Pravastatin reduces all-cause mortality in elderly individuals at risk of liver fibrosis: Post hoc analysis of the PROSPER trial

Background & Aims Metabolic dysfunction-associated steatotic liver disease (MASLD), especially the progressive stages accompanied by liver fibrosis, are associated with liver-related and cardiovascular (CV) complications in middle-aged cohorts. We evaluated whether liver fibrosis is associated with increased mortality and cause-specific endpoints in an elderly population, and whether statin treatment could reduce these risks. Methods PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) was a double-blind randomized clinical trial comparing pravastatin to placebo in an elderly Caucasian population of 5,804 patients (>70 years of age) at increased risk of CV disease. Endpoints were composite and single (CV) endpoints and all-cause mortality. The Fibrosis-4 index (FIB-4) score was classified as: low risk of liver fibrosis (FIB-4 <2.0), indeterminate risk (2.0≤ FIB-4 ≤2.66), and high risk (FIB-4 ≥2.67). Time-to-event data were analyzed using the Cox proportional hazards model. Results Most participants were classified in the low FIB-4 class (n = 3,919), followed by the indeterminate (n = 1,269) and high classes (n = 561). In the placebo group, the risk of all-cause mortality increased with a high FIB-4 classification: high-class hazard ratio (HR) = 1.54 (95% CI, 1.10–2.17), compared with the low class (reference group). In the pravastatin group, the HR for all-cause mortality was not associated with FIB-4 classification: high-class HR = 1.01 (95% CI, 0.69–1.49). The interaction between FIB-4 class and treatment was significant (p = 0.049). High FIB-4 classifications were not significantly associated with major adverse cardiovascular events (MACE) or other endpoints in either arms. Conclusions A high FIB-4 classification is associated with increased all-cause mortality in the elderly, although pravastatin appears to mitigate this increased risk. Clinical Trials registration The study is registered at www.isrctn.com/(ISRCTN40976937). Impact and implications The progressive stages of MASLD (liver fibrosis) are associated with liver-related and CV complications in middle-aged cohorts (∼55 years of age). The impact of liver fibrosis in elderly populations is less well studied. In addition, the use of statins has long been debated, but evidence appears to point to a beneficial effect in populations with MASLD. However, data from prospective trials remain limited. Our findings indicate a potential survival benefit associated with pravastatin use in the elderly (>70 years of age) with an indication of liver fibrosis.