Association of Daily Aspirin Therapy With Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B

Teng-Yu Lee; Yao-Chun Hsu; Hsiao-Ching Tseng; Shi-Hang Yu; Jaw-Town Lin; Ming-Shiang Wu; Chun-Ying Wu

doi:10.1001/jamainternmed.2018.8342

. 2019 Mar 18;179(5):633–640. doi: 10.1001/jamainternmed.2018.8342

Association of Daily Aspirin Therapy With Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B

Teng-Yu Lee ^1,², Yao-Chun Hsu ^3,^4,^5,⁶, Hsiao-Ching Tseng ⁷, Shi-Hang Yu ¹, Jaw-Town Lin ^4,⁸, Ming-Shiang Wu ⁹, Chun-Ying Wu ^7,^10,^11,^12,^✉

¹Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan

²Department of Medicine, Chung Shan Medical University, Taichung, Taiwan

³Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan

⁴School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan

⁵Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan

⁶Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan

⁷Division of Translational Medicine and Excellence Cancer Research Center, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

⁸Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan

⁹Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

¹⁰Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

¹¹College of Public Health and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

¹²National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan

^✉

Corresponding Author: Chun-Ying Wu, MD, PhD, Division of Translational Medicine, Department of Medical Research, Taipei Veterans General Hospital, No. 322, Sec. 2, Shipai Rd, Beitou District 11217, Taipei, Taiwan (cywu22@vghtpe.gov.tw).

Accepted for Publication: November 30, 2018.

Published Online: March 18, 2019. doi:10.1001/jamainternmed.2018.8342

Author Contributions: Drs Lee and Chun-Ying Wu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lee, Tseng, Lin, M.-S. Wu, C.-Y. Wu.

Acquisition, analysis, or interpretation of data: Lee, Hsu, Tseng, Yu, C.-Y. Wu.

Drafting of the manuscript: Lee, Tseng, Yu, C.-Y. Wu.

Critical revision of the manuscript for important intellectual content: Lee, Hsu, Lin, M.-S. Wu, C.-Y. Wu.

Statistical analysis: Lee, Hsu, Tseng, Yu, C.-Y. Wu.

Obtained funding: Lee, C.-Y. Wu.

Administrative, technical, or material support: M.-S. Wu.

Supervision: Lin.

Conflict of Interest Disclosures: Dr Hsu reported grants and personal fees from Gilead and personal fees from Bristol-Myers Squibb outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported in part by grants from the Ministry of Science and Technology (107-2314-B-075A-002), National Health Research Institutes (CA-106-PP-37), and Taichung Veterans General Hospital (106DHA0500150), Taiwan.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

^✉

Corresponding author.

PMCID: PMC6503573 PMID: 30882847

Key Points

Question

Is daily aspirin therapy associated with risk of hepatocellular carcinoma in patients with chronic hepatitis B?

Findings

In this Taiwan nationwide cohort study of 10 615 patients with chronic hepatitis B, there was a statistically significant 29% risk reduction of hepatocellular carcinoma in 2123 patients who received daily aspirin compared with the matched 8492 controls.

Meaning

Daily aspirin therapy may be of help to further improve the chemoprevention of hepatitis B virus–related hepatocellular carcinoma.

Abstract

Importance

Antiviral therapy cannot erase hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B, and it is not indicated for most hepatitis B virus (HBV) carriers. Another effective way of reducing HCC risk needs to be developed. Aspirin may prevent cancer development, but clinical evidence in patients with HBV-related HCC remains limited.

Objective

To investigate the association of daily aspirin therapy with HBV-related HCC risk.

Design, Setting, and Participants

In this Taiwan nationwide cohort study, we screened 204 507 patients with chronic hepatitis B for the period January 1, 1997, to December 31, 2012. After excluding patients with confounding conditions, 2123 patients who continuously received daily aspirin for 90 or more days (treated group) were randomly matched 1:4 with 8492 patients who had never received antiplatelet therapy (untreated group) by means of propensity scores, consisting of the follow-up index date, baseline characteristics, and potentially chemopreventive drug use during follow-up. Data were analyzed from August 1 to November 30, 2018.

Exposures

Daily aspirin therapy during the study period.

Main Outcomes and Measures

Both cumulative incidence of and hazard ratios (HRs) for HCC development were analyzed after adjusting patient mortality as a competing risk event.

Results

Of the 10 615 patients included in the analysis, 7690 (72.4%) were men; mean (SD) age was 58.8 (11.8) years. The cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group in 5 years (5.20%; 95% CI, 4.11%-6.29% vs 7.87%; 95% CI, 7.15%-8.60%; P < .001). In the multivariable regression analysis, aspirin therapy was independently associated with a reduced HCC risk (HR, 0.71; 95% CI, 0.58-0.86; P < .001). Sensitivity subgroup analyses also verified this association (all HRs <1.0). In addition, older age (HR, 1.01 per year; 95% CI, 1.00-1.02), male sex (HR, 1.75; 95% CI, 1.43-2.14), and cirrhosis (HR, 2.89; 95% CI, 2.45-3.40) were independently associated with an increased HCC risk, but nucleos(t)ide analogue (HR, 0.54; 95% CI, 0.41-0.71) or statin (HR, 0.62; 95% CI, 0.42-0.90) use was correlated with a decreased HCC risk.

Conclusions and Relevance

Daily aspirin therapy may be associated with a reduced risk of HBV-related HCC.

This nationwide cohort study examines the risk of hepatocellular carcinoma in Taiwanese patients with chronic hepatitis B who are receiving daily aspirin therapy.

Introduction

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and an effective therapy for the prevention of HCC development is needed.¹ Hepatitis B virus (HBV) is one of the most important HCC risk factors, and the prevalence of HCC is high in epidemic areas of chronic hepatitis B (CHB).² However, although current antiviral medicines, such as nucleos(t)ide analogue (NA) therapy, can effectively inhibit the replication of HBV, the possibility of developing a cure for CHB remains elusive.³ Therapy with NAs is associated with reductions in HCC risk, but the risk is not erased.⁴ Therefore, using only NA therapy may not be enough for HCC prevention. Antiviral therapy is not indicated in most HBV carriers,^5,6,7 so another effective way of reducing HCC risk needs to be developed.

Aspirin has been investigated to explore associations between its chemopreventive effect and cancers that are related to chronic inflammation.^8,9,10,11 Clinical research has demonstrated that aspirin can reduce cancer risk, particularly in the prevention of colorectal cancer.^12,13 In a study using an HBV transgenic mouse model, antiplatelet therapy diminished immune-mediated necroinflammatory reactions, the severity of liver fibrosis, and the development of HCC.¹⁴ However, clinical evidence supporting associations between chemopreventive effect and aspirin therapy on HCC remains limited. Because randomized clinical trials of aspirin therapy were mainly conducted in areas with low HCC annual incidence rates (the United States or Europe), the case number might be too low to show a statistically significant effect on HCC risk reduction.¹⁵ Thus, analyses using large databases should be encouraged.

Clinical studies particularly designed for HCC chemoprevention by aspirin therapy are relatively sparse. In 2 studies based on large databases, aspirin use was found to be associated with reduced HCC risk, but information regarding some confounding factors, such as viral hepatitis, cirrhosis, and other potentially chemopreventive drug use, was lacking.^16,17 In a recent hospital-based study, antiplatelet therapy was associated with a reduced HCC risk in patients with CHB after effective NA therapy.¹⁸ However, the drug therapy regimen (eg, frequency and duration) was not defined in that study. In addition, the chemopreventive effect of antiplatelet therapy in patients who did not receive NA therapy remains unclear. Therefore, we conducted a nationwide cohort study to evaluate the association of daily aspirin therapy with HBV-related HCC.

Methods

Study Design

The data used in this nationwide cohort study were obtained from the National Health Insurance Research Database (NHIRD) in Taiwan for the period January 1, 1997, to December 31, 2012. The NHIRD holds the claim data for more than 99% of Taiwan’s population of 23.38 million residents.¹⁹ As outlined in previous studies,^{4,20,21,22,23,24} the database contains comprehensive data, including patients’ demographic data, dates of clinic visits and hospitalizations, disease diagnosis codes, procedure codes, details of prescriptions, and costs. The date, drug name, dosage, administration route, frequency, and duration of prescriptions for each patient can be identified. The NHIRD had been updated every 6 months and was released after completion of the final update. Diseases were defined according to International Classification of Diseases, 9th Revision (ICD-9) codes. The quality of the NHIRD in terms of accuracy involving medications and related diseases has been well validated.^25,26 The ICD-9 codes used in this study are listed in the eMethods in the Supplement, and diseases must have been diagnosed at least 3 times in outpatient clinics or once during a hospitalization. The research ethics committee of the National Health Research Institutes in Taiwan approved the present study and waived informed consent.

Study Population

The patient selection process is presented in Figure 1. We screened 204 507 patients with CHB between January 1, 1997, and December 31, 2012. Patients with hepatitis C virus (HCV) infection, other viral hepatitis, HIV infection, and alcoholic liver disease were excluded. Because the effective duration of aspirin therapy for HCC prevention remains unclear, a selection criterion of 90 consecutive days was used for enrolling regular aspirin users. Patients who started to receive daily aspirin therapy and continued for 90 or more days were identified as the aspirin-treated cohort, and patients who never received antiplatelet therapy were assigned to the untreated cohort. A total of 2123 patients who received continuous aspirin therapy (treated group) were randomly matched 1:4 with 8492 patients who had never received aspirin (untreated group) by means of propensity scores, which consisted of index date to the start of follow-up, baseline characteristics (age, sex, cirrhosis, liver decompensation, diabetes, hyperlipidemia, and hypertension), and the use of potentially chemopreventive medicines (NAs, metformin, and statins) during the follow-up period.

Main Outcome Measurement

The occurrence of HCC was the main measured outcome. For avoiding immortal time bias, patients in the aspirin-treated and untreated groups were followed up from the 180th day of initiating aspirin therapy (the index date) and the matched dates of starting follow-up, respectively. Patients who developed HCC before the follow-up index dates were excluded as the data washing period. Study participants were followed up until the dates of HCC diagnosis, death, or the end of the study period (December 31, 2012). All patients who were admitted with a primary diagnosis of HCC were identified, and the diagnosis of HCC was further validated by the registration of patients in the Registry for Catastrophic Illness Patient Database.^21,22,23,24 This database is an official subsystem related to insurance reimbursement within the NHIRD, in which histopathologic confirmation or typical imaging characteristics are required for the diagnosis of HCC.

Risk Factor Assessment

Several major coexisting diseases that might be associated with the risk of HCC development were evaluated at the index date of outcome follow-up, including cirrhosis, liver decompensation, diabetes, hyperlipidemia, and hypertension. The use of potentially chemopreventive medications, including NAs, metformin, and statins, was also analyzed. As mentioned in previous studies,^4,21,22 NA reimbursement criteria require evidence of active viral hepatitis, such as blood alanine aminotransferase levels 2 times or more the upper limit of the reference range and HBV DNA titers 2000 IU/mL or more. The users of these drugs were defined as patients who took the medicines for more than 1 day per week during the outcome follow-up period.

Statistical Analysis

Propensity analysis was performed to examine the comparability of the 2 study groups.²⁷ A propensity score was calculated through the use of logistic regression to estimate the probabilities of assigning a patient to the treated group. Cumulative incidence rates of HCC development during the follow-up period were calculated, and the estimated rates along with 95% CIs are presented. To avoid risk overestimation, patient mortality before HCC development was treated as a competing risk event. After adjustment for competing mortality, cumulative incidence rates were calculated and compared using a modified Gray method and the Kaplan-Meier method, and the differences in the full time-to-event distributions between the aspirin-treated and untreated groups were compared by a modified log-rank test.²¹ Furthermore, univariable regression analysis was used to identify potential risk factors, and multivariable regression analyses were further conducted to determine independent risk factors for HCC development. Hazard ratios (HRs) were determined by Cox proportional hazards regression models. Moreover, multivariable stratified analysis was conducted as a sensitivity analysis to evaluate the outcomes of aspirin therapy in the patient subgroups. All analyses were 2-tailed and unpaired, with significance set at P < .05. All data were managed using SAS, version 9.3 software (SAS Institute Inc), and the Cox proportional hazard regression models were constructed using the cmprsk package for R to estimate cumulative incidence under competing mortality events.²⁸

Results

Participants

Of the 10 615 patients included in the analysis, 7690 (72.4%) were men; mean (SD) age was 58.8 (11.8) years. Further demographic characteristics are reported in Table 1. Most patients started aspirin therapy in middle age with a median age of 58.7 years (interquartile range, 50.4-67.7), and 1538 (72.4%) of the patients were men. The median duration of aspirin therapy was 3.1 years (interquartile range, 1.2-6.0). Regarding the daily dosage of aspirin therapy, 2079 (98.0%) of patients took 100 mg/d or less (≤325 mg for 99.9% of patients). Low-dose aspirin was used as an antiplatelet therapy for cardiovascular diseases. Moreover, 1744 patients (82.2%) displayed high-risk factors for cardiovascular diseases (ie, diabetes, hyperlipidemia, or hypertension), 875 patients (41.2%) had coronary arterial disease, and 798 (37.6%) had cerebral vascular disease. Less than 10% of patients had diagnoses other than cardiovascular disease such as cardiac dysrhythmia (147 [6.9%]) and peripheral vascular disease (16 [0.8%]). The HCC-related risk factors were not significantly different between the 2 groups. Small proportions of patients were diagnosed with cirrhosis (362 [17.1%]) or liver decompensation (94 [4.4%]).

Table 1. Demographic Characteristics of the Participants^a.

Characteristics	Treated (n = 2123)	Untreated (n = 8492)	P Value
Age, y
Mean (SD)	58.9 (11.8)	58.8 (11.8)	.82
Median (IQR)	58.7 (50.4-67.7)	58.6 (50.4-67.7)	.83
Sex, No. (%)
Male	1538 (72.4)	6152 (72.4)	>.99
Female	585 (27.6)	2340 (27.6)	>.99
Aspirin therapy duration, y
Mean (SD)	4.0 (3.4)
Median (IQR)	3.1 (1.2-6.0)
Daily aspirin dosage, No. (%), mg		NA
≤100	2079 (98.0)
101-325	42 (1.9)
>325	2 (0.1)
Possible reasons for the use of aspirin therapy, No. (%)		NA
Risk factors for cardiovascular diseases^b	1744 (82.2)
Coronary arterial disease	875 (41.2)
Cerebral vascular disease	798 (37.6)
Cardiac dysrhythmias	147 (6.9)
Peripheral vascular disease	16 (0.8)
Major liver-related diseases, No. (%)
Liver cirrhosis	362 (17.1)	1448 (17.1)	>.99
Liver decompensation	94 (4.4)	380 (4.5)	.97
Diabetes	620 (29.2)	2450 (28.9)	.77
Hyperlipidemia	664 (31.3)	2656 (31.3)	>.99
Hypertension	1386 (65.3)	5544 (65.3)	>.99
Drug use, No. (%)
Nucleos(t)ide analogues	336 (15.8)	1340 (15.8)	.98
Metformin	347 (16.3)	1414 (16.7)	.76
Statins	215 (10.1)	860 (10.1)	>.99
Propensity score
Mean (SD)	0.15 (0.14)	0.15 (0.14)	>.99
Median (IQR)	0.15 (0.03-0.21)	0.15 (0.03-0.21)	>.99

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Abbreviations: IQR, interquartile range; NA, not applicable.

^{^a}

Treated patients were those who received aspirin for 90 days or more; untreated, had never received antiplatelet therapy.

^{^b}

Diabetes, hyperlipidemia, hypertension.

Cumulative Incidence of HCC

The cumulative incidence of HCC is shown in Figure 2. After adjusting for competing mortality risk, the cumulative incidence of HCC in the aspirin-treated group was significantly lower than that in the untreated group in 5 years (5.20%; 95% CI, 4.11%-6.29% vs 7.87%; 95% CI, 7.15%-8.60%; P < .001). As shown in eFigure 1 and eFigure 2 in the Supplement, we redefined the aspirin user selection cutoff of continuous aspirin use for at least 1 or 2 years (median aspirin therapy duration, 4.4 or 5.6 years). The 5-year cumulative incidences of HCC in the aspirin-treated group were significantly lower than those in the untreated groups (cutoff of 1 year: 4.48%; 95% CI, 3.18%-5.79% vs 7.29%; 95% CI, 6.35%-8.24%; cutoff of 2 years: 3.99%; 95% CI, 2.54%-5.44% vs 7.52%; 95% CI, 6.38%-8.66%).

Multivariable Analysis of Risk Factors

As reported in Table 2, in the multivariable regression analysis that was adjusted for age, male sex, liver cirrhosis, diabetes, hyperlipidemia, hypertension, statin use, metformin use, and NA use, aspirin therapy remained an independent factor that was associated with a 29% risk reduction of HCC development (HR, 0.71; 95% CI, 0.58-0.86; P < .001). Older age (HR, 1.01; 95% CI, 1.00-1.02; P = .001), male sex (HR, 1.75; 95% CI, 1.43-2.14; P < .001), and liver cirrhosis (HR, 2.89; 95% CI, 2.45-3.40; P < .001) were still associated with a higher HCC risk, but the use of NAs (HR, 0.54; 95% CI, 0.41-0.71; P < .001) or statins (HR, 0.62; 95% CI, 0.42-0.90; P = .01) was associated with a lower HCC risk.

Table 2. Cox Proportional Hazards Regression Model Analysis for Risk of Hepatocellular Carcinoma.

Variable	Univariable		Multivariable
Variable	HR (95% CI)	P Value	HR (95% CI)	P Value
Treated vs untreated^a	0.68 (0.56-0.83)	<.001	0.71 (0.58-0.86)	<.001
Age per year	1.02 (1.01-1.03)	<.001	1.01 (1.00-1.02)	.001
Male sex	1.86 (1.52-2.27)	<.001	1.75 (1.43-2.14)	<.001
Liver cirrhosis	3.20 (2.75-3.72)	<.001	2.89 (2.45-3.40)	<.001
Diabetes	1.18 (1.00-1.38)	.048	1.17 (0.95-1.44)	.14
Hyperlipidemia	0.65 (0.54-0.78)	<.001	0.92 (0.75-1.11)	.38
Hypertension	1.17 (1.00-1.37)	.045	1.10 (0.94-1.30)	.22
Nucleos(t)ide analogues	0.62 (0.48-0.81)	<.001	0.54 (0.41-0.71)	<.001
Metformin	1.01 (0.83-1.23)	.93	1.07 (0.83-1.39)	.58
Statin	0.42 (0.29-0.61)	<.001	0.62 (0.42-0.90)	.01

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Abbreviations: HR, hazard ratio.

^{^a}

Treated patients were those who received aspirin for 90 days or more; untreated, had never received antiplatelet therapy.

Multivariable Stratified Analysis for Aspirin Therapy

As shown in Figure 3, multivariable stratified analysis was performed for subgroups of patients. Multivariable stratified analyses verified the association of aspirin therapy with reduced HCC risk, including in patients 60 years or younger (HR, 0.71; 95% CI, 0.53-0.95) or older than 60 years (HR, 0.71; 95% CI, 0.54-0.92), female sex (HR, 0.48; 95% CI, 0.28-0.81), male sex (HR, 0.75; 95% CI, 0.61-0.93), those without underlying cirrhosis (HR, 0.57; 95% CI, 0.44-0.75), those with (HR, 0.67; 95% CI, 0.47-0.95) or without (HR, 0.72; 95% CI, 0.57-0.91) coexisting diabetes, those with (HR, 0.71; 95% CI, 0.53-0.95) or without (HR, 0.71; 95% CI, 0.53-0.95) coexisting hyperlipidemia, those with coexisting hypertension (HR, 0.63; 95% CI, 0.50-0.81), non-NA users (HR, 0.69; 95% CI, 0.56-0.84), metformin users (HR, 0.61; 95% CI, 0.37-0.99) or nonusers (HR, 0.73; 95% CI, 0.59-0.90), and non-statin users (HR, 0.69; 95% CI, 0.57-0.85). However, although the HR for all findings was less than 1.0, statistical significance was not reached in several patient subgroups, including those with underlying cirrhosis (HR, 0.93; 95% CI, 0.70-1.25), without coexisting hypertension (HR, 0.87; 95% CI, 0.63-1.20), NA users (HR, 0.94; 95% CI, 0.52-1.70), and statin users (HR, 0.97; 95% CI, 0.42-2.28).

Peptic Ulcer Bleeding

Patients who were admitted with a diagnosis of peptic ulcer bleeding (PUB) were evaluated. As shown in eFigure 3 and eFigure 4 in the Supplement, the 5-year cumulative incidence of PUB in the aspirin-treated group was not significantly higher than those in the untreated group (6.13%; 95% CI, 5.05%-7.21% vs 5.52%; 95% CI, 4.99%-6.06%; P = .09). The PUB risk in patients receiving aspirin was not significantly higher in those with cirrhosis compared with those without cirrhosis (7.49%; 95% CI, 4.65%-10.32% vs 5.85%; 95% CI, 4.68%-7.01%; P = .41). However, patients selected in the treated group could tolerate aspirin therapy for at least 90 days; therefore, their PUB risk might be underestimated.

As shown in eFigure 5 and the eTable in the Supplement, for the purpose of comparing PUB risk for patients taking daily aspirin therapy for cardiovascular diseases (ie, coronary arterial disease, cerebrovascular disease, or diabetes), we selected risk factor–matched aspirin users who were free from common liver diseases (ie, HBV, HCV, alcoholic liver disease, and other viral hepatitis) from the database as the controls. The PUB risk in the CHB aspirin users was not significantly different compared with that in the aspirin users without liver disease (6.30%; 95% CI, 5.06%-7.55% vs 6.77%; 95% CI, 6.14%-7.39%).

Negative Control Study

As shown in eFigure 6 and eFigure 7 in the Supplement, the 5-year cumulative incidence of suicide or hip fracture in the aspirin-treated group was not significantly different from those in the untreated group.

Discussion

Owing to the limitations of databases in previous surveys of aspirin therapy, certain important information, such as the presence of HBV or HCV infection, was largely unknown.^15,29 Although a recent hospital-based study reported that antiplatelet therapy was associated with reduced HCC risk in patients with CHB after effective NA therapy,¹⁸ the drug regimen (eg, frequency and duration) should be further defined. In the present study, we report that daily aspirin therapy was associated with a reduced incidence of HCC in patients with CHB. In patients who did not receive NA therapy, aspirin therapy was also independently associated with a decreased HCC risk. Our findings may be of help in future efforts to further improve the chemoprevention of HBV-related HCC, and a proof-of-concept study is thus warranted.

The findings of experimental investigations also support the conclusion of this study. Platelets play an important role in the pathogenesis of HBV-related liver disease by sustaining inflammation.³⁰ Aspirin can block thromboxane A2 production and inhibit the pathways of platelet activation.^31,32 In an HBV transgenic mouse model of chronic immune-mediated necroinflammatory liver disease, antiplatelet therapy diminished the number of intrahepatic HBV-specific CD8 T cells, HBV-nonspecific inflammatory cells, the severity of liver fibrosis, and the development of HCC.¹⁴ In addition, aspirin could induce apoptosis of HCC cells in vitro^8,11 and inhibited HCC tumor growth in a nude mouse xenograft model.¹⁰ Furthermore, in a rat model of liver cirrhosis, aspirin also showed beneficial effects in terms of improved fibrosis grade and hepatic regenerative activity.³³ Hepatitis B virus–related HCC is generally a consequence of chronic inflammation due to hepatitis, fibrosis, dysplasia, and tumor growth³⁴; sustained suppression of inflammation may contribute to HCC chemoprevention.

Although NA therapy remains the mainstay for the prevention of HBV-related HCC, most HBV carriers do not receive NA therapy. In the subgroup analysis of this study, aspirin therapy could be associated with reductions in HCC risk for patients with CHB who did not receive NA therapy. However, statistical significance was not reached for patients with CHB who received NA therapy, and this study result might be explained by the high proportion of liver cirrhosis among NA users. Cirrhosis was the strongest independent risk factor for HCC development.³⁵ In the subgroup analysis, aspirin therapy was not associated with reduced HCC risk in patients with cirrhosis. Cirrhosis is a precancer stage, and aspirin therapy alone may not be enough to prevent HBV-related HCC. Although recent hospital-based research reported that antiplatelet therapy might reduce HCC risk after effective NA therapy, only a small proportion of patients with cirrhosis were recruited for analysis.¹⁸ Further well-designed studies are important for confirming the chemopreventive effect of aspirin therapy in NA users, especially for those with cirrhosis.

Several important confounding variables were adjusted for in this study, including the use of other potentially chemopreventive agents, including NAs, metformin, and statins.^15,36 In this study, NA use remained the strongest factor in lowering the risk for HBV-related HCC, and this finding is compatible with those of previous studies.^3,5,7 In patients for whom NA therapy is indicated, antiviral therapy should not be delayed. Consistent with findings reported in previous studies,^4,37,38 we also found that the use of statins was associated with a reduced HCC risk in the multivariable analysis. However, randomized clinical trials are required to confirm the chemopreventive effect of statins.

The concern regarding the risk of aspirin-induced bleeding in long-term users has been well studied.³⁹ Although the findings of this study suggest that the PUB risk may not be significantly increased in CHB aspirin users compared with that in typical aspirin users, the benefits and harms of aspirin therapy should be weighed as recommended in practice guidelines.⁴⁰ In addition, aspirin use in patients with cirrhosis should be monitored carefully, because stopping bleeding in them can be more difficult than in patients without cirrhosis. Before aspirin therapy is broadly adopted for HCC prevention in practice, a prospective trial should be conducted to assess its efficacy and safety.

Limitations

Several limitations of this study should be acknowledged. First, although we conducted a quasi-experimental design that took all potential confounders into account, a causal relationship between aspirin therapy and HCC risk could not be directly inferred owing to the observational nature of this study. A prospective proof-of-concept study is mandatory. Second, most patients were middle-aged or older, and therefore our results may not be generalizable to younger patients. However, the median age of patients with HCC was also not young, with most patients in their 60s,^22,41 and aspirin therapy in mid-life could still be beneficial for most patients with CHB. Third, detailed laboratory data, such as HBV viral load, could not be obtained from our database. However, NA therapy could be prescribed for patients with high viral loads according to the above-mentioned National Health Insurance reimbursement criteria, and the proportions of patients receiving NA therapy were not different between the 2 groups. Furthermore, the proportions of patients with cirrhosis or liver decompensation were also not different between the 2 groups. The severity of viral hepatitis was therefore likely the same in the 2 groups. To clarify this concern, a prospective study is needed.

Fourth, although most patients in the treated group continuously used aspirin, a proportion of patients stopped aspirin therapy during the study period (eFigure 8 in the Supplement). However, this study design is conservative in evaluating the effect of aspirin therapy, implying that HCC risk for the treated group could be overestimated. As shown in eFigure 2 in the Supplement, with longer median aspirin therapy duration of 5.6 years, the 5-year cumulative incidence of HCC became lower in patients receiving aspirin for at least 2 years. Therefore, the difference in HCC risk between the treated and the untreated groups could have been underestimated, and the conclusion of this study remains unchanged. Fifth, the NHIRD is limited by its insurance claim nature. For improving the accuracy of diagnostic variables in our studies, we used a double-checking system to confirm the diagnosis (ie, Registry for Catastrophic Illness Patient Database) of HCC. In addition, although all data descriptions regarding medicine are detailed, the accuracy may be limited by the patient’s adherence to the prescribed therapy. Furthermore, while some variations in drug use may exist in the real world, this problem among long-term aspirin users can be minimal.

Conclusions

The results of this long-term cohort study suggest that daily aspirin therapy may be associated with a reduced risk of HCC development in patients with CHB.

Supplement.

eMethods. The ICD Codes Used in This Study

eFigure 1. Cumulative Incidence of Hepatocellular Carcinoma Development in Aspirin-Treated (Continuous Aspirin Use for at Least 1 Year) or Untreated Groups

eFigure 2. Cumulative Incidence of Hepatocellular Carcinoma Development in Aspirin-Treated (Continuous Aspirin Use for at Least 2 Years) or Untreated Groups

eFigure 3. Cumulative Incidence of Peptic Ulcer Bleeding in the Aspirin-Treated or Untreated Groups

eFigure 4. Cumulative incidence of Peptic Ulcer Bleeding Among Cirrhotic or Non-Cirrhotic Patients in the Aspirin-Treated Group

eFigure 5. Cumulative Incidence of Peptic Ulcer Bleeding in Typical Aspirin Users With Liver Disease (Chronic Hepatitis B) or Without Liver Disease

eTable. Demographic Characteristics of Typical Patients Who Received Daily Aspirin Therapy for Cardiovascular Diseases

eFigure 6. Cumulative Incidence of Suicide in the Aspirin-Treated or Untreated Groups

eFigure 7. Cumulative Incidence of Hip Fracture in the Aspirin-Treated or Untreated Groups

eFigure 8. The Proportion of Patients Continuing Aspirin Therapy During the Study Period

Click here for additional data file.^{(463.7KB, pdf)}

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