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

Disclosures

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

In This Article

Results

Cohort Characteristics

The study population consisted of 107 428 cirrhotic adults identified from the Cerner Health Facts database after applying the inclusion and exclusion criteria. Among them, 5581 (5.20%) used carvedilol (continued use ≥30 days), 2353 (2.19%) used nadolol (continued use ≥30 days), 4273 (3.98%) used propranolol (continued use ≥30 days), and 95 221 (88.64%) did not use any beta-blockers. The cohort characteristics, as well as comparisons between three NSBBs and no beta-blocker before and after PSM with a ratio of 2:1, are listed in Table 1. After PSM, the factors that were relevant to the cirrhotic severity (including sex, risk factors and complications, comorbidities, and comedications) between NSBBs and no beta-blocker had almost no significant difference (most P values were > 0.05). The matched cohort datasets, which encompassed the same feature distribution, supported the impartial comparative analyses between NSBBs and no beta-blocker, including HCC incidence, HRs and ORs illustrated in the following sections.

HCC Incidence

For the full cohort, during a median follow-up of 4.62 years (min-max: 0.08–15.17 years), HCC newly developed in 4209 patients (3.92%). From the Kaplan-Meier estimator, the total distribution of cumulative HCC incidence between carvedilol and no beta-blocker, nadolol and no beta-blocker, and propranolol and no beta-blocker groups showed significant differences (all P values were < 0.0001 by log-rank test) in their full datasets (Figure 2), demonstrating all of them had protective effects of HCC. For the 100-month cumulative HCC incidence, carvedilol vs no beta-blocker was 11.24% (95% CI: 0.07–0.16) vs 15.69% (95% CI: 0.13–0.18), nadolol vs no beta-blocker was 27.55% (95% CI: 0.21–0.34) vs 32.11% (95% CI: 0.28–0.37), and propranolol vs no beta-blocker was 26.17% (95% CI: 0.22–0.31) vs 28.84% (95% CI: 0.26–0.32). For subgroups, including with complications, with varices/portal hypertension and non-alcoholic cirrhosis, the 100-month cumulative HCC incidence of three NSBB groups were also significantly lower than that of the no beta-blocker group.

Figure 2.

Cumulative incidence of HCC among carvedilol, nadolol, propranolol, and no beta-blockers

HRs of HCC

Figure 3 shows HRs of different variables associated with HCC incidence in the carvedilol—no beta-blocker group after PSM with the ratio 2:1 (n = 16 743) using multivariate Cox analysis. Taking 18 ≤ age < 45 as reference, the other three age groups (ie, 45 ≤ age < 65, 65 ≤ age < 80, and age ≥ 80) all demonstrate significantly higher HRs: 3.95 (95% CI: 2.36–6.62, P < 0.001), 4.86 (95% CI: 2.87–8.22, P < 0.001) and 5.92 (95% CI: 3.32–10.56, P < 0.001), respectively. Compared with males, females present a significant protective effect with HR 0.70 (95% CI: 0.59–0.82, P < 0.001). Using Caucasian as the baseline, among all other races, Hispanic shows significant higher risk with HR 2.31 (95% CI: 1.30–4.11, P = 0.004). For the co-medications, aspirin and statin use show significantly lower HRs (0.64 [95% CI: 0.53–0.77, P < 0.001] and 0.58 [95% CI: 0.49–0.68, P < 0.001], respectively), confirming their HCC protective effect reported from previous studies.[20,21]

Figure 3.

Hazard ratios of variables associated with HCC incidence in multivariate Cox analysis. *P-value <0.05; **P-value <0.005; ***P-value <0.001

Table 2 shows the HRs of HCC in both univariate and multivariate Cox analyses among cirrhotic patients who were treated by NSBBs vs those without beta-blockers. After multivariate adjustment for demographic feature and possible risk and protective factors, compared with the no beta-blocker group, the risk of HCC remains significantly smaller among carvedilol group not only in the full cohort (adjusted HR 0.61, 95% CI: 0.51–0.73, P < 0.001), but also in most subgroups, including cirrhosis with complications (adjusted HR 0.66, 95% CI: 0.54–0.80, P < 0.001), and with varices/portal hypertension (adjusted HR 0.77, 95% CI: 0.61–0.97, P < 0.001), and nonalcoholic cirrhosis (adjusted HR 0.40, 95% CI: 0.31–0.51, P < 0.001). The only exception was in the alcoholic cirrhosis subgroup (adjusted HR 0.88, 95% CI: 0.69–1.12, P = 0.286). Propranolol showed similar significant protective effects as carvedilol, though most of the HRs are relatively higher. It is interesting to note that nadolol is the only NSBB that has significant protective effects in full cohort and subgroup analyses, including in the alcoholic cirrhosis subgroup (adjusted HR 0.80, 95% CI 0.66–0.97, P = 0.024).

Assessment of Effect Modification of Beta-blockers and Risk of HCC

We also assessed effect modification of different subgroups stratified by the demographic characteristics and risk factors (Table 3). The effect modification aims to determine whether the effect of a treatment is different among groups of patients with different characteristics.[22,23] To avoid the flaw of using overlapping confidence intervals to assess effect modification or interaction,[24] we assessed the statistical P value interaction in the subgroup analysis. The subgroup analysis showed that carvedilol had protective effects for HCC in most subgroups regardless of gender status and risk factors (Table 3). All three NSBB groups showed significant protective effects in older groups (age ≥45 years). Interestingly, the protective effect of HCC among African Americans and Hispanics remain significant in the carvedilol group but not in the propranolol and nadolol group.

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