Systematic Review With Meta-analysis

The Effects of Non-steroidal Anti-inflammatory Drugs and Anti-platelet Therapy on the Incidence and Recurrence of Hepatocellular Carcinoma

Regina Zi Hwei Tan; Ian Lockart; Christina Abdel Shaheed; Mark Danta

Disclosures

Aliment Pharmacol Ther. 2021;54(4):356-367. 

In This Article

Discussion

Low-dose aspirin significantly reduced the risk of HCC incidence and reduced liver-related mortality in at-risk populations. Aspirin does not, however, seem to reduce HCC recurrence. Aspirin therapy was associated with only a small increased risk of gastrointestinal bleeding. This meta-analysis reveals that long-term use of aspirin has a stronger effect in at-risk populations compared to the general population in reducing HCC incidence, consistent with the two previous meta-analyses.[15,16]

The majority of participants in the 13 studies that reported aspirin usage were prescribed low-dose aspirin (75-150 mg) for a minimum of 3–12 months, with benefits in HCC risk reduction seen as early as less than 1 year of consistent aspirin use; aHR: 0.63. 95% CI: 0.48–0.83[31] In the largest study of a viral hepatitis cohort by Simon et al[29] the most favourable duration for low-dose aspirin is at least 5 years of continued usage, which was associated with a significant reduction in HCC incidence; aHR: 0.57, 95% CI: 0.42–0.70, and liver-related mortality; aHR: 0.63; 95% CI: 0.53–0.75.[29] Conversely, a study focusing on HCV infection by Liao et al[31] suggests that the most favourable duration of aspirin use was between 1 and 2 years (aHR: 0.33, 95% CI: 0.18–0.61). Unfortunately, the data in our study did not allow analysis for duration or dosage due to inconsistencies in the recording of drug dosage and duration. Prescriptions were recorded in different units (eg, milligrams, DDD, cDDD) and presentations (eg, exact dose, stratified ranges), which makes comparison difficult. Duration was also difficult to determine due to inconsistent usage and different methods of documentation (eg, months, years, person-years).

The meta-analysis also suggested that while NSAIDs were associated with a 20% decreased risk of HCC recurrence, only the non-aspirin NSAID group showed statistical significance in risk reduction without statistically increasing the bleeding risk, unlike the aspirin group. Interestingly, the study revealed that APT also reduced the risk of HCC incidence, recurrence and liver-related mortality. This should, however, be interpreted with caution as some of these analyses had few studies or small sample size.

The clinical benefit of NSAIDs and APT implies a critical role of platelets in the pathogenesis of HCC. In both cirrhosis and cancer, activated platelets produce pro-inflammatory cytokines that enable tissue regeneration through hepatocyte proliferation, which in turn can influence tumour cell proliferation.[48] It is theorised that significant COX upregulation in malignancies enhance prostaglandin synthesis which may promote excessive proliferation, invasion and angiogenesis.[49–51] Therefore, COX inhibition by NSAIDs may suppress neoplasia and promote endothelial cell apoptosis. Aspirin, a cyclooxygenase (COX)-1 inhibitor that impairs platelet aggregation through the suppression of TXA2 synthesis, is therefore of particular interest in its potential function of an anti-tumorigenic agent.[52] This may explain why aspirin works in both reducing primary liver cancer development and improving liver-related outcomes in HCC patients.

The novel aspect of this meta-analysis was the inclusion of only study populations at risk of HCC. Previous systematic reviews have used data that included the general population, where HCC is a rare malignancy. Since these previous meta-analyses there have been several new large cohort studies adding to the available data, in particular a recent large population-based viral hepatitis cohort study.[29] To our knowledge, this is the largest meta-analysis of the impact of NSAIDs or APT on an at-risk population. Our analysis, however, has some limitations. There was substantial heterogeneity present which influenced the strength of our conclusions. This was attributed to several potential confounders, including: population characteristics, follow-up time, dose and duration of drug intervention and concurrent use of other drugs. In particular, the non-aspirin studies were limited and had small sample sizes across all outcomes of interest. Due to the relatively short duration of drug intervention from the onset of HCC diagnosis to recurrence and death, associated findings in these areas are not as substantial as that of HCC incidence. Finally, liver-related mortality findings included studies with high risk of selection bias.

Prior to our study, several studies have been conducted to examine the association between the use of NSAIDs and HCC incidence in the general population.[53–63] However, conflicting information on subgroup analysis by drug was present among the studies. Pang et al's meta-analysis suggests that HCC incidence was significantly reduced among NSAID users in the general population, but results were only statistically significant among non-aspirin NSAID users, and not for aspirin users.[14] Conversely, Tao et al's meta-analysis revealed that only aspirin use decreased the risk of HCC incidence; not the non-aspirin NSAIDs group.[15] This is supported by Wang et al's review which showed a significant reduction of HCC incidence in aspirin users.[16] Our findings suggest that aspirin does in fact reduce the risk of HCC incidence; HR: 0.51, 95% CI: 0.36–0.72, and liver-related mortality; OR: 0.32; 95% CI: 0.15–0.70; among high-risk patients. In contrast to Pang et al, when analysing the risk for drug subtype individually, we found that aspirin and non-aspirin NSAIDs had no significant effect in reducing HCC recurrence. Furthermore, in contrast to Pang's study, our study revealed that NSAID use improved liver-related mortality among at-risk groups. This not only suggests improvements in HCC outcome but also reduced complications from liver disease related to portal hypertension and liver failure.

In summary, the findings suggest that long-term use of low-dose NSAIDs, especially aspirin, in at-risk patients reduces the risk of developing HCC and improves liver-related outcomes. This would be an inexpensive intervention for patients with chronic liver disease. The outcome of the meta-analysis suggests benefit at all stage of liver disease, but it is clear that the highest risk subpopulation is those with cirrhosis. A large prospective randomised study could definitively answer this question but would involve considerable resources that would unlikely be supported by industry. This meta-analysis in conjunction with existing data supports chemoprophylaxis for HCC.

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