Propranolol use beyond 6 months increases mortality in patients with Child‐Pugh C cirrhosis and ascites
Authors: Georgios N. Kalambokis, Dimitrios Christodoulou, Gerasimos Baltayiannis, Leonidas Christou
Journal: Hepatology (2016)

We read with interest the article by Bossen et al. on the impact of nonselective β-blockers (NSBBs) on mortality in patients with cirrhosis and ascites included in three satavaptan trials.1 There are some points on which we wish to comment. First, despite the occurrence of refractory ascites in 49.4% of the total cohort, 66% of the patients had Child-Pugh B and only 26% had Child-Pugh C cirrhosis. Obviously, most of the refractory ascites patients included in the satavaptan studies did not have end-stage cirrhosis as is encountered in common clinical practise. This might obscure potential adverse effects of NSBBs on survival in this patient subgroup and account for the differing results between the present study and the study of Sersté et al.2 Second, only the 1-year all-cause mortality could be estimated, while the duration of NSBB treatment prior to inclusion was not reported. Third, the impact of NSBBs on survival was not analyzed separately in different Child-Pugh classes. We retrospectively evaluated 96 Child-Pugh B and 75 Child-Pugh C patients with newly diagnosed cirrhosis (alcoholic/viral/other etiology: 64%/30%/6%) presented consecutively at our liver unit with clinically evident ascites between January 2000 and December 2012; 28 patients had Model for End-Stage Liver Disease (MELD) score ≥18 (16.3%). Propranolol was initiated concomitantly with the diagnosis of cirrhosis in 56 Child-Pugh B and 45 Child-Pugh C (C10-C13) patients with varices; 17 patients had MELD score ≥18. No patient had previous treatment with NSBBs, serum creatinine >1.5 mg/dL, hepatocellular carcinoma, or systolic arterial pressure <90 mm Hg or was lost to follow-up. Cirrhosis-related mortality was defined as in the report of Bossen et al. Survival data were recorded for more than 3 years or until initiation or discontinuation of propranolol in nonusers or users, respectively; death; or liver transplantation. Age, sex, etiology of cirrhosis, and MELD score at baseline were similar between propranolol-treated and nontreated patients in either Child-Pugh class. Four patients subsequently developed refractory ascites (all Child-Pugh C; propranolol-treated, n = 3). Forty-four Child-Pugh B (34 propranolol-treated) and 57 Child-Pugh C (41 propranolol-treated) patients died of cirrhosis-related complications. Compared to those nontreated, propranolol-treated Child-Pugh B patients showed significantly higher mortality after 2 years of follow-up. On the other hand, mortality became increasingly significant in propranolol-treated Child-Pugh C patients or those with MELD score ≥18 compared to nontreated patients after 6 months of follow-up (Fig. 1). Mean survival was 10.1 ± 1.1 months in propranolol-treated and 15 ± 1.4 months in nontreated Child-Pugh C patients (P = 0.03). The safety of NSBBs in advanced cirrhosis due to reduction in cardiac reserve has been an issue of intense debate in recent years.3 Unlike our observations, Mookerjee et al. recently presented data showing significantly higher survival in patients with advanced cirrhosis presenting with acute-on-chronic liver failure (ACLF) who were taking NSBBs compared to those who were not.4 However, among the 155 patients on NSBBs, 78 discontinued NSBB treatment after the diagnosis of ACLF. Mortality was also significantly higher in patients who stopped NSBBs after being diagnosed with ACLF compared to those who continued NSBBs, but the former patient group had significantly worse circulatory failure, respiratory failure, and Chronic Liver Failure Consortium ACLF score at diagnosis of ACLF. A more appropriate comparison should be between patients who did not discontinue NSBBs after ACLF diagnosis and patients not taking NSBBs prior to ACLF diagnosis. Yet untreated patients had higher rates of circulatory (18.9% versus 9.1%), respiratory (10.3% versus 3.9%), cerebral (27.6% versus 18.2%), and coagulation (35.7% versus 26%) failures as well as grade 3 ACLF (16.7% versus 3.9%) than patients on NSBBs, which might also result in a questionable survival benefit over the use of NSBBs. Consequently, it is reasonable to assume that the results might be different or even reversed if the two patient groups had similar organ failure characteristics and severity of ACLF. In addition, Mookerjee et al reported only on short-term (up to 3 months) survival. Considering the above limitations, the findings of Mookerjee et al. cannot be extrapolarated to patients with stable advanced cirrhosis, such as those included in our study, for whom a clinical decision for initiation of long-term treatment with NSBBs should be made. All in all, our observations justify the concerns recently raised over NSBB treatment in patients with decompensated cirrhosis. In particular, propranolol use beyond 6 months in Child-Pugh C patients with ascites is associated with increased mortality. Georgios N. Kalambokis, M.D.1 Dimitrios Christodoulou, M.D.2 Gerasimos Baltayiannis, M.D.2 Leonidas Christou, M.D.1 11st Division of Internal Medicine 2Division of Gastroenterology Medical School, University of Ioannina Ioannina, Greece