Recommendations

Key Recommendations

Management of varices focuses on preventing bleeding. Type of therapy depends primarily on risk stratification of patients. Acute esophageal variceal hemorrhage is a medical emergency.

Decompensated cirrhosis with acute variceal hemorrhage

Decompensated cirrhosis is defined as clinically significant portal hypertension (hepatic venous pressure gradient [HVPG] ≥10 mmHg) with overt clinical signs, which may include variceal hemorrhage.[5]​ The immediate goal of treatment is to stop the bleeding, and to prevent early recurrence.

Initial measures should focus on resuscitation, assessment of the airway, and obtaining peripheral venous access. Packed red blood cell transfusion should be undertaken using a restrictive strategy, targeting a hemoglobin level of 7 g/dL in patients without comorbidities.[5][37]​​​​​[38][45]​​​​​ Blood transfusion above this threshold may increase mortality.[46] In the context of resuscitation of an actively bleeding patient with hypotension, transfusion at higher hemoglobin levels may be appropriate given the equilibration that occurs with fluid resuscitation.[5][47]​​​ Patients with comorbidities such as ischemic heart disease may also merit higher hemoglobin transfusion targets.[5][45]​​​ Platelets and coagulation factors should be given in certain circumstances. Patients on antiplatelet treatment should not receive platelet transfusions.[48] Prolonged prothrombin time/international normalized ratio (PT/INR) should be corrected with fresh frozen plasma and/or vitamin K (phytonadione) in all patients except for those on warfarin treatment.[48] Prothrombin complex concentrate can be considered in patients on warfarin with a life-threatening gastrointestinal bleed or those with a supratherapeutic INR substantially exceeding the therapeutic range. Prothrombin complex concentrate can also be considered for patients in whom massive blood transfusion is undesirable because of its effect on coagulopathy or dilution of blood components.[48] Patients on direct oral anticoagulants (DOACs) should not routinely be given prothrombin complex concentrate; those on dabigatran should not routinely receive idarucizumab, and those on rivaroxaban or apixaban should not routinely receive recombinant coagulation factor Xa (andexanet alfa). These recommendations are based on limited evidence of benefit. However, reversal of anticoagulation with these agents may be considered in hospitalized patients with a life-threatening gastrointestinal bleed who have taken a DOAC within the past 24 hours.[48]

Patients on aspirin for secondary cardiovascular prevention should continue with this; if aspirin is stopped, it should be restarted on the day hemostasis is confirmed endoscopically.[48]

Short-term (until stability for discharge or 5 days, whichever is shorter) prophylactic antibiotics should be given to all patients with cirrhosis and variceal hemorrhage to cover gram-negative organisms. Prophylactic antibiotics reduce the rate of bacterial infection, treatment failure, rebleeding, and mortality.[5]

Intravenous ceftriaxone is recommended for patients with advanced cirrhosis, and in hospital settings with a high prevalence of fluoroquinolone-resistant bacterial infections; however, systemic antimicrobial choice should be tailored to local hospital antimicrobial resistance and stewardship policies.[5][49]​ An oral fluoroquinolone (e.g., ciprofloxacin) may be used in the remaining patients.[44]

Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behavior.[50]

  • Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics that are commonly recommended for the infection are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability).

  • Consult your local guidelines and drug information source for more information on suitability, contraindications, and precautions.

Pharmacologic therapy with a vasoactive drug (e.g., a somatostatin analog such as octreotide, or a vasopressin analog such as terlipressin) should be initiated as soon as variceal hemorrhage is suspected.[5][37]​​​[44][51][52]

Endoscopy should be performed within 12 hours of admission, once the patient is hemodynamically stable. If variceal hemorrhage is confirmed, it should be treated with endoscopic variceal ligation (EVL).[5][37]​​[38][44][53][54]​​ EVL is more effective than sclerotherapy for the control of bleeding, but sclerotherapy can be used when EVL is not feasible.[44]

The combination of a vasoactive drug plus EVL is considered first-line therapy.[5][44]

When combined pharmacologic and endoscopic treatment fails to control bleeding, transjugular intrahepatic porto-systemic shunt (TIPS) is indicated as a rescue therapy. However, in high-risk patients, such as those with Child-Pugh class C (with a score of <14), or class B with active bleeding at initial endoscopy despite concomitant treatment with vasoactive agents, early TIPS within 72 hours (ideally <24 hours) from EGD/EVL may be of benefit.[5][44][55][56]​ Patients may need prompt transfer to a specialized center for rescue or early TIPS.[56]

TIPS with polytetrafluoroethylene (PTFE)-covered stents should be used in preference to bare stents.[56]​ Patients who do not undergo early TIPS should continue on an intravenous vasoactive drug for 2-5 days and then begin nonselective beta-blocker therapy once the vasoactive drug is discontinued.[5] Rescue TIPS is indicated in these patients if hemorrhage cannot be controlled, or if bleeding recurs despite treatment with a vasoactive drug plus EVL. Once TIPS is performed successfully, the vasoactive drug can be discontinued.[5]

At any stage, uncontrollable bleeding should be treated by balloon tamponade (for up to 24 hours) as a bridge to more definitive treatments.[38][44]​ Self-expanding metal mesh stents are an alternative to balloon tamponade and allow for effective compression of esophageal varices and control of bleeding.[44] They are supplied with an insertion system and can be deployed without direct endoscopic or fluoroscopic guidance, and can be removed endoscopically using the accompanying stent removal device.[57]

Compensated cirrhosis with mild portal hypertension

Defined as HVPG >5 but <10 mmHg.[5][58]​ Patients do not have varices; the goal of therapy is to eliminate or suppress the etiologic factor (e.g., hepatitis B, hepatitis C, alcohol, and iron), make lifestyle modifications, and prevent clinically significant portal hypertension. Regression of cirrhosis may be possible in some patients. Nonselective beta-blockers are not recommended because they do not reduce the incidence of new varices, variceal bleeding, or clinical decompensation at this stage.[5]

Patients with compensated cirrhosis should undergo regular (6-monthly) ultrasound imaging to screen for hepatocellular carcinoma and portal vein thrombosis; special attention should be paid to imaging evidence indicating the development of clinically significant portal hypertension. Annual liver stiffness measurement can identify patients who would benefit from endoscopic screening.[5]

Compensated cirrhosis with clinically significant portal hypertension: without gastroesophageal varices

Clinically significant portal hypertension (CSPH; HVPG ≥10 mmHg) predicts formation of varices and clinical decompensation in patients with compensated cirrhosis.[5]

The principal goal of treatment for patients with compensated cirrhosis with clinically significant portal hypertension is to prevent clinical decompensation, followed by the prevention of gastroesophageal varices.[5] Nonselective beta-blockers should be considered to prevent decompensation.[5][59]

For patients who have a contraindication or intolerance to beta-blockers, surveillance endoscopy should be performed every 2 years if injury to the liver is ongoing, or every 3 years if the etiologic agent has been eliminated.[5]

Compensated cirrhosis with clinically significant portal hypertension: with gastroesophageal varices (no bleeding)

Defined as patients with compensated cirrhosis who have CSPH (lowest HVPG 10‐12 mmHg) and endoscopically proven esophageal varices that have not bled yet.[5]

The primary goal of treatment is the prevention of clinical decompensation. However, there are no studies designed specifically to assess treatments to prevent decompensation in patients with esophageal varices; therefore, treatment recommendations are aimed at the prevention of first variceal hemorrhage.[5]

Treatment to prevent first variceal hemorrhage in patients with small gastroesophageal varices

  • Nonselective beta-blockers are recommended to prevent first variceal hemorrhage in all patients with small gastroesophageal varices.[5][59]

  • Patients with compensated cirrhosis with small varices on endoscopy with contraindication or intolerance to beta-blockers should have endoscopy repeated every year (with ongoing liver injury) or every 2 years (if liver injury is quiescent, e.g., after viral elimination, alcohol abstinence).[5] 

Treatment to prevent first variceal hemorrhage in patients with medium/large gastroesophageal varices

  • Nonselective beta-blockers are recommended to prevent the first variceal hemorrhage in patients with medium to large varices.[5][38]

  • Esophageal varices ligation is also recommended for this group of patients.[5] Endoscopic variceal ligation (EVL) is the first-line alternative to nonselective beta-blockers.

  • TIPS should not be used as primary prophylaxis for variceal hemorrhage.[5]

  • Contraindications to each specific treatment, treatment tolerance, and compliance need to be considered.[4][5][38][44]

  • Patients with compensated cirrhosis with high-risk varices on endoscopy with contraindication or intolerance to beta-blockers should have endoscopy repeated every year (with ongoing liver injury) or every 2 years (if liver injury is quiescent, e.g., after viral elimination, alcohol abstinence).[5]

Prevention of recurrent variceal hemorrhage

The risk of rebleeding in patients who recover from an acute variceal hemorrhage is 60% at 1 year. The first-line treatment for prevention of rebleeding is a combination of nonselective beta-blocker plus EVL.[5][38][44][60][61]

Patients who have undergone successful TIPS during the acute bleeding episode do not require nonselective beta-blockers or EVL. Patency of TIPS should be assessed by doppler ultrasound at 1 week, 3 months, 6 months, and every 6 months thereafter.[56]

TIPS is recommended for patients who suffer from recurrent variceal hemorrhage despite nonselective beta-blocker and EVL therapy.[5] TIPS with polytetrafluoroethylene (PTFE)-covered stents should be used in preference to bare stents.[56] There is evidence that they are associated with a significantly higher primary patency rate and survival rate, and a significantly decreased rebleeding rate.[62]

Absolute contraindications to TIPS placement include:[56][63]​​

  • Severe pulmonary hypertension (mean pulmonary pressure >45 mmHg)

  • Severe tricuspid regurgitation

  • Congestive heart failure (Stage C or D or a documented ejection fraction of <50%)

  • Severe liver failure

  • Polycystic liver disease

  • Active sepsis or systemic infection

Relative contraindications to TIPS include:[56]

  • Untreated biliary obstruction

  • Uncorrectable severe coagulopathy

  • Severe obstructive arteriopathy

  • Hepatic artery and celiac trunk stenosis (preventing adequate sinusoidal perfusion by the hepatic artery)

  • Recurrent hepatic encephalopathy

  • Hepatocellular carcinoma and other liver tumors

  • Bile duct dilation

TIPS is not recommended in patients with a Model of End-stage Liver Disease (MELD) score >30, lactate >12 mmol/L, or Child-Pugh >13, unless it is a bridge to liver transplantation in the short term, due to the high risk of mortality post-TIPS in these patients.[56]

Although HVPG measurement is the most accurate guide to portal hypertension and response to vasoactive drug therapy (such as beta-blockers), it is moderately invasive and routine use is restricted to specialized centers. Noninvasive monitoring such as liver stiffness measurement can be used to guide therapy, with endoscopic surveillance limited to patients who are not taking nonselective beta-blockers and do not have access to liver stiffness measurement.[5]

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