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

Our metaanalysis adds to the accumulating weight of evidence that aspirin and NSAIDs are beneficial in hepatocellular carcinoma (HCC).1 The analysis clearly demonstrated that aspirin can act as a chemopreventive agent, with a 49% reduction in HCC incidence. This effect was greater than previous metaanalyses, probably reflecting the focus on atrisk populations. There also appears to be a role in secondary prevention for aspirin and NSAIDs, reducing recurrent HCC following treatment. The benefit, however, comes with a small increased risk of gastrointestinal bleeding. As outlined in the editorial, the metaanalysis does not provide enough evidence to be prescriptive about which populations and when aspirin should be used as a chemopreventive, or what the overall risks would be.2 An argument against aspirin, raised in the editorial, relates to potential toxicity. Aspirin and antiplatelet therapy, however, have been studied retrospectively in patients with cirrhosis. In patients with decompensated cirrhosis who were on a transplant waiting list, the use of aspirin in those with coronary disease was not associated with increased bleeding or liver dysfunction.3 Similarly, in patients with cirrhosis on antiplatelet therapy, including aspirin, following cerebrovascular accidents, there was no increased toxicity.4 Supporting this, our metaanalysis demonstrated a 62% decrease in liverrelated mortality, arguing against an overall detrimental impact, albeit in a wide spectrum of liver disease severity. A randomised control trial (RCT) would obviously provide more granular detail on the effect in specific populations and the toxicity beyond gastrointestinal bleeding, determining which patients with liver disease should receive aspirin chemoprevention and when HCC risk is dependent on the aetiology and severity of underlying liver disease. Patients recommended to have HCC screening would be the ideal population in which to study the impact of aspirin. Outcomes would include HCC incidence and liverrelated complications and mortality. This would probably exclude patients with decompensated cirrhosis who are at increased risk of the complications, as raised in the editorial. While this metaanalysis suggests benefit, there was significant heterogeneity among studies arising from varying degrees of liver disease, different aetiologies, potential confounding with other medications and alcohol, and variable definition of outcomes. A RCT could control for many of these factors, but the issues are manifold. There would be little appetite from the pharmaceutical indistry to support an outofpatent cheap medication in what would have to be large longterm study. Therefore, it would have to be funded through government or nongovernment organisations. 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 metaanalysis estimated the number needed to treat to prevent one HCC was 128.5 While race was not identified as a factor in our metaanalysis, 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. This should not only be based in the developed world. We believe that this metaanalysis provides more impetus to initiate a welldesigned RCT to determine the role of aspirin as a chemopreventive agent in liver disease.