Discussion

In this large, propensity score-matched retrospective cohort study, pre-injury statin use was associated with significantly lower 30-day mortality following ICH. Pre-injury statin use was also associated with lower observed rates of intensive care unit admission, mechanical ventilation, and external ventricular drain placement. Given the observational nature of this study, these findings should be interpreted as associations rather than evidence of a causal treatment effect.

These findings are consistent with prior observational studies reporting an association between statin use and improved outcomes following ICH [7,8]. Flint et al. reported lower in-hospital mortality and improved discharge disposition among patients maintained on statin therapy after ICH, while Tapia-Pérez et al. reported improved neurological recovery among patients who continued statin therapy following spontaneous hemorrhage [7,8]. Previous studies have also reported worse neurological outcomes following statin discontinuation, further supporting the need for continued investigation of statin therapy in cerebrovascular disease [9].

Although previous observational studies have reported an association between statin use and improved survival after ICH, many were limited by single-center designs or relatively small sample sizes. In contrast, the present study analyzed more than 165,000 propensity score-matched patients from a multinational electronic health record network, providing a large and diverse cohort. Propensity score matching achieved excellent balance across measured demographic characteristics, cardiovascular comorbidities, and concomitant medication use. However, despite adjustment for measured confounders, important determinants of ICH prognosis, including hematoma volume, hemorrhage location, intraventricular extension, admission neurological severity (GCS and NIHSS), ICH score, hematoma expansion, and surgical timing, were unavailable within the TriNetX database and therefore could not be incorporated into the matching process. Consequently, residual confounding remains possible, and the observed associations should be interpreted with appropriate caution. These prognostic factors are well established in the assessment and management of ICH and are incorporated into contemporary clinical frameworks and practice guidelines [10,11].

The observed association between pre-injury statin use and lower mortality is comparable to findings reported in previous retrospective analyses of patients with ICH. Our study expands upon the existing literature through the use of a substantially larger multicenter cohort and rigorous propensity score matching methodology, allowing for improved adjustment of measured baseline differences between cohorts. Nevertheless, because of the retrospective design and the potential for residual confounding, these findings should not be interpreted as demonstrating an independent mortality benefit attributable to statin therapy.

Several biological mechanisms may plausibly explain the observed associations. Beyond their lipid-lowering effects, statins possess anti-inflammatory, antioxidant, immunomodulatory, and endothelial-stabilizing properties that may attenuate secondary brain injury following ICH. Experimental and translational studies have demonstrated that statins reduce inflammatory cytokine production, preserve blood-brain barrier integrity, improve endothelial nitric oxide synthase activity, reduce oxidative stress, and enhance cerebral microvascular perfusion [2,3]. These effects may mitigate perihematomal edema, limit neuronal apoptosis, and improve cerebral autoregulation during the acute phase of hemorrhagic stroke. Statins have also been associated with enhanced angiogenesis, neurogenesis, and synaptic remodeling during recovery. While these proposed mechanisms provide biological plausibility for the observed associations, they do not establish causality and require confirmation in prospective clinical studies.

Patients with pre-injury statin use demonstrated a modestly higher rate of craniotomy or cerebrospinal fluid diversion procedures. Several explanations may account for this finding. Survivorship bias may have contributed, as patients surviving the acute phase of hemorrhage are more likely to undergo neurosurgical intervention. Alternatively, unmeasured differences in hemorrhage characteristics, including hematoma size, location, surgical accessibility, or other radiographic features unavailable within the database, may have influenced operative decision-making. Because these variables were not captured within TriNetX, the mechanism underlying this association cannot be determined.

No significant difference in seizure incidence was observed between groups, suggesting that pre-injury statin use was not associated with seizure occurrence within 30 days following ICH.

Clinical implications

Pre-injury statin use was associated with lower 30-day mortality and differences in several short-term clinical outcomes following ICH. However, these findings should be interpreted within the context of a retrospective observational study and do not establish a causal relationship between statin exposure and improved outcomes. Prospective studies incorporating detailed clinical, radiographic, and functional outcome data are needed to determine whether these observed associations represent a true therapeutic effect.

Limitations

This study has several important limitations. First, as a retrospective observational analysis, it is inherently susceptible to residual confounding despite propensity score matching. Although matching achieved excellent balance across measured covariates, several important predictors of ICH prognosis, including hematoma volume, hemorrhage location, intraventricular extension, perihematomal edema, hematoma expansion, admission neurological severity (GCS and NIHSS), ICH score, anticoagulation status at presentation, early neurological deterioration, and surgical timing, were unavailable within the TriNetX database and therefore could not be incorporated into the analyses.

Second, statin exposure was determined using documented prescription records within three months prior to the index hemorrhage. Medication adherence, pharmacy refill history, prescription persistence, cumulative statin exposure, statin intensity, and lipophilicity were not available and therefore could not be evaluated, introducing the potential for exposure misclassification.

Third, patients prescribed statins before ICH may differ systematically from non-users in ways that were not fully captured within the database. Healthy-user bias, differences in healthcare access, medication adherence, and other unmeasured factors may have contributed to the observed associations despite propensity score matching.

Fourth, secondary outcomes, such as intensive care unit admission, mechanical ventilation, external ventricular drain placement, and neurosurgical intervention, may be influenced by institutional practice patterns and provider decision-making in addition to disease severity. These outcomes should therefore be interpreted cautiously.

Finally, functional neurological outcome measures, including modified Rankin Scale, Barthel Index, discharge disposition, and long-term disability, were unavailable within the database, limiting assessment of long-term neurological recovery. Additional sensitivity analyses, including inverse probability weighting, multivariable Cox regression, and E-value analyses, as well as subgroup analyses according to statin type, intensity, lipophilicity, and cumulative exposure, were beyond the scope of the available dataset and represent important areas for future investigation. Despite these limitations, the large multicenter cohort and rigorous propensity score matching provide valuable real-world evidence describing the association between pre-injury statin use and short-term clinical outcomes following ICH.