Renin-angiotensin inhibitors were associated with improving outcomes of hepatocellular carcinoma with primary hypertension after hepatectomy

Abstract

Background: The activation of the renin-angiotensin system (RAS) promotes tumor progression. In this study, we aimed to assess whether RAS inhibitors (RASIs) could improve the outcome of hepatocellular carcinoma (HCC) patients with primary hypertension after curative liver resection.

Methods: Data on 387 consecutive patients with primary hypertension who underwent curative liver resection for HCC were reviewed. The study population was divided into two groups based on the type of anti-hypertensive medications: the RASI group (patients using RASIs) and the non-RASI group (patients using other anti-hypertensive drugs but not RASIs). Kaplan-Meier curves, log-rank tests and cox proportional hazards regression models were used to analyze time to recurrence (TTR) and overall survival (OS).

Results: There were 144 (37.2%) patients in RASI group and 243 (62.8%) in non-RASI group. The preoperative clinicopathological features were comparable between the two groups. Kaplan-Meier curves demonstrated HCC patients with RASIs had a longer TTR and OS than the patients with non-RASIs (both P<0.001). On multivariate analysis, RASIs administration was identified as an independent prognostic factor for TTR [hazard ratio (HR) =0.52, 95% confidence interval (CI), 0.38-0.70, P<0.001] and OS (HR =0.50, 95% CI, 0.34-0.74, P<0.001). Patients in the RASI group had lower rates of extrahepatic metastases than patients in the non-RASI group (2.8% vs. 7.8%, P<0.042).

Conclusions: Targeting the RAS was associated with a reduced risk of recurrence, decreased rate of extrahepatic metastases and prolonged survival of HCC patients with primary hypertension after curative liver resection.

Keywords: Hepatocellular carcinoma (HCC); hypertension; prognosis; renin-angiotensin system (RAS).

Figure 1

The flow chart of our study. HCC, hepatocellular carcinoma; RASI, the inhibitor of renin-angiotensin system.

Figure 2

Tumor recurrence and overall survival of the patients taking different anti-hypertensive drugs. Recurrence of patients who taking RASI or non-RASI patients (A), β-blocker or non-β-blocker (B), and CCB or non-CCB (C); overall survival of patients who taking RASI or non-RASI patients (D), β-blocker or non-β-blocker (E), and CCB or non-CCB (F). RASI, the inhibitor of Renin-angiotensin system; CCB, calcium channel blocker.

Figure 3

Recurrence and overall survival of ACEI and ARB. (A) Recurrence of ACEI and ARB patients; (B) overall survival of ACEI and ARB patients. ACEI, Angiotensin-converting enzyme inhibitors; ARB, Ang II type 1 receptor blocker.

Figure S1

The details of the anti-hypertensive drugs used in our study. (A) The details of the anti-hypertensive drugs used in all cases. A, angiotensin-converting enzyme inhibitors/Ang II type 1 receptor blocker; B, beta-blocker; C, calcium channel blocker; D, diuretic; O, others, including reserpine, Dihydralazine and Chinese patent drugs. (B), the anti-hypertensive drugs used in RASI Group. All the patients took RASIs and some took more than one anti-hypertensive drugs; (C) the anti-hypertensive drugs used in non-RASI Group. Most patients took calcium channel blocker.

Figure S2

Forest map of univariate analysis for overall survival. ALB, albumin; ALT, alanine transaminase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, γ-glutamyl transpeptidase; AFP, alpha fetal protein; PT, prothrombin time; INR, international normalized ratio; PLT, platelets; PM, Pringle maneuver; MVI, microvascular invasion; RASI, the inhibitor of Renin-angiotensin system; BCLC Stages, Barcelona Clinic Liver Cancer Staging.

Figure S3

Forest map of univariate analysis for recurrence. ALB, albumin; ALT, alanine transaminase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, γ-glutamyl transpeptidase; AFP, alpha fetal protein; PT, prothrombin time; INR, international normalized ratio; PLT, platelets; PM, Pringle maneuver; MVI, microvascular invasion; RASI, the inhibitor of Renin-angiotensin system; BCLC Stages, Barcelona Clinic Liver Cancer Staging.

Figure S4

Forest map of univariate analysis for overall survival of HBV-hepatocellular carcinoma patients. ALB, albumin; ALT, alanine transaminase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, γ-glutamyl transpeptidase; AFP, alpha fetal protein; PT, prothrombin time; INR, international normalized ratio; PLT, platelets; PM, Pringle maneuver; MVI, microvascular invasion; RASI, the inhibitor of Renin-angiotensin system; BCLC Stages, Barcelona Clinic Liver Cancer Staging.

Figure S5

Forest map of univariate analysis for recurrence of HBV-hepatocellular carcinoma patients. ALB, albumin; ALT, alanine transaminase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, γ-glutamyl transpeptidase; AFP, alpha fetal protein; PT, prothrombin time; INR, international normalized ratio; PLT, platelets; PM, Pringle maneuver; MVI, microvascular invasion; RASI, the inhibitor of Renin-angiotensin system; BCLC Stages, Barcelona Clinic Liver Cancer Staging.