Prevention of the development of varices and first portal hypertensive bleeding episode

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1 Best Practice & Research Clinical Gastroenterology Vol. 21, No. 1, pp. 31e42, 2007 doi: /j.bpg available online at 3 Prevention of the development of varices and first portal hypertensive bleeding episode Christos K. Triantos MD Clinical Fellow Andrew K. Burroughs* FRCP Professor Medicine Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital, Pond Street, London NW3 2QG, UK Variceal bleeding is a serious complication in patients with cirrhosis. Although bleeding related mortality rates have fallen recently, it continues to be amongst the leading causes of death. Cirrhotics should be screened for varices at diagnosis. Data on preventing formation/growth of oesophageal varices (pre-primary prophylaxis) are conflicting, with insufficient evidence to use beta-blockers. In order to prevent first bleeding, there is strong evidence in patients with medium/large size oesophageal varices that either non-selective beta-blockers or banding ligation can be used. Banding is superior with respect to bleeding but mortality is similar. Non-selective beta-blockers should remain first line treatment being effective, cheap and without serious complications. In contrast banding ligation is more expensive, requires specialised staff, cannot prevent bleeding from portal hypertensive gastropathy and can cause iatrogenic bleeding. Patients with small varices, particularly if they have progressive liver disease also benefit from beta-blockers, but fewer studies confirm this therapeutic approach. Key words: esophageal varices; bleeding; primary prevention. INTRODUCTION Cirrhosis causes 90% of portal hypertension in Europe and North America, resulting in the development of portosystemic collaterals which comprise oesophageal varices. 1 Any patient with chronic liver disease is at risk of developing oesophageal varices as long as a minimal portal pressure (indirectly assessed with HVPG e hepatic venous * Corresponding author. Tel.: þ ; Fax: þ address: andrew.burroughs@royalfree.nhs.uk (A.K. Burroughs) /$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.

2 32 C. K. Triantos and A. K. Burroughs pressure gradient) threshold of 10e12 mmhg is reached. Once oesophageal varices have developed, they tend to increase in size and eventually to bleed. 2 Mortality rates of variceal bleeding in patients with cirrhosis have fallen recently, now around 20%, 3e5 especially after the routine administration of prophylactic antibiotics. 6e8 However, portal hypertensive bleeding continues to be a leading cause of death in these patients.the risk of bleeding for patients with small varices is lower than with large varices, 9 but with grade C cirrhosis, patients with small varices and no red signs have an estimated risk of bleeding of 20% e a commonly used threshold to consider primary prophylaxis. 9 Progression of small varices to large ones is observed in 4% to 30% of cirrhotic patients each year 10 particularly in those with progressive liver disease. Regression is reported with mprovement in liver function and abstinence from alcohol. 11,12 The prognosis of bleeding has led to attempts to prevent the development of varices, identify high-risk patients for bleeding, and to prevent bleeding e this review focuses on these three issues. PREDICTING THE PRESENCE AND DEVELOPMENT OF OESOPHAGEAL VARICES Many studies have attempted to establish non-endoscopic parameters to determine predictive models for the presence and development of oesophageal varices. At the time of diagnosis, oesophageal varices are present in 30% of patients with well compensated cirrhosis and 60% of patients with decompensated cirrhosis. 4 Their size increases by 10e20% in the 1e2 years following their first endoscopic observation. 1 In a study 13 (with average 6 year follow-up), large varices developed in 4% of cirrhotics without varices, and 25% with small varices at the beginning of follow up, while in another study 11 with 2 year follow-up, large varices were developed in 31% without varices and 70% with first degree varices at initial endoscopy. The large differences are due to different definitions of variceal size and different proportions of patients with different aetiologies. 14 The presence of oesophageal varices has been correlated with platelet count, splenic size, albumin concentration, Child Pugh score, and spider naevi. 15 In 116 cirrhotics 16 platelet count and prothrombin time were indicators of oesophageal varices. In addition platelet count, prothrombin time and spider naevi also indicated large varices. In a cohort of 143 patients varices were correlated with PT index <70%, platelets < /mm 3 and ultrasound-determined portal vein diameter >13 mm. 17 In a recent study, 18 platelet count/spleen diameter ratio was validated as an effective means for ruling out the presence of oesophageal varices. Lastly thrombocytopenia, splenomegaly and ascites were reported as independent predictors of large oesophageal varices in patients with cirrhosis. 19 These efforts towards diagnosing varices without endoscopy using the various indirect indices listed above have not resulted in a final consensus as to whether these can substitute endoscopy 15e17,20 and consequently endoscopic screening is still the best test to detect varices. 21,22 As oesophageal varices are formed if portal pressure exceed 10e12 mmhg, screening for the development of varices has been proposed by using HVPG measurement, 20 as HVPG monitoring during pharmacotherapy also provides information on the risk of variceal bleeding. 23,24 However not all patients with raised portal pressure have varices at endoscopic examination. In an AASLD symposium 25 it was suggested that in Child Pugh A cirrhotics endoscopy should be performed when there are indications of portal hypertension (platelets < ,

3 Prevention of development of varices and portal hypertensive bleeding 33 portal vein diameter >13 mm, and ultrasound indication of collateral blood flow). In Child Pugh B, and C cirrhotics endoscopy should be performed at the time of diagnosis. Patients without varices should undergo endoscopy every 2 years if liver function is stable, or once a year if there are signs of deterioration. As progression to large varices is more rapid when are present at initial endoscopy compared to no varices, annual endoscopy for those with small varices is recommended. Recently a preliminary study of esophageal capsule endoscopy (Pilcam Eso) showed it to be comparable to endoscopy for screening/surveillance for oesophageal varices 26 but a larger mulicenter trial is needed to confirm this. The HVPG is presently the most reliable predictor of variceal development. 21,27e29 PREVENTION OF THE DEVELOPMENT AND GROWTH OF VARICES Pre-primary prophylaxis is the term used for the prevention of varices. Experimental studies had suggested benefit from treatment with unselective beta blockers in preventing collateral circulation. 30,31 Beta-blockers reduce portal pressure by an average of 15%e20%, independent of liver function, and severity of portal hypertension or systemic hemodynamic parameters. However, propranolol may not affect variceal size, although it reduces variceal pressure. 32 In portal pressure changes were reported following administration of nonselective beta-blockers (timolol) in 50 cirrhotics with or without oesophageal varices. Timolol reduced portal pressure significantly in all patients, and reduction was higher in patients without varices, supporting the opinion that non-selective beta-blockers would have increased efficacy if administered in early stages of cirrhosis. Two studies have addressed the question on the role of beta-blockers in the progression of oesophageal varices. 34,35 In the first study Cales et al 34 studied 206 cirrhotics with small varices or without varices: 102 received propranolol and 104 placebo. After 2 years of follow up the proportion of patients with large varices was 31% in the propranolol group compared with 14% in the placebo group ( p < 0.05). However this study was criticised as one-third of the patients were lost to follow-up, treatment was given as a fixed dose, without adjusting for individual pressure changes, and the incidence of large varices in patients receiving placebo was lower than expected at 2 years. 36 However, in a recent study 37 with 213 randomised patients without oesophageal varices (minimal HVPG of 6 mmhg) receiving either timolol in 108 patients or placebo in 105 patients, non-selective beta-blockers did not prevent varices formation. The majority of patients (88%) had Child A liver disease and 12% Child B. Median follow-up was 54.9 months; mean daily dose of timolol was 10.8 mg. Serious adverse events were more common among patients in the timolol group ( p ¼ 0.006). However varices developed less frequently among patients with a baseline HVPG < 10 mmhg and among those in whom the HVPG decreased by more than 10% at 1 year (independent of treatment). Recently, Merkel et al 35 compared nadolol in 83 patients to placebo in 78 patients with small varices (mean follow up 60 months). A significantly slower rate of enlargement of oesophageal varices occurred in nadolol treated patients with a significantly lower probability of variceal bleeding. However survival was not affected. The conclusion was that beta-blocker prophylaxis of variceal bleeding in cirrhotic patients should be started even if there are only small varices. This is consistent with the estimated probability of bleeding within 1 year: Child Pugh grade A patients with large varices and moderate red signs e 24% compared to 20% for Child C patients with small varices and no red signs. 9

4 34 C. K. Triantos and A. K. Burroughs Thus, some patients with small varices have an important risk of first bleeding. In addition there is accumulating evidence supporting the role of infection as a trigger for variceal bleeding, 7,8 which could be modified by beta-blockers. Reduction of portal pressure has been related to improvement of liver function, and haemodynamic response to pharmacotherapy has been associated with decreased probability of developing ascites and spontaneous bacterial peritonitis, lower likelihood of developing encephalopathy and needing liver transplantation, and better survival. 38 As beta-blockers therapy is inexpensive, early treatment is favoured from a pharmacoeconomic point of view compared with endoscopic surveillance and treatment when varices become large. 39 Thus patients with small varices should be treated with beta-blockers, particularly if they have progressive liver disease. In conclusion, currently there is only one study 35 showing that beta e blockers can slow down the progression of small to large varices in cirrhotics. However, taking into consideration the available data regarding the risk of bleeding in patients with small varices we consider that these drugs may be a reasonable therapeutic option particularly for patients with advanced liver disease, or living far from endoscopic units. PREVENTION OF FIRST VARICEAL BLEEDING Shunt surgery and sclerotherapy Randomised studies with shunt surgery of primary prevention of variceal bleeding 14 led to its abandonment because of increased risk of encephalopathy and diminished survival. Endoscopic sclerotherapy was widely used for primary prophylaxis. In one metanalysis 13 the available data were insufficient to recommend sclerotherapy for prophylaxis while in a second 14 although bleeding risk was decreased significantly, the mortality was increased. Two randomised studies have been published subsequently one in 43 cirrhotics with small varices: 21 sclerotherapy with ethanolamine oleate and 22 control group, with a mean of 60 months and endoscopic surveillance every 2 months for the first 2 years, and each 6e12 months thereafter. During the first 2 years five patients bled in the sclerotherapy group and none in the control group, with similar mortality. Long-term follow up again showed a higher prevalence of bleeding in the sclerotherapy group but mortality remained similar. 40 In the second randomised study 41 (166 patients with II, III, and IV degree oesophageal varices e 32 months follow-up), 25% bled in the sclerotherapy group and 28% in the no treatment group. Three year survival was 62% in both groups. These additional studies to the metaanalyses 13,14 suggest sclerotherapy may not necessarily decrease variceal haemorrhage in cirrhotics with low or medium bleeding risk. In addition, although bleeding related mortality decreased, overall mortality did not decrease. In view of the largest study 42 showing increased mortality endoscopic sclerotherapy has been abandoned. 4,13,21,42,43 Non-selective beta-blockers Non-selective beta-blockers not only decrease cardiac output but also reduce splanchnic blood flow, inducing splanchnic arterial vasoconstriction. 30,44 In addition haemodynamic responders to pharmacological therapy have a reduced incidence of spontaneous bacterial peritonitis (SBP) or bacteremia, 24 infection being a probable risk factor of variceal bleeding. 8 Furthermore lowering of portal pressure not only protects from variceal bleeding but also from portal hypertensive gastropathy which can be a significant source

5 Prevention of development of varices and portal hypertensive bleeding 35 of haemorrhagic episodes in cirrhotics. Endoscopic therapy does not protect from gastric mucosal bleeding. There are nine randomised studies 42,45e52 enrolling 996 patients; seven used propranolol, and two nadolol: 205 bleeding episodes occurred in 507 patients in control groups (40.4%) and 146 in 489 patients receiving treatment (29.9%); 261 deaths occurred in 507 patients in control patients (51%), and 211 in 489 patients receiving treatment (43%). The number needed to treat (NNT) is 11 patients in order to prevent one bleeding episode. If only studies with medium and large size varices are included, the effectiveness of beta-blockers is higher and the NNT is eight patients. 14 Treatment with propranolol is cost effective in all groups of cirrhotics. 53 In an individual patient meta-analysis 54 (four trials e 286 patients received betablockers and 303 placebo) the percentage that was free of bleeding was 78 3% and 65 3% ( p ¼ 0.002) and the 2 year survival rate was 71 3% and 68 3% ( p ¼ 0.34), respectively. Another meta-analysis 13 (nine randomised trials) showed a statistically significant reduction in the risk of bleeding (pooled odds ratio, % CI, 0.39 to 0.74), particularly in patients with large or medium size varices or in patients with varices and HVPG > 12 mmhg. However, only a trend in reducing mortality emerged. 14 When propranolol is discontinued, the likelihood of bleeding is similar to that of patients not receiving propranolol. 55 In conclusion there is enough evidence of an important reduction of bleeding risk, but there is no marked decrease in overall mortality using beta-blockers in this setting. 56 Isosorbite mononitrate (ISMN) ISMN has been assessed as there is a significant number of cirrhotics (15e25%) with contraindications or intolerance to beta blockers. In a multicenter randomised double e blind study (133 cirrhotics e 67 received ISMN, and 66 placebo) there was no difference regarding the prevention of bleeding. 57 Although it was initially thought that ISMN was a safe and effective alternative to propranolol 58 the same authors reported higher mortality rates in the ISMN group in the same cohort with a longer follow up. 59 Another study showed that ISMN was ineffective compared to nadolol. 60 Thus, it appears that beta-blocker therapy is superior to ISMN and the latter should not be used as monotherapy for primary prophylaxis of variceal bleeding. The addition of ISMN in beta-blockers gives greater reduction of portal pressure. In a study 61 (30 month follow-up), patients receiving nadolol had a bleeding rate of 18% compared to 7.5% in the combination group. Although the follow-up of these patients for more than 7 years confirmed the increased effectiveness of combination therapy versus single agent nadolol, 62 these results have not been confirmed by others. 63 In a larger randomised study 174 cirrhotics received propranolol and placebo and 175 propranolol and mononitrate isosorbide. The study confirmed that propranolol is effective in this setting but the risk of bleeding was not further decreased with the addition of ISMN. 63 In another study 57 cirrhotics with large oesophageal varices and red colour signs were randomised to receive either ISMN plus nadolol (30 patients), or nadolol plus placebo (27 patients). The study was interrupted, consequently it was not possible to draw valid conclusions. 64 Therefore there are insufficient data to support the combination of beta-blockers plus ISMN and it should not be used in primary prevention.

6 36 C. K. Triantos and A. K. Burroughs Endoscopic banding ligation (EBL) Several trials have been published comparing the efficacy of endoscopic banding ligation versus no treatment, 65e72 sclerotherapy 66,71,73 and beta-blockers 74e87 as primary prophylaxis. Meta-analysis of randomised trials shows that EBL reduces both the risk of first portal hypertensive bleeding (OR, 0.3 (95% CI, 0.17e0.53)) and mortality (OR, 0.42 (95% CI, 0.3e0.6)) compared to no treatment. 72 The ethics of these trials are debatable given that data existed concerning the effectiveness of beta-blockers. Ligation also reduces the risk of first bleeding (OR, 0.52 (95% CI, 0.37e0.71)), but not mortality (OR O.94 (95% CI, 0.68e1.28)) compared to betablockers (Figures 1 and 2). Four trials have been published in this area recently. 77,79,80,87 In three there was no significant difference between EBL and propranolol. 77,80,87 The fourth 79 suggested that propranolol-treated cirrhotics with high-risk oesophageal varices had a significantly higher rate of variceal bleeding and greater cumulative mortality than those who had EBL. We have challenged this interpretation 88 with concerns about the exclusion criteria (severe coagulopathy unresponsive to blood product transfusions, severe thrombocytopenia, gastric varices, documented hepatoma, portal or hepatic thrombosis and large-volume or tense ascites) and the strong conclusion that banding ligation is universally safe which is not supported by the literature. 72,85 In the trial by Schepke et al 85 bleeding from ligation occurred in five patients (6.7%) with one life-threatening bleeding and two fatal outcomes. In our trial 72 EBL versus no treatment was compared in cirrhotics with intolerance or contraindications to betablockers for prevention of first bleeding. Although a sample size of 214 was planned in patients with all size varices, the trial was stopped after the randomisation of 52 patients due to increased bleeding in the EBL group. Sixty percent of the bleeding in the banding group was probably iatrogenic, requiring the study to be stopped. This is the first study suggesting that EBL may be harmful when used as primary prophylaxis, similar to prophylactic sclerotherapy in the past. Although our trial 72 has been criticised because of the use of an unplanned interim analysis as well as the absence of an independent data monitoring committee 89 we emphasise that the investigators used the principle of primum non-nocere (enshrined in article 5 of the Helsinki Figure 1. Meta-analysis of randomised trials of banding ligation of oesophageal varices versus beta-blockers. Portal hypertensive bleeding (BB: beta-blockers, EBL: endoscopic band ligation). Data are expressed as OR (95% CI) in a log scale. (In the trial by Song et al 86 all episodes of gastrointestinal bleeding are included.)

7 Prevention of development of varices and portal hypertensive bleeding 37 Figure 2. Meta-analysis of randomised trials of banding ligation of oesophageal varices versus beta-blockers. Survival (BB: beta-blockers, EBL: endoscopic band ligation). Data are expressed as OR (95% CI) in a log scale. declaration) would have been breached by continuing the trial and secondly that the main conclusion was that banding ligation causes iatrogenic bleeding and thus may not be suitable as prophylactic therapy. It is one issue to use therapy that may not always be effective it is an another to use therapy that may cause the problem that one is trying to prevent. Our results hopefully will lead to a more careful management of patients in primary prevention setting. Combination treatment with ligation and beta-blockers has also been assessed (144 patients, high-risk varices, EBL plus propranolol vs. EBL). 90 There was no significant difference in the actuarial probability of first bleed at 20 months between the two groups. However, the recurrence of varices was lower if propranolol was added to EBL. SUMMARY Endoscopic examination for the presence of esophageal varices and evaluation of their size should be performed in every patient diagnosed with cirrhosis. Surgery and sclerotherapy have been abandoned in primary prevention setting. Recent recommendations at the Baveno IV Consensus Workshop which was held on April 28e29, 2005 include: 21 (a) all cirrhotics should be screened for varices at diagnosis, (b) EBL is useful in preventing variceal bleeding in patients with medium and large varices, (c) EBL is more effective than non-selective beta-blockers in preventing first variceal bleeding but does not improve survival rate, (d) EBL should be offered to patients with medium/large varices and contraindications or intolerance to beta-blockers. In addition EBL could be considered for patients who do not have haemodynamic response to beta-blocker administration but with great caution. However EBL is an expensive treatment requiring specialised staff and it cannot prevent bleeding from portal hypertensive gastropathy. However, the small number of patients enrolled in comparative studies, in association with the conflicting results and potential iatrogenic fatal bleeding and the cost of EBL, lead us to believe that beta-blockers should remain first line treatment in the primary prevention of variceal haemorrhage as it is effective, cheap, and easy to administer and also prevents bleeding from portal gastropathy 91 and may also protect against other complications of cirrhosis.

8 38 C. K. Triantos and A. K. Burroughs Practice points At present there are no satisfactory non-endoscopic indicators of the presence of varices Endoscopy should be performed in every cirrhotic at diagnosis in order to establish the presence of esophageal varices and to evaluate their size At present there is no indication to treat patients to prevent the formation of varices There is insufficient data for the use of isosorbide monotherapy or its combination with non-selective beta-blockers in the primary prevention setting Cirrhotics with medium and large oesophageal varices should be treated with non-selective beta-blockers or EBL Routine use of HVPG in order to evaluate the response to pharmacotherapy is not recommended due to the relative low risk of bleeding (20%) EBL is useful in preventing variceal bleeding in patients with medium and large varices and seems to be more effective than non-selective beta-blockers in preventing first variceal bleeding but does not improve survival rate EBL should be offered to patients with medium/large varices and contraindications or intolerance to beta-blockers EBL can cause iatrogenic bleeding Non-selective beta-blockers should remain first line treatment in the primary prevention of variceal haemorrhage as an effective therapy which is cheap and easy to administer and which also prevents bleeding from portal hypertensive gastropathy. Research agenda Further trials are required to evaluate the role of non-selective beta blockers in the progression of varices and prevention of bleeding in cirrhotics with small varices Non-invasive tests (compared to HVPG measurement) are required to detect patients with risk of development oesophageal varices The role of non-selective beta blockers in high risk populations of cirrhotics with small varices (red signs, Child Pugh C class patients or living far from endoscopic units) needs urgent study Identify subgroups who would benefit from the use of HVPG in order to evaluate the response to pharmacotherapy Comparison of EBL and non-selective beta blockers regarding quality of life Evaluation of combination of EBL plus non-selective beta blockers versus monotherapy in this setting Prevention of other complications of cirrhosis with beta-blockers Studies of specialist nurses assisted compliance with beta-blockers

9 Prevention of development of varices and portal hypertensive bleeding 39 REFERENCES 1. D Amico G & Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding. Baillieres Clin Gastroenterol 1997; 11: 243e Grace ND. Diagnosis and treatment of gastrointestinal bleeding secondary to portal hypertension. American College of Gastroenterology Practice Parameters Committee. Am J Gastroenterol 1997; 92: 1081e1091. *3. McCormick PA & O Keefe C. Improving prognosis following a first variceal haemorrhage over four decades. Gut 2001; 49: 682e D Amico G, Pagliaro L & Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995; 22: 332e Kleber G, Sauerbruch T, Ansari H et al. Prediction of variceal haemorrhage in cirrhosis: a prospective follow-up study. Gastroenterology 1991; 100: 1332e Bernard B, Cadranel JF, Valla D et al. Prognostic significance of bacterial infection in bleeding cirrhotic patients: a prospective study. Gastroenterology 1995; 108: 1828e1834. *7. Goulis J, Patch D & Burroughs AK. Bacterial infection in the pathogenesis of variceal bleeding. Lancet 1999; 353: 139e142. *8. Thalheimer U, Triantos CK, Samonakis DN et al. Infection, coagulation, and variceal bleeding in cirrhosis. Gut 2005; 54: 556e563. *9. The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal haemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988; 319: 983e Merli M, Nicolini G, Angeloni S et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003; 38: 266e272. *11. Cales P, Desmorat H, Vinel JP et al. Incidence of large oesophageal varices in patients with cirrhosis: application to prophylaxis of first bleeding. Gut 1990; 31: 1298e Vorobioff J, Groszmann RJ, Picabea E et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study. Gastroenterology 1996; 111: 701e Pagliaro L, D Amico G, Sorensen TI et al. Prevention of first bleeding in cirrhosis. A meta-analysis of randomised trials of non-surgical treatment. Ann Intern Med 1992; 117: 59e Vlachogiannakos J, Goulis J, Patch D et al. Review article: primary prophylaxis for portal hypertensive bleeding in cirrhosis. Aliment Pharmacol Ther 2000; 14: 851e Ong J. Clinical predictors of large esophageal varices: how accurate are they? Am J Gastroenterol 1999; 94: 3103e Pilette C, Oberti F, Aube C et al. Non-invasive diagnosis of esophageal varices in chronic liver diseases. J Hepatol 1999; 31: 867e Schepis F, Camma C, Niceforo D et al. Which patients with cirrhosis should undergo endoscopic screening for esophageal varices detection? Hepatology 2001; 33: 333e Giannini EG, Botta F, Borro P et al. Application of the platelet count/spleen diameter ratio to rule out the presence of oesophageal varices in patients with cirrhosis: a validation study based on follow-up. Dig Liver Dis 2005; 37: 779e Thomopoulos KC, Labropoulou-Karatza C, Mimidis KP et al. Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis. Dig Liver Dis 2003; 35: 473e Fleig WE. To scope or not to scope: still a question. Hepatology 2001; 33(2): 471e472. *21. de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005; 43: 167e Samonakis DN, Triantos CK, Thalheimer U et al. Management of portal hypertension. Postgrad Med J 2004; 80: 634e Escorsell A, Bordas JM, Castaneda B et al. Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension. Hepatology 2000; 31: 1061e1067. *24. Turnes J, Garcia-Pagan JC, Abraldes JG et al. Pharmacological reduction of portal pressure and longterm risk of first variceal bleeding in patients with cirrhosis. Am J Gastroenterol 2006; 101: 506e Grace ND, Groszmann RJ, Garcia-Tsao G et al. Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology 1998; 28: 868e880.

10 40 C. K. Triantos and A. K. Burroughs 26. de Franchis R, Eisen G, Eliakim R et al. Esophageal capsule endoscopy (PILLCAM ESO) is comparable to traditional endoscopy for screening/surveillance for esophageal varices [Abstract]. Hepatology 2005; 42(4(supplement 1)): 210A. *27. Armonis A, Patch D & Burroughs A. Hepatic venous pressure measurement: an old test as a new prognostic marker in cirrhosis? Hepatology 1997; 25: 245e Nevens F, Bustami R, Scheys I et al. Variceal pressure is a factor predicting the risk of a first variceal bleeding: a prospective cohort study in cirrhotic patients. Hepatology 1998; 27: 15e Gao H, Groszmann RJ, Garcia-Tsao G et al. Changes in portal pressure are associated with the development of gastroesophageal varices in compensated cirrhotic patients [Abstract]. Hepatology 2005; 42(4 (supplement 1)): 235A. 30. Lin HC, Soubrane O, Cailmail S et al. Early chronic administration of propranolol reduces the severity of portal hypertension and portal-systemic shunts in conscious portal vein stenosed rats. J Hepatol 1991; 13: 213e Sarin SK, Groszmann RJ, Mosca PG et al. Propranolol ameliorates the development of portal-systemic shunting in a chronic murine schistosomiasis model of portal hypertension. J Clin Invest 1991; 87: 1032e Feu F, Bordas JM, Garcia-Pagan JC et al. Double-blind investigation of the effects of propranolol and placebo on the pressure of esophageal varices in patients with portal hypertension. Hepatology 1991; 13: 917e922. *33. Escorsell A, Ferayorni L, Bosch J et al. The portal pressure response to beta-blockade is greater in cirrhotic patients without varices than in those with varices. Gastroenterology 1997; 112: 2012e2016. *34. Cales P, Oberti F, Payen JL et al. Lack of effect of propranolol in the prevention of large oesophageal varices in patients with cirrhosis: a randomised trial. French-Speaking Club for the Study of Portal Hypertension. Eur J Gastroenterol Hepatol 1999; 11: 741e Merkel C, Marin R, Angeli P et al. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology 2004; 127: 476e Merkel C, Bolognesi M & Gatta A. The cirrhotic patient with no varices and with small varices. In Groszmann R & Bosch J (eds.). Portal Hypertension in the 21st Century. Kluwer Academic Publishers; 2004, pp. 271e Groszmann RJ, Garcia-Tsao G, Bosch J et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005; 353: 2254e Villanueva C, Lopez-Balaguer JM, Aracil C et al. Maintenance of hemodynamic response to treatment for portal hypertension and influence on complications of cirrhosis. J Hepatol 2004; 40: 757e Merkel C, Escorsell A, Sieber CC et al. Preprimary prophylaxis: can (and should) we prevent the formation and growth of varices? In De Franchis R (ed.). Proceedings of the Third Baveno International Consensus Workshop on Definitions, Methodology and Therapeutics Strategies. Blackwell Science; pp. 97e Strauss E, Ribeiro MF, Albano A et al. Long-term follow up of a randomised, controlled trial on prophylactic sclerotherapy of small oesophageal varices in liver cirrhosis. J Gastroenterol Hepatol 1999; 14: 225e Van Buuren HR, Rasch MC, Batenburg PL et al. Endoscopic sclerotherapy compared with no specific treatment for the primary prevention of bleeding from esophageal varices. A randomised controlled multicentre trial [ISRCTN ]. BMC Gastroenterol 2003; 3: The Veterans Affairs Cooperative Variceal Sclerotherapy Group. Prophylactic Sclerotherapy for Esophageal Varices in Men with Alcoholic Liver Disease. A randomised, single-blind, multicenter clinical trial. N Engl J Med 1991; 324: 1779e Fardy JM & Laupacis A. A meta-analysis of prophylactic endoscopic sclerotherapy for esophageal varices. Am J Gastroenterol 1994; 89: 1938e Stanley AJ & Hayes PC. Portal hypertension and variceal haemorrhage. Lancet 1997; 350: 1235e The Italian Multicenter Project for Propranolol in Prevention of Bleeding. Propranolol Prevents First Gastrointestinal Bleeding in Non-Ascitic Cirrhotic Patients. Final report of a multicenter randomised trial. J Hepatol 1989; 9: 75e The PROVA Study Group. Prophylaxis of first haemorrhage from esophageal varices by sclerotherapy, propranolol or both in cirrhotic patients: a randomised multicenter trial. Hepatology 1991; 14: 1016e Andreani T, Poupon RE, Balkau BJ et al. Preventive therapy of first gastrointestinal bleeding in patients with cirrhosis: results of a controlled trial comparing propranolol, endoscopic sclerotherapy and placebo. Hepatology 1990; 12: 1413e1419.

11 Prevention of development of varices and portal hypertensive bleeding Conn HO, Grace ND, Bosch J et al. Propranolol in the prevention of the first haemorrhage from esophagogastric varices: a multicenter, randomised clinical trial. The Boston-New Haven-Barcelona Portal Hypertension Study Group. Hepatology 1991; 13: 902e Ideo G, Bellati G, Fesce E et al. Nadolol can prevent the first gastrointestinal bleeding in cirrhotics: a prospective, randomised study. Hepatology 1988; 8: 6e Lebrec D, Poynard T, Capron JP et al. Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis. A randomised trial. J Hepatol 1988; 7: 118e Pascal JP & Cales P. Propranolol in the prevention of first upper gastrointestinal tract haemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 1987; 317: 856e Strauss E, Desa MG, Albano A et al. A randomised controlled trial for the prevention of the 1st upper gastrointestinal bleeding due to portal hypertension in cirrhosis e sclerotherapy or propranolol versus control groups [Abstract]. Hepatology 1988; 8: Teran JC, Imperiale TF, Mullen KD et al. Primary prophylaxis of variceal bleeding in cirrhosis: a costeffectiveness analysis. Gastroenterology 1997; 112: 473e Poynard T, Cales P, Pasta L et al. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomised clinical trials. Franco-Italian Multicenter Study Group. N Engl J Med 1991; 324: 1532e Abraczinskas DR, Ookubo R, Grace ND et al. Propranolol for the prevention of first esophageal variceal haemorrhage: a lifetime commitment? Hepatology 2001; 34: 1096e Dagher L, Patch D & Burroughs A. Drug treatment for bleeding oesophageal varices. Baillieres Best Pract Res Clin Gastroenterol 2000; 14: 365e Garcia-Pagan JC, Villanueva C, Vila MC et al. Isosorbide mononitrate in the prevention of first variceal bleed in patients who cannot receive beta-blockers. Gastroenterology 2001; 121: 908e Angelico M, Carli L, Piat C et al. Isosorbide-5-mononitrate versus propranolol in the prevention of first bleeding in cirrhosis. Gastroenterology 1993; 104: 1460e Angelico M, Carli L, Piat C et al. Effects of isosorbide-5-mononitrate compared with propranolol on first bleeding and long-term survival in cirrhosis. Gastroenterology 1997; 113: 1632e Borroni G, Salerno F, Cazzaniga M et al. Nadolol is superior to isosorbide mononitrate for the prevention of the first variceal bleeding in cirrhotic patients with ascites. J Hepatol 2002; 37: 315e Merkel C, Marin R, Enzo E et al. Randomised trial of nadolol alone or with isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Gruppo-Triveneto per L ipertensione portale (GTIP). Lancet 1996; 348: 1677e Merkel C, Marin R, Sacerdoti D et al. Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2000; 31: 324e Spanish Variceal Bleeding Study Group. Propranolol þ placebo vs Propranolol þ isosorbide 5 mononitrate in the prevention of the first variceal bleeding, a multicenter double-blind randomised controlled trial [Abstract]. J Hepatol 1999; 30(S1): Pietrosi G, D amico G, Pasta L et al. Isosorbide mononitrate (IMN) with nadolol compared to nadolol alone for prevention of first bleeding in cirrhosis. A doubleeblind placeboecontrolled randomised trial [Abstract]. J Hepatol 1999; 30(S1): Chen C & Chang TT. Prophylactic endoscopic variceal ligation (EVL) for esophageal varices [Abstract]. Gastroenterology 1997; 112: A Gameel K, Waked I, Saleh S et al. Prophylactic endoscopic variceal band ligation (EVL) versus sclerotherapy (ES) for the prevention of variceal bleeding: an interim report of a prospective randomised controlled trial in schistosomal portal hypertension [Abstract]. Hepatology 1995; 22: 251A. 67. Lay CS, Tsai YT, Teg CY et al. Endoscopic variceal ligation in prophylaxis of first variceal bleeding in cirrhotic patients with high-risk esophageal varices. Hepatology 1997; 25: 1346e Lo GH, Lai KH, Cheng JS et al. Prophylactic banding ligation of high-risk esophageal varices in patients with cirrhosis: a prospective, randomised trial. J Hepatol 1999; 31: 451e Omar MM, Attia MH & Mostafa IM. Prophylactic band ligation to prevent first bleeding from large esophageal varices [Abstract]. Gastrointest Endosc 2000; 51: AB Sarin SK, Guptan RK, Jain AK et al. A randomised controlled trial of endoscopic variceal band ligation for primary prophylaxis of variceal bleeding. Eur J Gastroenterol Hepatol 1996; 8: 337e342.

12 42 C. K. Triantos and A. K. Burroughs 71. Svoboda P, Kantorova I, Ochmann J et al. A prospective randomised controlled trial of sclerotherapy vs ligation in the prophylactic treatment of high-risk esophageal varices. Surg Endosc 1999; 13: 580e Triantos C, Vlachogiannakos J, Armonis A et al. Primary prophylaxis of variceal bleeding in cirrhotics unable to take-blockers: a randomised trial of ligation. Alimentary Pharmacol Therap 2005; 21: 1435e Gotoh Y, Iwakiri R, Sakata Y et al. Evaluation of endoscopic variceal ligation in prophylactic therapy for bleeding of oesophageal varices: a prospective, controlled trial compared with endoscopic injection sclerotherapy. J Gastroenterol Hepatol 1999; 14: 241e Chen C, Sheu M & SU S. Prophylactic endoscopic variceal ligation (EVL) with multiple band ligator for esophageal varices [Abstract]. Gastroenterology 1998; 144: A De la Mora J, Farca-Belsaguy A, Uribe M et al. Ligation vs propranolol for primary prophylaxis of variceal bleeding using a multiple band ligator and objective measurements of treatment adequacy: preliminary results [Abstract]. Gastroenterology 2000; 1118: De BK, Ghoshal UC, Das T et al. Endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleed: preliminary report of a randomised controlled trial. J Gastroenterol Hepatol 1999; 14: 220e Drastich P, Lata J, Petryl J et al. Endoscopic variceal band ligation in comparison with propranolol in prophylaxis of first variceal bleeding in patients with liver cirrhosis [Abstract]. J Hepatol 2005; 42(supplement 2): Gheorge C, Gheorge L, Vadan R et al. Prophylactic banding ligation of high risk esophageal varices in patients on the waiting list for liver transplantation: an interim report [Abstract]. J Hepatol 2002; 36(supplement 1): Jutabha R, Jensen DM, Martin P et al. Randomised study comparing banding and propranolol to prevent initial variceal haemorrhage in cirrhotics with high-risk esophageal varices. Gastroenterology 2005; 128: 870e Lay CS, Tsai YT, Lee FY et al. Endoscopic variceal ligation versus propranolol in prophylaxis of first variceal bleeding in patients with cirrhosis. J Gastroenterol Hepatol 2006; 21: 413e Lo GH, Chen WC, Chen MH et al. Endoscopic ligation vs. nadolol in the prevention of first variceal bleeding in patients with cirrhosis. Gastrointest Endosc 2004; 59: 333e Lui HF, Stanley AJ, Forrest EH et al. Primary prophylaxis of variceal haemorrhage: a randomised controlled trial comparing band ligation, propranolol, and isosorbide mononitrate. Gastroenterology 2002; 123: 735e Psilopoulos D, Mavrogiannis C, Vafiadi I et al. A randomised controlled trial comparing endoscopic variceal ligation (EVL) with propranolol for primary prevention of variceal bleeding (preliminary report) [Abstract]. Gastrointest Endosc 2002; 55: T Sarin SK, Lamba GS, Kumar M et al. Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding. N Engl J Med 1999; 340: 988e Schepke M, Kleber G, Nurnberg D et al. Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2004; 40: 65e Song I, Shin J, Kim I et al. A prospective randomised trial between the prophylactic endoscopic variceal ligation and propranolol administration for prevention of first bleeding in cirrhotic patients with high risk esophageal varices [Abstract]. J Hepatol 2000; 32(supplement 2): Thuluvath PJ, Maheshwari A, Jagannath S et al. A randomised controlled trial of beta-blockers versus endoscopic band ligation for primary prophylaxis: a large sample size is required to show a difference in bleeding rates. Dig Dis Sci 2005; 50: 407e Triantos C, Vlachogiannakos J, Manolakopoulos S et al. Is banding ligation for primary prevention of variceal bleeding as effective as beta-blockers, and is it safe? Hepatology 2006; 43: 196e de Franchis R. Endoscopy critics vs. endoscopy enthusiasts for primary prophylaxis of variceal bleeding. Hepatology 2006; 43: 24e Sarin SK, Wadhawan M, Agarwal SR et al. Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary prophylaxis of variceal bleeding. Am J Gastroenterol 2005; 100: 797e Pique JM. Portal hypertensive gastropathy. Baillieres Clin Gastroenterol 1997; 11: 257e270.