Aspirin Use Is Associated with a Reduced Incidence of Hepatocellular Carcinoma: A Systematic Review and Meta‐analysis

Abstract

Hepatocellular carcinoma (HCC) is the third‐leading cause of cancer‐related death worldwide, with a growing incidence and poor prognosis. While some recent studies suggest an inverse association between aspirin use and reduced HCC incidence, other data are conflicting. To date, the precise magnitude of risk reduction—and whether there are dose‐dependent and duration‐dependent associations—remains unclear. To provide an updated and comprehensive assessment of the association between aspirin use and incident HCC risk, we conducted a systematic review and meta‐analysis of all observational studies published through September 2020. Using random‐effects meta‐analysis, we calculated the pooled relative risks (RRs) and 95% confidence intervals (CIs) for the association between aspirin use and incident HCC risk. Where data were available, we evaluated HCC risk according to the defined daily dose of aspirin use. Among 2,389,019 participants, and 20,479 cases of incident HCC, aspirin use was associated with significantly lower HCC risk (adjusted RR, 0.61; 95% CI, 0.51‐0.73; P ≤ 0.001; I2 = 90.4%). In subgroup analyses, the magnitude of benefit associated with aspirin was significantly stronger in studies that adjusted for concurrent statin and/or metformin use (RR, 0.45; 95% CI, 0.28‐0.64) versus those that did not (P heterogeneity = 0.02), studies that accounted for cirrhosis (RR, 0.49; 95% CI, 0.45‐0.52) versus those that did not (P heterogeneity = 0.02), and studies that confirmed HCC through imaging/biopsy (RR, 0.30; 95% CI, 0.15‐0.58) compared with billing codes (P heterogeneity < 0.001). In four studies, each defined daily dose was associated with significantly lower HCC risk (RR, 0.98; 95% CI, 0.97‐0.98), corresponding to an 8.4% risk reduction per year of aspirin use. Conclusion: In this comprehensive systematic review and meta‐analysis, aspirin use was associated with a significant reduction in HCC risk. These benefits appeared to increase with increasing dose and duration of aspirin use.

NAFLD-Associated HCC: Progress and Opportunities

“… 125 Effects on hepatic stellate cells, platelets, immune cell recruitment and cyclooxygenase 2 inhibition Large meta-analysis of all previous observational studies finding aspirin was associated with reduced HCC risk. 124 Abbreviations: NAFLD, nonalcoholic fatty liver disease; HCC, hepatocellular carcinoma. …”

“…NAFLD patients commonly take aspirin for either primary or secondary prevention of cardiovascular disease, however recent studies reveal that aspirin may also be beneficial in the treatment of NAFLD and prevention of HCC. 124–126 Aspirin is thought to ameliorate NAFLD progression and prevent HCC development through effects on hepatic stellate cells, cyclooxygenase 2 inhibition and immune cell recruitment. 95 , 127–129 A prospective cohort study of 361 biopsy-proven NAFLD patients showed a significantly lower odds ratio of progressing to NASH or fibrosis (0.68 and 0.54, respectively) in patients taking aspirin compared to those not taking aspirin.…”

“… 125 A subsequent meta-analysis confirmed this protective effect. 124 Although these studies are encouraging NAFLD patients are generally underrepresented in these primary prevention studies, therefore care is needed when extrapolating the results. Further studies powered to detect the effect on HCC risk in NAFLD specifically are awaited.…”

Hepatocellular Carcinoma Prevention by Aspirin: Are Platelets the Link?

“…TO THE EDITOR: Memel and colleagues (1) present a comprehensive meta-analysis including more than 2 million patients from all available clinical studies which shows that intake of aspirin was associated with a risk reduction for hepatocellular carcinoma (HCC) by 39%. This effect was robust to a variety of potentially confounding factors.…”

Editorial: aspirin and NSAID for chemoprevention of hepatocellular carcinoma – ready for their use? Authors' reply

“…Logistically, it would need a large population to power it adequately to answer both the efficacy and toxicity questions. Based on patients with cirrhosis, a recent meta‐analysis estimated the number needed to treat to prevent one HCC was 128 5 . While race was not identified as a factor in our meta‐analysis, any RCT should include African and Asian patients who are at risk and would probably have the most to gain from an accessible, cheap chemopreventive agent.…”