Patients with cirrhosis are at risk for developing complications that can negatively impact their survival.1 These complications include the development of hepatocellular carcinoma (HCC), sepsis, renal failure, and gastrointestinal bleeding, mainly variceal. The risk of bleeding is mainly related to the development of varices from portal hypertension. Bleeding from varices, whether esophageal or gastric, is associated with a mortality risk of 40% at 1 year.2
Twenty-nine years ago, a randomized controlled trial (RCT) from France involving 74 patients with cirrhosis with a history of gastrointestinal bleeding showed that propranolol, a nonselective beta-blocker (NSBB), significantly reduced the risk of rebleeding from esophageal varices.3 Since then, 615 articles have been published in the English literature on the use of propranolol or nadolol (the other NSBB) in cirrhosis, both for primary and secondary prophylaxis. In fact, NSBBs have become one of the most effective preventative therapies in patients with cirrhosis against variceal bleeding.4 The advantage of using NSBBs, however, must be weighed against the risks associated with their chronic use. NSBBs are contraindicated in patients with refractory asthma, respiratory failure, advanced atrio-ventricular block, and severe arterial hypotension. In order to improve the risk/benefit ratio, administration of beta-blockers is recommended only in patients with a substantial risk of bleeding such as those patients with medium or large varices or patients with small esophageal varices who have Child-Pugh class C cirrhosis.5, 6 If possible, hepatic venous pressure gradient (HVPG) should be measured before and 1-2 months after NSBB administration to identify responders (those with a final HVPG < 12 mm Hg or those who show a decrease of ≥20% in HVPG versus the pretreatment value) who are most likely to benefit from NSBB prophylaxis. Nonresponders should discontinue therapy so to prevent the development of side effects when their chances of any therapeutic benefits are small.7
In the ensuing 29 years since the original description of the effectiveness of propranolol in preventing variceal bleeding, many other drugs such as angiotensin receptor antagonists, selective beta-blockers, nitrates, alpha-receptor antagonists, and endothelin receptor antagonists, to name a few, have been investigated for their ability to decrease portal pressures. None of these agents has shown a more favorable profile than NSBBs in the prophylaxis against variceal bleeding.7 When compared with isosorbide mononitrate as primary prophylaxis against variceal bleeding in patients with decompensated cirrhosis, NSBBs showed better efficacy without increased adverse effects or decreased survival.8
However, almost all RCTs comparing propranolol or nadolol to placebo or to other pharmacotherapy excluded patients with advanced cirrhosis, especially patients with refractory ascites. Therefore, there is insufficient evidence on the relative risks and benefits of NSBB use in this subgroup of ill patients. The question of whether the risk/benefit ratio favors the use of NSBB in patients with advanced cirrhosis remains unresolved.
In this issue of HEPATOLOGY, Didier Lebrec, who originally described the effectiveness of propranolol in reducing the risk of variceal bleeding, and his colleagues from Clichy attempt to answer this crucial question. They report the results of an observational study on the survival of 151 patients with cirrhosis with refractory ascites,9 as defined by the International Ascites Club.10 Of the 151 patients enrolled, 77 (51%) had esophageal varices and were taking propranolol, whereas the remaining 74 patients without varices (except four cases) were not. It is unclear whether propranolol was given as primary or secondary prophylaxis against variceal bleeding. Patients treated with propranolol had a significantly lower median survival of 5 months versus 20 months in patients not taking propranolol. Multivariable analysis showed that treatment with NSBB was one of the four predictors of mortality in this population of patients with cirrhosis. The authors concluded that propranolol was potentially harmful in patients with cirrhosis with refractory ascites, and therefore should be contraindicated.
Before accepting the conclusion of this study, which involves a strong clinical recommendation, we believe that the characteristics of the study and the quality of the results should be scrupulously evaluated.
First, the study was not an RCT, which is the best way to evaluate the effects of specific medications. This is because the allocation of treatment by randomization is the only way to prevent selection bias. When treatment allocation is not randomized, unrecognized but often substantial differences between patient groups may alter the interpretation of results. For example, the group not receiving propranolol did not have varices, and this difference immediately separates the two groups of patients into different risk categories for mortality.1 However, the HVPG before the initiation of treatment was similar in both groups. It is important to emphasize that the HVPG was measured only in selected patients in both groups. It is possible that the HVPG may have been higher in the NSBB group if measurements were carried out in all patients; this possible difference could then explain the higher mortality in the patients treated with propranolol.
Second, the causes of death in two-thirds of cases were either progression of HCC or sepsis, 25 patients died from unknown causes, and nine patients were unaccounted for. It is difficult to assign causality to propranolol in the HCC-related deaths. In the cases of sepsis, it is possible that the NSBB-induced reduction in cardiac output would have made these patients less able to cope with the further vasodilatation caused by sepsis,11 because reduction in cardiac output has been shown to be associated with increased incidence of potentially fatal renal failure in patients with spontaneous bacterial peritonitis (SBP).12 It is interesting that none of the patients died from cardiovascular or pulmonary dysfunction, which would be expected from NSBB use.
Third, it is possible that the patients were not consecutively enrolled, especially because approximately half of patients enrolled did not have varices despite belonging to Child-Pugh class C. The patients on NSBB appeared slightly sicker, with higher bilirubin, lower albumin, and lower serum sodium, and more patients had Child-Pugh class C cirrhosis. Although individually, none of these parameters was significantly different from the non-NSBB group, it is difficult to assess whether the cumulative effects of all markers of hemodynamic abnormality and liver dysfunction would not have made the NSBB group more likely to succumb to their advanced cirrhosis.
Although all these methodological issues could have affected the statistical estimations and the applicability of these results to daily medical practice, the authors have raised an important question concerning the safety of propranolol in patients with cirrhosis and refractory ascites. From a physiological standpoint, the pathogenesis of refractory ascites is related to an intense hemodynamic derangement involving both the splanchnic and the systemic circulations. In the presence of high portal pressure, splanchnic vessels dilate and splanchnic pooling occurs, whereas the blood volume in the systemic circulation is relatively insufficient as a result of systemic arterial vasodilatation.13
Patients with cirrhosis and refractory ascites are characterized by low systemic blood pressure and reduced renal perfusion with low glomerular filtration progressing to type 2 hepatorenal syndrome (HRS) (Fig. 1). Such patients are also susceptible to complications such as sepsis including SBP, hepatic encephalopathy, and type 1 HRS. Therefore, one may suggest that propranolol, which has a hypotensive effect, could be detrimental for patients with refractory ascites and hemodynamic instability. This is precisely why the authors suggested that the development of post-paracentesis circulatory dysfunction could have contributed to the increased mortality among the propranolol group, although they did not provide any evidence in the report. Finally, the potential negative effects of propranolol on “cirrhotic cardiomyopathy”, which is common in patients with advanced cirrhosis,14 could have also contributed to the increased mortality. Cirrhotic cardiomyopathy is a newly recognized condition characterized by diastolic dysfunction, systolic incompetence under conditions of stress, and electrophysiological abnormalities.15 Some aspects of cirrhotic cardiomyopathy, such as diastolic dysfunction, reduced cardiac index, and Q-T interval prolongation, have been shown to be significantly associated with complications of cirrhosis, such as HRS, and death (Fig. 1).16, 17 Therefore, if NSBBs further impair cardiac function in a patient with cirrhotic cardiomyopathy, this could be another mechanism whereby propranolol administration would lead to an unfavorable outcome.
From the opposite standpoint, propranolol reduces the risk of bleeding, and therefore, bleeding-related death. By the same mechanism, NSBBs can also reduce bacterial translocation from the gut.18 Because bacterial translocation is the initial step in the pathogenesis of SBP, the use of propranolol has been shown to prevent the development of SBP18, 19 and postsurgical infections in cirrhosis (Fig. 1).20
It appears that the controversy regarding NSBB use in advanced cirrhosis might continue, the report from Lebrec et al. notwithstanding. NSBBs should continue to be used to prevent variceal bleeding. However, the risk/benefit ratio of such treatment may vary according to the stage of the cirrhosis, perhaps becoming unfavorable in patients with the most advanced stage. New studies are necessary to establish if NSBBs exert different effects in different subsets of patients with cirrhosis, although it is unlikely that such studies are currently under way. Pending the results of such studies, patients with ascites who are on NSBBs should be monitored closely, and consideration should be given to discontinuing NSBBs when either sepsis or HRS develop.