Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma

Table 1 Clinical studies on the effect of angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers exposure in patients affected or at high risk of hepatocellular carcinoma

Interventional studies
Authors	Patients	Treatment	HCC recurrence after 42-54 mo	P value
Yoshiji et al[13]	87 with RFA for prior HCC	I. Control	18/25	I vs II; < 0.01
		II. ACE-I + vit. K2	9/25
			19/19	I vs III, NS
		III. ACE-I	18/18
		IV. vit. K2		I vs IV; NS
Yoshiji et al[14]	89 with Insulin resistance and RFA for prior HCC	I. Control	16/26	I vs II; < 0.01
		II. ACE-I + BCAA	9/28
				I vs III, NS
			11/19
		III. ACE-I	9/16
		IV. BCAA		I vs IV; NS
Yoshiji et al[15]	54 with HCC randomized in 2 groups, before treatment	I. HCC treatment	77%	I vs II < 0.01
		II. HCC treatment + ACE-I and Vit. K
			40%
Observational studies
Authors	Patients	Treatment	OS, HR, OR	P value
Ho et al[16]	7724 HBV-patients	ACE-I or ARB (46.3% in HBV and 42.5% in HCV) within 6 mo after initiating DAAs	HCC risk after ACE-I and ARB exposure	NS1
	7873 HCV- patients		HR = 0.97, 95%CI: 0.81-1.16
	at high-risk of HCC development
			HR = 0.96, 95%CI: 0.80-1.16
			respectively
Hagberg et al[17]	490 HCC	ACE-I or ARBs	OR = 1.14, 95%CI: 0.85-1.55	NS2
	1909 controls		users vs non- users
Walker et al[18]	224 HCC	7% ACE-I users in HCC group	OR = 1.29, 95%CI: 0.88-1.88	NS3
		5.9% ACE-I users in control group
	2313 controls		unexposed vs exposed
Pinter et al[19]	156, with Sorafenib or supportive therapy	ACE-I or ARBs in 43 pts.	OS = 11.9 mo vs 6.8 mo	P = 0.014
				P = 0.011
			HR = 0.6, 95%CI: 0.4-0.9	P = 0.043
				P = 0.038
	76, (confirmation cohort) with sorafenib or supportive therapy
		ACE-I or ARBs in 38 pts.	OS = 19.5 mo vs 10.9 mo
			HR = 0.5, 95%CI: 0.3-1.0
Facciorusso et al[20]	153 with RFA for prior HCC	I: Control,73 pts	OS = 48 mo	I vs II, NS
		II: ACE-I, 49 pts	OS = 72 mo
			OS = 84 mo
				I < III, P < 0.002
		III. ARBs, 31 pts	HR4 = 0.39, 95%CI: 0.22-0.66
Kabori et al[21]	185 HCV-HCC pts. without cirrhosis	I. No hypert.	OS at 5 yr (76/106)	I vs II, NS
		II. Hypert. + ACE/ARB	OS at 5 yr (30/37)
				I > III, P < 0.001
			OS at 5 yr (11/42)
				II > III, P < 0.001
		III. Hypert. + other
		anti-hypertensives
	141 HCV-HCC pts. with cirrhosis	I. No hypertension	OS at 5 yr 51.6%	I and II > III, P = 0.029
			OS at 5 yr 76.7%
		II. Hypert. + ACE/ARB
			OS at 5 yr 37.3%
		III. Hypert. + other
	143 pts. with HCC related to other etiologies	I. No hypertension	OS at 5 yr 59%-74%	NS
			OS at 5 yr 60%-62%
		II. Hypertension

¹Adjusted for sex, age, liver cirrhosis, diabetes mellitus, alcohol consumption, hyperlipidemia, malignancies other than hepatocellular carcinoma (HCC), chronic obstructive pulmonary disease, end-stage renal disease, transplantation, aspirin, metformin, and statins.

²Adjusted odds ratio for HCC risk factors (body mass index, smoking status, alcohol abuse, hepatitis B virus and/or hepatitis C virus, rare metabolic disorders, liver disease, diabetes, and use of statins and acetaminophen) and duration of hypertension. The analysis was also repeated to cases and controls without diabetes and to cases and controls without liver disease demonstrating no significant difference.

³Adjusted for alcohol use, smoking, cirrhosis, and hepatitis.

⁴Adjusted for age, gender, Child-Pugh class and α-fetoprotein. Time to recurrence was significantly reduced in patients receiving angiotensin II type 1 receptor blockers (P = 0.009). RFA: Radiofrequency ablation; OS: Overall survival; OR: Odds ratio; HR: Hazard ratio; ACE-Is: Angiotensin-converting enzyme inhibitors; ARBs: Angiotensin II type 1 receptor blockers; Vit.: Vitamine; CI: Confidence interval; HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; Pts.: Patients. NS: No significance.