Incidental esophageal varices

Abstract

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. 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. 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.1Groszmann R.J Wongcharatrawee S The hepatic vein pressure gradient anything worth doing should be done right.Hepatology. 2004; 39: 280-282Crossref PubMed Scopus (419) Google Scholar 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.2Bosch J Garcia-Pagan J.C Pathophysiology of portal hypertension and its complications.in: Bircher J Benhamou J.P McIntire N Rizzetto M Rodes J Oxford textbook of clinical hepatology. Oxford University Press, Oxford1999: 653-659Google Scholar Clinically significant portal hypertension indicates the pressure level at which a patient is at risk of developing complications. It has been shown3Lebrec D Fleury P Rueff B Nahum M Benhamou J.P Portal hypertension, size of esophageal varices, and risk of gastrointestinal bleeding in alcoholic cirrhosis.Gastroenterology. 1980; 79: 1139PubMed Scopus (384) Google Scholar, 4Garcia-Tsao G Groszmann R Fisher R Conn H.O Atterbury C.E Glickman M Portal pressure, presence of gastroesophageal varices and variceal bleeding.Hepatology. 1985; 5: 419Crossref PubMed Scopus (733) Google Scholar, 5Groszmann R Bosch J Grace N Conn H.O 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: 1401Abstract PubMed Google Scholar 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.”6de 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: 846-852Abstract Full Text Full Text PDF PubMed Scopus (490) Google Scholar Portal hypertension, which is the result of an increase of both intrahepatic resistance and portal venous inflow,7Gupta T.K Chen L Groszmann R.J Pathophysiology of portal hypertension.in: Bosch J Bailliere’s clinical gastroenterology-portal hypertension. 11. Bailliere Tindall, London1997: 203-219Google Scholar 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.7Gupta T.K Chen L Groszmann R.J Pathophysiology of portal hypertension.in: Bosch J Bailliere’s clinical gastroenterology-portal hypertension. 11. Bailliere Tindall, London1997: 203-219Google Scholar Variceal rupture occurs when the tension in the wall of the varix exceeds a critical value8Polio J Groszmann R.J Hemodynamic factors involved in the development and rupture of esophageal varices a pathophysiologic approach to treatment.Semin Liver Dis. 1986; 6: 318-331Crossref PubMed Scopus (186) Google Scholar; 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. 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%.4Garcia-Tsao G Groszmann R Fisher R Conn H.O Atterbury C.E Glickman M Portal pressure, presence of gastroesophageal varices and variceal bleeding.Hepatology. 1985; 5: 419Crossref PubMed Scopus (733) Google Scholar However, at present, HVPG measurement is not applicable 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.9D’Amico G Garcia-Tsao G Calès P Escorsell A Nevens F Cestari R et al.Diagnosis of portal hypertension how and when.in: de Franchis R Portal hypertension III proceedings of the third Baveno international consensus workshop on definitions, methodology and therapeutic strategies. Blackwell Science, Oxford, UK2000: 36-64Google Scholar In addition, endoscopy allows the identification of other potentially bleeding lesions related to portal hypertension, such as portal hypertensive gastropathy. Longitudinal studies have shown that varices eventually develop in the majority of cirrhotic patients,10Christensen 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: 944-952Abstract Full Text PDF PubMed Scopus (190) Google Scholar, 11D’Amico G Luca A Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding.in: Bosch J Bailliere’s clinical gastroenterology-portal hypertension. 11. Bailliere Tindall, London1997: 243-256Google Scholar and that once they have developed, they tend to increase in size and to bleed.11D’Amico G Luca A Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding.in: Bosch J Bailliere’s clinical gastroenterology-portal hypertension. 11. Bailliere Tindall, London1997: 243-256Google Scholar The rate of development of new varices varies between 5% and 12% per year,10Christensen 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: 944-952Abstract Full Text PDF PubMed Scopus (190) Google Scholar, 12Pagliaro 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 R.J Portal hypertension, pathophysiology and treatment. Blackwell Scientific, Oxford1994: 72-92Google Scholar with rare exceptions,13de Franchis R Evaluation and follow-up of patients with cirrhosis and oesophageal varices.J Hepatol. 2003; 38: 361-363Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar while the rate of growth of varices from small to large ranges between 6% and 70% at 2 years.14Primignani M Albè R Preatoni P Carnevale P Bianchi M.B Parravicini E et al.“De novo” development of esophageal varices in patients with a recent histologic diagnosis of liver cirrhosis.Gastroenterology. 1998; 114 (abstr): A1324Google Scholar, 15Merli M Nicolini G Angeloni S Rinaldi V De Santis A Merkel C Attili A.F Riggio O Incidence and natural history of small oesophageal varices in cirrhotic patients.J Hepatol. 2003; 38: 266-272Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar, 16de 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: 643-646Abstract Full Text PDF PubMed Scopus (11) Google Scholar The risk of a first variceal bleeding episode varies between 8% and 35% at 2 years in untreated patients,17North-Italian Endoscopic Club for the study and treatment of esophageal varicesPrediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices.N Engl J Med. 1988; 319: 983-989Crossref PubMed Scopus (1074) Google Scholar, 18D’Amico G Pagliaro L Bosch J Pharmacologic treatment of portal hypertension an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Scopus (636) Google Scholar and in general is related to the size of the varices.17North-Italian Endoscopic Club for the study and treatment of esophageal varicesPrediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices.N Engl J Med. 1988; 319: 983-989Crossref PubMed Scopus (1074) Google Scholar, 18D’Amico G Pagliaro L Bosch J Pharmacologic treatment of portal hypertension an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Scopus (636) Google Scholar Despite important progress made over the last two decades, the first variceal bleeding still carries a mortality ranging around 20%.19D’Amico G de Franchis R a cooperative study groupUpper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators.Hepatology. 2003; 38: 599-612Crossref PubMed Scopus (693) Google Scholar, 20Chalasani N Kahi C Francois F Pinto A Marathe A Bini E.J et al.Improved patient survival after acute variceal bleeding a multicenter, cohort study.Am J Gastroenterol. 2003; 98: 653-659Crossref PubMed Scopus (331) Google Scholar, 21de Franchis R Primignani M Natural history of portal hypertension in patients with cirrhosis.in: Sanyal A Portal hypertension. Clinics in liver disease. 5. Saunders, Philadelphia, PA2001: 645-663Google Scholar 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,18D’Amico G Pagliaro L Bosch J Pharmacologic treatment of portal hypertension an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Scopus (636) Google Scholar screening seems a reasonable option. Since the prevalence of varices in unselected patient populations is extremely variable,22Pascal J.P Calès P Desmorat H Natural history of esophageal varices.in: Bosch J Rodès J Recent advances in the pathophysiology and treatment of portal hypertension. Serono Symposia review no. 22; Rome, Italy. 1989: 127-142Google Scholar 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 studies12Pagliaro 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 R.J Portal hypertension, pathophysiology and treatment. Blackwell Scientific, Oxford1994: 72-92Google Scholar, 23Garcia-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.Hepatology. 1997; 26 (abstr): 360AGoogle Scholar, 24Pilette C Oberti F Aube C Rousselet M.C Bedoussa P Gallois Y et al.N-invasive diagnosis of esophageal varices in chronic liver disease.J Hepatol. 1999; 31: 867-873Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 25Chalasani N Imperiale T.F Ismail A Sood G Carey M Wilcox C.M et al.Predictors of large esophageal varices in patients with cirrhosis.Am J Gastroenterol. 1999; 94: 3285-3291Crossref PubMed Google Scholar, 26Schepis F Cammà C Niceforo D Magnano A Pallio S Cinquegrani M D’Amico G Pasta L Craxı́ A Saitta A Raimondo G Which patients should undergo endoscopic screening for esophageal varices detection?.Hepatology. 2001; 33: 333-338Crossref PubMed Scopus (251) Google Scholar, 27Zaman 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: 2564-2570Crossref PubMed Scopus (139) Google Scholar, 28Madhotra R Mulcahy H.E Willner I Reuben A Prediction of esophageal varices in patients with cirrhosis.J Clin Gastroenterol. 2002; 34: 81-85Crossref PubMed Scopus (171) Google Scholar (Table 1), attempts at predicting the presence of varices before doing endoscopy have failed to produce workable predictive models.29Riggio O Angeloni S Nicolini G Merli M Merkel C Endoscopic screening for esophageal varices in cirrhotic patients.Hepatology. 2002; 35 (letter): 501-502Crossref PubMed Scopus (32) Google Scholar This implies that all cirrhotic patients should undergo an initial screening endoscopy to detect the presence of varices.6de 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: 846-852Abstract Full Text Full Text PDF PubMed Scopus (490) Google Scholar 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.Table 1Clinical-Biological Predictors of the Presence of Esophageal VaricesAuthorReferenceNumber of PatientsPredictorPagliaro et al. 199412Pagliaro 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 R.J Portal hypertension, pathophysiology and treatment. Blackwell Scientific, Oxford1994: 72-92Google Scholar494Low platelet count, portal vein diameter ≥13 mmGarcia-Tsao et al. 199723Garcia-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.Hepatology. 1997; 26 (abstr): 360AGoogle Scholar180Low platelet count, vascular spiders, low serum albuminPilette et al. 199924Pilette C Oberti F Aube C Rousselet M.C Bedoussa P Gallois Y et al.N-invasive diagnosis of esophageal varices in chronic liver disease.J Hepatol. 1999; 31: 867-873Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar118Low platelet count, low prothrombin activity, vascular spidersChalasani et al. 199925Chalasani N Imperiale T.F Ismail A Sood G Carey M Wilcox C.M et al.Predictors of large esophageal varices in patients with cirrhosis.Am J Gastroenterol. 1999; 94: 3285-3291Crossref PubMed Google Scholar346Low platelet count, splenomegalySchepis et al. 200126Schepis F Cammà C Niceforo D Magnano A Pallio S Cinquegrani M D’Amico G Pasta L Craxı́ A Saitta A Raimondo G Which patients should undergo endoscopic screening for esophageal varices detection?.Hepatology. 2001; 33: 333-338Crossref PubMed Scopus (251) Google Scholar143Low platelet count, low prothrombin activity, portal vein diameter ≥ 13 mmZaman et al. 200127Zaman 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: 2564-2570Crossref PubMed Scopus (139) Google Scholar300Low platelet count, Child scoreMadhotra et al. 200228Madhotra R Mulcahy H.E Willner I Reuben A Prediction of esophageal varices in patients with cirrhosis.J Clin Gastroenterol. 2002; 34: 81-85Crossref PubMed Scopus (171) Google Scholar184Low platelet count, splenomegaly, Child score Open table in a new tab 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 years6de 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: 846-852Abstract Full Text Full Text PDF PubMed Scopus (490) Google Scholar should be maintained, adopting the shorter interval for patients with alcoholic cirrhosis, with more severe impairment of liver function, and with endoscopic risk signs,15Merli M Nicolini G Angeloni S Rinaldi V De Santis A Merkel C Attili A.F Riggio O Incidence and natural history of small oesophageal varices in cirrhotic patients.J Hepatol. 2003; 38: 266-272Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar in whom the growth of varices appears to be faster. Since the risk of bleeding among cirrhotic patients with esophageal varices is variable, several prognostic indexes, based on combinations of different parameters, have been developed16de 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: 643-646Abstract Full Text PDF PubMed Scopus (11) Google Scholar 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),17North-Italian Endoscopic Club for the study and treatment of esophageal varicesPrediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices.N Engl J Med. 1988; 319: 983-989Crossref PubMed Scopus (1074) Google Scholar 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 validation21de Franchis R Primignani M Natural history of portal hypertension in patients with cirrhosis.in: Sanyal A Portal hypertension. Clinics in liver disease. 5. Saunders, Philadelphia, PA2001: 645-663Google Scholar 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,17North-Italian Endoscopic Club for the study and treatment of esophageal varicesPrediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices.N Engl J Med. 1988; 319: 983-989Crossref PubMed Scopus (1074) Google Scholar 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). Table 2Distribution of Variceal Bleeds Among Risk Classes of the NIEC IndexGrade of riskNumber who bled/total at risk (%)% of total bleedsLow18/149 (12.1)22.2Intermediate32/119 (26.9)39.5High31/59 (52.5)38.3Note. Data from North-Italian Endoscopic Club (NIEC) for the study and treatment of esophageal varices (1988).17North-Italian Endoscopic Club for the study and treatment of esophageal varicesPrediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices.N Engl J Med. 1988; 319: 983-989Crossref PubMed Scopus (1074) Google Scholar Open table in a new tab Note. Data from North-Italian Endoscopic Club (NIEC) for the study and treatment of esophageal varices (1988).17North-Italian Endoscopic Club for the study and treatment of esophageal varicesPrediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices.N Engl J Med. 1988; 319: 983-989Crossref PubMed Scopus (1074) Google Scholar 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. 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 β 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,30Garcia-Pagan J.C 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: 330-338Crossref Scopus (150) Google Scholar 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. Table 3Mechanisms of Action of Treatments for Portal HypertensionTreatmentAction onFlowResistancePortal pressureVaricose channelsVasoconstrictors↓ ↓↑↓—Vasodilators—↓↓—Vasoconstrictors + vasodilators↓↓↓ ↓—Shunts↑↓ ↓ ↓↓ ↓ ↓—Endoscopy———Obliteration Open table in a new tab When compared with placebo or no treatment, β-blockers,13de Franchis R Evaluation and follow-up of patients with cirrhosis and oesophageal varices.J Hepatol. 2003; 38: 361-363Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar band ligation31de Franchis R Primignani M Endoscopic treatments for portal hypertension.Semin Liver Dis. 1999; 19: 439-455Crossref PubMed Scopus (182) Google Scholar and shunt surgery32Conn H.O Lindenmuth W.W May C.J Ramsby G.R Prophylactic portacaval anastomosis a tale of two studies.Medicine. 1972; 51: 27-40Crossref PubMed Scopus (187) Google Scholar have all been shown to reduce the incidence of first variceal bleeding. In addition, band ligation significantly improves survival in comparison with no treatment51Imperiale T.F Chalasani N A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding.Hepatology. 2001; 33: 802-807Crossref PubMed Scopus (255) Google Scholar and β-blockers significantly reduce bleeding-related mortality.18D’Amico G Pagliaro L Bosch J Pharmacologic treatment of portal hypertension an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Scopus (636) Google Scholar These data indicate that primary prophylaxis is feasible and desirable. 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 β-blockers has been attempted in two studies,33Calés P Oberti F Payen J.L 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: 741-745Crossref PubMed Scopus (120) Google Scholar, 34Groszmann R Garcia-Tsao G Makuch R Bosch J Escorsell A Garcia-Pagan J.C 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: 206Crossref Google Scholar which gave negative results, in that the rate of development of varices and the occurrence of variceal bleeding were similar in patients treated with β-blockers or placebo. However, conflicting data exist about the prevention of the growth of varices from small to large with β-blockers.33Calés P Oberti F Payen J.L 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: 741-745Crossref PubMed Scopus (120) Google Scholar, 35Merkel 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: 217ACrossref Google Scholar Therefore, primary prophylaxis of variceal bleeding should focus on patients with medium-sized to large varices. When compared with placebo,18D’Amico G Pagliaro L Bosch J Pharmacologic treatment of portal hypertension an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Scopus (636) Google Scholar β-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 β-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 β-blockers decrease the HVPG to below 12 mm Hg are completely protected from bleeding,5Groszmann R Bosch J Grace N Conn H.O 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: 1401Abstract PubMed Google Scholar while a reduction of 20% from baseline values reduces the incidence of bleeding to less than 10%.36Feu F Garcia-Pagan J.C 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: 1056-1059Abstract Full Text PDF PubMed Scopus (509) Google Scholar Overall mortality is not influenced, while bleeding-related mortality is significantly reduced by β-blockers.18D’Amico G Pagliaro L Bosch J Pharmacologic treatment of portal hypertension an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Scopus (636) Google Scholar The main limitations of β-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.37Bernard 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: 312-324Abstract Full Text PDF PubMed Scopus (94) Google Scholar, 38Bernard B Lebrec D Mathurin P Opolon P Poynard T Beta-adrenergic antagonists in the prevention of gastrointestinal rebleeding in patients with cirrhosis a meta-analysis.Hepatology. 1997; 25: 63-70Crossref PubMed Scopus (222) Google Scholar, 39Bolognesi 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 Portal hypertension III. Proceedings of the third Baveno international consensus workshop on definitions, methodology and therapeutic strategies. Blackwell Science, Oxford2001: 180-201Google Scholar Because of these limitations, alternative means to prevent bleeding have been investigated. Nitrovasodilators have been considered for their ability to decrease portal pressure by decreasing hepatic and portocollateral resistance. In one study,40Angelico 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: 1460-1465PubMed Google Scholar, 41Angelico 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