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Varices Management: Current State of the Art

Varices Management: Current State of the Art. Atif Zaman, MD MPH Associate Professor of Medicine Director of Clinical Hepatology Oregon Health & Science University. VARICES AND VARICEAL HEMORRHAGE. Splanchnic arteriolar resistance. Resistance to portal flow. Portal blood inflow.

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Varices Management: Current State of the Art

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  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 Splanchnic arteriolar resistance Resistance to portal flow Portal blood inflow Portal pressure Variceal Growth Varices Cirrhosis

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

  4. 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

  5. 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 Medium 40 20 Small 0 Child C n=34 Overall n=494 Child A n=346 Child B n=114 Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72

  6. 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; 319:983

  7. LARGE VARICES ARE MORE LIKELY TO RUPTURE 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% 25 0 36 12 36 24 0 12 24 Time (months) *Merli et al., Hepatol 2003; 38:266, **Conn et al., Hepatology 1991; 13:902

  8. 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 <140,000, PV >13mm, 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)

  9. Prevalence and Predictors of LEV in Patients with Cirrhosis

  10. Capsule Endoscopy for Screening for Varcies Grade 3 Varices Grade 1 Varices

  11. 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 38:31-35DeFranchis et al,Hepatology 2008;47:1595-1603

  12. PREVENTION OF VARICEAL DEVELOPMENT Treatment of Varices / Variceal Hemorrhage Prevention of variceal development No varices Varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage

  13. 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

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

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

  16. PREVENTION OF FIRST VARICEAL HEMORRHAGE 0.1 1 10 Prevention of First Variceal Hemorrhage Bleeding Death Encephalopathy Porto-caval shunt -blockers * Sclerotherapy * Significantly heterogeneous * Relative risk Treated worse Treated better D’Amico et al., Hepatology 1995; 22;332

  17. 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) (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) D’Amico et al., Sem Liv Dis 1999; 19:475

  18. VARICEAL BAND LIGATION (VBL) VS. BETA-BLOCKERS (BB) IN THE PREVENTION OF FIRST VARICEAL HEMORRHAGE First hemorrhage Survival Chen 1998 Sarin 1999 De 1999 Jutabha 2000 De la Mora 2000 Lui 2002 Lo 2004 Schepke 2004 Total Relative risk 0 1 0 1 10 10 40 Favors BB Favors BB Favors VBL Favors VBL Variceal Band Ligation (VBL) vs. Beta-Blockers (BB) in the Prevention of First Variceal Bleed Khuroo, et al., Aliment Pharmacol Ther 2005; 21:347

  19. MANAGEMENT OF PATIENTS WITH VARICES WHO HAVE NEVER BLED Management depends on the size of varices Treatment of Varices / Variceal Hemorrhage No varices Varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage

  20. MANAGEMENT OF PATIENTS WITH MEDIUM/LARGE VARICES WITHOUT PRIOR HEMORRHAGE 1) -blockers (propranolol, nadolol) indefinitely 2) Endoscopic variceal ligation in patients intolerant to -blockers Treatment of Varices / Variceal Hemorrhage No varices Small varices No hemorrhage Medium/ large varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage

  21. MANAGEMENT OF PATIENTS WITH SMALL VARICES WITHOUT PRIOR HEMORRHAGE ? Prevention of variceal growth Treatment of Varices / Variceal Hemorrhage No varices Small varices No hemorrhage Medium/ large varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage

  22. NADOLOL MAY PREVENT THE GROWTH OF SMALL VARICES Nadolol May Prevent the Growth of Small Varices 100 Nadolol 80 Placebo % Probability of variceal growth p<0.001 60 40 20 36 60 24 48 0 10 Time (months) Merkel et al., Gastroenterology 2004; 127:476

  23. MANAGEMENT OF PATIENTS WITH SMALL VARICES WITHOUT PRIOR HEMORRHAGE • Repeat endoscopy in 1-2 years* • Beta-blockers? Treatment of Varices / Variceal Hemorrhage No varices Small varices No hemorrhage Medium/ large varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage *Sooner with cirrhosis decompensation

  24. CONTROL OF ACUTE VARICEAL HEMORRHAGE Control of hemorrhage Treatment of Varices / Variceal Hemorrhage No varices Small varices No hemorrhage Medium/ large varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage

  25. 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

  26. 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) Bernard et al., Hepatology 1999; 29:1655

  27. PROPHYLACTIC ANTIBIOTICS PREVENT EARLY VARICEAL REBLEEDING Probability of Remaining Free of Recurrent Variceal Hemorrhage 1.0 Prophylactic antibiotics (n=59) 0.8 No antibiotics (n=61) 0.6 % free of variceal hemorrhage 0.4 0.2 0 24 3 30 18 12 0 2 1 Follow-up (months) Hou M-C et al., Hepatology 2004; 39:746

  28. 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 0.8 1 1.2 1.4 1.6 1.8 2 Favors endoscopic therapy alone Favors endoscopic plus drug therapy Bañares R et al., Hepatology 2002; 35:609

  29. 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

  30. 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)

  31. MANAGEMENT OF PATIENTS WITH ACUTE VARICEAL HEMORRHAGE 1) Safe vasoactive drug + endoscopic therapy + antibiotic prophylaxis 2) TIPS / Shunt (rescue therapy) Treatment of Varices / Variceal Hemorrhage No varices Small varices No hemorrhage Medium/ large varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage

  32. 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  -blockers + ISMN Ligation HVPG-Responders* Ligation + -blockers (19 trials) (26 trials) (54 trials) (6 trials) (18 trials) (6 trials) (2 trials) * HVPG <12 mmHg or >20% from baseline Bosch and García-Pagán, Lancet 2003; 361:952

  33. PREVENTION OF RECURRENT VARICEAL HEMORRHAGE 1) -blockers + ISMN or EVL 2) -blockers + EVL may be preferable 3) TIPS / shunt surgery Treatment of Varices / Variceal Hemorrhage No varices Varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage

  34. 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

  35. 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

  36. 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

  37. 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

  38. The Future: Directed Therapy Using Portal Pressure Measurements

  39. 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)

  40. 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

  41. 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 (n=72) Varices Absent (n=15) 35 30 Hepatic Venous Pressure Gradient (mmHg) 25 20 P<0.01 15 12 10 5 Garcia-Tsao et. al., Hepatology 1985; 5:419

  42. 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 to < 12 mmHg HVPG decrease > 20% from baseline No change in HVPG Bosch and García-Pagán, Lancet 2003; 361:952

  43. SURVIVAL IMPROVES IN PATIENTS IN WHOM HVPG DECREASES (HVPG RESPONDERS) 100 95% HVPG responders p=0.003 75 HVPG non-responders Probability of Survival (%) 52% 50 25 0 0 12 24 36 48 60 72 84 96 Time (months) Survival Improves in Patients in Whom HVPG Decreases (HVPG Responders) Abraldes et al., Hepatology 2003; 37:902

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