Statin Use and Risk of Intracerebral Hemorrhage in Chinese Population: A Target Trial Emulation Study

Statins have been shown to prevent major vascular events in a wide range of individuals. However, their potential mechanisms-such as impairing fibrinogen cleavage and reducing thrombin generation-raise concerns on increased risk of intracerebral hemorrhage (ICH). Given the inconsistent findings of previous trials and observational studies, this study aims to assess the effect of statins on ICH risk in Chinese population.

Within the framework of target trial emulation, we used data from the Yinzhou Regional Health Care Database covering the years 2011-2020. The study included patients aged 50 years or older with no history of ICH and statin use. After applying inclusion and exclusion criteria, patients were categorized as statin initiators or noninitiators based on their initial treatment regimen during the 1-month enrollment period. Using the sequential trial approach, 60 target trials were emulated each month from 2011 to 2015. Propensity score (PS) matching was applied to balance characteristics between statin initiators and noninitiators within each emulated trial, and these trials were then stacked together into a single data set. Cox proportional hazards models were used to estimate the effects of statin on ICH risk, ICH-related mortality, and all-cause mortality.

A total of 53,413 statin initiators and 35,033,455 noninitiators from 60 emulated trials were included in the analysis. Statin initiators were generally older (mean age 65 vs 63 years), less likely to be male (45.5% vs 50.5%), and more likely to have a history of hypertension (69.0% vs 14.1%). After PS matching, all characteristics between the 2 groups were well balanced. With a median follow-up of 6.7 (interquartile range 5.6-8.1) years, the hazard ratio (HR) of ICH for statin initiators compared with noninitiators was 1.18 (95% CI 1.03-1.35). The HRs of ICH-related mortality and all-cause mortality were 1.16 (95% CI 0.91-1.46) and 0.92 (95% CI 0.88-0.97), respectively. Results remained consistent across various subgroup and sensitivity analyses.

Statin use may increase the risk of ICH in Chinese patients without history of ICH. However, the findings of this study may be limited by residual confounding, particularly the lack of cholesterol-related measurements.

This study provides Class III evidence that in Chinese populations, initiation of statins may increase the risk of ICH.