Association of aspirin therapy with risk of hepatocellular carcinoma: A systematic review and dose-response analysis of cohort studies with 2.5 million participants

Wang, Shuijing; Yu, Yinhua; Ryan, Paul M.; Dang, Minyan; Clark, Cain C. T.; Kontogiannis, Vasileios; Rahmani, Jamal; Varkaneh, Hamed Kord; Salehi‐Sahlabadi, Ammar; Day, Andrew S.; Zhang, Yong

doi:10.1016/j.phrs.2019.104585

Cited by 38 publications

(34 citation statements)

References 36 publications

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“…Although two recent meta-analyses have addressed the association between aspirin use and HCC risk, (26,27) those previous meta-analyses each included fewer than 50% of published observational studies. (12,13,17,18,23,24,(36)(37)(38) Furthermore, neither of those previous meta-analyses addressed key HCC risk factors, including viral hepatitis, cirrhosis, concurrent use of statins or metformin, or the methods by which aspirin use was ascertained or HCC cases were confirmed.…”

Section: Discussionmentioning

confidence: 99%

“…This is important, because failing to account for those factors could yield biased and imprecise risk estimates, with limited generalizability. In contrast, by incorporating 11 additional studies that were not part of the most recent published meta‐analysis, ( 26 ) and by conducting detailed subgroup and stratified analyses, the current study is able to provide a more comprehensive assessment of aspirin use in relation to HCC risk.…”

Section: Discussionmentioning

confidence: 99%

“…(5)(6)(7)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) Furthermore, inconsistencies in study design, and variability in definitions of aspirin exposure, outcomes or comorbidities, have rendered it difficult to compare effect sizes across studies. As a result, prior meta-analyses on this topic have included only a fraction of published studies, (8,(26)(27)(28) which can result in biased estimates of effect with limited generalizability.…”

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confidence: 99%

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

Memel

Arvind

Moninuola³

et al. 2021

Hepatology Communications

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Memel

Arvind

Moninuola³

et al. 2021

Hepatology Communications

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“…Aspirin is used for its antiplatelet, analgesic, and anti-inflammatory effects over a wide dosage ranging from 75 to 1,200 mg (16). Recent analyses indicate a significant inverse association between aspirin dose and the risk of liver cancer (17). Some studies have shown that similarly to aspirin, salicylic acid exhibits anti-proliferative and antitumor activity in vitro and in vivo (18,19), although in this study we specifically researched only the aspirin concentration.…”

Section: Discussionmentioning

confidence: 99%

Aspirin inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo via inducing cell cycle arrest and apoptosis

Shi

Fujita

et al. 2020

Oncol Rep

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Aspirin, a nonsteroidal anti-inflammatory drug (NSAID), is known to inhibit cell proliferation in a variety of cancers. However, the underlying mechanism of this inhibition remains unknown. We investigated the effects of aspirin on hepatocellular carcinoma (HCC) cells using in vitro and in vivo models. Six HCC cell lines and a liver cancer cell line including Huh-7 were used in assays that evaluated cell proliferation, cell cycle, and apoptosis. Flow cytometry, enzyme-linked immunosorbent assay (ELISA), western blot analysis, and phosphorylated receptor tyrosine kinase array were used to evaluate the effects of aspirin on the cells, and microRNAs (miRNAs) were analyzed by a miRNA array chip. The results were validated in vivo using a nude mouse model of Huh-7-xenografted tumors. Our results showed that aspirin exhibited an antiproliferative effect on all cell lines. Moreover, aspirin induced G 0 /G 1 cell cycle arrest and modulated the levels of cell cycle-related molecules such as cyclin E, cyclin D1, and cyclin-dependent kinase 2 (Cdk2). In addition, aspirin upregulated the levels of caspase-cleaved cytokeratin 18, increased the proportion of early apoptotic cells, decreased the levels of clusterin and heat shock protein 70 (HSP 70), upregulated the levels of miRNA-137 and inhibited epidermal growth factor receptor (EGFR) activation. In addition, we observed that aspirin suppressed cell proliferation partially through the miRNA-137/EGFR pathway. Our in vivo results showed that aspirin reduced the growth of xenograft tumors in nude mice. In conclusion, aspirin was able to inhibit the growth of HCC cells by cell cycle arrest, apoptosis, and alteration of miRNA levels in in vitro and in vivo models.

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“…On top of this, the study has other possible limitations including the reliance on a single collection of data on serum markers and clinical/environmental features, as properly acknowledged by the authors, and the lack of information on drug use, mainly aspirin and statins, which are commonly used for cardiovascular disease prevention and have been favorably related to all-cause mortality and incidence of liver cancer (Tran et al, 2020;Wang et al, 2019). Treatment with statins improves NAFLD/NASH and reduces cardiovascular morbidity and mortality (Athyros et al, 2017), and aspirin use has been associated to a reduced risk of fibrosis progression in patients with NAFLD and hepatocellular carcinoma risk (Simon et al, 2019).…”

Section: Commentmentioning

confidence: 99%

Clinical and Genetic Markers of Nonalcoholic Fatty Liver Disease and Prediction of Liver Disease Mortality: Ready for Population Screening?

2020

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Association of aspirin therapy with risk of hepatocellular carcinoma: A systematic review and dose-response analysis of cohort studies with 2.5 million participants

Cited by 38 publications

References 36 publications

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

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

Aspirin inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo via inducing cell cycle arrest and apoptosis

Clinical and Genetic Markers of Nonalcoholic Fatty Liver Disease and Prediction of Liver Disease Mortality: Ready for Population Screening?

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