Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis

Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis Guadalupe Garcia-Tsao,1 Arun J. Sanyal,2 Norman D. Grace,3 William Carey,4 and the Practice Guidelines Committee of the American Association for the Study of Liver Diseases, the Practice Parameters Committee of the American College of Gastroenterology This guideline has been approved by the American Asso- strength or certainty) of evidence to be assigned and re- ciation for the Study of Liver Diseases and the American ported with each recommendation (Table 1, adapted College of Gastroenterology and represents the position from the American College of Cardiology and the Amer- ican Heart Association Practice Guidelines3,4).
When little or no data exist from well-designed pro- Preamble
spective trials, emphasis is given to results from large seriesand reports from recognized experts. Further controlled clin- These recommendations provide a data-supported ap- ical studies are needed to clarify aspects of this statement, and proach to the management of patients with varices and revision may be necessary as new data appear. Clinical con- variceal hemorrhage. They are based on the following: (1)formal review and analysis of the recently published world siderations may justify a course of action that differs from literature on the topic (Medline search); (2) several con- these recommendations. These recommendations are fully sensus conferences among experts; (3) the American Col- endorsed by the American Association for the Study of Liver lege of Physicians’ Manual for Assessing Health Practices Diseases and the American College of Gastroenterology.
and Designing Practice Guidelines1; (4) guideline policies,including the American Association for the Study of Liver Introduction
Diseases’ Policy Statement on Development and Use of Portal hypertension is a progressive complication of Practice Guidelines and the American Gastroenterologi- cirrhosis. Therefore, the management of the patient with cal Association’s Policy Statement on the Use of Medical cirrhosis and portal hypertensive gastrointestinal bleeding Practice Guidelines2; and (5) the authors’ years of experi- depends on the phase of portal hypertension at which the ence caring for patients with cirrhosis and varices.
patient is situated, from the patient with cirrhosis and portal Intended for use by healthcare providers, these recom- hypertension who has not yet developed varices to the pa- mendations suggest preferred approaches to the diagnos-tic, therapeutic, and preventive aspects of care. As with tient with acute variceal hemorrhage for whom the objective other practice guidelines, this guideline is not intended to is to control the active episode and prevent rebleeding.
replace clinical judgment but rather to provide general Practice guidelines for the diagnosis and treatment of guidelines applicable to the majority of patients. They are gastroesophageal variceal hemorrhage, endorsed by the intended to be ﬂexible, in contrast to standards of care, American Association for the Study of Liver Diseases which are inﬂexible policies designed to be followed in (AASLD), American College of Gastroenterology (ACG), every case. Speciﬁc recommendations are based on rele- American Gastroenterological Association (AGA), and vant published information. To more fully characterize the quality of evidence supporting recommendations, the (ASGE), were published in 1997.5 Since then, a number Practice Guidelines Committee of the AASLD requires a of randomized controlled trials have advanced our ap- class (reﬂecting beneﬁt versus risk) and level (assessing proach to managing variceal hemorrhage. Three interna-tional consensus conferences have been held (Baveno IIIin 2000, Baveno IV in 2005, and an AASLD/EASL single 1From the Section of Digestive Diseases, Yale University School of Medicine and topic conference in 2007) in which experts in the ﬁeld VACT Healthcare System, New Haven, CT; 2Division of Gastroenterology, Vir- have evaluated the changes that have occurred in our un- ginia Commonwealth University Medical Center, Richmond, VA; 3Division of derstanding of the pathophysiology and management of Gastroenterology, Brigham and Women’s Hospital, Boston, MA; 4Department ofGastroenterology and Hepatology, The Cleveland Clinic, Cleveland, OH. gastroesophageal hemorrhage.6,7 In this updated practice Copyright 2007 by the American Association for the Study of Liver Diseases. guideline we have reviewed the randomized controlled Published online in Wiley InterScience (www.interscience.wiley.com). trials and meta-analyses published in the last decade and Potential conﬂict of interest: Nothing to report. have incorporated recommendations made by consensus.
Table 1. Grading System for Recommendations
shown to correlate very closely with portal pressure both Classiﬁcation
Description
in alcoholic and non-alcoholic cirrhosis.13 The WHVP isalways corrected for increases in intraabdominal pressure Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure or treatment is (e.g., ascites) by subtracting the free hepatic vein pressure (FHVP) or the intraabdominal inferior vena cava pres- Conditions for which there is conﬂicting evidence and/or a sure, which act as internal zeroes. The resultant pressure is divergence of opinion about the usefulness/efﬁcacy of adiagnostic evaluation, procedure or treatment.
the hepatic venous pressure gradient (HVPG), which is Weight of evidence/opinion is in favor of usefulness/efﬁcacy.
best accomplished with the use of a balloon catheter, usu- Usefulness/efﬁcacy is less well established by evidence/opinion.
ally taking triplicate readings and, when measured with a Conditions for which there is evidence and/or general agreement that a diagnostic evaluation/procedure/treatment is not proper technique, is very reproducible and reliable.14 useful/effective and in some cases may be harmful.
Since it is a measure of sinusoidal pressure, the HVPG will Level of
be elevated in intrahepatic causes of portal hypertension, Evidence
Description
such as cirrhosis, but will be normal in prehepatic causes Data derived from multiple randomized clinical trials or meta- of portal hypertension, such as portal vein thrombosis.
The normal HVPG is 3-5 mmHg. The HVPG and Data derived from a single randomized trial, or changes in HVPG that occur over time have predictive Only consensus opinion of experts, case studies, or standard- value for the development of esophagogastric varices,15,16 the risk of variceal hemorrhage,17-19 the development ofnon-variceal complications of portal hypertension,17,20,21and death.19,21-23 Single measurements are useful in the Pathophysiology of Portal Hypertension in
prognosis of both compensated and decompensated cir- Cirrhosis
rhosis, while repeat measurements are useful to monitorresponse to pharmacological therapy and progression of Cirrhosis, the end stage of any chronic liver disease, can liver disease. Limitations to the generalized use of HVPG lead to portal hypertension. Portal pressure increases ini- measurement are the lack of local expertise and poor ad- tially as a consequence of an increased resistance to ﬂow herence to guidelines that will ensure reliable and repro- mostly due to an architectural distortion of the liver sec- ducible measurements,14 as well as its invasive nature.
ondary to ﬁbrous tissue and regenerative nodules. In ad-dition to this structural resistance to blood ﬂow, there is Natural History of Varices
an active intrahepatic vasoconstriction that accounts for Gastroesophageal varices are the most relevant porto- 20%-30% of the increased intrahepatic resistance,8 and systemic collaterals because their rupture results in that is mostly due to a decrease in the endogenous pro- variceal hemorrhage, the most common lethal complica- duction of nitric oxide.9,10 Portal hypertension leads to tion of cirrhosis. Varices and variceal hemorrhage are the the formation of porto-systemic collaterals. However, complications of cirrhosis that result most directly from portal hypertension persists despite the development of portal hypertension. Patients with cirrhosis and gastro- these collaterals for 2 reasons: (1) an increase in portal esophageal varices have an HVPG of at least 10-12 mm venous inﬂow that results from splanchnic arteriolar va- sodilatation occurring concomitant with the formation of Gastroesophageal varices are present in approximately collaterals11; and (2) insufﬁcient portal decompression 50% of patients with cirrhosis. Their presence correlates through collaterals as these have a higher resistance than with the severity of liver disease (Table 2); while only 40% that of the normal liver.12 Therefore, an increased portal of Child A patients have varices, they are present in 85% pressure gradient results from both an increase in resis- of Child C patients.25 Patients with primary biliary cir- tance to portal ﬂow (intrahepatic and collateral) and an rhosis may develop varices and variceal hemorrhage early in the course of the disease even in the absence of estab-lished cirrhosis.26 It has also been shown that 16% of Evaluation of Portal Hypertension
patients with hepatitis C and bridging ﬁbrosis have esoph- The preferred, albeit indirect, method for assessing portal pressure is the wedged hepatic venous pressure Patients without varices develop them at a rate of 8% (WHVP) measurement, which is obtained by placing a per year,16,28 and the strongest predictor for development catheter in the hepatic vein and wedging it into a small of varices in those with cirrhosis who have no varices at the branch or, better still, by inﬂating a balloon and occluding time of initial endoscopic screening is an HVPG Ͼ10 a larger branch of the hepatic vein. The WHVP has been mmHg.16 Patients with small varices develop large varices Table 2. Child-Pugh Classiﬁcation of the Severity of Cirrhosis
*5-6 points: Child A; 7-9 points: Child B; 10-15 points: Child C.
at a rate of 8% per year. Decompensated cirrhosis (Child mmHg or at least 20% from baseline levels (“HVPG re- B/C), alcoholic cirrhosis, and presence of red wale marks sponders”) not only have a lower probability of develop- (deﬁned as longitudinal dilated venules resembling whip ing recurrent variceal hemorrhage,36 but also have a lower marks on the variceal surface) at the time of baseline en- risk of developing ascites, spontaneous bacterial peritoni- doscopy are the main factors associated with the progres- Variceal hemorrhage occurs at a yearly rate of 5%- Gastric Varices
15%, and the most important predictor of hemorrhage is Gastric varices are less prevalent than esophageal vari- the size of varices, with the highest risk of ﬁrst hemorrhage ces and are present in 5%-33% of patients with portal (15% per year) occurring in patients with large varices.29 hypertension with a reported incidence of bleeding of Other predictors of hemorrhage are decompensated cir- about 25% in 2 years, with a higher bleeding incidence rhosis (Child B/C) and the endoscopic presence of red for fundal varices.38 Risk factors for gastric variceal wale marks.29 Although bleeding from esophageal varices hemorrhage include the size of fundal varices ceases spontaneously in up to 40% of patients, and de- (largeϾmediumϾsmall, deﬁned as Ͼ10 mm, 5-10 mm, spite improvements in therapy over the last decade, it is and Ͻ5 mm, respectively), Child class (CϾBϾA), and associated with a mortality of at least 20% at 6 weeks.30-32 endoscopic presence of variceal red spots (deﬁned as lo- Patients with an HVPG Ͼ20 mmHg (measured within calized reddish mucosal area or spots on the mucosal sur- 24 hours of variceal hemorrhage) have been identiﬁed as face of a varix).39 Gastric varices are commonly classiﬁed being at a higher risk for early rebleeding (recurrent bleed- based on their relationship with esophageal varices as well ing within the ﬁrst week of admission) or failure to con- as their location in the stomach.38 Gastroesophageal var- trol bleeding (83% vs. 29%) and a higher 1-year mortality ices (GOV) are an extension of esophageal varices and are (64% vs. 20%) compared to those with lower pres- categorized into 2 types. The most common are Type 1 sure.33,34 Late rebleeding occurs in approximately 60% of (GOV1) varices, which extend along the lesser curvature.
untreated patients, mostly within 1-2 years of the index They are considered extensions of esophageal varices and should be managed similarly. Type 2 (GOV2) gastric var- Variceal wall tension is probably the main factor that ices extend along the fundus and tend to be longer and determines variceal rupture. Vessel diameter is one of the more tortuous. Isolated gastric varices (IGV) occur in the determinants of variceal tension. At an equal pressure, a absence of esophageal varices and are also classiﬁed into 2 large diameter vessel will rupture while a small diameter types. Type 1 (IGV1) are located in the fundus and tend vessel will not rupture.37 Besides vessel diameter, one of to be tortuous and complex, and type 2 (IVG2) are lo- the determinants of variceal wall tension is the pressure cated in the body, antrum, or around the pylorus. The within the varix, which is directly related to the HVPG.
presence of IGV1 fundal varices requires excluding the Therefore, a reduction in HVPG should lead to a decrease presence of splenic vein thrombosis.
in variceal wall tension, thereby decreasing the risk ofrupture. Indeed, variceal hemorrhage does not occur Diagnosis of Varices and Variceal
when the HVPG is reduced to Ͻ12 mmHg.17,20 It has Hemorrhage
also been shown that the risk of rebleeding decreases sig-niﬁcantly with reductions in HVPG greater than 20% The gold standard in the diagnosis of varices is esopha- from baseline.18 Patients whose HVPG decreases to Ͻ12 gogastroduodenoscopy (EGD). In a consensus meeting it was recommended that the size classiﬁcation be as simple Table 3. Effect on Portal Flow, Resistance and Pressure with
as possible, i.e., in 2 grades (small and large),40 either by the Different Therapies for Varices/Variceal Hemorrhage
semiquantitative morphological assessment or by quanti- tative size with a suggested cut-off diameter of 5 mm, with Treatment
resistance
pressure
large varices being those greater than 5 mm. When varices are classiﬁed in 3 sizes—small, medium, or large—as oc- curs in most centers by a semiquantitative morphological assessment (with small varices generally deﬁned as mini- *Although theoretically nitrates act by decreasing resistance, they actually act mally elevated veins above the esophageal mucosal sur- by decreasing portal ﬂow through a decrease in mean arterial pressure.
face, medium varices deﬁned as tortuous veins occupyingless than one-third of the esophageal lumen, and largevarices deﬁned as those occupying more than one-third of varices, the EGD should be repeated in 1-2 years.6 In the the esophageal lumen), recommendations for medium- presence of decompensated cirrhosis, EGD should be re- sized varices are the same as for large varices,29 because this is how they were grouped in prophylactic trials.
EGD is expensive and usually requires sedation. It can As shown below, nonselective ␤-blockers prevent be avoided in patients with cirrhosis who are already on bleeding in more than half of patients with medium or nonselective ␤-blockers for other reasons (e.g., arterial large varices. Therefore, it is recommended that patients hypertension. In those on a selective ␤-blocker (metopro- with cirrhosis undergo endoscopic screening for varices at lol, atenolol) for other reasons, switching to a nonselective the time of diagnosis.41,42 Since the point prevalence of ␤-blocker (propranolol, nadolol) would be necessary. A medium/large varices is approximately 15%-25%,25 the procedure that may replace EGD is esophageal capsule majority of subjects undergoing screening EGD either do endoscopy. Two recent pilot studies show that capsule not have varices or have varices that do not require pro- endoscopy is a safe and well-tolerated way to diagnose phylactic therapy. There is, therefore, considerable inter- esophageal varices,47,48 although its sensitivity remains to est in developing models to predict the presence of high- be established. Thus, capsule endoscopy may play a future risk varices by non-endoscopic methods. Several studies role in screening for esophageal varices if additional larger have evaluated possible noninvasive markers of esopha- geal varices in patients with cirrhosis, such as the platelet EGD also remains the main method for diagnosing count, Fibrotest, spleen size, portal vein diameter, and variceal hemorrhage.7,41 The diagnosis of variceal hemor- transient elastography.43,44 However, the predictive accu- rhage is made when diagnostic endoscopy shows one of racy of such noninvasive markers is still unsatisfactory, the following: active bleeding from a varix, a “white nip- and until large prospective studies of noninvasive markers ple” overlying a varix, clots overlying a varix, or varices are performed, endoscopic screening is still the main with no other potential source of bleeding.40 means of assessing for the presence of esophageal varices.43 Cost-effective analyses using Markov models have sug- Recommendations
gested either empiric ␤-blocker therapy for all patients 1. Screening esophagogastroduodenoscopy (EGD)
with cirrhosis45 or screening endoscopy for patients with for the diagnosis of esophageal and gastric varices is
compensated cirrhosis, and universal ␤-blocker therapy recommended when the diagnosis of cirrhosis is made
without screening EGD for patients with decompensated (Class IIa, Level C).
cirrhosis.46 Neither of these strategies considers a recent 2. On EGD, esophageal varices should be graded as
trial showing that ␤-blockers do not prevent the develop- small or large (>5 mm) with the latter classiﬁcation
ment of varices and are associated with signiﬁcant side encompassing medium-sized varices when 3 grades are
effects,16 nor do they consider endoscopic variceal ligation used (small, medium, large). The presence or absence
as an alternative prophylactic therapy. Until prospective of red signs (red wale marks or red spots) on varices
studies validate these approaches, screening EGD is still should be noted (Class IIa, Level C).
Management Recommendations
The frequency of surveillance endoscopies in patients with no or small varices depends on their natural history.
Rationale for the management of varices
EGD should be performed once the diagnosis of cirrhosis Current therapies for the management of varices/ is established.6,41 In patients with compensated cirrhosis variceal hemorrhage and their effect on portal venous in- who have no varices on screening endoscopy, the EGD ﬂow, portal resistance, and portal pressure are should be repeated in 2-3 years.6 In those who have small summarized in Table 3. Pharmacological therapy consists of splanchnic vasoconstrictors (vasopressin and ana- hepatic decompensation, EGD should be done at that
time and repeated annually (Class I, Level C).
␤-blockers) and venodilators (nitrates). Vasoconstrictorsact by producing splanchnic vasoconstriction and reduc- B. Patients with Cirrhosis and Small
ing portal venous inﬂow. Venodilators theoretically act by Varices That Have Not Bled
decreasing intrahepatic and/or portocollateral resistance.
A meta-analysis of trials evaluating nonselective However, all available venodilators (e.g., isosorbide ␤-blockers (i.e., propranolol, nadolol) in the prevention mononitrate) have a systemic hypotensive effect and the of ﬁrst variceal hemorrhage (primary prophylaxis) an- decrease in portal pressure appears to be more related to alyzed the results of 3 trials that included patients with hypotension (i.e., a decrease in ﬂow) rather than a de- small varices.35 In this meta-analysis, the incidence of crease in resistance.49 The combination of a vasoconstric- ﬁrst variceal hemorrhage was quite low (7% over 2 tor and a vasodilator has a synergistic portal pressure- years), and although it was reduced with ␤ -blockers reducing effect.50,51 Endoscopic therapies, such as (2% over 2 years), this reduction was not statistically sclerotherapy or endoscopic variceal ligation (EVL), are local therapies that have no effect on either portal ﬂow or Two studies have investigated the efﬁcacy of nonselec- resistance. Shunting therapy, either radiological (tran- tive ␤-blockers in preventing the enlargement of small sjugular intrahepatic portosystemic shunt) or surgical, by varices, with contradictory results. In the ﬁrst study,52 the bypassing the site of increased resistance, markedly re- 2-year proportion of patients with large varices was unex- duces portal pressure by bypassing the site of increased pectedly larger in the propranolol group compared to the placebo group (31% vs. 14%). However, the study en-rolled patients with no and small varices and over a third A. Patients with Cirrhosis and No Varices
of the patients were lost to follow-up. Another large mul- A large multicenter, placebo-controlled, double- ticenter, placebo-controlled, but single-blinded trial, blinded trial failed to show a beneﬁt of nonselective showed that patients with small varices treated with nado- ␤-blockers (timolol) in the prevention of varices in pa- lol had a signiﬁcantly slower progression to large varicestients with cirrhosis who had portal hypertension at base- (11% at 3 years) than patients who were randomized to line (HVPG Ͼ5 mmHg) but had not yet developed placebo (37% at 3 years), with no differences in survival.53 varices.16 The study did show, however, that patients who The risk of variceal bleeding was lower in patients who achieved even a mild reduction in HVPG after 1 year of started treatment with ␤-blockers when varices were small therapy (Ն10% from baseline) had a signiﬁcantly lower (12% at 5 years) compared with patients who started development of varices, and that a larger percentage of ␤-blockers once large varices were observed (22% at 5 patients on timolol showed this reduction in HVPG com- years). However, this beneﬁt was related to the longer pared to those on placebo. A signiﬁcantly larger number time patients remained in a condition of low-risk (i.e., of patients with moderate or severe adverse events were small) varices, given that once large varices developed and observed in the timolol group (48%) compared to the all patients were treated with ␤-blockers, the risk of bleed- placebo group (32%). Serious symptomatic adverse ing was very similar.53 Similar to other studies, a higher events occurred in 20 patients (18%) in the timolol group percentage of patients on ␤-blockers had to be withdrawn and in 6 patients (6%) in the placebo group. These results from the study because of adverse events (11%) compared do not support the suggested universal use of ␤-blockers to patients on placebo (1%). Prophylaxis with ␤-blockers in cirrhosis.45 Given the natural history of varices, expert should be used in patients with small varices who are at a consensus panels have determined that surveillance en- high risk for bleeding; that is, those with advanced liver doscopies should be performed every 2-3 years in these disease and the presence of red wale marks on varices.7 patients, and annually in the setting of decompensa- Other patients with small varices can receive ␤-blockers to prevent variceal growth, although their long-term beneﬁthas not been well established. In those who choose not to Recommendations
take ␤-blockers, expert consensus panels have determined 3. In patients with cirrhosis who do not have var-
that surveillance endoscopies should be performed every 2 ices, nonselective ␤-blockers cannot be recommended
years, and annually in the setting of decompensation.6,42 to prevent their development (Class III, Level B).
4. In patients who have compensated cirrhosis and
Recommendations
no varices on the initial EGD, it should be repeated in
5. In patients with cirrhosis and small varices that
3 years (Class I, Level C). If there is evidence of
have not bled but have criteria for increased risk of
hemorrhage (Child B/C or presence of red wale marks
a dose of 20 milligrams (mg) twice a day (BID). Nadolol on varices), nonselective ␤-blockers should be used for
is is usually started at a dose of 40 mg once a day (QD).
the prevention of ﬁrst variceal hemorrhage (Class IIa,
Because a randomized trial showed that the risk of bleed- Level C).
ing recurs when treatment with ␤-blockers is stopped,59 6. In patients with cirrhosis and small varices that
prophylactic therapy should be continued indeﬁnitely.
have not bled and have no criteria for increased risk
Approximately 15% of patients from trials have rela- of bleeding, ␤-blockers can be used, although their
tive contraindications to the use of ␤-blockers, such as long-term beneﬁt has not been established (Class III,
asthma, insulin-dependent diabetes (with episodes of hy- Level B).
poglycemia), and peripheral vascular disease.60 The most 7. In patients with small varices that have not bled
common side effects related to ␤-blockers in cirrhosis are and who are not receiving ␤-blockers, EGD should be
lightheadedness, fatigue, and shortness of breath. Al- repeated in 2 years (Class I, Level C). If there is
though some of these side effects disappear with time or evidence of hepatic decompensation, EGD should be
after dose reduction, treatment withdrawal occurs in 15% done at that time and repeated annually (Class I,
of patients. Trials in which nadolol was used have re- Level C). In patients with small varices who receive
ported lower rates of side effects (Ϸ10%) than those in- ␤-blockers, a follow-up EGD is not necessary.
comparisons have not been performed.
C. Patients with Cirrhosis and Medium/
Endoscopic variceal ligation (EVL) has been com- Large Varices That Have Not Bled
pared to ␤-blockers in several randomized trials in pa- A meta-analysis of 11 trials that included 1,189 pa- tients with high-risk varices (large varices with or without tients evaluating nonselective ␤-blockers (i.e., proprano- red wale markings). Two recent meta-analyses of these lol, nadolol) versus non-active treatment or placebo in the trials have been performed: the ﬁrst included 8 trials and prevention of ﬁrst variceal hemorrhage shows that the risk comprised 596 subjects (285 with EVL, 311 with of ﬁrst variceal bleeding in patients with large- or medium- ␤-blockers)61; and the second included 12 studies com- sized varices is signiﬁcantly reduced by ␤-blockers (30% prising 839 subjects (410 with EVL, 429 with ␤-block- in controls vs. 14% in ␤-blocker-treated patients),35 and ers).62 Both showed that EVL is associated with a small indicates that 1 bleeding episode is avoided for every 10 but signiﬁcant lower incidence of ﬁrst variceal hemor- patients treated with ␤-blockers. Mortality is also lower in rhage without differences in mortality. The results are the the ␤-blocker group compared with the control group same when only fully published trials or high-quality trials and this difference has recently been shown to be statisti- are analyzed. Although the EVL group has a signiﬁcantly cally signiﬁcant.54 Additionally, a cost-effectiveness study lower rate of adverse events (4% vs. 13%), the EVL events comparing nonselective ␤-blockers, sclerotherapy, and are more severe and include bleeding from ligation-in- shunt surgery shows that ␤-blockers were the only cost- duced esophageal ulcers in 10 patients (with 2 fatal out- effective form of prophylactic therapy.55 comes) and overtube-induced esophageal perforation in 1 Nonselective ␤-blockers (propranolol, nadolol) reduce patient. This last complication is currently less likely to portal pressure by decreasing cardiac output (␤-1 effect) occur given the use of multi-band ligation devices that and, more importantly, by producing splanchnic vaso- minimize the use of overtubes for band placement. In the constriction (␤-2 effect), thereby reducing portal blood ␤-blocker group, severe adverse events necessitating with- ﬂow. Selective ␤-blockers (atenolol, metoprolol) are less drawal (hypotension, fatigue, shortness of breath) re- effective and are suboptimal for primary prophylaxis of solved after discontinuation of the medication, although variceal hemorrhage. A decrease in HVPG Ͻ12 mmHg 10 patients bled on withdrawal of ␤-blockers (with 2 fatal essentially eliminates the risk of hemorrhage and im- outcomes). One of the more recent studies included in proves survival,17 while reductions Ͼ20% from baseline56 these meta-analyses had to be stopped before the planned or even Ͼ10% from baseline57 signiﬁcantly decrease the number of patients was enrolled and after a mean fol- low-up of only 18 months, because interim analysis In the majority of the published studies, the dose of showed a signiﬁcantly higher number of treatment “fail- ␤-blockers was titrated to decrease the heart rate 25% ures” (bleeding or a severe side effect) in the propranololfrom baseline. However, since HVPG measurement is group compared to the EVL group (6 vs. 0).63 The unfor- not widely available and a reduction in heart rate does not tunate premature discontinuation of this trial is discussed correlate with reduction in HVPG,58 the dose of nonse- in recent editorials that argue that bleeding rates were not lective ␤-blockers (propranolol, nadolol) is adjusted to signiﬁcantly different between groups, and that only one maximal tolerated doses. Propranolol is usually started at “failure” in the EVL group would have rendered the dif- ferences non-signiﬁcant.64,65 In contrast, the 2 largest ran- mortality in these patients by aggravating the vasodilatory domized trials66,67 and a more recent trial,68 not included state of the cirrhotic patient,77 as shown in shorter-term in the above cited meta-analyses, have shown that EVL is hemodynamic trials using other vasodilators such as losar- equivalent to nadolol66 or to propranolol67,68 in prevent- tan78 and irbesartan.79 In fact, in a recent multicenter ing the ﬁrst variceal hemorrhage. After careful review of trial, 133 cirrhotic patients with varices and contraindica- the available data, a recent consensus panel of experts tions or intolerance to ␤-blockers were randomized to concluded that both nonselective ␤-blockers and EVL are ISMN (n ϭ 67) or to placebo (n ϭ 66).80 Surprisingly, effective in preventing ﬁrst variceal hemorrhage and there was a greater 1- and 2-year probability of ﬁrst therefore the decision should be based on patient charac- variceal hemorrhage in the ISMN group (p ϭ 0.056), teristics and preferences, local resources and expertise.
with no differences in survival. Side effects were morefrequent in patients receiving ISMN. These results were Therapies not recommended for primary prophy-
further supported in another randomized trial of cirrhotic patients with ascites.81 Therefore, nitrates alone should The combination of a nonselective ␤-blocker and not be used in patients with cirrhosis.
isosorbide mononitrate (ISMN) has a synergistic portal Shunt surgery trials have shown conclusively that, al- pressure-reducing effect and could theoretically be more though very effective in preventing ﬁrst variceal hemor- effective than ␤-blockers alone in preventing ﬁrst variceal rhage, shunting blood away from the liver is accompanied hemorrhage.51 In fact, a non-blinded trial comparing by more frequent encephalopathy and higher mortality.82 nadolol alone with nadolol plus ISMN demonstrated a These results can be extrapolated to the transjugular in- signiﬁcantly lower rate of ﬁrst hemorrhage in the group trahepatic portosystemic shunt (TIPS) because its physi- treated with combination therapy.69 These results were ology is the same as that of surgical shunts (i.e., diversion maintained after 55 months of follow-up, without differ- of blood away from the liver).83 Therefore, shunt therapy ences in survival.70 However, 2 more recent larger double- (surgery or TIPS) should not be used in the primary pre- blinded, placebo-controlled trials were unable to conﬁrm these favorable results,71,72 and a greater number of side Endoscopic sclerotherapy trials have yielded contro- effects were noted in the combination therapy group.71 versial results. While early studies showed promising re- Therefore, the use of a combination of a ␤-blocker and sults, later studies showed no beneﬁt.82,84 A VA ISMN cannot be recommended currently for primary prospective, randomized, cooperative trial comparing prophylaxis until there is further proof of efﬁcacy.
prophylactic sclerotherapy and sham therapy had to be The combination of a nonselective ␤-blocker and spi- terminated 22.5 months after it began because the mor- ronolactone (which has been shown to lower portal pres- tality rate was signiﬁcantly higher in the sclerotherapy sure by reducing plasma volume and splanchnic blood ﬂow) group than in the sham-therapy group.85 Sclerotherapy has been recently examined in a preliminary double-blind, should therefore not be used for the primary prevention of placebo-controlled trial.73 The results suggest that the addi- tion of spironolactone does not increase the efﬁcacy of nado-lol in the prophylaxis of ﬁrst variceal hemorrhage.
Recommendations
The role of combination of a nonselective ␤-blocker 8. In patients with medium/large varices that have
and EVL in the prevention of ﬁrst variceal hemorrhage not bled but have a high risk of hemorrhage (Child
was recently evaluated in a randomized but not placebo- B/C or variceal red wale markings on endoscopy),
controlled trial performed in patients with and without nonselective ␤-blockers (propranolol or nadolol) or
cirrhosis who had high-risk varices.74 There were no dif- EVL may be recommended for the prevention of ﬁrst
ferences in the incidence of bleeding or death between variceal hemorrhage (Class I, Level A).
groups, and even though varices recurred more frequently 9. In patients with medium/large varices that have
in the EVL alone group, side effects were more common not bled and are not at the highest risk of hemorrhage
in the EVL ϩ propranolol group. Given the lack of dif- (Child A patients and no red signs), nonselective
ferences in the primary outcomes, combination therapy ␤-blockers (propranolol, nadolol) are preferred and
EVL should be considered in patients with contrain-
ISMN alone was shown in one study to be as effective dications or intolerance or non-compliance to
as propranolol in preventing ﬁrst variceal hemorrhage.75 ␤-blockers (Class I, Level A).
However, long-term follow-up of patients enrolled in this 10. If a patient is placed on a nonselective
study showed higher mortality in patients older than 50 ␤-blocker, it should be adjusted to the maximal tol-
years.76 ISMN, a potent venodilator, may lead to a higher erated dose; follow-up surveillance EGD is unneces-
sary. If a patient is treated with EVL, it should be
can be recommended in patients with coagulopathy and repeated every 1-2 weeks until obliteration with the
ﬁrst surveillance EGD performed 1-3 months after
Cirrhotic patients with upper GI bleeding have a high obliteration and then every 6-12 months to check for
risk of developing severe bacterial infections (spontaneous variceal recurrence (Class I, Level C).
bacterial peritonitis and other infections) that are associ- 11. Nitrates (either alone or in combination with
ated with early recurrence of variceal hemorrhage and a ␤-blockers), shunt therapy, or sclerotherapy should greater mortality.90,91 Although patients with less-severe
not be used in the primary prophylaxis of variceal
liver disease (i.e., Child A) are at an increased risk of hemorrhage (Class III, Level A).
developing bacterial infections, this risk is highest in thosewith more severe liver disease (i.e., Child B and C).92,93 D. Patients with Cirrhosis and an Acute
The use of short-term prophylactic antibiotics in patients Episode of Variceal Hemorrhage
with cirrhosis and GI hemorrhage with or without asciteshas been shown not only to decrease the rate of bacterial There is evidence that current treatment strategies for infections but also to increase survival.94,95 This improved acute variceal hemorrhage, including general and speciﬁc survival is partly related to a decrease in the incidence of measures, have resulted in an improved survival both in early rebleeding in patients with variceal hemorrhage who receive prophylactic antibiotics.96 Therefore, short-termantibiotic prophylaxis should be considered standard D.1. General measures
practice in all patients with cirrhosis and acute varicealhemorrhage.97 The recommended antibiotic schedule is Patients with suspected acute variceal hemorrhage norﬂoxacin administered orally at a dose of 400 mg BID should be admitted to an intensive care unit setting for for 7 days.97 The rationale behind the oral administration resuscitation and management. Initial resuscitation in- of norﬂoxacin, a poorly absorbed quinolone, is the selec- volves basic measures including assessing the patient’s air- tive eradication (or at least reduction) of gram-negative way and obtaining peripheral venous access.
bacteria in the gut, the source of bacteria. However, quin- Blood volume resuscitation should be undertaken olone antibiotics with similar spectrum of activity, such as promptly but with caution, with the goals of maintaining ciproﬂoxacin, could also be recommended. When oral hemodynamic stability and a hemoglobin of approxi- administration is not possible, quinolones can be admin- mately 8 g/dL.7 This recommendation is based on exper- istered intravenously (IV). In a recent study performed in imental studies that show that restitution of all lost blood patients with advanced cirrhosis (Child B/C) and GI leads to increases in portal pressure to levels higher than hemorrhage, IV ceftriaxone (1 g/day) was more effective baseline,87 and to more rebleeding and mortality.88 Sim- than oral norﬂoxacin in preventing bacterial infections,98 ilarly, vigorous resuscitation with saline solution should mostly those due to gram-negative organisms. The prev- generally be avoided because, in addition to possibly pre- alence of quinolone-resistant organisms in the study cen- cipitating recurrent variceal hemorrhage, this can worsen ters was not speciﬁed and this could have contributed or precipitate the accumulation of ascites or ﬂuid at other extravascular sites. Given that aspiration of blood can oc-cur, elective or more emergent tracheal intubation may be D.2. Speciﬁc measures to control acute
required for airway protection prior to endoscopy, partic- hemorrhage and prevent early recurrence
ularly in patients with concomitant hepatic encephalopa- Pharmacological therapy has the advantages of being generally applicable and capable of being initiated as soon The transfusion of fresh frozen plasma and platelets as a diagnosis of variceal hemorrhage is suspected, even can be considered in patients with signiﬁcant coagulopa- prior to diagnostic EGD. A recent meta-analysis of 15 thy and/or thrombocytopenia. A multicenter placebo- trials comparing emergency sclerotherapy and pharmaco- controlled trial of recombinant factor VIIa (rFVIIa) in logical treatment (vasopressin Ϯ nitroglycerin, terlipres- cirrhotic patients with gastrointestinal hemorrhage failed sin, somatostatin, or octreotide) shows a similar efﬁcacy to show a beneﬁcial effect of rFVIIa over standard therapy.89 with fewer side effects with pharmacological therapy, Although post hoc analysis of a subpopulation of Child- thereby suggesting that pharmacological therapy should Pugh B and C cirrhotic patients indicated that adminis- be considered ﬁrst-line treatment of variceal bleeding.99 tration of rFVIIa signiﬁcantly decreased the proportion of Beta-blockers should not be used in the acute setting as patients with failure to control variceal bleeding, conﬁr- they will decrease blood pressure and will blunt a physio- matory studies are needed before this expensive therapy logic increase in heart rate associated with bleeding.
Vasopressin is the most potent splanchnic vasocon- Even though pharmacological therapy, particularly safe strictor. It reduces blood ﬂow to all splanchnic organs, pharmacological therapy, should be initiated once the di- thereby leading to a decrease in portal venous inﬂow and agnosis of variceal hemorrhage is suspected, EGD should to a decrease in portal pressure. The clinical usefulness of be performed as soon as possible after admission (e.g., vasopressin is limited by its multiple side effects, which within 12 h) and endoscopic therapy should be performed are related to its potent vasoconstrictive properties, in- if the suspected variceal source of hemorrhage is con- cluding cardiac and peripheral ischemia, arrhythmias, hy- ﬁrmed.7 Regarding the best endoscopic therapy, a meta- pertension, and bowel ischemia.60 Although its efﬁcacy analysis of 10 randomized controlled trials including 404 and safety are signiﬁcantly improved by the addition of patients shows an almost signiﬁcant beneﬁt of EVL in the nitrates,50 side effects of combination therapy are still initial control of bleeding compared to sclerotherapy higher than those associated with terlipressin, somatosta- (pooled relative risk of 0.53 with a conﬁdence interval of tin, or somatostatin analogues35 and, therefore, it can only 0.28-1.01).62 In addition, one of the studies included in be used continuously at the highest effective dose for a the meta-analysis showed that although HVPG increased maximum of 24 hours to minimize the development of signiﬁcantly immediately after both EVL and sclerother- side effects. Vasopressin is administered at a continuous apy, it remained elevated for the duration of the study (5 IV infusion of 0.2-0.4 units/minute that can be increased days) in the sclerotherapy group while HVPG had de- to a maximal dose of 0.8 units/minute. It should always be creased to baseline levels by 48 hours after EVL.104 There- accompanied by IV nitroglycerin at a starting dose of 40 fore, by consensus, EVL is the preferred form of ␮g/minute, which can be increased to a maximum of 400 endoscopic therapy for acute esophageal variceal bleed- ␮g/minute, adjusted to maintain a systolic blood pressure ing, although sclerotherapy is recommended in patients in whom EVL is not technically feasible.7 Terlipressin, a synthetic analogue of vasopressin that Combination of pharmacological therapy and endo- has a longer biological activity and signiﬁcantly fewer side scopic therapy is the most rational approach in the treat- effects, is effective in controlling acute variceal hemor- ment of acute variceal hemorrhage. The use of rhage and has been associated with a decreased mortality,35 pharmacological agents with few side effects allows pro- but is not yet available in the United States. Terlipressin is longing therapy to 5 days, the period during which the administered at an initial dose of 2 mg IV every 4 hours risk of rebleeding is the highest. A meta-analysis of 8 trials and can be titrated down to 1 mg IV every 4 hours once showed that, compared to endoscopic therapy alone (scle- rotherapy or EVL), endoscopic plus pharmacological (oc- Somatostatin and analogues such as octreotide and va- treotide, somatostatin, vapreotide) therapy improved the preotide also cause splanchnic vasoconstriction at phar- initial control of bleeding and 5-day hemostasis without macological doses. Although it has been considered that differences in mortality or severe adverse events.105 this effect is due to an inhibition of the release of vasodi-latory peptides (mainly glucagon), recent studies suggest Rescue therapies
that octreotide has a local vasoconstrictive effect. The ad- Despite urgent endoscopic and/or pharmacological vantage of somatostatin and analogues such as octreotide therapy, variceal bleeding cannot be controlled or recurs and vapreotide is that they are safe and can be used con- early in about 10%-20% of patients. An elevated HVPG tinuously for 5 days or even longer. Of these, only oct- Ͼ20 mmHg (measured within 24 hours of presentation) reotide is available in the United States and it has been has been shown to be predictive of treatment failure.33 mostly used as an initial IV bolus of 50 ␮g followed by a Shunt therapy, either shunt surgery (in Child A patients) continuous infusion of 50 ␮g/hour. Use of somatostatin or TIPS, has proven clinical efﬁcacy as salvage therapy for consists of a 250 ␮g IV bolus followed by infusion of 250 patients who fail to respond to endoscopic or pharmaco- ␮g/hour. Vapreotide is given as a 50 ␮g IV bolus followed logical therapy.106,107 A surgical group has reported al-by infusion of 50 ␮g per hour. However, results of meta- most universal control of bleeding and a low mortality analyses of trials of octreotide are controversial35,100 and a with the performance of portocaval shunt within 8 hours more recent meta-analysis of trials of somatostatin ana- of onset of bleeding in unselected cirrhotic patients col- logues in general showed a negligible beneﬁcial effect.101 lected over a 30-year period.108 This approach has not The reason octreotide alone may not be useful is because been validated by other groups and is not widely prac- its administration has been associated with tachyphy- ticed. More recently, a small study has suggested that early laxis102 and a more transient effect when compared to TIPS placement (within 24 hours of hemorrhage) is asso- terlipressin.103 However, as shown below, octreotide ap- ciated with a signiﬁcant improvement in survival in pears to be useful as an adjunct to endoscopic therapy.
“high-risk” patients (deﬁned as those with an HVPG Ͼ20 mmHg) with acute variceal hemorrhage.34 These results Gastric Varices
will require conﬁrmation in a larger number of patients The literature on the management of gastric variceal followed for a longer period before early TIPS can be hemorrhage is not nearly as robust as that for esophageal recommended. The performance of both shunt surgery variceal hemorrhage. Because there are so few controlled and TIPS are dependent on local expertise.
clinical trials, much less conﬁdence can be placed on Balloon tamponade is very effective in controlling guidelines for the management of gastric varices. Type bleeding temporarily with immediate control of hemor- 1 gastric varices (GOV1) constitute an extension of rhage in over 80% of patients.109 However, its use is as- esophageal varices along the lesser curvature of the sociated with potentially lethal complications such as stomach. Therefore, the approach to their manage- aspiration, migration, and necrosis/perforation of the ment should be the same as for esophageal varices (see esophagus with mortality rates as high as 20%. Therefore, above). On the other hand, there are very limited data it should be restricted to patients with uncontrollable regarding the management of bleeding from fundal bleeding for whom a more deﬁnitive therapy (e.g., TIPS) varices, except when IGV1 are secondary to isolated is planned within 24 hours of placement. Airway protec- splenic vein thrombosis, in which case therapy consists tion is strongly recommended when balloon tamponade Compared to endoscopic sclerotherapy or EVL, endo- scopic variceal obturation with tissue adhesive such Recommendations
as N-butyl-cyanoacrylate, isobutyl-2-cyanoacrylate, or 12. Acute GI hemorrhage in a patient with cirrho-
thrombin is more effective for acute fundal gastric variceal sis is an emergency that requires prompt attention
bleeding, with better control of initial hemorrhage as well with intravascular volume support and blood trans-
as lower rates of rebleeding.110,111 A relatively large pro- fusions, being careful to maintain a hemoglobin of ϳ8
spective, randomized trial compared gastric variceal obtu- g/dL (Class I, Level B).
ration (GVO) with N-butyl-cyanoacrylate versus EVL in 13. Short-term (maximum 7 days) antibiotic pro-
patients with acute gastric variceal hemorrhage demon- phylaxis should be instituted in any patient with cir-
strating that control of active bleeding was similar in both rhosis and GI hemorrhage (Class I, Level A). Oral
groups but that rebleeding over a follow-up period of norﬂoxacin (400 mg BID) or intravenous ciproﬂoxa-
1.6-1.8 years occurred signiﬁcantly less frequently in the cin (in patients in whom oral administration is not
GVO group (23% vs. 47%), with an average of only 1.5 possible) is the recommended antibiotic (Class I, Level
sessions (range 1-3).112 In an uncontrolled pilot study, A). In patients with advanced cirrhosis intravenous
2-octyl cyanoacrylate, an agent approved for skin closure ceftriaxone (1 g/day) may be preferable particularly in
in the United States, has been described as effective for centers with a high prevalence of quinolone-resistant
achieving initial hemostasis and preventing rebleeding organisms (Class I, Level B).
from fundal varices.113 Therefore, the use of these agents 14. Pharmacological therapy (somatostatin or its
is preferred in the endoscopic therapy of fundal varices.
analogues octreotide and vapreotide; terlipressin)
However, in the absence of these agents or if the operator should be initiated as soon as variceal hemorrhage is
is unfamiliar with this type of therapy, TIPS should be suspected and continued for 3-5 days after diagnosis is
considered ﬁrst line therapy. Several studies demonstrate conﬁrmed (Class I, Level A).
the value of TIPS for uncontrolled bleeding from gastric 15. EGD, performed within 12 hours, should be used
varices with bleeding control rates of over 90%. Although to make the diagnosis and to treat variceal hemorrhage,
it had been suggested that bleeding from gastric varices either with EVL or sclerotherapy (Class I, Level A).
was more difﬁcult to control with TIPS than bleeding 16. TIPS is indicated in patients in whom hemor-
from esophageal varices, a prospective study compared rhage from esophageal varices cannot be controlled or
salvage TIPS in patients with uncontrolled gastric fundal in whom bleeding recurs despite combined pharmaco-
(n ϭ 28) versus uncontrolled esophageal (n ϭ 84) variceal logical and endoscopic therapy (Class I, Level C).
bleeding and showed equal efﬁcacy with control of hem- 17. Balloon tamponade should be used as a tem-
orrhage in all but one patient in each group.114 porizing measure (maximum 24 hours) in patients
The threshold to place TIPS for gastric variceal hemor- with uncontrollable bleeding for whom a more deﬁn-
rhage is lower than for esophageal variceal hemorrhage and itive therapy (e.g., TIPS or endoscopic therapy) is
TIPS can be recommended if endoscopic therapy is not pos- planned (Class I, Level B).
sible or after a single failure of endoscopic treatment.
Recommendations
Regarding endoscopic therapy, EVL is the endoscopic 18. In patients who bleed from gastric fundal var-
method of choice for preventing variceal rebleeding since ices, endoscopic variceal obturation using tissue adhe-
it has been shown to be superior to sclerotherapy.115,117 sives such as cyanoacrylate is preferred, where available.
Data collected from different randomized clinical trials Otherwise, EVL is an option (Class I, Level B).
show a median rebleeding rate in patients treated with 19. A TIPS should be considered in patients in
EVL of around 32%.36 EVL sessions are repeated at 7- to whom hemorrhage from fundal varices cannot be con-
14-day intervals until variceal obliteration, which usually trolled or in whom bleeding recurs despite combined
requires 2 to 4 sessions.118 Once eradicated, EGD is usu- pharmacological and endoscopic therapy (Class I,
ally repeated every 3 to 6 months to evaluate for variceal Level B).
recurrence and need for repeat EVL. Complications of E. Patients with Cirrhosis Who Have
EVL occur in about 14% of cases but are usually minor.
Recovered from Acute Variceal Hemorrhage
The most common complication is transient dysphagiaand chest discomfort. Shallow ulcers at the site of each Patients who survive an episode of acute variceal hem- ligation are the rule, and they may bleed. In a small (n ϭ orrhage have a very high risk of rebleeding and death. The 43) randomized placebo-controlled trial of pantoprazole median rebleeding rate in untreated individuals is around (40 mg IV after EVL followed by 40 mg oral every day for 60% within 1-2 years of the index hemorrhage, with a 9 days), the number of post-EVL ulcers at day 10 after mortality of 33%.35,36 It is therefore essential that patients EVL was the same in both groups; however, ulcers were who have recovered from an episode of variceal hemor- signiﬁcantly smaller in the pantoprazole group and, al- rhage and have had no evidence of hemorrhage for at least though not statistically signiﬁcant, all 3 post-EVL bleed- 24 hours be started on therapy to prevent recurrence prior ing episodes occurred in the placebo group.119 These to discharge from the hospital. Patients who required results would favor the use of proton pump inhibitors in shunt surgery/TIPS to control the acute episode do not require further preventive measures. All these patients Optimal pharmacological therapy (␤-blockers plus ni- should be referred to a transplant center if they are other- trates) versus optimal endoscopic therapy (EVL) has been wise a candidate (i.e., Child-Pugh score Ն7 or a MELD compared in 3 randomized studies showing different re- sults. One study showed a beneﬁt of combination phar- Nonselective ␤-blockers or sclerotherapy reduce rates macological therapy,23 another showed a beneﬁt of of variceal rebleeding to around 42-43%,35,36,82,115 al- EVL,120 and a third showed no difference between treat- though patients treated with sclerotherapy have a higher ment groups, despite a clear tendency in favor of pharma- rate of side effects. However, there are better pharmaco- cological therapy.121 These differences probably reﬂect logical and endoscopic therapeutic options.
the dosage of medications used, patient population and, Regarding pharmacological therapy, the combination ultimately, center expertise.122 Both therapies would ap- of a nonselective ␤-blocker and ISMN has a synergisticportal pressure-reducing effect and could theoretically be pear to be at least equivalent in the prevention of variceal more effective than ␤-blockers alone. Only one study has rebleeding with rebleeding rates of 32%-35%.
performed a direct comparison between the combination Combination endoscopic plus pharmacological ther- of propranolol plus ISMN and propranolol alone in pa- apy is the most rational approach because nonselective tients with prior variceal hemorrhage.116 This study ␤-blockers theoretically will protect against rebleeding showed a beneﬁt of combination therapy (33% vs. 41% prior to variceal obliteration and would prevent variceal rebleeding rate), but it was not statistically signiﬁcant.
recurrence. Two randomized trials demonstrate the supe- Data collected from different randomized clinical trials riority of combined therapy versus EVL alone.123,124 Re- show that the median rebleeding rate in patients treated bleeding rates in these 2 trials were 23% and 14%, with combined pharmacological therapy is around 33%- respectively, for EVL plus nadolol compared to 47% and 35%,35,36 lower than that obtained with ␤-blockers alone.
38% for EVL alone. These results support the use of Therefore, the pharmacological therapy of choice in the combination therapy to prevent rebleeding, even though prevention of variceal rebleeding is probably the combi- a recent consensus conference recommended EVL or nation of a nonselective ␤-blocker and a nitrate. How- ␤-blocker ϩ nitrates as ﬁrst-line therapy in treatment- ever, this combination has signiﬁcantly greater side effects naı¨ve patients.7 The combination EVL plus a nonselective compared to ␤-blockers alone35,116 and is poorly tolerated ␤-blocker is clearly recommended in patients who de- in clinical practice so that most patients end up taking velop variceal hemorrhage (ﬁrst or recurrent) while on The lowest rate of variceal rebleeding (Ϸ10%) is ob- surgical shunts,83 it is likely that TIPS will remain a second- tained in patients who are HVPG responders; that is, line therapy after endoscopic/pharmacological therapy.
patients in whom pharmacological therapy (either ␤-blockers alone or ␤-blockers ϩ nitrates) leads to a re- Therapies not recommended for secondary prophy-
duction in HVPG to Ͻ12 mmHg or a reduction Ͼ20% from baseline.19,36 In patients who are HVPG responders, Sclerotherapy should no longer be used in the second- it would not be rational to use endoscopic therapy. As ary prophylaxis of variceal hemorrhage. A meta-analysis of suggested recently, perhaps the most rational therapy 13 trials which included 1,091 patients comparing EVL would be to adapt the different therapies to prevent versus sclerotherapy in the prevention of variceal rebleed- variceal rebleeding in the context of HVPG re- ing showed that the risk of variceal rebleeding is signiﬁ- sponse125,126; however, this would require standardization cantly reduced by EVL (pooled odds ratio 0.46, 95% CI of the HVPG technique, including the best timing to 0.35-0.60). Furthermore, while there were no differences perform the repeat HVPG measurement. Existing studies in mortality, complications are signiﬁcantly less frequent have performed the second HVPG measurement a me- and less severe with EVL, and the number of endoscopic dian of 90 days after the ﬁrst measurement (range 19-159 sessions needed to achieve eradication is signiﬁcantly days), and there is evidence suggesting that the predictive value of the change in HVPG is reduced with increasing Trials suggest that EVL is followed by a higher rate of variceal recurrence in comparison with sclerotherapy.
Even though the above-mentioned meta-analysis foundno signiﬁcant difference in variceal recurrence between Shunt surgery is very effective in preventing rebleed- treatments,115 the efﬁcacy of combination EVL plus scle- ing. However, it markedly increases the risk of hepatic rotherapy compared with EVL alone in reducing variceal encephalopathy and has no effect on survival.82,127,128 Not recurrence has been explored. Two meta-analyses, one surprisingly, recent meta-analyses of 11 trials that com- comprising 7 trials134 and a more recent one comprising 8 pared TIPS to endoscopic therapy as ﬁrst-line therapy trials,135 show no differences in rebleeding, death, or show similar results.129,130 That is, even though rebleed- number of sessions to variceal obliteration between ing is signiﬁcantly less frequent with TIPS, post-treat- groups and a higher incidence of esophageal strictures in ment encephalopathy occurs signiﬁcantly more often the combination therapy group. Therefore, EVL should after TIPS, and there is no difference in mortality between groups. Furthermore, a recent trial showed that, eventhough pharmacological (propranolol plus nitrates) ther- Recommendations
apy was less effective than TIPS in preventing rebleeding, 20. Patients with cirrhosis who survive an episode
it was associated with less encephalopathy, identical sur- of active variceal hemorrhage should receive therapy
vival, and more frequent improvement in Child-Pugh to prevent recurrence of variceal hemorrhage (second-
class with lower costs than TIPS.131 Therefore, TIPS ary prophylaxis) (Class I, Level A).
should not be used as a ﬁrst-line treatment, but as a rescue 21. Combination of nonselective ␤-blockers plus
therapy for patients who have failed pharmacological plus EVL is the best option for secondary prophylaxis of
variceal hemorrhage (Class I, Level A).
A large multicenter trial of TIPS versus distal spleno- 22. The nonselective ␤-blocker should be adjusted
renal shunts (DSRS) showed similar rates of rebleeding, to the maximal tolerated dose. EVL should be repeated
encephalopathy, and mortality in patients with Child A every 1-2 weeks until obliteration with the ﬁrst sur-
or B cirrhosis who had failed pharmacological/endoscopic veillance EGD performed 1-3 months after oblitera-
therapy, with a higher rate of shunt dysfunction in the tion and then every 6-12 months to check for variceal
TIPS group.132 Because both procedures have equivalent recurrence (Class I, Level C).
outcomes, the choice is dependent on available expertise 23. TIPS should be considered in patients who are
and ability to monitor the shunt and reintervene when Child A or B who experience recurrent variceal hem-
orrhage despite combination pharmacological and en-
Notably, the above-mentioned trials have all been per- doscopic therapy. In centers where the expertise is
formed using uncovered TIPS stents. The advent of cov- available, surgical shunt can be considered in Child A
ered stents that have been shown to have a lower occlusion patients (Class I, Level A).
rate and lower rates of encephalopathy133 may increase the 24. Patients who are otherwise transplant candi-
enthusiasm for TIPS. However, given past results with dates should be referred to a transplant center for
evaluation (Class I, Level C).
extensive peer review of the manuscript. Members of theAASLD Practice Guidelines Committee include Marga- Suggestions for Future Research
ret C. Shuhart, M.D., M.S. (Committee Chair); Gary L.
Davis, M.D. (Board Liaison); Kiran Bambha, M.D.; An- The following are important areas in the diagnosis and dres Cardenas, M.D., M.M.Sc.; Stanley M. Cohen, treatment of varices and variceal hemorrhage where addi- M.D.; Timothy J. Davern, M.D.; Steven L. Flamm, M.D.; Steven-Huy B. Han, M.D.; Charles D. Howell, 1. Non-invasive markers that predict presence of high M.D.; David R. Nelson, M.D.; K. Rajender Reddy, M.D.; Bruce A. Runyon, M.D.; John B. Wong, M.D.; 2. Role of capsule endoscopy in the diagnosis of vari- Colina Yim, RN; and Nizar N. Zein, M.D. Members of the ACG Practice Parameters Committee include John Inadomi, M.D., FACG (Committee Chair); Darren Baroni, M.D.; David Bernstein, M.D., FACG; WilliamBrugge, M.D., FACG; Lin Chang, M.D.; William Chey, 5. New pharmacological therapies with a greater effect M.D., FACG; John Cunningham, M.D., FACG; Ken- neth DeVault, M.D., FACG; Steven Edmundowicz, 6. Best therapy for fundal varices and fundal variceal M.D.; Ronnie Fass, M.D, FACG; Kelvin Hornbuckle, M.D.; Costas Kefalas, M.D., FACG; Timothy Koch,M.D., FACG; Jenifer Lehrer, M.D.; Anthony Lembo, Conclusions
M.D.; John O’Brien, M.D.; John Papp, Sr., M.D., In the decade since the initial practice guidelines MACG; Henry Parkman, M.D., FACG; Albert Roach,Pharm.D., FACG; Richard Sampliner, M.D., MACG; were published, a number of advances have changed Amnon Sonnenberg, M.D., MSc, FACG; Subbaramiah our management of variceal hemorrhage. HVPG mea- Sridhar, M.D., FACG; Miguel Valdovinos, M.D.; John surements have clearly been established as a clinically Vargo, M.D., MPH, FACG; Marcelo Vela, M.D.; and important diagnostic and prognostic tool. Nonselec- tive ␤-blockers have no role in the prevention of thedevelopment of esophagogastric varices but are the References
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Abortion/Breast Cancer—No link at all? You Decide!INFebruary of 2003, the National Cancer Institute (NCI) claimed that no significant link had been found between abortion and the incidence of breast cancer. Most known risk factors for breast cancer are attributable to estrogen overexposure. The U.S. Department ofHealth and Human Services in the 11th Report on Carcinogens (Jan. 2005) list