Nonselective beta-blocker use is associated with increased hepatic encephalopathy-related readmissions in cirrhosis

Table 1 Baseline characteristics of the patients on the first liver-related hospitalization

	Whole group (n = 393)	NSBB group (n = 143)	No-NSBB group (n = 250)	P value
Age, yr	58.1 ± 10.2	57.5 ± 8.8	58.4 ± 11.0	0.392
Gender, male	229 (58.3)	88 (61.5)	141 (56.4)	0.323
Heart rate, bpm	84 (44-161)	76 (44-122)	87 (50-161)	< 0.0014
Etiology of liver disease1				0.323
Hepatitis C virus	129 (32.8)	55 (38.5)	74 (29.6)
Alcoholic	124 (31.6)	38 (26.6)	86 (34.4)
NASH	49 (12.5)	17 (11.9)	32 (12.8)
Cryptogenic	51 (13.0)	21 (14.7)	30 (12.0)
Other causes	56 (14.2)	23 (16.1)	33 (13.2)
CTP score				0.0543
A	28 (7.1)	13 (9.1)	15 (6.0)
B	172 (43.8)	71 (49.7)	101 (40.4)
C	193 (49.1)	59 (41.3)	134 (53.6)
MELD score	19 (6-40)	17 (6-39)	19 (6-40)	0.024
MELD-Na score	22 (6-40)	20 (6-39)	22.5 (6-40)	0.0054
History of hepatocellular carcinoma	29 (7.4)	8 (5.6)	21 (8.4)	0.313
History of esophageal varices	154 (39.2)	84 (58.7)	70 (28.0)	< 0.0013
History of TIPS	47 (12.0)	17 (11.9)	30 (12.0)	0.973
Presence of HE	323 (82.2)	113 (79.0)	210 (84.0)	0.223
Lactulose use	285 (72.5)	107 (74.8)	178 (71.2)	0.443
Rifaximin use	208 (52.9)	81 (56.6)	127 (50.8)	0.263
Presence of ascites	144 (36.7)	50 (35.0)	94 (37.8)	0.583
International normalized ratio	1.5 (1-14)	1.4 (1-4)	1.6 (1-14)	0.0034
Platelet count, × 10-3/mm3	84 (4-515)	72 (15-280)	95 (4-515)	0.0024
White cell count, × 10-3/mm3	6.8 (0.2-51.9)	5.7 (1.3-43.7)	7.7 (0.2-51.9)	< 0.0014
Creatinine, mg/dL	1.3 (0.3-33.0)	1.4 (0.4-33.0)	1.3 (0.3-9.3)	0.594
Total bilirubin, mg/dL	2.7 (0.2-137.0)	2.5 (0.2-43.0)	3.1 (0.3-137.0)	0.034
Serum Albumin, g/dL	2.7 (1.0-5.0)	2.8 (2.0-5.0)	2.6 (1.0-5.0)	0.024
Aspartate aminotransferase, U/L	59 (3-4048)	51 (8-677)	67 (3-4048)	< 0.0014
Alanine aminotransferase, U/L	39 (10-1180)	34 (13-538)	41 (10-1180)	0.024

Data are presented as n (%), mean ± SD or median (range).

¹The cumulative percent exceeds 100% as some patients had multiple etiologies of liver disease.

²P calculated by Independent-samples t-test.

³P calculated by χ² test.

⁴P calculated by Mann-Whitney U test.

CTP: Child-Turcotte-Pugh; HE: Hepatic encephalopathy; NSBB: Nonselective beta-blocker; MELD: Model for End-Stage Liver Disease; Na: Sodium; NASH: Non-alcoholic steatohepatitis; TIPS: Transjugular intrahepatic portosystemic shunt.

Table 2 Type, dose and number of patients on nonselective or selective beta-blockers

	Number of patients	Total daily dose (mg)
Nonselective beta-blocker (n = 143)
Nadolol	66 (46.2)	20 (20-80)
Propranolol	62 (43.4)	30 (10-80)
Carvedilol	15 (10.5)	12.50 (6.25-50.00)
Selective beta-blocker (n = 39)
Metoprolol	35 (89.7)	50.00 (12.50-200.00)
Atenolol	4 (10.3)	50 (25-100)

Data are presented as n (%) or median (range).

Table 3 Univariate and multivariate Cox regression predicting the first hepatic encephalopathy-related readmission

Variable	Unadjusted		Adjusted
	HR (95%CI)	P value	HR (95%CI)	P value
Age, yr	1.00 (0.99-1.02)	0.93
Gender, male	1.03 (0.77-1.38)	0.82
MELD-Na score (reference: MELD-Na score < 15)
15 ≤ MELD-Na score ≤ 24	1.26 (0.88-1.79)	0.21
25 ≤ MELD-Na score ≤ 34	0.89 (0.58-1.36)	0.60
MELD-Na score > 34	0.38 (0.09-1.55)	0.18
History of EV, presence of	1.24 (0.93-1.66)	0.15
History of TIPS, presence of	1.34 (0.89-2.01)	0.16	1.48 (0.98-2.25)	0.065
NSBB use, presence of	1.81 (1.35-2.41)	< 0.001	1.74 (1.29-2.34)	< 0.001
SBB use, presence of	0.90 (0.55-1.46)	0.66
Lactulose use, presence of	1.28 (0.89-1.82)	0.18
Rifaximin use, presence of	0.88 (0.66-1.18)	0.40
Ascites, presence of	1.10 (0.81-1.48)	0.55
Platelet count, × 10-3/mm3	0.996 (0.994-0.999)	0.008	0.997 (0.995-1.000)	0.07

EV: Esophageal varices; HR: Hazard ratio; MELD-Na: Model for End-Stage Liver Disease-Sodium; NSBB: Nonselective beta-blocker; SBB: Selective beta-blocker; TIPS: Transjugular intrahepatic portosystemic shunt.

Table 4 Negative binomial generalized regression model predicting hepatic encephalopathy-related admissions per person-month

Variable	IRR (95%CI)	P value	B value
Age, yr	0.99 (0.98-1.01)	0.19	-0.010
Gender, male	1.10 (0.82-1.48)	0.54	0.094
MELD-Na score	1.05 (1.03-1.08)	< 0.001	0.052
History of EV, presence of	0.98 (0.72-1.35)	0.92	-0.016
History of TIPS, presence of	1.93 (1.24-3.01)	0.003	0.660
NSBB use, presence of	1.50 (1.08-2.07)	0.015	0.403
SBB use, presence of	0.81 (0.50-1.31)	0.40	-0.208
Lactulose use, presence of	1.47 (1.00-2.15)	0.048	0.384
Rifaximin use, presence of	0.73 (0.53-1.00)	0.050	-0.319
Ascites, presence of	1.26 (0.93-1.72)	0.14	0.233
Platelet count, × 10-3/mm3	0.997 (0.995-1.000)	0.03	-0.003

EV: Esophageal varices; IRR: Incidence rate ratio; MELD-Na: Model for End-Stage Liver Disease-Sodium; NSBB: Nonselective beta-blocker; SBB: Selective beta-blocker; TIPS: Transjugular intrahepatic portosystemic shunt.