Beneficial Prognostic Effects of Aspirin in Patients Receiving Sorafenib for Hepatocellular Carcinoma: A Tale of Multiple Confounders

Simple Summary Low-dose aspirin has a preventive effect against multiple malignancies, including hepatocellular carcinoma. Whether aspirin could also ameliorate the prognosis of patients who already developed advanced cancer remains an elusive question. In the case of hepatocellular carcinoma, randomized clinical trials are difficult to design and observational studies suffer from multiple biases. We tried to address these problems performing a large-scale observational study, which allowed multiple corrections to reduce the main known biases. We found that among patients who received sorafenib as an antineoplastic treatment, patients who concurrently received aspirin had better outcomes than non-aspirin users. Once the confounders were properly addressed, this advantage was confirmed, albeit at the cost an increased rate of minor bleeding events. Even if we are aware that confirmatory randomized clinical trials are difficult to organize, our results warrant further investigation, as aspirin might be a low-cost, effective and safe additional treatment for selected patients with advanced hepatocellular carcinoma. Case-control observational studies suggested that aspirin might prevent hepatocellular carcinoma (HCC) in high-risk patients, even if randomized clinical trials are lacking. Information regarding aspirin in subjects who already developed HCC, especially in its advanced stage, are scarce. While aspirin might be a low-cost option to improve the prognosis, multiple confounders and safety concerns are to be considered. In our retrospective analyses of a prospective dataset (n = 699), after assessing the factors associated with aspirin prescription, we applied an inverse probability treatment weight analysis to address the prescription bias. Analyses of post-sorafenib survival were also performed to reduce the influence of subsequent medications. Among the study population, 133 (19%) patients were receiving aspirin at the time of sorafenib prescription. Aspirin users had a higher platelet count and a lower prevalence of esophageal varices, macrovascular invasion, and Child-Pugh B status. The benefit of aspirin was confirmed in terms of overall survival (HR 0.702, 95% CI 0.543-0.908), progression-free survival, disease control rate (58.6 vs. 49.5%, p < 0.001), and post-sorafenib survival even after weighting. Minor bleeding events were more frequent in the aspirin group. Aspirin use was associated with better outcomes, even after the correction for confounders. While safety concerns arguably remain a problem, prospective trials for patients at low risk of bleeding are warranted.