Association Between Aspirin Use and Risk of Hepatocellular Carcinoma

Abstract

Importance: Prospective data on the risk of hepatocellular carcinoma (HCC) according to dose and duration of aspirin therapy are limited.

Objective: To examine the potential benefits of aspirin use for primary HCC prevention at a range of doses and durations of use within 2 prospective, nationwide populations.

Design, setting, and participants: Pooled analysis of 2 prospective US cohort studies: the Nurses' Health Study and the Health Professionals Follow-up Study. Data were accessed from November 1, 2017, through March 7, 2018. A total of 133 371 health care professionals who reported data on aspirin use, frequency, dosage, and duration of use biennially since 1980 in women and 1986 in men were included. Individuals with a cancer diagnosis at baseline (except nonmelanoma skin cancer) were excluded.

Main outcomes and measures: Cox proportional hazards regression models were used to calculate multivariable adjusted hazard ratios (HRs) and 95% CIs for HCC.

Results: Of the 133 371 participants, 87 507 were women and 45 864 were men; in 1996, the median time of follow-up, the mean (SD) age was 62 (8) years for women and 64 (8) years for men. Over more than 26 years of follow-up encompassing 4 232 188 person-years, 108 incident HCC cases (65 women, 43 men) were documented. Compared with nonregular use, regular aspirin use (≥2 standard-dose [325-mg] tablets per week) was associated with reduced HCC risk (adjusted HR, 0.51; 95% CI, 0.34-0.77). This benefit appeared to be dose related: compared with nonuse, the multivariable-adjusted HR for HCC was 0.87 (95% CI, 0.51-1.48) for up to 1.5 standard-dose tablets per week, 0.51 (95% CI, 0.30-0.86) for more than 1.5 to 5 tablets per week, and 0.49 (95% CI, 0.28-0.96) for more than 5 tablets per week (P for trend = .006). Significantly lower HCC risk was observed with increasing duration (P for trend = .03); this decrease was apparent with use of 1.5 or more standard-dose aspirin tablets per week for 5 or more years (adjusted HR, 0.41; 95% CI, 0.21-0.77). In contrast, use of nonaspirin nonsteroidal anti-inflammatory drugs was not significantly associated with HCC risk (adjusted HR, 1.09; 95% CI, 0.78-1.51).

Conclusions and relevance: This study suggests that regular, long-term aspirin use is associated with a dose-dependent reduction in HCC risk, which is apparent after 5 or more years of use. Similar associations were not found with nonaspirin NSAIDs. Further research appears to be needed to clarify whether aspirin use represents a feasible strategy for primary prevention against HCC.

Figure.. Hepatocellular Carcinoma Risk in Relation to Duration of Aspirin Use and Time Since Aspirin Discontinuation

A, Duration of aspirin use and hepatocellular carcinoma risk. Categories of aspirin use duration were compared with individuals reporting never-use of aspirin (reference). The P value for trend was calculated using continuous duration of use (months) among aspirin users, compared with the lowest reported duration of use. P for trend = .03. B, Time since discontinuation of aspirin and hepatocellular carcinoma risk. Current aspirin use (reference group) was defined as consumption of 2 or more standard-dose (325-mg) aspirin tablets per week on the most recent questionnaire. Among prior aspirin users, time since discontinuation of regular use was defined as nonregular use on the most recent questionnaire but regular aspirin use less than 8 or 8 or more years in the past. P for trend was calculated using continuous elapsed time in months since last regular aspirin use among prior aspirin users. The multivariable-adjusted model was conditioned on age (continuous years), year of questionnaire return and sex (ie, cohort), and was further adjusted for race/ethnicity (white vs nonwhite), body mass index (continuous measure), alcohol intake (0-4.9, 5.0-14.9, ≥15.0 g/d), smoking status (current vs prior vs never), physical activity (<3.0, 3.0-8.9, ≥9 metabolic equivalent task–hours per week), diabetes (yes vs no), hypertension (yes vs no), dyslipidemia (yes vs no), regular multivitamin use (≥2 multivitamin tablets per week vs no), regular use of oral antidiabetic medications (yes vs no), and regular use of statins (yes vs no). All relevant covariates were updated over time. P for trend = .006. HR indicates hazard ratio; error bars, 95% CI.