Gastroesophageal Varices Amreen M. Dinani MD, FRCPC VTSGNA Fall Conference October 24, 2015

Objectives Understand the pathophysiology of portal hypertension and development of gastroesophageal varices Recognize and identify risk factors for developing gastroesophageal varices Understand the major principles in the management of gastroesophageal varices

Case 1 AST 56 ALT 42 Tbil 1.0 ALP 76 GGT 60 INR 1.4 Lipid Panel: Chol 230, TG 200, LDL 151, HDL M referred to your clinic for Hepatitis C treatment. Asymptomatic

Case 1 In addition to starting treatment for HCV, he undergoes an upper endoscopy as you believe he has cirrhosis Upper endoscopy reveals:

Question 1 What is the next step? 1.Start a beta blocker 2.Do nothing 3.Repeat upper endoscopy in 1 year 4.Repeat upper endoscopy in 3 years 5.Recommend endoscopic band ligation (EBL) 6.Recommend TIPS

Question 2 What are risk factors for development of GEV? 1.Presence of ascites 2.Cirrhosis secondary to alcohol 3.Cirrhosis secondary to Hepatitis C 4.Child’s Pugh Score B/C 5.Presence of red wale signs

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

Natural History Of Varices No varices Small varices Large varices 7-8%/yr Predictors of development  HPVG >10mmHg  AST Groszmann et al. NEJM 2005 Predictors of progression  Childs B/C  Red wale signs  EtOH cirrhosis Merli et al. Hepatology. 2003

Variceal hemorrhage Varices with red signs Predictors of hemorrhage  Size of varices  Childs B/C  Red wale signs Groszmann et al. NEJM 2005 Bleeding risk of pts with small varices and Childs C or red wale signs is same as moderate/large size varices Merli et al. J Hepatology 2003

Clinical Risk Factors For Variceal Hemorrhage Large esophageal varices Appearance: –Red wale marks –Cherry red spots –Diffuse erythema Childs-Pugh Class C cirrhosis Presence of tense ascites- sign of portal hypertension

High Risk Stigmata Red wale sign Cherry red spot Nipple sign

Prevention of Varices/Variceal Bleeding No varices Small varices No hemorrhage Large or high- risk small varices No hemorrhage Variceal hemorrhage Prevention of varicesPrevention of growthPrevention of 1 st growthPrevention of recurrence Pre-primary prophylaxis Secondary prophylaxis Primary prophylaxis

Non-Selective Beta-Blockers DO NOT Prevent Development Of Varices More severe side effects (18% vs 6%) n= 108 n= 105 Groszmann RJ, Garcia-Tsao et al. NEJM 2005

HVPG Was Not Significantly Different Between Study Groups Groszmann RJ, Garcia-Tsao et al. NEJM 2005

Baseline HVPG is the STRONGEST Predictor for Development of Varices Groszmann RJ, Garcia-Tsao et al. NEJM 2005

Development Of Large Varices In Patients With No Or Small Varices At Baseline % pts with large varices <0.05NS Cales et al. Eur J Gastroenterol Hepatol 1999;11:

Nadolol vs. Placebo In Patients With Small (not high-risk) Varices Variceal Hemorrhage Survival Merkel et al. Gastroenterology 2004

Recommendations- Pre-primary prophylaxis No varices Small varices No hemorrhage Large or high- risk small varices No hemorrhage Variceal hemorrhage No β-blockers Repeat EGD in 2-3yrs Consider β-blockers - ββ-> no repeat EGD - No -> repeat endoscopy in 1-2yrs Prevention of 1 st growthPrevention of recurrence

Primary Prophylaxis Prevention of variceal bleeding in a patient who has never bled previously 1 st line of treatment – Non-selective beta blockers (nadolol, propranol, carvedilol) OR – Endoscopic Band Ligation (EBL)

Primary Prophylaxis- Beta Blockers Mechanism of action: Blocks vasodilatory β- adrenergic receptors permitting unopposed α- adrenergic vasoconstriction in the mesenteric arterioles-> reducing portal venous inflow and pressure Reduce risk of bleeding from 25% to 15% compared to placebo Best predictor of response to ββ is sustained reduction in HVPG < 12mmHg Clinically- 25% reduction in HR, but not less than 55 beats/min – Only 20-30% of subjects achieve the goal HR – 15-20% of subjects cannot tolerate ββ

Primary Prophylaxis- Band Ligation

Meta-Analysis Of Trials of EBL vs ββ For Primary Prophylaxis Best Prac Res Clin Gastroenterol 2007;21:31-42

Cirrhosis Resistance to portal flow  Varices  Variceal growth  Variceal rupture Portal Pressure Portal blood inflow Splanchnic arteriolar resistance Non-selective β-blockers Β-2 blockade Β-1 blockade Cardiac output Propanolol Nadolol Coreg-- nonselective beta blocker/alpha-1 blocker Unable to tolerate BB-> EBL

Recommendations- Primary Prophylaxis No varices Small varices No hemorrhage Large or high- risk small varices No hemorrhage Variceal hemorrhage No β-blockers Repeat EGD in 2-3yrs Consider β-blockers - ββ-> no repeat EGD - No -> repeat endoscopy in 1-2yrs High risk stigmata- nonselective β- blockers OR EVL No high risk stigmata- Non- selective β-blockers preferred Combination of nonselective β- blockers plus EVL

Case 2 45M presents with a several hour history of hematemesis. His history is significant for long standing alcoholism PE: Tachycardia of 110 and SBP of 90 Labs on admission: Hgb of 10, plt 100,000 and INR of 2.0

Question 3 What would you do next? 1.Call GI for an urgent upper endoscopy 2.Start Nexium ggt, 2 units PRBC 3.Call IR for urgent TIPS 4.Intubate the patient and stabilize 5.Start Nexium ggt, Octreotide ggt, 2 unit PRBC

Active Variceal Hemorrhage General Measures Airway protection Gastric aspiration Hemodynamic resuscitation – Blood, crystalloid (avoid over-transfusion) – FFP, platelets are usually not necessary Antibiotics Metabolic support – Thiamine, DT’s monitoring, glucose/lytes

45-day mortality with Hgb goal >7 g/dl Villanueva C et al. N Engl J Med 2013;368:11-21

Death by 6 weeks Villanueva C et al. N Engl J Med 2013;368:11-21

Thresholds For Transfusion 9.0 g/dl for SBP 100 – NO DATA 10 g/dl with concomitant cardiac sx’s – SOME DATA 7.0 g/dl or less for everyone else – International Consensus Recommendation – RECENT GOOD DATA Barkun AN et al. Annals Intern Med 2010;152:

Antibiotic Prophylaxis Improves Mortality Overall MortalityMortality due to Bacterial Infections Chavez-Tapia NC et al. Aliment Pharmacol Ther. 2011;34(5):509-18

Pharmacologic Therapy in Active Variceal Hemorrhage Vasopressin – Causes splanchnic vasoconstriction reducing portal venous inflow and reducing portal pressure – Has severe toxicity (cardiac, bowel ischemia) Terlipressin – Semisynthetic analog of vasopressin – Less side effects than vasopressin – Evaluated in at least 20 clinical trials – Shown to increase survival in variceal bleeding – Not available in US

Pharmacologic Therapy in Active Variceal Hemorrhage Somatostatin – Decreases portal pressure and collateral blood flow by inhibiting release of glucagon – Also reduces post prandial mesenteric blood flow – Not available in the US – Half life in circulation of 1-3 minutes Octreotide – Somatostatin analog – Half life of minutes – Effect on portal pressure is not prolonged – Several studies have shown it to be superior to placebo in controlling variceal hemorrhage

Endoscopic Therapy for Acute Variceal Hemorrhage EVL- Preferred endoscopic modality for control of acute esophageal variceal bleeding and for prevention of rebleeding Varices at the GE junction are banded initially, and then more proximal varices are banded in a spiral manner about every 2 cms 80-90% of patients will stop bleeding with EVL and octreotide

Endoscopic Variceal Ligation

Factors Associated With Failure To Control Acute Hemorrhage Spurting varices High Child-Pugh score High HVPG Infection Portal Vein Thrombosis Factors Associated with Early Rebleeding Severe initial bleeding Overly aggressive volume resuscitation Infection High HVPG Complications of endoscopic therapy Renal failure

Secondary Prophylaxis Preventing hemorrhage in patients with a history of variceal hemorrhage After an index bleed, 70% of patients experience recurrent variceal hemorrhage within one year 1 st line of treatment: EVL and ββ

EVL + Nadolol vs. EVL * * p<.006 Hepatology 2005;41(3):572-8

Secondary Prophylaxis Summary EVL and ββ EVL every 2-3 weeks until varices eradicated Once eradicated -> Upper endoscopy + EVL every 3 to 6 months for treatment of recurrent varices TIPS if pharmacologic and endoscopic therapy fail Liver transplant referral- 60% mortality at 1 yr

Recommendations- Primary and Secondary Prophylaxis No varices Small varices No hemorrhage Large or high- risk small varices No hemorrhage Variceal hemorrhage No β-blockers Repeat EGD in 2-3yrs Consider β-blockers - ββ-> no repeat EGD - No -> repeat endoscopy in 1-2yrs High risk stigmata- nonselective β- blockers OR EVL No high risk stigmata- Non- selective β-blockers preferred Combination of nonselective β- blockers plus EVL

Case 3 43F with alcoholic liver disease presents with hematemesis VS 90/50 HR 110 Somnolent, somewhat confused Spider angiomas on chest Hgb 10, plt 64, INR 2.3, Alb 2.1, TB 3.2, AST 85, ALT 26 Childs Pugh Class C on admission

What worrisome features does this patient have that puts her at high risk of rebleeding or difficult to control?

Treatment of Early Rebleeding or Uncontrolled Active Bleeding

Early Use Of TIPS In Patients With Cirrhosis and Variceal Bleeding Inclusion Criteria Cirrhosis with acute variceal hemorrhage Treated with vasoactive drugs, endoscopic therapy and antibiotics. Child-Pugh class C (10-13) or Child Pugh class B (7-9) with active bleeding More than 10 Child-Pugh points excluded Garcia-Pagan, et al. NEJM 2010;362:

Probability of Remaining Free of Bleeding and of Survival Garcia-Pagan, et al. NEJM 2010;362:

Conclusion First priority: Hemodynamic stability and resuscitation No role for pharmacological therapy to prevent varices Non-selective beta blockers preferred over EVL for primary prophylaxis Treat infections aggressively Presence of ascites- indicative of portal hypertension Rescue measures: Blakemore/Minnesota Tube and TIPS +/- liver transplant referral