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Thomas Hargrave, M.D. March 24, 2012
Prevention and Management of Esophageal Variceal and Portal Hypertensive Hemorrhage Thomas Hargrave, M.D. March 24, 2012

Gastroesophageal Variceal Hemorrhage
Gastroesophageal variceal hemorrhage is one of the major complications of portal hypertension from cirrhosis Variceal hemorrhage occurs in 25-35% of cirrhotics and accounts for 70-80% of UGIB in these patients. Aprroximately 50% of cirrhotics will have varices at the time of diagnosis 7-8% develop de novo varices each year

PREVALENCE AND SIZE OF ESOPHAGEAL VARICES IN PATIENTS WITH NEWLY DIAGNOSED CIRRHOSIS
100 80 Large % Patients with varices 60 40 Medium Slide 84 PREVALENCE AND SIZE OF ESOPHAGEAL VARICES IN PATIENTS WITH NEWLY DIAGNOSED CIRRHOSIS Esophageal varices are present in approximately half of the patients with cirrhosis. The prevalence correlates to the severity of liver disease with Child C cirrhotic patients being twice as likely to have varices as Child A patients. In addition, Child C patients are more likely to have large varices than patients with less severe liver disease. Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994; 72 20 Small Overall n=494 Child A n=346 Child B n=114 Child C n=34 Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72

Gastroesophageal Variceal Hemorrhage
The 1-year risk of a first variceal hemorrhage is approximately 12% (5% for small varices and 15% for large varices). The 6-week mortality with each episode of variceal hemorrhage is approximately %, From 0% among patients with Child class A disease to 30% among patients with Child class C disease. The 1-year rate of recurrent variceal hemorrhage is approximately 60%.

Pathophysiology Portal Venous Anatomy

Hepatic/Portal Blood Flow
Blood accounts for 25-30% of the volume of the liver Total Hepatic Blood Flow: Hepatic arterial and portal venous blood flow Approximately 25% of the cardiac output Males: 1860 cc/min Females: 1550 cc/min Portal venous blood flow averages 1500 cc/min Normal portal venous pressure is 4-8 mmHg

Hepatic Lobular Anatomy

Pathophysiology Gastroesophageal varices are a direct consequence of portal hypertension that, in cirrhosis, results from Increased resistance to portal flow Structural (distortion of liver vascular architecture by fibrosis and regenerative nodules) and Dynamic (increased hepatic vascular tone due to endothelial dysfunction and decreased nitric oxide bioavailability). Increased portal venous blood inflow.

Intracellular Spaces (of Disse) in the Portal Sinusoids Large Enough for Chylomicroms to Pass

Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:823-832.
Figure 1. The Pathogenesis of Portal Hypertension, Varices, and Variceal Hemorrhage. The initial mechanism in the development of portal hypertension in cirrhosis is an increase in vascular resistance to portal flow. A subsequent increase in portal venous inflow maintains the portal hypertensive state. Portal hypertension leads to the formation of portosystemic collaterals, of which the most clinically relevant are gastroesophageal varices. The increase in flow through these collaterals, enhanced by the presence of splanchnic vasodilatation and increased portal blood inflow, leads to variceal growth and rupture. This process is modulated by angiogenic factors. VEGF denotes vascular endothelial growth factor. Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:

Portal venous blood flow observed Portal venous blood flow observed with
esophageal and gastric varices. (Adapted from Kitano et al. [17]

A THRESHOLD PORTAL PRESSURE OF ~12 mmHg IS NECESSARY FOR VARICES TO FORM
A Threshold Portal Pressure of ~12 mmHg is Necessary for Esophageal Varices to Form Varices Present (n=72) Varices Absent (n=15) 35 30 Hepatic Venous Pressure Gradient (mmHg) 25 20 P<0.01 Slide 85 A THRESHOLD PORTAL PRESSURE OF ~12 mmHg IS NECESSARY FOR VARICES TO FORM Initial dilatation of the esophageal collaterals depends on a threshold portal pressure below which varices do not develop. This threshold has been established at an hepatic venous pressure gradient (HVPG) of mmHg. Notably, patients with no varices may have an HVPG >12 mmHg. Therefore the threshold HVPG level is necessary but not sufficient for the development of gastroesophageal varices. Factors other than pressure, such as volume of blood flow and local anatomic factors may contribute to the formation of varices. Garcia-Tsao et al., Hepatology 1985; 5: 419 15 12 10 5 Garcia-Tsao et. al., Hepatology 1985; 5:419

Venous Layers of the Esophagus
Venous layers of the esophagus Venous layers of the esophagus. There are three parts of the venous system related to the esophagus: intrinsic veins, associated veins, and extrinsic veins. The two layers of veins in the wall of the esophagus are the superficial venous plexus (located in the lamina propria and muscularis mucosa) and the submucosal plexus (within the circular muscle). In the distal esophagus, venous blood drains first from a superficial mucosal network of small intraepithelial blood vessels into submucosal, longitudinally oriented deep intrinsic veins. Once in the intrinsic veins, blood drains through a system of transverse perforating veins with unidirectional valves into extrinsic serosal and periesophageal veins and ultimately into the left gastric vein inferiorly and the azygos vein superiorly. (Adapted from Kitano et al. [17]

VARICES INCREASE IN DIAMETER PROGRESSIVELY
Slide 82 VARICES INCREASE IN DIAMETER PROGRESSIVELY Both development of varices and growth of small varices occurs at a rate of 7-8% per year. Although there are no identified clinical predictors for the development of varices, factors associated with variceal growth are Child B/C cirrhosis, alcoholic etiology and presence of red wale marks on initial endoscopy. Merli et al., J Hepatol 2003; 38: 266 No varices Small varices Large varices 7-8%/year 7-8%/year Merli et al. J Hepatol 2003;38:266

Grade II Varices Grade III Varices

LARGE VARICES ARE MORE LIKELY TO RUPTURE
No Varices 100 p<0.01 * Small Varices 75 % Patients without bleeding Large Varices * * 50 2-year probability of first bleed: Small varices: 7% Large varices: 30% Slide 98 LARGE VARICES ARE MORE LIKELY TO RUPTURE The most important predictor of variceal hemorrhage is variceal size. The incidence of first variceal hemorrhage in patients with small varices is very small , at ~5% per year, while large varices bleed at a rate of ~15% per year. Merli M, et al. J Hepatol 2003; 38: 266 Conn HO, et al. Hepatology 1991; 13: 902 25 12 24 12 36 24 36 Time (months) *Merli et al., Hepatol 2003; 38:266, **Conn et al., Hepatology 1991; 13:902

Varix with red wale sign
Punctum Variceal hemorrhage Varix with red wale sign

Management of Variceal Bleeding
Primary Prophylaxis Pharmacologic Endoscopic Acute Variceal Hemorrhage TIPS Secondary Prophylaxis Pharmcologic

Primary Prophylaxis In view of the relatively high rate of bleeding from esophageal varices and the high associated mortality, an important goal of management of patients with cirrhosis is the primary prevention of variceal hemorrhage. As a result, all patients with cirrhosis should undergo diagnostic endoscopy to document the presence of varices and to determine their risk for variceal hemorrhage.

MANAGEMENT OF PATIENTS WITHOUT VARICES
Treatment of Varices / Variceal Hemorrhage Can we prevent formation of varices ? No varices Varices No hemorrhage Variceal hemorrhage Slide 112 MANAGEMENT OF PATIENTS WITHOUT VARICES In cirrhotic patients who have not yet developed varices, no specific therapy is recommended. However, a surveillance endoscopy should be performed every 2-3 years in compensated cirrhosis and annually in decompensated cirrhosis. Recurrent hemorrhage

NON-SELECTIVE BETA BLOCKERS DO NOT PREVENT DEVELOPMENT OF VARICES
Prevention of Esophageal Varices w/ Beta-Blockers? 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 In patients without varices, treatment with nonselective beta-blockers is not recommended Slide 111 NON-SELECTIVE BETA BLOCKERS DO NOT PREVENT DEVELOPMENT OF VARICES In a prospective randomized, placebo-controlled trial performed in patients with cirrhosis and portal hypertension (HVPG >5 mmHg) but without varices at baseline, the development of gastroesophageal varices was the same in patients randomized to a non-selective beta-blocker (timolol) compared to those randomized to placebo. Additionally, patients randomized to timolol had significantly greater number of serious adverse events compared to patients in the placebo group. The study demonstrates that a baseline HVPG of greater than 10 mmHg is the strongest predictor of the development of varices. Groszmann RJ, et al., Hepatology 2003; 38(suppl 1): 206A Groszmann, et al., Hepatology 2003;38 (suppl 1):206A

Treatment of Varices / Variceal Hemorrhage No specific therapy Repeat endoscopy in 2-3 yrs* No varices Varices No hemorrhage Variceal hemorrhage Slide 112 MANAGEMENT OF PATIENTS WITHOUT VARICES In cirrhotic patients who have not yet developed varices, no specific therapy is recommended. However, a surveillance endoscopy should be performed every 2-3 years in compensated cirrhosis and annually in decompensated cirrhosis. Recurrent hemorrhage * Sooner with cirrhosis decompensation

PREVENTION OF FIRST VARICEAL HEMORRHAGE
Treatment of Varices / Variceal Hemorrhage No varices Varices No hemorrhage Prevention of first variceal hemorrhage Variceal hemorrhage Slide 113 PREVENTION OF FIRST VARICEAL HEMORRHAGE The second stage in the management of varices/variceal hemorrhage is constituted by patients with varices who have never bled from them. Can the first episode of variceal hemorrhage be prevented in these patients? Recurrent hemorrhage

Primary Prophylaxis for Variceal Hemorrhage
Pharmacologic Therapy Beta Blockers Nitrates Endoscopic Therapies Band Ligation Sclerotherapy (historican interest only)

HVPG decrease to < 12 mmHg
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 Slide 102 DECREASE IN HEPATIC VENOUS PRESSURE GRADIENT (HVPG) REDUCES THE RISK OF VARICEAL BLEEDING Evidence from various randomized clinical trials of secondary prophylaxis of variceal hemorrhage and summarized in this slide confirms that reducing portal pressure results in a decreased risk of variceal hemorrhage. A decrease in HVPG to a level below 12 mmHg essentially eliminates the risk of recurrent variceal hemorrhage, while a reduction of at least 20% from baseline reduces this risk significantly (7-13%) compared to patients who do not achieve this reduction (rebleeding rate of 46-65%). Therefore, a rational goal of therapy of portal hypertension is to achieve a significant reduction in HVPG. Bosch and García-Pagán. Lancet 2003; 361:952 20 7-13% 0% HVPG decrease to < 12 mmHg HVPG decrease > 20% from baseline No change in HVPG Bosch and García-Pagán, Lancet 2003; 361:952

Primary Prophylaxis for Variceal Hemorrhage: Beta Blockers
Non-selective beta-blockers preferred Beta-1 antagonism: reduced cardiac output Beta-2 antagonism: splanchnic vasoconstriction Goal of therapy to reduce portal pressure by 20% or below 12 mm Hg Dose titrated to a resting HR of 55, or a 25% reduction in baseline Initial dose propranolol 40 mg bid, Average dose 160 mg/day Up to 1/3 intolerant to side effects resulting in discontinuation

NON-SELECTIVE BETA-BLOCKERS PREVENT FIRST VARICEAL HEMORRHAGE
Non-Selective Beta-Blockers Prevent First Variceal Hemorrhage: 11 Trials Bleeding rate Control Beta-blocker Absolute rate (~2 year) difference All varices 25% 15% -10% (11 trials) (n=600) (n=590) (-16 to -5) Large varices 30% 14% -16% (8 trials) (n=411) (n=400) (-24 to -8) Small varices 7% 2% -5% (3 trials) (n=100) (n=91) (-11 to 2) Slide 115 NON-SELECTIVE BETA-BLOCKERS PREVENT FIRST VARICEAL HEMORRHAGE A more recent meta-analysis of 11 randomized controlled trials of non-selective beta-adrenergic blockers for primary prophylaxis of variceal hemorrhage shows a significant lower 2-year risk of first variceal hemorrhage in patients treated with beta-blockers (15%) compared to controls (25%), with a greater benefit observed in patients with large varices. Although a small benefit was seen in patients with small varices, it did not reach statistical significance. There was a tendency for a survival benefit in patients treated with beta-blockers but this was not significant. D’Amico et al, Sem Liv Dis 1999; 19:475 D’Amico et al., Sem Liv Dis 1999; 19:475

Primary Prophylaxis against Variceal Hemorrhage.
Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:

Free of a first variceal bleeding
THE RISK OF FIRST VARICEAL HEMORRHAGE IS NOT REDUCED BY ADDING ISOSORBIDE MONONITRATE (ISMN) TO BETA-BLOCKERS The Risk of First Bleeding is Not Reduced by Adding Isosorbide Mononitrate (ISMN) to b-blockers Free of a first variceal bleeding Survival 100 100 ns ns 75 75 % 50 50 Slide 116 THE RISK OF FIRST VARICEAL HEMORRHAGE IS NOT REDUCED BY ADDING ISOSORBIDE MONONITRATE (ISMN) TO BETA-BLOCKERS In a randomized controlled trial, neither the probability of developing first variceal hemorrhage nor the probability of survival were different between patients randomized to combination therapy propranolol +ISMN and those randomized to propanolol + placebo. Patients on combination therapy had a greater rate of side effects. Garcia-Pagan JC, et al. Hepatology 2003; 37:1260 Propranolol + ISMN Propranolol + placebo Propranolol + ISMN Propranolol + placebo 25 25 1 2 1 2 Years Years García-Pagán et al., Hepatology 2003; 37:1260

ENDOSCOPIC VARICEAL BAND LIGATION
Slide 144 ENDOSCOPIC VARICEAL BAND LIGATION Endoscopic variceal ligation consists of the placement of rubber rings on variceal columns with the objective of interrupting blood flow and subsequently developing necrosis of mucosa and submucosa and replacement of varices by scar tissue. Endoscopic therapy is a local therapy that has no effect on the pathophysiologic mechanisms that lead to portal hypertension and variceal rupture. Even though it achieves variceal obliteration, varices will eventually recur. Bleeding is controlled in 90% of cases of acute variceal hemorrhage with a rebleeding rate of 30%. Meta-analysis of trials comparing ligation with sclerotherapy has shown that ligation is associated with lower rebleeding rates, lower number of sessions to achieve variceal obliteration and lower mortality. Complications of endoscopic therapy are related mainly to the development of esophageal ulceration and strictures, significantly more frequent after sclerotherapy than after ligation. Laine and Cook. Ann Intern Med 1995; 123:280

Primary Prophylaxis for Variceal Hemorrhage
3 randomized controlled trials published comparing band ligation to no treatment, showing lower bleeding rates and mortality. Meta-analysis of 8 trial show banding superior to beta blockers but no difference in survival One trial of band ligation and beta blockers: no benefit Prophylactic sclerotherapy definitely of no proven benefit, probably harmful.

VARICEAL BAND LIGATION (VBL) VS
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 First hemorrhage Survival Chen 1998 Sarin 1999 De 1999 Jutabha 2000 De la Mora 2000 Lui 2002 Lo 2004 Schepke 2004 Total Relative risk 1 10 40 Favors VBL Favors BB Favors BB Slide 119 VARICEAL BAND LIGATION (VBL) VS. BETA-BLOCKERS (BB) IN THE PREVENTION OF FIRST VARICEAL HEMORRHAGE In a recent meta-analysis of 8 trials, VBL was shown to be more effective than beta-blockers in the primary prophylaxis of variceal hemorrhage with no differences in survival. However, these trials are small and have a relatively short followup time. The trial with the largest number of patients and the longest followup showed equivalence between both therapies. Khuroo, et al., Aliment Pharmacol Ther 2005; 21: 347 Schepke et al. Hepatology 2004; 40:65 Khuroo, et al., Aliment Pharmacol Ther 2005; 21:347

Prophylaxis of Variceal Hemorrhage
MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARY Prophylaxis of Variceal Hemorrhage Diagnosis of Cirrhosis Endoscopy No Varices Follow-up EGD in 2-3 years* Small Varices Follow-up EGD in 1-2 years* Medium/Large Varices Child’s C or Stigmata Stepwise increase until maximally tolerated dose Continue beta-blocker (life-long) No role for repeated endoscopy!! No Contraindications Contraindications or Beta-blocker intolerance Beta-blocker therapy Endoscopic Variceal Band Ligation *EGD every year in decompensated cirrhosis Slide 135 MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARY No role for sclerotherapy or nitrates

Primary Prophylaxis for Variceal Hemorrhage: Conclusions
Propranolol is the most cost-effective treatment for the prevention of initial variceal bleeding The documented benefits of prophylactic beta blockers may be lost if discontinued due to a rebound in bleeding/ mortality. Life-long beta blocker treatment is therefore indicated Non-compliant patients may be better served by band ligation therapy, although at substantially higher costs ($1425 vs $4284) Hepatology 2001; 34(6):

TREATMENT OF ACUTE VARICEAL HEMORRHAGE
General Management: IV access and fluid resuscitation Antibiotic prophylaxis Correct coagulopathy Do not overtransfuse (hemoglobin ~ 7-8 g/dL) Empiric lactulose? Specific therapy: Pharmacological therapy: octreotide, vasopressin + nitroglycerin Early endoscopic therapy: band ligation Shunt therapy: TIPS, surgical shunt Slide 138 TREATMENT OF ACUTE VARICEAL HEMORRHAGE Treatment of acute variceal hemorrhage includes general and specific therapies. General management includes establishing intravenous access and fluid resuscitation. Vigorous fluid resuscitation and transfusion to hemoglobin levels >8 g/dL should be avoided as this could precipitate early variceal rebleeding. Prophylactic antibiotic therapy should be instituted promptly in any cirrhotic patient with gastrointestinal hemorrhage. Specific therapy includes pharmacological therapy, endoscopic therapy and shunt therapy.

Colomo A. et al , Abstract 232A (AASLD 2008)
Cautious Transfusion Improves Outcome in Cirrhotics with Variceal Hemorrhage 214 cirrhotics with UGIB randomized to restricted (Hgb 7-8 gm) or liberal transfusion (Hgb 9-10 gm) 69% esophageal variceal 7% gastric variceal 15% peptic ulcer % gastropathy Therapeutic failure occurred in 16% of restricted and 28% of liberal group (p<0.04) In subgroup with esophageal variceal bleed, the 6 week survival without therapeutic failure was better in restrictive group (84% vs 69%: p<0.02) 38% in restrictive group required no transfusion vs 9% in liberal group Colomo A. et al , Abstract 232A (AASLD 2008)

Colomo A. et al , Abstract 232A (AASLD 2008)
Cautious Transfusion Improves Outcome in Cirrhotics with Variceal Hemorrhage P= 0.02 P= 0.04 6-week survival in variceal bleeders who did not have therapeutic failure Colomo A. et al , Abstract 232A (AASLD 2008)

Prophylactic Antibiotics Improve Outcomes in Cirrhotic Patients with GI Hemorrhage
The use of prophylactic antibiotics in cirrhotics with GI hemorrhage has been shown by meta-analysis to reduce infection, increase survival, and reduce recurrent hemorrhage (13 prospective trials) Recommended antibiotics include oral norfloxacin, ciprofloxin, ofloacin, and amoxicillin clavulanate, ceftriaxone IV Slide 139 PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE Five randomized controlled trials analyze the effect of prophylactic antibiotics (oral or systemic) in preventing bacterial infections in patients with cirrhosis admitted with gastrointestinal hemorrhage. A meta-analysis of these trials shows that prophylactic antibiotics not only reduce the risk of bacterial infections, including spontaneous bacterial peritonitis and spontaneous bacteremia, but also lead to a significant decrease in mortality. Therefore, the use of antibiotics is considered standard of care in this setting. Bernard B, et al., Hepatology 1999; 29: 1655 Scand J. Gastro 2003;38:

Meta-analysis of 5 randomized trials
PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE Prophylactic Antibiotics Improve Outcomes in Cirrhotic Patients with GI Hemorrhage Control Antibiotic Absolute rate (n=270) (n=264) 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) Slide 139 PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE Five randomized controlled trials analyze the effect of prophylactic antibiotics (oral or systemic) in preventing bacterial infections in patients with cirrhosis admitted with gastrointestinal hemorrhage. A meta-analysis of these trials shows that prophylactic antibiotics not only reduce the risk of bacterial infections, including spontaneous bacterial peritonitis and spontaneous bacteremia, but also lead to a significant decrease in mortality. Therefore, the use of antibiotics is considered standard of care in this setting. Bernard B, et al., Hepatology 1999; 29: 1655 Meta-analysis of 5 randomized trials Bernard et al., Hepatology 1999; 29:1655

PROPHYLACTIC ANTIBIOTICS PREVENT EARLY VARICEAL REBLEEDING
Prophylactic Antibiotics Reduce Probability of Recurrent Variceal Hemorrhage 1.0 Prophylactic antibiotics (n=59) 0.8 No antibiotics (n=61) 0.6 % free of variceal hemorrhage 0.4 Slide 140 PROPHYLACTIC ANTIBIOTICS PREVENT EARLY VARICEAL REBLEEDING In a randomized controlled trial, patients randomized to prophylactic antibiotics had a significantly lower probability of developing early variceal rebleeding compared to patients who were randomized to on-demand antibiotics (that is, antibiotics given only in the presence of infection). Hou MC, et al., Hepatology 2004; 39: 746 Greatest benefit in first 7 days 0.2 1 2 3 12 18 24 30 Follow-up (months) Ofloxacin 200 mg iv q12 hr for 2 days, then oral 200 bid for 5 days Hou M-C et al., Hepatology 2004; 39:746

Phamacologic Treatment for Acute Variceal Hemorrhage
Octreotide: 50 microgram bolus and mcg/hr for up to 5 days (range 2-5 days) Vasopressin: Too dangerous for empiric initial therapy Contiunuous infusion U/min up to 1.0 U/min Recommended only in combination with i.v. TNG: mcg/min Titrate TNG infusion to maintain systolic BP >90 mmHg Continuous vasopressin> 24 hr not recommended

Prophylaxis of HSE in Acute Variceal Bleed
Lactulose 30 mL TID_QID until pts had non-melenic stools and then the dose was reduced so that patients had two to three semiformed stools per day

PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE
Endoscopic Therapy Now Standard in the Management of Variceal Hemorrhage Slide 139 PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE Five randomized controlled trials analyze the effect of prophylactic antibiotics (oral or systemic) in preventing bacterial infections in patients with cirrhosis admitted with gastrointestinal hemorrhage. A meta-analysis of these trials shows that prophylactic antibiotics not only reduce the risk of bacterial infections, including spontaneous bacterial peritonitis and spontaneous bacteremia, but also lead to a significant decrease in mortality. Therefore, the use of antibiotics is considered standard of care in this setting. Bernard B, et al., Hepatology 1999; 29: 1655

Non-Pharmacologic Treatment of Acute Variceal Hemorrhage
Endoscopic Band Ligation Transjugular Intrahepatic Portal-systemic Shunting (TIPS) Mostly Historical Interest Sengstaken-Blakemore Tube Embolization of varices Portacaval shunt surgery Injection Sclerotherapy

ENDOSCOPIC VARICEAL BAND LIGATION
Bleeding controlled in 90% Rebleeding rate 30% Compared with sclerotherapy: Less rebleeding Lower mortality Fewer complications Fewer treatment sessions Slide 144 ENDOSCOPIC VARICEAL BAND LIGATION Endoscopic variceal ligation consists of the placement of rubber rings on variceal columns with the objective of interrupting blood flow and subsequently developing necrosis of mucosa and submucosa and replacement of varices by scar tissue. Endoscopic therapy is a local therapy that has no effect on the pathophysiologic mechanisms that lead to portal hypertension and variceal rupture. Even though it achieves variceal obliteration, varices will eventually recur. Bleeding is controlled in 90% of cases of acute variceal hemorrhage with a rebleeding rate of 30%. Meta-analysis of trials comparing ligation with sclerotherapy has shown that ligation is associated with lower rebleeding rates, lower number of sessions to achieve variceal obliteration and lower mortality. Complications of endoscopic therapy are related mainly to the development of esophageal ulceration and strictures, significantly more frequent after sclerotherapy than after ligation. Laine and Cook. Ann Intern Med 1995; 123:280

Erythromycin improves visibility during endoscopy for variceal bleeding
Study involved 90 patients with cirrhosis who had been vomiting blood due to variceal bleeding during the previous 12 hours. The 47 patients randomized to the intervention group received an intravenous bolus infusion of 125 mg erythromycin lactobionate in 50 mL normal saline. The other 43 patients received only the saline. (All patients also received octreotide, esmoprazole, and ceftriaxone.) Gastrointest Endosc 2010.

Erythromycin improves visibility during endoscopy for variceal bleeding
On multivariate analysis, erythromycin was the only predictor of an empty stomach. As a result, the average time needed for endoscopy was also shorter after erythromycin (19 vs 26 min, p < 0.005). Physicians found that with erythromycin, they could control bleeding by band ligation more often (70% vs 49%, p < 0.04) and that hospital stays were shorter (3.4 vs 5.1 days, p < 0.002). Gastrointest Endosc 2010.

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 Slide 143 COMBINATION DRUG/ENDOSCOPIC THERAPY IS MORE EFFECTIVE THAN ENDOSCOPIC THERAPY ALONE A meta-analysis of 8 trials comparing endoscopic therapy (sclerotherapy or band ligation) vs. endoscopic therapy + vasoactive drugs (somatostatin, octreotide, vapreotide) shows that combination therapy was better than endoscopic therapy alone in the initial control of bleeding and in achieving 5-day hemostasis. However, there were no differences in survival. Bañares R, et al., Hepatology 2002; 35: 609 Relative Risk 0.8 1 1.2 1.4 1.6 1.8 2 Favors endoscopic therapy alone Favors endoscopic plus drug therapy No Mortality Difference Bañares R et al., Hepatology 2002; 35:609

THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT
vein TIPS Slide 147 THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT Portal hypertension can be corrected by creating a communication between the hypertensive portal system and low-pressure systemic veins, bypassing the liver, i.e., the site of increased resistance. This communication can be created surgically or by the transjugular placement of an intrahepatic stent that connects a branch of the portal vein with a branch of an hepatic vein, a procedure designated transjugular intrahepatic porto-systemic shunt (TIPS). TIPS is performed by advancing a catheter introduced through the jugular vein into a hepatic vein and into a main branch of the portal vein. An expandable stent is then introduced connecting hepatic and portal systems, and blood from the hypertensive portal vein and sinusoidal bed is shunted to the hepatic vein. The procedure is highly effective in correcting portal hypertension but can be associated with complications related to diversion of blood flow away from the liver, namely portal-systemic encephalopathy and liver failure. Splenic vein Portal vein Superior mesenteric vein

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 (10-20%) In patients with Child A/B cirrhosis, the distal spleno-renal shunt is as effective as TIPS (dependent on local expertise) Slide 149 TIPS IN THE TREATMENT OF VARICEAL HEMORRHAGE Given the complications associated to TIPS, its high obstruction rate and its elevated cost, TIPS has been relegated to a secondary position in the treatment of variceal bleeding. In the acute setting, it is used as rescue therapy after failure of two endoscopic therapy sessions. In the chronic setting, it is used in patients whose bleeding recurs despite combination endoscopic/pharmacological therapy. In patients with Child A/B cirrhosis, shunt surgery is an alternative to TIPS. Henderson et al. Hepatology 2004; 40 (Suppl. 1):725A

116 cirrhotics with acute variceal bleed
Early TIPS In Patients With Acute Variceal Hemorrhage and HVPG > 20 mmHg (High Risk) May Improve Survival 116 cirrhotics with acute variceal bleed Urgent assessment of wedged hepatic vein pressure 64 HVPG < 20 mmHg: routine therapy 52 HVPG > 20 mmHg randomized to TIPS vs routine therapy Early TIPS in patients with HVPG>20 associated with reduced transfusion, rebleed, in-hospital and 1 year mortality Monescillo et al., Hepatology 2004; 40:793

Probability of survival
EARLY TIPS IN PATIENTS WITH ACUTE VARICEAL HEMORRHAGE AND HVPG > 20 mmHg MAY IMPROVE SURVIVAL Early TIPS In Patients With Acute Variceal Hemorrhage and HVPG > 20 mmHg (High Risk) May Improve Survival 1 HVPG <20 0.8 0.6 HVPG >20 - TIPS Probability of survival 0.4 Slide 150 EARLY TIPS IN PATIENTS WITH ACUTE VARICEAL HEMORRHAGE AND HVPG > 20 mmHg MAY IMPROVE SURVIVAL In a small randomized study, patients with acute variceal hemorrhage and an HVPG >20 mmHg (predictive of a poor outcome) were randomized to placement of TIPS within 24 hours of the bleeding episode vs. standard therapy. It demonstrates a significantly better survival in patients randomized to TIPS. While these results are interesting and confirm the predictive value of an HVPG >20 mmHg in this setting, this strategy cannot be widely recommended. Monescillo A, et al., Hepatology 2004; 40:793 HVPG >20 – No TIPS 0.2 3 6 9 12 Months Monescillo et al., Hepatology 2004; 40:793

Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding
63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy Randomized to treatment with a polytetrafluoroethylene-covered stent within 72 hours after randomization (early-TIPS group, 32 patients) Vs continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapy–EBL group, 31 patients). García-Pagán JC et al. N Engl J Med 2010;362:

Figure 1. Screening and Randomization of Patients. EBL denotes endoscopic band ligation, and TIPS transjugular intrahepatic portosystemic shunt. García-Pagán JC et al. N Engl J Med 2010;362:

During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapy–EBL group as compared with 1 patient in the early-TIPS group (P=0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapy–EBL group versus 97% in the early-TIPS group (P<0.001). Sixteen patients died (12 in the pharmacotherapy–EBL group and 4 in the early-TIPS group, P=0.01). The 1-year actuarial survival was 61% in the pharmacotherapy–EBL group versus 86% in the early-TIPS group (P<0.001) García-Pagán JC et al. N Engl J Med 2010;362:

Actuarial Probability of the Primary Composite End Point and of Survival, According to Treatment Group. Figure 2. Actuarial Probability of the Primary Composite End Point and of Survival, According to Treatment Group. The probability of remaining free from uncontrolled variceal bleeding or variceal rebleeding is shown in Panel A, and the probability of survival is shown in Panel B. EBL denotes endoscopic band ligation, and TIPS transjugular intrahepatic portosystemic shunt. No significant differences were observed between the two treatment groups with respect to serious adverse events. García-Pagán JC et al. N Engl J Med 2010;362:

MANAGEMENT ALGORITHM IN ACUTE ESOPHAGEAL VARICEAL HEMORRHAGE
Management of Acute Variceal Hemorrhage MANAGEMENT ALGORITHM IN ACUTE ESOPHAGEAL VARICEAL HEMORRHAGE Variceal Hemorrhage Suspected Initial Management NO Rescue TIPS/Shunt surgery Balloon Tamponade YES Early rebleeding? Acute Hemorrhage Controlled? 2nd Endoscopy Further bleeding Prophylaxis against recurrent hemorrhage Slide 158 MANAGEMENT ALGORITHM IN ACUTE ESOPHAGEAL VARICEAL HEMORRHAGE

*  HVPG <12 mmHg or >20% from baseline
Lowest Rebleeding Rates are Obtained in HVPG Responders and With Ligation + -Blockers LOWEST REBLEEDING RATES ARE OBTAINED IN HVPG RESPONDERS AND IN PATIENTS TREATED WITH VARICEAL BAND LIGATION + BETA-BLOCKERS 80 60 % 40 Rebleeding 20 Slide 161 LOWEST REBLEEDING RATES ARE OBTAINED IN HVPG RESPONDERS AND IN PATIENTS TREATED WITH VARICEAL BAND LIGATION + BETA-BLOCKERS In addition to HVPG responders (i.e. patients who achieve a reduction in hepatic venous pressure gradient below 12 mmHg or >20% from baseline) in whom the rebleeding rate is around 10%, two trials comparing the combination of ligation + beta-blockers vs. ligation alone, show that combination therapy is more effective, with rebleeding rates of 14 and 23%, respectively. These therapies are placed in the context of no therapy (red bar) and other less effective therapies (orange bars). Bosch J, and Garcia-Pagan JC, Lancet 2003; 361; 952 Lo GH, et al., Hepatology 2000; 32: 461 De la Pena J, et al., Hepatology 2005; 41: 572 Untreated -blockers Sclero- therapy  -blockers + ISMN Ligation HVPG-Responders* Ligation + -blockers (19 trials) (26 trials) (54 trials) (6 trials) (18 trials) (6 trials) (2 trials) Bosch and García-Pagán, Lancet 2003; 361:952 *  HVPG <12 mmHg or >20% from baseline

Prophylaxis of Recurrent Variceal Hemorrhage
MANAGEMENT ALGORITHM FOR THE PREVENTION OF RECURRENT VARICEAL HEMORRHAGE Prophylaxis of Recurrent Variceal Hemorrhage Control of Acute Variceal Hemorrhage Prophylactic Pharmacotherapy and/or Endoscopic Variceal Band Ligation Recurrent Hemorrhage NO YES Slide 176 MANAGEMENT ALGORITHM FOR THE PREVENTION OF RECURRENT VARICEAL HEMORRHAGE Surveillance Endoscopy and/or Life-long Pharmacotherapy Is patient on EVL + Pharmacotherapy? NO YES Initiate combination Rx TIPS/Shunt Surgery Further bleeding

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 Slide 180 SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL HEMORRHAGE 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

Gastric Varices 10-15% of variceal bleeding episodes
Limited data from controlled trials Optimal therapy not known Vasoactive drugs used, but not studied Endoscopic cyanoacrylate injection: 90% control of bleeding Balloon tamponade with Linton-Nachlas tube TIPS: 90% control of bleeding Slide 182 GASTRIC VARICES Gastric varices account for 10-15% of variceal bleeding episodes. Because of limited data from controlled trials, optimal therapy is not known. Vasoactive drugs have been used, but not studied. Endoscopic cyanoacrylate obturation of the varices can result in control of up to 90% of patients. A Linton Nachlas tube, which has a gastric balloon of volume 600 mL, may be used for variceal tamponade. TIPS can result in control of bleeding in over 90 percent of patients.

CLASSIFICATION OF GASTRIC VARICES
GOV 2 GOV 1 IGV 1 Slide 181 CLASSIFICATION OF GASTRIC VARICES Gastric varices are those that extend from the esophagus into the stomach. They can be subclassified into 2 groups: gastroesophageal varices (GOV, gastric varices that are continuous with esophageal varices) and isolated gastric varices (IGV, gastric varices that occur in the absence of esophageal varices). GOV are in turn classified in GOV1 in which varices extend along the lesser curve for about 2–5 cm below the gastroesophageal junction; and GOV2 which are often long and tortuous and extending from the esophagus below the gastroesophageal junction toward the fundus. IGV are also subclassified into IGV1, varices located in the fundus that often are tortuous and complex in shape; and IGV2, ectopic varices in the antrum, corpus, and around the pylorus. For the purposes of some studies duodenal varices also have been included in this group. IGV 2 Sarin et al, Am J Gastro 1989; 84:1244

MANAGEMENT ALGORITHM FOR PATIENTS BLEEDING FROM GASTRIC VARICES
Management of Acute Gastric (Fundal) Variceal Bleeding Variceal Hemorrhage Suspected Transfuse to hemoglobin ~8 g/dL Early pharmacotherapy Antibiotic prophylaxis Initial Management Variceal obturation possible? NO YES Bleeding controlled? Slide 188 MANAGEMENT ALGORITHM FOR PATIENTS BLEEDING FROM GASTRIC VARICES In patients with acute gastric variceal bleeding, initial management consists of transfusion to a hemoglobin of 8 g/dL, pharmacotherapy with vasoactive agents, and antibiotic prophylaxis. Endoscopic treatment is carried out but, if acute hemorrhage is not controlled, TIPS is recommended. If the acute hemorrhage is controlled, and cyanoacrylate is available, obliteration of the gastric varices is attempted with cyanoacrylate. If cyanoacrylate is not available, then TIPS is recommended. A surgical shunt may be considered in patients with Child-Pugh class A cirrhosis. NO YES TIPS* Variceal obliteration +beta-blockers Not possible or rebleed *Surgical shunt may be considered for Child’s Class A

MANAGEMENT OF GASTRIC VARICES
Gastric varices that are continuous with esophageal varices and extend along the lesser curve (GOV1) should be treated in the same way as esophageal varices In patients with isolated fundal varices (IGV1), splenic vein thrombosis should be investigated. If present, treatment consists of splenectomy Cirrhotic patients bleeding from gastric fundal varices require specific treatment Slide 183 MANAGEMENT OF GASTRIC VARICES Gastric varices that are continuous with esophageal varices and extend along the lesser curvature of the stomach (GOV1) should be treated in the same way outlined for esophageal varices. In patients with isolated fundal varices, particularly in non-cirrhotic patients, the presence of splenic vein thrombosis should be investigated and, if present, treatment consists of splenectomy. Cirrhotic patients bleeding from gastric fundal varices require specific treatment which is different than that outlined for bleeding esophageal varices.

ENDOSCOPIC IMAGES OF GASTRIC VARICES
Slide 189 ENDOSCOPIC IMAGES OF GASTRIC VARICES The arrow on the panel on the left shows an actively bleeding gastric varix. The panel on the right shows the varix after treatment with cyanoacrylate. Pretreatment cyanoacrylate Post-treatment cyanoacrylate

PORTAL HYPERTENSIVE GASTROPATHY
Endoscopic changes seen in most patients with portal hypertension Characterized by a cobblestone appearance of the mucosa and red signs on endoscopy Often confused with: Gastric Antral Vascular Estasia (GAVE) Watermelon Stomach May be associated with chronic occult bleeding, anemia, and occasionally cause of acute UGI hemorrhage Slide 190 PORTAL HYPERTENSIVE GASTROPATHY Portal hypertensive gastropathy (PHG) is characterized endoscopically by a mosaic pattern with red signs. Changes can also be seen in the small intestine and colon, especially the right colon. PHG is a cause of chronic blood loss in cirrhotic patients, but can be a source of acute bleeding.

SEVERE PORTAL HYPERTENSIVE GASTROPATHY MAY BE DIFFICULT TO DISTINGUISH FROM DIFFUSE GAVE
Slide 201 SEVERE PORTAL HYPERTENSIVE GASTROPATHY MAY BE DIFFICULT TO DISTINGUISH FROM DIFFUSE GAVE This slide shows the difference between severe portal hypertensive gastropathy (left panel) and diffuse gastric antral vascular ectasia (GAVE, right panel). Note the mosaic pattern with severe PHG, but absence of a mosaic pattern in GAVE. Severe PHG Diffuse GAVE

ENDOSCOPIC IMAGES OF THE TWO TYPES OF GASTRIC ANTRAL VASCULAR ECTASIA
Slide 200 ENDOSCOPIC IMAGES OF THE TWO TYPES OF GASTRIC ANTRAL VASCULAR ECTASIA The panel on the left shows a typical watermelon stomach with linear aggregates of red signs without a background mosaic pattern. The panel on the right shows a diffuse variety of vascular ectasia with red signs in the absence of a background mosaic pattern. Typical GAVE “watermelon stomach” Diffuse GAVE

GASTRIC ANTRAL VASCULAR ECTASIA
Gastric Antral Vascular Ectasia (GAVE) Endoscopic findings: Red spots without background mosaic pattern Linear aggregates in antrum: “watermelon stomach” Diffuse lesions in proximal and distal stomach May be difficult to differentiate from portal hypertensive gastropathy (PHG) Ideal therapy not known Slide 198 GASTRIC ANTRAL VASCULAR ECTASIA Gastric antral vascular ectasia (GAVE) is less commonly seen than portal hypertensive gastropathy. It is characterized by red spots without a background mosaic pattern. The lesions are typically in the antrum. If there are aggregates in the antrum with a linear distribution, the term “watermelon stomach” is used. Lesions can be more diffuse and can also be seen in the proximal stomach. GAVE may occur in the absence of portal hypertension, is difficult to differentiate from PHG, and ideal therapy is not known.

Argon Plasma Coagulation for GAVE

Band Ligation for GAVE

VARICEAL WALL TENSION IS A MAJOR DETERMINANT OF VARICEAL RUPTURE
Variceal Wall Tension (T) is a Major Determinant of Variceal Rupture Esophagus Wall thickness (w) Radius (r) Transmural pressure (tp) Varix Slide 99 VARICEAL WALL TENSION IS A MAJOR DETERMINANT OF VARICEAL RUPTURE Rupture of a vessel occurs when the expanding force exceeds its maximal wall tension. The higher the tension, the greater the possibility of rupture. Tension in the varix (T) is directly proportional to transmural pressure (difference between the intravariceal and the intraluminal esophageal pressure) and to variceal radius (r) and is inversely proportional to variceal wall thickness. A large varix has a large radius and a thin wall and therefore a larger tension and a greater propensity to rupture. Groszmann RJ. Gastroenterology 1984; 80:1611 Tension (T) T = tp x r w Groszmann, Gastroenterology 1984; 80:1611

Treatment of Varices / Variceal Hemorrhage Prevent Formation of Varices ? No varices Varices No hemorrhage Prevent First Variceal Hemorrhage Control Bleeding: Reduce Mortality Variceal hemorrhage Slide 112 MANAGEMENT OF PATIENTS WITHOUT VARICES In cirrhotic patients who have not yet developed varices, no specific therapy is recommended. However, a surveillance endoscopy should be performed every 2-3 years in compensated cirrhosis and annually in decompensated cirrhosis. Prevent Recurrent Hemorrhage Recurrent hemorrhage

Endoscopic Findings Which is the best option? Start atenolol
Start propranolol Variceal band ligation Propranol and isosorbide mononitrate Band ligation and beta blockers

Bleeding controlled with band ligation, antibiotics an octreotide
No bleeding for 5 days Child score 10. MELD 15 MAP 90 mmHg Which is the best discharge regiment? 1) Beta blockers and nitrates 2) Serial ligation alone 3) Ligation and beta blockers 4) TIPS 5) Portacaval shunt

Prevention of Recurrent Bleeding TIPS vs. Drug Therapy
91 Childs-Pugh class B/C cirrhotic patients who survived first variceal hemorrhage Randomized to TIPS(47) vs propranolol plus isosorbide-5-mononitrate(44) Followed for 2 years Assess hepatic encephalopathy, recurrent variceal hemorrhage, costs, number of medical interventions, and survival Hepatology 2002;35:385-92

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