CLINICAL MANAGEMENT Loren Laine, M.D. Clinical Management Editor University of Southern California Los Angeles, California

GASTROENTEROLOGY 2004;126:1860 1867 CLINICAL MANAGEMENT Loren Laine, M.D. Clinical Management Editor University of Southern California Los Angeles, California Incidental Esophageal Varices ROBERTO DE FRANCHIS Gastroenterology and Gastrointestinal Endoscopy Service, University of Milan, IRCCS Policlinico Hospital, Milano, Italy Clinical Case A 44-year-old man with cirrhosis (Child Pugh Class B) is referred for consultation regarding the management of esophageal varices. The patient underwent screening endoscopy recently and was found to have moderate-size esophageal varices without gastric varices or other abnormalities. He has no history of GI bleeding and takes no medication. Background The presence of esophageal varices in a patient with cirrhosis indicates that he or she has developed portal hypertension. This condition plays a crucial role in the transition from the preclinical to the clinical phase of cirrhosis: portal hypertension contributes to the development of ascites and encephalopathy, and is a direct cause of the formation of esophago-gastric varices. Variceal bleeding is the most severe complication of cirrhosis, and is the cause of death in about one third of cirrhotic patients. Definitions Portal hypertension is an increase of portal pressure above the upper limit of normal; ideally, it should be evaluated by actually measuring the pressure in the portal vein. However, direct measurement of portal pressure is invasive and impractical. A reliable and practical surrogate is the measurement of the hepatic vein pressure gradient (HVPG), which gives an indirect but precise estimate of portal pressure. 1 Measuring the HVPG involves the catheterization of the hepatic vein via a transfemoral or a transjugular route; the HVPG is calculated by subtracting the free hepatic vein pressure from the wedged hepatic venous pressure. The normal upper limit of the HVPG is 5 mm Hg; values above this limit denote portal hypertension. 2 Clinically significant portal hypertension indicates the pressure level at which a patient is at risk of developing complications. It has been shown 3 5 that varices do not occur and do not bleed if the HVPG is below a threshold value of 10 12 mm Hg. As a consequence, the following definition has been agreed upon, clinically significant portal hypertension is defined by an increase in HVPG to a threshold above approximately 10 mm Hg. The presence of varices, variceal hemorrhage, and/or ascites is indicative of the presence of clinically significant portal hypertension. 6 From Portal Hypertension to Variceal Hemorrhage Portal hypertension, which is the result of an increase of both intrahepatic resistance and portal venous inflow, 7 leads to the development of portosystemic collateral channels, which tend to increase in size with time. Gastroesophageal collaterals, which have the greatest clinical importance because of their propensity to bleed, develop between the short gastric and coronary vein and the esophageal, azygos and intercostal veins, and lead to the formation of gastric and esophageal varices. 7 Variceal rupture occurs when the tension in the wall of the varix exceeds a critical value 8 ; wall tension is directly proportional to the transmural pressure gradient in the varix and to the radius of the varix, and inversely proportional to wall thickness. Diagnosis HVPG measurement is a safe and reproducible procedure: when a correct technique is used, the coefficient of variation of the method is 2.6% 2.6%. 4 However, at present, HVPG measurement is not appli- Abbreviations used in this paper: BB, -blockers; BL, band ligation; C, controls; CI, confidence intervals; HVPG, hepatic vein pressure gradient; I5Mn, Isosorbide-5-Mononitrate; NIEC, North-Italian Endoscopic Club; NNT, number needed to treat; TIPS, transjugular intrahepatic portosystemic stent shunt. 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2004.04.030

June 2004 CLINICAL MANAGEMENT 1861 Table 1. Clinical-Biological Predictors of the Presence of Esophageal Varices Author Reference Number of Patients Predictor Pagliaro et al. 1994 12 494 Low platelet count, portal vein diameter 13 mm Garcia-Tsao et al. 1997 23 180 Low platelet count, vascular spiders, low serum albumin Pilette et al. 1999 24 118 Low platelet count, low prothrombin activity, vascular spiders Chalasani et al. 1999 25 346 Low platelet count, splenomegaly Schepis et al. 2001 26 143 Low platelet count, low prothrombin activity, portal vein diameter 13 mm Zaman et al. 2001 27 300 Low platelet count, Child score Madhotra et al. 2002 28 184 Low platelet count, splenomegaly, Child score cable on a routine basis; therefore, alternative methods must be used. Upper GI endoscopy, which is far more widely available than HVPG measurement, is one such alternative method, since variceal size is clearly related to the risk of variceal hemorrhage. With this technique, both a good interobserver agreement in the assessment of variceal size, and a satisfactory degree of accuracy in the diagnosis of cirrhosis can be achieved. 9 In addition, endoscopy allows the identification of other potentially bleeding lesions related to portal hypertension, such as portal hypertensive gastropathy. Natural History Longitudinal studies have shown that varices eventually develop in the majority of cirrhotic patients, 10,11 and that once they have developed, they tend to increase in size and to bleed. 11 The rate of development of new varices varies between 5% and 12% per year, 10,12 with rare exceptions, 13 while the rate of growth of varices from small to large ranges between 6% and 70% at 2 years. 14 16 The risk of a first variceal bleeding episode varies between 8% and 35% at 2 years in untreated patients, 17,18 and in general is related to the size of the varices. 17,18 Despite important progress made over the last two decades, the first variceal bleeding still carries a mortality ranging around 20%. 19 21 Potential Management Strategies Should We Screen for Varices? In view of the natural history of portal hypertension, the question arises whether cirrhotic patients should be screened by endoscopy in order to identify those with varices at risk of bleeding, who should be offered prophylactic treatment to prevent the first variceal bleed. If we had no effective prophylactic treatment, screening would be useless, and we should only aim at treating patients who have bled from their varices. However, since effective prophylactic treatments do exist, 18 screening seems a reasonable option. Who Should Be Screened? Since the prevalence of varices in unselected patient populations is extremely variable, 22 performing upper GI endoscopy in all cirrhotic patients would imply a number of unnecessary endoscopies. If one could predict the presence of esophageal varices by noninvasive means, the performance of endoscopy could be restricted to those patients with a high probability of having varices, leading to substantial cost savings. However, although several predictors of the presence of varices have been identified in various studies 12,23 28 (Table 1), attempts at predicting the presence of varices before doing endoscopy have failed to produce workable predictive models. 29 This implies that all cirrhotic patients should undergo an initial screening endoscopy to detect the presence of varices. 6 The patients in whom no or small varices are detected at the screening examination should be followed up with surveillance endoscopies to detect the appearance of large varices. When Should Surveillance Endoscopy Be Performed? Decision about the optimal intervals for surveillance endoscopy to detect large varices depends on the rate of development and growth of varices and on the definition of an acceptable level of risk (i.e., what proportion of patients bleeding before starting prophylactic treatment we are willing to accept). If we set the acceptable level of risk at 10%, patients with no varices at baseline can be re-endoscoped at 3-years intervals; for patients with small varices at baseline, the recommended interval of 1 2 years 6 should be maintained, adopting the shorter interval for patients with alcoholic cirrhosis, with more severe impairment of liver function, and with endoscopic risk signs, 15 in whom the growth of varices appears to be faster. How Should We Select the Patients for Prophylaxis of the First Bleed? Since the risk of bleeding among cirrhotic patients with esophageal varices is variable, several prog-

1862 CLINICAL MANAGEMENT GASTROENTEROLOGY Vol. 126, No. 7 Table 2. Distribution of Variceal Bleeds Among Risk Classes of the NIEC Index Grade of risk Number who bled/total at risk (%) % of total bleeds Low 18/149 (12.1) 22.2 Intermediate 32/119 (26.9) 39.5 High 31/59 (52.5) 38.3 Note. Data from North-Italian Endoscopic Club (NIEC) for the study and treatment of esophageal varices (1988). 17 nostic indexes, based on combinations of different parameters, have been developed 16 with the aim of identifying the patients at the highest risk. The most used of these indexes is that proposed by the North Italian Endoscopic Club (NIEC Index), 17 which is based on three independent predictors of bleeding, i.e., the severity of liver disease (modified Child Class), the size of varices and the presence of red wale markings on the varices. Prospective validation 21 has shown that the NIEC index correctly stratifies patients into classes at increasing risk of bleeding. However, this and other prognostic indexes can correctly identify as high-risk patients a relatively small proportion of the patients who will eventually bleed. In the NIEC study, 17 for example, less than 40% of the patients who eventually bled had been identified as high-risk patients, and 22% of the bleeds occurred in patients classified as low risk (Table 2). Despite their limitations, the prognostic indexes such as the NIEC Index are the only presently available tools to predict variceal bleeding that can be used routinely to select patients for prophylactic treatments, and should be used until more accurate instruments are developed. Possible Prophylactic Therapies In order to prevent variceal formation, growth and rupture, several approaches can be considered. Portal pressure may be reduced by drugs that decrease portal venous inflow (such as nonselective blockers), or intrahepatic resistance (such as vasodilators). A greater reduction in portal pressure can be obtained by a combination of vasoconstrictors and vasodilators, which decreases both portal flow and intrahepatic resistance, 30 or by surgical or radiological shunt interventions, which divert the portal blood into the systemic circulation. Finally, variceal bleeding may be prevented by endoscopic treatments aimed at obliterating the varices, which, although not influencing portal pressure, decrease the risk of bleeding by closing the varicose channels. The mechanisms of action of the different therapeutic means to prevent and treat variceal bleeding are summarized in Table 3. Prophylaxis vs. No Prophylaxis When compared with placebo or no treatment, -blockers, 13 band ligation 31 and shunt surgery 32 have all been shown to reduce the incidence of first variceal bleeding. In addition, band ligation significantly improves survival in comparison with no treatment 51 and -blockers significantly reduce bleeding-related mortality. 18 These data indicate that primary prophylaxis is feasible and desirable. What Patients to Treat and When Theoretically, the prevention of the first variceal bleed could start at 3 different points in time: (1) When portal hypertension is present but varices have not yet appeared, to prevent variceal formation; (2) When small varices are present, aiming at preventing the growth of varices, and (3) When medium-sized to large varices are already present, to prevent variceal rupture. Prevention of variceal formation by the administration of -blockers has been attempted in two studies, 33,34 which gave negative results, in that the rate of development of varices and the occurrence of variceal bleeding were similar in patients treated with -blockers or placebo. However, conflicting data exist about the prevention of the growth of varices from small to large with -blockers. 33,35 Therefore, primary prophylaxis of variceal bleeding should focus on patients with mediumsized to large varices. Which Therapy -blockers. When compared with placebo, 18 -blockers reduce the incidence of bleeding from 25% to 15%, with a relative risk reduction of 40% and an absolute risk reduction of 10% (95% confidence intervals 16% to 5%). This means that 10 patients must be treated with -blockers to prevent one bleed that would have occurred if all patients had been treated with placebo (number needed to treat [NNT] 10). Patients in whom -blockers decrease the HVPG to below 12 mm Table 3. Mechanisms of Action of Treatments for Portal Hypertension Action on Portal Varicose Treatment Flow Resistance pressure channels Vasoconstrictors 22 1 2 Vasodilators 2 2 Vasoconstrictors 2 2 2 2 vasodilators Shunts 1 222 222 Endoscopy Obliteration

June 2004 CLINICAL MANAGEMENT 1863 Table 4. Randomized Controlled Trials of Prophylactic Rubber Band Ligation Author Yr Ref. No Patients C/BL Band Ligation (BL) Vs. No Treatment (C) % Bleeding C/BL % Bleeding rate difference % Mortality C/BL % Mortality rate difference Sarin 1996 46 33/35 42.4/8.6 33.8 24.2/11.4 12.8 Lay 1997 47 64/62 15.6/1.6 14.0 28.1/11.2 16.9 Chen 1997 48 76/80 36.8/8.8 28.0 40.8/18.8 22.0 Gameel 1997 49 64/60 32.8/8.3 24.5 40.6/28.3 12.3 Lo 1999 50 63/64 34.9/21.8 13.1 36.5/25 11.5 Pooled data 300/301 31.6/12.0 19.6 35.3/19.6 15.7 95% C.I. 95% C.I. 27 to 12 23 to 9 Author Yr Ref. No Patients BB/BL Band Ligation (BL) vs. -Blockers (BB) %Bleeding BB/BL % Bleeding rate difference % Mortality BB/BL % Mortality rate difference Chen 1998 52 28/26 7.1/3.8 3.3 10.7/13.0 2.3 Sarin 1999 53 44/45 27.3/8.9 18.4 11.4/11.1 0.3 Song 2000 54 30/31 23.3/19.4 3.9 26.6/16.1 10.5 Jutabha 2001 55 26/25 19.2/4.0 15.2 N.A. N.A. Lui 2002 56 66/44 13.6/6.8 6.8 16.7/31.8 15.1 Gheorghe 2002 57 28/25 46.4/12.0 34.2 17.9/4.0 13.9 Schepke 2003 58 77/75 28.6/25.3 3.3 42.8/45.3 2.5 Lo 2004 59 50/50 32.0/20.0 12.0 22.0/24.0 2.0 Pooled data 349/321 23.5/13.5 11.9 23.5/23.6 0.1 95% C.I. 95% C.I. 16 to 4 6.8 to 6.8 Hg are completely protected from bleeding, 5 while a reduction of 20% from baseline values reduces the incidence of bleeding to less than 10%. 36 Overall mortality is not influenced, while bleeding-related mortality is significantly reduced by -blockers. 18 The main limitations of -blockers are that responders (i.e., patients in whom a HVPG reduction by 20% from baseline or below 12 mm Hg can be achieved) are only about 35% and 20% of patients respectively, and that side effects occur in 16% 20% of cases, leading to the withdrawal of 6% 12% of patients from therapy. 37 39 Because of these limitations, alternative means to prevent bleeding have been investigated. Nitrovasodilators Nitrovasodilators have been considered for their ability to decrease portal pressure by decreasing hepatic and portocollateral resistance. In one study, 40 41 isosorbide-5-mononitrate (I5Mn) was equivalent to propranolol in preventing bleeding, 40 but with a higher longterm mortality in patients over 50 years of age. 41 In decompensated cirrhotic patients, 42 I5Mn had significantly fewer contraindications and side effects as compared to nadolol, but was significantly less effective in preventing bleeding. In patients with intolerance or contraindications to -blockers 43 there was no difference between I5Mn and placebo for the prevention of bleeding. Thus, isosorbide-5-mononitrate alone is not a suitable alternative to -blockers for prevention of the first variceal bleeding. Sclerotherapy Prophylactic sclerotherapy has been studied in 21 trials. 44 In different studies, sclerotherapy was found to be better, equal, or worse than no treatment, both for prevention of first bleeding and for survival. A review of these trials 44 concluded that the heterogeneity of trial results makes meta-analysis meaningless. Therefore, sclerotherapy cannot be recommended as prophylactic treatment of the first variceal bleeding. This conclusion was confirmed at 2 recent international consensus workshops on portal hypertension. 6,45 Band Ligation Band ligation, which has replaced sclerotherapy as the first-line endoscopic treatment to prevent rebleeding, 6 has also been evaluated for primary prophylaxis. Band ligation has been compared with no treatment in 5 trials 46 50 (Table 4). Meta-analysis of these studies 51 has shown that band ligation significantly decreases both the incidence of first bleeding and mortality. A comparison between band ligation and -blockers has been done in

1864 CLINICAL MANAGEMENT GASTROENTEROLOGY Vol. 126, No. 7 8 trials 52 59 (Table 4), only 3 of which 53,56,59 are published in full. In all studies, band ligation was more effective than -blockers in preventing first bleeding, but the difference reached statistical significance in only 2. 53,57 Meta-analysis of these trials shows that band ligation reduces the incidence of first bleeding from 24.6% to 12.7%, with a relative risk reduction of 48%, an absolute risk reduction of 11.9% (95% CI, 16% to 4%) and a number needed to treat of 8.4. Mortality was equal with the two treatments. It has been argued that in the only two trials that showed a significant difference in favor of band ligation, 53,57 the performance of -blockers was exceedingly poor. When these 2 trials are excluded from the meta-analysis, the difference decreases (bleeding: -blockers 22%, band ligation 13%, relative risk reduction 39%; absolute risk reduction 9% (95% CI, 12.6% to 0.009%; number needed to treat 11.1). TIPS TIPS has never been studied in randomized controlled studies as a prophylactic measure to prevent the first variceal bleed in cirrhotic patients. Shunt Surgery Historically, the surgical portacaval shunt was the first treatment used to prevent the first variceal hemorrhage in cirrhotic patients. However, although portacaval shunt was very effective in preventing the first variceal bleed, this form of therapy has been abandoned because shunted patients had a significantly higher mortality than controls. 32 Combination Medical Treatment In 3 studies comparing a combination of I5Mn and -blockers 13 with -blockers alone, the combined treatment was equivalent to -blockers alone in preventing bleeding, but showed a significantly higher incidence of side effects. A recent study has investigated the value of tailoring pharmacological treatment according to the HVPG response to -blockers. 60 In that study, nonresponders to propranolol received additional I5Mn. None of the patients who responded to propranolol alone or to propranolol I5Mn bled, as compared with 33% of nonresponders. This approach deserves further testing, particularly in view of the fact that its cost-effectiveness has recently been challenged. 61 Combination of Medical and Endoscopic Therapy Combination of -blockers and banding has never been used for prophylaxis of first variceal bleeding. A single trial 62 compared a combination of band ligation, blockers and sucralfate with band ligation alone for the prevention of rebleeding, showing that the combined therapy was better than ligation alone in preventing rebleeding and variceal recurrence. Whether these findings can be confirmed and apply to primary prophylaxis remains to be determined. Cost-effectiveness Considerations In recent years, several decision-analysis studies 63 67 have attempted to define the most cost-effective strategy for preventing the first variceal hemorrhage in cirrhosis. Some authors 66,67 have suggested that universal prophylaxis of all cirrhotic patients with -blockers, without doing screening endoscopy, is the most costeffective strategy, while others 65 have concluded that screening endoscopy followed by -blocker treatment in patients with high-risk varices is the most appropriate strategy in patients with compensated cirrhosis. As far as the preferred type of therapy is concerned, blockers have been shown to be more cost-effective than sclerotherapy in one study, 63 while band ligation was judged to be appropriate for the majority of patients in another. 64 In evaluating this type of study, one should be aware that decision analysis is largely based on assumptions and educated guesses rather than on hard data, and that by varying the assumptions the results of the decision analysis may vary greatly. This may help explain the discrepancies between studies. In summary, this kind of study should be used more to identify areas where new information is needed than to dictate policies in patient management. 68 At present, I believe that screening endoscopy followed by prophylactic treatment of patients with high-risk varices is the most appropriate strategy. Recommended Management Strategy This patient has been shown to have mediumsized varices with no red signs on screening endoscopy; in addition, he has moderate liver insufficiency (Child Pugh class B). According to the NIEC index, 17 if left untreated, this patient has an estimated 1-year risk of bleeding of about 16% (Table 5). Therefore, this patient should be treated prophylactically to prevent variceal bleeding. Both nonselective blockers and band ligation are effective for this purpose, as they can reduce the risk of bleeding by 40% 50%. 18,31 If there are no contraindications, I would start with -blockers, mainly because they are cheap and easy to use. To decide whether this patient can be treated with -blockers, the presence of contraindications such as

June 2004 CLINICAL MANAGEMENT 1865 Table 5. One-year Percentage Risk of First Variceal Bleeding in Patients With Cirrhosis and Esophageal Varices According to the NIEC Index Child Class A B C Size of varices Small Medium Large Small Medium Large Small Medium Large Red wale markings 6 10 16 10 16 24 14 25 36 10 18 28 17 26 40 26 38 56 Note. Data from North-Italian Endoscopic Club (NIEC) for the study and treatment of esophageal varices (1988). 17 chronic obstructive pulmonary disease, heart failure, atrioventricular heart block and peripheral arterial insufficiency 18 must first be excluded. Relative contraindications are also sinus bradycardia and insulin-dependent diabetes mellitus. If no contraindication exists, treatment is started, and the dose of -blockers is adjusted with the goal of achieving a 25% reduction in resting heart rate or down to 55 beats per minute (bpm) or development of symptoms. Some, but not all, patients treated with -blockers achieving these targets will be protected from variceal bleeding. However, there is no relationship between reduction in portal pressure or protection from variceal bleeding and the degree of -blockade, as assessed by the reduction in resting heart rate. Indeed, a reduction in HVPG below 12 mm Hg, or more than 20% from baseline, is the only tested parameter to detect those patients treated with -blockers who are protected from variceal bleeding. However, since about 60% of patients treated with -blockers who do not achieve these targets will not bleed, 36 in primary prophylaxis it is not mandatory to check the HVPG response. If the patient has a contraindication to -blockers, or cannot tolerate them because of side effects, or is unwilling to Figure 1. Algorithm for prevention of first variceal bleeding in cirrhosis. Dotted arrows with question marks denote steps that need to be verified. embark in a lifelong treatment, 69 I would offer him band ligation. Conclusions Prevention of first variceal bleeding should start when patients have medium-sized or large varices. -blockers remain the mainstay of treatment, mainly for their low cost and ease of use. However, band ligation is as effective as -blockers, and can be used as an alternative. In addition, band ligation should be the first-line treatment for patients with contraindications or intolerance to -blockers 6 (Figure 1). Whether the tailoring of pharmacological treatment based on HVPG monitoring is really worthwhile should be verified in larger patients series. References 1. Groszmann RJ, Wongcharatrawee S. The hepatic vein pressure gradient: anything worth doing should be done right. Hepatology 2004;39:280 282. 2. Bosch J, Garcia-Pagan JC. Pathophysiology of portal hypertension and its complications. In: Bircher J, Benhamou JP, McIntire N, Rizzetto M, Rodes J, eds. Oxford textbook of clinical hepatology. Oxford: Oxford University Press, 1999:653 659. 3. Lebrec D, Fleury P, Rueff B, Nahum M, Benhamou JP. Portal hypertension, size of esophageal varices, and risk of gastrointestinal bleeding in alcoholic cirrhosis. Gastroenterology 1980;79: 1139. 4. Garcia-Tsao G, Groszmann R, Fisher R, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985;5:419. 5. Groszmann R, Bosch J, Grace N, Conn HO, Garcia-Tsao G, Navasa M, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990;99:1401. 6. de Franchis R. Updating consensus in portal hypertension: report of the Baveno III consensus workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000;33:846 852. 7. Gupta TK, Chen L, Groszmann RJ. Pathophysiology of portal hypertension. In: Bosch J, ed. Bailliere s clinical gastroenterology portal hypertension. London: Bailliere Tindall, 1997;11:203 219. 8. Polio J, Groszmann RJ. Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment. Semin Liver Dis 1986;6:318 331. 9. D Amico G, Garcia-Tsao G, Calès P, Escorsell A, Nevens F, Cestari

1866 CLINICAL MANAGEMENT GASTROENTEROLOGY Vol. 126, No. 7 R, et al. Diagnosis of portal hypertension: how and when. In: de Franchis R, ed. Portal hypertension III: proceedings of the third Baveno international consensus workshop on definitions, methodology and therapeutic strategies. Oxford, UK: Blackwell Science, 2000:36 64. 10. Christensen E, Fauerholdt L, Schlichting P, Juhl E, Poulsen H, Tygstrup N. Aspects of natural history of gastrointestinal bleeding in cirrhosis and the effect of prednisone. Gastroenterology 1981; 81:944 952. 11. D Amico G, Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding. In: Bosch J, ed. Bailliere s clinical gastroenterology portal hypertension. London: Bailliere Tindall, 1997;11:243 256. 12. Pagliaro L, D Amico G, Pasta L, Politi F, Vizzini G, Traina M, Madonia S, Luca A, Guerrera D, Puleo A, D Antoni A. Portal hypertension in cirrhosis: natural history. In: Bosch J, Groszmann RJ, eds. Portal hypertension, pathophysiology and treatment. Oxford: Blackwell Scientific, 1994:72 92. 13. de Franchis R. Evaluation and follow-up of patients with cirrhosis and oesophageal varices. J Hepatol 2003;38:361 363. 14. Primignani M, Albè R, Preatoni P, Carnevale P, Bianchi MB, Parravicini E, et al. De novo development of esophageal varices in patients with a recent histologic diagnosis of liver cirrhosis (abstr). Gastroenterology 1998;114:A1324. 15. Merli M, Nicolini G, Angeloni S, Rinaldi V, De Santis A, Merkel C, Attili AF, Riggio O. Incidence and natural history of small oesophageal varices in cirrhotic patients. J Hepatol 2003;38:266 272. 16. de Franchis R, Dell Era A, Fazzini L, Zatelli S, Savojardo V, Primignani M. Evaluation and follow-up of patients with portal hypertension and esophageal varices: how and when. Dig Liver Dis 2001;33:643 646. 17. North-Italian Endoscopic Club for the study and treatment of esophageal varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 1988;319:983 989. 18. D Amico G, Pagliaro L, Bosch J. Pharmacologic treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 1999;19:475 505. 19. D Amico G, de Franchis R, and a cooperative study group. Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology 2003;38:599 612. 20. Chalasani N, Kahi C, Francois F, Pinto A, Marathe A, Bini EJ, et al. Improved patient survival after acute variceal bleeding: a multicenter, cohort study. Am J Gastroenterol 2003;98:653 659. 21. de Franchis R, Primignani M. Natural history of portal hypertension in patients with cirrhosis. In: Sanyal A, ed. Portal hypertension. Clinics in liver disease. Philadelphia, PA: Saunders, 2001;5:645 663. 22. Pascal JP, Calès P, Desmorat H. Natural history of esophageal varices. In: Bosch J, Rodès J, eds. Recent advances in the pathophysiology and treatment of portal hypertension. Serono Symposia review no. 22; Rome, Italy 1989:127 142. 23. Garcia-Tsao G, Escorsell A, Zakko M, Patch D, Matloff D, Grace N, et al. Predicting the presence of significant portal hypertension and esophageal varices in compensated cirrhotic patients (abstr). Hepatology 1997;26:360A. 24. Pilette C, Oberti F, Aube C, Rousselet MC, Bedoussa P, Gallois Y, et al. N-invasive diagnosis of esophageal varices in chronic liver disease. J Hepatol 1999;31:867 873. 25. Chalasani N, Imperiale TF, Ismail A, Sood G, Carey M, Wilcox CM, et al. Predictors of large esophageal varices in patients with cirrhosis. Am J Gastroenterol 1999;94:3285 3291. 26. Schepis F, Cammà C, Niceforo D, Magnano A, Pallio S, Cinquegrani M, D Amico G, Pasta L, Craxì A, Saitta A, Raimondo G. Which patients should undergo endoscopic screening for esophageal varices detection? Hepatology 2001;33:333 338. 27. Zaman A, Becker T, Lapidus J, Benner K. Risk factors for the presence of varices in cirrhotic patients without history of variceal hemorrhage. Arch Intern Med 2001;161:2564 2570. 28. Madhotra R, Mulcahy HE, Willner I, Reuben A. Prediction of esophageal varices in patients with cirrhosis. J Clin Gastroenterol 2002;34:81 85. 29. Riggio O, Angeloni S, Nicolini G, Merli M, Merkel C. Endoscopic screening for esophageal varices in cirrhotic patients (letter). Hepatology 2002;35:501 502. 30. Garcia-Pagan JC, Navasa M, Bosch J, Bru C, Pizcueta P, Rodés J. Enhancement of portal pressure reduction by the association of isosorbide-5 mononitrate to propranolol administration in patients with cirrhosis. Hepatology 1990;11:330 338. 31. de Franchis R, Primignani M. Endoscopic treatments for portal hypertension. Semin Liver Dis 1999;19:439 455. 32. Conn HO, Lindenmuth WW, May CJ, Ramsby GR. Prophylactic portacaval anastomosis: a tale of two studies. Medicine 1972; 51:27 40. 33. Calés P, Oberti F, Payen JL, Naveau S, Guyader D, Blanc P, et al. Lack of effect of propranolol in the prevention of large oesophageal varices in patients with cirrhosis: a randomized trial. Eur J Gastroenterol Hepatol 1999;11:741 745. 34. Groszmann R, Garcia-Tsao G, Makuch R, Bosch J, Escorsell A, Garcia-Pagan JC, et al. Multicenter randomized trial of non-selective beta-blockers in the prevention of complications of portal hypertension: final results and identification of a predictive factor. Hepatology 2003;38(Suppl.1):206. 35. Merkel C, Marin R, Angeli P, Zanella P, Felder M, Bernardinello E, et al. Beta-blockers in the prevention of the aggravation of esophageal varices in patients with cirrhosis and small varices: a placebo-controlled clinical trial. Hepatology 2003;38(Suppl.1): 217A. 36. Feu F, Garcia-Pagan JC, Bosch J, Luca A, Teres J, Escorsell A, et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal hemorrhage in patients with cirrhosis. Lancet 1995;346:1056 1059. 37. Bernard B, Lebrec D, Mathurin P, Opolon P, Poynard T. Propranolol and sclerotherapy in the prevention of gastrointestinal rebleeding in patients with cirrhosis: a meta-analysis. J Hepatol 1997;26:312 324. 38. Bernard B, Lebrec D, Mathurin P, Opolon P, Poynard T. Betaadrenergic antagonists in the prevention of gastrointestinal rebleeding in patients with cirrhosis: a meta-analysis. Hepatology 1997;25:63 70. 39. Bolognesi M, Balducci G, Garcia-Tsao G, Gatta A, Ginès P, Merli M, et al. Complications of the medical treatment of portal hypertension. In: de Franchis R, ed. Portal hypertension III. Proceedings of the third Baveno international consensus workshop on definitions, methodology and therapeutic strategies. Oxford: Blackwell Science, 2001:180 201. 40. Angelico M, Carli L, Piat C, Gentile S, Rinaldi V, Bologna E, Capocaccia L. Isosorbide-5-mononitrate versus propranolol in the prevention of first bleeding in cirrhosis. Gastroenterology 1993; 104:1460 1465. 41. Angelico M, Carli L, Piat C, Gentile S, Capocaccia L. Isosorbide- 5-mononitrate compared with propranolol on first bleeding and long-term survival in cirrhosis. Gastroenterology 1997;113: 1632 1639. 42. Borroni G, Salerno F, Cazzaniga M, Bissoli F, Lorenzano E, Maggi A, et al. Nadolol is superior to isosorbide mononitrate for the prevention of the first variceal bleeding in cirrhotic patients with ascites. J Hepatol 2002;37:315 321. 43. Garcia Pagán JC, Villanueva C, Vila C, Albillos A, Genescà J, Ruiz-del-Arbol L, et al. Isosorbide-5-mononitrate in the prevention of the first variceal bleed in patients who cannot receive betablockers. Gastroenterology 2001;121:908 914. 44. D Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995;22:332 354.

June 2004 CLINICAL MANAGEMENT 1867 45. de Franchis R. Developing consensus in portal hypertension. J Hepatol 1996;25:390 394. 46. Sarin SK, Guptan RKC, Jain AK, Sundaram KR. A randomized controlled trial of endoscopic variceal band ligation for primary prophylaxis of variceal bleeding. Eur J Gastroenterol Hepatol 1996;8:337 342. 47. Lay CS, Tsai YT, Teg CY, Shyu WS, Guo WS, Wu KL, Lo KJ. Endoscopic variceal ligation in prophylaxis of first variceal bleeding in cirrhotic patients with high-risk esophageal varices. Hepatology 1997;25:1346 1350. 48. Chen CY, Chen CY, Chang TT. Prophylactic endoscopic variceal ligation for esophageal varices (abstr). Gastroenterology 1997; 112:A1240. 49. Gameel K, Waked I, Saleh S, Sallam M, Abdel-Fattah S. Prophylactic endoscopic variceal band ligation (EVL) versus sclerotherapy (EVS) for the prevention of variceal bleeding in high risk varices: a prospective randomized controlled trial (abstr). Hepatology 1997;26(Suppl):361A. 50. Lo GH, Lai KH, Cheng JS, Lin CK, Hau PI, Chiang HT. Prophylactic banding ligation of high-risk esophageal varices in patients with cirrhosis: a prospective randomized trial. J Hepatol 1999;31: 451 456. 51. Imperiale TF, Chalasani N. A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding. Hepatology 2001;33:802 807. 52. Chen CY, Sheu MZ, Su SY. Prophylactic endoscopic variceal ligation (EVL) with multiple band ligator for esophageal varices (abstr). Gastroenterology 1998;114(Suppl):A1224. 53. Sarin SK, Lamba GS, Kumar M, Misra A, Murthy NS. Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding. N Engl J Med 1999;340:988 993. 54. Song IH, Shin JW, Kim IH, Choi J, Lin CY, Kim JW, et al. A prospective randomized trial between the prophylactic endoscopic variceal ligation and propranolol administration for prevention of first bleeding in cirrhotic patients with high-risk esophageal varices (abstr). J Hepatol 2000;32(Suppl. 2):41. 55. Jutabha R, Jensen DM, Martin P, Savides TJ, Chapman L, Jensen ME, et al. A randomized, prospective study of prophylactic rubber band ligation compared to propranolol for prevention of first variceal hemorrhage in cirrhotics with large esophageal varices (abstr). Gastrointest Endosc 2001;53:AB70. 56. Lui HF, Stanley AJ, Forrest EH, Jalan R, Hislop WS, Mills PR, et al. Primary prophylaxis of variceal hemorrhage: a randomized controlled trial comparing band ligation, propranolol, and isosorbide mononitrate. Gastroenterology 2002;123:735 744. 57. Gheorghe C, Gheorghe L, Vadan R, Hrehoret D, Popescu I. Prophylactic banding ligation of high risk esophageal varices in patients on the waiting list for liver transplantation: an interim analysis (abstr). J Hepatol 2002;36(Suppl. 1):38. 58. Schepke M, Goebel C, Nuernberg D, Willert J, Koch L, Sauerbruch T. Endoscopic banding ligation versus propranolol for the primary prevention of variceal bleeding in cirrhosis: a randomized controlled multicenter trial. Hepatology 2003;38(Suppl. 1):218A. 59. Lo GH, Chen WC, Chen MH, Lin CP, Lo CC, Hsu PI, Cheng JS, Lai KH. Endoscopic ligation vs. nadoilol in the prevention of first variceal bleeding in patients with cirrhosis. Gastrointest Endosc 2004;59:333 338. 60. Bureau C, Péron JM, Alric L, Morales J, Sanchez J, Barange K, et al. A la carte treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding. Hepatology 2002;36:1361 1366. 61. Hicken BL, Sharara AI, Abrams GA, Eloubeidi M, Fallon MB, Arguedas MR. Hepatic vein pressure gradient measurements to assess response to primary prophylaxis in patients with cirrhosis: a decision analytical study. Aliment Pharmacol Ther 2003; 17:145 153. 62. Lo GH, Lai KH, Cheng JS, Chen MH, Huang HC, Hsu PL, et al. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial. Hepatology 2000;32:461 465. 63. Teran JC, Imperiale TF, Mullen KD, Tavill AS, McCullough AJ. Primary prophylaxis of variceal bleeding in cirrhosis: a cost-effectiveness analysis. Gastroenterology 1997;112:473 482. 64. Aoki N, Kajiyama T, Beck JR, Cone RW, Soma K, Fukui T. Decision analysis of prophylactic treatment for patients with high-risk esophageal varices. Gastrointest Endosc 2000;52:707 714. 65. Arguedas MR, Heudebert GR, Eloubeidi MA, Abrams GA, Fallon MB. Cost-effectiveness of screening, surveillance and primary prophylaxis strategies for esophageal varices. Am J Gastroenterol 2002;97:2441 2452. 66. Saab S, De Rosa V, Nieto J, Durazo F, Han S, Roth B. Costs and clinical outcomes of primary prophylaxis of variceal bleeding in patients with hepatic cirrhosis: a decision analytic model. Am J Gastroenterol 2003;98:763 770. 67. Spiegel BMR, Targownik L, Dulai GS, Karsan HA, Gralnek IM. Endoscopic screening for esophageal varices in cirrhosis: is it ever cost-effective? Hepatology 2003;37:366 377. 68. Rubenstein JH, Inadomi JM. Empiric -blockers for the prophylaxis of variceal hemorrhage: cost effective or clinically applicable? Hepatology 2003;37:249 252. 69. Abraczinskas DR, Okubo R, Grace ND, Groszmann RJ, Bosch J, Garcia-Tsao G, et al. Propranolol for the prevention of first esophageal variceal hemorrhage: a lifetime commitment? Hepatology 2001;34:1096 1102. Address requests for repints to: Roberto de Franchis, M.D., Professor of Medicine, University of Milan, Head, Gastroenterology and Gastrointestinal Endoscopy Service, IRCCS Policlinico Hospital, Via Pace 9, 20122 Milano, Italy. e-mail: gastro@policlinico.mi.it; fax: (39) 02 5032 0747.