Prevention of recurrent bleeding from esophageal varices in patients with cirrhosis

INTRODUCTION — Patients with cirrhosis who develop portal hypertension (ie, increased pressure within the portal venous system) are at risk for complications, including bleeding from esophageal varices. Portal hypertension is the result of resistance to portal blood flow, which most often occurs in the liver. Variceal bleeding is a decompensating event with a high risk of rebleeding following initial recovery. Measures to prevent recurrent variceal bleeding such as eradicating esophageal varices and improving liver function are important for reducing the risk of mortality.

This topic will discuss the prevention of recurrent bleeding from esophageal varices in patients with cirrhosis. Management of other complications of cirrhosis and portal hypertension are discussed separately:

●(See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

●(See "Ascites in adults with cirrhosis: Initial therapy" and "Ascites in adults with cirrhosis: Diuretic-resistant ascites".)

●(See "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis".)

●(See "Portal hypertensive gastropathy".)

●(See "Hepatic hydrothorax".)

Risk assessment for and primary prevention of variceal bleeding in patients with cirrhosis are discussed separately. (See "Pathogenesis of variceal bleeding in patients with cirrhosis" and "Primary prevention of bleeding from esophageal varices in patients with cirrhosis".)

Management of acute bleeding from esophageal varices is discussed separately. (See "Overview of the management of patients with variceal bleeding" and "Methods to achieve hemostasis in patients with acute variceal hemorrhage".)

Technical aspects of endoscopic variceal ligation are discussed separately. (See "Endoscopic variceal ligation".)

The American Association for the Study of Liver Diseases (AASLD) has issued guidance regarding the management of variceal bleeding that is based upon the available evidence and consensus opinion [1]. The recommendations in this topic are consistent with AASLD guidance. Management of variceal bleeding is also addressed in guidelines or consensus statements from the British Society of Gastroenterology and by an international consensus statement (Baveno VII) [2,3].

DEFINITION OF REBLEEDING — The literature contains variations in the terminology used to define variceal rebleeding across studies. As a result, several definitions were agreed upon during a consensus conference and were used to develop practice guidelines [1,2] (see "Methods to achieve hemostasis in patients with acute variceal hemorrhage", section on 'Definitions'):

●Bleeding time frame:

•Acute variceal bleeding – The episode of acute bleeding is comprised of the time interval from hospital admission (time zero) to 120 hours (day 5).

•Variceal rebleeding – Variceal rebleeding describes bleeding that occurs ≥120 hours after the first hemorrhage, provided that hemostasis was initially achieved [2].

●Clinically significant bleeding – Defined by a transfusion requirement of two units of blood or more within 24 hours of time zero together with a systolic blood pressure below 100 mmHg, a postural systolic change of more than 20 mmHg, and/or a pulse rate above 100 beats per minute at time zero [2].

Active bleeding is defined by hematemesis, bright red blood in the nasogastric tube, melena, pulse rate >100 beats per minute, decrease in systolic blood pressure by ≥10 mmHg, and/or transfusion requirement to maintain hemoglobin in the target range [4]. Failure to control variceal bleeding has also been defined as an adjusted blood requirement index (ABRI) ≥0.75 [5]. The ABRI is calculated by using the number of units of red blood cells transfused and the change in hematocrit:

INCIDENCE AND RISK FACTORS — Left untreated, patients who recover from the first episode of esophageal variceal bleeding have a high rate of rebleeding (up to 60 percent during the first year) [1,6].

Risk factors specifically for rebleeding have not been well-defined, while factors linked to the risk of initial bleeding include the size of varices (picture 1), appearance of varices (ie, red wale marks) (picture 2), and the variceal pressure [7]. The development of esophageal varices and risk factors for bleeding are discussed in more detail separately. (See "Pathogenesis of variceal bleeding in patients with cirrhosis".)

INITIAL PREVENTIVE STRATEGY

Goals of prevention — Goals of prevention for patients who recover from the first episode of esophageal variceal bleeding include:

●Preventing recurrent variceal bleeding

●Improving survival

●Preventing complications (eg, infection, renal failure) (see "Overview of the management of patients with variceal bleeding", section on 'Complications')

General measures — The following measures apply to patients with cirrhosis who recover from an initial episode of bleeding:

●Optimize hemostasis – Management of hemostatic abnormalities in patients with cirrhosis is discussed separately.(See "Hemostatic abnormalities in patients with liver disease".)

●Refer for liver transplantation – We refer patients with a Model for End-stage Liver Disease (MELD) score ≥14 and history of esophageal variceal bleeding for liver transplantation evaluation, because transplantation is effective long-term therapy for variceal bleeding and other complications of portal hypertension. Selecting patients for liver transplantation and the pretransplant evaluation are discussed separately. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation" and "Model for End-stage Liver Disease (MELD)".)

●Manage chronic liver disease – Patients with cirrhosis are evaluated for interventions that will slow or reverse the progression of liver disease (ie, avoiding alcohol) and prevent additional insults to the liver (eg, adjusting medications, immunizing against hepatitis A virus and hepatitis B virus). The general management of patients with cirrhosis is discussed separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'General management'.)

Some patients with chronic hepatitis C virus (HCV) and decompensated cirrhosis may be candidates for antiviral therapy, which is associated with improved survival. Selecting patients with HCV for antiviral therapy is discussed separately. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection".)

Specific interventions

Indications — All patients with cirrhosis who recover from esophageal variceal bleeding and do not have a transjugular intrahepatic portosystemic shunt (TIPS) are at risk for rebleeding and should receive prophylactic intervention. Patients who had TIPS performed during the acute episode of bleeding do not require any further intervention specifically for esophageal varices. The role of TIPS in the management of acute variceal bleeding is discussed separately. (See "Overview of transjugular intrahepatic portosystemic shunts (TIPS)".)

Selecting a strategy — Selecting a preventive strategy for patients with cirrhosis takes into account the efficacy, risks, and adverse effects of the interventions, in addition to the patient characteristics that may limit the use of beta blockers or variceal ligation techniques. Our preferred strategy is endoscopic variceal ligation (EVL) combined with a beta blocker for patients without contraindications to beta blockers. (See 'Endoscopic variceal ligation plus beta blocker' below.)

Some patients may not want to undergo or cannot tolerate a series of upper endoscopies with EVL requiring anesthesia (ie, patients with multiple comorbidities). For such patients, we use a beta blocker alone, if there are no contraindications [8]. (See 'Beta blocker alone' below.)

For patients with contraindications to beta blockers, we use EVL alone. (See 'Endoscopic variceal ligation alone' below.)

We do not initiate beta blockers to prevent recurrent bleeding in patients with any of the following conditions because of the risk of adverse events (eg, decreased cardiac output, increased mortality):

●Hyponatremia (serum sodium concentration <130 mEq/L) (see "Hyponatremia in patients with cirrhosis", section on 'Discontinue beta blockers and other antihypertensive drugs').

●Acute kidney injury [9] (see "Overview of the management of acute kidney injury (AKI) in adults").

●Spontaneous bacterial peritonitis: Beta blocker therapy in patients with spontaneous bacterial peritonitis is associated with higher mortality risk [10] (see "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis", section on 'Discontinue nonselective beta blockers').

●Diuretic-resistant ascites: Beta blocker therapy in patients with diuretic-resistant ascites is associated with higher mortality risk, and this is discussed separately (see "Ascites in adults with cirrhosis: Diuretic-resistant ascites", section on 'Discontinuing beta blockers').

●History of adverse effects with beta blockers: Patients with a prior history of adverse effects related to beta blockers are not candidates for therapy (eg, bronchoconstriction, heart failure, acute kidney injury) (see "Major side effects of beta blockers").

●Systolic blood pressure <90 mmHg; this threshold is supported by consensus statement only [1]. Some UpToDate contributors for this topic use mean arterial pressure (MAP) <82 mmHg as the threshold for avoiding beta blockers because MAP <82 mmHg (calculator 1) predicts mortality in patients with cirrhosis and ascites [11].

Options

Endoscopic variceal ligation plus beta blocker — The preferred strategy for patients who recover from their first episode of variceal bleeding consists of endoscopic variceal ligation plus a beta blocker because this combination is effective for preventing rebleeding [12,13]:

●We perform EVL (also referred to as band ligation or banding) in one to two weeks after hospital discharge, and we repeat EVL every two to four weeks thereafter until the varices are eradicated. (See 'Endoscopic variceal ligation alone' below.)

●We begin a nonselective beta blocker at a low dose (eg, nadolol 20 mg once daily or propranolol 20 mg twice daily) on day 5 after the initial bleeding episode (provided that vasoconstricting drugs have been stopped and hemostasis has been achieved) for patients with cirrhosis who do not have a contraindication to beta blockers. (See 'Beta blocker alone' below and 'Selecting a strategy' above.)

Combining endoscopic ligation with a pharmacologic intervention containing a beta blocker results in lower rebleeding risk compared with either strategy alone [12,13]. In a meta-analysis of eight trials including 905 patients with a history of variceal bleeding, EVL plus a beta blocker (with or without isosorbide mononitrate) resulted in greater risk reduction for rebleeding compared with EVL alone (risk ratio [RR] 0.65, 95% CI 0.45-0.93) or pharmacologic intervention alone (RR 0.61, 95% CI 0.44-0.86) [13]. However, combining endoscopic and pharmacologic interventions did not significantly lower mortality risk compared with either approach alone. These data also support evaluating patients who do not tolerate beta blockers for transjugular intrahepatic portosystemic shunt (TIPS) if they are not at increased risk for adverse events (eg, encephalopathy) [14]. (See 'Transjugular intrahepatic portosystemic shunt' below.)

Endoscopic variceal ligation alone — The goal of EVL is to eradicate esophageal varices, and it is performed in one to two weeks after hospital discharge and repeated every two to four weeks until the varices are no longer visible endoscopically with insufflation of the esophageal lumen [15]. Most patients require between two and four sessions of endoscopic ligation to eradicate esophageal varices.

During an upper endoscopy, EVL is performed by attaching a device loaded with rubber bands to the tip of the endoscope. A varix is suctioned into the device and then the rubber band is deployed around the base of the varix, which results in occlusion. The technical aspects and complications of EVL are discussed separately. (See "Endoscopic variceal ligation".)

The benefits of endoscopic therapy were established by studies of endoscopic sclerotherapy (ES) [16-18]; however, EVL is preferred for treating esophageal varices because EVL results in greater risk reduction for rebleeding and mortality compared with ES [19]. In a meta-analysis of seven trials including 547 patients, patients treated with EVL had lower risk of rebleeding (Odds ratio [OR] 0.52, 95% CI 0.37-0.74) or mortality (OR 0.67, 95% CI 0.46-0.98) compared with sclerotherapy.

Beta blocker alone — We begin a nonselective beta blocker at low dose (ie, nadolol 20 mg once daily) on day 5 after the initial bleeding episode (provided that hemostasis has been achieved and vasoconstricting drugs [ie, octreotide] have been stopped) for patients with cirrhosis who do not have a contraindication or intolerance to beta blockers. We titrate the beta blocker dose according to the patient’s heart rate (goal resting heart rate is 55 to 60 beats per minute), and continue therapy indefinitely while monitoring for adverse effects (ie, hypotension).

In general, we use nadolol because of once daily dosing and begin with a low dose (ie, 20 mg daily). If nadolol 20 mg daily is started but does not achieve a resting heart rate of 55 to 60 beats per minute in one to two weeks, then the dose is increased to nadolol 40 mg daily, provided that the systolic blood pressure is ≥90 mmHg (or MAP >82 mmHg, if MAP is being used). (See 'Selecting a strategy' above.)

If the goal heart rate has not been achieved in one to two weeks following the first dose increase, then the dose is further increased to 60 mg daily, provided that the systolic blood pressure is ≥90 mmHg (or MAP >82 mmHg, if MAP is being used for monitoring). These steps are repeated until the patient’s heart rate declines to ≤60 beats per minute or the maximum nadolol dose is reached (ie, 160 mg daily in patients without ascites or 80 mg daily in patients with ascites) without developing adverse effects (eg, renal insufficiency).

The duration of beta blocker therapy varies depending on the patient’s disease course, the development of adverse effects, and clinician preference. Some UpToDate contributors for this topic discontinue beta blockers after esophageal varices have been eradicated with EVL. However, other UpToDate contributors for this topic continue beta blockers indefinitely, even after eradicating esophageal varices, unless liver recompensation occurs as in patients with alcohol-associated cirrhosis who abstain or patients with decompensated hepatitis B virus infection who respond to antiviral therapy. In addition, the patient's heart rate and blood pressure are assessed at each follow-up visit.

Hepatic venous pressure gradient (HVPG) is not routinely measured because it is invasive and more costly compared with noninvasive monitoring. However, measuring HVPG is an alternative for monitoring response to beta blocker if expertise in the technique is available. Patients are also monitored for adverse effects associated with beta blockers including shortness of breath, fatigue, bronchoconstriction, hypotension, and heart failure. (See 'Selecting a strategy' above.)

The goal of prevention with beta blockers is to lower the portal pressure by reducing portal blood flow, which is accomplished by reducing cardiac output and vasoconstricting the splanchnic circulation [20]. Higher portal pressure leads to larger varices that have a higher risk of bleeding [21]. (See "Pathogenesis of variceal bleeding in patients with cirrhosis", section on 'Predictive factors'.)

The use of a beta blockers alone reduces the risk of rebleeding and of death due to rebleeding. In a meta-analysis of 19 trials including 1050 patients with variceal bleeding, use of a beta blocker resulted in lower rates of rebleeding (37 versus 58 percent) and of death from rebleeding (9 versus 15 percent) compared with placebo or control group [22].

Interventions to avoid

●Endoscopic sclerotherapy – We do not use endoscopic sclerotherapy for prevention of variceal rebleeding. EVL is preferred in this setting because patients treated with EVL have lower rates rebleeding, mortality, and therapy-related complications (eg, esophageal ulcerations, strictures) compared with sclerotherapy [2]. (See 'Endoscopic variceal ligation alone' above.)

●Nitrates – We do not use isosorbide mononitrate in combination with beta blockers to prevent rebleeding because of the potential for adverse effects including headache, lightheadedness, and hypotension. While adding a nitrate to beta blocker therapy results in lower portal pressure, this potential benefit is not offset by the higher risk of adverse effects and the lack of improved efficacy [23]. In a meta-analysis of five trials including 459 patients, the risk of rebleeding or mortality was not significantly lower for patients given a beta blocker plus isosorbide mononitrate compared with beta blocker alone.

OPTIONS IF INITIAL STRATEGY FAILS

Transjugular intrahepatic portosystemic shunt

Strategy for long-term hemostasis — Transjugular intrahepatic portosystemic shunt (TIPS) with a covered stent is the preferred strategy for patients who recover from an initial bleeding episode but who then develop recurrent bleeding despite endoscopic variceal ligation and/or beta blocker therapy [3]. We define a failed response to endoscopic variceal ligation (EVL) as recurrent variceal bleeding despite at least one endoscopic treatment session, performed by an endoscopist who is experienced in EVL. In addition, some UpToDate contributors for this topic may perform TIPS for patients without encephalopathy and without severe hepatic dysfunction (ie, MELD <18) who cannot tolerate or have complications from beta blockers or EVL rather than using either intervention alone. (See "Model for End-stage Liver Disease (MELD)".)

When a patient with a history of varices presents with a second episode of bleeding, endoscopy is usually performed prior to TIPS to confirm the source of bleeding and exclude other causes (ie, peptic ulcer disease). General management of patients with upper gastrointestinal bleeding from esophageal varices or other sources is discussed separately. (See "Overview of the management of patients with variceal bleeding" and "Approach to acute upper gastrointestinal bleeding in adults".)

TIPS placement results in cessation of variceal bleeding and also serves to prevent further bleeding. TIPS is used to create a low resistance channel between the hepatic vein and the portal vein using angiographic techniques (figure 1). The stent functions in a manner similar to a surgically-created portacaval shunt but without the risks associated with major abdominal surgery. (See 'Other options' below.)

Some patients are not candidates for TIPS, and contraindications to TIPS placement (eg, heart failure, sepsis) are discussed separately. (See "Overview of transjugular intrahepatic portosystemic shunts (TIPS)".)

TIPS placement using a covered stent reduces the risk of rebleeding compared with endoscopic and pharmacologic strategies [24-27]. In a trial of 72 patients with either esophageal or gastric variceal bleeding followed for a median of 23 months, patients with TIPS had a lower rebleeding rate compared with patients treated with endoscopic intervention plus a beta blocker (0 versus 29 percent) [25]. A prior meta-analysis of 11 trials that utilized uncovered stents also demonstrated lower rebleeding rates in patients with TIPS compared with patients receiving endoscopic intervention [26].

Whether there are selected patients who would benefit from early TIPS placement (ie, within the first 72 hours of the initial bleeding episode) and who are not at increased risk for adverse events (eg, encephalopathy) remains uncertain [24,28-30]. However, in a trial comparing early TIPS placement with EVL plus beta blocker therapy in 63 patients with acute variceal bleeding, early TIPS resulted in lower rates of rebleeding within a median follow-up of 16 months (3 versus 50 percent) [24]. The use of TIPS for patients with acute variceal bleeding is discussed in more detail separately. (See "Overview of transjugular intrahepatic portosystemic shunts (TIPS)", section on 'Indications'.)

Complications — Complications associated with TIPS include hepatic encephalopathy or stent stenosis, which can lead to recurrence of portal hypertension and variceal bleeding. With the advent of polytetrafluoroethylene-covered stents, the risk of TIPS stenosis has declined substantially, but hepatic encephalopathy remains a concern [31,32]. In a trial of 72 patients with variceal bleeding, patients treated with TIPS initially had higher rates of encephalopathy compared with those treated with pharmacologic and endoscopic therapy (35 versus 14 percent); however, after one year, the encephalopathy rates were not significantly different between the groups (38 versus 23 percent) [25].

Monitoring for and management of stent stenosis and other complications related to TIPS are discussed separately. (See "Transjugular intrahepatic portosystemic shunts: Postprocedure care and complications".)

Liver transplantation — Liver transplantation provides successful long-term management of variceal bleeding and other complications of portal hypertension. The value of transplantation as a preventive intervention is limited by the frequently long waiting period before a donor liver is available. Selecting patients for liver transplantation evaluation on the basis of MELD score and complications of portal hypertension is discussed separately. (See 'General measures' above and "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

Other options — Historically, surgical creation of a shunt (eg, distal splenorenal shunt, portacaval shunt) was performed to control bleeding and prevent recurrent hemorrhage if other methods failed [33]. However, TIPS placement has become the preferred intervention in this setting because covered stents have favorable long-term patency rates and the risks and morbidity associated with major abdominal surgery are avoided. (See 'Transjugular intrahepatic portosystemic shunt' above and "Methods to achieve hemostasis in patients with acute variceal hemorrhage", section on 'Surgery'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cirrhosis" and "Society guideline links: Gastrointestinal bleeding in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Esophageal varices (The Basics)")

●Beyond the Basics topics (see "Patient education: Esophageal varices (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of prevention – For patients with cirrhosis who recover from an initial episode of esophageal variceal bleeding, the goals of a preventive strategy are (see 'Goals of prevention' above):

•Preventing recurrent variceal bleeding

•Improving survival

•Preventing complications (eg, infection, renal failure)

●General measures – For patients with cirrhosis who recover from an initial episode of esophageal variceal bleeding, general measures include (see 'General measures' above):

•Referral for liver transplantation – Patients with a MELD score ≥14 and history of esophageal variceal bleeding are referred for liver transplantation evaluation, because transplantation is effective long-term therapy for variceal bleeding and other complications of portal hypertension (see "Liver transplantation in adults: Patient selection and pretransplantation evaluation" and "Model for End-stage Liver Disease (MELD)").

•Management of chronic liver disease – Patients are evaluated for interventions that will slow or reverse progression of liver disease and prevent further injury to the liver (see "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'General management').

●Specific interventions – For patients with cirrhosis who have recovered from an episode of esophageal variceal bleeding, we recommend endoscopic variceal ligation to prevent rebleeding rather than endoscopic sclerotherapy (Grade 1B). We perform endoscopic variceal ligation in one to two weeks after hospital discharge and every two to four weeks thereafter until varices are eradicated. (See 'Endoscopic variceal ligation alone' above.)

For patients with cirrhosis who have recovered from an episode of variceal bleeding, we suggest therapy with a beta blocker rather than no pharmacologic intervention (Grade 2B). A nonselective beta blocker (eg, nadolol 20 mg once daily) is started on day 5 after the initial episode of bleeding, provided that vasoconstricting agents have been discontinued, hemostasis has been achieved, and there are no contraindications to beta blocker use. The duration of beta blocker therapy varies depending on the patient’s disease course, the development of adverse effects, and clinician preference. (See 'Beta blocker alone' above.)

For patients who have a contraindication to or cannot tolerate beta blockers, we use endoscopic variceal ligation alone to prevent recurrent variceal bleeding. (See 'Selecting a strategy' above.)

●Patients who do not respond to initial preventive strategies – For patients with cirrhosis who initially recover from variceal bleeding but who then develop recurrent bleeding despite endoscopic variceal ligation (EVL) and/or beta blocker, transjugular intrahepatic portosystemic shunt (TIPS) placement with a covered stent is the preferred strategy for long-term hemostasis, provided that there are no contraindications to TIPS placement. We define a failed response to EVL as recurrent variceal bleeding despite at least one session of endoscopic treatment. (See 'Transjugular intrahepatic portosystemic shunt' above.)

Contraindications to TIPS placement and monitoring for TIPS-related complications are discussed separately. (See "Transjugular intrahepatic portosystemic shunts: Postprocedure care and complications" and "Overview of transjugular intrahepatic portosystemic shunts (TIPS)".)

Liver transplantation provides successful long-term management of variceal bleeding for patients with cirrhosis; however, its value is limited by the frequently long waiting period before a donor liver is available. Selecting patients for liver transplantation and the pretransplant evaluation are discussed separately. (See 'General measures' above and "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)