Varices Management: Current State of the Art

1
Varices Management Current State of the Art

• Atif Zaman, MD MPH
• Associate Professor of Medicine
• Director of Clinical Hepatology
• Oregon Health Science University

2
VARICES AND VARICEAL HEMORRHAGE
Cirrhosis
3
VARICES INCREASE IN DIAMETER PROGRESSIVELY
Varices Increase in Diameter Progressively
Small varices
Large varices
No varices
7-8/year
7-8/year
Merli et al. J Hepatol 200338266
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PREVALENCE OF ESOPHAGEAL VARICES IN CIRRHOSIS
Prevalence of Esophageal Varices in Cirrhosis
100
80
60

40
20
0
Child C
Overall
Child A
Child B
Pagliaro et al., In Portal Hypertension
Pathophysiology and Management, 1994 72
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PREVALENCE AND SIZE OF ESOPHAGEAL VARICES IN
PATIENTS WITH NEWLY DIAGNOSED CIRRHOSIS
Prevalence and Size of Esophageal Varices in
Patients with Newly-Diagnosed Cirrhosis
100
80
Large
Patients with varices
60
40
Medium
20
Small
0
Child C n34
Overall n494
Child A n346
Child B n114
Pagliaro et al., In Portal Hypertension
Pathophysiology and Management, 1994 72
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PROGNOSTIC INDICATORS OF FIRST VARICEAL HEMORRHAGE
Varix with red signs
Variceal hemorrhage

• Predictors of hemorrhage
• Variceal size
• Red signs
• Child B/C

NIEC. N Engl J Med 1988 319983
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LARGE VARICES ARE MORE LIKELY TO RUPTURE
Large Varices Are More Likely To Rupture
No Varices
100
plt0.01
Small Varices
75
Patients without bleeding
Large Varices
50

• 2-year probability of first bleed
• Small varices 7
• Large varices 30

25
0
36
12
24
36
0
12
24
Time (months)
Merli et al., Hepatol 2003 38266, Conn et
al., Hepatology 1991 13902
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Screening for Varices

• Current recommendations for screening
• AASLD
• All patients with mod-severe cirrhosis (Child
  B/C)
• Child A with signs of portal hypertension (plts
  lt140,000, PV gt13mm, or evidence of collaterals)
• ACG All patients with cirrhosis upon diagnosis
  of cirrhosis
• A number of studies have attempted to determine
  risk factors for presence of large esophageal
  varices (LEV)

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Prevalence and Predictors of LEV in Patients with
Cirrhosis
Author No. patients Child A/B/C () LEV () Predictors
Pagliaro 496 70/23/7 9 Low plt count
Lavergne 52 49/35/16 19 Ascites
Barcia 95 34/49/17 36 Ascites Advanced CPC
Chalasani 346 22/48/30 20 Plts lt88,000 Splenomegaly
Madhotra 184 43/34/23 25 Splenomegaly, Plts lt68,000
Zaman 300 11/71/18 31 Plts lt80,000 Advanced CPC
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Capsule Endoscopy for Screening for Varcies
Grade 3 Varices
Grade 1 Varices
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Capsule Endoscopy vs. EGD for Variceal Screening

• If EGD is the gold standard for variceal
  detection
• Sensitivity of CE 100 (84)
• Specificity of CE 89 (88)
• PPV 96 (92)
• NPV 100 (77)

Eisen et al, Endoscopy 2006 3831-35 DeFranchis
et al, Hepatology 2008471595-1603

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PREVENTION OF VARICEAL DEVELOPMENT
Treatment of Varices / Variceal Hemorrhage
Prevention of variceal development
No varices
Varices No hemorrhage
Variceal hemorrhage
Recurrent hemorrhage
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NON-SELECTIVE BETA BLOCKERS DO NOT PREVENT
DEVELOPMENT OF VARICES
Pre-Primary Prophylaxis

• Multicenter, randomized, placebo-controlled trial
  of timolol (non-selective beta-blocker) vs.
  placebo in patients
• Beta-blockers did not prevent the development of
  varices and were associated with a higher rate of
  serious adverse events
• Hepatic venous pressure gradient was the
  strongest predictor of the development of varices

Groszmann, et al., NEJM 2006
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MANAGEMENT OF PATIENTS WITHOUT VARICES
Treatment of Varices / Variceal Hemorrhage
No varices
Varices No hemorrhage
Variceal hemorrhage
Recurrent hemorrhage
Sooner with cirrhosis decompensation
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PREVENTION OF FIRST VARICEAL HEMORRHAGE
Treatment of Varices / Variceal Hemorrhage
No varices
Prevention of first variceal hemorrhage
Varices No hemorrhage
Variceal hemorrhage
Recurrent hemorrhage
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PREVENTION OF FIRST VARICEAL HEMORRHAGE
Prevention of First Variceal Hemorrhage
Bleeding
Death
Encephalopathy
Porto-caval shunt
?-blockers

Sclerotherapy
Significantly heterogeneous

Relative risk
Treated worse
Treated better
DAmico et al., Hepatology 1995 22332
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NON-SELECTIVE BETA-BLOCKERS PREVENT FIRST
VARICEAL HEMORRHAGE
Non-Selective Beta-Blockers Prevent First
Variceal Hemorrhage
Bleeding rate Control Beta-blocker Absolute
rate (2 year) difference All
varices 25 15 -10 (11 trials) (n600) (n590)
(-16 to -5) Large varices 30 14 -16 (8
trials) (n411) (n400) (-24 to -8) Small
varices 7 2 -5 (3 trials) (n100) (n91) (-11
to 2)
DAmico et al., Sem Liv Dis 1999 19475
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VARICEAL BAND LIGATION (VBL) VS. BETA-BLOCKERS
(BB) IN THE PREVENTION OF FIRST VARICEAL
HEMORRHAGE
Variceal Band Ligation (VBL) vs. Beta-Blockers
(BB) in the Prevention of First Variceal Bleed
Khuroo, et al., Aliment Pharmacol Ther 2005
21347
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MANAGEMENT OF PATIENTS WITH VARICES WHO HAVE
NEVER BLED
Treatment of Varices / Variceal Hemorrhage
No varices
Varices No hemorrhage
Variceal hemorrhage
Recurrent hemorrhage
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MANAGEMENT OF PATIENTS WITH MEDIUM/LARGE VARICES
WITHOUT PRIOR HEMORRHAGE
Treatment of Varices / Variceal Hemorrhage
No varices
Small varices No hemorrhage
Medium/ large varices No hemorrhage
Variceal hemorrhage
Recurrent hemorrhage
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MANAGEMENT OF PATIENTS WITH SMALL VARICES WITHOUT
PRIOR HEMORRHAGE
Treatment of Varices / Variceal Hemorrhage
No varices
Small varices No hemorrhage
Medium/ large varices No hemorrhage
Variceal hemorrhage
Recurrent hemorrhage
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NADOLOL MAY PREVENT THE GROWTH OF SMALL VARICES
Nadolol May Prevent the Growth of Small Varices
100
Nadolol
80
Placebo
Probability of variceal growth
plt0.001
60
40
20
24
36
48
60
10
0
Time (months)
Merkel et al., Gastroenterology 2004 127476
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MANAGEMENT OF PATIENTS WITH SMALL VARICES WITHOUT
PRIOR HEMORRHAGE
Treatment of Varices / Variceal Hemorrhage
No varices
Small varices No hemorrhage
Medium/ large varices No hemorrhage
Variceal hemorrhage
Recurrent hemorrhage
Sooner with cirrhosis decompensation
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CONTROL OF ACUTE VARICEAL HEMORRHAGE
Treatment of Varices / Variceal Hemorrhage
No varices
Small varices No hemorrhage
Medium/ large varices No hemorrhage
Variceal hemorrhage
Recurrent hemorrhage
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TREATMENT OF ACUTE VARICEAL HEMORRHAGE
Treatment of Acute Variceal Hemorrhage

• General Management
• IV access and fluid resuscitation
• Do not overtransfuse (hemoglobin 8 g/dL)
• Antibiotic prophylaxis (IV ceftriaxone 1gm daily)
• Specific therapy
• Pharmacological therapy terlipressin,
  somatostatin and analogues, vasopressin
  nitroglycerin
• Endoscopic therapy ligation, sclerotherapy
• Shunt therapy TIPS, surgical shunt

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PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN
CIRRHOTIC PATIENTS WITH GI HEMORRHAGE
Prophylactic Antibiotics Improve Outcomes in
Cirrhotic Patients with GI Hemorrhage
Control Antibiotic Absolute rate (n270) (n264
) difference (95 CI) Infection 45 14 -32
(-42 to 23) SBP / Bacteremia 27 8 -18 (-26
to 11) Death 24 15 -9 (-15 to 3)
Bernard et al., Hepatology 1999 291655
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PROPHYLACTIC ANTIBIOTICS PREVENT EARLY VARICEAL
REBLEEDING
Probability of Remaining Free of Recurrent
Variceal Hemorrhage
1.0
Prophylactic antibiotics (n59)
0.8
No antibiotics (n61)
0.6
free of variceal hemorrhage
0.4
0.2
0
3
12
30
18
24
0
2
1
Follow-up (months)
Hou M-C et al., Hepatology 2004 39746
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COMBINATION DRUG/ENDOSCOPIC THERAPY IS MORE
EFFECTIVE THAN ENDOSCOPIC THERAPY ALONE
Combination Drug / Endoscopic Therapy is More
Effective Than Endoscopic Therapy Alone in
Achieving Five-Day Hemostasis
Sclero Octreotide Besson, 1995 Ligation
Octreotide Sung, 1995 Sclero Octreotide /
ST Signorelli, 1996 Sclero Octreotide Ceriani,
1997 Sclero Octreotide Signorelli, 1997 Sclero
ST Avgerinos, 1997 Sclero Octreotide Zuberi,
2000 Sclero / ligation Vapreotide Cales,
2001 TOTAL
Relative Risk
1
1.6
1.8
2
1.2
1.4
0.8
Favors endoscopic therapy alone
Favors endoscopic plus drug therapy
Bañares R et al., Hepatology 2002 35609
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ENDOSCOPIC VARICEAL BAND LIGATION
Endoscopic Variceal Band Ligation

• Bleeding controlled in 90
• Rebleeding rate 30
• Compared with sclerotherapy
• Less rebleeding
• Lower mortality
• Fewer complications
• Fewer treatment sessions

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TIPS IN THE TREATMENT OF VARICEAL HEMORRHAGE
TIPS in the Treatment of Variceal Hemorrhage

• TIPS is rescue therapy for recurrent variceal
  hemorrhage
• (at second rebleed for esophageal varices, at
  first rebleed for gastric varices)
• TIPS is indicated in patients who rebleed on
  combination endoscopic plus pharmacologic therapy
• In patients with Child A/B cirrhosis, the distal
  spleno-renal shunt is as effective as TIPS
• (dependent on local expertise)

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MANAGEMENT OF PATIENTS WITH ACUTE VARICEAL
HEMORRHAGE
Treatment of Varices / Variceal Hemorrhage
No varices
Small varices No hemorrhage
Medium/ large varices No hemorrhage
Variceal hemorrhage
Recurrent hemorrhage
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LOWEST REBLEEDING RATES ARE OBTAINED IN HVPG
RESPONDERS AND IN PATIENTS TREATED WITH VARICEAL
BAND LIGATION BETA-BLOCKERS
Lowest Rebleeding Rates are Obtained in HVPG
Responders and With Ligation ?-Blockers
80
60

40
Rebleeding
20
0
Untreated
?-blockers
Sclero- therapy
Ligation
HVPG-Responders
? -blockers ISMN
Ligation ?-blockers
(19 trials)
(26 trials)
(54 trials)
(18 trials)
(6 trials)
(6 trials)
(2 trials)
? HVPG lt12 mmHg or gt20 from baseline
Bosch and García-Pagán, Lancet 2003 361952
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PREVENTION OF RECURRENT VARICEAL HEMORRHAGE
Treatment of Varices / Variceal Hemorrhage
No varices
Varices No hemorrhage
Variceal hemorrhage
Recurrent hemorrhage
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SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL
HEMORRHAGE
Evolution of Varices
Level of Intervention
Management Recommendations
Cirrhosis with no varices

• Repeat endoscopy in 2-3 years
• No specific therapy

Pre-primary prophylaxis
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SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL
HEMORRHAGE
Evolution of Varices
Level of Intervention
Management Recommendations
Cirrhosis with no varices

• Repeat endoscopy in 2-3 years
• No specific therapy

Pre-primary prophylaxis
Small varices No hemorrhage

• Small varices
• Repeat endoscopy in 1-2 years
• No specific therapy
• ? beta-blocker to prevent enlargement
• Medium/Large varices
• Non-selective beta-blockers
• EVL in those who are intolerant to drugs

Medium / large varices No hemorrhage
Primary prophylaxis
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SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL
HEMORRHAGE
Evolution of Varices
Level of Intervention
Management Recommendations
Cirrhosis with no varices

• Repeat endoscopy in 2-3 years
• No specific therapy

Pre-primary prophylaxis
Small varices No hemorrhage

• Small varices
• Repeat endoscopy in 1-2 years
• No specific therapy
• ? beta-blocker to prevent enlargement
• Medium/Large varices
• Non-selective beta-blockers
• EVL in those who are intolerant to drugs

Medium / large varices No hemorrhage
Primary prophylaxis

• Endoscopic/pharmacologic therapy
• Antibiotics in all patients
• TIPS or shunt surgery as rescue therapy

Variceal hemorrhage
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SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL
HEMORRHAGE
Evolution of Varices
Level of Intervention
Management Recommendations
Cirrhosis with no varices

• Repeat endoscopy in 2-3 years
• No specific therapy

Pre-primary prophylaxis
Small varices No hemorrhage

• Small varices
• Repeat endoscopy in 1-2 years
• No specific therapy
• ? beta-blocker to prevent enlargement
• Medium/Large varices
• Non-selective beta-blockers
• EVL in those intolerant to drugs

Medium / large varices No hemorrhage
Primary prophylaxis

• Endoscopic/pharmacologic therapy
• Antibiotics in all patients
• TIPS or shunt surgery as rescue therapy

Variceal hemorrhage

• Beta-blockers nitrates or EVL
• Beta-blockers EVL ?
• TIPS or shunt surgery as rescue therapy

Secondary prophylaxis
Recurrent variceal hemorrhage
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The Future Directed Therapy Using Portal
Pressure Measurements
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PORTAL PRESSURE MEASUREMENTS
Portal Pressure Measurements

• Definitive method to establish the diagnosis of
  portal hypertension
• Direct methods (percutaneous, transjugular) are
  cumbersome and may be associated with
  complications
• The safest and most reproducible method is
  measurement of the hepatic venous pressure
  gradient (HVPG)

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PORTAL PRESSURE MEASUREMENTS
Portal Pressure Measurements

• The hepatic venous pressure gradient (HVPG) is
  obtained by subtracting the free hepatic venous
  pressure (FHVP) from the wedged hepatic venous
  pressure (WHVP)
• The FHVP acts as an internal zero to correct for
  extravascular, intraabdominal pressure increases
  (e.g. ascites)

HVPG WHVP - FHVP
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A THRESHOLD PORTAL PRESSURE OF 12 mmHg IS
NECESSARY FOR VARICES TO FORM
A Threshold Portal Pressure of 12 mmHg is
Necessary for Varices to Form
Varices Present (n72)
Varices Absent (n15)
35
30
Hepatic Venous Pressure Gradient (mmHg)
25
20
Plt0.01
15
12
10
5
Garcia-Tsao et. al., Hepatology 1985 5419
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DECREASE IN HEPATIC VENOUS PRESSURE GRADIENT
(HVPG) REDUCES THE RISK OF VARICEAL BLEEDING
Decrease In Hepatic Venous Pressure Gradient
(HVPG) Reduces Risk of Variceal Bleeding
100
80
46-65
60
Rebleeding
40
7-13
20
0
0
HVPG decrease gt 20 from baseline
HVPG decrease to lt 12 mmHg
No change in HVPG
Bosch and García-Pagán, Lancet 2003 361952
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SURVIVAL IMPROVES IN PATIENTS IN WHOM HVPG
DECREASES (HVPG RESPONDERS)
Survival Improves in Patients in Whom HVPG
Decreases (HVPG Responders)
Abraldes et al., Hepatology 2003 37902