BLEEDING ESOPHAGEAL VARICES

BLEEDING ESOPHAGEAL VARICES

  1. 1
    Current Diagnosis

    • Endoscopic screening for esophageal varices is recommended in patients with liver cirrhosis.

    • Noninvasive predictors of the presence of large varices, such as splenomegaly and thrombocytopenia, have limited accuracy.

    • A combination of clinical and endoscopic findings including the Child-Pugh class, size of varices, and the presence of red wale markings correlates with the risk of first bleeding in patients with cirrhosis.

    • Measurement of hepatic venous pressure gradient may be the best indicator of risk and severity of bleeding in patients with varices. It is an invasive test and is not widely available or used routinely in practice.

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  2. 2
    Current Therapy

    • Nonselective β-blockers and endoscopic band ligation are both effective first-line therapy in the primary prophylaxis of esophageal varices.

    • The management of acute variceal hemorrhage consists of prompt resuscitation and correction of coagulation abnormalities, followed by endoscopic and pharmacologic therapy with vasoactive agents. Antibiotic prophylaxis is given to decrease the risk of infection and of rebleeding. Transjugular intrahepatic portosystemic shunt (TIPS) is reserved for refractory, uncontrolled, acute variceal bleeding.

    • Strategies for secondary prophylaxis of variceal bleeding include endoscopic band ligation, pharmacologic therapy with nonselective β-blockers with or without nitrates, TIPS, and surgical shunts.

    • Comparative cost-effectiveness of secondary prophylaxis strategies is unknown but should take into consideration the cost of failed therapy (e.g., rebleeding, shunt revision) and that of treatment related-complications (e.g., encephalopathy, esophageal stricture).

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  3. 3
    Epidemiology

    Bleeding of esophageal varices is a major complication of portal hypertension, usually in the setting of liver cirrhosis, accounting for 10% to 30% of all cases of upper gastrointestinal hemorrhage. More than any other cause of gastrointestinal bleeding, this complication results in considerable morbidity and mortality, prolonged hospitalization, and increased affiliated costs. Variceal bleeding develops in 25% to 35% of patients with cirrhosis and accounts for up to 90% of upper gastrointestinal bleeding episodes in these patients.

    About 10% to 30% of these episodes are fatal, and as many as 70% of survivors rebleed following an index variceal hemorrhage. Following such events, the 1-year survival is 34% to 80%, being inversely related to the severity of the underlying liver disease.

    Treatment of patients with esophageal varices includes preventing the initial bleeding episode (primary prophylaxis), controlling active variceal hemorrhage, and preventing recurrent bleeding after a first episode (secondary prophylaxis). Data on the optimal management of gastric varices are much more limited, and this topic is not covered in this article.

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  4. 4
    Pathophysiology

    Chronic liver disease leading to cirrhosis is the most common cause of portal hypertension. The level of increased resistance to flow varies with the level of circulatory breach and can be divided into prehepatic, hepatic or sinusoidal, and posthepatic. In cirrhosis, several organ systems are involved in the pathophysiology of portal hypertension. At the splanchnic vascular bed level there is marked vasodilatation and increase in angiogenesis, leading to increase in portal blood flow and formation of collateral circulation, such as gastroesophageal varices, along with decrease in response to vasoconstrictors. At the systemic circulation level, there is an increase in cardiac output, decrease in vascular resistance, and hypervolemia. This hyperkinetic syndrome leads to an effective hypovolemia, with a resultant increase in vasoactive factors to maintain a normal arterial blood pressure.

    Varices represent portosystemic collaterals derived from dilatation of preexisting embryonic vascular channels, such as those between the coronary and short gastric veins and the intercostal, esophageal, and azygous veins. In the distal esophagus, over an area extending 2 to 5 cm from the gastroesophageal junction, veins are found more superficially in the lamina propria rather than the submucosa. This results in reduced support from surrounding tissues owing to the predominant intraluminal location of these varices and might explain the predilection for bleeding at this site. The opening and dilation of portosystemic collaterals appears to depend on a threshold portal pressure gradient (measured as hepatic venous pressure gradient [HVPG]) of 12 mm Hg, below which varices do not form. This pressure gradient is necessary but not sufficient for the development of gastroesophageal varices.

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  5. 5
    Diagnosis

    The current consensus states that every patient with liver cirrhosis should undergo an upper endoscopy to detect gastroesophageal varices. The main aim behind screening for gastroesophageal varices is to identify patients requiring prophylactic treatment or further surveillance. Several invasive and noninvasive procedures help in detecting portal hypertension and can, with variable accuracy, predict the presence of gastroesophageal varices. Unfortunately, none are sensitive enough to replace endoscopy. A recent meta-analysis showed that transient elastography may be a useful screening tool for the detection of significant liver fibrosis and associated portal hypertension, but it is not useful at predicting the presence or size of esophageal varices. Smaller trials have evaluated the usefulness of spleen and liver MR elastography in assessing portal hypertension and varices, but this modality has not yet found its way into clinical practice. The combination of an elastography value below 20 kPa together and a platelet count above 150,000 nearly excludes the presence of esophageal varices requiring treatment. Endoscopic videocapsule is a new modality introduced for visualizing the esophagus; it allows correct identification of varices in 80% of cases but can have poor accuracy in identifying the presence of hypertensive gastropathy and gastric varices.

    Not all esophageal varices bleed; hemorrhage occurs in only 30% to 35% of patients with cirrhosis. Variceal rupture is directly related to physical factors such as the radius, thickness, and elastic properties of the vessel in addition to intravariceal and intraluminal pressure and tension. Endoscopic findings that predict a higher risk of bleeding include larger size of varices and the presence of endoscopic red signs (described as red wale markings) on the variceal wall, indicating dilated intraepithelial and subepithelial superficial veins. A combination of clinical and endoscopic findings, including the Child- Pugh class, size of varices, and the presence or absence of red wale markings, was found to correlate highly with the risk of first bleeding in patients with cirrhosis. Hemodynamic parameters examined as predictors of bleeding include HVPG, azygous blood flow, and direct measurement of intravariceal pressure.

    HVPG, calculated by the gradient of wedged and free hepatic vein pressure (normal value, 5 mm Hg), is used most often and provides reliable measurement of portal pressure in patients with cirrhosis. The extent of elevation of HVPG may be the best indicator of risk of bleeding, severity of bleeding, and survival. A rise in pressure in a patient with known varices increases the risk of bleeding, and the extent of portal pressure elevation has an inverse relationship to prognosis after hemorrhage has occurred. In general, however, a linear relationship between the degree of portal hypertension and the risk of variceal hemorrhage or formation of varices does not exist, so this technique cannot be used routinely to identify individual patients at high risk for bleeding.

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  6. 6
    Treatment

    Primary Prophylaxis

    The natural evolution of gastroesophageal varices without treatment is characterized by an increase in size from small to large varices, which eventually rupture and bleed. The progression rate ranges from 5% to 30% per year. The incidence of bleeding from small esophageal varices is estimated to be 4% per year, and it is as high as 15% per year for medium to large varices. In a randomized, controlled trial, the nonselective β-blocker timolol (Blocadren)1 failed to reduce the development of varices or variceal bleeding in patients without varices. Adverse events were more common in the timolol group.

    Therefore, it is not recommended to start β-blockers in patients who do not yet have esophageal varices.

    Based on prospective studies of cirrhotic patients with varices identified at endoscopy and of untreated groups in randomized controlled trials, the risk of bleeding from esophageal varices has been estimated at 25% to 35% at 1 year. Therapy for primary prophylaxis against variceal bleeding (prevention of a first variceal bleeding) is summarized in Table 1.

    Table 1

    Summary of Therapy for Esophageal Varices

    Abbreviations: HVPG = hepatic venous pressure gradient; TIPS = transjugular intrahepatic portosystemic shunt.

    1  Not FDA approved for this indication.

    2  Not available in the United States.

    5  Investigational drug in the United States.

    * Upon documentation of varices, variceal hemorrhage occurs in 25%–30% of patients by 2 years. β-Blockers reduce the risk to 15%–18%, and combination β-blockers plus nitrates reduce the risk to 7.5%–10%.

    Pharmacologic Therapy

    The general objective of pharmacologic therapy for variceal bleeding is to reduce portal pressure and consequently intravariceal pressure. Drugs that reduce portocollateral venous flow (vasoconstrictors) or intrahepatic vascular resistance (vasodilators) have been used and include β-blockers, nitrates, β2-adrenergic blockers, spironolactone (Aldactone),1pentoxifylline (Trental),1 molsidomine (Corvaton),2 and simvastatin (Zocor).1 Because varices do not bleed at an HVPG less than 12 mm Hg, reduction to this level is ideal, but substantial reductions in HVPG (i.e., by >20%) are also clinically meaningful.

    β-Blockers exert their beneficial effect on portal venous pressure by diminishing splanchnic blood flow and consequently gastroesophageal collateral and azygous blood flow. The effectiveness of β-blockers for primary prophylaxis against variceal bleeding has been demonstrated in several controlled trials. Meta-analyses have revealed a 40% to 50% reduction in bleeding and a trend toward improved survival. The estimated overall response rate is 49%, with bleeding rates of 6% in responders and 32% in nonresponders, with a number needed to treat (NNT) of 10.

    The nonselective β-blockers, such as propranolol (Inderal)1 and nadolol (Corgard),1 are preferred because of the dual benefit of β1- and β2-receptor blockade. In the absence of HVPG determination, β- blockers are titrated to achieve a reduction in resting heart rate to 55 beats/min or 25% of baseline. Propranolol is generally given as a long- acting preparation and titrated to a maximum dose of 320 mg/day.

    Nadolol is initiated at 80 mg daily up to a maximum daily dose of 240 mg. Carvedilol (Coreg)1 is initiated at 6.25 mg daily and increased if tolerated to 12.5 mg/day. Carvedilol is superior to propranolol at reducing portal hypertension although available data do not allow a satisfactory comparison of adverse events. The portal pressure– reducing effects of β-blockers are not predictable; the resultant reduction in heart rate or the measurement of drug blood levels are not good indicators of response to therapy. For example, portal venous pressure is reduced in about 60% to 70% of patients who receive propranolol therapy, but only 10% to 30% of these patients show a substantial response (i.e., >20% reduction). Additionally, approximately 20% to 25% of patients have no measurable decline in portal pressure despite increasing dosage of propranolol. Of note, there is increasing evidence that the use of beta-blockers can be deleterious in patients with decompensated liver cirrhosis and refractory ascites (Sersté) or in patients with spontaneous bacterial peritonitis (Mandorfer).

    In addition to β-blockers, a number of vasodilators have been investigated in patients with portal hypertension and in animal models of portal hypertension, most notably isosorbide mononitrate (Imdur).1 Of note, there is increasing evidence that the use of β- blockers can be deleterious in patients with decompensated liver cirrhosis and refractory ascites or in patients with spontaneous bacterial peritonitis. The exact mechanism of action of nitrates is unclear but is thought to be mediated primarily by reducing intrahepatic resistance and possibly by splanchnic arterial vasoconstriction induced in response to venous pooling and vasodilation in other regional vascular beds. Monotherapy with nitrates is ineffective in primary prophylaxis and can have detrimental effects, particularly in cirrhotic patients with ascites, and should not be used.

    The addition of isosorbide mononitrate to β-blockers, however, has been shown to result in an enhanced reduction in portal pressure in humans. In a randomized, controlled trial involving 42 patients with cirrhosis and esophageal varices, a reduction of greater than 20% in HVPG was documented in only 10% in the propranolol group compared to 50% in the combination therapy group. In patients with Child-Pugh class A and B cirrhosis, the addition of isosorbide mononitrate to nadolol has been shown, in a randomized trial, to result in a greater than 50% additional reduction in variceal bleeding rate when compared with nadolol monotherapy (12% versus 29%).

    However, a large subsequent double-blind, placebo-controlled study failed to confirm these results. Based on the existing evidence, the combination of β-blockers and isosorbide is not recommended in primary prophylaxis.

    Endoscopic Therapy

    Endoscopic therapies play a prominent role in treatment of esophageal varices. Endoscopic band ligation (EBL) is the endoscopic procedure of choice in the management of esophageal varices. As of 2010, 16 randomized, controlled trials have compared EBL to β- blockers in the primary prevention of variceal bleeding. These studies suffered from significant heterogeneity, and a large number were published in abstract form. Two meta-analyses of these trials showed a slight advantage of EBL over β-blockers in terms of primary prevention of variceal bleeding, but there were no differences in mortality. A recent Cochrane database systematic review found a beneficial effect of band ligation compared to β-blockers in primary prevention of upper gastrointestinal bleeding in adult patients with esophageal varices. Again, there was no difference in mortality.

    β-Blockers are cheaper and much easier to administer but are associated with issues of noncompliance and a higher incidence of adverse events (e.g., hypotension, impotence, insomnia) than EBL. However, most of these side effects are easy to manage and none require hospitalization or result in direct mortality. On the other hand, adverse events related to EBL, such as bleeding from band-related ulcers, albeit infrequent, are more significant, often requiring hospitalization and blood transfusion, and may rarely be associated with death.

    According to the Baveno consensus conference, nonselective β- blockers should be considered as a first choice for preventing first variceal bleeding in high-risk patients who have not bled, and EBL should be provided for patients with contraindications or intolerance to β-blockers. The recent guidelines by the American College of Gastroenterology (ACG) and American Association for the Study of Liver Diseases (AASLD) recommend using β-blockers in low-risk patients who have medium to large varices but suggest both EBL and β-blockers for high-risk patients as first-line therapy. The optimal primary prophylaxis in patients with decompensated cirrhosis remains unclear and is arguably expedited liver transplantation. The combination of pharmacologic plus endoscopic therapy has been investigated in such patients with conflicting results. In one study, EBL plus β-blockers offered no benefit in terms of prevention of first bleeding when compared to EBL alone. In a more recent study, combination therapy significantly reduced the occurrence of the first episode of variceal bleeding and improved bleeding-related survival in a group of cirrhotic patients with high-risk esophageal varices awaiting liver transplantation.

    Management of Acute Variceal Hemorrhage

    Variceal hemorrhage is usually an acute clinical event characterized by rapid gastrointestinal blood loss manifesting as hematemesis (which can be massive), with or without melena or hematochezia.

    Hemodynamic instability (tachycardia, hypotension) is common. Although variceal bleeding is common in patients with cirrhosis presenting with acute upper gastrointestinal hemorrhage, other causes of bleeding, such as ulcer disease, must be considered. Urgent initiation of empiric pharmacologic therapy with vasoactive agents is indicated in situations where variceal hemorrhage is likely.

    Subsequently, direct endoscopic examination is critical to establish an accurate diagnosis and to provide the rationale for immediate and subsequent therapies. The immediate steps in the management of acute variceal bleeding include: volume resuscitation, prevention of complications, ensuring hemostasis, and initiating measures to prevent early and delayed rebleeding.

    Patients with variceal hemorrhage and ascites are at increased risk for bacterial infections, particularly spontaneous bacterial peritonitis. This risk appears to be increased in the setting of uncontrolled hemorrhage or as a result of transient bacteremia following endoscopic sclerotherapy or variceal ligation. Short-term systemic antibiotics (e.g., third-generation cephalosporins or fluoroquinolones for 4–10 days) have been shown to decrease the risk of bacterial infections and to reduce rebleeding as well as mortality in cirrhotic patients with gastrointestinal bleeding.

    The role of platelet transfusion or fresh frozen plasma administration has not been assessed appropriately. The use of recombinant activated coagulation factor VII (rFVIIa [Novoseven]),1 which corrects prothrombin time in cirrhotic patients, has been assessed in two randomized, controlled trials. The first trial showed, in a post hoc analysis, that rFVIIa administration might significantly improve the results of conventional therapy in patients with moderate and advanced liver failure (Child-Pugh B and C) without increasing the incidence of adverse events. A more recent trial tested rVIIa in patients with active bleeding at endoscopy and with a Child-Pugh score 8 points or higher. This trial failed to show a benefit of rVIIa in terms of decreasing the risk of 5-day failure, but it did show improved 6-week mortality. In a small prospective study involving cirrhotic patients with acute variceal bleeding and new portal vein thrombosis identified by positive intra-thrombus enhancement on contrast ultrasonography, the use of low molecular weight heparin after hemostasis is achieved by band ligation was shown to be safe, well tolerated, and effective, with complete recanalization of the portal vein within 2 to 11 days and no recurrence of bleeding.

    Pharmacologic Therapy

    Pharmacologic therapy can be administered early, requires no special technical expertise, and is thus a desirable first-line option for managing acute variceal hemorrhage. Drugs that reduce portocollateral venous flow (vasoconstrictors) or intrahepatic vascular resistance (vasodilators) or both have been used to achieve this effect. Vasoconstrictors work by decreasing splanchnic arterial flow, and vasodilators are used in combination with vasoconstrictors to reduce their systemic side effects, but they can also exert an added beneficial effect on intrahepatic resistance (see Table 1).

    Vasopressin and Terlipressin

    Vasopressin (Pitressin)1 is a nonselective vasoconstricting agent that causes a reduction of splanchnic blood flow and thereby a reduced portal pressure. Vasopressin, which is associated with severe vascular complications, has been largely replaced by other vasoconstrictors such as its synthetic analogue, triglycyl-lysine vasopressin (terlipressin [Glypressin]).2 Terlipressin has fewer side effects and a longer biological half-life, allowing its use as a bolus intravenous injection (2 mg every 4 hours for the initial 24 hours, then 1 mg every 4 hours for the next 24–48 hours). Terlipressin has been shown in numerous placebo-controlled trials to control bleeding in about 80% of cases and is the only pharmacologic therapy proven, as of 2010, to reduce mortality from acute variceal hemorrhage. In patients with esophageal variceal bleeding, a 24-hour course of terlipressin was shown to be as effective as a 72-hour course when used as adjunct therapy to successful variceal band ligation. Terlipressin is not currently available in the United States.

    Somatostatin, Octreotide, and Vapreotide

    Somatostatin,2 a naturally occurring peptide, and its analogues, octreotide (Sandostatin)1 and vapreotide (Sanvar),5 stop variceal hemorrhage in up to 80% of patients and are generally considered equivalent to vasopressin (Pitressin), terlipressin2 (Glypressin), and endoscopic therapy for the control of acute variceal bleeding. Their precise mechanism of action is unclear but might result from an effect on the release of vasoactive peptides or from reduction of postprandial hyperemia. Somatostatin is used as a continuous intravenous infusion of 250 µg/hour following a 250-µg bolus injection. Octreotide is used as a continuous infusion of 50 µg/hour and does not require a bolus injection. Side effects are minor, including hyperglycemia and mild abdominal cramps. The addition of octreotide or vapreotide to endoscopic sclerotherapy or banding improves control of bleeding and reduces transfusion requirements, with no change in overall mortality. A continuous infusion of octreotide or vapreotide is therefore recommended for 2 to 5 days following emergency endoscopic therapy.

    Endoscopy

    Endoscopic sclerotherapy stops variceal hemorrhage in 80% to 90% of cases. Its drawbacks include a significant risk of local complications including ulceration, bleeding, stricture, and perforation. Rare systemic complications have been reported including bacteremia with endocarditis, formation of splenic or brain abscesses, and portal vein thrombosis. Randomized trials in patients with acute variceal bleeding have shown that EBL is essentially equivalent to endoscopic sclerotherapy in achieving initial hemostasis with lesser complications. These include superficial ulcerations, transient chest discomfort, and, rarely, stricture formation. Erythromycin infusion before endoscopy1 in patients with acute variceal bleeding has been shown to significantly improve endoscopic visibility and to shorten the duration of the procedure.

    Balloon Tamponade/SEMS

    The use of the Sengstaken-Blakemore or Minnesota tube for hemostasis of variceal bleeding is based on the principle of the application of direct pressure on the bleeding varix by an inflatable— esophageal or gastric—balloon fitted on a rubber nasogastric tube.

    When properly applied, balloon tamponade is successful in achieving immediate hemostasis in almost all cases. However, early rebleeding following balloon decompression is high. Complications of balloon tamponade include esophageal perforation or rupture, aspiration, and asphyxiation from upper airway obstruction. Balloon tamponade or use of SEMS is generally not recommended and should largely be reserved for rescue of cases of hemorrhage uncontrolled by pharmacologic and endoscopic methods and as a temporary bridge to more definitive therapy. Self-expandable metal stents (SEMS) have recently been shown to be effective in controlling severe bleeding.

    Transjugular Intrahepatic Portosystemic Shunt

    Treatment with a transjugular intrahepatic portosystemic shunt (TIPS) consists of the vascular placement of an expandable metal stent across a tract created between a hepatic vein and a major intrahepatic branch of the portal system. TIPS can be successfully performed in 90% to 100% of patients, resulting in hemodynamic changes similar to a partially decompressive side-to-side portocaval shunt while avoiding the morbidity and mortality associated with a major surgical procedure. TIPS has been shown to be effective in treating refractory, uncontrolled, acute variceal bleeding. Patients with advanced liver disease and multiorgan failure at the time of TIPS have a 30-day mortality that approaches 100%.

    Surgery

    Surgery is generally considered in the setting of continued hemorrhage or recurrent early rebleeding—uncontrolled by repeated endoscopic or continued pharmacologic therapy—and when TIPS is not available or is not technically feasible. Surgical options include portosystemic shunting or esophageal staple transection alone or with esophagogastric devascularization and splenectomy (Sugiura procedure). Devascularization procedures may be useful in patients who cannot receive a shunt because of splanchnic venous thrombosis. Regardless of the choice of surgical technique, morbidity is high and the 30-day mortality for emergency surgery approaches 80% in some series. Understandably, rescue liver transplantation is not a practical option in patients with uncontrolled variceal hemorrhage.

    Secondary Prophylaxis

    Variceal hemorrhage recurs in approximately two thirds of patients, most commonly within the first 6 weeks after the initial episode.

    Patients with advanced liver disease (MELD [model for end-stage liver disease] score ≥18) have an increased risk of early rebleeding and death. Early rebleeding (within the first 5 days) is reduced by the adjuvant use of octreotide1 or vapreotide5—and possibly terlipressin2 and somatostatin2—after initial endoscopic or pharmacologic control of hemorrhage.

    The severity of portal hypertension correlates closely with the severity and risk of rebleeding as well as actuarial probability of survival following an index episode. In a cohort of patients presenting with variceal hemorrhage, those with an initial HVPG greater than 20 mm Hg had a 1-year mortality of 64% compared to 20% for patients with lesser elevations in portal pressure. Given the high risk of recurrent hemorrhage and its associated morbidity and mortality, strategies aimed at prevention should be rapidly instituted following the index episode. The choice of preventive therapy should, therefore, take into consideration the efficacy of therapy, the side effects of the selected treatment, the patient’s expected survival, and overall cost.

    Preventive strategies include pharmacologic, endoscopic, and surgical methods and are listed in Table 1. Relative effectiveness of these strategies is shown in Figure 1

    FIGURE 1    Relative effectiveness of available therapies for  preventing recurrent variceal bleeding. The estimates shown are based on the cumulative data available in the literature for recurrent bleeding at 1 year. Abbreviations: EBL = endoscopic band ligation; ES = endoscopic sclerotherapy; TIPS = transjugular intrahepatic portosystemic  shunt.

    Pharmacologic Therapy

    Reducing the portal pressure by more than 20% from the baseline value pharmacologically results in a reduction in the cumulative probability of recurrent bleeding from 28% at 1 year, 39% at 2 years, and 66% at 3 years to 4%, 9%, and 9%, respectively. Although adjustment of medical therapy based on portal pressure measurement would be ideal, HVPG determination might not be readily available, and treatment must be adjusted using empiric clinical parameters.

    Several randomized, controlled trials, including a meta-analysis, have demonstrated that β-blockers prevent rebleeding and prolong survival. The addition of isosorbide mononitrate1 to β-blockers appears to enhance the protective effect of β-blockers alone for preventing recurrent variceal bleeding but offers no survival advantage and reduces the tolerability of therapy. A recent randomized controlled trial showed that carvedilol1 is as effective as the combination of nadolol plus isorsorbide-5 mononitrate in the prevention of gastroesophageal variceal rebleeding, with fewer severe adverse events and similar survival. Compared with either sclerotherapy or endoscopic band ligation, combination medical therapy is superior in reducing the risk of recurrent bleeding in patients with esophageal variceal hemorrhage, primarily in patients with Child-Pugh class A and B cirrhosis. Notably, in patients who show a significant hemodynamic response to therapy (defined as a reduction in the hepatic venous pressure gradient to <12 mm Hg or>20% of the baseline value), the risk of recurrent bleeding and of death is significantly reduced.

    Endoscopy

    Endoscopic therapy has been established over the past decade as a therapeutic cornerstone for preventing esophageal variceal rebleeding. Gastric varices, however, are not effectively treated by sclerotherapy or ligation. Patients with recurrent gastric variceal hemorrhage are best treated by N-butyl-2-cyanoacrylate injection1 or by nonendoscopic means such as TIPS. On the other hand, EBL is highly effective at obliterating esophageal varices and is considered the endoscopic therapy of choice for secondary prophylaxis.

    Combination modality approaches, usually including an endoscopic and pharmacologic treatment, are pathophysiologically attractive and may be more effective than single therapy. Two randomized, controlled trials have shown that adding β-blockers to EBL reduces the risk of rebleeding and variceal recurrence, suggesting that if EBL is used, it should be used in association with β-blockers. One randomized, controlled trial has evaluated whether EBL could improve the efficacy of the combined administration of nadolol1 plus isosorbide.1 In this study, adding band ligation to nadolol plus isosorbide was shown to be superior to nadolol plus isosorbide alone in preventing variceal rebleeding, but there were no significant differences in mortality. The combination of the best endoscopic treatment (EBL) and the best pharmacologic treatment (β-blockers plus isosorbide) may be the best choice in preventing rebleeding but needs further studies for confirmation. Statins improve liver generation of NO and hepatic endothelial dysfunction in experimental models of cirrhosis and may also reduce liver fibrosis. Randomized placebo-controlled trials found that simvastatin1 decreased HVPG and improved liver perfusion and had an additive effect in patients treated with NSBB, and showed survival benefit in patients with early stages of cirrhosis and variceal bleeding.

    Transjugular Intrahepatic Portosystemic Shunt

    Transjugular shunting is more effective than endoscopic therapy for preventing variceal rebleeding but offers no survival benefit. The cumulative risk of rebleeding following TIPS placement is 8% to 18% at 1 year. The trade-off, however, is that TIPS is associated with a higher incidence of clinically significant hepatic encephalopathy (new or worsened portosystemic encephalopathy was noted in about 25% of patients after TIPS). Advanced liver disease is the main determinant of poor outcome following TIPS. Consequently, in patients with advanced liver disease, TIPS is best used as a bridge to liver transplantation.

    TIPS, using bare stents, has been compared with surgical shunts in two studies (8 mm portocaval H-graft shunt in one and distal splenorenal shunt in the second). Although the first study showed a significantly lower rebleeding rate in the surgical group, the second and larger trial did not find any differences in rebleeding rates, hepatic encephalopathy, or mortality, but it found a significantly higher reintervention rate in the TIPS group. However, the obstruction and reintervention rates are markedly decreased with the recent use of polytetrafluoroethylene (PTFE)-covered stents.

    According to these data, TIPS using PTFE-covered stents represents the best rescue therapy for failures of medical and endoscopic treatment.

    Surgery

    Portosystemic shunt surgery is the most effective means by which to reduce portal pressure. Although effective at eradicating varices and preventing rebleeding, nonselective portocaval shunts are associated with a significant incidence of hepatic encephalopathy, portal vein thrombosis, and occasionally liver failure. Commonly used shunts include the distal splenorenal shunt and the low-diameter (mesocaval or portocaval) interposition shunt. Rates of recurrent bleeding are on the order of 10%, with the highest risk of bleeding occurring in the first month after surgery. Devascularization procedures (i.e., esophageal transection and gastroesophageal devascularization) are usually considered in patients who cannot receive shunts because of splanchnic venous thrombosis and should be performed only by experienced surgeons. Surgical therapy has been largely supplanted by TIPS.

    Cost-Effectiveness of Available Therapies

    Data examining the cost of variceal bleeding and the cost-effectiveness of commonly used therapies are limited. The treatment cost of an episode of variceal bleeding has been estimated at $15,000 to $40,000. The cost-effectiveness of diagnostic methods used to guide therapy is unclear. For example, HVPG determination, which can accurately predict pharmacologic response to therapy, is an attractive, although invasive, adjunct in the management of patients with variceal bleeding, but its cost-effectiveness remains in question. Further, screening endoscopy for detecting large varices, while recommended, has not been demonstrated to be cost-effective.

    There are areas in which management is controversial and not standardized. For example, given the right expertise, secondary prophylaxis with surgical shunts or TIPS may be more effective than medical or endoscopic therapy in Child-Pugh class A patients. On the other hand, patients with advanced cirrhosis are often intolerant of β- blockers—let alone in combination with nitrates—and therefore the use of combination therapy remains controversial in such patients.

    Arguably, the preferred treatment for such patients is TIPS as a bridge to early liver transplantation.

    Therefore, when choosing a specific treatment plan, the clinician must take into consideration the direct costs of health care utilization, as well as the efficacy and morbidity of therapy. The treatment chosen should be tailored to fit the patient’s clinical condition while also taking into account the possibility that the patient’s liver disease can progress and thus necessitate transplantation. The cost-effectiveness of various treatment modalities should factor in the cost of failed therapy (e.g., rebleeding, shunt revision) and that of treatment-related complications (e.g., encephalopathy, esophageal stricture).

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    Summary

    Esophageal variceal hemorrhage is a common and devastating complication of portal hypertension and is a leading cause of morbidity and mortality in patients with cirrhosis. Because the clinical outcomes are poor once variceal bleeding has occurred, primary prophylaxis with β-blockers or EBL should be considered in high-risk patients. The treatment of acute variceal hemorrhage is aimed at volume resuscitation and ensuring hemostasis with pharmacologic agents and endoscopic techniques as well as prevention of complications, such as infections by the use of prophylactic antibiotics.

    A high risk of rebleeding after an index episode mandates the institution of preventive strategies. Wedge pressure-guided medical therapy may be the preferred mode of secondary prophylaxis in patients with Child Pugh class A or B cirrhosis, but is invasive and not widely available. Patients at high risk for rebleeding, including those with decompensated or advanced liver disease, should be considered for TIPS followed by liver transplantation when applicable. Treatment with a combination of methods is pathophysiologically attractive, but the choice of therapy should ultimately be tailored to fit the patient’s clinical condition, risk factors, and prognosis, taking into account issues of risk-to-benefit ratio, compliance, and cost.

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    References

    Abraldes JG, Villanueva C, Aracil C, et al: Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis, Gastroenterology 2016 Jan 13. Epub ahead of print.

    Azam Z., Hamid S., Jafri W., et al. Short course adjuvant terlipressin in acute variceal bleeding: a randomized double blind dummy controlled trial. J Hepatol. 2012;56:819–824.

    Bambha K., Kim W.R., Pedersen R., et al. Predictors of early rebleeding and mortality after acute variceal haemorrhage in patients with cirrhosis. Gut. 2008;57:814–820.

    de Franchis R, Baveno VIF: Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension, J Hepatol 63(3):743–752, 2015.

    Feu F., Garcia-Pagan J.C., Bosch J., et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet.

    1995;346:1056–1059.

    Garcia Pagan J.C., De Gottardi A., Bosch J. Review article: the modern management of portal hypertension—primary and secondary prophylaxis of variceal bleeding in cirrhotic patients. Aliment Pharmacol Ther. 2008;28:178–186.

    Garcia-Pagan J.C., Feu F., Bosch J., Rodes J. Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. A randomized controlled study. Ann Intern Med. 1991;114:869–873.

    Gluud L.L., Krag A. Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst Rev. 2012;8: CD004544.

    Laine L., Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A meta-analysis. Ann Intern Med. 1995;123:280–287.

    Lo G.H., Chen W.C., Wang H.M., Yu H.C. Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding. J Gastroenterol Hepatol. 2012;27(11):1681–1687.

    Mandorfer M., Bota S., Schwabl P., et al. Nonselective β-blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis.

    Gastroenterology. 2014;146:1680–1690.

    Maruyama H., Takahashi M., Shimada T., Yokosuka O. Emergency anticoagulation treatment for cirrhosis patients with portal vein thrombosis and acute variceal bleeding. Scand J Gastroenterol. 2012;47:686–691.

    Merkel C., Marin R., Sacerdoti D., et al. Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis.

    Hepatology. 2000;31:324–329.

    Moitinho E., Escorsell A., Bandi J.C., et al. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology. 1999;117:626–631.

    North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices: A prospective multicenter study. N Engl J Med. 1988;319:983–989.

    Polio J., Groszmann R.J. Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment. Semin Liver Dis.

    1986;6:318–331.

    Poynard T., Cales P., Pasta L., et al. β-Adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group. N Engl

    J Med. 1991;324:1532–1538.

    Sersté T., Melot C., Francoz C., et al. Deleterious effects of beta- blockers on survival in patients with cirrhosis and refractory ascites. Hepatology. 2010;52:1017–1022.

    Sharara A.I., Rockey D.C. Gastroesophageal variceal hemorrhage. N Engl J Med. 2001;345:669–681.

    Shi K.Q., Fan Y.C., Pan Z.Z., et al. Transient elastography: a meta-analysis of diagnostic accuracy in evaluation of portal hypertension in chronic liver disease. Liver Int. 2013;33:62–71.

    Sinagra E., Perricone G., D’Amico M. Tiné F, D’Amico G. Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis. Aliment Pharmacol Ther. 2014;39:557–568.

    Villanueva C., Minana J., Ortiz J., et al. Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med. 2001;345:647–655.

    1  Not FDA approved for this  indication.

    2  Not available in the United  States.

    1 Not FDA approved for this indication. 1 Not FDA approved for this indication. 2  Not available in the United  States.

    5  Investigational drug in the United  States.

    1  Not FDA approved for this  indication.

    5  Investigational drug in the United  States.

    2  Not available in the United  States.

    1  Not FDA approved for this  indication.

    1  Not FDA approved for this  indication.

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Genomic Medicine UK is the home of comprehensive genomic testing in London. Our consultant medical doctors work tirelessly to provide the highest standards of medical laboratory testing for personalised medical treatments, genomic risk assessments for common diseases and genomic risk assessment for cancers at an affordable cost for everybody. We use state-of-the-art modern technologies of next-generation sequencing and DNA chip microarray to provide all of our patients and partner doctors with a reliable, evidence-based, thorough and valuable medical service.

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