Proton pump inhibitor use increases mortality and hepatic decompensation in liver cirrhosis

Table 1 Baseline characteristics between non-users and proton pump inhibitor users for the 6-mo landmark period

Baseline characteristics	Non-user(n = 57)	PPI user(n = 238)	P value
Gender, n (%)			0.96
Male	39 (68.4)	162 (68.1)
Female	18 (31.6)	76 (31.9)
Age in yr, Mean (± SD)	60.0 ± 13.3	63.3 ± 12.4	0.07
Race, n (%)			0.95
Chinese	33 (57.9)	132 (55.5)
Malay	10 (17.5)	50 (21.0)
Indian	8 (14.0)	33 (13.9)
Others	6 (10.5)	23 (9.7)
Aetiology of cirrhosis, n (%)			0.07
Hepatitis B	11 (19.3	42 (17.6)
Alcohol	16 (28.1)	42 (17.6)
Hepatitis C	11 (19.3)	52 (21.8)
NASH	9 (15.8)	74 (31.1)
Autoimmune	4 (7.0)	4 (1.7)
Others	6 (10.5)	24 (10.1)
Index hepatic event, n (%)
HCC	6 (10.5)	20 (8.4)	0.61
Ascites	37 (64.9)	121 (50.8)	0.06
SBP	4 (7.0)	15 (6.3)	0.77
HE	9 (15.8)	59 (24.8)	0.15
Variceal bleed	8 (14.0)	53 (22.3)	0.17
History of the following, n (%)
HCC	0 (0.0)	9 (3.8)	0.21
Ascites	9 (15.8)	32 (13.4)	0.65
HE	1 (1.8)	10 (4.2)	0.70
Variceal bleed	9 (15.8)	42 (17.6)	0.74
SBP	2 (3.5)	6 (2.5)	0.65
Biochemical results at baseline;
Mean (± SD) or median (IQR)
Albumin in g/L	27.0 ± 4.7	28.1 ± 6.2	0.14
INR	1.12 (1.01-1.26)	1.13 (1.03-1.28)	0.73
Creatinine in μmol/L	79.0 (65.0-124.5)	86.0 (66.8-117.0)	0.58
Bilirubin in μmol/L	29.4 (17.0-56.8)	25.9 (16.3-74.0)	0.16
Platelet count as 109/L	105.5 (67.3-150.3)	104.0 (71.0-159.0)	0.82
Haemoglobin in g/dL	11.4 ± 2.3	10.8 ± 2.6	0.15
MELD, median (IQR)	11.0 (8.0-14.5)	10.5 (8.0-14.3)	0.56
Medical comorbidities, n (%)
GERD	0 (0.0)	19 (8.0)	0.03
Esophagitis	4 (7.0)	17 (7.1)	1.00
Peptic ulcer disease	1 (1.8)	32 (13.4)	0.01
Type 2 diabetes1			0.16
None	33 (57.9)	105 (44.1)
Uncomplicated	14 (24.6)	70 (29.4)
End-organ damage	10 (17.5)	63 (26.5)
Malignancy1			0.84
None	47 (82.5)	199 (83.6)
Leukaemia/lymphoma/localised solid tumour	8 (14.0)	33 (13.9)
Metastatic solid tumour	2 (3.5)	6 (2.5)
HIV/AIDS1	1 (1.8)	2 (0.8)
Renal impairment1	9 (15.8)	51 (21.4)
Congestive heart failure1	4 (7.0)	21 (8.8)
Myocardial infarct1	2 (3.5)	33 (13.9)
COPD1	2 (3.5)	9 (3.8)
PVD1	0 (0.0)	4 (1.7)
CVA/TIA1	2 (3.5)	24 (10.1)
Dementia1	1 (1.8)	9 (3.8)
Hemiplegia1	0 (0.0)	3 (1.3)
	2 (3.5)	4 (1.7)
Connective tissue disease1
Baseline medications:
Antivirals for viral hepatitis:
Chronic HBV on long-term antivirals	2/11 (18.2)	14/42 (33.3)	0.48
Chronic HCV treated with DAA2	0/11 (0.0)	3/52 (5.8)	1.00
Use of other concurrent medications, > 3 mo use
Insulin	2 (3.5)	42 (17.6)	0.01
Sulphonylureas	8 (14.0)	51 (21.4)	0.21
Insulin sensitisers	2 (3.5)	24 (10.1)	0.11
Metformin	5 (8.8)	45 (18.9)	0.07
DPP4 inhibitors	4 (7.0)	2 (0.8)	0.01
Antiplatelet	5 (8.8)	45 (18.9)	0.067
Aspirin	5 (8.8)	38 (16.0)	0.17
Statins	2 (3.5)	29 (12.2)	0.06
ACE-I/ARB	4 (7.0)	43 (18.1)	0.04
Non-selective beta blockers	8 (14.0)	81 (34.0)	0.003
Selective beta blockers	2 (3.5)	22 (9.2)	0.19

¹As defined by Charlson’s comorbidity index;

²3 patients given 12 wk of sofosbuvir/daclatasvir/ribavirin for hepatitis C virus cirrhosis; direct acting antiviral only became fully funded in early 2017. NASH: Non-alcoholic steatohepatitis; MELD: Model of end-stage liver disease; GERD: Gastroesophageal reflux disease; HIV/AIDS: Human immunodeficiency virus/acquired immune deficiency syndrome; COPD-Chronic obstructive pulmonary disease; PVD: Peripheral vascular disease; CVA/TIA: Cerebrovascular accident/transient ischemic attack; DPP4: Dipeptidyl peptidase-4; ACE-I/ARB: Angiotensin converting enzyme inhibitor/angiotensin II receptor blocker; DAA: Direct acting antiviral; HE: Hepatic encephalopathy; SBP: Spontaneous bacterial peritonitis; HCC: Hepatocellular carcinoma; IQR: Interquartile range; PPI: Proton pump inhibitor.

Table 2 Mortality risk of proton pump inhibitor users by landmark periods and cumulative dose exposure

Periods	Number of patients	Adjusted HR (95%CI)	P value
6-mo landmark: (-3 to +6 mo)	Non-user = 57 PPI user = 238	Ref 2.10 (1.20-3.67)	0.009
3-mo landmark: (-3 to +3 mo)	Non-user = 71 PPI user = 261	Ref 1.36 (0.90-2.06)	0.143
9-mo landmark: (-3 to +9 mo)	Non-user = 42 PPI user = 221	Ref 3.44 (1.50-7.85)	0.003
Variable Dose Exposure	Number of patients	Adjusted HR (95%CI)	P value
6-mo landmark: (-3 to +6 mo)
Non-user	57	Ref
cDDD 28-90	18	1.34 (0.48-3.73)	0.579
cDDD 91-180	27	2.27 (1.10-5.14)	0.038
cDDD > 180	193	2.08 (1.17-3.61)	0.011
3-mo landmark: (-3 to +3 mo)
Non-user	71	Ref
cDDD 28-90	24	1.49 (0.74-3.03)	0.266
cDDD 91-180	34	2.04 (1.13-3.07)	0.019
cDDD > 180	203	1.33 (0.87 – 2.03)	0.188
9-mo landmark : (-3 to + 9 mo)
Non-user	42	Ref
cDDD 28-90	20	4.02 (1.33-12.12)	0.013
cDDD 91-180	22	3.38 (1.17 – 9.82)	0.025
cDDD > 180	179	3.52 (1.53 – 8.09)	0.003

HR: Hazard ratio (with propensity score adjustment); CI: Confidence interval; cDDD: Cumulative defined daily dose; PPI: Proton pump inhibitor.

Table 3 Hospital admissions for hepatic decompensation for proton pump inhibitor users and non-users with decompensated liver cirrhosis

	Number of patients	Hospital admissions for liver decompensation
		Adjusted RR (95%CI)	P value
Entire cohort	PPI user = 335 Non-user = 116	1.61 (1.30-2.11)	< 0.001
Dose exposure
Non-user	116	Ref
cDDD 28-90	49	0.65 (0.39-1.08)	0.10
cDDD 91-180	61	1.08 (0.74-1.59)	0.69
cDDD > 180	225	1.91 (1.49-2.45)	< 0.001

cDDD: Cumulative defined daily dose; RR: Relative risk; CI: Confidence interval; PPI: Proton pump inhibitor.