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