Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide and remains a major public health concern [1]. The established risk factors for HCC include chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, exposure to dietary aflatoxin, non-alcoholic steatohepatitis (NASH), alcohol-induced cirrhosis, obesity, smoking, diabetes, and iron overload [2]. The primary prevention strategy by HBV immunization is a milestone in reducing the incidence of HCC in children [3]. Secondary prevention by screening or surveillance in patients at a high risk of HCC is the strategy for reducing the associated mortality by providing interventions in the early stage of HCC [4, 5].

Chemoprevention is another attractive strategy for reducing the cancer incidence by administering drugs, typically for other reasons. For example, since angiotensin II stimulates neovascularization and could act as a growth factor for cancer, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) could conceivably reduce cancer risk [6, 7]. Results of the study done by Chiang et al. suggested ACEI/ARB use lowers cancer risk [8]. On the contrary, a meta-analysis of randomized controlled trials suggests ARBs are associated with a modestly increased risk of new cancer diagnosis [9].Whether ACEIs or ARBs reduce cancer risk remains an issue to debate [7].

Though the chemopreventive effects of ACEIs and ARBs against HCC development and recurrence have been demonstrated in animal studies [10‐12] and small clinical studies [13‐15], large-scale study remains lacking. Numerous other medications have been reported to be associated with HCC chemoprevention, including HBV medications [16], interferons [17], metformin [18‐20], statins [21, 22], aspirin [18], and nonsteroidal anti-inflammatory drugs [23, 24]. Similar as ACEI and ARB, some of the results are inconsistent and remain controversial [25, 26]. Considering that multiple risk and protective factors may coexist in patients at a high risk of HCC in real-world settings, the true comparative and competitive effectiveness of these chemopreventive drugs has not been comprehensively investigated.

The precise biological mechanisms underlying the protective effects of ACEIs or ARBs against cancer development is that the angiotensin I–VII levels increase during the inhibition of the ACE–angiotensin II–angiotensin II type 1 receptor (AT1R) axis, resulting in the activation of the Mas receptor and subsequent inhibition of cell proliferation and angiogenesis [27, 28]. Moreover, ACEIs or ARBs have been reported to reduce liver fibrosis in human studies [29, 30]. Further studies are warranted to determine whether these positive scientific findings can be used to extrapolate the efficacy of ACEIs or ARBs into clinical practice and translate this rationale into effective health intervention for high-risk populations [31]. The present study analyzed the comparative effectiveness of ACEIs and ARBs in the chemoprevention of HCC in high-risk cohorts.

This was a retrospective study using nationwide cohorts of HBV and HCV patients with hypertension identified from a pseudonymied database. The primary outcome was HCC occurrence and the main exposure was the use of ACEIs or ARBs. The Institutional Review Board of National Taiwan University Hospital, Taipei, Taiwan, approved this study (NTUH REC: 201601007 W) and the need for informed consent was waived.

The present nationwide cohort study of hypertensive patients with HBV and HCV infection who required antiviral therapy for alleviating the risk of primary HCC yielded four main findings. First, the estimated 7-year risks of primary HCC were 12% and 10% in the HBV and HCV cohorts, respectively. In addition, the risk did not significantly differ between patients exposed and not exposed to ACEIs or ARBs within 6 months after antiviral therapy. Second, after adjustment for comorbidities (including liver cirrhosis, DM, and hyperlipidemia) and time-dependent variables of medications (aspirin, metformin, and statins), ACEI and ARB use was not a significant predictor of primary HCC in the HBV cohort (aHR: 0.97, 95% CI: 0.81–1.16) and in the HCV cohort (aHR: 0.96, 95% CI: 0.80–1.16). Third, liver cirrhosis was a universal risk factor in both cohorts and in all subgroups. Finally, in the HCV cohort, ACEI or ARB use was associated with increased HCC risk in subgroups of patients without cirrhosis, DM, and hyperlipidemia.

The 5-year cumulative incidence of HCC in HBV patients with cirrhosis was 10%–17% [35]; the incidence was 11% in HCV patients with cirrhosis after a median follow-up of 6 years [36]. The present study yielded similar observations. Through regression modeling, competitive variables can be weight-based and compared. Among all comorbidities, liver cirrhosis was the strongest risk factor (aHR: 2.40, 95% CI: 1.74–3.32) in the HBV cohort, followed by DM (aHR: 1.46, 95% CI: 1.18–1.81); however, the effect of liver cirrhosis in the HCV cohort (aHR: 1.76, 95% CI: 1.23–2.50) was not this large. Because advanced cirrhosis is a relative contraindication for interferon therapy in patients with HCV [37], the use of interferon therapy as a patient selection criterion in this study may explain the significant but relatively low effect of liver cirrhosis on HCC development in the HCV cohort. Meanwhile, HBV patients with advanced liver cirrhosis or decompensation are candidates for HBV medication in the reimbursement program of Taiwan’s National Health Insurance. Therefore, these patients were recruited in this study. Nonetheless, the comparative effect of ACEIs and ARBs in the study cohorts was marginal and insignificant. These findings are important for developing policies on the selection of chemopreventive medications against HCC in high-risk groups.

Hepatocarcinogenesis is a complex multistep process in which many signaling cascades are altered, yielding a heterogeneous molecular profile [38]. Signaling pathways, such as the epithelial growth factor receptor (EGFR) and Ras, mammalian target of rapamycin, insulin-like growth factor receptor 1, hepatocyte growth factor and c-Met, Wingless, and angiogenesis, were, even if not entirely, involved in the complex and interactive system that formulates this hypervascular tumor entity [38]. The phenomenon of HCC heterogeneity not only exists in different tumors [39] but can also occur within a tumor [40]. The contemporary view of the involvement of the renin–angiotensin system in cancer, particularly HCC, might involve EGFR transactivation by AT1R and angiotensin II-independent, antiangiogenic effects of angiotensinogen [6, 41].The microenvironment in hepatocarcinogenesis becomes more complex in cases of viral infection and involves the transactivation of transcription factors and stimulation of inflammatory responses, thus resulting in oxidative damage, fibrosis, and genetic mutations [42]. Renin–angiotensin system signaling may have a potential role in hepatocarcinogenesis; however, the actual real-world comparative and competitive influences associated with other signaling pathways in HBV or HCV infection remain unknown. Limited human studies have reported the potential of ACEIs in reducing HCC recurrence after curative treatment [13‐15]. Consistently, high gene expression of angiotensin-converting enzyme 2 in patients with HCC was associated with poor survival.

[43]. However, no human studies have investigated the primary prevention of HCC (targeting the initiation of hepatocarcinogenesis), probably because the recurrence rate of HCC is only adequately high in patients after curative resection [44]. Thus, the study endpoint could be reached in a manageable period.

Many possible reasons explain the gap between laboratory success and population insignificance. The dose–response relationship in vitro may not be applicable in standard dosage for hypertension. The doses recommended for cancer treatment are typically higher than the regular doses for treating non-cancer diseases. For example, the suggested dosing of everolimus, a mechanistic target of rapamycin inhibitor, in renal cell carcinoma is 10 mg per day, while it is 1.5 mg per day as an immunosuppressant in the setting of renal transplantation [45]. Therefore, there exists a translational inconsistency between laboratory and clinical practices. Our results can save the time and effort of researchers when conducting future human investigations.

Statistical results derived from a population-based database typically yield narrow point estimates and show statistical significance with ease, even when the absolute differences between groups are too small to have biological relevance (e.g., age difference of less than 1 year in adults). Therefore, the clinical significance may warrant further confirmation. The results may sometimes be misleading and induce population panic [46, 47]. We used multivariate Cox regression including time-dependent variables for medication use to carefully minimize the time-related bias associated with potential confounding medications in an observational study [25]. The neutral (or considered “negative”) effectiveness of ACEIs and ARBs in high-risk cohorts suggested that their association with the prevention of HCC, if it ever existed, was weak.

In human studies supporting the protective effects of ACEI or ARB [13‐15], the outcome was HCC recurrence, which was different from the current study. Patients with history of HCC carry a much higher risk of HCC recurrence after treatment (and hence, a larger effect size) than those without history of HCC. Use of ACEI or ARB might, therefore, provide a “sufficient cause” for outcome prevention in the “super risky” population. Based on the results of this study, we estimated that a total of 34,058 and 19,274 event cases for HBV and HCV cohorts, respectively, are required to reach statistically significant. The effect sizes would be unrealistic since the current study already included the high-risk nationwide population at a largest and eligible scale.

In contrary, our study suggested that the use of ACEIs and ARBs was associated with an increased risk of HCC in HCV patients without cirrhosis, DM, and hyperlipidemia. ACEI exposure has been shown to be associated with breast cancer recurrence [48]. However, the mechanism underlying this observation and whether the impact is cancer-specific remain unknown [48]. As reported for ACEI, also ARB seem to increase new-cancer occurrence of lung [9], breast [49] and prostate [49], probably due to the unopposed effect on angiogenesis through angiotensin receptor 2 stimulation under angiotensin receptor 1 blockade [49]. Further study is warranted to confirm our finding and explore the pathophysiological mechanisms.

This study has some limitations. The NHIRD is a claims data source, which might lead to misleading findings if the study is solely based on it without validation. However, the selected cohorts (patients who received HBV and HCV therapy) in our study were strictly audited, and the outcome, HCC incidence, was retrieved from the RCIPD, a stringent certificate database. These confirmations minimized the bias of uncertainty in our study. We could not identify NASH patients accurately by ICD-9 classification, which is also a risk factor for HCC [50]. Future studies using the 10th version of diagnosis coding, in which there is a specific code for NASH, will help resolve this limitation. The other limitation of this study is that it did not consider some dietary [51, 52] and lifestyle-modifying factors, such as smoking [53], which might be involved in hepatic carcinogenesis and patient survival. Direct-acting antiviral therapy, which may reduce HCC incidence after HCV eradication [54], was not accessible in our cohorts. Furthermore, we did not investigate whether liver fibrosis can be resolved using ACEIs and ARBs.

In conclusion, in the presence of other significant risk and protective factors for HCC, the use of ACEIs or ARBs in the HBV and HCV cohorts having a high risk of HCC was not associated with adequate protective effectiveness under standard dosages.