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

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Presentation on theme: "Prevention and Management of Esophageal Variceal and Portal Hypertensive Hemorrhage Thomas Hargrave, M.D. March 24, 2012 Thomas Hargrave, M.D. March 24,"— Presentation transcript:

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

2 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  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

3 Prevalence and Size of Esophageal Varices in Patients with Newly-Diagnosed Cirrhosis % Patients with varices % Patients with varices Overall n=494 Overall n=494 Child A n=346 Child A n=346 Child B n=114 Child B n= Child C n=34 Child C n=34 Large Medium Small Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72 PREVALENCE AND SIZE OF ESOPHAGEAL VARICES IN PATIENTS WITH NEWLY DIAGNOSED CIRRHOSIS

4 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%.  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%.

5 Portal Venous Anatomy Pathophysiology

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7 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  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

8 Hepatic Lobular Anatomy

9 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.  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.

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

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12 Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:

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14 A Threshold Portal Pressure of ~12 mmHg is Necessary for Esophageal Varices to Form P< Hepatic Venous Pressure Gradient (mmHg) Hepatic Venous Pressure Gradient (mmHg) Garcia-Tsao et. al., Hepatology 1985; 5:419 Varices Present (n=72) Varices Present (n=72) Varices Absent (n=15) Varices Absent (n=15) A THRESHOLD PORTAL PRESSURE OF ~12 mmHg IS NECESSARY FOR VARICES TO FORM

15 Venous Layers of the Esophagus

16 Small varices Large varices No varices 7-8%/year Varices Increase in Diameter Progressively Merli et al. J Hepatol 2003;38:266 VARICES INCREASE IN DIAMETER PROGRESSIVELY

17 Grade II Varices Grade III Varices

18 Large Varices Are More Likely To Rupture % Patients without bleeding % Patients without bleeding Large Varices * * p<0.01 * 2-year probability of first bleed:  Small varices: 7%  Large varices: 30% 2-year probability of first bleed:  Small varices: 7%  Large varices: 30% Time (months) No Varices Small Varices * Merli et al., Hepatol 2003; 38:266, ** Conn et al., Hepatology 1991; 13:902 LARGE VARICES ARE MORE LIKELY TO RUPTURE

19 Varix with red wale sign Variceal hemorrhage Punctum

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

21 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.  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.

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23 Treatment of Varices / Variceal Hemorrhage No varices Varices No hemorrhage Varices No hemorrhage Variceal hemorrhage Variceal hemorrhage Recurrent hemorrhage Recurrent hemorrhage Can we prevent formation of varices ? MANAGEMENT OF PATIENTS WITHOUT VARICES

24 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  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 Groszmann, et al., Hepatology 2003;38 (suppl 1):206A NON-SELECTIVE BETA BLOCKERS DO NOT PREVENT DEVELOPMENT OF VARICES

25 Treatment of Varices / Variceal Hemorrhage No varices Varices No hemorrhage Varices No hemorrhage Variceal hemorrhage Variceal hemorrhage Recurrent hemorrhage Recurrent hemorrhage No specific therapy Repeat endoscopy in 2-3 yrs* No specific therapy Repeat endoscopy in 2-3 yrs* * Sooner with cirrhosis decompensation MANAGEMENT OF PATIENTS WITHOUT VARICES

26 Treatment of Varices / Variceal Hemorrhage No varices Varices No hemorrhage Varices No hemorrhage Variceal hemorrhage Variceal hemorrhage Recurrent hemorrhage Recurrent hemorrhage Prevention of first variceal hemorrhage PREVENTION OF FIRST VARICEAL HEMORRHAGE

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

28 % Rebleeding % Rebleeding Decrease In Hepatic Venous Pressure Gradient (HVPG) Reduces Risk of Variceal Bleeding HVPG decrease > 20% from baseline HVPG decrease > 20% from baseline HVPG decrease to < 12 mmHg 0% 46-65% 7-13% No change in HVPG No change in HVPG Bosch and García-Pagán, Lancet 2003; 361:952 DECREASE IN HEPATIC VENOUS PRESSURE GRADIENT (HVPG) REDUCES THE RISK OF VARICEAL BLEEDING

29 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 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

30 Non-Selective Beta-Blockers Prevent First Variceal Hemorrhage: 11 Trials Bleeding rateControlBeta-blockerAbsolute rate (~2 year) difference All varices25%15%-10% (11 trials)(n=600)(n=590)(-16 to -5) Large varices30% 14% -16% (8 trials)(n=411)(n=400) (-24 to -8) Small varices7%2%-5% (3 trials)(n=100)(n=91)(-11 to 2) Bleeding rateControlBeta-blockerAbsolute rate (~2 year) difference All varices25%15%-10% (11 trials)(n=600)(n=590)(-16 to -5) Large varices30% 14% -16% (8 trials)(n=411)(n=400) (-24 to -8) Small varices7%2%-5% (3 trials)(n=100)(n=91)(-11 to 2) D’Amico et al., Sem Liv Dis 1999; 19:475 NON-SELECTIVE BETA-BLOCKERS PREVENT FIRST VARICEAL HEMORRHAGE

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

32 García-Pagán et al., Hepatology 2003; 37:1260 The Risk of First Bleeding is Not Reduced by Adding Isosorbide Mononitrate (ISMN) to  -blockers % % Years Years 2 2 ns Free of a first variceal bleeding Survival Propranolol + ISMN Propranolol + placebo Propranolol + ISMN Propranolol + placebo THE RISK OF FIRST VARICEAL HEMORRHAGE IS NOT REDUCED BY ADDING ISOSORBIDE MONONITRATE (ISMN) TO BETA-BLOCKERS

33 Endoscopic Variceal Band Ligation ENDOSCOPIC VARICEAL BAND LIGATION

34 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.  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.

35 Variceal Band Ligation (VBL) vs. Beta-Blockers (BB) in the Prevention of First Variceal Bleed Khuroo, et al., Aliment Pharmacol Ther 2005; 21:347 First hemorrhage Survival Chen 1998 Sarin 1999 De 1999 Jutabha2000 De la Mora 2000 Lui 2002 Lo 2004 Schepke 2004 Total Chen 1998 Sarin 1999 De 1999 Jutabha2000 De la Mora 2000 Lui 2002 Lo 2004 Schepke 2004 Total Relative risk Favors VBL Favors BB VARICEAL BAND LIGATION (VBL) VS. BETA-BLOCKERS (BB) IN THE PREVENTION OF FIRST VARICEAL HEMORRHAGE

36 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 Medium/Large Varices Child’s C or Stigmata Stepwise increase until maximally tolerated dose Continue beta-blocker (life-long) No role for repeated endoscopy!! Stepwise increase until maximally tolerated dose Continue beta-blocker (life-long) No role for repeated endoscopy!! No Contraindications Contraindications or Beta-blocker intolerance Contraindications or Beta-blocker intolerance Beta-blocker therapy Endoscopic Variceal Band Ligation *EGD every year in decompensated cirrhosis MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARY No role for sclerotherapy or nitrates

37 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)  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):

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

39 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 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 TREATMENT OF ACUTE VARICEAL HEMORRHAGE

40 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 3% 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  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 3% 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)

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

42 Prophylactic Antibiotics Improve Outcomes in Cirrhotic Patients with GI Hemorrhage 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  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 Scand J. Gastro 2003;38:

43 Prophylactic Antibiotics Improve Outcomes in Cirrhotic Patients with GI Hemorrhage ControlAntibioticAbsolute rate (n=270)(n=264) difference (95% CI) Infection45%14%-32% (-42 to –23) SBP / Bacteremia27%8%-18% (-26 to –11) Death24%15%-9% (-15 to –3) ControlAntibioticAbsolute rate (n=270)(n=264) difference (95% CI) Infection45%14%-32% (-42 to –23) SBP / Bacteremia27%8%-18% (-26 to –11) Death24%15%-9% (-15 to –3) Bernard et al., Hepatology 1999; 29:1655 PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE Meta-analysis of 5 randomized trials

44 Prophylactic Antibiotics Reduce Probability of Recurrent Variceal Hemorrhage Hou M-C et al., Hepatology 2004; 39:746 Prophylactic antibiotics (n=59) % free of variceal hemorrhage % free of variceal hemorrhage No antibiotics (n=61) Follow-up (months) PROPHYLACTIC ANTIBIOTICS PREVENT EARLY VARICEAL REBLEEDING Ofloxacin 200 mg iv q12 hr for 2 days, then oral 200 bid for 5 days Greatest benefit in first 7 days

45 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  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

46 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 Prophylaxis of HSE in Acute Variceal Bleed

47 Endoscopic Therapy Now Standard in the Management of Variceal Hemorrhage PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE

48 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 Band Ligation  Transjugular Intrahepatic Portal- systemic Shunting (TIPS)  Mostly Historical Interest  Sengstaken-Blakemore Tube  Embolization of varices  Portacaval shunt surgery  Injection Sclerotherapy

49 Endoscopic Variceal Band Ligation  Bleeding controlled in 90%  Rebleeding rate 30%  Compared with sclerotherapy:  Less rebleeding  Lower mortality  Fewer complications  Fewer treatment sessions  Bleeding controlled in 90%  Rebleeding rate 30%  Compared with sclerotherapy:  Less rebleeding  Lower mortality  Fewer complications  Fewer treatment sessions ENDOSCOPIC VARICEAL BAND LIGATION

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51 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.)  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.

52 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).  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.

53 Bañares R et al., Hepatology 2002; 35:609 Combination Drug / Endoscopic Therapy is More Effective Than Endoscopic Therapy Alone in Achieving Five-Day Hemostasis Sclero + OctreotideBesson, 1995 Ligation + Octreotide Sung, 1995 Sclero + Octreotide / STSignorelli, 1996 Sclero + Octreotide Ceriani, 1997 Sclero + Octreotide Signorelli, 1997 Sclero + STAvgerinos, 1997 Sclero + Octreotide Zuberi, 2000 Sclero / ligation + VapreotideCales, 2001 TOTAL Sclero + OctreotideBesson, 1995 Ligation + Octreotide Sung, 1995 Sclero + Octreotide / STSignorelli, 1996 Sclero + Octreotide Ceriani, 1997 Sclero + Octreotide Signorelli, 1997 Sclero + STAvgerinos, 1997 Sclero + Octreotide Zuberi, 2000 Sclero / ligation + VapreotideCales, 2001 TOTAL Favors endoscopic therapy alone Favors endoscopic plus drug therapy Relative Risk COMBINATION DRUG/ENDOSCOPIC THERAPY IS MORE EFFECTIVE THAN ENDOSCOPIC THERAPY ALONE No Mortality Difference

54 Transjugular Intrahepatic Portosystemic Shunt Hepatic vein Hepatic vein Portal vein Splenic vein Splenic vein Superior mesenteric vein TIPS THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT

55 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)  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) TIPS IN THE TREATMENT OF VARICEAL HEMORRHAGE

56  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  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 Early TIPS In Patients With Acute Variceal Hemorrhage and HVPG > 20 mmHg (High Risk) May Improve Survival Monescillo et al., Hepatology 2004; 40:793

57 Early TIPS In Patients With Acute Variceal Hemorrhage and HVPG > 20 mmHg (High Risk) May Improve Survival HVPG <20 HVPG >20 - TIPS HVPG >20 – No TIPS Probability of survival Monescillo et al., Hepatology 2004; 40:793 Months EARLY TIPS IN PATIENTS WITH ACUTE VARICEAL HEMORRHAGE AND HVPG > 20 mmHg MAY IMPROVE SURVIVAL

58 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).  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:

59 Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding

60  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)  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) Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding García-Pagán JC et al. N Engl J Med 2010;362:

61 Actuarial Probability of the Primary Composite End Point and of Survival, According to Treatment Group. García-Pagán JC et al. N Engl J Med 2010;362: No significant differences were observed between the two treatment groups with respect to serious adverse events.

62 Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding

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

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

65 Lowest Rebleeding Rates are Obtained in HVPG Responders and With Ligation +  -Blockers (19 trials) (26 trials) (54 trials) % % Rebleeding Untreated  -blockers Sclero- therapy Sclero- therapy (18 trials) Ligation (6 trials) HVPG- Responders* (6 trials)  -blockers + ISMN  -blockers + ISMN (2 trials) Ligation +  -blockers Ligation +  -blockers Bosch and García-Pagán, Lancet 2003; 361:952 *  HVPG 20% from baseline LOWEST REBLEEDING RATES ARE OBTAINED IN HVPG RESPONDERS AND IN PATIENTS TREATED WITH VARICEAL BAND LIGATION + BETA-BLOCKERS

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

67 Evolution of Varices Level of Intervention Management Recommendations Cirrhosis with no varices Small varices No hemorrhage Small varices No hemorrhage Medium / large varices No hemorrhage Medium / large varices No hemorrhage Variceal hemorrhage Recurrent variceal hemorrhage Pre-primary prophylaxis Primary prophylaxis Secondary prophylaxis  Repeat endoscopy in 2-3 years  No specific therapy  Repeat endoscopy in 2-3 years  No specific therapy 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 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  Endoscopic/pharmacologic therapy  Antibiotics in all patients  TIPS or shunt surgery as rescue therapy  Endoscopic/pharmacologic therapy  Antibiotics in all patients  TIPS or shunt surgery as rescue therapy  Beta-blockers + nitrates or EVL  Beta-blockers + EVL ?  TIPS or shunt surgery as rescue therapy  Beta-blockers + nitrates or EVL  Beta-blockers + EVL ?  TIPS or shunt surgery as rescue therapy SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL HEMORRHAGE

68

69 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  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 GASTRIC VARICES

70 Classification of Gastric Varices GOV 1 GOV 2 IGV 1 IGV 2 Sarin et al, Am J Gastro 1989; 84:1244 CLASSIFICATION OF GASTRIC VARICES

71 TIPS* Variceal Hemorrhage Suspected Initial Management NO Bleeding controlled? Variceal obturation possible? Variceal obliteration +beta-blockers YES Management of Acute Gastric (Fundal) Variceal Bleeding Not possible or rebleed NO *Surgical shunt may be considered for Child’s Class A Transfuse to hemoglobin ~8 g/dL Early pharmacotherapy Antibiotic prophylaxis MANAGEMENT ALGORITHM FOR PATIENTS BLEEDING FROM GASTRIC VARICES

72 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  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 MANAGEMENT OF GASTRIC VARICES

73 Gastric Varices Pretreatment cyanoacrylate Post-treatment cyanoacrylate ENDOSCOPIC IMAGES OF GASTRIC VARICES

74 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  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 PORTAL HYPERTENSIVE GASTROPATHY

75 Diffuse GAVE Severe Severe Portal Hypertensive Gastropathy May be Difficult to Distinguish from Diffuse GAVE Severe PHG SEVERE PORTAL HYPERTENSIVE GASTROPATHY MAY BE DIFFICULT TO DISTINGUISH FROM DIFFUSE GAVE

76 Typical GAVE “watermelon stomach” Types of Gastric Antral Vascular Ectasia Diffuse GAVE ENDOSCOPIC IMAGES OF THE TWO TYPES OF GASTRIC ANTRAL VASCULAR ECTASIA

77  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  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 Gastric Antral Vascular Ectasia (GAVE) GASTRIC ANTRAL VASCULAR ECTASIA

78 Argon Plasma Coagulation for GAVE

79 Band Ligation for GAVE

80 Tension (T) Wall thickness (w) Groszmann, Gastroenterology 1984; 80:1611 T = tp x rwrw rwrw Variceal Wall Tension (T) is a Major Determinant of Variceal Rupture Transmural pressure (tp) Radius (r) Esophagus Varix VARICEAL WALL TENSION IS A MAJOR DETERMINANT OF VARICEAL RUPTURE

81 Treatment of Varices / Variceal Hemorrhage No varices Varices No hemorrhage Varices No hemorrhage Variceal hemorrhage Variceal hemorrhage Recurrent hemorrhage Recurrent hemorrhage Prevent Formation of Varices ? MANAGEMENT OF PATIENTS WITHOUT VARICES Prevent First Variceal Hemorrhage Control Bleeding: Reduce Mortality Prevent Recurrent Hemorrhage

82 Endoscopic Findings Which is the best option? 1)Start atenolol 2)Start propranolol 3)Variceal band ligation 4)Propranol and isosorbide mononitrate 5)Band ligation and beta blockers Which is the best option? 1)Start atenolol 2)Start propranolol 3)Variceal band ligation 4)Propranol and isosorbide mononitrate 5)Band ligation and beta blockers

83  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  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

84 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  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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