Beta‐blockers in 2016: Still the safest and most useful drugs for portal hypertension?
Authors: Gennaro D'Amico, Giuseppe Malizia, Jaime Bosch
Journal: Hepatology (2016)

Potential conflict of interest: Jaime Bosch consults for Gilead, Conatus, Intercept, Actelion, and Falk and has received grants from Exalenz. See Article on Page 1968 Because of their beneficial effect on the prevention of variceal bleeding, nonselective beta‐blockers (NSBBs) have become a cornerstone of the treatment of portal hypertension for the last three decades. In addition to prevention of variceal bleeding, they also reduce bacterial translocation and the risk of spontaneous bacterial peritonitis (SBP), refractory ascites, hepatorenal syndrome (HRS), and death.1 However, a few years ago Sersté et al.2 reported an increased risk of death from NSBBs in patients with refractory ascites in an observational retrospective study.2 This study bore some risk of bias, however, because the patients who received NSBBs had more advanced liver disease with more severe portal hypertension, and the multivariable adjustment of the reported hazard ratio was insufficient. In addition, almost one half of the patients who were using NSBBs received a standard dosage of 160 mg long‐acting propranolol per day, which is unusual in clinical practice. In a small crossover study, the same investigators reported an increased risk of a post‐paracentesis surge in plasma renin activity under NSBB treatment, but not after NSBB withdrawal.3 Although this increase had no deleterious effects on renal function, and despite the major drawbacks of this study (i.e., only 10 patients were included, and diuretic therapy was not considered), a debate ensued about whether and when NSBB treatment should be discontinued in cases of advanced cirrhosis. A window for NSBB treatment has been hypothesized1: no benefit in the early disease stage when there are no esophageal varices and the effect of NSBB on portal pressure is very small4; benefit in patients with medium‐large varices or who have bled; possible harm in patients with more advanced disease, typically characterized by resistant or refractory ascites, when the cardiac compensatory reserve might be impaired5 and may be further reduced by NSBB,1 especially at high doses. More recently, Mandorfer et al.5 investigated the interaction between NSBBs and SBP in a retrospective study that included 607 patients at their first paracentesis. NSBB treatment improved transplant‐free survival significantly in patients who did not experience SBP, but reduced significantly survival after SBP. The uncertainty raised by the aforementioned studies has been mitigated recently by a single‐center retrospective study including 322 patients with ascites listed for liver transplantation, 159 of whom were receiving treatment with NSBBs.6 Competing‐risks multivariable regression analysis (for transplant competing) showed that NSBBs were associated with a nonsignificant survival benefit that was however significant in 208 patients (104 NSBB, 104 nonNSBB) matched by propensity score. In the subgroup of 117 patients with refractory ascites, treatment with NSBBs was associated with significant improvement of survival, both in the whole group and in the propensity score−matched patients, suggesting that the results reported by Sersté and colleagues2 are at least not generalizable. The lack of a harmful effect of NSBBs in refractory ascites has also been confirmed in two other small retrospective studies.7 In this issue of Hepatology, Bossen et al.9 report an individual patient‐data meta‐analysis from three satavaptan trials including 1198 patients with cirrhosis and ascites. NSBB users had more frequently previous variceal bleeding, but less Child‐Pugh class C, hyponatremia, and refractory ascites. The 1‐year mortality was 23.2% in NSBB users and 25.3% in nonusers. In addition, in the 588 patients with refractory ascites, mortality was not increased by NSBB treatment (adjusted hazard ratio, 1.02; 95% confidence interval, 0.74‐1.40), and the same was observed in patients with previous SBP. However, 29% of NSBB users stopped treatment after experiencing a clinically relevant event causing hospitalization, such as variceal bleeding, infections, or HRS. A major strength of this study is that data were prospectively collected in the context of randomized clinical trials (RCTs), minimizing the risk of bias. Availability of individual patient data allowed for robust analyses in patients with refractory ascites (n = 558), previous variceal bleeding (n = 250), and previous SBP (n = 176). Multivariable Cox proportional hazards analysis was performed to adjust the NSBB effect for sex, age, etiology of cirrhosis, Model for End‐Stage Liver Disease and Child‐Pugh scores, previous variceal bleeding, and responsiveness of ascites to diuretic therapy. The study has some limitations. The first is the lack of information on the presence of esophageal varices, although information on previous bleeding was complete. One might agree with the authors' consideration that NSBBs are indicated for patients with medium/large varices that predictably have worse prognosis, which makes a bias favoring NSBBs unlikely. However, because a sizable proportion of patients with large varices are not on NSBBs at their first bleeding, adjustment for medium/large varices would have reduced the risk of bias. Another limitation is the 29% NSBB discontinuation rate, which is higher than that reported in most RCTs, where the average is approximately 20%. Although discontinuation was associated with a significant increase in risk of death and coincided with hospitalization, infection, refractory ascites, HRS, and variceal bleeding, the specific reasons for discontinuation were not recorded. Therefore, it remains possible that mortality could have been higher if no patient had discontinued NSBB treatment at the time of complications. However, only an RCT might answer this question. Of note, in the study by Sersté et al. reporting increased mortality with NSBB,2 there is no mention of treatment discontinuation. A second question is: What is the correct indication/right moment for discontinuation of NSBBs? The present study identifies clinical events coincident with discontinuation but does not address the specific reasons, which are the needed information to make a decision on whether to discontinue NSBB or not in clinical practice. According to our own experience, NSBBs are usually withdrawn in patients experiencing acute variceal bleeding or circulatory shock of any kind, patients requiring assisted ventilation, and patients with deep encephalopathy; we think that even in specifically designed RCTs, NSBBs would be withdrawn under these circumstances. Thus, the best one can conclude from the study by Bossen et al.9 is that the lack of increase in risk of death in patients with (refractory) ascites receiving NSBBs was observed using an approach that allowed the attending physicians to withdraw NSBB treatment. How should we translate this information in clinical practice? In their conclusion, Bossen et al.9 suggest that we should continue to use NSBBs as was done before the first Sersté study,2 discontinuing treatment when there are clinical signs of hemodynamic impairment, hypotension, infection, or acute kidney injury. Although clear‐cut indicators of when to discontinue NSBBs can only come from controlled studies, it was agreed upon at the Baveno VI consensus conference10 that in patients who have refractory ascites, NSBBs should be reduced or discontinued when systolic blood pressure is <90 mm Hg, when serum sodium concentration is <130 mEq/L, or in cases of acute kidney injury. These specific limits for systolic blood pressure and serum sodium concentration follow data from the study by Mandorfer et al.5 and unpublished data presented at the Baveno VI consensus conference by Thomas Reiberger, who found that the likelihood of hypotension was directly related to the dose of NSBB, being higher at doses over 120 mg/day. In summary, the study by Bossen et al.9 provides a solid argument against a harmful effect of NSBBs in refractory ascites and supports the Baveno VI recommendations. Their conclusions may be translated in clinical practice as follows: (1) NSBBs should not be used in compensated cirrhosis free of esophageal varices; (2) NSBBs should be used in patients with varices at risk of (re)bleeding regardless of whether they have ascites; and (3) NSBBs can be used in the presence of refractory ascites, but dose reduction or discontinuation should be considered according to systolic blood pressure, serum sodium concentration, and renal function.