS: Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and <1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23-1.71) ( p <0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999. CONCLUSIONS: In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis.

Myosteatosis is closely associated with sarcopenia and significantly worse outcomes in patients with cirrhosis.

BACKGROUND & AIMS: Sarcopenia and myosteatosis are common in patients with cirrhosis. This study aimed to determine the prevalence of these muscle changes, their interrelations and their prognostic impact over a 12-month period. METHODS: We conducted a prospective multicentre study involving 433 patients. Sarcopenia and myosteatosis were evaluated using computed tomography scans. The 1-year cumulative incidence of relevant events was assessed by competing risk analysis. We used a Fine-Gray model adjusted for known prognostic factors to evaluate the impact of sarcopenia and myosteatosis on mortality, hospitalization, and liver decompensation. RESULTS: At enrolment, 166 patients presented with isolated myosteatosis, 36 with isolated sarcopenia, 135 with combined sarcopenia and myosteatosis and 96 patients showed no muscle changes. The 1-year cumulative incidence of death in patients with either sarcopenia and myosteatosis (13.8%) or isolated myosteatosis (13.4%) was over twice that of patients without muscle changes (5.2%) or with isolated sarcopenia (5.6%). The adjusted sub-hazard ratio for death in patients with muscle changes was 1.36 (95% CI 0.99-1.86, p = 0.058). The cumulative incidence of hospitalization was significantly higher in patients with combined sarcopenia and myosteatosis than in patients without muscle changes (adjusted sub-hazard ratio 1.18, 95% CI 1.04-1.35). The cumulative incidence of liver decompensation was greater in patients with combined sarcopenia and myosteatosis (p = 0.018) and those with isolated sarcopenia (p = 0.046) than in patients without muscle changes. Lastly, we found a strong correlation of function tests and frailty scores with the presence of muscle changes. CONCLUSIONS: Myosteatosis, whether alone or combined with sarcopenia, is highly prevalent in patients with cirrhosis and is associated with significantly worse outcomes. The prognostic role of sarcopenia should always be evaluated in relation to the presence of myosteatosis. IMPACT AND IMPLICATIONS: This study investigates the prognostic role of muscle changes in patients with cirrhosis. The novelty of this study is its multicentre, prospective nature and the fact that it distinguishes between the impact of individual muscle changes and their combination on prognosis in cirrhosis. This study highlights the prognostic role of myosteatosis, especially when combined with sarcopenia. On the other hand, the relevance of sarcopenia could be mitigated when considered together with myosteatosis. The implication from these findings is that sarcopenia should never be evaluated individually and that myosteatosis may play a dominant role in the prognosis of patients with cirrhosis.

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.

Towards a new definition of decompensated cirrhosis.

There is a universal agreement that the occurrence of clinical complications, such as ascites, hepatic encephalopathy, gastrointestinal bleeding, and jaundice mark the transition from the compensated to the decompensated stage of cirrhosis. Decompensation is associated with a substantial worsening of patient prognosis and is therefore considered the most important stratification variable for the risk of death. However, this classification is an oversimplification, as it does not discriminate between the prognostic subgroups that characterise the course of decompensation, which depends on the type and number of decompensating events. A deeper insight into the clinical course of decompensated cirrhosis is provided by observational studies characterising acute decompensation (AD), which occurs mostly in patients who have already experienced decompensating events. Decompensation presents as AD in a portion of patients while in many others it presents as a slow development of ascites or mild grade 1 or 2 hepatic encephalopathy, or jaundice, not requiring hospitalisation. Thus, we propose that decompensation of cirrhosis occurs through 2 distinct pathways: a non-acute and an acute (which includes acute-on-chronic liver failure) pathway. Moreover, while non-acute decompensation is the most frequent pathway of the first decompensation, AD mostly represents further decompensation.

New clinical and pathophysiological perspectives defining the trajectory of cirrhosis.

Traditionally, the complications of cirrhosis, namely variceal bleeding, ascites and hepatic encephalopathy, were thought to result predominantly from circulatory dysfunction and altered organ perfusion arising as a result of portal hypertension. Over the past 20 years, large, international prospective studies have indicated the importance of systemic inflammation and organ immunopathology as additional determinants of organ dysfunction in cirrhosis, which not only manifests in the liver, brain, circulation and the kidneys, but also the immune system, gut, muscles, adrenal glands, reproductive organs, heart and lungs. This review provides an overview of the traditional and emerging concepts around the initiation and maintenance of organ dysfunction in cirrhosis and proposes a new paradigm based upon a better understanding of acute decompensation of cirrhosis. The interaction between the traditional concepts and the emerging perspectives remains a matter of great interest and the basis for future research.

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.

Ordinal Outcomes Are Superior to Binary Outcomes for Designing and Evaluating Clinical Trials in Compensated Cirrhosis.

BACKGROUND AND AIMS: Prevention of decompensation is a primary therapeutic target in patients with compensated cirrhosis (CC). However, a major problem is the large sample size and long follow-up required to demonstrate a significant treatment effect because of the relatively low baseline risk. For this reason, it has been recently suggested that ordinal outcomes may be used in this area to gain power and reduce sample size. The aim of this study was to assess the applicability of ordinal outcomes in cirrhosis. APPROACH AND RESULTS: An inception cohort of 202 patients with CC (no ascites, gastrointestinal bleeding, encephalopathy, or jaundice) without esophageal varices was included, and 5-year outcome is reported. Etiology was mostly viral and alcoholic, and there were no dropouts. Ordinal outcome was set according to six grades with a previously established prognostic ordinality: grade 1 = no disease progression; grade 2 = development of varices; grade 3 = bleeding alone; grade 4 = nonbleeding single decompensation; grade 5 = more than one decompensating event; and grade 6 = death. At the 60-month time point, patients were distributed in grades 1 through 6 as follows: 129, 43, 2, 7, 5, and 16, respectively. Emulation of a clinical trial performed by dividing patients based on baseline platelet count into two groups (cutoff, 150 × 109 /L) demonstrated a statistically significant outcome difference between groups when using ordinal outcomes not detectable by binary logistic or chi-square or time-to-event analyses. Additionally, using ordinal outcomes in a hypothetical study to prevent decompensation resulted in sample-size estimates 3-to 4-fold lower than using a binary composite endpoint. CONCLUSIONS: Compared to traditional binary outcomes, the use of ordinal outcomes in trials of cirrhosis decompensation may provide more power and thus may require a smaller sample size.

Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension.

Portal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta-blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners.

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.

Clinical states of cirrhosis and competing risks.

The clinical course of cirrhosis is mostly determined by the progressive increase of portal hypertension, hyperdynamic circulation, bacterial translocation and activation of systemic inflammation. Different disease states, encompassing compensated and decompensated cirrhosis and a late decompensated state, are related to the progression of these mechanisms and may be recognised by haemodynamic or clinical characteristics. While these disease states do not follow a predictable sequence, they correspond to varying mortality risk. Acute-on-chronic liver failure may occur either in decompensated or in compensated cirrhosis and is always associated with a high short-term mortality. The increasing severity of these disease states prompted the concept of clinical states of cirrhosis. A multistate approach has been considered to describe the clinical course of the disease. Such an approach requires the assessment of the probabilities of different outcomes in each state, which compete with each other to occur first and mark the transition towards a different state. This requires the use of competing risks analysis, since the traditional Kaplan-Meier analysis should only be used in two-state settings. Accounting for competing risks also has implications for prognosis and treatment efficacy research. The aim of this review is to summarise relevant clinical states and to show examples of competing risks analysis in multistate models of cirrhosis.

Effect of recombinant Factor VIIa on outcome of acute variceal bleeding: an individual patient based meta-analysis of two controlled trials.

BACKGROUND & AIMS: Two randomized controlled studies have evaluated the effect of recombinant Factor VIIa (rFVIIa) on variceal bleeding in cirrhosis without showing significant benefit. The aim of the present study was to perform a meta-analysis of the two trials on individual patient data with special focus on high risk patients. METHODS: The primary outcome measure was the effect of rFVIIa on a composite five day endpoint: failure to control bleeding, 5-day rebleeding or death. Analysis was based on intention to treat. High risk was defined as active bleeding on endoscopy while under vasoactive drug infusion and Child-Pugh score >8. RESULTS: 497 patients were eligible for the meta-analysis; 308 (62%) had active variceal bleeding at endoscopy (oozing or spurting) and 283 of these had a Child-Pugh score >8. Analysis on the composite endpoint in all patients with bleeding from oesophageal varices did not show any beneficial treatment effect. However, failure rate for the primary composite end-point was significantly lower in treated patients with active bleeding at endoscopy (17%) compared to placebo (26%, p=0.049). This difference was highly significant in patients with Child-Pugh score >8 and active bleeding at endoscopy (rFVIIa 16%, placebo 27%; p=0.023). No significant treatment effect was found at 42 days. Five thromboembolic events occurred in rFVIIa treated patients compared to none in placebo treated patients. CONCLUSIONS: The current meta-analysis shows a beneficial effect of rFVIIa on the primary composite endpoint of control of acute bleeding, prevention of rebleeding day 1-5 and 5-day mortality in patients with advanced cirrhosis and active bleeding from oesophageal varices at endoscopy. A major drawback of the treatment is a potential increased risk of arterial thrombo-embolic events. This treatment might be considered in patients with lack of control of bleeding after standard treatment.

The potential role of machine learning in modelling advanced chronic liver disease.

The use of artificial intelligence is rapidly increasing in medicine to support clinical decision making mostly through diagnostic and prediction models. Such models derive from huge databases (big data) including a large variety of health-related individual patient data (input) and the corresponding diagnosis and/or outcome (labels). Various types of algorithms (e.g. neural networks) based on powerful computational ability (machine), allow to detect the relationship between input and labels (learning). More complex algorithms, like recurrent neural network can learn from previous as well as actual input (deep learning) and are used for more complex tasks like imaging analysis and personalized (bespoke) medicine. The prompt availability of big data makes that artificial intelligence can provide rapid answers to questions that would require years of traditional clinical research. It may therefore be a key tool to overcome several major gaps in the model of advanced chronic liver disease, mostly transition from mild to clinically significant portal hypertension, the impact of acute decompensation and the role of further decompensation and treatment efficiency. However, several limitations of artificial intelligence should be overcome before its application in clinical practice. Assessment of the risk of bias, understandability of the black boxes developing the models and models' validation are the most important areas deserving clarification for artificial intelligence to be widely accepted from physicians and patients.

Renal failure and cirrhosis: a systematic review of mortality and prognosis.

BACKGROUND & AIMS: To evaluate renal failure (RF) in cirrhosis to determine and quantify its prognostic significance. METHODS: Studies were identified by MEDLINE, EMBASE, Cochrane, ISI Web of Science (1977-2010); search terms included renal failure, mortality, and cirrhosis. Included studies (n=74) reported >10 patients and mortality data (8088 patients). Mortality at 1, 3, and 12 months was evaluated with respect to Child-Pugh score, serum creatinine, ascites, ICU status or sepsis, prospective study design, and publication year. Pooled odds ratio (POR) for death was compared for RF vs. non-RF (5668 patients). RESULTS: Overall median mortality for RF patients was 67%: 58% at 1 month and 63% (IQR 54-79) at 12 months. POR for death RF vs. non-RF patients was 7.6 (95%CI 5.4-10.8). Overall mortality before 2005 (1264 patients) was 74% and after 2005 (2833 patients) was 63% with a marked reduction only at 30 days (71% vs. 52%). CONCLUSIONS: This study provides a measure of the increased risk of death in cirrhosis with renal failure. RF increases mortality 7-fold, with 50% of patients dying within one month. Preventative strategies for RF are needed.