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Primary Prophylaxis of Variceal Bleeding
REVIEW ARTICLE Primary prophylaxis of variceal bleeding Paul J. Thuluvath, MD, FRCP, Aruna Krishnan, MD Baltimore, Maryland
Morphologic changes in the liver increase resistance to portal blood flow in patients with chronic liver disease. In addition to the fixed defect caused by cirrhosis, the reversible contractile component induced by decreased synthesis of NO in the hepatic vascular bed and the hyperdynamic splanchnic circulation, induced by the local and systemic neurohumoral mechanisms, aggravate the portal hypertension and the development of gastroesophageal varices.1 The presence of gastroesophageal varices is not universal among patients with cirrhosis. In cross-sectional studies, gastroesophageal varices were seen in only a third of patients with cirrhosis. A longitudinal surveillance study found that only 31% of patients (83/265) with primary biliary cirrhosis developed varices during a median follow-up of 5.6 years.2 In this study, serum bilirubin and histopathologic staging were independent predictors for the development of varices, and, among patients who developed varices, 1-year and 3-year bleeding rates were, respectively, 33% and 41%. Current evidence suggests that a third of patients with documented esophageal varices bleed within 2 years from the time of diagnosis. Bleeding from varices is an unpredictable complication of cirrhosis that has an associated mortality of 20% to 40% with each episode.3-6 In a recent study, it was demonstrated that the in-hospital mortality rate for acute variceal bleeding has remained around 20% during the past decade despite advances in the management of acute variceal bleeding.7 Many patients who survive the immediate post-bleeding period subsequently die from the complications of bleeding, including sepsis, bacterial peritonitis, and renal failure. The mortality associated with variceal bleeding is related directly to the severity of liver disease with a relatively low mortality for patients with Current affiliations: Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Reprint requests: Paul J. Thuluvath, MD, FRCP, The Johns Hopkins Hospital, Rm. 429, 1830 Bldg., 1830 E. Monument St., Baltimore, MD 21205. Copyright © 2003 by the American Society for Gastrointestinal Endoscopy 0016-5107/2003/$30.00 + 0 PII:S0016-5107(03)01971-0 558
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Child A cirrhosis (∼10%-20%) and an extremely high mortality (∼70%) for those with Child C cirrhosis.3-6 Only a third of all deaths in patients with cirrhosis are directly attributed to variceal bleeding, an important consideration when the results of clinical trials are analyzed. Unfortunately, many interventional studies have lacked adequate sample size to show a difference in overall mortality or bleedingrelated mortality. The rationale for primary prophylaxis (prevention of first bleeding episode) is based on the extremely high mortality associated with each bleeding episode. The aim of primary prophylaxis is to treat high-risk patients with minimal complications. The treatment should be relatively inexpensive, effective, and should reduce bleeding-associated mortality and improve overall survival. In this review, the risk factors are discussed for first variceal bleeding, the optimal treatment, and the efficacy and cost-effectiveness of primary prophylaxis. PREDICTING FIRST BLEEDING Endoscopic screening It is difficult to show any benefit with primary prophylaxis in unselected patients with cirrhosis because of the notably low bleeding rates in patients without risk factors (discussed below) for bleeding. Although β-blockers are considered effective in preventing first bleeding, studies in unselected patients with cirrhosis have failed to demonstrate any significant benefit with β-blockers. In a study where 319 “unselected” (not selected based on risk factors) patients with chronic liver disease were randomized to either propranolol or placebo, overall frequency of bleeding within the first year was only 3.5% (11/319), with similar rates of bleeding in both groups.8 The findings of this study emphasize the importance of endoscopic screening and staging of esophageal varices before primary prophylaxis inasmuch as such treatment is likely to benefit only those with risk factors. Independent risk factors that reportedly predict the presence of esophageal varices include elevated prothrombin time, low platelet count, splenomegaly and portal vein (PV) diameter greater than 13 mm by US.9-12 Based on these findings, it has been suggested that screening may be restricted to those patients with cirrhosis who also have prothrombin activity less than 70% of normal, a platelet count less than 100 × 109/L, splenomegaly, or a US PV diameter greater than 13 mm.9-11 Despite the results of these studies, screening is recommended for esophageal varices by endoscopy in all patients with cirrhosis because of the high mortality associated with variceal bleeding (cost-effectiveness of VOLUME 58, NO. 4, 2003
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F1
A
F2
B
F3
C
Figure 1. Endoscopic views showing grading of varices by size (F1, F2, F3).
routine endoscopic screening is discussed below). Patients who are unlikely to benefit from prophylactic therapies and those with short life expectancy may be excluded from screening.12 When no varices VOLUME 58, NO. 4, 2003
Figure 2. Endoscopic views showing various red color signs. A, Cherry red spots (arrows). B, Wale markings (arrow). C, Hematocystic spot (arrow); note hematocystic spot protrudes from varix like a bleb.
or small varices without stigmata (low-risk varices) are found on initial screening endoscopy, repeat endoscopy is recommended every 2 years. GASTROINTESTINAL ENDOSCOPY
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Figure 3. Endoscopic view showing large fundal varix (arrow).
Staging of esophageal varices Because only 30% to 40% of patients with varices bleed during the first 2 years after the diagnosis of esophageal varices, it is important to identify the subgroup (those with risk-factors) in which bleeding is most likely to occur and offer the most effective treatment to these patients.2,13 Reproducible criteria for staging of varices are extremely important for many reasons, including accurate description (common terminology), surveillance (reproducibility), treatment, and research (identify high-risk subjects) purposes. However, too many classifications have been described, and many are subjective, with significant intra- and interobserver variations.13-16 Based on our GI training program, a minor modification of the Japanese Research Society for Portal Hypertension staging classification for varices is recommended.14,17 In this classification, esophageal varices are described by the extent (distance from GE junction in cm), size (F0, no varices; F1, small and non-tortuous; F2, tortuous but less than 50% radius of esophagus; F3, very large and tortuous), color (blue or white), and presence of red signs (red wale markings, cherry red spots, hematocystic spots) (Figs. 1 and 2). Gastric varices are described by location (cardia or fundus) and size (small and large) (Fig. 3). Classification should be kept as simple as possible to improve inter- and intra-observer agreement and reproducibility. Risk factors for variceal bleeding Many risk factors have been identified as predictors of first bleeding in patients with esophageal varices. There is a general consensus that patients with advanced cirrhosis (Child B and C), large varices, varices with red signs (cherry red spot, wale marking, hematocystic spot), and those with high 560
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portal pressure (hepatic venous wedge pressure gradient ≥12 mm Hg) are more likely to bleed.13,14,18-20 The risk of bleeding is higher with proximal extension of varices (63% with proximal third vs. 26% distal third alone), larger varices (F1, 15%; F2, 32%; F3, 68%), blue as opposed to white varices (80% vs. 45%), with red spots and wale markings (76% vs. 17% without), and with hematocystic spots (100% vs. 49% when absent).14 Many studies have confirmed that the hepatic venous wedge pressure gradient (HVWPG) is directly related to the risk of bleeding.19-22 It has been shown consistently that patients do not bleed if the HVWPG is less than 12 mm of Hg.19,21 Pharmacologic intervention studies have confirmed that the risk of bleeding is absent or markedly diminished (bleeding risk reduced by 80%) if the HVWPG is reduced below 12 mm Hg or more than 25% below the baseline pressure.1,20 Other risk factors for variceal bleeding include continued ingestion of alcohol and hepatocellular carcinoma.13,23 THERAPEUTIC OPTIONS FOR PRIMARY PROPHYLAXIS Surgery and transjugular intrahepatic portosystemic shunt In the 1960s, before the endoscopic era, a number of randomized, controlled trials were conducted of surgical shunt for primary prophylaxis of variceal bleeding. Although these consistently demonstrated a significant reduction in variceal and gastric mucosal bleeding in patients who had shunts, the mortality and the frequency of chronic hepatic encephalopathy were significantly higher for patients in the shunt groups compared with those in the control groups.24 These poor results and rapid technical advances in endoscopy led to abandonment of shunt surgery for primary prophylaxis. Esophageal transection with devascularization has been tried for primary prophylaxis, but there is no convincing evidence to recommend this type of surgery, which may make future liver transplantation technically more difficult, for primary prophylaxis. The transjugular intrahepatic portosystemic shunt (TIPS) as primary prophylaxis has not been studied, but, based on secondary prevention trials, it is unlikely to be beneficial and may be even be detrimental.25 Based on current evidence, there is no role for surgery or TIPS in primary prophylaxis. Endoscopic sclerotherapy Prophylactic sclerotherapy has been the subject of many small and large randomized, controlled studies. Earlier reports claimed a reduced bleeding rate and improved survival for patients who had sclerotherapy compared with control patients, but VOLUME 58, NO. 4, 2003
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more recent studies have not confirmed these results. A large, multicenter trial (n = 281) in men with moderate to severe alcoholic liver disease was terminated prematurely (after 22.5 months) because of a higher mortality rate in the sclerotherapy arm compared with the sham therapy arm (32.2% vs. 17.4%; p = 0.004).26 It has been argued that inclusion of patients with a lower risk of bleeding in these trials may have masked the benefits in patients who had a higher risk of bleeding. To test this hypothesis, a number of trials were conducted in which only patients with a high risk of bleeding were enrolled. These studies also failed to show a consistent improvement in survival for treated vs. control patients. A meta-analysis performed on 8 controlled studies found that prophylactic sclerotherapy may reduce mortality by 11% (95% CI 4%19%).27 However, the results of this meta-analysis should be interpreted with caution because the difference was only marginal, and the analysis included pooled data from heterogeneous studies.27,28 Currently available evidence suggests that, even in high-risk patients, the benefits from prophylactic sclerotherapy are marginal and that such therapy is not cost effective. Therefore, endoscopic injection sclerotherapy for primary prophylaxis is not recommended. β-Blockers Nonselective β-blockers reduce portal pressure by reducing cardiac output and by reducing portal inflow via antagonism of the β2 receptors on the splanchnic vessels. β-Blockers also may increase portocollateral resistance and, hence, reduce collateral blood flow. Many trials have assessed the efficacy of non-selective β-blockers such as propranolol or nadolol for primary prophylaxis. Although some earlier studies did not find significant differences in bleeding rates in patients treated with propranolol,8,29-32 a majority of studies have demonstrated that non-selective β-blockers reduced (by about 50%) the risk of first bleeding in patients with large varices.30 Meta-analyses on these trials have shown a definite benefit in the treated group with regard to bleeding (about 50% reduction, pool) and mortality (25%-45% reduction).24,31,32 A number of studies have shown that patients with varices are unlikely to bleed if HVWPG is maintained below 12 mm Hg.20 Unfortunately, this can be achieved only in a small group of patients treated with currently available drugs. It is difficult to justify repeated HVWPG measurements, unless a reliable noninvasive method is developed in the future to determine whether a drug therapy is effective. So, for all practices, the end point of treatment VOLUME 58, NO. 4, 2003
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is to achieve a resting heart rate of less than 60 per minute or a 25% reduction from the baseline heart rate. The major disadvantage of the β-blocker is poor tolerance and compliance. Despite these limitations, use of non-selective β-blockers is cost-effective and should be the treatment of choice for primary prophylaxis for patients with advanced liver disease and large gastroesophageal varices. Use of longacting preparations, gradual increases in dosage, and better patient education may improve compliance. The current practice is to continue treatment with a β-blocker indefinitely or until liver transplantation in patients with cirrhosis. Although there are no convincing data to support this strategy, a small study seems to indicate that the risk of bleeding returns to that expected in an untreated population when treatment with propranolol is discontinued.33 It has been suggested that the hemodynamic response to a β-blocker may predict the risk of subsequent bleeding. Merkel et al.34 measured HVWPG before and 1 to 3 months after treatment with either nadolol or nadolol plus isosorbide mononitrate (ISMN) in 49 patients with large varices and no previous variceal bleeding. A good response, defined as a reduction in HVWPG to less than 12 mm of Hg (n = 12) or reduction in HVWPG by more than 20% from baseline (n = 18), was noted in 30 (61%) patients. During a follow-up of 5 years, 7 (7/19) “poor responders” and two (2/30) “good responders” had variceal bleeding. The probability of bleeding at 3 years was 41% in poor responders and 7% in good responders (p = 0.0008). As in many previous studies, none of the 12 patients who had a reduction in HVWPG to less than 12 mm Hg had variceal bleeding. Although this is perhaps the “optimal” treatment strategy and the best predictor of bleeding, the costs related to measurement of the HVWPG may be prohibitive for routine clinical care. In addition, the invasive nature of HVWPG measurement (twice in the same patient) may increase the risks and reduce compliance. An alternative strategy was tested in another study where HVWPG was measured before and 90 minutes after a single dose of 80 mg of propranolol in 33 patients.35 Of the 22 patients who had a 20% or greater reduction in HVWPG, only one had variceal bleeding during a follow-up of 9 to 38 months, and none of the patients who had reduction in HVWPG below 12 mm Hg had bleeding. Although this is a small study, if these results are reproduced in larger studies, a similar strategy could be recommended, provided cost is not an issue, to all patients with large varices before initiating primary prophylaxis with β-blockers. Those in whom HVWPG is not reduced could be offered alternative treatments. GASTROINTESTINAL ENDOSCOPY
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By using hypothetical models, Hicken et al.36 examined the role of the HVWPG in patients with varices at risk for bleeding. These investigators compared β-blocker therapy without measurement of HVWPG to one measurement 4 weeks after the initiation of treatment or two measurements (one before and another 4 weeks after initiation of treatment). Compared with the standard practice (no measurement of HVWPG), the incremental cost with one HVWPG measurement was $108,185 per bleeding episode prevented and $355,200 per death averted. The similar figures for two measurements of HVWPG were, respectively, $202,796 and $719,300. Although these cost estimates may not be a true reflection of actual costs, nevertheless they suggest that HVWPG may be extremely expensive for routine use. Less invasive techniques need to be developed to measure portal pressure for “optimal” and effective primary prophylaxis. Nitrates β-Blockers are not tolerated by about a third of patients with cirrhosis because of side effects, including hypotension and severe fatigue. Of the vasodilators that also have been studied for primary prophylaxis, nitrates have been the most promising. Although the mechanism of action is not clearly understood, it is thought that nitrates may reduce intrahepatic resistance and may reduce portal pressure “by means of reflex splanchnic arterial vasoconstriction in response to vasodilatation in other vascular beds.”37 Isosorbide mononitrate has been studied for primary prophylaxis in patients, and the results have been mixed. In a double blind, randomized, controlled trial, Garcia-Pagan et al.38 compared ISMN (n = 67) and placebo (n = 66) in 113 consecutive patients with cirrhosis and varices who could not tolerate β-blockers or had contraindications to their use. The variceal bleeding rate was similar at 1 and 2 years in both groups. In multivariate analysis, the presence of variceal red sign was the only independent predictor of bleeding (relative risk 3.4; p < 0.01). Based on this study, GarciaPagan et al.38 concluded that ISMN does not have any role for primary prophylaxis. Another study of ISMN vs. placebo found an increased mortality with ISMN in patients above 50 years of age.39 In addition, a tendency for ascites to increase in patients undergoing nitrate monotherapy has been reported. Variceal band ligation (banding) Primary prophylactic sclerotherapy failed to achieve any distinct advantage over “no treatment” because the benefits of sclerotherapy were negated by the local complications of sclerotherapy. Banding, 562
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which has fewer local complications, is a logical alternative to sclerotherapy.40 Many studies have assessed the role of endoscopic variceal ligation for primary prophylaxis.41-46 Sarin et al.41 randomized 35 patients to banding and 33 to no treatment and found a lower bleeding rate in the banding group (3/35, 8.6%) compared with the no treatment group (13/33, 39.4%; p < 0.01) at a mean follow-up of 14 months. Although overall mortality was similar (11.4% vs. 24.2%), there was a trend toward lower bleeding-related mortality in the banding group (2.9% vs. 15.2%; p = 0.08). Another prospective, randomized trial of prophylactic endoscopic variceal ligation (EVL) vs. no treatment found that banding was associated with a significantly decreased risk of variceal hemorrhage and overall mortality.42 In this study, EVL was more effective in patients with Child A cirrhosis as compared with those with decompensated disease (Child B and C). A prospective, randomized trial conducted in Taiwan found that patients with Child-Pugh class B cirrhosis and high-risk varices (F2 or F3 with red color signs) had a significantly lower risk of variceal bleeding than untreated patients.43 In addition, a trend toward reduced mortality and a reduction in blood transfusion requirements were observed in patients undergoing banding. Apart from small sample size, the major concern with these studies was the no-treatment arm because the standard of care for primary prophylaxis during the time periods when these studies were conducted was β-blocker therapy, and one may consider that it is unethical to include a no-treatment arm for such studies. Band ligation has been compared with sclerotherapy or no treatment for primary prophylaxis of variceal bleeding, and no difference in efficacy was found between sclerotherapy and banding.44 As in secondary prevention trials, fewer sessions were needed to eradicate varices by band ligation, but the recurrence rate of varices was higher in patients treated with ligation. Because the “best available” treatment for primary prophylaxis is a non-selective β-blocker, new treatment modalities need to be tested against this standard. Sarin et al.45 addressed this by comparing banding with propranolol in a study (high-risk patients with large varices and red signs) where 44 patients were randomized to propranolol and 45 to endoscopic banding. At a mean follow-up of approximately 14 months, 12 patients in the propranolol group, and 4 in the ligation group had variceal bleeding with an actuarial probability of bleeding of 43% in the propranolol group and 15% in the ligation group (p = 0.04). Three of 4 patients in the banding group experienced first bleeding before varices were obliterated completely. Overall VOLUME 58, NO. 4, 2003
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mortality and bleeding-related mortality were similar in both groups. In this study, 7 of 89 patients had non-cirrhotic portal hypertension. Moreover, the study has been criticized as using an inadequate dose of propranolol (mean 70 mg vs. 123 mg in other studies).32,46 The higher bleeding rate in the propranolol group (43% vs. 22% as compared with that in other trials) may have been because of inadequate treatment with the β-blocker.32 Despite some criticisms and small sample size, this study was important and provocative and stimulated further research into the role of variceal banding for primary prophylaxis. In a 3-arm study, Lui et al.47 compared endoscopic banding (n = 44), propranolol (n = 66), and ISMN (n = 62) in 172 patients with grade II to III varices over a period of 6 years. At a mean follow-up of 20 months, by intention-to-treat analysis, variceal bleeding occurred in 7% in the banding group, 14% in the propranolol group, and 23% in ISMN group. Two-year actuarial risk of first bleeding was, respectively, 6.2%, 19.4%, and 27.5%. Side effects were significantly more frequent in the propranolol (45%) and ISMN (42%) groups as compared with the banding group (2%; p < 0.001), and this resulted in withdrawal of treatment in 30% of patients in the propranolol group and 21% in the ISMN group. When patients were analyzed based on the treatment received, actuarial bleeding rate was significantly different only between banding and ISMN groups (7.5% vs. 33%; log rank test p = 0.03); there was no difference when the banding and propranolol groups were compared.47 A meta-analysis of 601 patients from 5 randomized, controlled trials comparing banding with no treatment confirmed that banding reduced first variceal bleeding (relative risk [RR] 0.36: 95% CI [0.26,0.5]), bleeding related mortality (RR 0.20: 95% CI [0.11,0.39]), and overall mortality (RR 0.55: 95% CI [0.43,0.71]).48 However, when banding was compared with β-blockers in 283 patients from 4 randomized trials, the only benefit for variceal banding was in the reduction of first variceal bleeding (RR 0.48: 95% CI [0.24,0.96]). Bleeding related mortality and overall mortality were similar for banding and propranolol, suggesting that a role for variceal banding may be the treatment of patients who cannot tolerate β-blockers because of side effects or hypotension. If noninvasive, reliable methods for measurement of portal pressure are identified, it will be appropriate to offer banding to patients in whom pharmacotherapy fails to significantly reduce portal pressure (<25% reduction from baseline). Current methods of measuring HVWPG are not applicable or VOLUME 58, NO. 4, 2003
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cost-effective for a majority of patients with large esophageal varices. Combination treatment Sclerotherapy plus β-blocker. Combination treatment with endoscopic sclerotherapy and β-blockers has not been found to have any advantage over βblockers alone for primary porphylaxis. In one study, 86 patients with high intravariceal pressure (>18 mm Hg) were randomized to either propranolol alone (n = 42) or propranolol plus sclerotherapy (n = 44).49 There was a trend toward a higher bleeding rate (23%) in the combination group as compared with those who received only propranolol (14%; p = ns) at a median follow-up of approximately 24 months. There was a significantly higher complication rate in the combination group (52% vs. 19%; p = 0.002), but mortality rates were similar (14% vs. 18%; p = ns). Predictably, this study demonstrated that there is no role for sclerotherapy in combination with β-blockers for primary prophylaxis. β-Blocker plus isosorbide mononitrate. Although β-blockers reduce the risk of bleeding in patients with large varices, a significant number of patients nevertheless experience variceal bleeding while being treated with β-blockers. This is perhaps because of a combination of factors, including poor compliance, intolerance to maximal treatment, and, more importantly, inadequate reduction in portal pressure. Because it is not practical or cost-effective to monitor HVWPG before and after treatment with β-blockers to assess the hemodynamic response, many investigators have studied the effect of a combination of β-blockers and ISMN on bleeding rates and mortality; these studies have produced conflicting results. Merkel et al.50 compared nadolol alone (n = 74) and nadolol plus ISMN (n = 72) in 146 patients with large esophageal varices. Treatment with nadolol was initiated at a dose of 40 mg daily and increased every second day to achieve a 20% to 25% reduction in resting heart rate. In the combination therapy group, treatment with ISMN was started simultaneously with nadolol, and the dose of ISMN was increased from 10 mg twice daily to 20 mg twice daily if patients were able to tolerate the drug. At a median follow-up of 30 months, 11 (11/74) patients in the nadolol alone group and 4 (4/72) in the combination group had experienced a first episode of variceal bleeding (p = 0.03 by Kaplan-Meier analysis). The cumulative risk of bleeding was 18% with nadolol alone and 7.5% with combination therapy. The mortality was not statistically significant different (14/74 vs. 8/72) between the groups, but there was a trend favoring the combination therapy GASTROINTESTINAL ENDOSCOPY
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group. As a follow-up to this study, Merkel et al.51 reported the long-term results (up to 7 years followup) for the same cohort. During the study period, 16 patients in the nadolol alone group and 8 in the combination therapy group had variceal bleeding (p = 0.02) with a cumulative bleeding risk of, respectively, 29% and 12%. However, the mortality remained similar in both groups. In contrast, a multicenter, prospective, double-blind, randomized, controlled trial (n = 349) comparing propranolol plus placebo (n = 174) with propranolol plus ISMN (n = 175) found no significant difference in the risk of first variceal hemorrhage at 1 year (8.3% vs. 5%) and 2 years (10.6% vs. 12.5%).52 In addition, adverse side effects were significantly more frequent (mainly headache) in the combination group. These observations suggest that combination treatment with βblockers plus ISMN is a reasonable option for primary prophylaxis if patients cannot tolerate maximal doses of β-blockers. There is no role for combination treatment with β-blockers and ISMN for routine primary prophylaxis. Other treatments. Other drugs, including spironolactone, have been studied for primary prophylaxis. In one such trial, combination therapy with nadolol plus spironolactone for primary prophylaxis of variceal hemorrhage was not found to have any additive effect.53 COST-EFFECTIVENESS OF SCREENING AND PROPHYLAXIS There is overwhelming evidence to suggest that primary prophylaxis with β-blockers is beneficial in patients with cirrhosis and large varices with stigmata of imminent bleeding. However, screening is not routinely performed in a majority of patients with advanced cirrhosis. One study found that only 46% of patients referred to a tertiary center for liver transplantation had undergone either endoscopy or barium contrast radiography to assess the presence of esophageal varices.54 A major impact is unlikely in terms of a reduction in the occurrence of first bleeding episodes without better adherence to screening and prophylaxis among the community gastroenterologists. Although there are no rigid criteria, it has been suggested that all patients with cirrhosis should have a screening endoscopy. If large varices are found, the patient should be offered prophylactic therapy. If varices are absent, they should have surveillance endoscopy every 2 years. If small varices are present, endoscopy should be repeated every 1 to 2 years based on the severity of liver disease. Many studies have examined the cost-effectiveness of primary prophylaxis for variceal bleeding. By using a Markov model, Teran et al.55 compared 564
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the cost-effectiveness of propranolol, sclerotherapy, and shunt surgery after stratifying patients by risk of bleeding. Although sclerotherapy had no advantage with respect to quality of life, shunt surgery was associated with decreased quality of life. Propranolol was most cost-effective (cost saving $450-$14,600 over a 5-year period) followed by sclerotherapy and shunt surgery. In another study that used Markov modeling, Spiegel et al.56 examined whether it was costeffective to treat all patients with cirrhosis without screening endoscopy. Six different strategies were compared: universal screening followed by βblockers if there are varices (strategy 1); screening, followed by banding (strategy 2); selective screening only in high-risk patients, followed by treatment with β-blockers if varices are present (strategy 3); selective screening, followed by banding (strategy 4); empiric β-blocker therapy for all patients (strategy 5); and no prophylactic therapy (strategy 6). Costs were estimated from a third-party payer perspective and the outcome measure was the cost of first variceal bleeding prevented by the 6 strategies. As expected, strategy 6 was the least expensive, and, in comparison, the cost of strategy 5 was $12,408 per additional variceal bleeding prevented. Strategies 2 and 3 were the most expensive ($175,000 per additional bleeding episode prevented); strategies 4 and 5 were intermediate in terms of cost. Based on this mathematical modeling, Spiegel et al.56 recommended universal β-blocker therapy for all patients with cirrhosis. Another strategy not examined in this study is the use of screening endoscopy in only those patients who do not tolerate β-blockers. Other investigators also have addressed the costeffectiveness of screening and no prophylaxis or prophylaxis with either β-blockers or banding by using Markov models.57,58 Saab et al.57 recommended universal prophylaxis with β-blockers because it was associated with lower costs ($34,100) and higher quality-adjusted life-years (6.5). In contrast, costs and quality adjusted life-years were $36,600 and 4.84 for no prophylaxis, and $37,300 and 5.72 for screening followed by treatment with β-blockers for patients with large varices. In another study, a Markov simulation model was created in two cohorts of patients 50 years of age with compensated or decompensated cirrhosis.58 Four strategies were examined including no screening or prophylaxis; screening, followed by βblocker; screening, followed by banding; and universal prophylaxis with β-blockers. In patients with compensated cirrhosis, screening, followed by β-blocker was cost-effective ($3605 per year of life saved), and, in decompensated cirrhosis, universal β-blocker was cost-effective ($1154 per year of life saved). VOLUME 58, NO. 4, 2003
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Table 1. Variceal bleeding (%) in primary prophylaxis trials VA study, 199126 Pascal et al., 198730 Andreani et al., 199059 Lay et al., 199742 Lo et al., 199943 Sarin et al., 199945 Lui et al., 200247
Number
Control
281 230 126 126 127 89 172
13.8% 61% 31.7% 60% 22.2%
EIS
β-Blocker
EBL
p Value
19% 12.5% 15% 6.2%
<0.05 <0.05 <0.03* 0.0001 0.2 0.04 NS
7.0% 21.4%
26% 4.7%
12% 19.4%
EIS, Endoscopic injection sclerotherapy; EBL, endoscopic band ligation; NS, not significant. *Also when EIS and β-blocker are compared.
Table 2. Bleeding-related mortality in primary prophylaxis trials Lay et al., 199742 Lo et al., 199943 Sarin et al., 199945 Lui et al., 200247
Number
Control
126 127 89 172
16% 11.1%
β-Blocker
EBL
p Value
9% 6.1%
19% 12.5% 7% 2.3%
<0.05 0.15 NS NS
EBL
p Value
28% 25% 11% 25%
0.004 <0.05 NS 0.001 0.2 0.7 NS
Please note that many trials did not report bleeding-related mortality. EIS, Endoscopic injection sclerotherapy; EBL, endoscopic band ligation.
Table 3. Overall mortality (%) in primary prophylaxis trials VA study, 199126 Pascal et al., 198730 Andreani et al., 199059 Lay et al., 199742 Lo et al., 199943 Sarin et al., 199945 Lui et al., 200247
Number
Control
EIS
281 230 126 126 127 89 172
17.4% 49% 44% 58% 36.5%
32.2% 43%
β-Blocker 28% 30%
11% 27.3%
EIS, Endoscopic injection sclerotherapy; EBL, endoscopic band ligation; NS, not significant.
Table 4. Comparison of prophylactic options to “no treatment” Variceal bleeding Bleed-related mortality Overall mortality
EIS
β-Blocker
EBL
+ +/– –
+++ ++ ++
+++* +† +†
EIS, Endoscopic injection sclerotherapy; EBL, endoscopic band ligation; –, negative trend; +/–, conflicting data; +, possible; ++, probable; +++, definite. *Probable reduction in bleeding when compared with β-blockers. †No benefit when compared with β-blockers; when compared with no treatment, there is a positive trend.
The results based on Markov models are highly sensitive to the prevalence of esophageal varices, risk of bleeding, cost of endoscopy, and primary prophylaxis. In the absence of clinical trials, it is believed that it is premature to abandon screening or surveillance endoscopy before initiating prophylactic treatment with a β-blocker because of the high frequency of side effects associated with such therapy and the extremely low risk of bleeding in patients VOLUME 58, NO. 4, 2003
with small varices.8 Moreover, the awareness of the presence of large esophageal varices may improve patient compliance. In addition, alternative treatment (variceal banding) can be offered to the highrisk patients who do not tolerate β-blockers. GASTRIC AND ECTOPIC VARICES The frequency of gastric varices among patients with cirrhosis in published reports ranges from 6% to 16% and the frequency appears to increase after esophageal variceal obliteration. Gastric varices (Fig. 3) usually are seen in association with esophageal varices or rarely in isolation as in splenic vein thrombosis (segmental portal hypertension). Overall, the mortality rate for patients with bleeding gastric varices is greater than 50%. The proportion of patients with bleeding from non-gastroesophageal sites (ectopic varies) ranges from 1.6% to 5% in large series. The common ectopic sites, usually seen in association with esophageal varices, are duodenum, colon, anorectum, and enterostomy. Rarely, ectopic varices may be localized, especially in the colon, and GASTROINTESTINAL ENDOSCOPY
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result from superior or inferior vein thrombosis, tumor infiltration, adhesions, or congenital malformation. Because there are no controlled data for primary prophylaxis of gastric or ectopic varices, it is difficult to recommend any specific strategy. However, based on data from studies of esophageal varices, it is recommended that all patients with large gastric or ectopic varices be treated with nonselective β-blockers. RECOMMENDATIONS Based on the results of large randomized trials and meta-analysis of many other trials, it is clear that non-selective β-blocker therapy remains the treatment of choice for primary prophylaxis in patients with cirrhosis and large varices or those with risk factors for bleeding (Tables 1 through 4). Endoscopic sclerotherapy, the surgical shunt, and TIPS have no role in primary prophylaxis. Endoscopic band ligation is an option for those with risk factors for bleeding who do not tolerate or are poorly responsive to β-blockers. Endoscopic band ligation must be compared with β-blockers in a rigorous fashion, in large randomized controlled trials in high-risk patients (advanced liver disease [Child B and C], large varices with red signs and HVWPG ≥ 12 mm Hg), before it can be recommended for routine primary prophylaxis.
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REFERENCES 1. Bosch J, Garcia-Pagan JC. Complications of cirrhosis. 1. Portal hypertension. J Hepatol 2000;32(1 Suppl):141-56. 2. Gores GJ, Wiesner RH, Dickson ER, Zinsmeister AR, Jorgensen RA, Langworthy A. Prospective evaluation of esophageal varices in primary biliary cirrhosis: development, natural history, and influence on survival. Gastroenterology 1989;96:1552-9. 3. Merigan TC, Plotkin GR, Davidson CS. Effect of intravenously administered posterior pituitary extract on hemorrhage from bleeding esophageal varices. N Engl J Med 1962;266: 134-5. 4. Conn HO, Ramsby GR, Storer EH, Mutchnick MG, Joshi PH, Phillips MM, et al. Intraarterial vasopressin in the treatment of upper gastrointestinal hemorrhage: a prospective controlled clinical trial. Gastroenterology 1975;68:211-21. 5. Fogel RM, Knauer MC, Andres LL, Mahal AS, Stein D, Kemeney JM, et al. Continuous intravenous vasopressin in active upper gastrointestinal bleeding. A placebo controlled trial. Ann Intern Med 1982;96:565-9. 6. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9. 7. Dy SM, Cromwell DM, Thuluvath PJ, Bass EB. Hospital experience and outcomes for esophageal variceal bleeding. Int J Qual Health Care 2003;15:139-46. 8. Plevris JN, Elliot R, Mills PR, Hislop WS, Davies JM, Bouchier IA, Hayes PC. Effect of propranolol on prevention of first variceal bleed and survival in patients with chronic liver disease. Aliment Pharmacol Ther 1994;8:63-70. 9. Schepis F, Camma C, Niceforo D, Magnano A, Pallio S, 566
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Cinquegrani M, et al. Which patients with cirrhosis should undergo endoscopic screening for esophageal varices detection? Hepatology 2001;33:333-8. Zaman A, Becker T, Lapidus J, Benner K. Risk factors for the presence of varices in cirrhotic patients without a history of variceal hemorrhage. Arch Intern Med 2001;161:2564-70. 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;94:3285-91. Jensen DM. Endoscopic screening for varices in cirrhosis: findings, implications, and outcomes. Gastroenterology 2002; 122:1620-30. The 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: a prospective multi-center study. N Engl J Med 1988;319:983-9. Beppu K, Inokuchi K, Koyanagi N, Nakayama S, Sakata H, Kitano S, et al. Prediction of variceal hemorrhage by esophageal endoscopy. Gastrointest Endosc 1981;27:213-8. Sarin SK, Sundaram KR, Ahuja RK. Predictors of variceal bleeding: an analysis of clinical, endoscopic and hemodynamic variables, with special reference to intravariceal pressure. Gut 1989;30:1757-64. Bendsten F, Skovgaard LT, Sorensen TI, Matzen P. Agreement among multiple observers on endoscopic diagnosis of esophageal varices before bleeding. Hepatology 1990;11:341-7. Idezuki Y. General rules for recording endoscopic findings of esophagogastric varices (1991). Japanese Society for Portal Hypertension. World J Surg 1995;19:420-2. Dagradi AE. The natural history of esophageal varices in patients with alcoholic liver cirrhosis. An endoscopic and clinical study. Am J Gastroenterol 1972;57:520-40. Viallet A, Marleau D, Huet M, Martin F, Farley A, Villeneuve JP, Lavoie P. Hemodynamic evaluation of patients with intrahepatic portal hypertension: relationship between bleeding varices and portohepatic gradient. Gastroenterology 1975;69: 1297-1300. Groszmann RJ, Bosch J, Grace ND, Conn HO, Garcia-Tso G, Navasa M, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of variceal hemorrhage. Gastroenterology 1990;99:1401-7. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985;5:419-24. Vorobioff J, Groszmann RJ, Picabea E, Gamen M, Villavicencio R, Bordato J, et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study. Gastroenterology 1996;111:701-9. Akanuma M, Yoshida H, Okamoto M, Ogura K, Maeda S, Hata Y, et al. Risk factors for esophageal variceal bleeding in patients with hepatocellular carcinoma. Hepatogastroenterology 2002;49:1039-44. D’Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995;22: 332-54. Papatheodoridis GV, Goulis J, Leandro G, Patch D, Burroughs AK. Transjugular intrahepatic portosystemic shunt compared with endoscopic treatment for prevention bleeding: A meta-analysis. Hepatology 1999;30:612-22. The Veterans Affairs Cooperative Variceal Sclerotherapy Group. Prophylactic sclerotherapy for esophageal varices in alcoholic liver disease: a randomized, single-blind, multicenter clinical trial. N Engl J Med 1991;324:1779-84. VOLUME 58, NO. 4, 2003
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27. Van Ruiswyk J, Byrd JC. Efficacy of prophylactic sclerotherapy for prevention of a first variceal hemorrhage. Gastroenterology 1992;102:587-97. 28. Pagliaro L, D’Amico G, Sorensen TI, Lebrec D, Burroughs AK, Morabito A, et al. Prevention of first bleeding in cirrhosis: a meta-analysis of randomized trials of non-surgical treatment. Ann Intern Med 1992;117:59-70. 29. Lebrec D, Corbic M, Nouel O, Benhamou P. Propranolol: a medical treatment for portal hypertension. Lancet 1980;2:180-2. 30. Pascal JP, Cales P, Multicenter Study Group. Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varies. N Engl J Med 1987;317:856-61. 31. Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, Lebrec D. Beta-adrenergic antagonists in the prevention of first gastrointestinal bleeding in patients with cirrhosis and oesophageal varices. Analysis of data and prognostic factors in 589 patients from four randomized clinical trial. N Engl J Med 1991;324:1532-8. 32. Hayes PC, Davis JM, Lewis JA, Bouchier IAD. Meta-analysis of value of propranolol in prevention of variceal haemorrhage. Lancet 1990;336:153-6. 33. Abraczinskas DR, Ookubo 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;34:1096-102. 34. Merkel C, Bolognesi M, Sacerdoti D, Bombonato G, Bellini B, Bighin R, Gatta L. The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2000;32:930-4. 35. De BK, Sen S, Biswas PK, Sengupta D, Biswas J, Santra A, et al. Propranolol in primary and secondary prophylaxis of variceal bleeding among cirrhotics in India: a hemodynamic evaluation. Am J Gastroenterol 2002;95:1862-4. 36. Hicken BL, Sharara AI, Abrams GA, Eloubeidi M, Fallon MB, Arguedas MR. Hepatic venous pressure gradient measurements to assess response to primary prophylaxis in patients with cirrhosis: a decision analytical study. Aliment Pharmacol Ther 2003;17:145-53. 37. Rockey DC. Vasoactive agents in intrahepatic portal hypertension and fibrogenesis: implications for therapy. Gastroenterology 2000;118:1261-5. 38. Garcia-Pagan JC, Villanueva C, Vila MC, Albillos A, Genesca J, Ruiz-Del-Arbol L, et al. Isosorbide mononitrate in the prevention of first variceal bleed in patients who cannot receive beta-blockers. Gastroenterology 2001;121:908-14. 39. Angelico M, Carli L, Piat C, Gentile S, Capocaccia L. Effects of isosorbide-5-mononitrate compared with propranolol on first bleeding and long-term survival in cirrhosis. Gastroenterology 1997;113:1632-9. 40. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding: a meta-analysis. Ann Intern Med 1995;123:280-7. 41. Sarin SK, Gupta RK, Jain AK, Sundaram KR. A randomized controlled trial of endoscopic variceal band ligation for primary prophylaxis of variceal bleeding. Eur J Gastroenterol Hepatol 1996;8:337-42. 42. Lay CS, Tsai YT, Teg CY, Shyu WS, Guo WS, Wu KL, et al. Endoscopic variceal ligation in prophylaxis of first variceal bleeding in cirrhotic patients with high-risk esophageal varices. Hepatology 1997;25:1346-50. 43. Lo GH, Lai KH, Cheng JS, Lin CK, Hsu PI, Chiang HT. Prophylactic banding ligation of high-risk esophageal varices
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in patients with cirrhosis: a prospective, randomized trial. J Hepatol 1999;31:451-6. Svoboda P, Kantorova I, Ochmann J, Kozumplik L, Marsova J. A prospective randomized controlled trial of sclerotherapy vs. ligation in the prophylactic treatment of high-risk esophageal varices. Surg Endosc 1999;13:580-4. 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;340:988-93. Burroughs AK, Patch D. Primary prevention of bleeding from esophageal varices. N Engl J Med 1999;340:1033-5. 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;123:735-44. Imperiale TF, Chalasani N. A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding. Hepatology 2001;33:802-7. Avgerinos A, Armonis A, Manolakopoulos S, Rekoumis G, Argirakis G, Viazis N, et al. Endoscopic sclerotherapy plus propranolol versus propranolol alone in the primary prevention of bleeding in high risk cirrhotic patients with esophageal varices: a prospective multicenter randomized trial. Gastrointest Endosc 2000;51:652-8. Merkel C, Marin R, Enzo E, Donada C, Cavallarin G, Torboli P, et al. Randomized trial of nadolol alone or with isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Lancet 1996;348:1677-81. Merkel C, Marin R, Sacerdoti D, Donada C, Cavallarin G, Torboli P, 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: 324-9. Garcia-Pagan JC, Feu F, Bosch J, Rodes J. Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. Ann Intern Med 1991;114:869-73. Abecasis R, Kravetz D, Fassio E, Ameigeiras B, Garcia D, Isla R, et al. Nadolol plus spironolactone in the prophylaxis of first variceal bleed in nonascitic cirrhotic patients: a preliminary study. Hepatology 2003;37:359-65. Arguedas MR, McGuire BM, Fallon MB, Abrams GA. The use of screening and preventive therapies for gastroesophageal varices in patients referred for evaluation of orthotopic liver transplantation. Am J Gastroenterol 2001;96:833-7. Teran JC, Imperiale TF, Mullen KD, Tavill AS, McCullough AJ. Primary prophylaxis of variceal bleeding in cirrhosis: a costeffectiveness analysis. Gastroenterology 1997;112:473-82. Spiegel BM, Targownik L, Dulai GS, Karsan HA, Gralnek IM. Endoscopic screening for esophageal varices in cirrhosis: is it ever cost effective? Hepatology 2003;37:366-77. Saab S, DeRosa 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;98:763-70. 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;97:2441-52. Andreani T, Poupon RE, Balkau BJ, Trinchet JC, Grange JD, Peigney N, 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;12:1413-9.
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Morphologic changes in the liver increase resistance to portal blood flow in patients with chronic liver disease. In addition to the fixed defect caused by cirrhosis, the reversible contractile component induced by decreased synthesis of NO in the hepatic vascular bed and the hyperdynamic splanchnic circulation, induced by the local and systemic neurohumoral mechanisms, aggravate the portal hypertension and the development of gastroesophageal varices.1 The presence of gastroesophageal varices is not universal among patients with cirrhosis. In cross-sectional studies, gastroesophageal varices were seen in only a third of patients with cirrhosis. A longitudinal surveillance study found that only 31% of patients (83/265) with primary biliary cirrhosis developed varices during a median follow-up of 5.6 years.2 In this study, serum bilirubin and histopathologic staging were independent predictors for the development of varices, and, among patients who developed varices, 1-year and 3-year bleeding rates were, respectively, 33% and 41%. Current evidence suggests that a third of patients with documented esophageal varices bleed within 2 years from the time of diagnosis. Bleeding from varices is an unpredictable complication of cirrhosis that has an associated mortality of 20% to 40% with each episode.3-6 In a recent study, it was demonstrated that the in-hospital mortality rate for acute variceal bleeding has remained around 20% during the past decade despite advances in the management of acute variceal bleeding.7 Many patients who survive the immediate post-bleeding period subsequently die from the complications of bleeding, including sepsis, bacterial peritonitis, and renal failure. The mortality associated with variceal bleeding is related directly to the severity of liver disease with a relatively low mortality for patients with Current affiliations: Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Reprint requests: Paul J. Thuluvath, MD, FRCP, The Johns Hopkins Hospital, Rm. 429, 1830 Bldg., 1830 E. Monument St., Baltimore, MD 21205. Copyright © 2003 by the American Society for Gastrointestinal Endoscopy 0016-5107/2003/$30.00 + 0 PII:S0016-5107(03)01971-0 558
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Child A cirrhosis (∼10%-20%) and an extremely high mortality (∼70%) for those with Child C cirrhosis.3-6 Only a third of all deaths in patients with cirrhosis are directly attributed to variceal bleeding, an important consideration when the results of clinical trials are analyzed. Unfortunately, many interventional studies have lacked adequate sample size to show a difference in overall mortality or bleedingrelated mortality. The rationale for primary prophylaxis (prevention of first bleeding episode) is based on the extremely high mortality associated with each bleeding episode. The aim of primary prophylaxis is to treat high-risk patients with minimal complications. The treatment should be relatively inexpensive, effective, and should reduce bleeding-associated mortality and improve overall survival. In this review, the risk factors are discussed for first variceal bleeding, the optimal treatment, and the efficacy and cost-effectiveness of primary prophylaxis. PREDICTING FIRST BLEEDING Endoscopic screening It is difficult to show any benefit with primary prophylaxis in unselected patients with cirrhosis because of the notably low bleeding rates in patients without risk factors (discussed below) for bleeding. Although β-blockers are considered effective in preventing first bleeding, studies in unselected patients with cirrhosis have failed to demonstrate any significant benefit with β-blockers. In a study where 319 “unselected” (not selected based on risk factors) patients with chronic liver disease were randomized to either propranolol or placebo, overall frequency of bleeding within the first year was only 3.5% (11/319), with similar rates of bleeding in both groups.8 The findings of this study emphasize the importance of endoscopic screening and staging of esophageal varices before primary prophylaxis inasmuch as such treatment is likely to benefit only those with risk factors. Independent risk factors that reportedly predict the presence of esophageal varices include elevated prothrombin time, low platelet count, splenomegaly and portal vein (PV) diameter greater than 13 mm by US.9-12 Based on these findings, it has been suggested that screening may be restricted to those patients with cirrhosis who also have prothrombin activity less than 70% of normal, a platelet count less than 100 × 109/L, splenomegaly, or a US PV diameter greater than 13 mm.9-11 Despite the results of these studies, screening is recommended for esophageal varices by endoscopy in all patients with cirrhosis because of the high mortality associated with variceal bleeding (cost-effectiveness of VOLUME 58, NO. 4, 2003
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Figure 1. Endoscopic views showing grading of varices by size (F1, F2, F3).
routine endoscopic screening is discussed below). Patients who are unlikely to benefit from prophylactic therapies and those with short life expectancy may be excluded from screening.12 When no varices VOLUME 58, NO. 4, 2003
Figure 2. Endoscopic views showing various red color signs. A, Cherry red spots (arrows). B, Wale markings (arrow). C, Hematocystic spot (arrow); note hematocystic spot protrudes from varix like a bleb.
or small varices without stigmata (low-risk varices) are found on initial screening endoscopy, repeat endoscopy is recommended every 2 years. GASTROINTESTINAL ENDOSCOPY
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Figure 3. Endoscopic view showing large fundal varix (arrow).
Staging of esophageal varices Because only 30% to 40% of patients with varices bleed during the first 2 years after the diagnosis of esophageal varices, it is important to identify the subgroup (those with risk-factors) in which bleeding is most likely to occur and offer the most effective treatment to these patients.2,13 Reproducible criteria for staging of varices are extremely important for many reasons, including accurate description (common terminology), surveillance (reproducibility), treatment, and research (identify high-risk subjects) purposes. However, too many classifications have been described, and many are subjective, with significant intra- and interobserver variations.13-16 Based on our GI training program, a minor modification of the Japanese Research Society for Portal Hypertension staging classification for varices is recommended.14,17 In this classification, esophageal varices are described by the extent (distance from GE junction in cm), size (F0, no varices; F1, small and non-tortuous; F2, tortuous but less than 50% radius of esophagus; F3, very large and tortuous), color (blue or white), and presence of red signs (red wale markings, cherry red spots, hematocystic spots) (Figs. 1 and 2). Gastric varices are described by location (cardia or fundus) and size (small and large) (Fig. 3). Classification should be kept as simple as possible to improve inter- and intra-observer agreement and reproducibility. Risk factors for variceal bleeding Many risk factors have been identified as predictors of first bleeding in patients with esophageal varices. There is a general consensus that patients with advanced cirrhosis (Child B and C), large varices, varices with red signs (cherry red spot, wale marking, hematocystic spot), and those with high 560
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portal pressure (hepatic venous wedge pressure gradient ≥12 mm Hg) are more likely to bleed.13,14,18-20 The risk of bleeding is higher with proximal extension of varices (63% with proximal third vs. 26% distal third alone), larger varices (F1, 15%; F2, 32%; F3, 68%), blue as opposed to white varices (80% vs. 45%), with red spots and wale markings (76% vs. 17% without), and with hematocystic spots (100% vs. 49% when absent).14 Many studies have confirmed that the hepatic venous wedge pressure gradient (HVWPG) is directly related to the risk of bleeding.19-22 It has been shown consistently that patients do not bleed if the HVWPG is less than 12 mm of Hg.19,21 Pharmacologic intervention studies have confirmed that the risk of bleeding is absent or markedly diminished (bleeding risk reduced by 80%) if the HVWPG is reduced below 12 mm Hg or more than 25% below the baseline pressure.1,20 Other risk factors for variceal bleeding include continued ingestion of alcohol and hepatocellular carcinoma.13,23 THERAPEUTIC OPTIONS FOR PRIMARY PROPHYLAXIS Surgery and transjugular intrahepatic portosystemic shunt In the 1960s, before the endoscopic era, a number of randomized, controlled trials were conducted of surgical shunt for primary prophylaxis of variceal bleeding. Although these consistently demonstrated a significant reduction in variceal and gastric mucosal bleeding in patients who had shunts, the mortality and the frequency of chronic hepatic encephalopathy were significantly higher for patients in the shunt groups compared with those in the control groups.24 These poor results and rapid technical advances in endoscopy led to abandonment of shunt surgery for primary prophylaxis. Esophageal transection with devascularization has been tried for primary prophylaxis, but there is no convincing evidence to recommend this type of surgery, which may make future liver transplantation technically more difficult, for primary prophylaxis. The transjugular intrahepatic portosystemic shunt (TIPS) as primary prophylaxis has not been studied, but, based on secondary prevention trials, it is unlikely to be beneficial and may be even be detrimental.25 Based on current evidence, there is no role for surgery or TIPS in primary prophylaxis. Endoscopic sclerotherapy Prophylactic sclerotherapy has been the subject of many small and large randomized, controlled studies. Earlier reports claimed a reduced bleeding rate and improved survival for patients who had sclerotherapy compared with control patients, but VOLUME 58, NO. 4, 2003
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more recent studies have not confirmed these results. A large, multicenter trial (n = 281) in men with moderate to severe alcoholic liver disease was terminated prematurely (after 22.5 months) because of a higher mortality rate in the sclerotherapy arm compared with the sham therapy arm (32.2% vs. 17.4%; p = 0.004).26 It has been argued that inclusion of patients with a lower risk of bleeding in these trials may have masked the benefits in patients who had a higher risk of bleeding. To test this hypothesis, a number of trials were conducted in which only patients with a high risk of bleeding were enrolled. These studies also failed to show a consistent improvement in survival for treated vs. control patients. A meta-analysis performed on 8 controlled studies found that prophylactic sclerotherapy may reduce mortality by 11% (95% CI 4%19%).27 However, the results of this meta-analysis should be interpreted with caution because the difference was only marginal, and the analysis included pooled data from heterogeneous studies.27,28 Currently available evidence suggests that, even in high-risk patients, the benefits from prophylactic sclerotherapy are marginal and that such therapy is not cost effective. Therefore, endoscopic injection sclerotherapy for primary prophylaxis is not recommended. β-Blockers Nonselective β-blockers reduce portal pressure by reducing cardiac output and by reducing portal inflow via antagonism of the β2 receptors on the splanchnic vessels. β-Blockers also may increase portocollateral resistance and, hence, reduce collateral blood flow. Many trials have assessed the efficacy of non-selective β-blockers such as propranolol or nadolol for primary prophylaxis. Although some earlier studies did not find significant differences in bleeding rates in patients treated with propranolol,8,29-32 a majority of studies have demonstrated that non-selective β-blockers reduced (by about 50%) the risk of first bleeding in patients with large varices.30 Meta-analyses on these trials have shown a definite benefit in the treated group with regard to bleeding (about 50% reduction, pool) and mortality (25%-45% reduction).24,31,32 A number of studies have shown that patients with varices are unlikely to bleed if HVWPG is maintained below 12 mm Hg.20 Unfortunately, this can be achieved only in a small group of patients treated with currently available drugs. It is difficult to justify repeated HVWPG measurements, unless a reliable noninvasive method is developed in the future to determine whether a drug therapy is effective. So, for all practices, the end point of treatment VOLUME 58, NO. 4, 2003
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is to achieve a resting heart rate of less than 60 per minute or a 25% reduction from the baseline heart rate. The major disadvantage of the β-blocker is poor tolerance and compliance. Despite these limitations, use of non-selective β-blockers is cost-effective and should be the treatment of choice for primary prophylaxis for patients with advanced liver disease and large gastroesophageal varices. Use of longacting preparations, gradual increases in dosage, and better patient education may improve compliance. The current practice is to continue treatment with a β-blocker indefinitely or until liver transplantation in patients with cirrhosis. Although there are no convincing data to support this strategy, a small study seems to indicate that the risk of bleeding returns to that expected in an untreated population when treatment with propranolol is discontinued.33 It has been suggested that the hemodynamic response to a β-blocker may predict the risk of subsequent bleeding. Merkel et al.34 measured HVWPG before and 1 to 3 months after treatment with either nadolol or nadolol plus isosorbide mononitrate (ISMN) in 49 patients with large varices and no previous variceal bleeding. A good response, defined as a reduction in HVWPG to less than 12 mm of Hg (n = 12) or reduction in HVWPG by more than 20% from baseline (n = 18), was noted in 30 (61%) patients. During a follow-up of 5 years, 7 (7/19) “poor responders” and two (2/30) “good responders” had variceal bleeding. The probability of bleeding at 3 years was 41% in poor responders and 7% in good responders (p = 0.0008). As in many previous studies, none of the 12 patients who had a reduction in HVWPG to less than 12 mm Hg had variceal bleeding. Although this is perhaps the “optimal” treatment strategy and the best predictor of bleeding, the costs related to measurement of the HVWPG may be prohibitive for routine clinical care. In addition, the invasive nature of HVWPG measurement (twice in the same patient) may increase the risks and reduce compliance. An alternative strategy was tested in another study where HVWPG was measured before and 90 minutes after a single dose of 80 mg of propranolol in 33 patients.35 Of the 22 patients who had a 20% or greater reduction in HVWPG, only one had variceal bleeding during a follow-up of 9 to 38 months, and none of the patients who had reduction in HVWPG below 12 mm Hg had bleeding. Although this is a small study, if these results are reproduced in larger studies, a similar strategy could be recommended, provided cost is not an issue, to all patients with large varices before initiating primary prophylaxis with β-blockers. Those in whom HVWPG is not reduced could be offered alternative treatments. GASTROINTESTINAL ENDOSCOPY
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By using hypothetical models, Hicken et al.36 examined the role of the HVWPG in patients with varices at risk for bleeding. These investigators compared β-blocker therapy without measurement of HVWPG to one measurement 4 weeks after the initiation of treatment or two measurements (one before and another 4 weeks after initiation of treatment). Compared with the standard practice (no measurement of HVWPG), the incremental cost with one HVWPG measurement was $108,185 per bleeding episode prevented and $355,200 per death averted. The similar figures for two measurements of HVWPG were, respectively, $202,796 and $719,300. Although these cost estimates may not be a true reflection of actual costs, nevertheless they suggest that HVWPG may be extremely expensive for routine use. Less invasive techniques need to be developed to measure portal pressure for “optimal” and effective primary prophylaxis. Nitrates β-Blockers are not tolerated by about a third of patients with cirrhosis because of side effects, including hypotension and severe fatigue. Of the vasodilators that also have been studied for primary prophylaxis, nitrates have been the most promising. Although the mechanism of action is not clearly understood, it is thought that nitrates may reduce intrahepatic resistance and may reduce portal pressure “by means of reflex splanchnic arterial vasoconstriction in response to vasodilatation in other vascular beds.”37 Isosorbide mononitrate has been studied for primary prophylaxis in patients, and the results have been mixed. In a double blind, randomized, controlled trial, Garcia-Pagan et al.38 compared ISMN (n = 67) and placebo (n = 66) in 113 consecutive patients with cirrhosis and varices who could not tolerate β-blockers or had contraindications to their use. The variceal bleeding rate was similar at 1 and 2 years in both groups. In multivariate analysis, the presence of variceal red sign was the only independent predictor of bleeding (relative risk 3.4; p < 0.01). Based on this study, GarciaPagan et al.38 concluded that ISMN does not have any role for primary prophylaxis. Another study of ISMN vs. placebo found an increased mortality with ISMN in patients above 50 years of age.39 In addition, a tendency for ascites to increase in patients undergoing nitrate monotherapy has been reported. Variceal band ligation (banding) Primary prophylactic sclerotherapy failed to achieve any distinct advantage over “no treatment” because the benefits of sclerotherapy were negated by the local complications of sclerotherapy. Banding, 562
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which has fewer local complications, is a logical alternative to sclerotherapy.40 Many studies have assessed the role of endoscopic variceal ligation for primary prophylaxis.41-46 Sarin et al.41 randomized 35 patients to banding and 33 to no treatment and found a lower bleeding rate in the banding group (3/35, 8.6%) compared with the no treatment group (13/33, 39.4%; p < 0.01) at a mean follow-up of 14 months. Although overall mortality was similar (11.4% vs. 24.2%), there was a trend toward lower bleeding-related mortality in the banding group (2.9% vs. 15.2%; p = 0.08). Another prospective, randomized trial of prophylactic endoscopic variceal ligation (EVL) vs. no treatment found that banding was associated with a significantly decreased risk of variceal hemorrhage and overall mortality.42 In this study, EVL was more effective in patients with Child A cirrhosis as compared with those with decompensated disease (Child B and C). A prospective, randomized trial conducted in Taiwan found that patients with Child-Pugh class B cirrhosis and high-risk varices (F2 or F3 with red color signs) had a significantly lower risk of variceal bleeding than untreated patients.43 In addition, a trend toward reduced mortality and a reduction in blood transfusion requirements were observed in patients undergoing banding. Apart from small sample size, the major concern with these studies was the no-treatment arm because the standard of care for primary prophylaxis during the time periods when these studies were conducted was β-blocker therapy, and one may consider that it is unethical to include a no-treatment arm for such studies. Band ligation has been compared with sclerotherapy or no treatment for primary prophylaxis of variceal bleeding, and no difference in efficacy was found between sclerotherapy and banding.44 As in secondary prevention trials, fewer sessions were needed to eradicate varices by band ligation, but the recurrence rate of varices was higher in patients treated with ligation. Because the “best available” treatment for primary prophylaxis is a non-selective β-blocker, new treatment modalities need to be tested against this standard. Sarin et al.45 addressed this by comparing banding with propranolol in a study (high-risk patients with large varices and red signs) where 44 patients were randomized to propranolol and 45 to endoscopic banding. At a mean follow-up of approximately 14 months, 12 patients in the propranolol group, and 4 in the ligation group had variceal bleeding with an actuarial probability of bleeding of 43% in the propranolol group and 15% in the ligation group (p = 0.04). Three of 4 patients in the banding group experienced first bleeding before varices were obliterated completely. Overall VOLUME 58, NO. 4, 2003
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mortality and bleeding-related mortality were similar in both groups. In this study, 7 of 89 patients had non-cirrhotic portal hypertension. Moreover, the study has been criticized as using an inadequate dose of propranolol (mean 70 mg vs. 123 mg in other studies).32,46 The higher bleeding rate in the propranolol group (43% vs. 22% as compared with that in other trials) may have been because of inadequate treatment with the β-blocker.32 Despite some criticisms and small sample size, this study was important and provocative and stimulated further research into the role of variceal banding for primary prophylaxis. In a 3-arm study, Lui et al.47 compared endoscopic banding (n = 44), propranolol (n = 66), and ISMN (n = 62) in 172 patients with grade II to III varices over a period of 6 years. At a mean follow-up of 20 months, by intention-to-treat analysis, variceal bleeding occurred in 7% in the banding group, 14% in the propranolol group, and 23% in ISMN group. Two-year actuarial risk of first bleeding was, respectively, 6.2%, 19.4%, and 27.5%. Side effects were significantly more frequent in the propranolol (45%) and ISMN (42%) groups as compared with the banding group (2%; p < 0.001), and this resulted in withdrawal of treatment in 30% of patients in the propranolol group and 21% in the ISMN group. When patients were analyzed based on the treatment received, actuarial bleeding rate was significantly different only between banding and ISMN groups (7.5% vs. 33%; log rank test p = 0.03); there was no difference when the banding and propranolol groups were compared.47 A meta-analysis of 601 patients from 5 randomized, controlled trials comparing banding with no treatment confirmed that banding reduced first variceal bleeding (relative risk [RR] 0.36: 95% CI [0.26,0.5]), bleeding related mortality (RR 0.20: 95% CI [0.11,0.39]), and overall mortality (RR 0.55: 95% CI [0.43,0.71]).48 However, when banding was compared with β-blockers in 283 patients from 4 randomized trials, the only benefit for variceal banding was in the reduction of first variceal bleeding (RR 0.48: 95% CI [0.24,0.96]). Bleeding related mortality and overall mortality were similar for banding and propranolol, suggesting that a role for variceal banding may be the treatment of patients who cannot tolerate β-blockers because of side effects or hypotension. If noninvasive, reliable methods for measurement of portal pressure are identified, it will be appropriate to offer banding to patients in whom pharmacotherapy fails to significantly reduce portal pressure (<25% reduction from baseline). Current methods of measuring HVWPG are not applicable or VOLUME 58, NO. 4, 2003
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cost-effective for a majority of patients with large esophageal varices. Combination treatment Sclerotherapy plus β-blocker. Combination treatment with endoscopic sclerotherapy and β-blockers has not been found to have any advantage over βblockers alone for primary porphylaxis. In one study, 86 patients with high intravariceal pressure (>18 mm Hg) were randomized to either propranolol alone (n = 42) or propranolol plus sclerotherapy (n = 44).49 There was a trend toward a higher bleeding rate (23%) in the combination group as compared with those who received only propranolol (14%; p = ns) at a median follow-up of approximately 24 months. There was a significantly higher complication rate in the combination group (52% vs. 19%; p = 0.002), but mortality rates were similar (14% vs. 18%; p = ns). Predictably, this study demonstrated that there is no role for sclerotherapy in combination with β-blockers for primary prophylaxis. β-Blocker plus isosorbide mononitrate. Although β-blockers reduce the risk of bleeding in patients with large varices, a significant number of patients nevertheless experience variceal bleeding while being treated with β-blockers. This is perhaps because of a combination of factors, including poor compliance, intolerance to maximal treatment, and, more importantly, inadequate reduction in portal pressure. Because it is not practical or cost-effective to monitor HVWPG before and after treatment with β-blockers to assess the hemodynamic response, many investigators have studied the effect of a combination of β-blockers and ISMN on bleeding rates and mortality; these studies have produced conflicting results. Merkel et al.50 compared nadolol alone (n = 74) and nadolol plus ISMN (n = 72) in 146 patients with large esophageal varices. Treatment with nadolol was initiated at a dose of 40 mg daily and increased every second day to achieve a 20% to 25% reduction in resting heart rate. In the combination therapy group, treatment with ISMN was started simultaneously with nadolol, and the dose of ISMN was increased from 10 mg twice daily to 20 mg twice daily if patients were able to tolerate the drug. At a median follow-up of 30 months, 11 (11/74) patients in the nadolol alone group and 4 (4/72) in the combination group had experienced a first episode of variceal bleeding (p = 0.03 by Kaplan-Meier analysis). The cumulative risk of bleeding was 18% with nadolol alone and 7.5% with combination therapy. The mortality was not statistically significant different (14/74 vs. 8/72) between the groups, but there was a trend favoring the combination therapy GASTROINTESTINAL ENDOSCOPY
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group. As a follow-up to this study, Merkel et al.51 reported the long-term results (up to 7 years followup) for the same cohort. During the study period, 16 patients in the nadolol alone group and 8 in the combination therapy group had variceal bleeding (p = 0.02) with a cumulative bleeding risk of, respectively, 29% and 12%. However, the mortality remained similar in both groups. In contrast, a multicenter, prospective, double-blind, randomized, controlled trial (n = 349) comparing propranolol plus placebo (n = 174) with propranolol plus ISMN (n = 175) found no significant difference in the risk of first variceal hemorrhage at 1 year (8.3% vs. 5%) and 2 years (10.6% vs. 12.5%).52 In addition, adverse side effects were significantly more frequent (mainly headache) in the combination group. These observations suggest that combination treatment with βblockers plus ISMN is a reasonable option for primary prophylaxis if patients cannot tolerate maximal doses of β-blockers. There is no role for combination treatment with β-blockers and ISMN for routine primary prophylaxis. Other treatments. Other drugs, including spironolactone, have been studied for primary prophylaxis. In one such trial, combination therapy with nadolol plus spironolactone for primary prophylaxis of variceal hemorrhage was not found to have any additive effect.53 COST-EFFECTIVENESS OF SCREENING AND PROPHYLAXIS There is overwhelming evidence to suggest that primary prophylaxis with β-blockers is beneficial in patients with cirrhosis and large varices with stigmata of imminent bleeding. However, screening is not routinely performed in a majority of patients with advanced cirrhosis. One study found that only 46% of patients referred to a tertiary center for liver transplantation had undergone either endoscopy or barium contrast radiography to assess the presence of esophageal varices.54 A major impact is unlikely in terms of a reduction in the occurrence of first bleeding episodes without better adherence to screening and prophylaxis among the community gastroenterologists. Although there are no rigid criteria, it has been suggested that all patients with cirrhosis should have a screening endoscopy. If large varices are found, the patient should be offered prophylactic therapy. If varices are absent, they should have surveillance endoscopy every 2 years. If small varices are present, endoscopy should be repeated every 1 to 2 years based on the severity of liver disease. Many studies have examined the cost-effectiveness of primary prophylaxis for variceal bleeding. By using a Markov model, Teran et al.55 compared 564
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the cost-effectiveness of propranolol, sclerotherapy, and shunt surgery after stratifying patients by risk of bleeding. Although sclerotherapy had no advantage with respect to quality of life, shunt surgery was associated with decreased quality of life. Propranolol was most cost-effective (cost saving $450-$14,600 over a 5-year period) followed by sclerotherapy and shunt surgery. In another study that used Markov modeling, Spiegel et al.56 examined whether it was costeffective to treat all patients with cirrhosis without screening endoscopy. Six different strategies were compared: universal screening followed by βblockers if there are varices (strategy 1); screening, followed by banding (strategy 2); selective screening only in high-risk patients, followed by treatment with β-blockers if varices are present (strategy 3); selective screening, followed by banding (strategy 4); empiric β-blocker therapy for all patients (strategy 5); and no prophylactic therapy (strategy 6). Costs were estimated from a third-party payer perspective and the outcome measure was the cost of first variceal bleeding prevented by the 6 strategies. As expected, strategy 6 was the least expensive, and, in comparison, the cost of strategy 5 was $12,408 per additional variceal bleeding prevented. Strategies 2 and 3 were the most expensive ($175,000 per additional bleeding episode prevented); strategies 4 and 5 were intermediate in terms of cost. Based on this mathematical modeling, Spiegel et al.56 recommended universal β-blocker therapy for all patients with cirrhosis. Another strategy not examined in this study is the use of screening endoscopy in only those patients who do not tolerate β-blockers. Other investigators also have addressed the costeffectiveness of screening and no prophylaxis or prophylaxis with either β-blockers or banding by using Markov models.57,58 Saab et al.57 recommended universal prophylaxis with β-blockers because it was associated with lower costs ($34,100) and higher quality-adjusted life-years (6.5). In contrast, costs and quality adjusted life-years were $36,600 and 4.84 for no prophylaxis, and $37,300 and 5.72 for screening followed by treatment with β-blockers for patients with large varices. In another study, a Markov simulation model was created in two cohorts of patients 50 years of age with compensated or decompensated cirrhosis.58 Four strategies were examined including no screening or prophylaxis; screening, followed by βblocker; screening, followed by banding; and universal prophylaxis with β-blockers. In patients with compensated cirrhosis, screening, followed by β-blocker was cost-effective ($3605 per year of life saved), and, in decompensated cirrhosis, universal β-blocker was cost-effective ($1154 per year of life saved). VOLUME 58, NO. 4, 2003
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Table 1. Variceal bleeding (%) in primary prophylaxis trials VA study, 199126 Pascal et al., 198730 Andreani et al., 199059 Lay et al., 199742 Lo et al., 199943 Sarin et al., 199945 Lui et al., 200247
Number
Control
281 230 126 126 127 89 172
13.8% 61% 31.7% 60% 22.2%
EIS
β-Blocker
EBL
p Value
19% 12.5% 15% 6.2%
<0.05 <0.05 <0.03* 0.0001 0.2 0.04 NS
7.0% 21.4%
26% 4.7%
12% 19.4%
EIS, Endoscopic injection sclerotherapy; EBL, endoscopic band ligation; NS, not significant. *Also when EIS and β-blocker are compared.
Table 2. Bleeding-related mortality in primary prophylaxis trials Lay et al., 199742 Lo et al., 199943 Sarin et al., 199945 Lui et al., 200247
Number
Control
126 127 89 172
16% 11.1%
β-Blocker
EBL
p Value
9% 6.1%
19% 12.5% 7% 2.3%
<0.05 0.15 NS NS
EBL
p Value
28% 25% 11% 25%
0.004 <0.05 NS 0.001 0.2 0.7 NS
Please note that many trials did not report bleeding-related mortality. EIS, Endoscopic injection sclerotherapy; EBL, endoscopic band ligation.
Table 3. Overall mortality (%) in primary prophylaxis trials VA study, 199126 Pascal et al., 198730 Andreani et al., 199059 Lay et al., 199742 Lo et al., 199943 Sarin et al., 199945 Lui et al., 200247
Number
Control
EIS
281 230 126 126 127 89 172
17.4% 49% 44% 58% 36.5%
32.2% 43%
β-Blocker 28% 30%
11% 27.3%
EIS, Endoscopic injection sclerotherapy; EBL, endoscopic band ligation; NS, not significant.
Table 4. Comparison of prophylactic options to “no treatment” Variceal bleeding Bleed-related mortality Overall mortality
EIS
β-Blocker
EBL
+ +/– –
+++ ++ ++
+++* +† +†
EIS, Endoscopic injection sclerotherapy; EBL, endoscopic band ligation; –, negative trend; +/–, conflicting data; +, possible; ++, probable; +++, definite. *Probable reduction in bleeding when compared with β-blockers. †No benefit when compared with β-blockers; when compared with no treatment, there is a positive trend.
The results based on Markov models are highly sensitive to the prevalence of esophageal varices, risk of bleeding, cost of endoscopy, and primary prophylaxis. In the absence of clinical trials, it is believed that it is premature to abandon screening or surveillance endoscopy before initiating prophylactic treatment with a β-blocker because of the high frequency of side effects associated with such therapy and the extremely low risk of bleeding in patients VOLUME 58, NO. 4, 2003
with small varices.8 Moreover, the awareness of the presence of large esophageal varices may improve patient compliance. In addition, alternative treatment (variceal banding) can be offered to the highrisk patients who do not tolerate β-blockers. GASTRIC AND ECTOPIC VARICES The frequency of gastric varices among patients with cirrhosis in published reports ranges from 6% to 16% and the frequency appears to increase after esophageal variceal obliteration. Gastric varices (Fig. 3) usually are seen in association with esophageal varices or rarely in isolation as in splenic vein thrombosis (segmental portal hypertension). Overall, the mortality rate for patients with bleeding gastric varices is greater than 50%. The proportion of patients with bleeding from non-gastroesophageal sites (ectopic varies) ranges from 1.6% to 5% in large series. The common ectopic sites, usually seen in association with esophageal varices, are duodenum, colon, anorectum, and enterostomy. Rarely, ectopic varices may be localized, especially in the colon, and GASTROINTESTINAL ENDOSCOPY
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result from superior or inferior vein thrombosis, tumor infiltration, adhesions, or congenital malformation. Because there are no controlled data for primary prophylaxis of gastric or ectopic varices, it is difficult to recommend any specific strategy. However, based on data from studies of esophageal varices, it is recommended that all patients with large gastric or ectopic varices be treated with nonselective β-blockers. RECOMMENDATIONS Based on the results of large randomized trials and meta-analysis of many other trials, it is clear that non-selective β-blocker therapy remains the treatment of choice for primary prophylaxis in patients with cirrhosis and large varices or those with risk factors for bleeding (Tables 1 through 4). Endoscopic sclerotherapy, the surgical shunt, and TIPS have no role in primary prophylaxis. Endoscopic band ligation is an option for those with risk factors for bleeding who do not tolerate or are poorly responsive to β-blockers. Endoscopic band ligation must be compared with β-blockers in a rigorous fashion, in large randomized controlled trials in high-risk patients (advanced liver disease [Child B and C], large varices with red signs and HVWPG ≥ 12 mm Hg), before it can be recommended for routine primary prophylaxis.
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