Review JOURNAL

OF HEPATOLOGY

Clinical states of cirrhosis and competing risks

Gennaro D’Amico1,⇑, Alberto Morabito2, Mario D’Amico3, Linda Pasta1, Giuseppe Malizia1,
Paola Rebora4, Maria Grazia Valsecchi4

Summary Keywords: Cirrhosis; Clinical

The clinical course of cirrhosis is mostly determined by the progressive increase of portal hypertension, course of cirrhosis; Portal
hypertension; Clinical states of
hyperdynamic circulation, bacterial translocation and activation of systemic inflammation. Different dis- cirrhosis; Competing risks;
ease states, encompassing compensated and decompensated cirrhosis and a late decompensated state, Cumulative incidence function;
are related to the progression of these mechanisms and may be recognised by haemodynamic or clinical Multistate models for cirrhosis.
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 compen- Received 23 July 2017; received
in revised form 26 September
sated cirrhosis and is always associated with a high short-term mortality. The increasing severity of 2017; accepted 24 October 2017
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 compet-
ing 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 mod-
els of cirrhosis.
Ó 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction
Cirrhosis is typically classified as compensated or
decompensated, based on the absence or presence
(or previous history) of variceal bleeding, ascites,
jaundice or encephalopathy.1–3 The significantly
longer survival, usually symptomless, and better
quality of life experienced by patients with com-
pensated cirrhosis compared to those with decom-
pensated cirrhosis, has brought about the concept
1
Gastroenterology Unit, Ospedale
not capture clinical state transitions following V. Cervello, Via Trabucco 180,
Palermo, Italy
the occurrence of a competing event, before the 2
Medical Statistics Unit,
event of interest. For example, decompensation Università di Milano, Milano, Italy
3
before death is not captured by a survival curve Radiology Department,
Università di Palermo, Palermo,
of compensated cirrhosis. In this situation, the
Italy
cumulative incidence function (CIF), based on the 4
Dipartimento di Medicina e
Aalen-Johansen estimator allows a more realistic Chirurgia Università di
description of the disease course, by providing Milano-Bicocca, Milano, Italy

that compensated and decompensated cirrhosis
are distinct clinical states of the disease.4,5 Further
disease states have been identified according to
the presence of oesophageal varices and to the
presence of only one or more disease complica-
tions.4,6–10
Development of gastro-oesophageal varices
and decompensation usually do not occur below
the portal pressure threshold of clinically signifi-
cant portal hypertension (CSPH) defined by hep-
atic venous pressure gradient (HVPG) ≥10
mmHg.11–13 Increasing portal pressure, bacterial
translocation, inflammation and hyperdynamic
circulation are likely mechanisms of decompensa-
tion,14 which progresses to a late decompensation
state characterised by further worsening of liver
function associated with other organ dysfunction,
while acute-on-chronic liver failure (ACLF) may
occur in any disease state. Histological stages15
of cirrhosis also parallel the progression of portal
hypertension16,17 and clinical states of the
disease.18,19
This body of evidence supports a multistate
approach to the clinical course of cirrhosis, which
implies a specific statistical methodology, since
the Kaplan-Meier (KM) survival curves20,21 may
the incidence of the competing events.22–24
Herein, the clinical course, competing risks and Key point
clinical states of cirrhosis will be reviewed and
The clinical course of cir-
examples of possible multistate models of the dis-
rhosis encompasses several
ease will be provided. disease states which
require multistate models
and competing risks anal-
The clinical course of cirrhosis ysis for proper assessment.
Cirrhosis may result from chronic liver inflamma-
tion from any cause, following parenchymal
necrosis, activated fibrogenesis, angiogenesis and
profound vascular changes. Increased hepatic
resistance to blood flow, derived from both
mechanical obstacle and vasoconstriction result-
ing from endothelial dysfunction and hepatic stel-
late cells contraction, gradually leads to portal
hypertension. The ensuing adaptive splanchnic
vasodilation further contributes to aggravate por-
tal hypertension and progressively results in
⇑ Corresponding author.
hyperdynamic circulation.25–27
Address: Gastroenterology Unit,
When established, cirrhosis remains compen- Ospedale V Cervello, Via
sated for a variably long time, depending on cur- Trabucco 180, 90146 Palermo,
ability of the underlying disease. In this state, Italy. Tel.: +39 091 6802780 or
+39 091 6802730; fax: +39 091
persistence of liver damage results in increasing
6802739.
fibrosis and portal hypertension.16,17,28 Decom- E-mail address: gedamico@
pensation and oesophageal varices may occur libero.it (G. D’Amico).

Journal of Hepatology 2018 vol. 68 j 563–576

Review
Key point
The earliest consequence
of cirrhosis is a progressive
increase in portal pressure
up to the CSPH threshold of
≥10 mmHg. Bleeding,
ascites, encephalopathy
and jaundice indicate
decompensated cirrhosis.
Renal function impair-
ment, refractory ascites,
infections and circulatory
dysfunction indicate more
advanced decompensation
and are associated with
very poor survival.
564
above the CSPH threshold (HVPG ≥10 mmHg)13,29
and hence decompensation is more frequent in
patients with oesophageal varices.6,7,10 In com-
pensated cirrhosis, the rate of development of
oesophageal varices and of decompensation is
about 7–8% and 5% per year, respectively.11,30,31
Following their appearance, varices grow in cali-
bre at a similar rate30,32 and may rupture in 5%
to 15% of patients per year, with a higher risk in
patients with large oesophageal varices and red
signs or Child B-C class.33 The ensuing variceal
bleeding is one of the most critical emergencies
in medicine, with a mortality rate of 10–20%34,35
(it was 50% in the early eighties).36 In untreated
patients, rebleeding and death occur in approxi-
mately 60% and 30% of patients, respectively, one
to two years after the index bleeding,37,38 and
are significantly reduced by non-selective beta-
blockers plus endoscopic variceal ligation or, in
selected patients, by early transjugular intrahep-
atic portosystemic shunt (TIPS).39–41
Ascites is a hallmark of decompensation and is
associated with a five-year mortality of about
50%.9,42 The progression of the hyperdynamic cir-
culation and the activation of pro-inflammatory
mechanisms14 result in deterioration of renal
function, and ascites may become refractory. The
cumulative risk of refractory ascites is in the order
of 20% within five years of the development of
ascites.42 Two-year mortality following refractory
ascites is approximately 65% and may be reduced
by TIPS in selected patients.43,44
Overt hepatic encephalopathy and/or jaundice
typically occur in advanced cirrhosis, rarely as a
first sign of decompensation and are associated
with a five-year survival of about 20%.8,10 The
prognostic weight of covert hepatic encephalopa-
thy45 remains to be defined, and is possibly more
dependent on the grade I encephalopathy compo-
nent than on minimal encephalopathy.46–48
Renal function is often impaired in patients
with advanced cirrhosis, as a consequence of
either progressive haemodynamic derangement
or acute events such as bleeding, infections or
nephrotoxicity. The usual clinical presentation is
that of acute kidney injury (AKI), including hepa-
torenal syndrome type 1 or 2.49–51 AKI is usually
followed by progressive worsening of renal func-
tion, and progressive reduction of mean arterial
pressure, indicating progressive cardiac and
haemodynamic impairment.52 One-year mortality,
following renal failure in this advanced disease
state, is in the order of 60%,53,54 although it varies
according to the definition used.49–51
Because of bacterial translocation driven by the
progression of portal hypertension and liver dys-
function,55 infections are common in advanced
cirrhosis,56–62 particularly in patients with ascites.
The inflammatory response is frequently severe
and associated with organ failures.55,60 Mortality
may reach 38%,58 while discharged patients have
a 30-day readmission rate of 35% and six-month
Journal of Hepatology 2018 vol. 68 j 563–576
mortality of 23%.61 Overall mortality within one
year of the infectious episode is 60%.63 However,
infections are relatively frequent, as well as being
significant events also in compensated cirrhosis,
where they are associated with increased risks of
long-term decompensation and mortality.64
Hepatocellular carcinoma (HCC) occurs in 2–8%
patients per year.65–70 The risk is higher in
patients with CSPH, higher body mass index, oeso-
phageal varices and decompensated cirrhosis.70,71
Median survival after HCC detection is nine
months in untreated patients72 and approximately
two years in treated patients, ranging from >10
years in Barcelona Clinic Liver Cancer (BCLC) stage
0,73 to <6 months in stage D.74
Liver failure, bleeding, HCC, infections, hepa-
torenal syndrome, and ACLF are the most frequent
causes of death in patients with cirrhosis.
Acute-on-chronic liver failure (ACLF) is charac-
terised by acute decompensation, organ failure(s)
and high short-term mortality75–78 and may occur
either in compensated or in decompensated cir-
rhosis. Organ failures (liver, renal, coagulation,
cerebral, respiratory and circulatory) are defined
according to the Chronic Liver Failure-Sequential
Organ Failure (CLIF-SOFA) score or by its simplified
version Chronic Liver Failure-Organ Failure Assess-
ment (CLIF-OF) score.75,76 Severity of ACLF is
graded according to the number of organ failures
as ACLF-1, ACLF-2, and ACLF-3. There is a large
body of evidence indicating that ACLF is triggered
by a systemic inflammatory response78–82 to sev-
eral critical events, which may act as intra- or
extrahepatic factors.83,84 Bacterial by-products ter-
med pathogen associated molecular patterns
(PAMPS) and damage associated molecular pat-
terns (DAMP) released after liver tissue injury play
a key role in triggering inflammation.14 Infections
are not only a triggering factor in up to 37% of
patients, but they also occur during follow-up in
46% of patients free of infection at ACLF diagnosis,
and are associated with a significantly increased
mortality risk in ACLF grades 1–2.85 No triggering
factors may be identified in up to 40% of
patients,75,84 in whom PAMPs resulting from sub-
clinical bacterial translocation55 or DAMPs result-
ing from liver tissue injury86,87 may be key-factors.
ACLF is a dynamic syndrome and 28-day mor-
tality ranges from 10% to 87% depending on the
number of failing organs between day three and
seven.78,77,88 The CLIF-C ACLF score enables pre-
diction of mortality risk more accurately than the
MELD, MELD sodium and Child-Pugh scores,89
while another specific prognostic score has been
developed for patients with acute decompensation
without ACLF, the CLIF-C AD score.90
In patients with ACLF, 23% of those with mostly
alcohol and/or hepatitis C virus (HCV)-related cir-
rhosis,75 and 45–52% of those with mostly HBV-
related cirrhosis83,91 may not have history of pre-
vious decompensation. However, in a recently
reported study of the incidence of ACLF in outpa-

tients,92 during the first year of follow-up 61
patients developed ACLF: 93% of them had a previ-
ous history of decompensation while only 7% did
not. The overall incidence rate of ACLF was 7/100
patient-years.
The clinical course of cirrhosis may not be con-
sidered as unidirectional anymore (Fig. 1). There is
in fact a large body of evidence that aetiologic cure
may result in progressive reduction of fibrosis, and
even regression of cirrhosis93,94 and parallel
reduction of portal hypertension,95–97 reducing
the risk of the major disease complications, when
HVPG returns below 12 mmHg. However, even fol-
lowing complete aetiological cure, like sustained
virologic response in HCV cirrhosis, occurrence of
oesophageal varices, decompensation and HCC
have been reported.98–102 Similarly, the risk of
HCC is not fully abolished after successful HBV
suppression.103 Therefore, watchful follow-up of
patients in whom the cause of cirrhosis has been
successfully treated is recommended.104,105
Clinical states in cirrhosis
Several clinical conditions associated with signifi-
cantly different outcomes have been proposed as
relevant clinical states during the course of the
disease4,5,8,10,14,106,107 (Fig. 1). However, it is nota-
ble that there is no predictable sequence of such
clinical states and that they may not be considered
as progressive disease stages. However, clinical
states enable the classification of patients accord-
ing to increasing mortality risk. Moreover, assess-
ing transitions across states may facilitate the
description of the clinical course of the disease in
a multistate model.
Compensated cirrhosis without varices (state 1).
This is the earliest clinical state with a low inci-
dence rate of decompensation and very low mor-
tality.4,6,7,10,11 Approximately 50% of patients in
this state13 still have mild portal hypertension
(MPH) (HVPG >5 mmHg and <10 mmHg), while
CSPH is already present in the remaining patients.
Importantly, liver stiffness measurement (LSM)
≥20–25 kPa alone or in combination with platelet
count and spleen size108–111 may identify patients
with compensated cirrhosis, without gastro-
oesophageal varices, and a very high probability
of CSPH (specificity 0.90),111 while compensated
advanced chronic liver disease (cACLD, or com-
pensated cirrhosis) is identified by an LSM >15
kPa.104 It is therefore conceivable that the clinical
state of compensated cirrhosis without varices may
be split into compensated without CSPH (state 0)
and compensated without varices with CSPH (state
1), the latter being associated with higher risk of
developing varices, decompensation11–13 and
HCC.70 Moreover, patients with MPH have a very
low or no haemodynamic response to non-
selective beta-blockers (NSBB),13 while their HVPG
is significantly reduced by viral eradication in
those with chronic HCV infection,97 suggesting
Journal of Hepatology 2018 vol. 68 j 563–576
JOURNAL
OF HEPATOLOGY
that the prevention of disease progression in
patients without CSPH should be primarily based
on aetiological cure of the underlying disease.
Compensated cirrhosis with varices (state 2).
These patients have CSPH13 and are at risk of var-
iceal bleeding and decompensation. Thus, they Key point
require a different monitoring schedule and speci-
ACLF is characterised by
fic treatment according to the severity of acute liver decompensa-
risk.104,107 By competing risks analysis10 five- tion, organ failure(s) and
year event probabilities are: death before decom- high 28-day mortality.
pensation 10%, variceal bleeding 8%, one single Systemic inflammatory
non-bleeding decompensating event (mostly response to several critical
ascites) 20%, more than one decompensating event events is the most impor-
tant mechanism activating
at the same time 4%.
ACLF, even when a clear
Decompensation defined by the development of triggering event is not
at least one among variceal bleeding, ascites, jaun- identifiable (in up to 40% of
dice or encephalopathy, occurs in 4–12% per patients).
year.4,6–8,10,11,112–118 According to studies8,10 using
competing risks analysis, the first decompensating
event is most frequently ascites (18–27%), fol-
lowed by bleeding (9.5–18%), encephalopathy (2– Key point
7%) and jaundice (1.5%). More than one decompen- Aetiological treatment of
sating event at once (mostly ascites plus bleeding) cirrhosis may halt or even
occur in approximately 13% of patients. The first reverse the clinical course
decompensation may also present with ACLF, of the disease, particularly
although its incidence rate is not well defined in when it is still in a com-
pensated state.
patients without previous decompensation.92
Variceal bleeding (state 3). Patients with bleed-
ing alone have better outcomes than patients with
ascites without bleeding, and much better out-
comes than patients with bleeding and ascites.8–
10
Better survival rates are also consistently
reported for acute variceal bleeding in patients
whose cirrhosis is otherwise compensated.35,119
According to competing risks analysis, the
Key point
reported five-year risks in this state are:8,10 death
before other complications 18%–20%, further Clinical states of cirrhosis
decompensation 54%–45% and rebleeding before are based on distinct out-
further decompensation 19%. come patterns and have a
prognostic classification
First non-bleeding decompensation (state 4).
value. The progression of
Ascites is the most frequent first non-bleeding cirrhosis across clinical
decompensating event4,8,10,112–118,120 and is in fact states is not predictable,
considered the hallmark of decompensation. although it parallels the
Although much more rarely, encephalopathy and progression of liver dam-
jaundice may also present as a first non-bleeding age with its haemody-
decompensation.8,10 Overall five-year mortality namic, inflammatory and
functional consequences.
following the development of any of these decom-
pensating events is in the range of 55%–
80%.4,8,10,112,115,118,120–127 Five-year mortality
before the development of further decompensat-
ing events is in the order of 25% according to com-
peting risks analysis.8,10
Further decompensation (state 5). Following any
first decompensating event, most patients develop
further decompensation before dying. The most
frequent combination is bleeding and ascites,
although jaundice and encephalopathy are also
frequent8,10 Irrespective of the combination, five-
year mortality may reach 88%.8–10,118
Late advanced decompensation (state 6). The
progressive increase in splanchnic vasodilatation,
hyperdynamic circulation, bacterial translocation
565
Review
METAVIR 4A
MPH
HVPG >5 and <10 mmHg
Minimal/absent SAV
and normal CO
Compensated cirrhosis
No varices
Mild PH CSPH
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.
Key point
LSM>15 identify cACLD
which is equivalent to
compensated cirrhosis and
values ≥20–25 KPa denote
CSPH with 0.90 specificity.
MPH (HVPG >5mmHg and
<10mmHg), CSPH and
gastroesophageal varices
are associated with
increasing disease severity
in compensated cirrhosis.
Bleeding alone, any first
decompensating event and
≥2 decompensating events
are associated with
worsening outcome of
decompensated cirrhosis.
Key point
Refractory ascites, HRS,
infections, circulatory dys-
function and ACLF are
markers of late advanced
decompensation and very
poor survival, although
ACLF may also occur in
compensated cirrhosis.
566
Increasing fibrosis
METAVIR 4B
Increasing portal hypertension
CSPH
HVPG ≥10 mmHg
Increasing bacterial translocation/inflammation
Moderate SAV Significant SAV
compensated by no further CO
↑ CO compensation
Increasing clinical severity
Decompensated cirrhosis
Varices Bleeding Non-bleeding
(CSPH) alone decompensation
ACLF
Aetiological cure
and systemic inflammation result in a more
advanced, late decompensation state where
multi-organ dysfunction becomes clinically evi-
dent.14,49,53,59–63,127–131 Refractory ascites, infec-
tions, persistent encephalopathy and/or jaundice,
renal, circulatory and respiratory dysfunctions
are typical presentations of this disease state.
One-year mortality for these conditions ranges
from 60 to 80%.
ACLF72–75 may occur in any disease state and is
associated with six-month mortality from 38% to
96%.77 Patients resolving ACLF, may remain in a
decompensated state with or without organ dys-
function or even in a compensated state, although
the proportions of these state transitions are not
clearly defined.
Management implications of clinical states
of cirrhosis
Recognising different clinical states may have
important implications on the most likely clinical
outcomes. Hence, clinical states may be used to
inform treatment interventions to prevent disease
progression. In fact, there is evidence that in com-
pensated patients without varices (state 1) the
most appropriate approach is aetiological treat-
ment, particularly in those with MPH (state 0) in
whom NSBBs do not appreciably reduce portal
hypertension.13,97 In these patients, non-invasive
monitoring based on LSM and platelet count may
identify patients at risk of CSPH and guide endo-
scopic screening for oesophageal varices.104,109,110
Journal of Hepatology 2018 vol. 68 j 563–576
METAVIR 4C
Higher risk of major events
HVPG ≥12
Severe hemodynamics
Severe SAV
impairment;
↓ CO
↓ organ perfusion
Late decompensation
Refractory ascites; PSE/jaundice;
≥2 decompensating
HRS, other organs
events
dysfunction; ACLF
Although timolol (an NSBB) has been proven inef-
fective in preventing development of oesophageal
varices,11 since prevention of decompensation is
now recognised as a major management objective
in these patients (states 0–2),104,107 other preven-
tative approaches, aiming at reducing intrahepatic
resistance and splanchnic flow, should undergo
appropriate clinical trials. Patients in states 3–5
should be appropriately treated for the prevention
of bleeding, rebleeding104,107 and further decom-
pensation. Patients in state 6 and those with ACLF
require a multidisciplinary approach to their man-
agement, with access to specific treatments and
early selection of candidates for liver transplanta-
tion.132–134
Competing risks in cirrhosis
A competing risk is the risk of an event whose
occurrence either precludes the occurrence of
another event or modifies the probability that it
will occur. Along the clinical course of cirrhosis,
many clinical conditions, or states, may be charac-
terised by competing outcomes which require
competing risks analysis to correctly assess the
relevant risks. Several such conditions are shown
(Table 1), where examples of outcomes of interest
are reported together with potentially relevant
competing events, according to the baseline condi-
tion and the research aim requiring competing
risks analysis.135
It is important to note that in decompensated
cirrhosis the underlying risk of death is high, with
 JOURNAL
OF HEPATOLOGY

Table 1. Examples of clinically relevant outcomes and potentially relevant competing events according to several baseline conditions and specific
research aims.
Clinical condition Event of interest Potentially relevant Aims of competing risks analysis
competing events
Compensated cirrhosis
Decompensation Death Decompensation; death before decompensation
Specific Death; other decompensating First event to occur in compensated cirrhosis
decompensating event events
ACLF Death; decompensation ACLF before overt decompensation; death before ACLF
HCC Death; decompensation HCC in compensated cirrhosis; death before HCC
MPH (HVPG >5 and Oesophago-gastric Death; decompensation Development of varices before decompensation; death before
<10 mmHg) varices varices and decompensation
CSPH (HVPG ≥10 Oesophago-gastric Death; decompensation Development of varices before decompensation; death before
mmHg) varices varices and decompensation
Oesophageal varices Bleeding Death, decompensation Assessment of bleeding before decompensation
Decompensated cirrhosis
Variceal bleeding Rebleeding Death; decompensating Incidence of rebleeding before other decompensating events
events
Variceal bleeding Rebleeding Death Incidence of rebleeding; death before rebleeding
Ascites Refractory ascites Death Incidence of refractory ascites; death before refractory ascites
Ascites Other decompensating Death; other decompensating First new clinically relevant event; death before other events
events events
≥1 decompensating Other decompensating Death; other decompensating First new clinically relevant event; death before other events
events events events
Any type of ACLF; HCC; HRS Death ACLF, death before ACLF; HCC, death before HCC; HRS, death before
decompensation HRS
Late decompensation
Refractory ascites Death OLT Death before OLT; OLT
Major infections Death OLT Death before OLT; OLT
Renal failure Death OLT Death before OLT; OLT
Acute on chronic liver Death OLT Death before OLT; OLT
failure
ACLF, acute-on-chronic liver failure; CSPH, clinically significant portal hypertension; HCC, hepatocellular carcinoma; HRS, hepatorenal syndrome; HVPG, hepatic venous
pressure gradient; OLT, orthotopic liver transplantation; MPH, mild portal hypertension.

a median survival of approximately two years.4
This implies that whenever assessing the inci-
dence of any further decompensating event, like
refractory ascites, hepatorenal syndrome, infec-
tions and ACLF, it is important to consider death
as a competing event to achieve reliable risk
estimates.135
Competing risks analysis
Recognising competing risks is important because,
in the presence of competing risks, the KM estima-
tor21 invariably results in upward biased esti-
mates.22–24,135 Competing risks analysis is based
on the CIF which, by using the Aalen-Johansen
estimator,23 partitions the probability of any event
into the probabilities that each event occurs first,
resulting in an overall event probability (or the
sum of the probabilities of each event) correctly
ranging from zero to one. The essential difference
between the two methods is that the KM estima-
tor counts only the events of interest and censors
or ignores the competing events, while the
Aalen-Johansen estimator correctly counts both
the event of interest and the competing events.
As a practical example consider assessing the
incidence of oesophageal varices, and the proba-
bility of survival without developing varices, in a
cohort of patients included in a prospective study
of the natural history of cirrhosis.10 Death before
developing varices is clearly a competing event
for the occurrence of oesophageal varices. When
using the KM estimator (Fig. 2A) the 20-year 1-
KM estimate of the probability of developing
varices was 0.61. The 20-year 1-KM cumulative
probability of death without varices was 0.46.
Since the two risks are mutually exclusive, they
Key point
are clearly upward biased, summing up to 1.07
instead of ≤1. Notably, when assessing the risk of Competing risks are fre-
varices the KM estimator censors death, and when quent in cirrhosis. Death
should always be consid-
estimating the risk of death without varices it cen-
ered a competing risk for
sors the occurrence of varices: for this reason the
any clinically relevant
number of patients at risk per each observation event in the course of the
period is identical for the two KM estimates. To disease, particularly for
show how competing risks analysis works we decompensated cirrhosis.
assessed the risk (1-KM estimate) of the composite
outcome (death or varices, whichever occurs first):
in this way neither event is censored. By doing
this, we have reduced the three-state model (no
varices, varices, death) into a two-state model
([no varices] ? [varices or death]), the situation
where the KM method may be safely applied.20,21
This estimate in our cohort is plotted (Fig. 2B [1-
KM curve]) together with the CIF of each of the
two competing events obtained by the competing
risks analysis. It may be seen that the 1-KM esti-
mate for the risk of the composite outcome death
or varices (0.79) corresponds exactly to the sum of
each of the two risks (0.53 varices + 0.26 death =
0.79 composite) computed by the competing risks

Journal of Hepatology 2018 vol. 68 j 563–576 567

Review

Key point
Competing risks analysis is
based on the Aalen-
Johansen estimator which
partitions the risk of any
competing event in the
probabilities that each
competing event occurs
first.
analysis. The example shows that the competing
risks analysis partitions the risk of any of the com-
peting events (whichever occurs first) into the risk
that each of the competing events occurs first.
Therefore, the real risk of developing varices in
the included cohort of patients was 0.53 as esti-
mated by the CIF and not 0.61 as estimated by
the KM estimator. Moreover, censoring death like
it was not a clinically relevant event does not make
sense and is technically wrong.135 The correspond-
ing real probability of dying before developing
varices was 0.26 and not the 0.46 1-KM estimate.
By considering any death (before or after varices)
we could have correctly estimated the overall mor-
tality by the KM estimator, however this estimate
would not consider the possible change of mortal-
ity risk after the development of varices.
Another example of a situation where the com-
peting risks analysis should be applied is the
assessment of the probability that a clinically rel-
evant event will be the first to occur among sev-
eral events. In such a situation all the assessed
events are mutually exclusive, because only one
of them may be the next to occur, and the sum
of all the probabilities shall range between zero
and one. However, by the KM model the sum of
the probabilities obtained may be higher than
one, because per each assessed event, the occur-
rence of the competing events is ignored or cen-
sored. For example, looking for the next event to
occur in a cohort of 377 patients with compen-
sated cirrhosis,10 the 1-KM estimates showed that
20-year cumulative risk of death was 0.63, ascites
0.51, variceal bleeding 0.35 and HCC 0.28 (Fig. 3A),
yielding a total probability of 1.77, which is of
course impossible for mutually exclusive risks. In
fact, this analysis does not provide us with the
probability of the next event to occur, but instead
gives us the 20-year cumulative risk of each event,
independently of the occurrence of other events,
in a hypothetical world where death (or the other
events) do not exist. In particular, the KM curve on
death is the correct estimate of the overall mortal-
ity, as defined before. Note that, as already men-
tioned, death is censored when estimating the
risk of each of the other events, while for any other
event of interest, patients experiencing the com-
peting events are still at risk of the event of inter-
est. Competing risks analysis showed that the 20-
year probability of being the next event to occur
was 0.29 for ascites, 0.16 bleeding, 0.15 HCC,
0.12 death summing up to 0.72 (Fig. 3B). In a sim-
ilar study117 it was erroneously concluded that
HCC was the first event to occur based on a 17-
year 1-KM cumulative risk of 0.55 compared with
0.35 ascites, 0.27 jaundice, 0.10 bleeding, 0.03
encephalopathy, summing up to a total probability
of 1.3. An inference from this study would be that
HCC is the most likely first event in an ideal world
where the other events do not exist.
More insight into the reason why the use of the
KM estimator is correct only in two-state settings
is provided by the relationship between rate (or
incidence rate) and risk. This has been thoroughly
explained elsewhere.22,135 Here we only recall that
while the incidence rate is the ratio D/Y (number of

A 1.0
1-KM estimate
B 1.0
0.79
0.8 0.8 Varices or death
estimated by 1-KM
Probability

0.61
0.6
Probability

0.6 0.53
Varices
Varices (CIF)

0.4 0.46
0.4
Death 0.26
Death (CIF)
0.2 0.2

0.0 0.0
0 60 120 180 240 0 60 120 180 240
Months Months
Patients
at risk 243 153 98 74 52 243 153 98 74 52

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.

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 JOURNAL
OF HEPATOLOGY

A 1.0
Cumulative risks
by the KM estimator
B 1.0 Cumulative incidence
by the Aalen-Johansen estimator

0.8 0.8
Death
Death
Ascites
Bleeding
0.63 Ascites
0.6 0.6

Probability
Bleeding
Probability

HCC
0.51 HCC

0.4 0.35 0.4 0.15

0.29

0.28 0.2 0.16

0.2

0.12
0.0 0.0
0 60 120 180 240 0 60 120 180 240
Months Months
Patients 377 309 251 207 141 377 276 201 142 106
at risk
377 288 219 160 120
377 292 231 164 125
377 304 244 178 131

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.

subjects developing the disease/the total amount
of person-time at risk), the risk is the ratio D/N,
(number of subjects who develop the disease/
number of subjects disease-free at the beginning
of the observation time).136 Therefore, while the
incidence rate is essentially an average measure
of the speed of occurrence of the event of interest,
assuming a constant hazard over time, and is
expressed as the number of events occurring per
unit of time, the risk is a measure of the cumula-
tive probability of the event in a given observation
time. Consequently, while the cumulative risk may
not decrease over time (because D either increases
or is constant with time), the incidence rate may
increase, remain near constant or decrease.
It may be noted that while in two-state set-
tings, there is a direct one to one relationship
between rate and risk, because the number of sub-
jects at risk and of events taken as a basis for cal-
culations is the same for rate and risk, in a
multistate setting (competing risks) this unique
relationship is lost, because the number of sub-
jects at risk decreases whenever one of the com-
peting events occurs. In fact, here the interest is
in the next event to occur, and the risk depends
on more than one rate of events.
In other words, the KM assumes that there is
only one event of interest and that only this will
contribute to reduce the number of patients at
risk. When more than one event causes the reduc-
tion of patients at risk, like in the competing risks
situation, the Aalen-Johansen estimator correctly
estimates the risk that each of several events of
interest occurs first, by the CIF.
These concepts also imply that the association
of covariates with the rate of one event of interest
may be different from their association with the
risk of that event, in the presence of competing
risks. For this reason, the Cox model137 may not
be appropriate to estimate the risk of events in dif-
ferent groups135 in a competing risks setting,
because it assumes a one to one relationship
between rate and risk.
Building multistate models in cirrhosis
Clinical states should be conceived as a flexible
Key point
concept and specific clinical states should be
defined whenever a specific prognostic question In two-state settings there
makes it appropriate (Table 1). As an example, in is a direct one to one
the same study of the clinical course of cirrhosis relation between rate and
risk, this is lost in
referred to earlier,10 the 20-year cumulative prob-
multi-state settings, where
ability of death (1-KM) was 0.62, in 377 patients
the number of subjects at
with compensated cirrhosis, and 0.93 after decom- risk decreases at any time
pensation in 224 patients who developed decom- one of the competing
pensation during the follow-up (Fig. 4A). events occurs.
However, in clinical practice, it might also be of
interest to know the probability of decompensa-
tion and of death before decompensation. These
probabilities are appropriately assessed by the
competing risks analysis (Fig. 4B), which shows a
20-year cumulative probability of 0.58 and 0.14
for decompensation and death before decompen-
sation, respectively. The probability of death after

Journal of Hepatology 2018 vol. 68 j 563–576 569

Review

tion in the decompensated state have a very low

A 1-KM estimates B Competing risks analysis
survival time. The analysis also shows that 20
1.0 1.0 (Aalen-Johansen estimator)
0.93 years after the diagnosis of compensated cirrhosis
0.8 0.8 there is a 41% probability of death after decom-
Death probability

Decompensated

Event probability
0.6
n = 224
0.62
pensation, and 34% of being alive in a compen-
0.6 Decompensation 0.58
sated state.
0.4 0.4 A schematic representation of a hypothetical
Compensated multistate model encompassing the whole course
0.2 n = 377 0.2 Death before decompensation 0.14
of cirrhosis is shown (Fig. 5).
0.0 0.0
0 60 120 180 240 0 60 120 180 240
Months Months Competing risks and clinical research
Patients 377 309 251 186 141 Patients 377 274 203 146 109
at risk 224 62 35 23 10 at risk As shown in previous sections in this article, the
Alive, compensated Dead after decompensation most obvious field of application for competing
C D100 Alive, decompensated Dead without decompensation
risks analysis is the study of the clinical course of
Compensated diseases in every situation where relevant compet-
Prediction probabilities %

34
80 46 ing risks are identified.
59

60
0.58 0.14
40
20
Decompensated Death
0.93
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, decompen-
sated and death. The probability of being dead after decompensation or before decompen-
sation 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.
decompensation is already known by the KM anal-
ysis and the full three-state model is shown
(Fig. 4C).
In a multistate model it is also possible to
assess the probability of patients in the earliest
state occupying one of the other possible states
after a certain observation time.135 In the three-
state model above, the possible outcomes along
the disease course are: alive still compensated,
alive decompensated, dead before decompensa-
tion, dead after decompensation. The relevant
state occupation probabilities may be estimated
by the Aalen-Johansen estimator, which is an
extension of the KM estimator for multistate mod-
els. Statistical software for this kind of analysis are
available in the R statistical package (msSurv or
mstate routins).138 State occupation probabilities
for the above model are shown (Fig. 4D) at differ-
ent observation times over the whole disease
course. The probability of being alive in a decom-
pensated state is low, and this is coherent with
the current knowledge that patients who transi-
78 8 A second relevant field where competing risks
100 10 should be appropriately accounted for is prognosis
13
41 research. A major aim of this type of research is to
10 18
31
find accurate predictors of a disease outcome in a
7
13 17 given time. The hypothesis underlying this
5 10
0
0 60 120 180 240 research is that one or more among several patient
Months or disease characteristics may be linked to the dis-
ease outcome through a causal mechanism (causal
factors) or through indirect association (predictive
factors). In studies of causal factors, the hypothesis
is that some biological mechanism links the candi-
date predictor to the event under study. In this
type of study the interest is in assessing whether
the event occurs earlier in patients presenting
the candidate causal factor than in those without,
thus focussing on the rate, not the risk. In this sit-
uation, the cause specific Cox model138 is appro-
priate, since it looks at the instantaneous rate of
only the event of interest and may disclose a cau-
sal effect when all the potential confounders are
accounted for.
When the interest is in identifying factors asso-
ciated with the occurrence of the event of interest
(risk predictors), competing events, which may
modify the risk of the event of interest must be
accounted for. In this type of research, the stan-
dard Cox model is not appropriate because it
ignores the competing events and may result in
upwards biased estimates similar to the KM
estimator. A specific multiple regression propor-
tional hazards model has been developed for com-
peting risks, by Fine and Gray.139 This model
provides the sub(distribution)-hazard ratio (sHR),
which measures the relationship between the
candidate predictive factor and the outcome,
accounting for both the association between the
factor and the outcome and for the modifying
effect of the competing events on this association.
Although it does not have a meaningful interpreta-
tion, it allows for risk predictions in individual
patients.140
Therefore, it is important when planning
research on prognostic indicators, to ensure that
the statistical method used is appropriate for the
specific research aims. The Cox model should be

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 JOURNAL
OF HEPATOLOGY
used to study causal associations, while the Fine
and Gray model is more appropriate for risk pre- Compensated Decompensated
diction in individual patients, in the presence of
State 0: no varices, MPH State 3:
competing risks.140
LSM >15 and <20 bleeding
An example of how the two models may yield or HVPG >5 and <10 mmHg
different results is provided by an analysis per- State 4:
State 1: no varices, CSPH first non-bleeding
formed to investigate the role of oesophageal decompensation
LSM ≥20 or HVPG ≥10 mmHg
varices on the risk of decompensation in patients
with compensated cirrhosis, accounting for death State 2: State 5:
Varices (= CSPH) second decompensating event
as a competing risk, in 377 compensated
patients.10 Platelet count and the Child-Pugh score
were also included to adjust for other important End state
prognostic indicators in cirrhosis.4 Both models State 6: late decompensation:
found a significant association between varices refractory ascites, persistent PSE
or Jaundice, infections,renal, other
and decompensation: the cause specific Cox model organs dysfunction
(hazard ratio 1.51, 95% CI 1.14–1.99) suggested a
potential causal role (possibly through some plau- ACLF
sible biological mechanism like more advanced
portal hypertension), whereas the Fine and Gray DEATH
model (sub-hazard distribution ratio 1.43, 95% CI
1.08–1.89) suggested a significant difference in Fig. 5. Schematic representation of a comprehensive multistate model for the clinical
the risk of decompensation in patients with and course of cirrhosis. ACLF, acute-on-chronic liver failure; CSPH, clinically significant portal
without oesophageal varices. Moreover, both hypertension; HVPG: hepatic venous pressure gradient; LSM, liver stiffness measurement;
models showed a significant effect of platelet MPH, moderate portal hypertension; PSE, portosystemic encephalopathy.
count and Child-Pugh score on the risk. The indi-
vidual patient risks predicted by the two models
are plotted against the observed risks (estimated event it may also be important to account for rel-
by the Aalen-Johansen estimator [Fig. 6]) to show evant competing risks, because the sample size
how the Cox model tends to overestimate the risk estimation may be different according to whether
in the presence of competing risks, compared to relevant competing risks are accounted for or not.
the Fine and Gray model. As an example, if one would plan an RCT to pre-
vent the formation of oesophageal varices based Key point
A third research area where competing risks
analysis may help to interpret observations may on the baseline risk of 0.61 calculated by the KM In prognosis research of
be treatment efficacy research. This is usually estimator (Fig. 2A), with the hypothesis of a haz- causal factors, where the
based on risks comparison without accounting ard ratio of 0.7 for the two treatments, a = 0.05 interest is in rate not in
for competing risks. To illustrate how competing and b = 0.20, the total number of events needed risk, the Cox model is
would be 247 (two-sided test with arms of equal appropriate even in the
risks analysis may provide more insight into the presence of competing
interpretation of results, we report an extended risks. However, in progno-
analysis accounting for competing risks of a previ- sis research of risk predic-
ously published randomised, double-blind, clinical 1.0 tors (not causal factors)
trial of octreotide vs. placebo for rebleeding, in Fine and Gray model where the major interest is
Cox model
patients with cirrhosis over 42 days.141 The trial 0.8 in risk, in presence of
competing risks, the Fine
showed a barely significant reduction of rebleed-
Observed risk

and Grey proportional

ing with octreotide (p = 0.04, log rank test) 0.6
hazards model should be
(Fig. 7): 42/101 patients rebled in the placebo used.
group and 27/101 in the octreotide group; there 0.4
were eight and ten deaths, respectively. Compet-
ing risks analysis showed that the reduction in 0.2
rebleeding risk with octreotide was slightly higher
than found by the KM estimator, and that five of 0.0
ten deaths in the octreotide group occurred before 0.0 0.2 0.4 0.6 0.8 1.0
Predicted probability
rebleeding, compared to only one of eight in the
placebo group. This observation, together with Fig. 6. Calibration of predicted probabilities of decompen-
the higher number of rebleeding episodes and of sation, according to the Cox model and to the Fine and Gray
blood unit transfusions in the placebo group sug- model, adjusted for the presence of oesophageal varices,
platelet count and Child-Pugh score in a cohort of 377
gests that octreotide was associated not only with patients with compensated cirrhosis at diagnosis.10 Predicted
a reduction in the rebleeding risk, but also with a probabilities are computed according to each of the two
lower severity of rebleeding episodes. models in nine groups of patients of approximately equal
When planning randomised controlled trials size. Per each group the median predicted probability of
decompensation is plotted against the median observed risk.
(RCTs) the cause specific hazard Cox model should
The dashed line represents perfect correspondence between
always be used, as the interest lies in causal rela- predicted and observed risks. The figure shows that the Cox
tionships. However, to estimate the risk of an model tends to overestimate predicted probabilities.

Journal of Hepatology 2018 vol. 68 j 563–576 571

Review

Octreotide with extreme hyperdynamic circulation, bacterial

A 1.0 Placebo
1-KM estimate
B 1.0 1-KM estimate
translocation and inflammation. The progression
0.8 across such states does not occur through a pre-
Death probability

0.8

Death probability
0.6 dictable sequence, because of the variable inter-
0.6
Rebleeding 0.41 play between pathophysiological mechanisms.
0.4 0.4 Rebleeding 0.28
Therefore, a multistate approach provides a more
0.2 Death 0.08 0.2 Death 0.10
realistic description of the disease course. Mul-
0.0
tistate models require competing risks analysis
0.0
0 7 14 21 28 35 42 0 7 14 21 28 35 42 to assess the probabilities of transition across
Days Days states and appropriate multiple regression models
Patients 101
at risk
82 77 71 67 65 61 Patients
at risk
97 82 80 71 74 71 66 to investigate prognostic indicators, because the
101 99 99 97 94 94 93 97 95 94 90 89 89 87
traditional KM estimator and the Cox model may
Placebo Octreotide provide biased results in the presence of compet-
C 1.0 Competing risks analysis D 1.0 Competing risks analysis ing risks. These concepts should be thoroughly
(Aalen-Johansen estimator) (Aalen-Johansen estimator)
accounted for when planning clinical research
0.8 0.8
either of prognosis or of treatment efficacy in
Death probability

Death probability

0.6 0.6 cirrhosis.

Rebleeding 0.40
0.4 0.4 Rebleeding 0.26

0.2 0.2 Financial support

Death 0.01 Death 0.05
P. Rebora was supported by the grant of the Italian
0.0 0.0
0 7 14 21 28 35 42 0 7 14 21 28 35 42
Minister of Education, University and Research
Days Days (MIUR) – Italy SIR 2014 (RBSI14LOVD).
Patients 101 81 76 70 66 64 60 Patients 97 82 80 74 71 71 60
at risk at risk

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
Conflict of interest
group and in (B) the octreotide group, respectively. (C) Placebo group and (D) octreotide The authors declare no conflicts of interest that
group: rebleeding and death cumulative incidence functions, estimated by the Aalen-Johansen pertain to this work.
estimator in the same trial. The fig. shows that deaths occurred mostly after rebleeding in the Please refer to the accompanying ICMJE disclo-
placebo group, while half of the total deaths in the octreotide group occurred before sure forms for further details.
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.

Authors’ contribution
size) and the total number of patients included Gennaro D’Amico: review concepts and project,
would need to be 452. Instead, by using the 0.53 data collection, elaboration of examples, text and
risk derived by the competing risks analysis, figures. Alberto Morabito: statistical concepts
accounting for death before the formation of and data analysis for examples. Mario D’Amico:
varices (Fig. 2B), the total number of patients data collection; cohort study for the examples
needed would be 520 under the assumption of a included in the review; text revision. Linda Pasta:
hazard ratio of 0.7 as before.142 Therefore, it is responsible for the cohort study used for the
likely that even if the correct hypothesis has been examples included in the review. Giuseppe Mal-
made, the trial would be underpowered if the izia: review project and text revision. Paola Reb-
competing risk of death has not been appropri- ora: statistical concepts, examples and text
Key point ately accounted for.143 revision. Maria Grazia Valsecchi: statistical con-
cepts, examples, text revision.
Accounting for competing
risks may enable a more
adequate sample size esti-
Conclusions
mation when planning The clinical spectrum of cirrhosis encompasses Supplementary data
clinical research, particu- several clinical states, from a very early state of Supplementary data associated with this article
larly when analysing compensated cirrhosis with subclinical portal can be found, in the online version, at
treatment efficacy. hypertension, to the late decompensation state https://doi.org/10.1016/j.jhep.2017.10.020.

572 Journal of Hepatology 2018 vol. 68 j 563–576


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