Nonselective Beta-blockers Are Associated With a Lower Risk of Hepatocellular Carcinoma Among Cirrhotic Patients in the United States

Karn Wijarnpreecha; Fang Li; Yang Xiang; Xun Xu; Cong Zhu; Vahed Maroufy; Qing Wang; Wei Tao; Yifang Dang; Huy Anh Pham; Yujia Zhou; Jianfu Li; Xinyuan Zhang; Hua Xu; C. Burcin Taner; Liu Yang; Cui Tao


Aliment Pharmacol Ther. 2021;54(4):481-492. 

In This Article

Abstract and Introduction


Background: Previous studies have demonstrated an association between nonselective beta-blockers (NSBBs) and lower risk of hepatocellular carcinoma (HCC) in cirrhosis. However, there has been no population-based study investigating the risk of HCC among cirrhotic patients treated using carvedilol.

Aims: To determine the risk of HCC among cirrhotic patients with NSBBs including carvedilol.

Methods: This retrospective cohort study utilised the Cerner Health Facts database in the United States from 2000 to 2017. Kaplan-Meier estimate, Cox proportional hazards regression, and propensity score matching (PSM) were used to test the HCC risk among the carvedilol, nadolol, and propranolol groups compared with no beta-blocker group.

Results: The final cohort comprised 107 428 eligible patients. The 100-month cumulative HCC incidence of NSBBs was significantly lower than the no beta-blocker group (carvedilol (11.24%) vs no beta-blocker (15.69%), nadolol (27.55%) vs no beta-blocker (32.11%), and propranolol (26.17%) vs no beta-blocker (28.84%) (P values < 0.0001). NSBBs were associated with a significantly lower risk of HCC (Hazard ratio: carvedilol 0.61 (95% CI 0.51–0.73), nadolol 0.74 (95% CI 0.63–0.87), propranolol 0.75 (95% CI 0.66–0.84) after PSM in the multivariate cox analysis. In subgroup analysis, NSBBs reduced the risk of HCC in cirrhosis with complications and non-alcoholic cirrhosis.

Conclusions: NSBBs, including carvedilol, were associated with a significantly decreased risk of HCC in patients with cirrhosis when compared with no beta-blocker regardless of complications status. Future randomised-controlled studies comparing the incidence of HCC among NSBBs should elucidate which NSBB would be the best option to prevent HCC in cirrhosis.


Liver cirrhosis is an important public health concern and an increasing cause of morbidity and mortality in the United States.[1] It can be subclassified into distinct clinical prognostic stages, with 1-year mortality ranging from 1% to 57% depending on the stage.[2] Portal hypertension underlies many of its fatal complications.[3] Nonselective beta-blockers (NSBBs) have been recommended for bleeding prophylaxis in cirrhotic patients with esophageal varices.[4] The NSBBs that are commonly used to treat portal hypertension are propranolol and nadolol. The newer option is carvedilol, which also has the alpha-adrenergic vasodilating effect that decreases intrahepatic resistance and causes a marked reduction in portal pressure compared to propranolol and nadolol.[5,6] Recent studies revealed that NSBBs were not associated with increased mortality in patients with cirrhosis and ascites.[7,8] In addition, carvedilol treatment was associated with improved survival in patients with cirrhosis and ascites according to the latest research.[3,9]

Interestingly, aside from the benefit in preventing variceal bleeding, the study suggested that NSBBs may prevent hepatocellular carcinoma (HCC) in patients with cirrhosis based on the meta-analysis of 23 randomised trials.[10] Cirrhosis of any cause generally increases the risk of HCC between 3 and 5 percent annually.[11,12] The blockage of beta-adrenergic receptors has effects not only on the portal pressure but also on non-hemodynamic parameters, including a decrease in angiogenesis, which may prevent the development of HCC, and reduce bacterial translocation.[13] Other than impacts on the beta-adrenergic receptor, carvedilol also has additional effects on calcium influx, and inhibition of the ROS-mediated PI3K/AKT signaling pathway, both of which have inhibitory effects on carcinogenesis or tumor progression.[14] Multiple studies have compared the incidence of HCC among cirrhotic patients treated with propranolol or nadolol with those receiving no beta-blocker treatment.[10] However, no study has ever investigated the potential difference in the incidence of HCC among cirrhotic patients treated with carvedilol vs no beta-blocker group. Furthermore, no data compared the incidence of HCC between patients with compensated cirrhosis vs decompensated cirrhosis who take carvedilol vs no beta-blocker. Thus, we conducted this study to compare the HCC incidence among the NSBBs group (propranolol, nadolol, and carvedilol) with no beta-blocker group, and to elucidate the association between NSBBs and risk of HCC in cirrhotic patients.