Clinical states of cirrhosis and competing risks Gennaro D'Amico, Alberto Morabito, Mario D'Amico, Linda Pasta, Giuseppe Malizia, Paola Rebora, Maria Grazia Valsecchi  Journal of Hepatology  Volume 68, Issue 3, Pages 563-576 (March 2018) DOI: 10.1016/j.jhep.2017.10.020 Copyright © 2017 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Schematic representation of the progression of pathophysiological mechanisms, haemodynamic and clinical manifestations of cirrhosis according to increasing severity along the course of the disease. METAVIR 4A, 4B, 4C: substaging of METAVIR fibrosis stage 4 according to increasing thickness of septa and decreasing nodules size. ACLF, acute-on-chronic liver failure; CO, cardiac output; CSPH, clinically significant portal hypertension; HRS, hepatorenal syndrome; HVPG, hepatic venous pressure gradient; MPH, mild portal hypertension; PSE, portosystemic encephalopathy; SAV, splanchnic arteriolar vasodilatation. Journal of Hepatology 2018 68, 563-576DOI: (10.1016/j.jhep.2017.10.020) Copyright © 2017 European Association for the Study of the Liver Terms and Conditions

Fig. 2 Development of oesophageal varices and mortality in 243 patients free of varices at diagnosis of compensated cirrhosis.10 (A) 1-KM estimates of the cumulative risks of developing oesophageal varices (death censored) and of dying before developing varices (varices censored). The sum of the two risks is higher than 1 (0.46 + 0.61 = 1.07). (B) Cumulative incidence of varices and of death assessed by the competing risks analysis CIF, estimated by the Aalen-Johansen estimator. The 1-KM estimate of the composite endpoint (death or development of varices) is also plotted to show how the CIF partitions the risk of any event in the risks of each event (0.53 + 0.26 = 0.79). (A, B) The abscissa denotes the number of months of observation and the numbers below the abscissa are the number of patients at risk per each observation period. Note that the number of patients at risk per each observation period for the two KM plots in (A) is the same because when estimating the risk of death without developing varices, the KM estimator censors the occurrence of varices and when estimating the risk of varices it censors deaths. Therefore, per each observation period the number of patients at risk is the number at risk at the beginning of the previous observation period – (n developing varices + n death + n with truncated observation) for both curves. For the same reason, the number of patients at risk in the competing risks analysis and in the 1-KM plot in the right side of the figure are the same as those in the plots of the left side. CIF, cumulative incidence function; KM, Kaplan-Meier. Journal of Hepatology 2018 68, 563-576DOI: (10.1016/j.jhep.2017.10.020) Copyright © 2017 European Association for the Study of the Liver Terms and Conditions

Fig. 3 Occurrence of death, ascites, bleeding and HCC in a cohort of 377 patients with compensated cirrhosis at diagnosis.10 (A) Cumulative risk of each event by the KM estimator plotted as 1-KM estimates. (B) Competing risks analysis showing the cumulative incidence function for the same events, computed by the Aalen-Johansen estimator. Each curve in (B) plots the probability for each event to be the first to occur along the disease course. (A, B) The abscissa denotes the number of months of observation and the numbers below the abscissa are the number of patients at risk per each observation period. It is to note that in (A), the number of patients at risk is the same for all the assessed events at the first observation but it differs thereafter because the Kaplan-Meier estimator considers only one event of interest and does not account for the others. Therefore, it is the occurrence of only the event of interest to reduce the number of subjects at risk per each relevant curve and hence the number of subjects at risk may be different for different events. By contrast in the competing risks analysis by the Aalen-Johansen estimator shown in (B), all the patients are at risk of all the considered events and at any time one of the considered events occurs, the number of subjects at risk is correspondingly reduced for all the considered events. Therefore, the number of subjects at risk is the same for any event at each observation time. HCC, hepatocellular carcinoma; KM, Kaplan-Meier. Journal of Hepatology 2018 68, 563-576DOI: (10.1016/j.jhep.2017.10.020) Copyright © 2017 European Association for the Study of the Liver Terms and Conditions

Fig. 4 A three-state model for cirrhosis is shown, including compensated cirrhosis, decompensated cirrhosis and death. The model is derived from a cohort of 377 patients with compensated cirrhosis at diagnosis.10 (A) 20-year Cumulative risk of death for 377 patients with compensated cirrhosis at diagnosis and of death after decompensation in the 224 of them who developed decompensation during the observation period. The risks are estimated by the KM estimator and plotted as 1-KM estimates. (B) Cumulative incidence of decompensation or death by competing risks analysis of for the 377 patients with compensated cirrhosis shown in (A) The CIF by the Aalen-Johansen estimator is plotted for the two competing events. (C) Three-state model showing 20-year transition probabilities from compensated cirrhosis towards decompensation and death and from decompensation to death in the same cohort as in previous panels. (D) Five, ten, fifteen and twenty-year state occupation probabilities for the three-state model shown in (C). The disease states considered are compensated, decompensated and death. The probability of being dead after decompensation or before decompensation are exploited to allow a more complete prognostic assessment. (A, B, D) the abscissa denotes the number of months of observation; (A, B) the numbers below the abscissa are the numbers of patients at risk per each observation period. CIF, cumulative incidence function; KM, Kaplan-Meier. Journal of Hepatology 2018 68, 563-576DOI: (10.1016/j.jhep.2017.10.020) Copyright © 2017 European Association for the Study of the Liver Terms and Conditions

Fig. 5 Schematic representation of a comprehensive multistate model for the clinical course of cirrhosis. ACLF, acute-on-chronic liver failure; CSPH, clinically significant portal hypertension; HVPG: hepatic venous pressure gradient; LSM, liver stiffness measurement; MPH, moderate portal hypertension; PSE, portosystemic encephalopathy. Journal of Hepatology 2018 68, 563-576DOI: (10.1016/j.jhep.2017.10.020) Copyright © 2017 European Association for the Study of the Liver Terms and Conditions

Fig. 6 Calibration of predicted probabilities of decompensation, according to the Cox model and to the Fine and Gray model, adjusted for the presence of oesophageal varices, platelet count and Child-Pugh score in a cohort of 377 patients with compensated cirrhosis at diagnosis.10 Predicted probabilities are computed according to each of the two models in nine groups of patients of approximately equal size. Per each group the median predicted probability of decompensation is plotted against the median observed risk. The dashed line represents perfect correspondence between predicted and observed risks. The figure shows that the Cox model tends to overestimate predicted probabilities. Journal of Hepatology 2018 68, 563-576DOI: (10.1016/j.jhep.2017.10.020) Copyright © 2017 European Association for the Study of the Liver Terms and Conditions

Fig. 7 Estimates of rebleeding and death risks in a double blind, placebo controlled randomised clinical trial of octreotide.141 (A, B) 1-Kaplan-Meier estimates in (A) the placebo group and in (B) the octreotide group, respectively. (C) Placebo group and (D) octreotide group: rebleeding and death cumulative incidence functions, estimated by the Aalen-Johansen estimator in the same trial. The fig. shows that deaths occurred mostly after rebleeding in the placebo group, while half of the total deaths in the octreotide group occurred before rebleeding. (A–D) The abscissa denotes the number of months of observation and the numbers below the abscissa are the numbers of patients at risk per each observation period. Journal of Hepatology 2018 68, 563-576DOI: (10.1016/j.jhep.2017.10.020) Copyright © 2017 European Association for the Study of the Liver Terms and Conditions