portal hypertension and gastrointestinal bleeding€¦ · portal hypertension and gastrointestinal...

Portal Hypertension and GastrointestinalBleedingJaime Bosch, M.D., Ph.D.,1,2 Juan G. Abraldes, M.D.,1,2

Annalisa Berzigotti, M.D.,3,4 and Juan Carlos Garcia-Pagan, M.D.1,2

ABSTRACT

Variceal bleeding is one of the most serious complications of portal hypertension.The driving force for the development of varices is an increase in portal pressure. As portalhypertension progresses, varices dilate until they finally rupture and bleed. This sequence ofevents might be prevented by achieving a sufficient decrease in portal pressure or by actinglocally at the varices with endoscopic treatments. This article reviews the rationale for themanagement of portal hypertension and the current recommendations for the preventionand treatment of variceal bleeding.

KEYWORDS: Cirrhosis, varices, endoscopic band ligation, TIPS, b-adrenergic blockers,

hepatic venous pressure gradient

Portal hypertension is a common clinical syn-drome defined by a pathologic increase of portal venouspressure. As a consequence, the gradient between portalpressure (PP) and inferior vena cava pressure (IVC)(portal pressure gradient, PPG) is increased above theupper normal value of 5 mm Hg. Portal hypertension canbe due to many different causes, at prehepatic, intra-hepatic, and posthepatic sites (Table 1). Cirrhosis of theliver accounts for �90% of cases of portal hypertensionin Western countries.

The importance of portal hypertensive syndromeis defined by the frequency and severity of its complica-tions, including upper gastrointestinal bleeding fromruptured gastroesophageal varices, ascites, and hepatore-nal syndrome, which represent the leading causesof death and of liver transplantation in patients withcirrhosis. This article focuses on esophageal varices andgastrointestinal bleeding in cirrhosis.

Portal hypertension is considered to be clinicallysignificant (CSPH) when PPG, or its clinical equivalent

hepatic venous pressure gradient (HVPG), exceeds 10 to12 mm Hg, since this is the threshold for the clinicalmanifestations of portal hypertensive syndrome to ap-pear. The vast majority of patients with cirrhosis developCSPH along the course of the disease, and data from arecent multicentric study indicate that CSPH is alreadypresent at diagnosis in �60% of histologically proven,well-compensated cirrhosis cases.1

NATURAL HISTORY AND PROGNOSISVariceal bleeding is the last step of a chain of eventsinitiated by an increase in PP, followed by the develop-ment and progressive dilation of varices until thesefinally rupture and bleed. According to recent data,2

the appearance of varices in compensated patients in-dicates a change from a clinical stage with a very low riskof death at 1 year (stage 1; 1% risk) to an intermediate-risk stage (stage 2; 3.4% risk). The occurrence of varicealbleeding is a dreadful event, marking the progression to

1Hepatic Hemodynamic Laboratory, Liver Unit, Institut d’Investiga-cions Biomediques August Pi i Sunyer (IDIBAPS), University ofBarcelona, Spain; 2Centro de Investigacion Biomedica en Red deEnfermedades Hepaticas y Digestivas (CIBEREHD), University ofBarcelona, Spain; 3Centre Diagnostic per la Imatge, Hospital Clinic,Barcelona, Spain; 4Department of Internal Medicine, Cardioangiol-ogy, Hepatology, Policlinico S. Orsola, University of Bologna, Italy.

Address for correspondence and reprint requests: Professor Jaime

Bosch, M.D., Ph.D., Hepatic Hemodynamic Laboratory, Liver Unit,Hospital Clınic, Villarroel 170, 08036 Barcelona, Spain (e-mail:[email protected]).

Complications of Cirrhosis; Guest Editor, Pere Gines, M.D.Semin Liver Dis 2008;28:3–25. Copyright # 2008 by Thieme

Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,USA. Tel: +1(212) 584-4662.DOI 10.1055/s-2008-1040318. ISSN 0272-8087.

3

decompensation of the liver disease and to a very highrisk of death stage (stage 4; 57% risk) (Fig. 1).

Prevalence and Formation of Esophageal

Varices

When cirrhosis is first diagnosed, varices are present in�30 to 40% of compensated patients and in 60% ofdecompensated.1,3,4 Clinical-hemodynamic correlationshave shown that varices may appear when HVPGincreases to over 10 mm Hg.1,5 Since portal hypertensioneventually develops in almost every patient with cirrhosisit is thought that, if cirrhotic patients are followed longenough, virtually all of them will develop varices.6

In those cirrhotic patients without varices at firstendoscopy, the annual incidence of new varices is a meanof 7%, ranging from 5 to 10% in published series.6–8 AnHVPG over 10 mm Hg is a strong predictor for the

development of varices,1 confirming that PP plays apivotal role as the driving force for the development ofcollaterals.

Progression of Esophageal Varices from Small

to Large

Once developed, varices increase in size from small tolarge before they eventually rupture and bleed. Studiesassessing the progression from small to large varices arecontroversial, showing rates of progression of varicesranging from 5 to 30% per year.7–10 The most likelyreasons for such variability are differences in patientselection and follow-up endoscopy schedule.10 The fac-tor that has been most consistently associated withvariceal progression is Child-Pugh class.7–9,11 Otherfactors include alcoholic etiology of cirrhosis and pres-ence of red wale markings in the esophageal varices.8,10

Changes in HVPG (either ‘‘spontaneous’’ or caused bydrug therapy or transjugular intrahepatic portal-systemicshunts [TIPS]) are usually accompanied by parallelvariations in the size of the esophageal varices, whichare significantly reduced when HVPG decreases below12 mm Hg.12,13 Thus, an increased HVPG plays a keyrole both in development and progression of the varices.

Incidence and Risk Indicators of First Bleeding

from Esophageal Varices

First variceal bleeding has an incidence of �4% per year;this risk increases to 15% per year in patients withmedium-large varices.4

The most important predictive factors related tothe risk of bleeding are variceal size, severity of liverdysfunction as assessed by the Child-Pugh classification,and presence of red signs.14 Variceal size and red colorsigns are associated with increased bleeding risk probablybecause they reflect direct parameters determining var-iceal wall tension (radius, wall thickness), which is thedecisive factor determining variceal rupture. In addition,many studies have shown that variceal bleeding onlyoccurs if the HVPG reaches a threshold value of 12 mmHg.5,12,15 Conversely, if the HVPG is substantiallyreduced (below 12 mm Hg or by more than 20% ofbaseline levels), there is a marked reduction in the risk ofbleeding.12,16 This is of outstanding importance, sinceit demonstrates that the portal hypertension syndromeis reversible by pharmacological treatment effectivelydecreasing PP (Fig. 2).

DIAGNOSIS

HVPG Measurement

Measurement of HVPG by hepatic vein catheterizationis an objective and quantitative equivalent of PP in

Table 1 Etiology of Portal Hypertension According tothe Site of Increased Resistance to Portal Blood Flow

Prehepatic

Splenic vein thrombosis

Portal vein thrombosis

Congenital stenosis of the portal vein

Extrinsic compression of the portal vein

Arteriovenous fistulae

Intrahepatic

Cirrhosis (viral, alcoholic, biliary, metabolic)

Partial nodular transformation

Nodular regenerative hyperplasia

Congenital hepatic fibrosis

Peliosis hepatic

Polycystic disease

Idiopathic portal hypertension

Hypervitaminosis A

Arsenic, copper sulfate, vinyl chloride monomer poisoning

Granulomatous diseases (sarcoidosis, tuberculosis, primary

biliary cirrhosis, schistosomiasis)

Amyloidosis

Mastocytosis

Rendu-Osler-Weber syndrome

Liver infiltration in hematologic diseases

Acute fatty liver of pregnancy

Severe acute viral and alcoholic hepatitis

Chronic active hepatitis

Hepatocellular carcinoma

Cyanamide toxicity

Veno-occlusive disease

Posthepatic

Hepatic veins thrombosis (Budd-Chiari syndrome)

Congenital malformation and thrombosis of the inferior

vena cava

Constrictive pericarditis

Tricuspid valve diseases

4 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1 2008

cirrhosis.17 HVPG has proved to add prognostic infor-mation in many settings, including compensated cirrho-sis,18 acute variceal bleeding,19 and patients awaitingliver transplantation.20

However, as previously mentioned, not all pa-tients with increased HVPG have varices. Patients withCSPH are at high risk of varices and should undergoendoscopic screening.

Endoscopy

The current consensus is that every cirrhotic patientshould be endoscopically screened for varices at thetime of diagnosis.21 The aim of the screening foresophageal varices is to detect patients requiring pro-phylactic treatment.

In patients without varices on initial endoscopy,further evaluations should be performed to detect the

Figure 1 Clinical stages of cirrhosis according to clinical features Four clinical stages can be identified, each with distinct

clinical characteristics and a markedly different prognosis. Each stage is defined by the presence or absence of complications of

cirrhosis. As shown, the onset of esophageal varices in compensated patients indicates a change from a clinical stage with a

very low risk of death at 1 year to an intermediate risk stage, while the occurrence of variceal bleeding situates the patient in the

highest risk stage. (Modified from D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in

cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217–231).174

Figure 2 Natural history of esophageal varices as a function of variceal wall tension. The solid line shows the evolution of

untreated patients: variceal wall tension increases markedly as a result of an increase of hepatic venous pressure gradient (HVPG)

above 10 mm Hg, enlargement of the varix, and decrease of wall thickness. Once wall tension increases to values exceeding the

elastic limit of the vessel, the patient may experience his or her first bleeding episode. Afterward, the patient remains at risk

unless wall tension is decreased by means of medical therapy (decrease of HVPG to < 12 mm Hg or by > 20% versus baseline

value) (discontinuous line). Primary prophylaxis (dotted line) prevents or delays wall tension from reaching the rupture point, so

reducing the bleeding risk. (Modified from Escorsell A, Bosch J. Pathophysiology of variceal bleeding. In: Groszmann RJ, Bosch J,

eds. Portal Hypertension in the 21st Century. Dordrecht/Boston/London: Kluwer Academic Publishers; 2004:155–166.)

PORTAL HYPERTENSION AND GI BLEEDING/BOSCH ET AL 5

development of varices. The current consensus is thatendoscopy should be repeated after 2 to 3 years inpatients without varices at the first endoscopy. Theexpected incidence of moderate/large varices and/orvariceal bleeding in these patients (and, thus, the riskof leaving patients without prophylaxis) is less than 10%at 3 years.8,10 In those centers in which hepatic hemo-dynamic studies are available it is advisable to measureHVPG. An HVPG over 10 mm Hg indicates a morerapid progression to complications of cirrhosis, and callsfor shorter surveillance intervals.22

In patients with small varices on initial endos-copy, the aim of subsequent evaluations is to detect theprogression of small to moderate/large varices because ofits important prognostic and therapeutic implications.Based on an expected 10 to 15% per year rateof progression of variceal size, endoscopy should berepeated every 2 years in patients with small varices.In patients with advanced cirrhosis or red wale marks, a1-year interval might be recommended.8,10

Endoscopic Videocapsule

Patients are frequently intolerant to repeated conventionalendoscopies, and often require sedation. Recently, endo-scopic videocapsule has been suggested, as this may

improve patients’ tolerance. Once swallowed, the video-capsule records images at predetermined intervals. In thetwo published studies, capsule endoscopy allowed a correctidentification of varices in 80% of cases23,24; in one ofthese studies, capsule endoscopy proved a correct identi-fication of red wale marks.23 However, it may not be asgood in assessing variceal size and it may have pooraccuracy in identifying the presence of hypertensive gas-tropathy and gastric varices.25 Therefore, endoscopic vid-eocapsule cannot be currently recommended as the routinescreening method for the evaluation of gastroesophagealvarices or portal hypertensive gastropathy in cirrhosis.

Noninvasive Tests

The ideal method to diagnose and follow up portalhypertension should be reproducible, inexpensive, andnoninvasive (Fig. 3). No noninvasive procedure hasproved, so far, to be accurate enough to avoid endoscopyin patients with negative indicators.26,27 However, someclinical, laboratory, and imaging variables may help toselect patients with high risk for varices.28,29

CLINICAL SIGNS AND LABORATORY FINDINGS

The presence of splenomegaly, or enlarged spleen size,is the clinical sign most often reported in studies on

Figure 3 Existing diagnostic tools in the clinical assessment of portal hypertension. The ideal method to diagnose portal

hypertension should be noninvasive, accurate, objective, and reproducible. HVPG, hepatic venous pressure gradient; CT,

computed tomography; MRI, magnetic resonance imaging; CDUS, color-Doppler ultrasonography.


noninvasive prediction of portal hypertension andesophageal varices. Platelet count, and platelet to spleenratio,29 have been suggested as useful to select patientswith high probability of having large esophageal varices.However, the cut-offs vary a lot across studies (plateletcount from 68,000 to 160,000/mm3), indicating lowspecificity. In addition, in viral cirrhosis, platelet countcan decrease independently from the development ofportal hypertension. Other laboratory data independ-ently correlated with the presence of varices or largevarices are indicators of liver failure, such as hypoalbu-minemia, low prothrombin time, and hyperbilirubine-mia,30 or their combination in the Child-Pugh score.31

Some indicators of liver fibrosis, such as hyaluronicacid level32 or the Fibrotest, have also been suggestedto correlate with the presence of esophageal varices.

IMAGING TECHNIQUES

Ultrasonography (US)/color Doppler-US (CDUS) isthe preferred initial examination in patients with sus-pected portal hypertension. US can detect signs of portalhypertension such as splenomegaly, presence of porto-collateral vessels, and ascites, and complement this in-formation with data on liver size, echotexture, andmargins, which can suggest underlying cirrhosis. Amongthe US parameters, spleen length is the strongest in-dependent predictive marker of esophageal varices. Por-tal vein diameter (above 13 mm), portal blood flowvelocity (mean velocity below 12 cm/s),33 lack or reducedrespiratory variations of splenic and superior mesentericvein diameter,34 congestion index of portal vein, alteredhepatic venous Doppler pattern, increased intraparen-chymal hepatic and splenic artery impedance,35 increasedintraparenchymal renal artery impedance,36 and reducedmesenteric artery impedance37 have all been found tocorrelate with the presence of CSPH and esophagealvarices. However, these variables do not show a satis-factory predictive accuracy in independent sets ofpatients, probably due to the high interobserver andintraobserver variability.

Computed tomography (CT) scan and MRI(magnetic resonance imaging) allow a good visualizationof the portal venous system, and both techniques permitthe diagnosis of esophageal varices.38,39 The measure-ment of azygos blood flow by angio-MR has shown acorrelation with the presence of esophageal varices andthe risk of variceal bleeding. However, the technicalcomplexity and cost of these techniques makes theiruse unlikely for the screening of gastroesophageal varicesin cirrhosis.

LIVER STIFFNESS (FibroScan)

Transient elastography (FibroScan1) is a noninvasivemethod recently developed for assessing liver fibrosis.40

Because fibrosis and scarring of the liver tissue are majorfactors contributing to the development of portal hyper-

tension, liver stiffness measurement has theoretical po-tential for the evaluation of portal hypertension. Recentstudies demonstrate that liver stiffness shows a goodcorrelation with HVPG: in a study in liver transplantrecipients with hepatitis C virus recurrence, a liver stiff-ness value � 8.74 kPa had a sensitivity and specificity of90% and 81% for the diagnosis of increased PP (HVPG� 6 mm Hg).41 In three different studies, two publishedas abstracts42,43 and one as a full paper,44 the authorsfound that liver stiffness can detect accurately an HVPGover 12 mm Hg in patients with cirrhosis or long-lastingchronic liver disease. However, different cut-off valueswere found, namely 17 kPa, 23 kPa, and 13.6 kPa.Interestingly, in the study by Vizzutti and colleagues,44

it was shown that above the threshold value of 13.6 kPathere was not a good correlation between liver stiffnessand HVPG, probably since structural abnormalitieswithin the liver (e.g., fibrosis) are not the only mecha-nisms promoting portal hypertension, which is alsodetermined by the magnitude of portocollateral bloodflow and changes in hepatic vascular tone (which arenot reflected by the Fibroscan).

As for the prediction of esophageal varices, thestudy by Kazemi and associates suggested that liverstiffness might be used to select those patients likely tohave large varices and requiring screening endoscopy.45

In this study, however, endoscopic assessment was retro-spective, and transient elastography performed no betterthan other simple noninvasive variables that are routinelyobtained in these patients, such as blood test and ultra-sonography. Additionally, transient elastography wasnot discriminative to detect small varices, since the bestcut-off for detecting all types of varices overlapped withthat for detecting cirrhosis.46

Further studies are therefore needed beforerecommendation can be given on the routine use ofFibroscan for the detection of CSPH and varices.

RATIONAL BASIS OF THERAPYIn cirrhosis, portal hypertension is due to increasedresistance to portal blood flow through the cirrhoticliver, and increased blood flow in the portal and collateralcirculation. Portal hypertension can therefore be attenu-ated by decreasing intrahepatic resistance, reducing por-tocollateral blood flow, or both47 (Fig. 4). These targetscan be addressed by means of medical treatment, localtreatments, or derivative procedures.

The initial factor in the pathophysiology of portalhypertension is the increase in vascular resistance toportal blood flow. In cirrhosis this increase in resistanceoccurs at the hepatic microcirculation (sinusoidal portalhypertension). Increased hepatic vascular resistance incirrhosis is not only a mechanical consequence of thehepatic architectural disorder caused by the liver disease,as there is also a dynamic component due to the active


contraction of portal/septal myofibroblasts, activatedhepatic stellate cells, and vascular smooth muscle cellsin portal venules.48 This increased hepatic vascular toneis due to an imbalance between endogenous vasodilatoryand vasoconstrictor stimuli, the former being insufficientto counteract the influence of the latter.49 Indeed, whilevasoconstrictors are increased, intrahepatic nitric oxide(NO) production is clearly decreased.49,50 This deficientintrahepatic NO production is due to endothelial dys-function in the liver microvascultature50,51 and may alsofavor local thrombosis and fibrogenesis.49 This findingprovides a rational basis for drug therapies aimed atincreasing NO within the liver either by the use of NOdonors or by enhancing e-NOS activity with statins.Oxidative stress is in part responsible for reduced intra-hepatic NO bioavailability, which provides a rationalbasis for testing antioxidants, such as ascorbic acid.52

The increased resistance through the cirrhoticliver can also be targeted by ‘‘mechanical’’ means, by-passing the liver. This can be achieved by portal-systemicshunt surgery and by TIPS. These procedures are highlyeffective in decreasing PP, but have the detrimentaleffect that, by further decreasing portal blood flowthrough the liver and by increasing portal-systemic

shunting, they may enhance liver failure and facilitatehepatic encephalopathy.

The second factor contributing to portal hyper-tension is an increased blood flow through the portalvenous system. This is due to splanchnic arteriolarvasodilation, probably due to excessive release of endog-enous vasodilators (endothelial and neurohumoral).53–55

Splanchnic hyperemia contributes to the increase in PPand explains why portal hypertension persists, despitethe establishment of an extensive network of portosys-temic collaterals that may divert over 80% of the portalblood flow. The increased portal venous inflow can becorrected pharmacologically by means of splanchnicvasoconstrictors, such as vasopressin and its derivatives,somatostatin and its analogues, and nonselective b-adrenergic blockers. These are the drugs that havemore widely been used in the treatment of portal hyper-tension. Splanchnic vasodilation is in part due to anincreased release of NO in splanchnic arteries, whichis amenable to pharmacological manipulation. However,this presents the difficulty of inhibiting NO synthesisselectively in the splanchnic arterial bed, which isnot feasible at present. Splanchnic vasodilation is ac-companied by increased cardiac index and hypervolemia,

Figure 4 Rational basis of therapy. A mechanical increase in hepatic resistance due to structural alterations of liver

parenchyma is the initial factor that leads to portal hypertension. This might be overcome by TIPS placement. The recognition

of a functional and, thus, reversible component in the increased hepatic resistance sets the rationale for the use of vasodilators

in portal hypertension. Furthermore, portal hypertension leads to a cascade of disturbances in the splanchnic and systemic

circulation characterized by vasodilation, sodium and water retention, and plasma volume expansion that lead to an increase in

portal blood inflow that contributes to maintain and worsen portal hypertension. This sets the rationale for the use of

vasoconstrictors and diuretics in the treatment of portal hypertension. Varices are the result of the development of

portosystemic collaterals. Endoscopic treatments are directed at locally ‘‘eradicating’’ the varices, but do not decrease portal

pressure. TIPS, transjugular intrahepatic portal-systemic shunts; PSS, portal-systemic shunt; CO, carbon monoxide; NE,

norepinephrine; VP, vasopressin; A-II, angiotensin-II; Na, sodium.


representing the hyperkinetic circulatory syndrome as-sociated with portal hypertension. An expandedblood volume is necessary to maintain the hyperdynamiccirculation, which provides a rationale for the use oflow-sodium diet and spironolactone to attenuate thehyperkinetic syndrome and the PP elevation in patientswith cirrhosis.56

Combined pharmacological therapy consists inassociating vasoconstrictive drugs, which will decreaseportal blood inflow, and vasodilators, which may reducethe intrahepatic vascular resistance. The best-knownexample is the association of propranolol or nadololand isosorbide-5-mononitrate (ISMN).

Therapeutic strategies aimed at decreasing PPhave the advantage of potentially preventing other portalhypertension-related complications, such as portal hy-pertensive gastropathy, ascites, spontaneous bacterialperitonitis, and hepatorenal syndrome.

Local treatments at the varices complete thespectrum of treatments for complications of portal hy-pertension. These treatments do not decrease PP andtherefore have no potential for preventing other com-plications of portal hypertension. Endoscopic therapy isdirected at eradicating the varices either by injecting avariety of irritating substances into or around the varicesto promote thrombosis and fibrosis, or by ligating thevarices using elastic bands. It is possible that the efficacyof endoscopic therapy can be enhanced if combined withan agent that effectively lowers PP.

Finally, hemostatic agents, such as recombinantactivated factor VII, are being explored as adjuvantsto conventional therapy to arrest variceal bleeding inpatients with poor liver function.57,58

Clinical Scenarios

The treatment of portal hypertension includes the pre-vention of variceal hemorrhage in patients who havenever bled, the treatment of the acute bleeding episode,and the prevention of rebleeding in patients who havesurvived a bleeding episode from esophageal or gastricvarices. The main difference among these scenarios isthat natural history and prognosis are quite differentfrom one to another.

THE ACUTE BLEEDING EPISODE

Natural History and Prognosis

Ruptured esophageal varices cause 70% of all uppergastrointestinal bleeding episodes in patients with portalhypertension.59 Thus, in any cirrhotic patient with acuteupper gastrointestinal bleeding, a variceal origin shouldbe suspected. Diagnosis is established at emergencyendoscopy based on observing one of the following: (1)active bleeding from a varix (observation of blood spurt-

ing or oozing from the varix) (nearly 20% of patients);(2) white nipple or clot adherent to a varix; (3) presenceof varices without other potential sources of bleeding.

INITIAL CONTROL OF BLEEDING

Because variceal bleeding is frequently intermittent, it isdifficult to assess when the bleeding stops and when anew hematemesis or melena should be considered anepisode of rebleeding. Several consensus conferenceshave addressed this issue and set definitions for eventsand timing of events related to episodes of varicealbleeding.21 Using these definitions, data from placebocontrolled clinical trials show that variceal bleeding isspontaneously controlled in 40 to 50% of patients.60

Currently available treatments increase control of bleed-ing to �80% of the patients.59

EARLY REBLEEDING

The incidence of early rebleeding ranges between 30%and 40% in the first 6 weeks. The risk peaks in the first5 days, with 40% of all rebleeding episodes occurring inthis very early period, remains high during the first 2weeks, and then declines slowly in the next 4 weeks.After 6 weeks the risk of further bleeding becomesvirtually equal to that before bleeding.61 Currentlyavailable treatments have reduced the 6-week rebleedingrate to 20%.59 Early rebleeding is a strong predictor ofdeath from variceal bleeding. Prognostic indicators forearly rebleeding were assessed in most studies togetherwith initial failure to control bleeding and 5-day riskfor death, forming a composite end point referredto as ‘‘5-day failure.’’ Bacterial infection,62,63 activebleeding at emergency endoscopy,59,63 Child-Pugh classor score,59,63,64 AST levels,59 presence of portal veinthrombosis59 and an HVPG > 20 mm Hg measuredshortly after admission19,64,65 have been reported assignificant predictors of risk for 5-day failure.

MORTALITY

Mortality from variceal bleeding has greatly decreased inthe last two decades, from 42% mortality in the Grahamand Smith study in 198161 to the current 15 to 20%.59,66–

68 This is probably due to implementation of effectivetreatments (endoscopic and pharmacological therapiesand TIPS), as well as improved general medical care (i.e.,antibiotic prophylaxis). Since it may be difficult to assessthe true cause of death (i.e., bleeding versus liver failureor other adverse events), the general consensus is thatany death occurring within 6 weeks from hospitaladmission for variceal bleeding should be considered asa bleeding-related death.21 Immediate mortality fromuncontrolled bleeding is in the range of 4 to 8%.4,59

Prehospital mortality from variceal bleeding might bearound 3%.69 Like the risk for rebleeding, the risk formortality peaks the first days after bleeding, slowlydeclines thereafter, and after 6 weeks becomes constant


and virtually equal to that before bleeding.60,61 Atpresent, only 40% of the deaths are directly related tobleeding, while most are caused by liver failure, infec-tions, and hepatorenal syndrome.59 Thus, although thereis still room for improving hemostatic treatments, tosubstantially decrease mortality from variceal bleeding,therapies should be able to prevent deterioration of liverand renal function.

The most consistently reported death risk indica-tors are Child-Pugh classification or its components,blood urea nitrogen or serum creatinine, active bleedingon endoscopy, hypovolemic shock, and hepatocellularcarcinoma.59,61,62,70 Prognostic indicators gathered inthe early follow-up include early rebleeding, bacterialinfection, and renal failure.70 From these data it is clearthat management of bleeding cirrhotic patients shouldbe aimed not only at controlling the bleeding, but alsoat preventing early rebleeding, infection, and renalfailure.

Treatment of Acute Variceal Bleeding

Acute variceal bleeding should be managed in an in-tensive care setting by a team of experienced medicalstaff, including well-trained nurses, clinical hepatolo-gists, endoscopists, interventional radiologists, and sur-geons. Lack of an appropriate facility or staff demandsimmediate referral. Decision-making shall follow theguidelines set up in a written protocol developed tooptimize the resources of each center.

GENERAL MANAGEMENT

The general management of the bleeding patient isaimed at correcting hypovolemic shock (with judiciousvolume replacement and transfusion) and at preventingcomplications associated with gastrointestinal bleeding(bacterial infections, hepatic decompensation, renalfailure), which are independent of the cause of thehemorrhage and demand immediate management.

Initial resuscitation should follow the classicAirway, Breathing, Circulation scheme, and is aimed atrestoring an appropriate delivery of oxygen to the tissues(which depends on SaO2, cardiac output, and hemoglo-bin concentration).

Airway should be immediately secured, especiallyin encephalopathic patients, since the patient is at risk ofbronchial aspiration of gastric content and blood. Thisrisk is further exacerbated by endoscopic procedures.Endotracheal intubation is mandatory if there is anyconcern about the safety of the airway. Blood volumereplacement should be initiated as soon as possible withplasma expanders, aiming at maintaining systolic bloodpressure around 100 mm Hg. Avoiding prolonged hy-potension is particularly important to prevent infectionand renal failure, which are associated with increased riskof rebleeding and death.70 Transfusion policy should be

conservative, since it may induce rebound increases in PPand rebleeding.71,72 The use of vasopressin analogues orsomatostatin blunt the increase in PP induced by volumeexpansion.73,74 Blood transfusion should aim at main-taining the hematocrit at 0.21 to 0.24 (Hb 7 to 8 g/L),21

except in patients with rapid ongoing bleeding or withischemic heart disease. The role of platelet transfusion orfresh frozen plasma administration has not been assessedappropriately. The use of recombinant activated factorVII (rVIIa, Novoseven1), which corrects prothrombintime in cirrhotics,75 has been assessed in two randomizedcontrolled trials. The first trial showed, in a post hocanalysis, that rFVIIa administration may significantlyimprove the results of conventional therapy in patientswith moderate and advanced liver failure (stages B and Cof the Child-Pugh classification) without increasing theincidence of adverse events.57 A more recent trial testedrVIIa in patients with active bleeding at endoscopy andwith a Child-Pugh score � 8 points. This trial failed toshow a benefit of rVIIa in terms of decreasing the risk of5-day failure but improved 6-week mortality.58

Infection is a strong prognostic indicator in acutevariceal bleeding.63 The most frequent infections arespontaneous bacterial peritonitis (50%), urinary tractinfections (25%), and pneumonia (25%). The use ofprophylactic antibiotics in patients with acute varicealbleeding has been shown to reduce both the risk ofrebleeding76 and mortality.77 Therefore, antibioticsshould be given to all patients from admission. Quino-lones are frequently used due to their easy administrationand low cost.78 In high-risk patients (hypovolemicshock, ascites, jaundice, or malnutrition) intravenousceftriaxone has recently been shown to be superior tooral norfloxacin.79

Variceal bleeding can trigger hepatic encephalop-athy. However, there are no data to support the prophy-lactic use of lactulose or lactitol.21

SPECIFIC THERAPY FOR CONTROL OF BLEEDING

Initial therapy for acute variceal bleeding is based onthe combination of vasoactive drugs with endoscopictherapy. Rescue therapies for failures include balloontamponade and portal-systemic shunts, either surgical orTIPS.

Pharmacological Therapy Vasoactive drugs act toreduce variceal pressure by decreasing variceal bloodflow. The selection of the drug depends on the localresources. Terlipressin should be the first choice ifavailable, since it is the only drug that has been shownto improve survival.60,80 Somatostatin, octreotide, orvapreotide are the second choice.60,81 If these drugs arenot available, vasopressin plus transdermal nitroglycerinis an acceptable option.60

Terlipressin is a long-acting triglycyl lysine deriv-ative of vasopressin. Clinical studies have consistently


shown less frequent and severe side effects with terli-pressin than with vasopressin, even when vasopressin isassociated with nitroglycerin. The most common sideeffect of this drug is abdominal pain. Serious side effectssuch as peripheral or myocardial ischemia occur in lessthan 3% of the patients.82 Terlipressin may be initiatedas early as variceal bleeding is suspected at a dose of2 mg/4 hours for the first 48 hours, and it may bemaintained for up to 5 days at a dose of 1 mg/4 hours toprevent rebleeding.82 Compared with placebo or non-active treatment, terlipressin significantly improves therate of control of bleeding and survival.83 This is the onlytreatment that has been shown to improve prognosis ofvariceal bleeding in placebo-controlled randomized clin-ical trials (RCTs) and meta-analysis.60,83 Terlipressin isas effective as any other effective therapy, includingendoscopic injection sclerotherapy (EIS), and is saferthan vasopressinþ nitroglycerin and EIS.60,82,83 Theoverall efficacy of terlipressin in controlling acute varicealbleeding at 48 hours is 75 to 80% across trials,83 and 67%at 5 days.82 Terlipressin is also useful in hepatorenalsyndrome.84 Thus the use of terlipressin for varicealbleeding may prevent renal failure, which is frequentlyprecipitated by variceal bleeding.70

Somatostatin is commonly used as an initial bolusof 250 mg followed by a 250-mg/h infusion that ismaintained until the achievement of a 24-hour bleed-free period. The bolus injection can be repeated up tothree times in the first hour if bleeding is uncontrolled.Therapy may be further maintained for up to 5 daysto prevent early rebleeding.85 The use of higherdoses (500 mg/h) causes a greater fall in HVPG andtranslates into increased clinical efficacy in the subset ofpatients with more difficult bleedings (those with activebleeding at emergency endoscopy).86 Major side effectswith somatostatin are rare. Minor side effects, such asnausea, vomiting, and hyperglycemia occur in up 30% ofpatients.85–87 Several randomized controlled trialsshowed that somatostatin significantly improves therate of control of bleeding compared with placebo ornonactive treatment.60,81 However, despite the beneficialeffect on control of bleeding, somatostatin did notreduce mortality.60 Somatostatin has been comparedwith terlipressin and no differences were found for fail-ure to control bleeding, rebleeding, mortality, or in theincidence of adverse events in both treatment groups.60

Octreotide is a somatostatin analogue with longerhalf-life. This, however, is not associated with longerhemodynamic effects than somatostatin.88 The optimaldoses are not well determined. It is usually given as aninitial bolus of 50 mg, followed by an infusion of 25 or 50mg/h.81 As with somatostatin, therapy can be maintainedfor 5 days to prevent early rebleeding. The safety profile ofoctreotide is close to that of somatostatin. The efficacy ofoctreotide as a single therapy for variceal bleeding iscontroversial. No benefit from octreotide was found in

the only trial using octreotide or placebo as initial treat-ment,89 which may be due to rapid development oftachyphylaxis.88 However, RCTs using octreotide ontop of sclerotherapy have shown a significant benefit interms of reducing early rebleeding.90 It has been specu-lated that this may be related to its sustained ability toprevent postprandial increase in PP.81 Mortality, how-ever, was not affected.60,90 These results suggest thatoctreotide may improve the results of endoscopic therapybut has uncertain effects if used alone. When comparedwith other vasoactive drugs, octreotide was better thanvasopressin and equivalent to terlipressin, again suggest-ing a clinical value from the use of octreotide, although allthese studies were underpowered and none was doubleblind.60

Endoscopic Therapy Both sclerotherapy and endo-scopic band ligation (EBL) have been shown to beeffective in the control of acute variceal bleeding. Tworandomized trials specifically compared band ligationand sclerotherapy in acute variceal bleeding.91,92 In oneof them all patients also received pharmacological ther-apy (somatostatin).92 In eight additional trials these twomodalities were compared both in acute bleeding and inthe prevention of rebleeding. Meta-analysis shows thatEBL is better than sclerotherapy in the initial control ofbleeding, and is associated with fewer adverse events andimproved mortality. Additionally, sclerotherapy, but notEBL, may induce a sustained increase in PP.93 ThereforeEBL should be the endoscopic therapy of choice in acutevariceal bleeding, though injection sclerotherapy is ac-ceptable if band ligation is not available or is technicallydifficult. Endoscopic therapy can be performed at thetime of diagnostic endoscopy, early after admission,provided that a skilled endoscopist is available. This isimportant since there has been an increased frequencyof aspiration pneumonia since emergency endoscopictherapy has become a universal practice.

Current Recommendation for Initial Treat-ment The current recommendation is to combinethese two approaches, starting vasoactive drug therapyearly (ideally during the transfer to the hospital, even ifactive bleeding is only suspected) and performing EBL(or injection sclerotherapy if band ligation is technicallydifficult) after initial resuscitation when the patient isstable and bleeding has ceased or slowed (Table 2). Therationale for that comes from several RCTs demonstrat-ing that early administration of a vasoactive drug facili-tates endoscopy and improves control of bleeding and5-day rebleeding.80,87,94,95 Drug therapy also improvesthe results of endoscopic treatment if started just aftersclerotherapy or band ligation.60,90 Conversely, the asso-ciation of endoscopic therapy also improves the efficacy ofvasoactive treatment.87 However, this combined appro-ach failed to significantly improve 6-week mortality with


respect to endoscopic therapy96 or a vasoactive drug87

alone. The optimal duration of drug therapy is not wellestablished and requires evaluation. Current recommen-dation is to maintain the drug for 2 to 5 days, to coverthe period of maximum risk of rebleeding.21

RESCUE THERAPIES: TAMPONADE, SURGERY, AND TIPS

In 10 to 20% of patients, variceal bleeding is unrespon-sive to initial endoscopic and/or pharmacologic treat-ment. If bleeding is mild and the patient is stable, asecond endoscopic therapy (if technically possible) mightbe attempted. If this fails, or bleeding is severe, thepatient should be offered a derivative treatment, beforethe clinical status of the patient further deteriorates.Balloon tamponade achieves hemostasis in 60 to 90%of variceal bleedings3 but should only be used in the caseof a massive bleeding, for a short period of time (lessthan 24 hours) as a temporal ‘‘bridge’’ until definitetreatment is instituted. Bleeding recurs after deflationin over half of the cases and severe complications arecommon. A recent report suggests that the use ofesophageal covered stents might achieve hemostasis inmost patients with refractory bleeding,97 with the ad-vantage over tamponade of less severe complicationsdespite much longer periods of treatment. Adequatelydesigned trials should confirm these findings.

Both TIPS and surgical shunts are extremelyeffective for controlling variceal bleeding (control rateapproaches 95%), but due to worsening of liver functionand encephalopathy mortality remains high.3,98 TIPS isthe first choice, since most patients requiring rescuetreatment have advanced liver disease. However, rarely,if ever, will a patient with a Child-Pugh score over 13survive TIPS. This clearly indicates that some patients donot benefit from TIPS in this setting, and sometimes it is

difficult to make a clinicallybased decision. Prognosticscores99 may provide objective parameters to ease thedecision of not offering invasive treatments in difficultcases.

SPECIAL PROBLEMS IN MANAGEMENT

The Patient with Poor Prognostic Indicators Thecurrent consensus is to apply to all patients the sametreatment. However, it is plausible that patients withpoor prognostic indicators might benefit from a moreaggressive therapeutic approach ab initio. This wasrecently explored in a randomized trial in which patientswith high PP (> 20 mm Hg) were randomized to receivestandard therapy or TIPS. Those who underwent earlyTIPS had significantly less treatment failure and lowermortality than patients undergoing standard therapy.65

However, the standard therapy used in the control armof this trial was only endoscopic therapy, which is not thecurrent standard of combination of vasoactive drugs andendoscopic treatment.21 An ongoing multicenter studywill answer whether early TIPS (performed with coveredstents) is superior to combination therapy in high-riskpatients (ISRCTN58150114).

Gastric Varices Gastric varices develop in �20% ofpatients with portal hypertension.100 They are the sourceof 5 to 10% of all upper digestive bleeding episodes inpatients with cirrhosis. The risk of gastric varicealbleeding is lower than that of esophageal variceal bleed-ing, but gastric variceal bleeding, in particular that fromfundal varices, tends to be more severe, to require moretransfusions, and to have a higher mortality rate.100

Fundal varices account for 1 to 3% of variceal bleeds.The optimal treatment of gastric fundal varices

has not been determined, since there are only a fewRCTs and most data come from retrospective seriesand case reports. The initial treatment is similar tothat of esophageal variceal bleeding, including theadministration of a vasoactive drug (either terlipressin,somatostatin, or a somatostatin analogue) and generalmanagement for hemodynamic stabilization and theprevention of complications. However, the efficacy ofvasoactive drugs has not been assessed specifically.Balloon tamponade, with the Linton-Nachlas tube,has been used with limited success,101,102 but may serveas a bridge to derivative treatments in massive bleedings.

Some endoscopic therapies are promising, butquality information is scarce, and most studies includeboth fundal varices and gastroesophageal varices. Scle-rotherapy, variceal obturation with tissue adhesives(‘‘glue injection’’), thrombin, elastic band ligation, andligation with large detachable snares have been re-ported.103 In most uncontrolled series, cyanoacrylate ishighly effective, on the order of 90%.104 Two recentrandomized trials compared banding ligation with

Table 2 Treatment of Acute Variceal Bleeding:Recommendations

� The best approach is the combined use of a pharmacological

agent, started from admission (or even during transfer

to hospital), and an endoscopic procedure.

� Terlipressin, somatostatin, octreotide, and

vasopressinþ nitroglycerin (in this order of preference) may be

used; drug therapy should be maintained for at least 2 to

5 days.

� Endoscopic band ligation or injection sclerotherapy (in this

order of preference) are the endoscopic treatments of choice

in bleeding esophageal varices; in bleeding gastric varices

the best endoscopic choice is obturation with cyanoacrylate.

� Prophylaxis of infection with broad spectrum antibiotics

should be given to all patients.

� TIPS should be used as a rescue procedure when medical

and endoscopic therapies fail; patients bleeding from gastric

varices may require an earlier decision for TIPS.

TIPS, transjugular intrahepatic portal-systemic shunts.


cyanoacrylate injection in patients with acute varicealbleeding. In one trial cyanoacrylate injection was moreeffective and safer than band ligation in the control ofacute bleeding, and was associated with less rebleed-ing.105 In another trial both treatments were equallyeffective in the control acute of bleeding, but rebleedingwas more frequent in the ligation group.106 In anotherRCT by Sarin and coworkers, cyanoacrylate was betterthan alcohol injection in achieving initial hemostasis andin achieving faster variceal obliteration.107 These trialssuggest that cyanoacrylate injection is the endoscopictherapy of choice in acute bleeding from gastric varices.This technique requires expertise, and is usually notfeasible during active bleeding.

TIPS is very effective in the treatment of bleedinggastric varices, with more than a 90% success rate forinitial hemostasis and a low rebleeding rate.108,109 TIPSis usually associated with the embolization of the collat-eral vessels that feed the varices. Derivative and devas-cularization surgery are also effective, but with limitedapplicability in advanced cirrhosis.

The authors’ recommendation is to start with avasoactive drug. If bleeding is not controlled and if anexpert endoscopist is available, variceal obturation withtissue adhesives should be attempted. In cases of massivebleeding or after failure of previous therapies, TIPS (orsurgical shunt in Child-Pugh class A patients) is man-datory. In some patients, especially in those with massiveinitial bleeding or in centers with reduced endoscopicexperience in the treatment of gastric varices, TIPS maybe used even before attempting endoscopic therapy.

Portal Hypertensive Gastropathy Portal hyperten-sive gastropathy (PHG) is a macroscopic finding of acharacteristic mosaic-like pattern of the gastric mucosa(‘‘mild’’ PHG), red-point lesions, cherry red spots, and/or black-brown spots (‘‘severe’’ PHG).110 These lesions,however, are not entirely specific, that is, they can occurin the absence of portal hypertension. In PHG there ismarked dilation of the vasculature of the gastric mucosaand submucosa, together with an increased blood flowand tendency to decreased acid secretion. PHG is un-related to Helicobacter pylori infection. The overall prev-alence of PHG in patients with cirrhosis stronglycorrelates with the severity of the disease and rangesbetween 11% and 80%.110 The incidence of acute bleed-ing is low (less than 3% at 3 years) with a mortality of12.5%; for chronic bleeding the incidence is around 10 to15% at 3 years. In acute bleeding, PHG b-adrenergicblockers, somatostatin, octreotide, vassopressin, terli-pressin, and estrogens have been proposed based ontheir ability to decrease gastric perfusion in this con-dition.111–114 However, only one uncontrolled study sofar has evaluated one of these drugs (somatostatin) inacute bleeding from PHG.115 Hemostasis was achievedin all patients.

PREVENTION OF FIRST BLEEDING

Prophylactic Therapy: Who Benefits?

PATIENTS WITHOUT VARICES

The observation that nonselective b-blockers attenu-ated or delayed the development of collaterals inexperimental models of portal hypertension116

prompted studies to investigate whether these agentscould prevent the development of esophageal varices inpatients with cirrhosis. A recent study randomized 213patients with cirrhosis and portal hypertensionbut without varices to receive timolol (a nonselectiveb-adrenergic blocker) or placebo for a median of55 months.1 The primary end point was developmentof esophageal varices or variceal hemorrhage. The rateof development of the primary end point did not differbetween the two treatment groups (intention to treat).The incidence of secondary end points (i.e, ascites,encephalopathy, liver transplantation, or death) wasalso not significantly different. Adverse events weremore frequent in the timolol group. Therefore, b-adrenergic blockers cannot be recommended for theprevention of the development of esophageal varices.Recent studies have shown that blockade of the vascularendothelial growth factor signaling cascade is highlyeffective in reducing the formation of collaterals inexperimental models,117,118 but no study has exploredthis clinically. A different approach, which is easilyavailable, is to prevent the progression of cirrhosis(i.e., abstinence in alcoholics, antivirals in viral cirrho-sis, lifestyle change in nonalcoholic steatohepatitis,corticosteroids in autoimmune hepatitis, phlebotomiesin hemochromatosis, copper chelators in Wilson’sdisease).

PATIENTS WITH VARICES

In the past, only patients with medium to largevarices were considered for prophylactic treatment ofvariceal bleeding. This was because most studies withb-adrenergic blockers were performed in patients withmedium to large varices, while the beneficial effects of b-blockers are less clear in patients with small varices.60

However, the classification of varices according to theirsize is very subjective. In fact, in the recent Baveno IVconsensus conference it was not possible to agree on adefinition of small and big varices.21 On the other hand,it is well established that small varices with red signs orin Child-Pugh class C patients have a bleeding risksimilar to that of big varices.14 Additionally, b-adrener-gic blockers may reduce the rate of progression fromsmall to large varices, and decrease the incidence ofvariceal bleeding in patients with small varices.7 There-fore, the current recommendation is to extend prophy-lactic treatment to patients with small varices with redsigns or Child-Pugh C.21


Screening for Varices: When and How

As previously discussed, the current consensus is thatevery cirrhotic patient should be endoscopically screenedfor varices at the time of diagnosis.7 In patients withoutvarices on initial endoscopy, a second (follow-up) eval-uation should be performed after 2 to 3 years.21 Sinceendoscopy is unpleasant for the patient, and screening inall cirrhotic patients is a substantial burden, empirical b-blocker therapy for all patients has been proposed. Twostudies suggest that this strategy is cost-effective,119,120

but a third suggested that empiric b-blockers are cost-effective only in patients with decompensated cirrho-sis.121 The lack of effectiveness of b-adrenergic blockersto prevent the development of varices, and the high rateof side effects observed in well-compensated patients,1

call into question the use of b-adrenergic blockerswithout screening.

Treatments for the Prevention of First Bleeding:

b-Adrenergic Blockers versus EBL

Nonselective b-adrenergic blockers (propranolol ornadolol) have been shown to reduce the risk of firstvariceal bleeding (from 24 to 15% after a medianfollow-up of 2 years).60 Mortality was also reduced(from 27 to 23%) though this did not achieve statisticalsignificance.60 It is important to note that b-blockersare among the safest and least expensive drugs inEurope. However, about 25% of cirrhotic patientswith medium/large esophageal varices may have eithercontraindications for the administration of nonselectiveb-blockers or cannot tolerate these drugs, and thedegree of protection afforded (�40% relative riskreduction) is far from ideal, which has stimulated thesearch for alternative treatments.

EBL is effective in preventing the first varicealbleeding in patients with medium to large varices.122

Sixteen trials have compared EBL with b-adrenergicblockers as a first-line option for primary prophylaxis ofvariceal bleeding.123–138 The meta-analysis of these trialsshows an advantage of EBL over b-adrenergic blockersin terms of prevention of first bleeding, without differ-ences in mortality (Fig. 5). Six of these trials are onlyavailable in abstract, which makes it difficult to evaluatetheir quality, and most trials were underpowered or lackany sample size calculation (11 out of 16 included fewerthan 100 patients). Four of the trials were prematurelystopped after an interim analysis, due to futility in threecases125,131,138 or to an apparently significant benefitof banding in a small study.130 When meta-analysisis restricted to published studies with a quality scoreabove 5 (out of 10), there is no significant benefit fromEBL.

These data have led to considerable controversyover whether ß-blockers should remain the first treat-ment option to prevent first variceal bleeding, since in

addition to the higher efficacy of banding ligation,adverse events requiring treatment discontinuationwere significantly more frequent in patients treatedwith nonselective b-blockers.139 However, the typeand severity of side effects was different between thetwo therapies.140 Indeed, most side effects related tob-blockers (hypotension, tiredness, breathlessness, poormemory, insomnia) were subjective and were easilymanaged by adjusting the dose or discontinuing b-blockers, did not require hospital admission, and resultedin no fatalities. In contrast, side effects related to EBLincluded 12 bleeding episodes and 1 esophageal perfo-ration. In most cases, these complications requiredhospitalization and blood transfusion and resulted in 3deaths.125,138 Further, because of the short duration offollow-up in most of these studies, the long-term safetyand benefits of prophylactic EBL are still uncertain.On the contrary, long-term safety and efficacy ofnonselective b-adrenergic blockers are well estab-lished.141,142 Bleeding episodes after discontinuingb-blockers because of side effects have also been con-sidered as an argument against their use as first choice.However, most of these bleedings occurred months oryears after b-blockers were withdrawn, suggesting thatif an alternative therapy, such as EBL, had been offeredto these patients, some of these bleeding episodes couldhave been prevented. The cost-effectiveness of EBLversus ß-blockers for primary prophylaxis has beencompared in three decision-analysis studies. Differentassumptions on the incidence of variceal bleeding,quality of life with each treatment, mortality, or otherportal hypertensive complications led to conflictingconclusions.119,121,143

The recommendation made at the 2005 Bavenoconsensus conference is that nonselective b-blockersshould be considered as first-choice treatment to preventfirst variceal bleeding, while EBL should be offered topatients with medium/large varices and contraindica-tions or intolerance to b-blockers (Table 3).21 Even inthis case, a recent trial shed some doubts on the use ofEBL. In that trial EBL was compared with no treatmentin patients with contraindications to b-blockers. Thetrial was prematurely stopped due to a high rate (12%) ofiatrogenic bleeding in the band ligation group.144 How-ever, the early termination of the trial frustrated thepossibility of obtaining clear-cut evidence to support arecommendation.

The combination of EBL plus b-adrenergicblockers appears to offer no benefit in terms of preven-tion of first bleeding when compared with EBL alone.145

There is a lower rate of recurrence of varices in patientstreated with EBL plus propranolol but at the expense ofmore side effects. Probably more studies would berequired, although these are unlikely to be performeddue to the very large number of patients that would beneeded.


Unanswered Issues

HVPG MONITORING

Three longitudinal studies have demonstrated that asufficient HVPG decrease (to 12 mm Hg or below orof more than 20% from baseline) is associated with aneffective protection from first variceal bleeding.12,18,142

This leads to the question of whether HVPG measure-ments should be used to monitor PP response to drugtreatment in clinical practice. Two simulation analyseshave yielded conflicting results, one suggesting that

HVPG monitoring might be cost-effective in primaryprophylaxis,146 and the other arriving at the oppositeconclusion.147 The main problem is that the assumptionsof these analyses (i.e., how to manage nonresponders tomedical treatment) have never been tested in random-ized controlled trials. A recent study of HVPG-guidedtherapy suggested that the shift of nonresponders fromb-blockers to EBL does not improve the outcome.148

The issue will remain hypothetical until HVPG-guidedtherapy is proven to be better than empirical approachesin randomized controlled trials.

Figure 5 Prevention of first variceal bleeding. Meta-analysis (random effects model) of randomized controlled trials

comparing endoscopic band ligation with b-adrenergic blockers in the prevention of first variceal bleeding. (A) Bleeding. (B)

Mortality. EBL, endoscopic band ligation; RR, relative risk; CI, confidence interval.


THE COMBINATION OF b-ADRENERGIC BLOCKERS WITH

NITRATES

The addition of ISMN has been shown to significantlyincrease the long-term HVPG response to b-adrener-gic blockers.149 However, it is less clear whetherthe greater effect of this combination on PP translatesinto a greater clinical efficacy in primary prophylaxis.An open trial comparing nadolol to nado-lolþ isosorbide mononitrate demonstrated a signifi-cantly lower rate of first bleeding in the combinationgroup, without survival advantage.150,151 However,a subsequent double-blind, placebo-controlled study

including a large number of patients failed to confirmthese results.152

ENDOSCOPIC TREATMENT: HOW FREQUENT, HOW TO

MONITOR THE TREATMENT

There is no agreement on how frequently the varicesshould be ligated in the initial course of eradication.Some authors wait a minimum of 1 month betweenbanding procedures,130 while others perform EBL on aweekly basis.125 Reported frequency of complicationswith the former strategy was lower than with the latter.A recent trial evaluated the effectiveness and complica-tions of EBL performed every 2 weeks compared with-every 2 months. This trial included patients with andwithout previous bleeding, though most patients weretreated for primary prophylaxis.153 The 2-month intervalscheme obtained a higher total eradication rate and alower recurrence rate. No patient in either group devel-oped variceal bleeding. Thus, although admittedly weak,current evidence favors monthly intervals. Follow-upendoscopies should be performed every 6 months andvarices should be re-eradicated upon recurrence. This isin marked contrast to prophylaxis with b-blockers, inwhich no follow-up endoscopies are needed.

PREVENTION OF RECURRENT BLEEDINGFROM ESOPHAGEAL VARICESPatients surviving a first episode of variceal bleeding havea high risk of recurrent bleeding, of over 60% within1 year from the first bleeding. Because of this, all patientssurviving a variceal bleeding should receive active treat-ments for the prevention of rebleeding21 (Fig. 6, Table 4).

Figure 6 Reported variceal rebleeding rate with different treatment options. Constructed from data of randomized clinical

trials for secondary prevention of variceal rebleeding. EIS, endoscopic injection sclerotherapy; BB, beta-blockers; EBL,

endoscopic band ligation; ISMN, isosorbide-5-mononitrate; TIPS, transjugular intrahepatic portal-systemic shunts; DSRS, distal

splenorenal shunt; HVPG, hepatic venous pressure gradient. (Based on data from Bosch J, Garcia-Pagan J. Prevention of

variceal rebleeding. Lancet 2003;361:952–954.)

Table 3 Prophylaxis of First Variceal Bleeding:Recommendations

� Patients without varices should be screened endoscopically

for the appearance of varices every 2 to 3 years.

� Patients with moderate/large varices should be treated with a

nonselective b-blocker if there are no contraindications.

� Patients with small varices with red signs or with advanced

liver failure (Child-Pugh C) are at similar risk of bleeding as

those with moderate/large varices and should be considered

for preventive therapy.

� Patients with moderate/large varices with contraindications to

or who cannot tolerate b-blockers should undergo endoscopic

band ligation; band ligation might be used as the first choice in

patients with large varices depending on patient’s preferences

and local resources.

� If no bleeding occurs treatment should be maintained for life

(unless the liver disease improves and significant portal

hypertension disappears).


Pharmacological Treatment

The efficacy of nonselective b-blockers in the preventionof variceal rebleeding has been proven in many RCTs,and these drugs are now widely accepted as the first-linepharmacological therapy in this setting21. Several meta-analyses have consistently found a marked benefit fromb-blockers showing a reduction in rebleeding rate from63% in controls to 42% in treated patients.60 Mortalitywas significantly reduced, from 27 to 20%60 and mortal-ity from bleeding was also significantly reduced.154 Beta-blockers have been compared with endoscopic varicealsclerotherapy in the prevention of rebleeding. No sig-nificant differences were found either for rebleeding orfor mortality but side effects were significantly lessfrequent and severe with b-blockers.60

The combined administration of propranolol ornadolol plus ISMN was introduced after demonstratingthat ISMN enhanced the PP-reducing effect of non-selective b-blockers.149 There is insufficient informationon whether this translates into a clinical advantage, sincethere are only two studies of ISMN associated withpropranolol155 or nadolol156 versus the correspondingb-blocker alone, in the prevention of rebleeding. Oneof these studies showed significant benefit, but not thesecond (which is still available only in abstract form).156

However, the association of ISMN with propranolol ornadolol has been found to be superior to endoscopicsclerotherapy in one study.157 In addition, the associa-tion of propranolol/nadolol and ISMN has been com-pared with EBL in four studies.158–161 Meta-analysis ofthese four studies has shown no significant differences

between the treatments in preventing rebleeding or inmortality.

Compared with TIPS, the combination of ISMNand propranolol is less effective for the prevention ofrebleeding but it is associated with significantly lessencephalopathy, similar mortality, and much lowercost.162

Treatment dosage and schedules for propranolol,nadolol, and ISMN are the same as for the prevention offirst bleeding.

Endoscopic Treatment

Endoscopic injection sclerotherapy of esophageal varicessignificantly reduces both the rebleeding and deathrisk. It takes four to six endoscopic sessions to eradicatevarices, but recurrence of varices occurs in nearly 40% ofpatients within 1 year from eradication. This requiresfurther endoscopic sessions to maintain eradication. Themost serious side effects of therapy are dysphagia,esophageal stenosis, and bleeding from esophageal ul-cers, which may account for as much as 14% of all therebleeding episodes. As noted above, sclerotherapyhas no advantage over drug therapy and causes morefrequent and severe side effects.

Endoscopic banding ligation has been provensuperior to sclerotherapy.140 Complications are signifi-cantly less frequent and severe with banding ligation.Therefore, banding ligation should be preferred tosclerotherapy.21 Surprisingly, despite decreasing rebleed-ing rates, endoscopic ligation does not significantlyimprove survival compared with sclerotherapy. Althoughvariceal eradication is achieved with a lower number ofEBL sessions than with sclerotherapy, there is evidencethat it is associated with higher recurrence of varices.140

Combined Endoscopic Treatment

In the approach using banding ligation combined withsclerotherapy, sclerotherapy has been added (either simul-taneously or after the reduction of variceal size to small)to EBL and compared with band ligation alone, yieldingcontrasting results. The meta-analysis of these studiesdoes not show any benefit either for rebleeding or formortality, and importantly, it shows a trend towardan increasing complication rate with combination endo-scopic therapy.

Combined Endoscopic and Pharmacological

Treatment

The association of injection sclerotherapy and b-block-ers has been compared with either sclerotherapy orb-blockers alone. The meta-analysis of the RCTs com-paring combination therapy with sclerotherapy aloneshowed a significant reduction of the rebleeding

Table 4 Prevention of Variceal Rebleeding:Recommendations

� All patients surviving a bleeding episode should be treated

to prevent recurrent bleeding; in patients who bled and were

not receiving b-blockers, either b-blockers� ISMN, band

ligation, or both can be used.

� Patients who bled while on b-blocker or under prophylactic

EBL should be treated with the combination of EBL plus

b-blockers.

� Patients who are intolerant to or who have contraindications

to b-blockers should be treated with EBL.

� The efficacy of TIPS in the prevention of recurrent bleeding

from esophageal varices is not different from that of shunt

surgery (distal splenorenal shunt or 8-mm Hg graft shunt),

especially since the introduction of PTFE-covered stents.

� Failures of medical therapy are preferably managed with

PTFE-TIPS; this is the only option in poor surgical candidates.

� Patients who survive a bleeding episode and have advanced

liver failure (Child-Pugh score > 8 or MELD >16) should be

considered for liver transplantation.

ISMN, isosorbide-5-mononitrate; EBL, endoscopic band ligation;TIPS, transjugular intrahepatic portal-systemic shunt; PTFE, polyte-trafluoroethylene; MELD, model for end-stage liver disease.


risk with combination therapy, but no differences inmortality.3 Also, when compared with b-blockers alone,combination therapy significantly reduced the rebleed-ing risk without advantage for survival.60

Two RCTs have shown that the combination ofbanding ligation plus b-blockers is superior to bandingligation alone in terms of recurrence of varices andrecurrence of bleeding.163,164 In addition, in one RCT,adding band ligation to nadolol plus ISMN was shownto be superior to nadololþ ISMN alone in preventingvariceal rebleeding. However, no significant differenceswere observed when considering rebleeding episodes ofany cause. This was due to a greater number of ulcer-related bleeding episodes in the treatment arm includingbanding.165 All together, these results emphasize thatthe possible greater clinical efficacy of the combinationof endoscopic plus drug treatment in the prevention ofrebleeding should be further evaluated. However, untilthen the recommendation is to use the combination inpatients who bled under either treatment alone. In thesepatients, the substitution of the failing treatment withthe other should not be preferred to their combination.

TIPS

TIPS has been compared with sclerotherapy andwith banding ligation showing almost consistently thatTIPS is superior to either endoscopic therapy for theprevention of rebleeding. Similarly, TIPS has also beenshown to be superior to the combination of ISMN andpropranolol.162 Not surprisingly, this impressive efficacyin preventing recurrent bleeding is associated with amarked increase in the risk of encephalopathy withoutreducing either overall mortality or mortality frombleeding.

TIPS has been compared with surgical shunts intwo RCTs.166 In the first study, TIPS was comparedwith 8-mm portocaval H-graft shunt.166,167 A signifi-cantly lower rebleeding rate was found with the surgicalshunt. Significantly more patients required liver trans-plant in the TIPS group than in the surgical shunt group.There was no difference in mortality. The composite endpoint of ‘‘failures’’ which included rebleeding, shuntthrombosis, deaths, and need for transplant, was signifi-cantly higher for the TIPS. In the second trial TIPS wascompared with the distal splenorenal shunt (DSRS) inChild-Pugh class A and B patients.167 No significantdifferences in rebleeding rate (5.5% in the DSRS group,and 9% in the TIPS group), incidence of hepaticencephalopathy, liver transplantation, or mortality wasfound. However, to obtain these results the reinterven-tion rate was significantly higher in the TIPS group(82%) than in the DSRS group (11%). However, newpolytetrafluoroethylene (PTFE)-covered stents havesolved one of the major drawbacks of TIPS’ use ofbare stents, that is, its high rate of occlusion or dysfunc-

tion. Indeed, a multicenter RCT reported much lowerobstruction and reintervention rates with the use ofPTFE stents, which was associated with lower rates ofrecurrent bleeding or ascites without an increase in theincidence of encephalopathy, than with the use of barestents.168 These results suggest that the small disadvant-age of TIPS versus surgical shunt would be overcome bythe use of PTFE-covered stents.

HVPG-Guided Therapy in the Prevention of

Rebleeding

Pharmacological (or spontaneous) reduction of HVPGto < 12 mm Hg or by � 20% of the baseline value(HVPG responders) markedly decreases the risk ofrebleeding and also reduces mortality.169 Indeed,achieving such a hemodynamic response is associatedwith a rebleeding risk that is even lower than thatachieved using surgical shunts or TIPS170 (Fig. 7). Asa consequence, to add further treatment (i.e., bandligation) to these patients is likely to not enhanceefficacy but to increase the side effects. On the otherhand, it is still unclear whether patients with aninsufficient hemodynamic response to pharmacologicaltherapy would benefit from adding other drugs oralternative treatments.

As previously discussed, a decision analysis doesnot clearly suggest that HVPG-guided therapy is cost-effective in the primary prevention of variceal bleeding.However, probably because of the higher risk of varicealhemorrhage in secondary prophylaxis, a recent studyconcluded that the use of nonselective b-blockersþ -long-acting nitrates offering EBL to HVPG nonres-ponders was cost-effective and only marginally moreexpensive than EBL or pharmacological treatment with-out HVPG monitoring.171 However, decision analysismodels are limited by the many assumptions on whichthese are based. Because of these, the value of HVPG-guided therapy must be demonstrated in randomizedclinical studies. A first attempt was done by Bureau andcolleagues148 In this study, HVPG nonresponders tob-blockers were given ISMN and if their conditionremained unchanged, they were shifted to EBL.Although the study included low numbers, it suggestedthat band ligation is not a good alternative in HVPGnonresponders. Preliminary data from a Spanish multi-center RCT comparing nadololþ ISMN with nado-lolþ ISMNþEBL165 found no significant differencesin rebleeding rates in HVPG nonresponders treated withdrugs alone or with drugsþEBL, suggesting that add-ing EBL may not be the best alternative to reducerebleeding in HVPG nonresponders. It is thereforepossible that more effective and aggressive therapiesare required to reduce the high rebleeding tendency ofHVPG nonresponders (46 to 65% in a recent survey170).The recent study by Gonzalez et al found a 19%


rebleeding rate in the HVPG nonresponders that wereshifted to receive TIPS, suggesting that this might be anoption.172 Unfortunately, the study included a smallnumber of patients and had no control group. Therefore,investigators should continue to study HVPG-guidedtherapy in order to be able to make clear recommenda-tions.

Treatment of Gastric Varices

The optimal treatment to prevent gastric (fundal) vari-ceal bleeding is not well defined, due to the relatively lowincidence of this condition. In clinical practice, non-selective b-blockers or the tissue adhesive isobutyl-2-cyanoacrylate (bucrylate) are used as first line therapy.PTFE-TIPS or shunt surgery is recommended infailures.

Treatment of PHG

Prevention of recurrent bleeding from PHG should bebased on nonselective b-blockers, at the same dosage asfor treating esophageal varices.173 Adequate iron sup-plementation may be useful to prevent or correct chroniciron-deficient anemia in patients with severe PHG.173

Rare patients who have repeated severe bleeding from

PHG despite pharmacological therapy may benefit fromendoscopic ablation, either by argon plasma coagulation,neodymium:yttrium-aluminum-garnet (Nd:YAG) laser,or heater probe. If this is not feasible or fails, TIPS maybe considered as an alternative therapy. PHG reversesafter liver transplantation.

ACKNOWLEDGMENTS

We thank Ms. Clara Esteva for expert secretarial sup-port. This study was supported in part by grants from theMinisterio de Educacion y Ciencia (SAF-04/04783),and from Instituto de Salud Carlos III (FIS 06/0623and 05/0519).

ABBREVIATIONSCDUS color Doppler ultrasoundCSPH clinically significant portal hypertensionCT computed tomographyDSRS distal splenorenal shuntEBL endoscopic band ligationHVPG hepatic venous pressure gradientISMN isosorbide-5-mononitrateIVC inferior vena cavaMRI magnetic resonance imaging

Figure 7 Meta-analysis of the randomized clinical trial (RCTs) comparing b-blockersþ isosorbide-5-mononitrate (ISMN) with

endoscopic band ligation (EBL) of esophageal varices to prevent recurrent variceal bleeding and mortality. Each RCT is identified

by the name of the first author and the year of publication. Squares indicate the odds ratio (OR) with the two treatments for each

RCT. Horizontal bars denote the 95% confidence interval (CI) of the OR. The vertical line represents the line of identity of effect

of the two treatments. The diamonds represent 95% CIs of the pooled OR.


NO nitric oxidePHG portal hypertensive gastropathyPP portal pressurePPG portal pressure gradientPTFE polytetrafluoroethyleneRCT randomized clinical trialTIPS transjugular intrahepatic portal-systemic

shuntsUS ultrasound

REFERENCES

1. Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients withcirrhosis. N Engl J Med 2005;353:2254–2261

2. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural historyand prognostic indicators of survival in cirrhosis: a system-atic review of 118 studies. J Hepatol 2006;44:217–231

3. D’Amico G, Pagliaro L, Bosch J. The treatment of portalhypertension: a meta-analytic review. Hepatology 1995;22:332–354

4. D’Amico G, Luca A. Natural history—clinical-haemody-namic correlations: prediction of the risk of bleeding.Baillieres Clin Gastroenterol 1997;11:243–256

5. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO,Atterbury CE, Glickman M. Portal pressure, presence ofgastroesophageal varices and variceal bleeding. Hepatology1985;5:419–424

6. Christensen E, Fauerholdt L, Schlichting P, Juhl E, PoulsenH, Tygstrup N. Aspects of the natural history of gastro-intestinal bleeding in cirrhosis and the effect of prednisone.Gastroenterology 1981;81:944–952

7. Merkel C, Marin R, Angeli P, et al. A placebo-controlledclinical trial of nadolol in the prophylaxis of growth of smallesophageal varices in cirrhosis. Gastroenterology 2004;127:476–484

8. Merli M, Nicolini G, Angeloni S, et al. Incidence andnatural history of small esophageal varices in cirrhoticpatients. J Hepatol 2003;38:266–272

9. Zoli M, Merkel C, Magalotti D, et al. Natural history ofcirrhotic patients with small esophageal varices: a prospec-tive study. Am J Gastroenterol 2000;95:503–508

10. de Franchis R. Evaluation and follow-up of patients withcirrhosis and oesophageal varices. J Hepatol 2003;38:361–363

11. Cales P, Oberti F, Payen JL, et al. Lack of effect ofpropranolol in the prevention of large oesophageal varices inpatients with cirrhosis: a randomized trial. French-SpeakingClub for the Study of Portal Hypertension. Eur J Gastro-enterol Hepatol 1999;11:741–745

12. Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamicevents in a prospective randomized trial of propranolol versusplacebo in the prevention of a first variceal hemorrhage [seecomments]. Gastroenterology 1990;99:1401–1407

13. Vorobioff J, Groszmann RJ, Picabea E, et al. Prognosticvalue of hepatic venous pressure gradient measurements inalcoholic cirrhosis: a 10-year prospective study. Gastro-enterology 1996;111:701–709

14. North Italian Endoscopic Club. Prediction of the firstvariceal hemorrhage in patients with cirrhosis of the liverand esophageal varices: a prospective multicenter study. TheNorth Italian Endoscopic Club for the Study and Treatment

of Esophageal Varices [see comments]. N Engl J Med1988;319:983–989

15. Casado M, Bosch J, Garcia-Pagan JC, et al. Clinical eventsafter transjugular intrahepatic portosystemic shunt: correla-tion with hemodynamic findings. Gastroenterology 1998;114:1296–1303

16. Feu F, Garcia-Pagan JC, Bosch J, et al. Relation betweenportal pressure response to pharmacotherapy and risk ofrecurrent variceal haemorrhage in patients with cirrhosis.Lancet 1995;346:1056–1059

17. Bosch J, Garcia-Pagan JC, Berzigotti A, Abraldes JG.Measurement of portal pressure and its role in the manage-ment of chronic liver disease. Semin Liver Dis 2006;26:348–362

18. Merkel C, Bolognesi M, Sacerdoti D, et al. Thehemodynamic response to medical treatment of portalhypertension as a predictor of clinical effectiveness in theprimary prophylaxis of variceal bleeding in cirrhosis.Hepatology 2000;32:930–934

19. Moitinho E, Escorsell A, Bandi JC, et al. Prognostic valueof early measurements of portal pressure in acute varicealbleeding. Gastroenterology 1999;117:626–631

20. Ripoll C, Banares R, Rincon D, et al. Influence of hepaticvenous pressure gradient on the prediction of survival ofpatients with cirrhosis in the MELD era. Hepatology 2005;42:793–801

21. de Franchis R. Evolving consensus in portal hypertension:report of the Baveno IV consensus workshop on method-ology of diagnosis and therapy in portal hypertension.J Hepatol 2005;43:167–176

22. Groszmann RJ, Merkel C, Iwakiri Y, et al. Prevention of theformation of varices (pre-primary prophylaxis). In: deFranchis R, ed. Proceedings of the IV Baveno InternationalConsensus Workshop on Definitions, Methodology andTherapeutic Strategies. Oxford: Blackwell-Science; 2005:103–151

23. Eisen GM, Eliakim R, Zaman A, et al. The accuracy ofPillCam ESO capsule endoscopy versus conventional upperendoscopy for the diagnosis of esophageal varices: a pro-spective three-center pilot study. Endoscopy 2006;38:31–35

24. Lapalus MG, Dumortier J, Fumex F, et al. Esophagealcapsule endoscopy versus esophagogastroduodenoscopy forevaluating portal hypertension: a prospective comparativestudy of performance and tolerance. Endoscopy 2006;38:36–41

25. Frenette C, Kuldau JG, Hillebrand D, Lane J, Pockros PJ.Comparison of esophageal pill endoscopy and conventionalendoscopy for variceal screening. Hepatology 2006;44(suppl 1):445A

26. D’Amico G, Morabito A. Noninvasive markers of esoph-ageal varices: another round, not the last. Hepatology 2004;39:30–34

27. de Franchis R. Noninvasive diagnosis of esophageal varices:is it feasible? Am J Gastroenterol 2006;101:2520–2522

28. Chalasani N, Imperiale TF, Ismail A, et al. Predictorsof large esophageal varices in patients with cirrhosis[see comments]. Am J Gastroenterol 1999;94:3285–3291

29. Giannini E, Botta F, Borro P, et al. Platelet count/spleendiameter ratio: proposal and validation of a non-invasiveparameter to predict the presence of oesophageal varices inpatients with liver cirrhosis. Gut 2003;52:1200–1205

30. Sanyal AJ, Fontana RJ, Di Bisceglie AM, et al. Theprevalence and risk factors associated with esophageal


varices in subjects with hepatitis C and advanced fibrosis.Gastrointest Endosc 2006;64:855–864

31. Schepis F, Camma C, Niceforo D, et al. Which patientswith cirrhosis should undergo endoscopic screening foresophageal varices detection? Hepatology 2001;33:333–338

32. Vanbiervliet G, Barjoan-Marine E, Anty R, et al. Serumfibrosis markers can detect large oesophageal varices with ahigh accuracy. Eur J Gastroenterol Hepatol 2005;17:333–338

33. Zoli M, Iervese T, Merkel C, et al. Prognostic significanceof portal hemodynamics in patients with compensatedcirrhosis. J Hepatol 1993;17:56–61

34. Bolondi L, Gandolfi L, Arienti V, et al. Ultrasonography inthe diagnosis of portal hypertension: diminished response ofportal vessels to respiration. Radiology 1982;142:167–172

35. Sacerdoti D, Merkel C, Bolognesi M, Amodio P, Angeli P,Gatta A. Hepatic arterial resistance in cirrhosis with andwithout portal vein thrombosis: relationships with portalhemodynamics. Gastroenterology 1995;108:1152–1158

36. Berzigotti A, Casadei A, Magalotti D, et al. Renovascularimpedance correlates with portal pressure in patients withliver cirrhosis. Radiology 2006;240:581–586

37. Taourel P, Blanc P, Dauzat M, et al. Doppler study ofmesenteric, hepatic, and portal circulation in alcoholiccirrhosis: relationship between quantitative Doppler meas-urements and the severity of portal hypertension and hepaticfailure. Hepatology 1998;28:932–936

38. Cho KC, Patel YD, Wachsberg RH, Seeff J. Varices inportal hypertension: evaluation with CT. Radiographics1995;15:609–622

39. Johnson CD, Ehman RL, Rakela J, Ilstrup DM. MRangiography in portal hypertension: detection of varices andimaging techniques. J Comput Assist Tomogr 1991;15:578–584

40. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasiveassessment of liver fibrosis by measurement of stiffness inpatients with chronic hepatitis C. Hepatology 2005;41:48–54

41. Carrion JA, Navasa M, Bosch J, Bruguera M, Gilabert R,Forns X. Transient elastography for diagnosis of advancedfibrosis and portal hypertension in patients with hepatitis Crecurrence after liver transplantation. Liver Transpl2006;12:1791–1798

42. Lemoine M, Katsahian S, Nahon P, et al. Liver stiffnessmeasurement is correlated with hepatic venous pressuregradient in patients with uncomplicated alcoholic and/orHVC related cirrhosis. Hepatology 2006;44(suppl 1):204A

43. Bureau C, Metivier S, Peron JM, et al. Prospectiveassessment of liver stiffness for the non-invasive predictionof portal hypertension. J Hepatol 2007;46(suppl 1):S34

44. Vizzutti F, Arena U, Romanelli RG, et al. Liver stiffnessmeasurement predicts severe portal hypertension in patientswith HCV-related cirrhosis. Hepatology 2007;45:1290–1297

45. Kazemi F, Kettaneh A, N’kontchou G, et al. Liver stiffnessmeasurement selects patients with cirrhosis at risk of bearinglarge oesophageal varices. J Hepatol 2006;45:230–235

46. Bosch J. Predictions from a hard liver. J Hepatol 2006;45:174–177

47. Bosch J, Abraldes JG, Groszmann RJ. Current managementof portal hypertension. J Hepatol 2003;38:S54–S68

48. Pinzani M, Gentilini P. Biology of hepatic stellate cells andtheir possible relevance in the pathogenesis of portal

hypertension in cirrhosis. Semin Liver Dis 1999;19:397–410

49. Wiest R, Groszmann RJ. The paradox of nitric oxide incirrhosis and portal hypertension: too much, not enough.Hepatology 2002;35:478–491

50. Gupta TK, Toruner M, Chung MK, Groszmann RJ.Endothelial dysfunction and decreased production of nitricoxide in the intrahepatic microcirculation of cirrhotic rats.Hepatology 1998;28:926–931

51. Rockey DC, Chung JJ. Reduced nitric oxide production byendothelial cells in cirrhotic rat liver: endothelial dysfunc-tion in portal hypertension. Gastroenterology 1998;114:344–351

52. Hernandez-Guerra M, Garcia-Pagan JC, Turnes J, et al.Ascorbic acid improves the intrahepatic endothelial dys-function of patients with cirrhosis and portal hypertension.Hepatology 2006;43:485–491

53. Vorobioff J, Bredfeldt J, Groszmann RJ. Hyperdynamiccirculation in a portal hypertensive rat model: a primaryfactor for maintenance of chronic portal hypertension. Am JPhysiol 1983;244:G52–G56

54. Pizcueta MP, Pique JM, Bosch J, Whittle BJ, Moncada S.Effects of inhibiting nitric oxide biosynthesis on thesystemic and splanchnic circulation of rats with portalhypertension. Br J Pharmacol 1992;105:184–190

55. Pizcueta P, Pique JM, Fernandez M, et al. Modulation ofthe hyperdynamic circulation of cirrhotic rats by nitric oxideinhibition. Gastroenterology 1992;103:1909–1915

56. Garcia-Pagan JC, Salmeron JM, Feu F, et al. Effects oflow-sodium diet and spironolactone on portal pressure inpatients with compensated cirrhosis. Hepatology 1994;19:1095–1099

57. Bosch J, Thabut D, Bendtsen F, et al. Recombinant factorVIIa for upper gastrointestinal bleeding in patients withcirrhosis: a randomized, double-blind trial. Gastroenterol-ogy 2004;127:1123–1130

58. Bosch J, Thabut D, Albillos A, et al. Recombinant FactorVIIA (RFVIIA) for active variceal bleeding in patients withadvanced cirrhosis: a multi-centre randomized double-blindplacebo-controlled trial. J Hepatol 2007;46(suppl 1):S295

59. D’Amico G, de Franchis R. Upper digestive bleeding incirrhosis: post-therapeutic outcome and prognostic indica-tors. Hepatology 2003;38:599–612

60. D’Amico G, Pagliaro L, Bosch J. Pharmacological treat-ment of portal hypertension: an evidence-based approach.Semin Liver Dis 1999;19:475–505

61. Graham DY, Smith JL. The course of patients after varicealhemorrhage. Gastroenterology 1981;80:800–809

62. Bernard B, Cadranel JF, Valla D, Escolano S, Jarlier V,Opolon P. Prognostic significance of bacterial infection inbleeding cirrhotic patients: a prospective study. Gastro-enterology 1995;108:1828–1834

63. Goulis J, Armonis A, Patch D, Sabin C, Greenslade L,Burroughs AK. Bacterial infection is independently asso-ciated with failure to control bleeding in cirrhotic patientswith gastrointestinal hemorrhage. Hepatology 1998;27:1207–1212

64. Abraldes JG, Aracil C, Catalina MV, et al. Value ofHVPG predicting 5-day treatment failure in acute varicealbleeding: comparison with clinical variables. J Hepatol2006;44(suppl 2):12A

65. Monescillo A, Martinez-Lagares F, Ruiz-del-Arbol L, et al.Influence of portal hypertension and its early decompression


by TIPS placement on the outcome of variceal bleeding.Hepatology 2004;40:793–801

66. Carbonell N, Pauwels A, Serfaty L, Fourdan O, Levy VG,Poupon R. Improved survival after variceal bleeding inpatients with cirrhosis over the past two decades. Hepatology2004;40:652–659

67. Chalasani N, Kahi C, Francois F, et al. Improved patientsurvival after acute variceal bleeding: a multicenter, cohortstudy. Am J Gastroenterol 2003;98:653–659

68. Stokkeland K, Brandt L, Ekbom A, Hultcrantz R.Improved prognosis for patients hospitalized with esoph-ageal varices in Sweden 1969–2002. Hepatology 2006;43:500–505

69. Nidegger D, Ragot S, Berthelemy P, et al. Cirrhosis andbleeding: the need for very early management. J Hepatol2003;39:509–514

70. Cardenas A, Gines P, Uriz J, et al. Renal failure after uppergastrointestinal bleeding in cirrhosis: incidence, clinicalcourse, predictive factors, and short-term prognosis.Hepatology 2001;34(4 Pt 1):671–676

71. McCormick PA, Jenkins SA, McIntyre N, Burroughs AK.Why portal hypertensive varices bleed and bleed: ahypothesis. Gut 1995;36:100–103

72. Castaneda B, Debernardi-Venon W, Bandi JC, et al. Therole of portal pressure in the severity of bleeding in portalhypertensive rats. Hepatology 2000;31:581–586

73. Villanueva C, Ortiz J, Minana J, et al. Somatostatintreatment and risk stratification by continuous portalpressure monitoring during acute variceal bleeding. Gastro-enterology 2001;121:110–117

74. Morales J, Moitinho E, Abraldes JG, Fernandez M, BoschJ. Effects of the V1a vasopressin agonist F-180 on portalhypertension-related bleeding in portal hypertensive rats.Hepatology 2003;38:1378–1383

75. Ejlersen E, Melsen T, Ingerslev J, Andreasen RB, VilstrupH. Recombinant activated factor VII (rFVIIa) acutelynormalizes prothrombin time in patients with cirrhosisduring bleeding from oesophageal varices. Scand J Gastro-enterol 2001;36:1081–1085

76. Hou MC, Lin HC, Liu TT, et al. Antibiotic prophylaxisafter endoscopic therapy prevents rebleeding in acutevariceal hemorrhage: a randomized trial. Hepatology 2004;39:746–753

77. Bernard B, Grange JD, Khac EN, Amiot X, Opolon P,Poynard T. Antibiotic prophylaxis for the prevention ofbacterial infections in cirrhotic patients with gastrointestinalbleeding: a meta-analysis. Hepatology 1999;29:1655–1661

78. Rimola A, Garcia-Tsao G, Navasa M, et al. Diagnosis,treatment and prophylaxis of spontaneous bacterial peri-tonitis: a consensus document. International Ascites Club.J Hepatol 2000;32:142–153

79. Fernandez J, Ruiz-del-Arbol L, Gomez C, Durandez R,et al. Norfloxacin vs ceftriaxone in the prophylaxis ofinfections in patients with advanced cirrhosis and hemor-rhage. Gastroenterology 2006;131:1049–1056

80. Levacher S, Letoumelin P, Pateron D, Blaise M, LapandryC, Pourriat JL. Early administration of terlipressinplus glyceryl trinitrate to control active upper gastro-intestinal bleeding in cirrhotic patients. Lancet 1995;346:865–868

81. Abraldes JG, Bosch J. Somatostatin and analogues in portalhypertension. Hepatology 2002;35:1305–1312

82. Escorsell A, Ruiz-del-Arbol L, Planas R, Albillos A, et al.Multicenter randomized controlled trial of terlipressinversus sclerotherapy in the treatment of acute varicealbleeding: the TEST study. Hepatology 2000;32:471–476

83. Ioannou GN, Doust J, Rockey DC. Systematic review:terlipressin in acute oesophageal variceal haemorrhage.Aliment Pharmacol Ther 2003;17:53–64

84. Uriz J, Gines P, Cardenas A, et al. Terlipressin plus albumininfusion: an effective and safe therapy of hepatorenalsyndrome. J Hepatol 2000;33:43–48

85. Escorsell A, Bordas JM, del Arbol LR, et al. Randomizedcontrolled trial of sclerotherapy versus somatostatin infusionin the prevention of early rebleeding following acute varicealhemorrhage in patients with cirrhosis. Variceal BleedingStudy Group. J Hepatol 1998;29:779–788

86. Moitinho E, Planas R, Banares R, et al. Multicenterrandomized controlled trial comparing different schedules ofsomatostatin in the treatment of acute variceal bleeding.J Hepatol 2001;35:712–718

87. Villanueva C, Ortiz J, Sabat M, et al. Somatostatin alone orcombined with emergency sclerotherapy in the treatment ofacute esophageal variceal bleeding: a prospective randomizedtrial. Hepatology 1999;30:384–389

88. Escorsell A, Bandi JC, Andreu V, et al. Desensitization tothe effects of intravenous octreotide in cirrhotic patientswith portal hypertension. Gastroenterology 2001;120:161–169

89. International Octreotide Varices Study Group, BurroughsAK. Double blind RCT of 5 day octreotide versus placebo,associated with sclerotherapy for trial failures. Hepatology1996;24:352A

90. Corley DA, Cello JP, Adkisson W, Ko WF, Kerlikowske K.Octreotide for acute esophageal variceal bleeding: a meta-analysis. Gastroenterology 2001;120:946–954

91. Lo GH, Lai KH, Cheng JS, et al. Emergency bandingligation versus sclerotherapy for the control of activebleeding from esophageal varices. Hepatology 1997;25:1101–1104

92. Villanueva C, Piqueras M, Aracil C, et al. A randomizedcontrolled trial comparing ligation and sclerotherapy asemergency endoscopic treatment added to somatostatin inacute variceal bleeding. J Hepatol 2006;45:560–567

93. Avgerinos A, Armonis A, Stefanidis G, et al. Sustained riseof portal pressure after sclerotherapy, but not band ligation,in acute variceal bleeding in cirrhosis. Hepatology 2004;39:1623–1630

94. Avgerinos A, Nevens F, Raptis S, Fevery J. Earlyadministration of somatostatin and efficacy of sclerotherapyin acute oesophageal variceal bleeds: the European AcuteBleeding Oesophageal Variceal Episodes (ABOVE) rand-omised trial. Lancet 1997;350:1495–1499

95. Cales P, Masliah C, Bernard B, et al. Early administrationof vapreotide for variceal bleeding in patients with cirrhosis.French Club for the Study of Portal Hypertension. N Engl JMed 2001;344:23–28

96. Banares R, Albillos A, Rincon D, et al. Endoscopic treatmentversus endoscopic plus pharmacologic treatment for acutevariceal bleeding: a meta-analysis. Hepatology 2002;35:609–615

97. Hubmann R, Bodlaj G, Czompo M, et al. The use of self-expanding metal stents to treat acute esophageal varicealbleeding. Endoscopy 2006;38:896–901


98. Bosch J. Salvage transjugular intrahepatic portosystemicshunt: is it really life-saving? J Hepatol 2001;35:658–660

99. Patch D, Nikolopoulou V, McCormick A, et al. Factorsrelated to early mortality after transjugular intrahepaticportosystemic shunt for failed endoscopic therapy in acutevariceal bleeding. J Hepatol 1998;28:454–460

100. Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK.Prevalence, classification and natural history of gastricvarices: a long-term follow-up study in 568 portal hyper-tension patients. Hepatology 1992;16:1343–1349

101. Teres J, Cecilia A, Bordas JM, Rimola A, Bru C, Rodes J.Esophageal tamponade for bleeding varices: controlled trialbetween the Sengstaken-Blakemore tube and the Linton-Nachlas tube. Gastroenterology 1978;75:566–569

102. Panes J, Teres J, Bosch J, Rodes J. Efficacy of balloontamponade in treatment of bleeding gastric and esophagealvarices: results in 151 consecutive episodes. Dig Dis Sci1988;33:454–459

103. Sarin SK, Agarwal SR. Gastric varices and portal hyper-tensive gastropathy. Clin Liver Dis 2001;5:727–767

104. Huang YH, Yeh HZ, Chen GH, et al. Endoscopictreatment of bleeding gastric varices by N-butyl-2-cyanoa-crylate (Histoacryl) injection: long-term efficacy and safety.Gastrointest Endosc 2000;52:160–167

105. Lo GH, Lai KH, Cheng JS, Chen MH, Chiang HT. Aprospective, randomized trial of butyl cyanoacrylate injectionversus band ligation in the management of bleeding gastricvarices. Hepatology 2001;33:1060–1064

106. Tan PC, Hou MC, Lin HC, et al. A randomized trial ofendoscopic treatment of acute gastric variceal hemorrhage:N-butyl-2-cyanoacrylate injection versus band ligation.Hepatology 2006;43:690–697

107. Sarin SK, Jain AK, Jain M, Gupta R. A randomizedcontrolled trial of cyanoacrylate versus alcohol injection inpatients with isolated fundic varices. Am J Gastroenterol2002;97:1010–1015

108. Chau TN, Patch D, Chan YW, Nagral A, Dick R,Burroughs AK. ‘‘Salvage’’ transjugular intrahepatic porto-systemic shunts: gastric fundal compared with esophagealvariceal bleeding. Gastroenterology 1998;114:981–987

109. Barange K, Peron JM, Imani K, et al. Transjugularintrahepatic portosystemic shunt in the treatment ofrefractory bleeding from ruptured gastric varices. Hepatol-ogy 1999;30:1139–1143

110. Primignani M, Carpinelli L, Preatoni P, et al. Naturalhistory of portal hypertensive gastropathy in patients withliver cirrhosis. The New Italian Endoscopic Club forthe study and treatment of esophageal varices (NIEC).Gastroenterology 2000;119:181–187

111. Panes J, Bordas JM, Pique JM, et al. Effects of propranolol ongastric mucosal perfusion in cirrhotic patients with portalhypertensive gastropathy. Hepatology 1993;17:213–218

112. Panes J, Pique JM, Bordas JM, et al. Reduction of gastrichyperemia by glypressin and vasopressin administration incirrhotic patients with portal hypertensive gastropathy.Hepatology 1994;19:55–60

113. Panes J, Pique JM, Bordas JM, et al. Effect of bolusinjection and continuous infusion of somatostatin on gastricperfusion in cirrhotic patients with portal-hypertensivegastropathy. Hepatology 1994;20:336–341

114. Panes J, Casadevall M, Fernandez M, et al. Gastricmicrocirculatory changes of portal-hypertensive rats can be

attenuated by long-term estrogen-progestagen treatment.Hepatology 1994;20:1261–1270

115. Kouroumalis EA, Koutroubakis IE, Manousos ON. Soma-tostatin for acute severe bleeding from portal hypertensivegastropathy. Eur J Gastroenterol Hepatol 1998;10:509–512

116. Sarin SK, Groszmann RJ, Mosca PG, et al. Propranololameliorates the development of portal-systemic shunting ina chronic murine schistosomiasis model of portal hyper-tension. J Clin Invest 1991;87:1032–1036

117. Fernandez M, Vizzutti F, Garcia-Pagan JC, Rodes J,Bosch J. Anti-VEGF receptor-2 monoclonal antibodyprevents portal-systemic collateral vessel formation inportal hypertensive mice. Gastroenterology 2004;126:886–894

118. Fernandez M, Mejias M, Angermayr B, Garcia-Pagan JC,Rodes J, Bosch J. Inhibition of VEGF receptor-2 decreasesthe development of hyperdynamic splanchnic circulationand portal-systemic collateral vessels in portal hypertensiverats. J Hepatol 2005;43:98–103

119. Saab S, DeRosa V, Nieto J, Durazo F, Han S, Roth B.Costs and clinical outcomes of primary prophylaxis ofvariceal bleeding in patients with hepatic cirrhosis: adecision analytic model. Am J Gastroenterol 2003;98:763–770

120. Spiegel BM, Targownik L, Dulai GS, Karsan HA, GralnekIM. Endoscopic screening for esophageal varices incirrhosis: is it ever cost-effective? Hepatology 2003;37:366–377

121. Arguedas MR, Heudebert GR, Eloubeidi MA, AbramsGA, Fallon MB. Cost-effectiveness of screening, surveil-lance, and primary prophylaxis strategies for esophagealvarices. Am J Gastroenterol 2002;97:2441–2452

122. Imperiale TF, Chalasani N. A meta-analysis of endoscopicvariceal ligation for primary prophylaxis of esophagealvariceal bleeding. Hepatology 2001;33:802–807

123. Lo GH, Chen WC, Chen MH, et al. Endoscopic ligationvs. nadolol in the prevention of first variceal bleeding inpatients with cirrhosis. Gastrointest Endosc 2004;59:333–338

124. Chen CY, Sheu MZ, Tsai TL, Lin YL. Endoscopic varicealligation with multiple band ligator for prophylaxis of firsthemorrage esophageal varices. Endoscopy 1999;31(suppl 1):35A

125. Schepke M, Kleber G, Nurnberg D, et al. Ligation versuspropranolol for the primary prophylaxis of variceal bleedingin cirrhosis. Hepatology 2004;40:65–72

126. Song H, Shin JW, Kim HI, et al. A prospective randomizedtrial between the prophylactic endoscopic variceal ligationand propranolol administration for prevention of firstbleeding in cirrhotic patients with high-risk esophagealvarices. J Hepatol 2000;32(suppl 2):41A

127. Sarin SK, Lamba GS, Kumar M, Misra A, Murthy NS.Comparison of endoscopic ligation and propranolol for theprimary prevention of variceal bleeding [see comments].N Engl J Med 1999;340:988–993

128. de la Mora G, Farca-Belsaguy AA, Uribe M, de Hoyos-Garza A. Ligation vs propranolol for primary prophylaxis ofvariceal bleeding using multiple band ligator and objectivemeasurements of treatment adequacy: preliminary results.Gastroenterology 2000;118:6511A

129. Lui HF, Stanley AJ, Forrest EH, et al. Primary prophylaxisof variceal hemorrhage: a randomized controlled trial


comparing band ligation, propranolol, and isosorbidemononitrate. Gastroenterology 2002;123:735–744

130. Jutabha R, Jensen DM, Martin P, Savides T, Han SH,Gornbein J. Randomized study comparing banding andpropranolol to prevent initial variceal hemorrhage incirrhotics with high-risk esophageal varices. Gastroenterol-ogy 2005;128:870–881

131. Thuluvath PJ, Maheshwari A, Jagannath S, Arepally A. Arandomized controlled trial of beta-blockers versus endo-scopic band ligation for primary prophylaxis: a large samplesize is required to show a difference in bleeding rates. DigDis Sci 2005;50:407–410

132. De BK, Ghoshal UC, Das T, Santra A, Biswas PK.Endoscopic variceal ligation for primary prophylaxis ofoesophageal variceal bleed: preliminary report of a random-ized controlled trial. J Gastroenterol Hepatol 1999;14:220–224

133. Drastich P, Lata J, Petrtyl J, et al. Endoscopic variceal bandligation in comparison with propranolol in prophylaxisof first variceal bleeding in patients with liver cirrhosis.J Hepatol 2005;42:202A

134. Lay CS, Tsai YT, Lee FY, et al. Endoscopic variceal ligationversus propranolol in prophylaxis of first variceal bleeding inpatients with cirrhosis. J Gastroenterol Hepatol 2006;21:413–419

135. Psilopoulos D, Galanis P, Goulas S, et al. Endoscopicvariceal ligation vs. propranolol for prevention of firstvariceal bleeding: a randomized controlled trial. Eur JGastroenterol Hepatol 2005;17:1111–1117

136. Abdelfattah MH, Rashed MA, Elfakhry AA, Soliman MA,Shiha GH. Endoscopic variceal ligation versus pharmaco-logical treatment for primary prophylaxis of varicealbleeding: a randomized study. J Hepatol 2006;44(suppl 2):83A

137. Gheorghe C, Gheorghe L, Vadan R, Hrehoret D, PopescuI. Prophylactic banding ligation of high-risk esophagealvarices in patients on the waiting list for liver trans-plantation: an interim analysis. J Hepatol 2002;36(suppl 1):38A

138. Norberto L, Polese L, Cillo U, et al. A randomized studycomparing ligation with propranolol for primary prophylaxisof variceal bleeding in candidates for liver transplantation.Liver Transpl 2007;13:1272–1278

139. Khuroo MS, Khuroo NS, Farahat KL, Khuroo YS, SofiAA, Dahab ST. Meta-analysis: endoscopic variceal ligationfor primary prophylaxis of oesophageal variceal bleeding.Aliment Pharmacol Ther 2005;21:347–361

140. Garcia-Pagan JC, Bosch J. Endoscopic band ligation in thetreatment of portal hypertension. Nat Clin Pract Gastro-enterol Hepatol 2005;2:526–535

141. Abraczinskas DR, Ookubo R, Grace ND, et al.Propranolol for the prevention of first esophageal varicealhemorrhage: a lifetime commitment? Hepatology 2001;34:1096–1102

142. Turnes J, Garcia-Pagan JC, Abraldes JG, Hernandez-Guerra M, Dell’Era A, Bosch J. Pharmacological reductionof portal pressure and long-term risk of first varicealbleeding in patients with cirrhosis. Am J Gastroenterol2006;101:506–512

143. Imperiale TF, Klein RW, Chalasani N. Cost-effectivenessanalysis of variceal ligation vs. beta-blockers for primaryprevention of variceal bleeding. Hepatology 2007;45:870–878

144. Triantos C, Vlachogiannakos J, Armonis A, et al. Primaryprophylaxis of variceal bleeding in cirrhotics unable to takebeta-blockers: a randomized trial of ligation. AlimentPharmacol Ther 2005;21:1435–1443

145. Sarin SK, Wadhawan M, Agarwal SR, Tyagi P, SharmaBC. Endoscopic variceal ligation plus propranolol versusendoscopic variceal ligation alone in primary prophylaxisof variceal bleeding. Am J Gastroenterol 2005;100:797–804

146. Imperiale TF, Chalasani N, Klein RW. Measuring thehemodynamic response to primary pharmacoprophylaxis ofvariceal bleeding: a cost-effectiveness analysis. Am J Gastro-enterol 2003;98:2742–2750

147. Hicken BL, Sharara AI, Abrams GA, Eloubeidi M, FallonMB, Arguedas MR. Hepatic venous pressure gradientmeasurements to assess response to primary prophylaxis inpatients with cirrhosis: a decision analytical study. AlimentPharmacol Ther 2003;17:145–153

148. Bureau C, Peron JM, Alric L, et al. ‘‘A la carte’’ treatment ofportal hypertension: adapting medical therapy to hemody-namic response for the prevention of bleeding. Hepatology2002;36:1361–1366

149. Garcia-Pagan JC, Feu F, Bosch J, Rodes J. Propranololcompared with propranolol plus isosorbide-5-mononitratefor portal hypertension in cirrhosis: a randomized controlledstudy. Ann Intern Med 1991;114:869–873

150. Merkel C, Marin R, Enzo E, et al. Randomised trial ofnadolol alone or with isosorbide mononitrate for primaryprophylaxis of variceal bleeding in cirrhosis. Gruppo-Triveneto per L’ipertensione portale (GTIP) [see com-ments]. Lancet 1996;348:1677–1681

151. Merkel C, Marin R, Sacerdoti D, et al. Long-term results ofa clinical trial of nadolol with or without isosorbidemononitrate for primary prophylaxis of variceal bleeding incirrhosis. Hepatology 2000;31:324–329

152. Garcia-Pagan J, Morillas R, Banares R, et al. Propranololplus placebo vs propranolol plus isosorbide-5-mononitratein the prevention of the first variceal bleed: a double blindRCT. Hepatology 2003;37:1260–1266

153. Yoshida H, Mamada Y, Taniai N, et al. A randomizedcontrol trial of bi-monthly versus bi-weekly endoscopicvariceal ligation of esophageal varices. Am J Gastroenterol2005;100:2005–2009

154. Bernard B, Lebrec D, Mathurin P, Opolon P, Poynard T.Beta-adrenergic antagonists in the prevention of gastro-intestinal rebleeding in patients with cirrhosis: a meta-analysis. Hepatology 1997;25:63–70

155. Gournay J, Masliah C, Martin T, Perrin D, Galmiche JP.Isosorbide mononitrate and propranolol compared withpropranolol alone for the prevention of variceal rebleeding.Hepatology 2000;31:1239–1245

156. Rosalia P, Pasta L, D’Amico G, et al. Isosorbide mono-nitrate with nadolol compared to nadolol alone forprevention of recurrent bleeding in cirrhosis: a double blindplacebo controlled randomized trial—final report. J Hepatol2001;34(suppl 1):63A

157. Villanueva C, Balanzo J, Novella MT, et al. Nadolol plusisosorbide mononitrate compared with sclerotherapy for theprevention of variceal rebleeding. N Engl J Med 1996;334:1624–1629

158. Villanueva C, Minana J, Ortiz J, et al. Endoscopic ligationcompared with combined treatment with nadolol andisosorbide mononitrate to prevent recurrent variceal bleed-ing. N Engl J Med 2001;345:647–655


159. Patch D, Sabin CA, Goulis J, et al. A randomized,controlled trial of medical therapy versus endoscopic ligationfor the prevention of variceal rebleeding in patients withcirrhosis. Gastroenterology 2002;123:1013–1019

160. Lo GH, Chen WC, Chen MH, et al. Banding ligationversus nadolol and isosorbide mononitrate for the preven-tion of esophageal variceal rebleeding. Gastroenterology2002;123:728–734

161. Romero G, Kravetz D, Argonz J, et al. Comparative studybetween nadolol and 5-isosorbide mononitrate vs. endo-scopic band ligation plus sclerotherapy in the prevention ofvariceal rebleeding in cirrhotic patients: a randomizedcontrolled trial. Aliment Pharmacol Ther 2006;24:601–611

162. Escorsell A, Banares R, Garcia-Pagan JC, et al. TIPS versusdrug therapy in preventing variceal rebleeding in advancedcirrhosis: a randomized controlled trial. Hepatology 2002;35:385–392

163. Lo GH, Lai KH, Cheng JS, et al. Endoscopic varicealligation plus nadolol and sucralfate compared with ligationalone for the prevention of variceal rebleeding: a prospective,randomized trial. Hepatology 2000;32:461–465

164. de la Pena J, Brullet E, Sanchez-Hernandez E, Rivero Met al. Variceal ligation plus nadolol compared with ligationfor prophylaxis of variceal rebleeding: a multicenter trial.Hepatology 2005;41:572–578

165. Spanish Cooperative Variceal Rebleeding Study Group.Multicenter RCT comparing drug therapy vs the combina-tion of drug therapy plus endoscopic band ligation inthe prevention of rebleeding in patients with cirrhosis.Hepatology 2007;44:202A

166. Rosemurgy AS, Serafini FM, Zweibel BR, et al. Trans-jugular intrahepatic portosystemic shunt vs. small-diameterprosthetic H-graft portacaval shunt: extended follow-up of

an expanded randomized prospective trial. J GastrointestSurg 2000;4:589–597

167. Henderson JM, Boyer TD, Kutner MH, et al. Distalsplenorenal shunt versus transjugular intrahepatic portalsystematic shunt for variceal bleeding: a randomized trial.Gastroenterology 2006;130:1643–1651

168. Bureau C, Garcia-Pagan JC, Otal P, et al. Improved clinicaloutcome using polytetrafluoroethylene-coated stents for tips:results of a randomized study. Gastroenterology 2004;126:469–475

169. D’Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepaticvein pressure gradient reduction and prevention of varicealbleeding in cirrhosis: a systematic review. Gastroenterology2006;131:1611–1624

170. Bosch J, Garcia-Pagan J. Prevention of variceal rebleeding.Lancet 2003;361:952–954

171. Targownik LE, Spiegel BM, Dulai GS, Karsan HA, GralnekIM. The cost-effectiveness of hepatic venous pressuregradient monitoring in the prevention of recurrentvariceal hemorrhage. Am J Gastroenterol 2004;99:1306–1315

172. Gonzalez A, Augustin S, Perez M, et al. Hemodynamicresponse-guided therapy for prevention of variceal rebleed-ing: an uncontrolled pilot study. Hepatology 2006;44:806–812

173. Perez-Ayuso RM, Pique JM, Bosch J, et al. Propranololin prevention of recurrent bleeding from severe portalhypertensive gastropathy in cirrhosis. Lancet 1991;337:1431–1434

174. Escorsell A, Bosch J. Pathophysiology of variceal bleeding.In: Groszmann RJ, Bosch J, eds. Portal Hypertension in the21st Century. Dordrecht/Boston/London: Kluwer AcademicPublishers; 2004:155–166


portal hypertension and gastrointestinal bleeding€¦ · portal hypertension and gastrointestinal...

Documents