Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality

Abstract

Background: More information is needed about the long-term effects of low-dose aspirin (≤160 mg) on incident hepatocellular carcinoma, liver-related mortality, and gastrointestinal bleeding in persons with chronic hepatitis B or hepatitis C virus infection.

Methods: Using nationwide Swedish registries, we identified all adults who received a diagnosis of chronic hepatitis B or hepatitis C from 2005 through 2015 and who did not have a history of aspirin use (50,275 patients). Patients who were starting to take low-dose aspirin (14,205 patients) were identified by their first filled prescriptions for 90 or more consecutive doses of aspirin. We constructed a propensity score and applied inverse probability of treatment weighting to balance baseline characteristics between groups. Using Cox proportional-hazards regression modeling, we estimated the risk of hepatocellular carcinoma and liver-related mortality, accounting for competing events.

Results: With a median of 7.9 years of follow-up, the estimated cumulative incidence of hepatocellular carcinoma was 4.0% among aspirin users and 8.3% among nonusers of aspirin (difference, -4.3 percentage points; 95% confidence interval [CI], -5.0 to -3.6; adjusted hazard ratio, 0.69; 95% CI, 0.62 to 0.76). This inverse association appeared to be duration-dependent; as compared with short-term use (3 months to <1 year), the adjusted hazard ratios were 0.90 (95% CI, 0.76 to 1.06) for 1 to less than 3 years of use, 0.66 (95% CI, 0.56 to 0.78) for 3 to less than 5 years of use, and 0.57 (95% CI, 0.42 to 0.70) for 5 or more years of use. Ten-year liver-related mortality was 11.0% among aspirin users and 17.9% among nonusers (difference, -6.9 percentage points [95% CI, -8.1 to -5.7]; adjusted hazard ratio, 0.73 [95% CI, 0.67 to 0.81]). However, the 10-year risk of gastrointestinal bleeding did not differ significantly between users and nonusers of aspirin (7.8% and 6.9%, respectively; difference, 0.9 percentage points; 95% CI, -0.6 to 2.4).

Conclusions: In a nationwide study of patients with chronic viral hepatitis in Sweden, use of low-dose aspirin was associated with a significantly lower risk of hepatocellular carcinoma and lower liver-related mortality than no use of aspirin, without a significantly higher risk of gastrointestinal bleeding. (Funded by the National Institutes of Health and others.).

Figure 1.. Cumulative Incidence of Hepatocellular Carcinoma among Aspirin Users and Nonusers.

Aspirin use was defined as a filled prescription for 90 or more consecutive cumulative defined daily doses of low-dose aspirin after the index date (the date on which a patient filled the first aspirin prescription after the 180-day entry period); nonuse was defined as fewer than 90 consecutive cumulative defined daily doses — or no use — during the same 90-day interval after the 180-day entry period. We calculated the P value using Gray’s test for equality of the cumulative incidence functions between each exposure group after inverse probability of treatment weighting, accounting for competing risks of death, emigration, and liver transplantation. The inset shows the same data on an expanded y axis.

Figure 2.. Liver-Related Mortality among Aspirin Users and Nonusers.

Aspirin use was defined as a filled prescription for 90 or more consecutive cumulative defined daily doses of low-dose aspirin after the index date (the date on which a patient filled the first aspirin prescription after the 180-day entry period); nonuse was defined as fewer than 90 consecutive cumulative defined daily doses — or no use — during the same 90-day interval after the 180-day entry period. We calculated the P value using Gray’s test for equality of the cumulative incidence functions between each exposure group after inverse probability of treatment weighting, accounting for competing risks of nonliver-related death, emigration, and liver transplantation. The inset shows the same data on an expanded y axis.