Prevention of Variceal Rebleeding: Endoscopes, Drugs, and More

Variceal bleeding is a serious complication of portal hypertension and a leading cause of death in patients with cirrhosis.1 The patients who survive an initial episode have a risk of rebleeding approaching 80% at 2 years.1,2 Thus, therapy to prevent rebleeding is widely endorsed, to the point that trials including a no-treatment or placebo arm are considered ethically indefensible.3,4 One result is that studies of combination therapy will be increasingly the norm.5-10 The study by Lo et al., published in this issue of HEPATOLOGY,5 reflects this trend. The authors report that the combination of endoscopic band ligation (EBL), nadolol, and sucralfate is superior to EBL alone in preventing rebleeding (from any source and from esophageal varices). The authors found a reduction in transfusion requirements during follow-up, reduced recurrence of varices after initial obliteration, and even a trend toward improved survival. The rationale behind the use of combination therapy is that agents acting through different mechanisms may be additive in terms of their benefit or even synergistic.6 Recent years have seen major progress in understanding the pathophysiologic mechanisms leading to portal hypertension due in part to experimental rat models.4 A key concept concerns the hyperdynamic circulation in cirrhosis,11,12 which increases both portal venous inflow and portal pressure. This provides the rationale for the use of nonselective b-blockers (such as propranolol or nadolol) to prevent initial or recurrent variceal bleeding13: these vasoactive agents reduce portal pressure by decreasing splanchnic blood flow and the hyperdynamic circulation.14,15 Randomized controlled trials and meta-analyses have confirmed their benefit.9,16-18 Another key concept is that the increased intrahepatic vascular resistance of cirrhosis is due not only to fixed anatomical changes inherent to cirrhosis but also to active contraction of vascular smooth muscle cells and the abundant myofibroblasts present in the scar tissue and, possibly, activated hepatic stellate cells.19,20 This active contraction involves reduced production of the endogenous vasodilator, nitric oxide, by hepatic endothelial cells and overexpression of endogenous vasoconstrictors (endothelins, leukotrienes, and activated neurohumoral systems). 21,22 The dynamic component can be counteracted in part by vasodilators,19 including the nitric oxide donors nitroglycerin23 and isosorbide-5-mononitrate (ISMN),24 adrenergic antagonists such as prazosin,25 angiotensin blockers such as losartan, and anti-endothelins.26 A problem with vasodilators as therapy, however, is that they may cause systemic vasodilation, reducing arterial pressure and peripheral resistance, and aggravating renal dysfunction and sodium retention in cirrhotic patients with ascites.25,26 Another step forward was the demonstration that when the hepatic venous pressure gradient (HVPG) is below 12 mm Hg, the risk of bleeding from varices is essentially nil.27 A drop of more than 20% from baseline HVPG also is associated with a very low residual risk of variceal rebleeding in patients treated with b-blockers.28 Unfortunately, nonselective b-blockers achieve these target reductions in HVPG in only about one third of patients.14,28 Hence, the introduction of combined pharmacologic therapy.7,29 It was proposed that propranolol or nadolol (which reduces HVPG by decreasing splanchnic blood flow) in combination with low-dose ISMN (which decreases HVPG by reducing hepatic resistance) would be superior to either agent alone. The combination was postulated to be additive in reducing portal pressure, whereas b blockade would exert mild systemic vasoconstrictor effects, preventing most of the adverse vasodilatory effects of ISMN.29 Subsequent trials have confirmed the synergistic effect of this drug combination on the HVPG,7 its lack of significant adverse effects on renal function,30 and its increased efficacy in the prevention of recurrent variceal bleeding.31 A variation on combined therapy consists of endoscopic obliteration of varices together with a portal hypotensive agent such as propranolol or nadolol.10,17 The goals are to reduce the risk of rebleeding during the course of initial endoscopic therapy (which is actually the period with the higher risk of rebleeding)2 and to decrease the risk of recurrent varices and rebleeding after initial endoscopic therapy is completed.1 Previous studies suggested that the combination approach achieves better results than either treatment alone, and this was confirmed by meta-analysis,9,10 although the small size of the studies weakened the conclusions.9 Now that sclerotherapy has been replaced almost universally by EBL,10 the combination of EBL and b-blockers was the next logical step. The results of Lo et al.5 with this combination, while encouraging, carry some caveats: (1) the study was not doubleblind and, therefore, is subject to observer bias; (2) the study was conducted in a single center, which entails possible selection bias; (3) serial measurements of HVPG were not performed, which would have established whether the clinical benefit from combination therapy was caused by a decrease in HVPG and the degree to which HVPG must be decreased to realize a benefit comparable with that of EBL alone; and (4) the use of sucralfate as part of the combination therapy is difficult to evaluate without an appropriate control group. The first concern (observer bias) is probably unavoidable in assessing procedures until future technological improvements allow for a “blind” endoscopist. This disadvantage, Abbreviations: EBL, endoscopic band ligation; ISMN, isosorbide-5-mononitrate; HVPG, hepatic venous pressure gradient. From the Liver Unit, IMD, Hospital Clı́nic and IDIBAPS (Institut de Investigaciò Biomèdica August-Pi-Sunyer), University of Barcelona, Barcelona, Spain. Received June 21, 2000; accepted July 5, 2000. Supported by grants 00/0044 from Fondo de Investigación Sanitaria and SAF99-0007, Dirección General de Enseñanza Superior e Investigación Cientı́fica. Address reprint requests to: Jaime Bosch, M.D., Hepatic Hemodynamics Laboratory, Liver Unit, Hospital Clı́nic, C Villarroel 170, 08036 Barcelona, Spain. E-mail: jbosch@medicina.ub. es. Copyright © 2000 by the American Association for the Study of Liver Diseases. 0270-9139/00/3203-0033$3.00/0 doi:10.1053/jhep.2000. 16663