Primary Prophylaxis o f Var i c e a l B l e e d i n g Jawad A. Ilyas,
a MD, MS ,
Fasiha Kanwal,
MD, MSHS
a,b,
*
KEYWORDS Portal hypertension Cirrhosis Hemorrhage KEY POINTS Both nonselective beta-blockers and endoscopic band ligation form the cornerstone of prophylactic therapy for varices. In the absence of accurate noninvasive markers of hepatic venous pressure gradient, variceal size, high-risk stigmata of variceal bleeding, and the stage of underlying liver disease dictate the choice of prophylactic therapy. The major challenge is to screen patients in a timely manner and institute a form of therapy that has the highest chance of success in terms of both compliance and effectiveness. Without systematic efforts targeted at reducing these gaps in health care delivery, recent advances in the efficacy of primary prophylaxis may not translate into effective varices care at the bedside.
BACKGROUND
Cirrhosis is a common and burdensome condition. It is responsible for approximately 1 million days of work lost and 32,000 annual deaths in the United States, and thus has a substantial effect on productivity and survival.1 The high mortality in cirrhosis is attributable, in part, to the development of varices and subsequent hemorrhage. Despite substantial advances in medical management of variceal bleeding, each episode of active variceal bleeding is fatal in 30% of cases.2,3 Development of varices is a direct consequence of portal hypertension and reflects abnormal changes in both portal resistance and flow. Portal hypertension is commonly
Funding: This work is partly funded by the Houston Veterans Affairs Health Services Research and Development Center of Excellence HFP90-020. Disclosures: No conflicts of interest exist. Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. a Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, 6620 Main St., Houston, TX 77030, USA; b Center for Innovations in Quality, Effectiveness, and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA * Corresponding author. 2002 Holcombe Boulevard, Houston, TX 77030. E-mail address: [email protected] Gastroenterol Clin N Am 43 (2014) 783–794 http://dx.doi.org/10.1016/j.gtc.2014.08.008 0889-8553/14/$ – see front matter Published by Elsevier Inc.
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measured using the hepatic venous pressure gradient (HVPG), which is the difference between wedged and free hepatic venous pressure. Varices generally develop when the hepatic venous pressure gradient (HVPG) exceeds 5 to 10 mm Hg as a compensatory mechanism to decompress the portal system; variceal bleeding occurs when the HVPG exceeds 12 mm Hg.4 Esophageal varices are present in approximately 40% of patients with cirrhosis and as many as 60% of patients with cirrhosis and ascites. In patients without varices, new varices develop at the rate of 5% to 8% per year.4 In patients with small varices at the time of initial endoscopic screening, progression to large varices occurs at a rate of 10% to 15% per year.4 One of the largest prospective studies that followed the natural history of variceal progression enrolled 206 patients with cirrhosis. Of these, 113 patients did not have varices at baseline and 93 patients had small varices. After an average follow-up of 37 months, 28% of patients (without varices) developed varices, whereas 31% of patients (with small varices) experienced progression in variceal size. The strongest predictors of progression were the Child-Pugh score at baseline, presence of stigmata of bleeding (red wale markings), baseline platelet count, and alcohol-related liver disease. The risk of variceal bleeding was significantly higher in the patients who had small varices at baseline compared with those who did not have varices (12% vs 2% at 2 years).5 A more recent study using data from the HALT-C trial found a similar rate of de novo varices development and progression (26.2% and 35.3%, respectively) during a median follow-up of 48 months.6 Hispanic race and lower baseline albumin level were both strongly associated with the risk of varices development. Several clinical and physiologic factors are associated with the risk of first variceal hemorrhage. These include variceal location, size, appearance of the varices, underlying HVPG, and the degree of hepatic dysfunction.1 Of these, HVPG is the most important and a potentially modifiable risk factor. HVPG serves as an accurate surrogate marker of variceal development, as well as the risk of variceal bleeding. In a systematic review of prospective studies, a reduction in the HVPG to 12 mm Hg or lower, or a reduction of 20% or more from baseline significantly reduced the risk of first variceal bleeding (pooled odds ratio 0.21, 95% confidence interval [CI] 0.05–0.80).7 Therapies aimed at reducing the HVPG below this threshold can affect the progression of varices and reduce the risk of first variceal bleeding. PRIMARY PROPHYLAXIS
Prophylaxis is derived from the Greek word prophulaktikos, meaning “prevention.” Primary prophylaxis entails prevention of the first episode of variceal bleeding after diagnosis of varices. However, this concept can be expanded to (1) prevention of formation of varices (preprimary prophylaxis), (2) prevention of progression of variceal size (early-primary prophylaxis), and (3) prevention of the first episode of bleeding (primary prophylaxis). SCREENING FOR VARICES
Although the point prevalence of varices in patients with cirrhosis is relatively high, most patients with cirrhosis may not have varices. As a result, guidelines recommend screening for the presence of varices in patients with cirrhosis8–10 and initiating treatment targeted at primary prophylaxis for patients identified to have high-risk varices. Esophagogastroduodenoscopy (EGD) is considered the gold standard for the diagnosis of varices. However, EGD is relatively expensive and requires specialized expertise to perform. Moreover, as mentioned previously, most patients undergoing EGD either do not have varices or have varices that do not require prophylactic treatment
Primary Prophylaxis of Variceal Bleeding
(see later in this article), thus substantially increasing the cost associated with screening with EGD. The alternative strategies to universal screening with EGD are empiric beta-blocker therapy (ie, without prior screening) or screening with less expensive and less invasive diagnostic tools. A randomized controlled trial (RCT) showed that empiric, nonselective betablockers are ineffective in preventing varices in patients with cirrhosis and portal hypertension and are associated with an increased number of adverse events.4 However, only a small proportion of patients included in this trial had Child class B cirrhosis (10%) and none had Child class C cirrhosis. Therefore, it is unclear if the strategy of empiric beta-blockers would be effective in patients with a high probability of underlying varices, such as those with decompensated cirrhosis. Nonetheless, in light of these data, beta-blockers cannot be recommended empirically in patients without documented varices. Given its noninvasive nature and relative ease of administration, video capsule endoscopy (VCE) may play a role in screening for varices. However, a multicenter trial designed to assess the diagnostic performance of VCE in comparison with EGD found that EGD was superior to VCE in identifying patients with varices.11 Overall, EGD identified esophageal varices in 180 (62.5%) of 292 patients. VCE identified esophageal varices in 152 of these patients (difference 15.6%; 95% CI 11.4–19.8 in favor of EGD). VCE had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 84%, 88%, 92%, and 77%, respectively, for identifying patients with esophageal varices compared with the gold standard of EGD. In differentiating between medium/large varices requiring treatment and absent/small varices requiring surveillance, the sensitivity, specificity, PPV, and NPV for VCE were 78%, 96%, 87%, and 92%, respectively. In another study, 120 patients with both cirrhotic and noncirrhotic portal hypertension underwent VCE followed by EGD at the time of screening.12 The sensitivity, specificity, NPV, and PPV of VCE for diagnosis of varices was 77%, 86%, 69%, and 90%, respectively. The interobserver concordance was generally poor (diagnosis of varices 79.4%; grading of varices 66.4%; indication for prophylaxis 89.7%) in this study. Several studies have evaluated the predictive accuracy of multidetector computerized tomography (CT) esophagography to detect and grade esophageal varices.13,14 This procedure requires esophageal insufflation via a transnasal catheter and thus is minimally invasive. The study by Kim and colleagues13 included 90 patients with cirrhosis (65 men, mean age 54.8 years); 30 patients had endoscopic evidence of large esophageal varices. There was close correlation and substantial agreement between endoscopic and CT esophagographic grades (k 5 0.831). CT esophagography performed well in differentiating between low- and high-risk varices with the area under the receiver operating characteristic curve (AUROC) of 0.93 to 0.95. Perri and colleagues14 prospectively evaluated 102 patients who underwent both CT and endoscopic screening for gastroesophageal varices. The multidetector CT scan with intravenous contrast was highly sensitive in identifying large esophageal varices (sensitivity 5 90% compared with EGD). However, the specificity was limited (specificity 5 50%). Patients preferred CT scan over EGD in both studies. The use of the platelet count/spleen diameter ratio has also been proposed as a noninvasive tool to predict the presence of varices. This ratio is calculated by dividing the platelet count (number/mm3) by the maximum spleen diameter (in mm) as estimated by abdominal ultrasound. In using a cutoff value of 909, Giannini and colleagues15 found that the PPV and NPV of platelet count/spleen diameter ratio for the presence of varices were 96% and 100%, respectively, the AUROC was 0.98.
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However, restricting the analysis to patients with compensated cirrhosis (the population in which this index may have the highest clinical utility), the PPV dropped to 74%. In an independent multicenter cohort study, the PPV and NPV of the platelet count/ spleen diameter ratio were 76.6% and 87.0%, respectively.16 Neither study demonstrated this index to be a reliable predictor of varices. In summary Several noninvasive and minimally invasive means of identifying patients with varices have been tested in the recent years. However, the predictive accuracy of these markers is still unsatisfactory. Until large prospective studies are conducted, EGD screening remains the principal means of assessing for the presence of varices. More studies are needed to ascertain whether the simplicity and improved patient tolerance of VCE or CT esophagography over EGD can increase the rate of adherence to screening programs. For the time being, these modalities may be used in selected patients who are unwilling or unable to undergo EGD. PRE-PRIMARY PROPHYLAXIS
Currently, the most effective strategy in preventing development of varices is effective management of the underlying liver disease. For example, in a prospective study by Bruno and colleagues,17 only one of the patients with chronic hepatitis C cirrhosis who achieved a sustained virological response (SVR) developed varices during a 12-year follow-up period. In contrast, 32% of untreated patients and 39% of patients who were treated but did not achieve SVR developed varices. Thus, the most effective strategy in preventing development of varices in patients with cirrhosis is effective management of the underlying liver disease PRIMARY PROPHYLAXIS IN PATIENTS WITH SMALL VARICES
There has been one meta-analysis evaluating the role of nonselective beta-blockers in the prevention of a first variceal bleed in patients with small varices.18 Since the publication of this meta-analysis, 2 additional trials have evaluated this same question.19,20 Combining these data, the incidence of first variceal bleeding was 2.5% in the treatment group compared with 7.4% in the control group over 2-year follow-up (a statistically nonsignificant difference). Two of these studies investigated the efficacy of beta-blockers in preventing the enlargement of small varices with contradictory results. In the first study,19 2-year proportion of patients with large varices was higher in the propranolol group compared with the placebo group (31% vs 14%). However, more patients in the propranolol group had varices at baseline compared with the placebo group (52% vs 30%). Moreover, one-third of the patients in this study were lost to follow-up. In the second larger randomized trial,20 patients with small varices treated with nadolol had a significantly slower progression to larger varices (11% at 3 years) than patients who received placebo (37% at 3 years). In this study, patients received beta-blockers within 3 (2.5) months of varices diagnosis. Collectively, these data suggest that the risk of variceal bleeding is low in patients with small varices, and that beta-blockers do not reduce this risk further, at least in the intermediate term. Beta-blockers may slow the progression of varices, but this effect needs to be confirmed in future studies. Patients with small varices and no high-risk features should undergo routine surveillance to monitor for development of variceal enlargement and high-risk features. Of note, none of these aforementioned
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studies presented data stratified on the basis of the severity of underlying liver disease or presence versus absence of high-risk endoscopic features to inform decisions based on these factors. Given the available data, the American Association for Study of Liver Diseases (AASLD) and the Baveno V guidelines provide the following recommendations for patients who have small varices. In patients with cirrhosis and small varices that have not bled and have no criteria for increased risk of bleeding, beta-blockers can be used, although their longterm benefit has not been established In patients with cirrhosis and small varices that have not bled but have criteria for increased risk of bleeding (child class B or C or presence of red wale markings on varices), beta-blockers should be used for the prevention of first variceal hemorrhage. PRIMARY PROPHYLAXIS IN PATIENTS WITH LARGE VARICES
The 2 most common treatment modalities used for primary prophylaxis of variceal bleeding in patients with large varices include the use of nonselective beta-blockers or endoscopic band ligation. Nonselective Beta-Blockers
A meta-analysis of 11 randomized trials that included 1189 patients with medium to large varices evaluated the efficacy of beta-blockers (propranolol, nadolol) versus placebo in the prevention of first variceal bleed. The risk of first variceal bleed in patients with medium or large varices was significantly reduced by beta-blockers (30% vs 14%, number needed to treat 5 10) during 2 years of follow-up.18 The disadvantages of nonselective beta-blockers include relatively common contraindications and side effects (fatigue and shortness of breath) that preclude treatment or require discontinuation in 15% to 20% of patients. These data support the use of beta-blockers for the primary prophylaxis of variceal bleeding in patients with large varices. Both the AASLD and Baveno V guidelines agree with using beta-blockers in this subgroup and provide the following recommendations. In patients with large varices that have not bled, nonselective beta-blockers may be recommended for the prevention of first variceal hemorrhage. This applies to patients with or without any high-risk features (Childs B or C and/or red wale markings on varices). Choice of Nonselective Beta-Blocker
Both nadolol and propranolol have been recommended as agents of choice in primary prevention of variceal bleeding. Both drugs result in unopposed alpha adrenergic– mediated splanchnic vasoconstriction and reduction of portal inflow (as a result of reduction in cardiac output).21 Dose titration can be achieved by monitoring patients’ resting heart rate or their HVPG. When the heart rate is used, beta-blockers are uptitrated to achieve a 20% reduction from baseline or achieve a target heart rate of 55 to 60 beats per minute. In some European centers, HVPG is routinely measured to guide titration of therapy and is recommended in the Baveno V guidelines. A reduction of HVPG to 12 mm Hg or lower or to 20% or less of the baseline HVPG value reduces the risk of variceal bleeding.7 However, HVPG monitoring is invasive and is not routinely practiced in the United States outside of clinical trials.
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Carvedilol, a beta-blocker with alpha adrenergic activity also has been studied as a pharmacologic agent for primary prophylaxis.10,22,23 Multiple studies examining the effects of carvedilol on portal hypertension have shown a dose-related decrease in HVPG (20% from baseline), which is higher than seen with propranolol.24,25 A recent meta-analysis that included a total of 175 patients from 5 studies compared the hemodynamic effects of carvedilol with propranolol.26 Carvedilol resulted in a greater reduction in HVPG both in the short term (mean weighted difference in HVPG –7.70 mm Hg [95% CI 12.40 to 3.00] at 60–90 minutes after drug administration) and the long term (mean weighted difference in HVPG –6.81 mm Hg [95% CI 11.35 to 2.26] after 7–90 days of therapy) (Fig. 1). The risk of failure to achieve a hemodynamic response with carvedilol was lower than that with propranolol (relative risk [RR] 0.66, 95% CI 0.44–1.00). Adverse events were more frequent and serious with carvedilol; however, this difference failed to reach statistical significance. A recent trial examined 104 patients with esophageal varices (mean HVPG 20.4 mm Hg) who underwent HVPG monitoring before and during propranolol treatment (80–160 mg per day).25 Patients without a hemodynamic response to propranolol (defined as lack of a reduction in HVPG 20% compared with baseline or an absolute value 12 mm Hg on repeat HVPG) or those who did not tolerate propranolol (n 5 10) were treated with carvedilol (6.25–50 mg per day). Of the 67 patients who met these criteria for propranolol nonresponse, 56% achieved a hemodynamic response with carvedilol. The decrease in HVPG was significantly greater with carvedilol than with propranolol (–19% 10% vs –12% 11%, P10 mm Hg). SUMMARY
In summary, both nonselective beta-blockers and endoscopic band ligation form the cornerstone of prophylactic therapy for varices. In the absence of accurate noninvasive markers of HVPG, variceal size, high-risk stigmata of variceal bleeding, and the stage of underlying liver disease dictate the choice of prophylactic therapy. The major challenge is to screen patients in a timely manner and institute a form of therapy that has the highest chance of success in terms of both compliance and effectiveness. Specifically, in a retrospective cohort study of 550 patients with cirrhosis who sought care at 3 Department of Veterans Affairs facilities between 2000 and 2007, we found that only 24.3% (95% CI 20.2%–28.3%) of patients had an upper endoscopy during the first year after their cirrhosis diagnosis and 60% (95% CI 50.2%–70.7%) of patients with varices received any form of primary prophylaxis of variceal bleeding.36 Without systematic efforts targeted at reducing these gaps in health care delivery, recent advances in the efficacy of primary prophylaxis may not translate into effective varices care at the bedside. REFERENCES
1. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010;362:823–32. 2. Smith JL, Graham DY. Variceal hemorrhage: a critical evaluation of survival analysis. Gastroenterology 1982;82:968–73. 3. Graham DY, Smith JL. The course of patients after variceal hemorrhage. Gastroenterology 1981;80:800–9. 4. Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005;353: 2254–61.
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5. Merli M, Nicolini G, Angeloni S, et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003;38:266–72. 6. Fontana RJ, Sanyal AJ, Ghany MG, et al. Factors that determine the development and progression of gastroesophageal varices in patients with chronic hepatitis C. Gastroenterology 2010;138:2321–31, 2331. 7. D’Amico G, Garcia-Pagan JC, Luca A, et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006;131:1611–24. 8. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922–38. 9. Sarin SK, Kumar A, Angus PW, et al. Primary prophylaxis of gastroesophageal variceal bleeding: consensus recommendations of the Asian Pacific Association for the Study of the Liver. Hepatol Int 2008;2:429–39. 10. de FR. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010;53:762–8. 11. de FR, Eisen GM, Laine L, et al. Esophageal capsule endoscopy for screening and surveillance of esophageal varices in patients with portal hypertension. Hepatology 2008;47:1595–603. 12. Lapalus MG, Ben SE, Gaudric M, et al. Esophageal capsule endoscopy vs. EGD for the evaluation of portal hypertension: a French prospective multicenter comparative study. Am J Gastroenterol 2009;104:1112–8. 13. Kim SH, Kim YJ, Lee JM, et al. Esophageal varices in patients with cirrhosis: multidetector CT esophagography—comparison with endoscopy. Radiology 2007; 242:759–68. 14. Perri RE, Chiorean MV, Fidler JL, et al. A prospective evaluation of computerized tomographic (CT) scanning as a screening modality for esophageal varices. Hepatology 2008;47:1587–94. 15. Giannini E, Botta F, Borro P, et al. Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis. Gut 2003;52:1200–5. 16. Giannini EG, Zaman A, Kreil A, et al. Platelet count/spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results of a multicenter, prospective, validation study. Am J Gastroenterol 2006;101:2511–9. 17. Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. Hepatology 2010;51:2069–76. 18. D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 1999;19:475–505. 19. Cales P, Oberti F, Payen JL, et al. Lack of effect of propranolol in the prevention of large oesophageal varices in patients with cirrhosis: a randomized trial. FrenchSpeaking Club for the Study of Portal Hypertension. Eur J Gastroenterol Hepatol 1999;11:741–5. 20. Merkel C, Marin R, Angeli P, et al. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology 2004;127:476–84. 21. Villanueva C, Aracil C, Colomo A, et al. Acute hemodynamic response to betablockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding. Gastroenterology 2009;137:119–28.
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22. Tripathi D, Ferguson JW, Kochar N, et al. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Hepatology 2009;50:825–33. 23. Shah HA, Azam Z, Rauf J, et al. Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: a multicentre randomized controlled trial. J Hepatol 2014;60(4):757–64. 24. Banares R, Moitinho E, Piqueras B, et al. Carvedilol, a new nonselective beta-blocker with intrinsic anti-Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis. Hepatology 1999; 30:79–83. 25. Reiberger T, Ulbrich G, Ferlitsch A, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013;62:1634–41. 26. Sinagra E, Perricone G, D’Amico M, et al. Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis. Aliment Pharmacol Ther 2014;39(6):557–68. 27. Imperiale TF, Chalasani N. A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding. Hepatology 2001;33:802–7. 28. Khuroo MS, Khuroo NS, Farahat KL, et al. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding. Aliment Pharmacol Ther 2005;21:347–61. 29. Gluud LL, Klingenberg S, Nikolova D, et al. Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices: systematic review of randomized trials. Am J Gastroenterol 2007;102:2842–8. 30. Li L, Yu C, Li Y. Endoscopic band ligation versus pharmacological therapy for variceal bleeding in cirrhosis: a meta-analysis. Can J Gastroenterol 2011;25:147–55. 31. Gluud LL, Krag A. Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst Rev 2012;(8):CD004544. 32. Imperiale TF, Klein RW, Chalasani N. Cost-effectiveness analysis of variceal ligation vs. beta-blockers for primary prevention of variceal bleeding. Hepatology 2007;45:870–8. 33. Avgerinos A, Armonis A, Manolakopoulos S, 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. 34. Sarin SK, Lahoti D, Saxena SP, et al. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology 1992;16:1343–9. 35. Mishra SR, Sharma BC, Kumar A, et al. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and beta-blockers: a randomized controlled trial. J Hepatol 2011;54:1161–7. 36. Buchanan P, Kramer J, El-Serag H, et al. The quality of care provided to patients with varices. Am J Gastroenterol 2014;109(7):934–40.
a MD, MS ,
Fasiha Kanwal,
MD, MSHS
a,b,
*
KEYWORDS Portal hypertension Cirrhosis Hemorrhage KEY POINTS Both nonselective beta-blockers and endoscopic band ligation form the cornerstone of prophylactic therapy for varices. In the absence of accurate noninvasive markers of hepatic venous pressure gradient, variceal size, high-risk stigmata of variceal bleeding, and the stage of underlying liver disease dictate the choice of prophylactic therapy. The major challenge is to screen patients in a timely manner and institute a form of therapy that has the highest chance of success in terms of both compliance and effectiveness. Without systematic efforts targeted at reducing these gaps in health care delivery, recent advances in the efficacy of primary prophylaxis may not translate into effective varices care at the bedside.
BACKGROUND
Cirrhosis is a common and burdensome condition. It is responsible for approximately 1 million days of work lost and 32,000 annual deaths in the United States, and thus has a substantial effect on productivity and survival.1 The high mortality in cirrhosis is attributable, in part, to the development of varices and subsequent hemorrhage. Despite substantial advances in medical management of variceal bleeding, each episode of active variceal bleeding is fatal in 30% of cases.2,3 Development of varices is a direct consequence of portal hypertension and reflects abnormal changes in both portal resistance and flow. Portal hypertension is commonly
Funding: This work is partly funded by the Houston Veterans Affairs Health Services Research and Development Center of Excellence HFP90-020. Disclosures: No conflicts of interest exist. Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. a Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, 6620 Main St., Houston, TX 77030, USA; b Center for Innovations in Quality, Effectiveness, and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA * Corresponding author. 2002 Holcombe Boulevard, Houston, TX 77030. E-mail address: [email protected] Gastroenterol Clin N Am 43 (2014) 783–794 http://dx.doi.org/10.1016/j.gtc.2014.08.008 0889-8553/14/$ – see front matter Published by Elsevier Inc.
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measured using the hepatic venous pressure gradient (HVPG), which is the difference between wedged and free hepatic venous pressure. Varices generally develop when the hepatic venous pressure gradient (HVPG) exceeds 5 to 10 mm Hg as a compensatory mechanism to decompress the portal system; variceal bleeding occurs when the HVPG exceeds 12 mm Hg.4 Esophageal varices are present in approximately 40% of patients with cirrhosis and as many as 60% of patients with cirrhosis and ascites. In patients without varices, new varices develop at the rate of 5% to 8% per year.4 In patients with small varices at the time of initial endoscopic screening, progression to large varices occurs at a rate of 10% to 15% per year.4 One of the largest prospective studies that followed the natural history of variceal progression enrolled 206 patients with cirrhosis. Of these, 113 patients did not have varices at baseline and 93 patients had small varices. After an average follow-up of 37 months, 28% of patients (without varices) developed varices, whereas 31% of patients (with small varices) experienced progression in variceal size. The strongest predictors of progression were the Child-Pugh score at baseline, presence of stigmata of bleeding (red wale markings), baseline platelet count, and alcohol-related liver disease. The risk of variceal bleeding was significantly higher in the patients who had small varices at baseline compared with those who did not have varices (12% vs 2% at 2 years).5 A more recent study using data from the HALT-C trial found a similar rate of de novo varices development and progression (26.2% and 35.3%, respectively) during a median follow-up of 48 months.6 Hispanic race and lower baseline albumin level were both strongly associated with the risk of varices development. Several clinical and physiologic factors are associated with the risk of first variceal hemorrhage. These include variceal location, size, appearance of the varices, underlying HVPG, and the degree of hepatic dysfunction.1 Of these, HVPG is the most important and a potentially modifiable risk factor. HVPG serves as an accurate surrogate marker of variceal development, as well as the risk of variceal bleeding. In a systematic review of prospective studies, a reduction in the HVPG to 12 mm Hg or lower, or a reduction of 20% or more from baseline significantly reduced the risk of first variceal bleeding (pooled odds ratio 0.21, 95% confidence interval [CI] 0.05–0.80).7 Therapies aimed at reducing the HVPG below this threshold can affect the progression of varices and reduce the risk of first variceal bleeding. PRIMARY PROPHYLAXIS
Prophylaxis is derived from the Greek word prophulaktikos, meaning “prevention.” Primary prophylaxis entails prevention of the first episode of variceal bleeding after diagnosis of varices. However, this concept can be expanded to (1) prevention of formation of varices (preprimary prophylaxis), (2) prevention of progression of variceal size (early-primary prophylaxis), and (3) prevention of the first episode of bleeding (primary prophylaxis). SCREENING FOR VARICES
Although the point prevalence of varices in patients with cirrhosis is relatively high, most patients with cirrhosis may not have varices. As a result, guidelines recommend screening for the presence of varices in patients with cirrhosis8–10 and initiating treatment targeted at primary prophylaxis for patients identified to have high-risk varices. Esophagogastroduodenoscopy (EGD) is considered the gold standard for the diagnosis of varices. However, EGD is relatively expensive and requires specialized expertise to perform. Moreover, as mentioned previously, most patients undergoing EGD either do not have varices or have varices that do not require prophylactic treatment
Primary Prophylaxis of Variceal Bleeding
(see later in this article), thus substantially increasing the cost associated with screening with EGD. The alternative strategies to universal screening with EGD are empiric beta-blocker therapy (ie, without prior screening) or screening with less expensive and less invasive diagnostic tools. A randomized controlled trial (RCT) showed that empiric, nonselective betablockers are ineffective in preventing varices in patients with cirrhosis and portal hypertension and are associated with an increased number of adverse events.4 However, only a small proportion of patients included in this trial had Child class B cirrhosis (10%) and none had Child class C cirrhosis. Therefore, it is unclear if the strategy of empiric beta-blockers would be effective in patients with a high probability of underlying varices, such as those with decompensated cirrhosis. Nonetheless, in light of these data, beta-blockers cannot be recommended empirically in patients without documented varices. Given its noninvasive nature and relative ease of administration, video capsule endoscopy (VCE) may play a role in screening for varices. However, a multicenter trial designed to assess the diagnostic performance of VCE in comparison with EGD found that EGD was superior to VCE in identifying patients with varices.11 Overall, EGD identified esophageal varices in 180 (62.5%) of 292 patients. VCE identified esophageal varices in 152 of these patients (difference 15.6%; 95% CI 11.4–19.8 in favor of EGD). VCE had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 84%, 88%, 92%, and 77%, respectively, for identifying patients with esophageal varices compared with the gold standard of EGD. In differentiating between medium/large varices requiring treatment and absent/small varices requiring surveillance, the sensitivity, specificity, PPV, and NPV for VCE were 78%, 96%, 87%, and 92%, respectively. In another study, 120 patients with both cirrhotic and noncirrhotic portal hypertension underwent VCE followed by EGD at the time of screening.12 The sensitivity, specificity, NPV, and PPV of VCE for diagnosis of varices was 77%, 86%, 69%, and 90%, respectively. The interobserver concordance was generally poor (diagnosis of varices 79.4%; grading of varices 66.4%; indication for prophylaxis 89.7%) in this study. Several studies have evaluated the predictive accuracy of multidetector computerized tomography (CT) esophagography to detect and grade esophageal varices.13,14 This procedure requires esophageal insufflation via a transnasal catheter and thus is minimally invasive. The study by Kim and colleagues13 included 90 patients with cirrhosis (65 men, mean age 54.8 years); 30 patients had endoscopic evidence of large esophageal varices. There was close correlation and substantial agreement between endoscopic and CT esophagographic grades (k 5 0.831). CT esophagography performed well in differentiating between low- and high-risk varices with the area under the receiver operating characteristic curve (AUROC) of 0.93 to 0.95. Perri and colleagues14 prospectively evaluated 102 patients who underwent both CT and endoscopic screening for gastroesophageal varices. The multidetector CT scan with intravenous contrast was highly sensitive in identifying large esophageal varices (sensitivity 5 90% compared with EGD). However, the specificity was limited (specificity 5 50%). Patients preferred CT scan over EGD in both studies. The use of the platelet count/spleen diameter ratio has also been proposed as a noninvasive tool to predict the presence of varices. This ratio is calculated by dividing the platelet count (number/mm3) by the maximum spleen diameter (in mm) as estimated by abdominal ultrasound. In using a cutoff value of 909, Giannini and colleagues15 found that the PPV and NPV of platelet count/spleen diameter ratio for the presence of varices were 96% and 100%, respectively, the AUROC was 0.98.
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However, restricting the analysis to patients with compensated cirrhosis (the population in which this index may have the highest clinical utility), the PPV dropped to 74%. In an independent multicenter cohort study, the PPV and NPV of the platelet count/ spleen diameter ratio were 76.6% and 87.0%, respectively.16 Neither study demonstrated this index to be a reliable predictor of varices. In summary Several noninvasive and minimally invasive means of identifying patients with varices have been tested in the recent years. However, the predictive accuracy of these markers is still unsatisfactory. Until large prospective studies are conducted, EGD screening remains the principal means of assessing for the presence of varices. More studies are needed to ascertain whether the simplicity and improved patient tolerance of VCE or CT esophagography over EGD can increase the rate of adherence to screening programs. For the time being, these modalities may be used in selected patients who are unwilling or unable to undergo EGD. PRE-PRIMARY PROPHYLAXIS
Currently, the most effective strategy in preventing development of varices is effective management of the underlying liver disease. For example, in a prospective study by Bruno and colleagues,17 only one of the patients with chronic hepatitis C cirrhosis who achieved a sustained virological response (SVR) developed varices during a 12-year follow-up period. In contrast, 32% of untreated patients and 39% of patients who were treated but did not achieve SVR developed varices. Thus, the most effective strategy in preventing development of varices in patients with cirrhosis is effective management of the underlying liver disease PRIMARY PROPHYLAXIS IN PATIENTS WITH SMALL VARICES
There has been one meta-analysis evaluating the role of nonselective beta-blockers in the prevention of a first variceal bleed in patients with small varices.18 Since the publication of this meta-analysis, 2 additional trials have evaluated this same question.19,20 Combining these data, the incidence of first variceal bleeding was 2.5% in the treatment group compared with 7.4% in the control group over 2-year follow-up (a statistically nonsignificant difference). Two of these studies investigated the efficacy of beta-blockers in preventing the enlargement of small varices with contradictory results. In the first study,19 2-year proportion of patients with large varices was higher in the propranolol group compared with the placebo group (31% vs 14%). However, more patients in the propranolol group had varices at baseline compared with the placebo group (52% vs 30%). Moreover, one-third of the patients in this study were lost to follow-up. In the second larger randomized trial,20 patients with small varices treated with nadolol had a significantly slower progression to larger varices (11% at 3 years) than patients who received placebo (37% at 3 years). In this study, patients received beta-blockers within 3 (2.5) months of varices diagnosis. Collectively, these data suggest that the risk of variceal bleeding is low in patients with small varices, and that beta-blockers do not reduce this risk further, at least in the intermediate term. Beta-blockers may slow the progression of varices, but this effect needs to be confirmed in future studies. Patients with small varices and no high-risk features should undergo routine surveillance to monitor for development of variceal enlargement and high-risk features. Of note, none of these aforementioned
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studies presented data stratified on the basis of the severity of underlying liver disease or presence versus absence of high-risk endoscopic features to inform decisions based on these factors. Given the available data, the American Association for Study of Liver Diseases (AASLD) and the Baveno V guidelines provide the following recommendations for patients who have small varices. In patients with cirrhosis and small varices that have not bled and have no criteria for increased risk of bleeding, beta-blockers can be used, although their longterm benefit has not been established In patients with cirrhosis and small varices that have not bled but have criteria for increased risk of bleeding (child class B or C or presence of red wale markings on varices), beta-blockers should be used for the prevention of first variceal hemorrhage. PRIMARY PROPHYLAXIS IN PATIENTS WITH LARGE VARICES
The 2 most common treatment modalities used for primary prophylaxis of variceal bleeding in patients with large varices include the use of nonselective beta-blockers or endoscopic band ligation. Nonselective Beta-Blockers
A meta-analysis of 11 randomized trials that included 1189 patients with medium to large varices evaluated the efficacy of beta-blockers (propranolol, nadolol) versus placebo in the prevention of first variceal bleed. The risk of first variceal bleed in patients with medium or large varices was significantly reduced by beta-blockers (30% vs 14%, number needed to treat 5 10) during 2 years of follow-up.18 The disadvantages of nonselective beta-blockers include relatively common contraindications and side effects (fatigue and shortness of breath) that preclude treatment or require discontinuation in 15% to 20% of patients. These data support the use of beta-blockers for the primary prophylaxis of variceal bleeding in patients with large varices. Both the AASLD and Baveno V guidelines agree with using beta-blockers in this subgroup and provide the following recommendations. In patients with large varices that have not bled, nonselective beta-blockers may be recommended for the prevention of first variceal hemorrhage. This applies to patients with or without any high-risk features (Childs B or C and/or red wale markings on varices). Choice of Nonselective Beta-Blocker
Both nadolol and propranolol have been recommended as agents of choice in primary prevention of variceal bleeding. Both drugs result in unopposed alpha adrenergic– mediated splanchnic vasoconstriction and reduction of portal inflow (as a result of reduction in cardiac output).21 Dose titration can be achieved by monitoring patients’ resting heart rate or their HVPG. When the heart rate is used, beta-blockers are uptitrated to achieve a 20% reduction from baseline or achieve a target heart rate of 55 to 60 beats per minute. In some European centers, HVPG is routinely measured to guide titration of therapy and is recommended in the Baveno V guidelines. A reduction of HVPG to 12 mm Hg or lower or to 20% or less of the baseline HVPG value reduces the risk of variceal bleeding.7 However, HVPG monitoring is invasive and is not routinely practiced in the United States outside of clinical trials.
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Carvedilol, a beta-blocker with alpha adrenergic activity also has been studied as a pharmacologic agent for primary prophylaxis.10,22,23 Multiple studies examining the effects of carvedilol on portal hypertension have shown a dose-related decrease in HVPG (20% from baseline), which is higher than seen with propranolol.24,25 A recent meta-analysis that included a total of 175 patients from 5 studies compared the hemodynamic effects of carvedilol with propranolol.26 Carvedilol resulted in a greater reduction in HVPG both in the short term (mean weighted difference in HVPG –7.70 mm Hg [95% CI 12.40 to 3.00] at 60–90 minutes after drug administration) and the long term (mean weighted difference in HVPG –6.81 mm Hg [95% CI 11.35 to 2.26] after 7–90 days of therapy) (Fig. 1). The risk of failure to achieve a hemodynamic response with carvedilol was lower than that with propranolol (relative risk [RR] 0.66, 95% CI 0.44–1.00). Adverse events were more frequent and serious with carvedilol; however, this difference failed to reach statistical significance. A recent trial examined 104 patients with esophageal varices (mean HVPG 20.4 mm Hg) who underwent HVPG monitoring before and during propranolol treatment (80–160 mg per day).25 Patients without a hemodynamic response to propranolol (defined as lack of a reduction in HVPG 20% compared with baseline or an absolute value 12 mm Hg on repeat HVPG) or those who did not tolerate propranolol (n 5 10) were treated with carvedilol (6.25–50 mg per day). Of the 67 patients who met these criteria for propranolol nonresponse, 56% achieved a hemodynamic response with carvedilol. The decrease in HVPG was significantly greater with carvedilol than with propranolol (–19% 10% vs –12% 11%, P10 mm Hg). SUMMARY
In summary, both nonselective beta-blockers and endoscopic band ligation form the cornerstone of prophylactic therapy for varices. In the absence of accurate noninvasive markers of HVPG, variceal size, high-risk stigmata of variceal bleeding, and the stage of underlying liver disease dictate the choice of prophylactic therapy. The major challenge is to screen patients in a timely manner and institute a form of therapy that has the highest chance of success in terms of both compliance and effectiveness. Specifically, in a retrospective cohort study of 550 patients with cirrhosis who sought care at 3 Department of Veterans Affairs facilities between 2000 and 2007, we found that only 24.3% (95% CI 20.2%–28.3%) of patients had an upper endoscopy during the first year after their cirrhosis diagnosis and 60% (95% CI 50.2%–70.7%) of patients with varices received any form of primary prophylaxis of variceal bleeding.36 Without systematic efforts targeted at reducing these gaps in health care delivery, recent advances in the efficacy of primary prophylaxis may not translate into effective varices care at the bedside. REFERENCES
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5. Merli M, Nicolini G, Angeloni S, et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003;38:266–72. 6. Fontana RJ, Sanyal AJ, Ghany MG, et al. Factors that determine the development and progression of gastroesophageal varices in patients with chronic hepatitis C. Gastroenterology 2010;138:2321–31, 2331. 7. D’Amico G, Garcia-Pagan JC, Luca A, et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006;131:1611–24. 8. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922–38. 9. Sarin SK, Kumar A, Angus PW, et al. Primary prophylaxis of gastroesophageal variceal bleeding: consensus recommendations of the Asian Pacific Association for the Study of the Liver. Hepatol Int 2008;2:429–39. 10. de FR. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010;53:762–8. 11. de FR, Eisen GM, Laine L, et al. Esophageal capsule endoscopy for screening and surveillance of esophageal varices in patients with portal hypertension. Hepatology 2008;47:1595–603. 12. Lapalus MG, Ben SE, Gaudric M, et al. Esophageal capsule endoscopy vs. EGD for the evaluation of portal hypertension: a French prospective multicenter comparative study. Am J Gastroenterol 2009;104:1112–8. 13. Kim SH, Kim YJ, Lee JM, et al. Esophageal varices in patients with cirrhosis: multidetector CT esophagography—comparison with endoscopy. Radiology 2007; 242:759–68. 14. Perri RE, Chiorean MV, Fidler JL, et al. A prospective evaluation of computerized tomographic (CT) scanning as a screening modality for esophageal varices. Hepatology 2008;47:1587–94. 15. Giannini E, Botta F, Borro P, et al. Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis. Gut 2003;52:1200–5. 16. Giannini EG, Zaman A, Kreil A, et al. Platelet count/spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results of a multicenter, prospective, validation study. Am J Gastroenterol 2006;101:2511–9. 17. Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. Hepatology 2010;51:2069–76. 18. D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 1999;19:475–505. 19. Cales P, Oberti F, Payen JL, et al. Lack of effect of propranolol in the prevention of large oesophageal varices in patients with cirrhosis: a randomized trial. FrenchSpeaking Club for the Study of Portal Hypertension. Eur J Gastroenterol Hepatol 1999;11:741–5. 20. Merkel C, Marin R, Angeli P, et al. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology 2004;127:476–84. 21. Villanueva C, Aracil C, Colomo A, et al. Acute hemodynamic response to betablockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding. Gastroenterology 2009;137:119–28.
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22. Tripathi D, Ferguson JW, Kochar N, et al. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Hepatology 2009;50:825–33. 23. Shah HA, Azam Z, Rauf J, et al. Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: a multicentre randomized controlled trial. J Hepatol 2014;60(4):757–64. 24. Banares R, Moitinho E, Piqueras B, et al. Carvedilol, a new nonselective beta-blocker with intrinsic anti-Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis. Hepatology 1999; 30:79–83. 25. Reiberger T, Ulbrich G, Ferlitsch A, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013;62:1634–41. 26. Sinagra E, Perricone G, D’Amico M, et al. Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis. Aliment Pharmacol Ther 2014;39(6):557–68. 27. Imperiale TF, Chalasani N. A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding. Hepatology 2001;33:802–7. 28. Khuroo MS, Khuroo NS, Farahat KL, et al. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding. Aliment Pharmacol Ther 2005;21:347–61. 29. Gluud LL, Klingenberg S, Nikolova D, et al. Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices: systematic review of randomized trials. Am J Gastroenterol 2007;102:2842–8. 30. Li L, Yu C, Li Y. Endoscopic band ligation versus pharmacological therapy for variceal bleeding in cirrhosis: a meta-analysis. Can J Gastroenterol 2011;25:147–55. 31. Gluud LL, Krag A. Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst Rev 2012;(8):CD004544. 32. Imperiale TF, Klein RW, Chalasani N. Cost-effectiveness analysis of variceal ligation vs. beta-blockers for primary prevention of variceal bleeding. Hepatology 2007;45:870–8. 33. Avgerinos A, Armonis A, Manolakopoulos S, 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. 34. Sarin SK, Lahoti D, Saxena SP, et al. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology 1992;16:1343–9. 35. Mishra SR, Sharma BC, Kumar A, et al. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and beta-blockers: a randomized controlled trial. J Hepatol 2011;54:1161–7. 36. Buchanan P, Kramer J, El-Serag H, et al. The quality of care provided to patients with varices. Am J Gastroenterol 2014;109(7):934–40.
