Nonselective β‐blockers do not affect mortality in cirrhosis patients with ascites: Post Hoc analysis of three randomized controlled trials with 1198 patients

Abstract

The safety of nonselective b-blockers (NSBBs) in advanced cirrhosis has been questioned. We used data from three satavaptan trials to examine whether NSBBs increase mortality in cirrhosis patients with ascites. The trials were conducted in 2006-2008 and included 1198 cirrhosis patients with ascites followed for 1 year. We used Cox regression to compare allcause mortality and cirrhosis-related mortality between patients who did and those who did not use NSBBs at randomization, controlling for age, gender, Model for End-Stage Liver Disease score, Child-Pugh score, serum sodium, previous variceal bleeding, cirrhosis etiology, and ascites severity. Moreover, we identified clinical events predicting that a patient would stop NSBB treatment. At randomization, the 559 NSBB users were more likely than the 629 nonusers to have a history of variceal bleeding but less likely to have Child-Pugh class C cirrhosis, hyponatremia, or refractory ascites. The 52-week cumulative all-cause mortality was similar in the NSBB user and nonuser groups (23.2% versus 25.3%, adjusted hazard ratio 5 0.92, 95% confidence interval 0.72-1.18), and NSBBs also did not increase mortality in the subgroup of patients with refractory ascites (588 patients, adjusted hazard ratio 5 1.02, 95% confidence interval 0.74-1.40) or in any other subgroup. Similarly, NSBBs did not increase cirrhosis-related mortality (adjusted hazard ratio 5 1.00, 95% confidence interval 0.76-1.31). During follow-up, 29% of initial NSBB users stopped taking NSBBs, and the decision to stop NSBB treatment marked a sharp rise in mortality and coincided with hospitalization, variceal bleeding, bacterial infection, and/or development of hepatorenal syndrome. Conclusion: This large and detailed data set on worldwide nonprotocol use of NSBBs in cirrhosis patients with ascites shows that NSBBs did not increase mortality; the decision to stop NSBB treatment in relation to stressful events may have added to the safety. (HEPATOLOGY 2016;63:1968-1976 SEE EDITORIAL ON PAGE 1771U se of nonselective b-blockers (NSBBs) as secondary prevention of variceal bleeding was introduced in 1981. (1) Since then, numerous randomized trials and meta-analyses have documented NSBBs' efficacy in preventing variceal bleeding, (2,3) and today NSBBs are the standard pharmacological treatment for primary and secondary prevention of variceal bleeding. (4,5) They reduce portal pressure by decreasing cardiac output (b 1 -blockade) and splanchnic blood flow (b 2 -blockade). (6) Surprisingly, in 2010 serious concerns about the safety of NSBB use in cirrhosis patients with refractory ascites were raised by a single-center observational Abbreviations: CI, confidence interval; HR, hazard ratio; HRS, hepatorenal syndrome; MAP, mean arterial pressure; MELD, Model for End-Stage Liver Disease; NSBB, nonselective b-blocker; SBP, spontaneous bacterial peritonitis.

Current Management of the Complications of Cirrhosis and Portal Hypertension: Variceal Hemorrhage, Ascites, and Spontaneous Bacterial Peritonitis

“…In the first of these studies, a propensity score-matched study in a cohort of patients with cirrhosis on the transplant wait list showed a survival advantage of patients with refractory ascites on NSBB compared to those not on NSBB and, interestingly, showed that the use of carvedilol (a NSBB with vasodilatory properties that has been shown to lead to a larger decrease in blood pressure compared to propranolol [16] ) had an intermediate survival between patients with propranolol (lowest mortality) and those not on NSBB (highest mortality) [17] . The second study, a post-hoc analysis of data from 3 RCTs about V 2 receptor antagonists in the treatment of ascites, showed no differences in mortality between those on and off NSBB, even when adjusted by MELD, mean arterial pressure, dose of beta-blockers or study group (satavaptan vs. placebo) [18] .…”

Novel Approaches to Reducing the Risk of Variceal Hemorrhage

“…Other retrospective studies and meta analyses could not confirm this [24][25][26], but it is nevertheless possible that in a subset of patients with refractory ascites in whom the cardiac response to hypotension may be inadequate, NSBB may lead to a disturbance in the circulatory status, and therefore the Baveno consensus meeting recommended that for the given time, NSBB should be used cautiously in case of a systolic blood pressure <90 mm Hg, serum sodium <130 mEq/L or acute kidney injury [5] . In this regard, a recent study demonstrated that there was no clinical or hemodynamic rebound after abrupt interruption of NSBB in patients with cirrhosis [27] .…”

Variceal Bleeding: Update of Recommendations From the Brazilian Association of Hepatology

“…According to the size, presence of red signs on varices and Child-Pugh score either traditional NSBB or EVL According to the size, presence of red signs on varices and Child-Pugh score, either traditional NSBB, EVL or carvedilol can be used (27,31) Avoidance of carvedilol in decompensated cirrhosis and caution with the use of NSBB in refractory ascites (3,6,11,15,19,20,25,26) Statins are promising (1) Hepatic vein pressure gradient-guided therapy useful but not widely available to assess response to NSBB (11,15) Carvedilol promotes greater reduction of portal hypertension when compared to propranolol, and is as efficacious or better than EVL and can be used in patients unresponsive to traditional NSBB (22,27,31) Simvastatin can lower portal hypertension …”