Effects of statins and aspirin on HCC risk in alcohol-related cirrhosis: nationwide emulated trials

Abstract

Background and Aims: Observational studies have shown an association between statin or aspirin use and a decreased risk of HCC, but the effects of a well-defined treatment strategy remain unknown. We emulated trials of the effects of continuous statin or aspirin use on HCC risk in patients with cirrhosis due to alcohol-related liver disease (ALD cirrhosis). Approach and Results: We specified target trials for statins and, separately, aspirin and emulated them using Danish health care registries. All eligible patients with ALD cirrhosis diagnosed in 2000–2018 were included in either an exposed or an unexposed arm. Patients were followed until HCC or death without HCC. The 5-year risk of HCC was estimated using marginal structural models with inverse probability weighting. Using statins continuously for 5 years compared with not using statins resulted in a relative risk (RR) of HCC of 0.67 (95% CI: 0.45–0.91). The RR of death without HCC was 0.69 (95% CI: 0.65–0.77). For aspirin, the RR was 1.05 (95% CI: 0.60–1.42) for HCC and 1.02 (95% CI: 0.95–1.09) for death without HCC. Conclusions: In patients with ALD cirrhosis, 5 years of continuous statin use resulted in a 33% RR reduction of HCC (number needed to treat = 94) and a 31% RR reduction of death without HCC (number needed to treat = 7). Such strong causal effects are implausible and best explained by uncontrollable confounding, highlighting the need for randomized trials. Aspirin use likely does not affect the risk of HCC or death without HCC.

The Effect of Aspirin Use on Incident Hepatocellular Carcinoma—An Updated Systematic Review and Meta-Analysis

“…A total of 20 studies were excluded due to overlapping study populations (eight in South Korea, seven in Taiwan, two in the USA, two in Hong Kong, one in Sweden), and the details of these are outlined in Table 1 . There was finally a total of sixteen studies, twelve cohort [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ] and four case-control [ 46 , 47 , 48 , 49 ], selected for inclusion. The overall search and study selection process is summarised in Figure 1 .…”

“…A total of five cohort studies reported on patients with a diagnosis of cirrhosis specifically, involving a large number of patients (n = 122,645). Two studies [ 37 , 39 ] (n = 6768) performed a subgroup analysis for patients with hepatitis B-related cirrhosis, while the other three [ 34 , 38 , 44 ] (n = 115,877) wholly comprised patients with cirrhosis. One study encompassed the breadth of the aetiology of cirrhosis [ 44 ], one focused on patients with only alcohol-related cirrhosis [ 38 ], and the final study involved patients with solely HBV- and HCV-related cirrhosis [ 34 ].…”

“…Two studies [ 37 , 39 ] (n = 6768) performed a subgroup analysis for patients with hepatitis B-related cirrhosis, while the other three [ 34 , 38 , 44 ] (n = 115,877) wholly comprised patients with cirrhosis. One study encompassed the breadth of the aetiology of cirrhosis [ 44 ], one focused on patients with only alcohol-related cirrhosis [ 38 ], and the final study involved patients with solely HBV- and HCV-related cirrhosis [ 34 ]. In patients with cirrhosis, aspirin use appeared to have a non-significant effect on HCC incidence (adjusted HR 0.96, 95% CI 0.84–1.09, p = 0.52), without significant statistical heterogeneity ( I 2 = 0%, p = 0.05) ( Figure 5 ).…”

“…By mistakenly including the same subjects and HCC cases more than once, the estimate of precision of these analyses will have been overestimated and, depending on which populations were duplicated, the overall risk estimate may have been significantly swayed. Due to concern for the unreliability of previous meta-analyses on this basis, as well as the interval publication of further high-quality studies [ 37 , 38 ], we sought to perform an updated and methodologically sound meta-analysis, in order to provide the most accurate and updated insights into the effect of aspirin use on HCC incidence.…”

Pour some sugar on me: Glycemic control and the prevention of liver disease

“…First is the lack of accounting for the use of medications. Multiple cohort studies have suggested that both metformin and statins are associated with reduced risks of cirrhosis and HCC, 9 yet the VA study did not account for metformin use, and the UK Biobank study did not account for either. Other time-varying co-variates that can impact the development of cirrhosis and HCC (changes in body mass index, alcohol consumption etc.)…”