Statin, aspirin and metformin use and risk of hepatocellular carcinoma related outcomes following liver transplantation: A retrospective study

doi:10.5500/wjt.v14.i3.94914

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World Journal of Transplantation

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2220-3230

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Retrospective Study

World J Transplant. Sep 18, 2024; 14(3): 94914
Published online Sep 18, 2024. doi: 10.5500/wjt.v14.i3.94914

Table 1 Summary patient characteristics

	n	%
Patients	305
Sex (Male)	253	82.95
Age at LT [median (Q1-3)]	58.90 (53.8-63)
Aetiology of liver disease
HBV	73	23.93
HCV	150	49.18
Alcohol related liver disease	86	28.20
NAFLD	33	10.82
Co-morbidities prior to LT
Diabetes	96	31.48
Hypertension	73	23.93
Stroke	6	1.97
Obesity (BMI > 30)	103	33.77
Total cholesterol ≥ 4 mmol/L	253	82.95
AFP ≥ 100 ng/mL	26	8.52
Regional therapy ≥ 3	140	45.90
Largest diameter of HCC ≥ 3 cm	97	31.80
Histology
Microvascular invasion	40	13.11
Beyond Milan criteria	90	29.51
Beyond Up-to-7 criteria	52	17.05
Complete response at LT	107	35.08
Follow up time [median months (Q1-Q3)]	59.90 (27.93-99.61)
HCC-recurrence (overall)	34	11.15
HCC-recurrence after 24 months	16	5.25
All-cause mortality	48	15.74
Composite endpoint of HCC-recurrence or all-cause mortality	65	21.31
HCC-related mortality	17	5.57

LT: Liver transplantation; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NAFLD: Non-alcoholic fatty liver disease; AFP: Alfa-fetoprotein; BMI: Body mass index; HCC: Hepatocellular carcinoma.

Table 2 Summary of pharmacotherapy use within 24 months of liver transplantation

	n	%
Statin use	56	18.36
Aspirin use	51	16.72
Metformin use	50	16.39
Statins, aspirin or metformin use	126	41.31
MTORi use	85	27.87

Pharmacotherapy included only if prescribed for ≥ 29 days, within 2 years following liver transplantation. LT: Liver transplantation; MTORi: Mammalian target of rapamycin inhibitor.

Table 3 Summary patient characteristics of those who had hepatocellular carcinoma -recurrence vs no hepatocellular carcinoma – recurrence, n (%)

Characteristics	HCC-recurrence	No HCC-recurrence	P value
Total	34	277
Sex (male)	30 (88.24)	223 (82.29)	0.39
Age at LT [median (Q1-Q3)]	58.83 (53.85-62.35)	58.9 (53.9-63.1)	0.79
Aetiology of liver disease
HBV	12 (35.29)	61 (22.51)	0.1
HCV	20 (58.82)	130 (47.97)	0.23
Alcohol related liver disease	5 (14.71)	81 (29.89)	0.064
NAFLD	3 (8.82)	30 (11.07)	0.69
Pre LT co-morbidities
Diabetes	9 (26.47)	87 (32.10)	0.51
Hypertension	7 (20.59)	66 (24.35)	0.63
Stroke	2 (5.88)	5 (1.85)	0.67
Ischaemic heart disease	0 (0)	7 (2.58)	0.35
Obesity (BMI > 30)	12 (35.29)	91 (33.58)	0.84
Total cholesterol ≥ 4 mmol/L [median (Q1-Q3)]	26 (76.47)	227 (83.76)	0.29
Pre-LT AFP ≥ 100 ng/mL	9 (26.47)	17 (6.27)	< 0.01
Pre-LT regional therapy ≥ 3	22 (64.71)	118 (43.54)	0.02
Pre-LT largest diameter of HCC ≥ 3 cm	19 (55.88)	78 (28.78)	< 0.01
Histology: Microvascular invasion	13 (38.24)	27 (9.96)	< 0.01
All-cause mortality	18 (52.84)	30 (11.07)	< 0.01
Death within 2 years	11 (32.35)	11 (4.06)	< 0.01
Beyond Milan criteria	20 (58.82)	70 (25.83)	< 0.01
Beyond up-to-7 criteria	14 (41.18)	38 (14.03)	< 0.01
Complete response prior to LT	6 (17.65)	101 (37.27)	0.024
Chemoprophylaxis
Statins	4 (11.76)	52 (19.19)	0.29
Aspirin	15 (44.12)	36 (13.28)	< 0.01
Metformin	6 (17.65)	44 (16.24)	0.84
Statins, metformin or aspirin use	20 (58.82)	106 (39.11)	0.028
MTORi use	10 (29.41)	75 (27.68)	0.83
Follow up time [median months (Q1-Q3)]	30.46 (8.97-58.87)	65.99 (30.97-104.70)	< 0.01

Statin, aspirin and metformin use was defined as use for at least 29 days, started within 24 months of liver transplantation. Comparison between groups by Mann-Whitney U test. LT: Liver transplantation; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NAFLD: Non-alcoholic fatty liver disease; AFP: Alfa-fetoprotein; BMI: Body mass index; HCC: Hepatocellular carcinoma; MTORi: Mammalian target of rapamycin inhibitor.

Table 4 Univariate and multivariate analysis for the composite endpoint of hepatocellular carcinoma recurrence or all-cause mortality

	Univariate analysis	P value	Multivariate analysis	P value
Variables
Sex	1.94 (95%CI: 0.79-4.76)	0.15	2.02 (95%CI: 0.82-4.96)	0.12
Age at LT	1.03 (95%CI: 1.00-1.06)	0.10	1.02 (95%CI: 0.98-1.05)	0.33
Aetiology of liver disease
HBV	1.33 (95%CI: 0.72-2.44)	0.37
HCV	1.21 (95%CI: 0.70-2.10)	0.50
NAFLD	0.97 (95%CI: 0.39-2.41)	0.95
Statin use	1.20 (95%CI: 0.59-2.41)	0.62	1.16 (95%CI: 0.58-2.30)	0.67
Aspirin use	1.01 (95%CI: 0.22-4.61)	0.99	1.21 (95%CI: 0.28-5.27)	0.80
Metformin use	0.68 (95%CI: 0.31-1.50)	0.34	0.61 (95%CI: 0.27-1.36)	0.23
Statins, aspirin or metformin use¹	1.10 (95%CI: 0.60-2.01)	0.76	1.06 (95%CI: 0.56-1.91)	0.85
MTORi use	1.14 (95%CI: 0.59-2.21)	0.70	0.81 (95%CI: 0.43-1.53)	0.51
Pre LT co-morbidities
Diabetes	1.08 (95%CI: 0.61-1.93)	0.79
Stroke	0.98 (95%CI: 0.14-7.02)	0.99
Hypertension	0.68 (95%CI: 0.35-1.33)	0.26
Obesity	0.68 (95%CI: 0.37-1.26)	0.22
Ischaemic heart disease	2.08 (95%CI: 0.52-8.22)	0.27
Total cholesterol mmol/L	0.58 (95%CI: 0.30-1.12)	0.11
Other variables
Microvascular invasion	3.54 (95%CI: 1.97-6.34)	< 0.01	2.82 (95%CI: 1.51-5.27)	< 0.01
Pre-LT AFP ≥ 100 ng/mL pre-LT	3.04 (95%CI: 1.53-6.02)	< 0.01	2.73 (95%CI: 1.38-5.40)	< 0.01
Pre-LT Regional treatments ≥ 3	1.26 (95%CI: 0.73-2.18)	0.41
Pre-LT size of largest lesion ≥ 3 cm	1.62 (95%CI: 0.93-2.83)	0.092	1.50 (95%CI: 0.86-2.61)	0.16
Beyond Milan	2.06 (95%CI: 1.19-3.56)	0.01
Beyond up-to-7	2.25 (95%CI: 1.23-4.10)	< 0.01	1.68 (95%CI: 0.94-2.99)	0.077
Complete response at LT	0.77 (95%CI: 0.43-1.38)	0.38

¹Multivariate analysis performed separately with the composite variable of statins, aspirin or metformin use included a priori.

Hypertension Systolic Blood Pressure > 140 mmHg. HBV: Hepatitis B virus; HCV: Hepatitis C virus; NAFLD: Non-alcoholic fatty liver disease; AFP: Alfa-fetoprotein; BMI: Body mass index; MTORi: Mammalian target of rapamycin inhibitor; LT: Liver transplantation.

Table 5 Univariate and multivariate analysis for the endpoint of hepatocellular carcinoma recurrence

Variables	Univariate analysis		Multivariate analysis
Variables	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value
Sex	1.88 (95%CI: 0.63-5.60)	0.26	2.27 (95%CI: 0.64-8.02)	0.22
Age at LT	1.02 (95%CI: 0.98-1.07)	0.84	1.01 (95%CI: 0.96-1.05)	0.81
Aetiology of liver disease
HBV	2.09 (95%CI: 0.98-4.45)	0.06	1.98 (95%CI: 0.92-4.27)	0.081
HCV	1.68 (95%CI: 0.80-3.49)	0.17
NAFLD	0.50 (95%CI: 0.14-1.78)	0.28
Statin use	0.52 (95%CI: 0.22-1.26)	0.40	0.52 (95%CI: 0.20-1.35)	0.18
Aspirin use	0.32 (95%CI: 0.07-1.43)	0.14	0.51 (95%CI: 0.14-1.93)	0.32
Metformin use	0.90 (95%CI: 0.33-2.46)	0.84	1.0 (95%CI: 0.37-2.72)	1.00
Statin, aspirin or metformin use¹	0.61 (95%CI: 0.27-1.37)	0.45	0.64 (95% 0.27-1.53)	0.31
MTORi use	0.97 (95%CI: 0.49-1.93)	0.94	0.68 (95%CI: 0.41-1.13)	0.14
Pre LT co-morbidities
Diabetes	0.67 (95%CI: 0.30-1.51)	0.33
Stroke	1.88 (95%CI: 0.26-13.50)	0.53
Hypertension	0.67 (95%CI: 0.26-1.73)	0.41
Obesity	0.96 (95%CI: 0.45-2.08)	0.92
Ischaemic heart disease	N/A	N/A
Total cholesterol mmol/L	0.59 (95%CI: 0.25-1.42)	0.24
Other variables
Microvascular invasion	5.34 (95%CI: 2.54-11.21)	< 0.01	4.04 (95%CI: 1.81-9.04)	< 0.01
AFP > 100 ng/mL pre-LT	4.20 (95%CI: 1.86-9.51)	< 0.01	3.14 (95%CI: 1.33-7.41)	< 0.01
Pre-LT regional treatments ≥ 3	2.27 (95%CI: 1.07-4.84)	0.033	1.46 (95%CI: 0.60-3.52)	0.40
Pre-LT size of largest lesion ≥ 3 cm	3 (95%CI: 1.43-6.31)	< 0.01	2.21 (0.96-5.06)	0.062
Beyond Milan	4.31 (95%CI: 2.09-8.89)	< 0.01
Beyond up-to-7	4.59 (95%CI: 2.22-9.49)	< 0.01	2.82 (95%CI: 1.35-5.89)	< 0.01
Complete response at LT	0.36 (95%CI: 0.14-0.92))	0.034	0.66 (95%CI: 0.24-1.81)	0.42

¹Multivariate analysis performed separately with the composite variable of statins, aspirin or metformin use included a priori.

N/A indicates numbers insufficient to calculate hazard ratio, confidence interval, and P value. Hypertension: Systolic blood pressure > 140 mmHg. HBV: Hepatitis B; HCV: Hepatitis C; NAFLD: Non-alcoholic fatty liver disease; AFP: Alfa-fetoprotein; BMI: Body mass index; LT: Liver transplantation.

Table 6 Univariate and multivariate analysis for the endpoint of hepatocellular carcinoma related mortality

Variables	Univariate analysis		Multivariate analysis
Variables	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value
Sex	0.87 (95%CI: 0.20-3.84)	0.86	0.90 (95%CI: 0.23-3.56)	0.88
Age at LT	1.02 (95%CI: 0.93-1.12)	0.68	1.05 (95%CI: 0.94-1.17)	0.36
Aetiology of liver disease
HBV	1.19 (95%CI: 0.34-4.21)	0.78
HCV	1.41 (95%CI: 0.41-4.21)	0.57
NAFLD	0.80 (95%CI: 0.16-3.90)	0.78
Statin use	0.46 (95%CI: 0.059-3.53)	0.45	0.32 (95%CI: 0.033-3.09)	0.32
Aspirin use	0.50 (95%CI: 0.10-2.40)	0.39	0.71 (95%CI: 0.14-3.73)	0.69
Metformin use	1.27 (95%CI: 0.36-4.49)	0.71	1.57 (95%CI: 0.61-4.04)	0.35
Statins, aspirin or metformin use¹	0.67 (95%CI: 0.21-2.08)	0.48	0.61 (95%CI: 0.18-2.08)	0.43
MTORi use	0.96 (95%CI: 0.35-2.65)	0.93	0.63 (95%CI: 0.26-1.49)	0.29
Pre LT co-morbidities
Diabetes	0.62 (95%CI: 0.11-3.51)	0.59
Stroke	N/A
Hypertension	0.29 (95%CI: 0.06-1.47)	0.14
Obesity	0.35 (95%CI: 0.10-1.15)	0.08	0.23 (95%CI: 0.06-0.85)	0.027
Ischaemic heart disease	N/A	N/A
Total cholesterol mmol/L	0.77 (95%CI: 0.17-3.45)	0.74
Other variables
Microvascular invasion	7.52 (95%CI: 2.22-25.47)	< 0.01	8.05 (95%CI: 2.63-24.68)	< 0.01
AFP > 100 ng/mL immediately pre-LT	2.83 (95%CI: 0.85-9.44)	0.09	3.11 (95%CI: 0.70-13.76)	0.14
Pre-LT regional treatments ≥ 3	1.58 (95%CI: 0.45-5.52)	0.48
Pre-LT size of largest lesion ≥ 3 cm	2.19 (95%CI: 0.60-7.96)	0.23
Beyond Milan	2.72 (95%CI: 0.80-9.30)	0.11
Beyond up-to-7	5.29 (95%CI: 1.55-18.13)	< 0.01	4.14 (95%CI: 1.09-15.81)	0.038
Complete response at LT	0.32 (95%CI: 0.055-1.88)	0.21

¹Multivariate analysis performed separately with the composite variable of statins, aspirin or metformin use included a priori.

N/A indicates numbers insufficient to calculate hazard ratio and P value. Hypertension: Systolic blood pressure > 140 mmHg. HBV: Hepatitis B virus; HCV: Hepatitis C virus; NAFLD: Non-alcoholic fatty liver disease; AFP: Alfa-fetoprotein; BMI: Body mass index; LT: Liver transplantation.

Citation: Chung W, Wong K, Ravindranayagam N, Tang L, Grace J, Wong D, Con D, Sinclair M, Majumdar A, Kutaiba N, Hui S, Gow P, Muralidharan V, Dobrovic A, Testro A. Statin, aspirin and metformin use and risk of hepatocellular carcinoma related outcomes following liver transplantation: A retrospective study. World J Transplant 2024; 14(3): 94914
URL: https://www.wjgnet.com/2220-3230/full/v14/i3/94914.htm
DOI: https://dx.doi.org/10.5500/wjt.v14.i3.94914