Beta-Blockers to Prevent Gastroesophageal Varices in Cirrhosis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The report by Groszmann et al. (Nov. 24 issue)1 answers a question my colleagues and I first raised several years ago2 — namely, that of the potential value of nonselective beta-blockade in the treatment of unselected patients with cirrhosis. We hypothesized that the use of nonselective beta-blockers would lead to a lower rate of esophageal variceal hemorrhage, death, or both, if these agents were given to all such patients.
With regard to the study by Groszmann et al., the classification of a therapy-induced drop in the heart rate to below 50 beats per minute as a serious adverse effect in an asymptomatic patient is debatable. This was the serious adverse effect in 7 of 20 patients in the timolol group; if these 7 patients were removed, the rate of adverse events would be similar to that in the placebo group. Esophageal varices alone are not the problem in cirrhosis; the problem is the complications of portal hypertension. It is possible that nonselective beta-blockers may not prevent the development of varices, but they could still lead to long-term improved survival by lowering portal hypertension. In fact, in this study there was a trend toward a decreased rate of death in the timolol group (9 percent), as compared with the placebo group (14 percent).
Anthony B. Post, M.D.
University Hospitals of Cleveland
Cleveland, OH 44106
anthony.post@uhhs.com
References
Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005;353:2254-2261.
Post AB, Sterling RS, Cooper GS. Cost-effective analysis of three management strategies for primary prophylaxis of variceal bleeding. Hepatology 1996;24:208A-208A.
To the Editor: Groszmann et al. report that timolol was ineffective in preventing the new formation of esophageal varices in patients with cirrhosis. This study may change our daily clinical practice, but it would have been more informative if it had indicated whether timolol prevented the development of portal hypertensive gastropathy or portosystemic shunting, since portosystemic collaterals may develop before the appearance of varices and can be diagnosed noninvasively.1 We suggest that long-term down-regulation of 1- and 2-adrenergic receptors in the splanchnic vessels may be involved in those patients with cirrhosis in whom a favorable response in terms of the hepatic venous pressure gradient (HVPG) did not occur.2
Nimer N. Assy, M.D.
Technion Institute
13100 Safed, Israel
assy.n@ziv.health.gov.il
Sorina E. Schlesinger, M.D.
Ossamah A. Hussein, M.D.
Sieff Hospital
13100 Safed, Israel
References
de Franchis R. Evolving consensus in portal hypertension: report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005;43:167-176.
Wang T, Kaumann AJ, Brown MJ. (–)-Timolol is a more potent antagonist of the positive inotropic effects of (–)-adrenaline than of those of (–)-noradrenaline in human atrium. Br J Clin Pharmacol 1996;42:217-223.
The authors reply: Although portal hypertensive gastropathy is common in patients with cirrhosis and portal hypertension, its presence correlates with the presence of varices and the Child–Pugh score.1 One of the primary end points in our study was severe bleeding from portal hypertensive gastropathy, which occurred in only one patient receiving timolol.
Although portosystemic collaterals must appear before (or, at least, at the same time as) varices (collaterals that protrude into the esophageal lumen), the prevention of varices is important, because their presence has important prognostic implications.2 Noninvasive techniques to estimate the progression of collaterals to varices are being investigated. However, it is uncertain whether any technique will be sensitive enough to detect early collateralization of the portal system and its progression and, more important, to detect the effect of pharmacologic therapy on this process.
Beta-receptor down-regulation is not observed during long-term administration of beta-blockers. Whether long-term down-regulation of 1- and 2-adrenergic receptors in the splanchnic vessels plays a role in the reduced response observed in our patients with mild portal hypertension remains to be investigated.
Our study started in 1993 under the auspices of the National Institute of Diabetes and Digestive and Kidney Diseases and was completed in 2003. The analysis by Post et al.3 added value to an issue that was resolved by our study — that is, that beta-blockers should not be used in all patients with cirrhosis. According to our protocol, severe bradycardia was defined by a heart rate of fewer than 50 beats per minute in a symptomatic patient. We thank Dr. Post for allowing us to clarify this issue. All our patients with bradycardia were symptomatic (they had fatigue, lightheadedness, or both), and therefore discontinuation of beta-blockers was not a debatable issue. Differences in mortality were not statistically significant, and five additional deaths in the placebo group would hardly represent a trend. In fact, with respect to deaths that were not due to hepatocellular carcinoma or to causes unrelated to liver disease (Table 2 in our article), the death rate was essentially the same in both groups (4 of 108 patients, or 3.7 percent, in the timolol group vs. 6 of 105, or 5.7 percent, in the placebo group). We suggest that the use of beta-blockers in patients who have cirrhosis without varices would be justified only for those in whom there is an HVPG response.
Roberto J. Groszmann, M.D.
Guadalupe Garcia-Tsao, M.D.
Veterans Affairs Connecticut Healthcare System
West Haven, CT 06516
Jaime Bosch, M.D.
University of Barcelona
08007 Barcelona, Spain
References
Merli M, Nicolini G, Angeloni S, Gentili F, Attili AF, Riggio O. The natural history of portal hypertensive gastropathy in patients with liver cirrhosis and mild portal hypertension. Am J Gastroenterol 2004;99:1959-1965.
D'Amico G. Natural history of compensated cirrhosis and varices. In: Boyer TD, Groszmann RJ, eds. Complications of cirrhosis: pathogenesis, consequences and therapy. Alexandria, Va.: American Association for the Study of Liver Diseases postgraduate course, 2001:118-23.
Post AB, Sterling RS, Cooper GS. Cost-effective analysis of three management strategies for primary prophylaxis of variceal bleeding. Hepatology 1996;24:208A-208A.
With regard to the study by Groszmann et al., the classification of a therapy-induced drop in the heart rate to below 50 beats per minute as a serious adverse effect in an asymptomatic patient is debatable. This was the serious adverse effect in 7 of 20 patients in the timolol group; if these 7 patients were removed, the rate of adverse events would be similar to that in the placebo group. Esophageal varices alone are not the problem in cirrhosis; the problem is the complications of portal hypertension. It is possible that nonselective beta-blockers may not prevent the development of varices, but they could still lead to long-term improved survival by lowering portal hypertension. In fact, in this study there was a trend toward a decreased rate of death in the timolol group (9 percent), as compared with the placebo group (14 percent).
Anthony B. Post, M.D.
University Hospitals of Cleveland
Cleveland, OH 44106
anthony.post@uhhs.com
References
Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005;353:2254-2261.
Post AB, Sterling RS, Cooper GS. Cost-effective analysis of three management strategies for primary prophylaxis of variceal bleeding. Hepatology 1996;24:208A-208A.
To the Editor: Groszmann et al. report that timolol was ineffective in preventing the new formation of esophageal varices in patients with cirrhosis. This study may change our daily clinical practice, but it would have been more informative if it had indicated whether timolol prevented the development of portal hypertensive gastropathy or portosystemic shunting, since portosystemic collaterals may develop before the appearance of varices and can be diagnosed noninvasively.1 We suggest that long-term down-regulation of 1- and 2-adrenergic receptors in the splanchnic vessels may be involved in those patients with cirrhosis in whom a favorable response in terms of the hepatic venous pressure gradient (HVPG) did not occur.2
Nimer N. Assy, M.D.
Technion Institute
13100 Safed, Israel
assy.n@ziv.health.gov.il
Sorina E. Schlesinger, M.D.
Ossamah A. Hussein, M.D.
Sieff Hospital
13100 Safed, Israel
References
de Franchis R. Evolving consensus in portal hypertension: report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005;43:167-176.
Wang T, Kaumann AJ, Brown MJ. (–)-Timolol is a more potent antagonist of the positive inotropic effects of (–)-adrenaline than of those of (–)-noradrenaline in human atrium. Br J Clin Pharmacol 1996;42:217-223.
The authors reply: Although portal hypertensive gastropathy is common in patients with cirrhosis and portal hypertension, its presence correlates with the presence of varices and the Child–Pugh score.1 One of the primary end points in our study was severe bleeding from portal hypertensive gastropathy, which occurred in only one patient receiving timolol.
Although portosystemic collaterals must appear before (or, at least, at the same time as) varices (collaterals that protrude into the esophageal lumen), the prevention of varices is important, because their presence has important prognostic implications.2 Noninvasive techniques to estimate the progression of collaterals to varices are being investigated. However, it is uncertain whether any technique will be sensitive enough to detect early collateralization of the portal system and its progression and, more important, to detect the effect of pharmacologic therapy on this process.
Beta-receptor down-regulation is not observed during long-term administration of beta-blockers. Whether long-term down-regulation of 1- and 2-adrenergic receptors in the splanchnic vessels plays a role in the reduced response observed in our patients with mild portal hypertension remains to be investigated.
Our study started in 1993 under the auspices of the National Institute of Diabetes and Digestive and Kidney Diseases and was completed in 2003. The analysis by Post et al.3 added value to an issue that was resolved by our study — that is, that beta-blockers should not be used in all patients with cirrhosis. According to our protocol, severe bradycardia was defined by a heart rate of fewer than 50 beats per minute in a symptomatic patient. We thank Dr. Post for allowing us to clarify this issue. All our patients with bradycardia were symptomatic (they had fatigue, lightheadedness, or both), and therefore discontinuation of beta-blockers was not a debatable issue. Differences in mortality were not statistically significant, and five additional deaths in the placebo group would hardly represent a trend. In fact, with respect to deaths that were not due to hepatocellular carcinoma or to causes unrelated to liver disease (Table 2 in our article), the death rate was essentially the same in both groups (4 of 108 patients, or 3.7 percent, in the timolol group vs. 6 of 105, or 5.7 percent, in the placebo group). We suggest that the use of beta-blockers in patients who have cirrhosis without varices would be justified only for those in whom there is an HVPG response.
Roberto J. Groszmann, M.D.
Guadalupe Garcia-Tsao, M.D.
Veterans Affairs Connecticut Healthcare System
West Haven, CT 06516
Jaime Bosch, M.D.
University of Barcelona
08007 Barcelona, Spain
References
Merli M, Nicolini G, Angeloni S, Gentili F, Attili AF, Riggio O. The natural history of portal hypertensive gastropathy in patients with liver cirrhosis and mild portal hypertension. Am J Gastroenterol 2004;99:1959-1965.
D'Amico G. Natural history of compensated cirrhosis and varices. In: Boyer TD, Groszmann RJ, eds. Complications of cirrhosis: pathogenesis, consequences and therapy. Alexandria, Va.: American Association for the Study of Liver Diseases postgraduate course, 2001:118-23.
Post AB, Sterling RS, Cooper GS. Cost-effective analysis of three management strategies for primary prophylaxis of variceal bleeding. Hepatology 1996;24:208A-208A.