In a nationwide study conducted in Sweden among adults with chronic viral hepatitis, low-dose aspirin use was associated with a duration-dependent significantly lower risk of incident hepatocellular carcinoma and liver-related death than no use of aspirin, without a significantly higher risk of gastrointestinal bleeding. The findings support the need for randomised clinical trials designed to test the benefits of aspirin for primary prevention of hepatocellular carcinoma. The study findings are published on 12 March 2020 in The New England Journal of Medicine.
Worldwide, more than 500,000 cases of incident hepatocellular carcinoma are diagnosed each year, related primarily to chronic infection with hepatitis B or hepatitis C virus. Although the incidences of hepatocellular carcinoma and liver-related death are reduced with hepatitis B viral suppression or hepatitis C eradication, they nonetheless persist in high-risk patients, including those with advanced fibrosis. Thus, an urgent need remains to develop effective strategies to prevent hepatocellular carcinoma and reduce mortality from cirrhosis.
Experimental and clinical data suggest that aspirin may prevent progression of liver disease and hepatocarcinogenesis through diverse potential mechanisms including prevention of platelet degranulation, modulation of bioactive lipids, and inhibition of the proinflammatory cyclooxygenase-2 enzyme. However, epidemiologic data remain limited, the authors wrote in the study background.
Three prior observational studies of this issue lacked detailed data regarding key determinants of hepatic outcomes, including underlying viral hepatitis, cirrhosis, and use of antiviral medication. Moreover, information about aspirin-related bleeding events from an unselected population of patients with established chronic viral hepatitis would be valuable.
The study team examined the use of low-dose aspirin (≤160 mg) in relation to incident hepatocellular carcinoma, liver-related mortality, and gastrointestinal bleeding among adults in Sweden with confirmed chronic hepatitis B or hepatitis C infection. The investigators identified 50,275 adults who were diagnosed with chronic hepatitis B or hepatitis C from 2005 through 2015 and who did not have a history of aspirin use. In total 14,205 patients who were starting to take low-dose aspirin were identified by their first filled prescriptions for 90 or more consecutive doses of aspirin.
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 non-users of aspirin (difference, −4.3 percentage points; 95% confidence interval [CI], −5.0 to −3.6; adjusted hazard ratio [HR], 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 HRs 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 HR 0.73 [95% CI, 0.67 to 0.81]).
However, the 10-year risk of gastrointestinal bleeding did not differ significantly between users and non-users of aspirin (7.8% and 6.9%, respectively; difference, 0.9 percentage points; 95% CI, −0.6 to 2.4).
The authors concluded that in this registry study among adults 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. The findings were consistent regardless of sex, cause of hepatitis, or underlying compensated cirrhosis, which suggests that the benefits of aspirin may apply to a broad at-risk population. The results support the need for randomised clinical trials.
The study was supported by grants from the National Institutes of Health, Nyckelfonden and Region Stockholm County. The authors’ work was also supported by the American Association for the Study of Liver Diseases, Boston Nutrition Obesity Research Council, Region Örebro County, and Karolinska Institutet.
Simon TG, Duberg A-S, Aleman S, et al. Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality. N Engl J Med 2020; 382:1018-1028 DOI: 10.1056/NEJMoa1912035