Accepted Manuscript

Position paper
EXPANDING CONSENSUS IN PORTAL HYPERTENSION Report of the
Baveno VI Consensus Workshop: stratifying risk and individualizing care for
portal hypertension
Roberto de Franchis, on behalf of the Baveno VI Faculty
PII:
DOI:
Reference:

S0168-8278(15)00349-9
http://dx.doi.org/10.1016/j.jhep.2015.05.022
JHEPAT 5694

To appear in:

Journal of Hepatology

Received Date:
Revised Date:
Accepted Date:

29 April 2015
14 May 2015
27 May 2015

Please cite this article as: de Franchis, R., on behalf of the Baveno VI Faculty, EXPANDING CONSENSUS IN
PORTAL HYPERTENSION Report of the Baveno VI Consensus Workshop: stratifying risk and individualizing
care for portal hypertension, Journal of Hepatology (2015), doi: http://dx.doi.org/10.1016/j.jhep.2015.05.022

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de Franchis

Expanding consensus in portal hypertension

EXPANDING CONSENSUS IN PORTAL HYPERTENSION

Report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal
hypertension
Roberto de Franchis, MD*, AGAF, on behalf of the Baveno VI Faculty1
Department of Biomedical and Clinical Sciences, University of Milan; Gastroenterology Unit, Luigi
Sacco University Hospital, Milan
Short title: expanding consensus in portal hypertension
*Corresponding Author:
Roberto de Franchis, MD, AGAF
Department of Biomedical and Clinical Sciences, University of Milan; Gastroenterology Unit, Luigi
Sacco University Hospital, Milan, via G.B Grassi 74, 20157 Milan, Italy
Phone: +39 02 3904 3300
Fax: +39 02 5031 9838
e-mail: [email protected]
1

The members of the Baveno VI Faculty are given before the references

Word count: this paper contains 6669 words

de Franchis

Expanding consensus in portal hypertension

Portal hypertension is the haemodynamic abnormality associated with the most severe
complications of cirrhosis, including ascites, hepatic encephalopathy and bleeding from
gastroesophageal varices. Variceal bleeding is a medical emergency associated with a mortality
that, in spite of recent progress, is still in the order of 10-20% at 6 weeks. The evaluation of
diagnostic tools and the design and conduct of good clinical trials for the treatment of portal
hypertension have always been difficult. Awareness of these difficulties has led to the organisation
of a series of consensus meetings. The first one was organized by Andrew Burroughs in Groningen,
the Netherlands in 1986[1]. After Groningen, other meetings followed, in Baveno, Italy in 1990
(Baveno I)[2], and in 1995 (Baveno II)[3,4], in Milan, Italy in 1992 [5], in Reston, U.S.A.[6], in
1996, in Stresa, Italy, in 2000 (Baveno III)[7,8], again in Baveno in 2005 (Baveno IV) [9,10], in
Atlanta in 2007 [11], and again in Stresa in 2010 (Baveno V)[12,13].
The aims of these meetings were to develop definitions of key events in portal hypertension and
variceal bleeding, to review the existing evidence on the natural history, the diagnosis and the
therapeutic modalities of portal hypertension, and to issue evidence-based recommendations for the
conduct of clinical trials and the management of patients. All these meetings were successful and
produced consensus statements on some important points, although several issues remained
unsettled.
To continue the work of the previous meetings, a Baveno VI workshop was held on April 10-11,
2015. The workshop was attended by many of the experts responsible for most of the major
achievements of the last years in this field. Many of them had attended the previous meetings as
well.
A concept that has gained wide acceptance over the past few years is the fact that patients in
different stages of cirrhosis have different risks of developing complications and of dying.
Accordingly, the Baveno VI workshop was entitled Stratifying risk and individualizing care for
portal hypertension. The main fields of discussion were the use of invasive and non-invasive
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de Franchis

Expanding consensus in portal hypertension

methods for the screening and surveillance of gastroesophageal varices and of portal hypertension,
the impact of etiological therapy for cirrhosis, the primary prevention of decompensation, the
management of the acute bleeding episode, the prevention of recurrent haemorrhage and other
decompensating events, and vascular diseases of the liver in cirrhotic and non-cirrhotic patients. For
each of these topics, a series of consensus statements were discussed and agreed upon. Whenever
applicable, the level of existing evidence was evaluated and the recommendations were ranked
according to the Oxford System [14]. The presentations given during the workshop are reported in
extenso in the Baveno VI proceedings [15]. A summary of the most important conclusions is
reported here. Whenever relevant, the changes from previous consensus statements are outlined.
The areas where major new recommendations were made are: screening and surveillance, the
importance of obesity, comorbidities and malnutrition, the use of beta-blockers in patients with
refractory ascites/end-stage liver disease, and anticoagulation and portal vein thrombosis in liver
cirrhosis.
Definitions of key events regarding the bleeding episode (changed from Baveno V)

Six-week mortality should be the primary endpoint for studies for treatment of acute
variceal bleeding. (5;D)

5 day treatment failure is defined using Baveno IV/V criteria without ABRI (adjusted blood
requirement index) and with a clear definition of hypovolemic shock (1b; A).

Baveno IV/V criteria correlate with 6-week mortality (1b;A) and should be included in
future studies as a secondary endpoint to allow further validation (5;D).

Additional endpoints should be reported including: need for salvage therapy (tamponade,
additional endoscopic therapy, TIPS, surgery); blood transfusion requirements and days
of ICU/hospital Stay (5;D).

Screening and surveillance: invasive and non-invasive methods (changed from Baveno III-V)
Definition of compensated advanced chronic liver disease (cACLD) (new)

de Franchis

Expanding consensus in portal hypertension

The introduction of transient elastography (TE) in clinical practice has allowed the early
identification of patients with chronic liver disease (CLD) at risk of developing clinically
significant portal hypertension (CSPH) (1b;A).

For these patients, the alternative term compensated advanced chronic liver disease
(cACLD) has been proposed to better reflect that the spectrum of severe fibrosis and
cirrhosis is a continuum in asymptomatic patients, and that distinguishing between the two
is often not possible on clinical grounds. (5; D)

Currently, both terms : cACLD and compensated cirrhosis are acceptable. (5; D)

Patients with suspicion of cACLD should be referred to a liver disease specialist for
confirmation, follow-up and treatment (5;D)

Criteria to suspect cACLD (new)

Liver stiffness by transient elastography is sufficient to suspect cACLD in asymptomatic

subjects with known causes of CLD (1b;A)

Transient elastography often has false positive results; hence 2 measurements on different
days are recommended in fasting conditions (5;D)

TE values < 10 kPa in the absence of other known clinical signs rule-out cACLD; values
between 10 and 15 kPa are suggestive of cACLD but need further test for confirmation;
values > 15 kPa are highly suggestive of cACLD (1b;A)

Criteria to confirm cACLD (new)

Invasive methods are employed in referral centres in a stepwise approach when the
diagnosis is in doubt or as confirmatory tests

Methods and findings that confirm the diagnosis of cACLD are :

Liver biopsy showing severe fibrosis or established cirrhosis (1a;A);
Collagen proportionate area (CPA) measurement on histology provides quantitative
data on the amount of fibrosis and holds prognostic value (2b;B) and its assessment
is recommended (5;D)
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Expanding consensus in portal hypertension

Upper GI endoscopy showing gastroesophageal varices (1b;A)

Hepatic venous pressure gradient (HVPG) measurement; values > 5 mmHg indicate
sinusoidal portal hypertension (1b;A)
Diagnosis of clinically significant portal hypertension (CSPH) in patients with cACLD (new)

HVPG measurement is the gold-standard method to assess the presence of clinically

significant portal hypertension, which is defined as HVPG10 mmHg (1b;A)

By definition, patients without CSPH have no gastroesophageal varices, and have a low 5-yr
risk of developing them (1b;A)

In patients with virus related cACLD non-invasive methods are sufficient to rule-in CSPH,
defining the group of patients at risk of having endoscopic signs of PH. The following can
be used (2b; B):
Liver stiffness by TE (20-25 kPa; at least two measurements on different days in
fasting condition; caution should be paid to flares of ALT; refer to EASL guidelines
for correct interpretation criteria), alone or combined to Platelets and spleen size

The diagnostic value of TE for CSPH in other aetiologies remains to be ascertained (5;D)

Imaging showing collateral circulation is sufficient to rule-in CSPH in patients with

cACLD of all aetiologies (2b;B)

Identification of patients with cACLD who can safely avoid screening endoscopy (new)

Patients with a liver stiffness < 20 kPa and with a platelet count > 150,000 have a very low
risk of having varices requiring treatment, and can avoid screening endoscopy (1b;A)

These patients can be followed up by yearly repetition of TE and platelet count (5;D)

If liver stiffness increases or platelet count declines, these patients should undergo screening
EGD (5;D)

Surveillance of oesophageal varices (changed from Baveno V)

de Franchis

Expanding consensus in portal hypertension

In compensated patients with no varices at screening endoscopy and with ongoing liver
injury (e.g. active drinking in alcoholics, lack of SVR in HCV), surveillance endoscopy
should be repeated at 2 year intervals (5;D)

In compensated patients with small varices and with ongoing liver injury (e.g. active
drinking in alcoholics, lack of SVR in HCV), surveillance endoscopy should be repeated at
1 year intervals (5;D)

In compensated patients with no varices at screening endoscopy in whom the etiological

factor has been removed (e.g. achievement of SVR in HCV; long-lasting abstinence in
alcoholics) and who have no co-factors (e.g. obesity), surveillance endoscopy should be
repeated at 3 year intervals (5;D) .

In compensated patients with small varices at screening endoscopy in whom the etiological
factor has been removed (e.g. achievement of SVR in HCV; long-lasting abstinence in
alcoholics) and who have no co-factors (e.g. obesity), surveillance endoscopy should be
repeated at 2 year intervals (5;D)

Cost considerations (new)

Whatever policy and method is adopted for screening and surveillance, cost should be taken
into account in future studies (5;D)

Research agenda

Future studies should explore the possibility to stop surveillance after 2 controls showing no
varices

Long term data are needed concerning the benefits of screening and surveillance programs

Impact of etiological therapy (new)

Management of patients with cirrhosis should focus on preventing the advent of all
complications whilst in the compensated phase (1b;A).

de Franchis

Expanding consensus in portal hypertension

Due to different prognosis, patients with compensated cirrhosis should be divided in those
with and without clinically significant portal hypertension (CSPH) (1b;A). The goal of
treatment in the first is to prevent CSPH while in the second is to prevent decompensation.

The concept of CSPH is HVPG-driven and cannot completely be substituted at present by

non-invasive tools (NIT) (1b;A).

Etiological treatment of the underlying liver disease may reduce portal hypertension and
prevents complications in patients with established cirrhosis (1b;A) (unchanged)

HVPG change is an acceptable surrogate of clinical outcome in patients with non-cholestatic

cirrhosis (2b;B). An HVPG-change of 10% or more is to be considered significant (1b;A).

Obesity worsens the natural history of compensated cirrhosis of all aetiologies (1b;A) . A
lifestyle modification with diet and exercise decreases body weight and HVPG in cirrhosis
with obesity (2b;B)

Alcohol abstinence should be encouraged in all patients with cirrhosis irrespective of

aetiology (2b;B)

The clinical use of statins is promising and should be evaluated in further phase 3 studies
(1b;A)

Research agenda

Studies should focus on tools, either invasive (e.g. quantitative fibrosis assessment with
CPA) and/or preferably non-invasive (e.g. elastography, biomarkers, or combinations or
other means), to predict/select patients at risk of decompensation in liver diseases of
different aetiology

Anti-fibrotic strategies and approaches to target, amongst others, the coagulation system,
FXR-pathway, renin-angiotensin system, angiogenesis and the gut-liver axis , should be
further explored for prevention of decompensation in patients with cirrhosis and CSPH

Changing scenarios: Prevention of decompensation (partly changed from Baveno V)

Cure of the etiologic agent
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de Franchis

Expanding consensus in portal hypertension

Successful cure of the etiologic agent in chronic liver disease may improve both liver
structure and function, and this could translate into a portal pressure reduction (1b;A).

Co-morbidities and malnutrition (new)

Comorbidities (obesity, diabetes, cancer, osteoporosis, pulmonary, renal and cardiovascular

diseases) are frequently present in patients with compensated cirrhosis. Some of them can
contribute to decompensation, while others are a consequence of liver disease (2b;B).

Malnutrition and sarcopenia have been shown to have an impact on hepatic encephalopathy,
development of ascites, incidence of infections and survival in cirrhotic patients (1b;A). As
the evidence was mainly reported in decompensated patients further studies are needed to
draw definitive conclusions on this topic also in patients with compensated cirrhosis (5;D).

Patients with no varices or small varices (unchanged)

There is no indication, at this time, to use beta-blockers to prevent the formation of varices
(1b;A).

Patients with small varices with red wale marks or Child C class have an increased risk of
bleeding (1b;A) and should be treated with nonselective beta-blockers (NSBB) (5;D).

Patients with small varices without signs of increased risk may be treated with NSBB to
prevent bleeding (1b;A). Further studies are required to confirm their benefit.

Patients with medium-large varices (unchanged)

Either NSBB or endoscopic band ligation (EBL) is recommended for the prevention of the
first variceal bleeding of medium or large varices (1a;A).

The choice of treatment should be based on local resources and expertise, patient preference
and characteristics, contra-indications and adverse events (5;D).

Carvedilol (changed from Baveno V)

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de Franchis

Expanding consensus in portal hypertension

Traditional NSBB (propranolol, nadolol) (1a;A) and carvedilol (1b; A) are valid first line
treatments.

Carvedilol is more effective than traditional NSBB in reducing HVPG (1a;A) but has not
been adequately compared head-to-head to traditional NSBB in clinical trials.

Patients with gastric varices (changed from Baveno V)

Although a single study suggested that cyanoacrylate injection is more effective than betablockers in preventing first bleeding in patients with large gastroesophageal varices type 2
or isolated gastric varices type 1 (1b;A), further studies are needed to evaluate the
risk/benefit ratio of using cyanoacrylate in this setting before a recommendation can be
made (5;D).

Role of HVPG measurement (changed from Baveno V)

The decision to treat with beta-blockers should be taken when indicated, independent of the
possibility of measuring HVPG (1a, A).

HVPG measurement provides prognostic information (1b, A).

HVPG change is a relevant surrogate outcome (1b;A)

Measurement of HVPG response to therapy offers additional relevant information: a

decrease in HVPG of at least 10 % from baseline or to 12 mm Hg after chronic treatment
with NSBB is clinically relevant in the setting of primary prophylaxis (1b;A). Similarly,
acute HVPG response to intravenous propranolol may be used to identify responders to
beta-blockers, specifically a decrease in HVPG of 10% or to 12 mm Hg may be relevant in
this setting (1b;A).

HVPG response to NSBBs is associated with a significant reduction in risk of variceal

bleeding (1a; A) and decompensation (1b; A).

de Franchis

Expanding consensus in portal hypertension

HVPG measurements should be encouraged in clinical trials investigating novel therapies,

but are not essential if portal hypertension-associated endpoints are well defined (5;D).

Use of nonselective beta blockers (NSBB) in patients with end-stage liver disease (new)

The safety of NSBB in subgroups with end-stage disease (refractory ascites and/or SBP) has
been questioned (2b;B).

NSBB contraindications may be absent when the therapy is firstly prescribed but need to be
monitored during the evolution of the disease (5;D).

Close monitoring is necessary in patients with refractory ascites, and reduction of dose or
discontinuation can be considered in those who develop low blood pressure and impairment
in renal function (4;C).

If NSBB are stopped EBL should be performed (5;D).

Research agenda

More data are needed to unravel the course of disease after cure of the etiological factor.

Successful treatment of the underlying liver disease (alcohol abstinence, antiviral therapy)
may reduce HVPG, size of varices and risk of bleeding. Novel antivirals are expected to
expand this knowledge and reinforce data to suggest changes in surveillance intervals of
varices and other complications

Competing risks from comorbidities should be taken into account in future studies .

Future studies are required to describe the impact of early detection and treatment of
comorbidities

The impact of treatments to improve nutritional status on prognosis and mortality should be
evaluated

New prospective studies to assess the safety of NSBB in end-stage disease are warranted.

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Expanding consensus in portal hypertension

Management of the acute bleeding episode (partly changed from Baveno V)

Blood volume restitution (unchanged from Baveno V)

The goal of resuscitation is to preserve tissue perfusion. Volume restitution should be

initiated to restore and maintain hemodynamic stability.

PRBC transfusion should be done conservatively at a target haemoglobin level between 7-8
g/dl., although transfusion policy in individual patients should also consider other factors
such as cardiovascular disorders, age, hemodynamic status and ongoing bleeding (1b;A)

Recommendations regarding management of coagulopathy and thrombocytopenia cannot be

made on the basis of currently available data. (5;D)

PT/INR is not a reliable indicator of the coagulation status in patients with cirrhosis (1b;A)

Antibiotic prophylaxis (partly changed from Baveno V)

Antibiotic prophylaxis is an integral part of therapy for patients with cirrhosis presenting
with upper gastrointestinal bleeding and should be instituted from admission (1a;A).

The risk of bacterial infection and mortality are very low in patients with Child Pugh A
cirrhosis (2b;B), but more prospective studies are needed to assess whether antibiotic
prophylaxis can be avoided in this subgroup of patients.

Individual patient risk characteristics and local antimicrobial susceptibility patterns must be
considered when determining appropriate first-line acute variceal haemorrhage (AVH)
antimicrobial prophylaxis at each centre.(5;D)

Intravenous ceftriaxone 1g/24h should be considered in patients with advanced cirrhosis

(1b;A), in hospital settings with high prevalence of quinolone-resistant bacterial infections
and in patients on previous quinolone prophylaxis (5;D).

Prevention of hepatic encephalopathy (changed from Baveno V)

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Expanding consensus in portal hypertension

Recent studies suggest that either lactulose or rifaximin may prevent hepatic encephalopathy
in patients with cirrhosis and upper GI bleeding (1b;A). However, further studies are needed
to evaluate the risk/benefit ratio and to identify high risk patients before a formal
recommendation can be made (5;D).

Although, there are no specific studies in acute variceal bleeding, it is recommended to

adopt the recent EASL/AASLD HE guidelines which state that episodic HE should be
treated with lactulose (25 mL q 12 hours until 2-3 soft bowel movements are produced,
followed by dose titration to maintain 2-3 soft bowel movements per day) (5;D).

Assessment of prognosis (unchanged from Baveno V)

Child-Pugh class C, the updated MELD score, and failure to achieve primary haemostasis
are the variables most consistently found to predict 6-week mortality. (2b;B)

Pharmacological treatment (partly changed from Baveno V)

In suspected variceal bleeding, vasoactive drugs should be started as soon as possible,

before endoscopy. (1b;A)

Vasoactive drugs (terlipressin, somatostatin, octreotide) should be used in combination with

endoscopic therapy and continued for up to 5 days. (1a;A)

Hyponatremia has been described in patients under terlipressin, especially in patients with
preserved liver function. Therefore, sodium levels must be monitored (1b;A)

Endoscopy (changed from Baveno V)

Following hemodynamic resuscitation, patients with upper GI bleeding and features

suggesting cirrhosis should undergo esophagogastroduodenoscopy (EGD) within 12 hours
of presentation (5;D)

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Expanding consensus in portal hypertension

In the absence of contraindications (QT prolongation), pre-endoscopy infusion of

erythromycin (250mg IV 30-120 minutes before endoscopy) should be considered (1b;A)

The availability both of an on-call GI endoscopist proficient in endoscopic haemostasis and

on-call support staff with technical expertise in the usage of endoscopic devices enables
performance of endoscopy on a 24/7 basis and is recommended (5;D)

Patients with acute variceal haemorrhage should be considered for ICU or other well
monitored units. (5;D)

In patients with altered consciousness, endoscopy should be performed with protection of

the airway (5;D)

Ligation is the recommended form of endoscopic therapy for acute oesophageal variceal
bleeding (1b;A)

Endoscopic therapy with tissue adhesive (e.g. N-butyl-cyanoacrylate) is recommended for

acute bleeding from isolated gastric varices (IGV) (1b;A) and those gastroesophageal
varices type 2 (GOV2) that extend beyond the cardia (5;D).

To prevent rebleeding from gastric varices, consideration should be given to additional glue
injection (after 2 to 4 weeks), beta-blocker treatment or both combined or TIPS (5;D). More
data in this area are needed.

EVL or tissue adhesive can be used in bleeding from gastroesophageal varices type 1
(GOV1).(5;D)

Early TIPS placement (changed from Baveno V)

An early TIPS with PTFE-covered stents within 72 hours (ideally < 24 hours) must be
considered in patients bleeding from EV, GOV1 and GOV2 at high-risk of treatment failure
(e.g. Child-Pugh class C <14 points or Child class B with active bleeding) after initial
pharmacological and endoscopic therapy (1b;A). Criteria for high-risk patients should be
refined.
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Expanding consensus in portal hypertension

Balloon tamponade (changed from Baveno V)

Balloon tamponade, given the high incidence of its severe adverse events, should only be
used in refractory oesophageal bleeding, as a temporary bridge (for a maximum of 24 h)
with intensive care monitoring and considering intubation, until definitive treatment can be
instituted (5;D).

Use of self-expandable metal stents (changed from Baveno V)

Data suggest that self-expanding covered oesophageal metal stents may be as efficacious
and a safer option than BT in refractory oesophageal variceal bleeding (4;C)

Management of treatment failures (unchanged from Baveno V)

Persistent bleeding despite combined pharmacological and endoscopic therapy is best

managed by PTFE-covered TIPS (2b;B).

Rebleeding during the first 5 days may be managed by a second attempt at endoscopic
therapy. If rebleeding is severe, PTFE-covered TIPS is likely the best option. (2b;B)

Research agenda

Trials of preventative strategies in acute kidney injury (AKI) in variceal bleeding should be
undertaken

Treatment and prevention of HE.

Optimal use of glue obliteration in gastric variceal bleeding

Role of EUS in variceal injection therapy

Alternative endoscopic haemostasis techniques in EVB, e.g., haemostatic powders

Improve prognostic models: Better stratification of risk to determine applicability of updated

MELD or other potential new models to improve stratification of risk to determine type of
treatment.
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Expanding consensus in portal hypertension

Applicability of models to determine other issues such as timing of the initial endoscopy,
duration of the drug therapy and type of treatment.

Use of early TIPS in gastric varices

Use of Balloon occluded retrograde transvenous obliteration (BRTO) in IGV

Preventing recurrent variceal haemorrhage and other decompensating events (changed from
Baveno V)
Prevention of recurrent variceal haemorrhage (changed from Baveno V)

First line therapy for all patients is the combination of NSBB (propranolol or nadolol) +
EVL (1a;A)

EVL should not be used as monotherapy unless there is intolerance/ contraindications to

NSBB (1a;A)

NSBB should be used as monotherapy in patients with cirrhosis who are unable or unwilling
to be treated with EVL (1a;A)

Covered TIPS is the treatment of choice in patients that fail first line therapy (NSBB +
EVL) (2b;B)

Because carvedilol has not been compared to current standard of care, its use cannot be
recommended in the prevention of rebleeding (5;D)

Secondary prophylaxis in patients with refractory ascites (new)

In patients with cirrhosis and refractory ascites [16] NSBB (propranolol, nadolol) should be
used cautiously with close monitoring of blood pressure, serum sodium and serum creatinine
(4;C)

Until randomized trials are available NSBB should be reduced/discontinued if a patient with
refractory ascites develops any of the following events (5;D):
Systolic blood pressure <90 mmHg
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Expanding consensus in portal hypertension

Hyponatremia (<130 mEq/L)

Acute kidney injury [17]

[This assumes that drugs that could precipitate these events (e.g. NSAIDs, diuretics) have
been removed]

The consequences of discontinuing NSBB in the setting of secondary prophylaxis are

unknown

If there was a clear precipitant for these events (e.g. spontaneous bacterial peritonitis,
haemorrhage), reinitiation of NSBB should be considered after these abnormal parameters
return to baseline values after resolution of the precipitant (5;D)

If reinitiating NSBBs, dose should be re-titrated, starting at the lowest dose (5;D)

If the patient continues to be intolerant to NSBB and is an appropriate TIPS candidate,

covered TIPS placement may be considered (5;D).

Secondary prophylaxis of portal hypertensive gastropathy (PHG) (changed from Baveno V):

PHG has to be distinguished from GAVE because treatments are different (4;C)

NSBB are first line therapy in preventing recurrent bleeding from PHG (1b;A)

TIPS might be considered in patients with transfusion-dependent PHG in whom NSBB

and/or endoscopic therapies fail (4;C)

Trial Design (new)(5;D)

Primary endpoints in patients after variceal haemorrhage depend on the presence of other
complications (ascites, encephalopathy, jaundice):
Patients without additional complications (low risk of death): endpoint should be
development of an additional complication, including variceal rebleeding
Patients with an additional complication (high risk of death): endpoint should be
mortality
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Expanding consensus in portal hypertension

The use of all-cause rebleeding is a good strategy to minimize bias in definition of

rebleeding.

Patients in these trials should be randomized 5 to 10 days after the index bleed

HVPG-response assessment is needed as a surrogate marker in trials where a low rate of

events is expected

Sample size and outcomes should be assessed by using competing risk analyses in settings
where transplant rates are predictably high

The impact of co-morbidities and successful treatment of the underlying aetiology on

disease progression and mortality requires further evaluation

Research agenda

Efficacy/safety assessment of promising drugs (statins, FXR agonists, anticoagulants and

rifaximin) and nutritional optimization

HVPG-guided therapy

Role of covered-TIPS as first-line therapy after variceal bleeding (secondary prophylaxis)

Non-invasive predictors of drug response

Effect of current therapies on patient-reported outcomes, particularly in low-mortality

patients

Innovative trials for small subpopulations of patients who have bled from varices (e.g.
children, fundal varices, HCC, patients who have bled while on NSBB prophylaxis)

Vascular diseases of the liver in cirrhotic and non-cirrhotic portal hypertension (changed
from Baveno V)
Etiological work-up in primary thrombosis of the portal venous system or hepatic venous outflow
tract

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Expanding consensus in portal hypertension

Close collaboration with haematologists is suggested for complete work-up for

prothrombotic factors including inherited and acquired thrombophilic factors, PNH and
autoimmune disorders (5;D).

Myeloproliferative neoplasia (MPN) should be investigated in all adult patients, first by

testing for V617F JAK2 mutation in peripheral blood (2b; B).

When V617F JAK2 is undetectable, further tests for MPN (including somatic Calreticulin)
may detect additional cases of JAK2-negative MPN (2b;B).

Irrespective of peripheral blood cell counts, bone marrow biopsy is recommended for the
diagnosis of MPN in patients without any bio-marker of MPN. Bone marrow biopsy may be
useful for the characterization of the subtype of MPN in patients with any positive biomarker (2b; B).

Use of anticoagulants and anti-platelet drugs in vascular liver diseases

Low Molecular Weight Heparin (LMWH) and Vitamin K Antagonists (VKA) are widely
accepted and used in primary thrombosis of the portal venous system or hepatic venous
outflow tract [1b; A].

No current recommendation can be made on Direct Oral Anticoagulants (DOACs) and antiplatelet drugs due to limited data [5;D].

Anticoagulation and portal vein thrombosis (PVT) in cirrhosis

Screening for PVT is indicated in patients on the waiting list for liver transplant (LT) every
six months (5;D).

Occurrence of PVT in presence of hepatocellular carcinoma (HCC) does not imply vascular
malignant invasion, but further imaging is recommended (5;D).

Anticoagulation should be considered in potential candidates with thrombosis of the main

portal vein trunk or progressive PVT (3a;B).
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Expanding consensus in portal hypertension

In this setting, the goal is to permit/facilitate LT and reduce post-transplant

mortality/morbidity, and anticoagulation should be maintained until transplantation to
prevent re-thrombosis (4;C).

In untreated potential LT candidates with PVT, an imaging follow-up every 3 months is

recommended. Anticoagulation is recommended in case of progression (5;D).

In non-candidates to LT no recommendation regarding anticoagulation treatment can be

made at present. Anticoagulation could be considered in selected cases (extension to
superior mesenteric vein, known strong prothrombotic conditions) (5;D).

Patients with low platelet count (e.g. < 50x109/L) are at higher risk of both PVT and
bleeding complications under anticoagulation and require more caution (5;D).

The benefit/risk ratio of anticoagulation for preventing or treating PVT in cirrhotic patients
requires further randomized controlled trials (RCTs) (5;D).

LMWH and VKA appear to be equally effective in cirrhotic individuals with PVT (5;D).
Data on DOACs are scarce. There is an urgent need for improved tools for monitoring
anticoagulation in cirrhotic patients. Measurement of thrombin generation might be an
option (5; D).

Budd-Chiari-Syndrome (BCS)/ Hepatic venous outflow tract obstruction (HVOTO)

Definition (unchanged from Baveno V)

Hepatic venous outflow tract obstruction (HVOTO) also known as Budd-Chiari-Syndrome

(BCS) is the consequence of obstruction to hepatic venous outflow

BCS/HVOTO can be located from the level of the small hepatic veins to the level of the
termination of inferior vena cava into the right atrium.

BCS/HVOTO is an heterogeneous condition with regard to causes and pathogenesis.

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BCS/HVOTO is considered secondary when the mechanism for HVOTO is

compression/invasion by a benign or malignant tumour, abscess or cyst.

BCS/HVOTO is considered primary otherwise.

Diagnosis (partly changed from Baveno V)

BCS/HVOTO is diagnosed by the demonstration of an obstruction of the venous lumen, or

by the presence of hepatic vein collaterals (2b;B).

Liver biopsy is not necessary to make a diagnosis of BCS/HVOTO when vascular imaging
has demonstrated obstruction of the hepatic venous outflow tract (4;C).

Liver biopsy is the only means to make a diagnosis of BCS/HVOTO of the small
intrahepatic veins (4;C).

Hepatic nodules are frequent and most often are benign. However HCC may occur and
therefore patients should be monitored with periodic imaging and alpha-fetoprotein
measurements and referred to centres experienced in managing BCS/HVOTO (2a;B).

Management (partly changed from Baveno V)

Management of BCS/HVOTO should be undertaken using a step-wise approach including

anticoagulation, angioplasty/thrombolysis, TIPS and OLT at experienced centres (3b;B).

Long-term anticoagulation should be given to all patients, although there is no definitive

evidence for patients without identified risk factors (5;D).

Portal hypertension should be treated since it is the major risk factor for bleeding, while
excess anticoagulation plays a secondary role (4;C).

Complications of portal hypertension should be treated as recommended for the other types
of liver diseases (4;C).

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Previous bleeding related to portal hypertension is not considered a major contra-indication

for anticoagulation, provided appropriate prophylaxis for recurrent bleeding is initiated
(4;C).

Stenoses that are amenable to percutaneous angioplasty/stenting (short-length stenoses)

should be actively looked for, and treated accordingly (5;D).

TIPS insertion should be attempted by experts when angioplasty/stenting is not feasible, and
when the patient does not improve on medical therapy (4;C).

BCS-TIPS Prognostic Index score may predict outcome in patients with TIPS (3b;B).

Patients with high BCS-TIPS Prognostic Index score (7) are likely to have poor outcome
following TIPS and OLT should be considered (3b;B).

Liver transplantation should be considered in patients with manifestations refractory to the

above procedures (5;D).

Extra-hepatic portal vein obstruction (EHPVO)

Definition (partly changed from Baveno V)

EHPVO is the obstruction of the extra-hepatic portal vein, with or without involvement of
the intra-hepatic portal veins or other segments of the splanchnic venous axis. It does not
include isolated thrombosis of splenic vein or superior mesenteric vein (SMV).

EHPVO is characterized by features of recent thrombosis or of portal hypertension with

portal cavernoma as a sequel of portal vein obstruction.

Presence of cirrhosis, other underlying liver diseases (i.e. non-cirrhotic portal hypertension)
and/or malignancy should be ruled out. EHPVO in those situations should be considered as
different entities.

Diagnosis (changed from Baveno V)

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EHPVO is diagnosed by Doppler US, CT- or MRI- angiography, which demonstrate portal
vein obstruction, presence of solid intraluminal material or portal vein cavernoma (2a;B).

Doppler US should be considered first line investigation and CT- or MRI-angiography

should be performed subsequently for assessment of thrombosis extension and of potential
local factors (2a;B).

EHPVO in adults is frequently associated with one or more risk factors for thrombosis,
which may be occult at presentation and should be investigated (3a;B).

Liver biopsy and HVPG are recommended, if the liver is dysmorphic on imaging or liver
tests are persistently abnormal, to rule out cirrhosis or idiopathic non-cirrhotic portal
hypertension (1b;B). Liver stiffness by TE may be useful to exclude cirrhosis (5;D)

Anticoagulation in recent EHPVO (changed from Baveno V)

Recent EHPVO rarely resolves spontaneously (3a,A).

Low molecular weight heparin should be started immediately followed by oral anticoagulant
therapy (2b;B). Most patients treated with early anticoagulation have a good clinical
outcome. Therefore, even failure of recanalization does not warrant further interventions
(e.g. local thrombolysis) in most cases (2b;B).

Anticoagulation should be given for at least six months. When an underlying persistent
prothrombotic state has been documented long-term anticoagulation is recommended
(1b;A).

Antibiotic therapy should be given if there is any evidence of SIRS/infection (5;D).

In patients with persistent abdominal pain, bloody diarrhoea and lactic acidosis the risk of
intestinal infarction and organ failure is increased, repermeabilization and surgical
intervention should be considered (3b;B).

Anticoagulation in chronic EHPVO (changed from Baveno V)

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In patients without underlying prothrombotic disease, there is scarce information to

recommend anticoagulant therapy (5;D).

In patients with a persistent documented prothrombotic state, recurrent thrombosis or

intestinal infarction long-term anticoagulant therapy is recommended (3b;B).

Anticoagulation should be started after adequate portal hypertensive bleeding prophylaxis

has been initiated (5;D).

Treatment of portal hypertension in EHPVO (partly changed from Baveno V)

All patients in whom thrombosis has not been recanalised should be screened for
gastroesophageal varices within six months of the acute episode. In the absence of varices,
endoscopy should be repeated at 12 months and 2 years thereafter (5;D).

There is insufficient data on whether beta-blockers or endoscopic therapy should be

preferred for primary prophylaxis. Thus, guidelines for cirrhosis should be applied (5;D).

For the control of acute variceal bleeding, endoscopic therapy is effective (1a;A).

Evidence suggests that beta-blockers are as effective as endoscopic ligation therapy for
secondary prophylaxis (2b;B)

Mesenteric-left portal vein bypass (Meso-Rex operation) should be considered in all

children with complications of chronic EHPVO, who should be referred to centres with
experience in treating this condition (5;D).

Idiopathic portal hypertension/Non-cirrhotic portal fibrosis/Idiopathic non-cirrhotic portal

hypertension (IPH, NCPF, INCPH) (new)

Idiopathic portal hypertension, non-cirrhotic portal fibrosis and Idiopathic non-cirrhotic

portal hypertension indicate the same clinical entity (5;D). This includes the histological
diagnosis of obliterative portal venopathy.

Diagnosis of IPH/NCPF/INCPH (new)

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Expanding consensus in portal hypertension

Diagnosis requires the exclusion of cirrhosis and other causes of non-cirrhotic portal
hypertension (2b;B)

A liver biopsy is mandatory and HVPG is recommended for the diagnosis (2b;B).

Immunological diseases and prothrombotic disorders should be screened (5;D).

Management of IPH/NCPF/INCPH (new)

There is insufficient data on which therapy should be preferred for portal hypertension
prophylaxis. Management according to cirrhosis guidelines is recommended (5;D).

Screening for the development of portal vein thrombosis. There is no data on the best
screening method and interval. Doppler ultrasound at least every 6 months is suggested
(5;D).

In those patients that develop portal vein thrombosis anticoagulant therapy should be started
(5;D).

Research agenda

Further etiological investigations using whole genome sequencing in primary thrombosis of

the portal venous system or hepatic venous outflow tract .

Role of PVT in the course of liver cirrhosis.

Identify risk factors for PVT in cirrhosis.

The benefit/risk ratio of anticoagulation for preventing or treating PVT in cirrhotic patients
requires further RCTs.

Improved tools for monitoring anticoagulation in cirrhotic patients.

Efficacy and safety of the new oral anticoagulants in patients with vascular disorders of the
liver, either with cirrhosis or not.

Role of anti-platelet drugs as add-on antithrombotic treatment.

Role of anticoagulation and other treatments in chronic EHPVO.

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Further characterization and treatment of IPH/NCPF/INCPH.

Other issues
Besides the consensus sessions, five lectures were given in Baveno VI. The topics of these lectures
were the concept of risk stratification, competing risks and prognostic stages of cirrhosis, the basic
and clinical aspects of the relationship between the gut microbiome and cirrhosis, and the 2015
report on controversies and challenges in paediatrics. The texts of these lectures are reported in the
Baveno VI proceedings book [15]. The Baveno VI consensus workshop was followed by a
paediatric satellite meeting in which the controversies in the management of varices in children
were discussed.
Conclusions
The consensus definitions of treatment failure in variceal bleeding have been simplified in view of
the results of the evaluation of their performance in the field. The use of these definitions, as well as
of the other end points proposed, in future studies is encouraged to provide further validation.
Several statements agreed upon in previous Baveno workshops were taken for granted and not
discussed in Baveno VI. Interested readers can refer to the Baveno I-V reports [2-4,7-10;12-13]
The topics listed in the research agenda reflect the opinions of the experts about the areas where
new information is most needed.

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Baveno VI Faculty
The following were members of the Baveno VI Scientific Committee:
Roberto de Franchis [Mlan, Italy (Chair)], Juan G Abraldes (Edmonton, Canada), Jasmohan Bajaj
(Richmond, USA), Annalisa Berzigotti (Bern, Switzerland), Jaime Bosch (Barcelona, Spain),
Andrew K Burroughs (London, UK) , Gennaro DAmico (Palermo, Italy), Alessandra DellEra
(Milan, Italy), Juan Carlos Garcia-Pagn (Barcelona, Spain), Guadalupe Garcia-Tsao (West Haven,
USA), Norman Grace (Boston, USA), Roberto Groszmann (New Haven, USA), Aleksander Krag
(Odense, Denmark), Wim Laleman (Leuven, Belgium), Vincenzo La Mura (Milan, Italy), Didier
Lebrec (Clichy, France), Gin Ho Lo (Taipei, Taiwan) Carlo Merkel (Padua, Italy), James OBeirne
(London, UK), Markus Peck (Vienna, Austria), Massimo Primignani (Mlan, Italy), Francesco
Salerno (Milan, Italy), Shiv K Sarin (New Delhi, India), Dominique Thabut (Paris, France), Jonel
Trebicka (Bonn, Germany), Alexander Zipprich (Halle, Germany).

The following chaired sessions or lectures:

Juan G Abraldes (Edmonton, Canada), Annalisa Berzigotti (Bern, Switzerland), Jaime Bosch
(Barcelona, Spain), Roberto de Franchis (Mlan, Italy), Juan Carlos Garcia-Pagn (Barcelona,
Spain), Guadalupe Garcia-Tsao (West Haven, USA), Norman Grace (Boston, USA), Roberto
Groszmann (New Haven, USA), Aleksander Krag (Odense, Denmark), Wim Laleman (Leuven,
Belgium), Didier Lebrec (Clichy, France), Carlo Merkel (Padua, Italy), Massimo Primignani
(Mlan, Italy), Shiv K Sarin (New Delhi, India), Dominique Thabut (Paris, France), Jonel Trebicka
(Bonn, Germany).
The following participated in the presentations and the discussions as panelists in the consensus
sessions:
Lars Aabakken (Oslo, Norway), Augustin Albillos (Madrid, Spain), Salvador Augustin
(Barcelona, Spain), Rafael Baares (Madrid, Spain), Tom Boyer (Tucson , USA), Christophe
Bureau (Toulouse, France), Laurent Castera (Clichy, France), Andrea De Gottardi (Bern,
Switzerland) , Alessandra DellEra (Milan, Italy), Angels Escorsell (Barcelona, Spain), Joan
Genesca (Barcelona, Spain) , Ian Gralnek (Haifa, Israel), Roberto Groszmann (New Haven, USA),
Virginia Hernandez-Gea (Barcelona, Spain) , Vincenzo La Mura (Milan, Italy) , Frank Leebeek
(Rotterdam, The Netherlands), Gin Ho Lo (Taipei, Taiwan), Manuela Merli (Rome, Italy), Richard
Moreau (Clichy, France) , Frederik Nevens (Leuven, Belgium), James OBeirne (London, UK),
Markus Peck (Vienna, Austria), Massimo Pinzani (London, UK), Thomas Reiberger (Boston,
USA), Cristina Ripoll (Halle, Germany), Marika Rudler (Paris, France) ,Francesco Salerno
(Milan, Italy), Shiv K Sarin (New Delhi, India), Susana Seijo (New York, USA), Puneeta Tandon
(Edmonton, Canada), Emmanouil Tsochatzis (London, UK), Dominique Valla (Clichy, France) ,
Candid Villanueva (Barcelona, Spain) , Julio Vorobioff (Rosario, Argentina), Alexander Zipprich
(Halle, Germany).
The following gave review lectures:
Jasmohan Bajaj (Richmond, USA), Gennaro DAmico (Palermo, Italy), Ben Shneider (Houston,
USA), Jayant Talwalkar (Rochester, USA), Reiner Wiest (Bern, Switzerland)
Conflict of interest
The authors that have taken part in this study declared that they do not have anything to disclose
regarding funding or conflict of interest with respect to this manuscript.
ACKNOWLEDGEMENTS
The Baveno VI Consensus workshop was supported in part by a grant from EASL
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