Prior statin and short‐term outcomes of primary intracerebral hemorrhage: From a large‐scale nationwide longitudinal registry

Abstract Introduction The relationship between statins and intracerebral hemorrhage outcomes is unclear. Aim We aimed to compare the in‐hospital mortality and evacuation of intracranial hematoma rates in patients with primary intracerebral hemorrhage between prior statin users and nonusers. Results The final study population included 66,263 patients. Multivariable logistics analyses showed that prior statin use was not associated with in‐hospital mortality for primary intracerebral hemorrhage (adjusted odd ratio 0.78, 95% CI 0.61–1.01), but reduced the proportion of patients undergoing evacuation of intracranial hematoma (adjusted odd ratio 0.70, 95% CI 0.61–0.82). Propensity score matching analyses yielded similar results. Conclusion Prior statin use was not associated with in‐hospital mortality but did reduce evacuation of intracranial hematoma rates.


| INTRODUC TI ON
Primary intracerebral hemorrhage (ICH) has a higher mortality and disability rate than other types of stroke, with an independence rate ranging from 12% to 39%. [1][2][3] Although statins can lower serum lipid levels and stabilize atherosclerotic plaques to reduce the risk of ischemic stroke recurrence, their effects on ICH remain unclear.
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial enrolled 4731 patients and showed that 80 mg atorvastatin doubled the risk of ICH. 4 A nationwide case-control study that included 7696 cases of ICH and 14,670 controls reported that statins were associated with a 32% lower risk of incident ICH. 5 Cohort studies have revealed that statins could reduce by threefold the odds of mortality in patients diagnosed with ICH. 6 A large-scale study (n = 17,980) based on the National Health Insurance Research Database in Taiwan also showed that patients prescribed with statins after ICH had a lower risk of all-cause mortality and cardiovascular death. 7 Currently, there is no consensus regarding the effect of statin use prior to ICH. 8 The ongoing Statins in Intracerebral Hemorrhage (SATURN) trial (Clini calTr ials.gov Identifier: NCT03936361), specifically designed to investigate the efficacy and safety of continuation vs. discontinuation of statin drugs after primary lobar ICH, will provide more information on this topic.
In the current study, we compared the in-hospital mortality and evacuation rates of intracranial hematoma between statin users and non-statin users to investigate the relationship between prior statin treatment and ICH clinical outcomes. Moreover, we conducted an additional analysis to investigate the relationship between prior statin treatment and ICH outcomes in subgroups of patients with a history of stroke, as well as those with and without a history of dyslipidemia.

| Participants
We derived data from the China Stroke Center Alliance (CSCA), a national multicenter registry cohort initiated to promote the quality of the diagnosis and treatment of stroke in 1476 hospitals in China. 9 From 2015 to 2019, 1,006,798 patients with stroke or transient ischemic attack were consecutively enrolled in the CSCA, 10

| Subgroup analyses
Subgroup analyses were conducted in patients with a history of (1) stroke, (2) ischemic stroke, (3) hemorrhagic stroke, or (4) dyslipidemia, as well as in (5) patients without a history of dyslipidemia, to determine the association of prior statin use with in-hospital mortality and evacuation rates of intracranial hematoma.

| Statistical analysis
Data were tested for normal distribution using the Kolmogorov-Smirnov test. In the univariate analyses, comparison between prior statin users and non-users was performed in normally distributed data using the Student's t-test and in skewed data using the Mann-Whitney U test. Categorical variables were analyzed using the Pearson's χ 2 or Fisher's exact test, as appropriate. Considering the extensive sample size, using an absolute standardized difference of ≥10 was more appropriate than p < 0.05 in demonstrating a clinically significant difference in baseline characteristics. Propensity score matching (PSM) 11 was used to balance the baseline characteristics of statin users and non-users. For the PSM analysis, a 1:1 matching was performed based on the nearest-neighbor matching algorithm with a caliper width of 0.25 of the propensity score using the medical history of hypertension, diabetes mellitus, atrial fibrillation, myocardial infarction, heart failure, ischemic stroke, cerebral hemorrhage, medication history of antiplatelet agents, anticoagulant agents, antihypertensive agents, antidiabetic agents, fasting plasma glucose, systolic blood pressure, diastolic blood pressure, and international normalized ratio as covariates. Multiple logistic regression analyses were used to test the correlation of statin use with the in-hospital mortality and evacuation rates of intracranial hematoma. Statistical significance was defined as a two-sided p < 0.05. All analyses were performed using the SAS software (version 9.4; SAS Institute, Inc.).

| Patient characteristics
A total of 66,263 patients were included in the study. Among the enrolled patients, the mean age was 66.4 years (SD 10.3), and 40,360 (60.9%) were men. In total, 4190 (6.3%) patients were included in the prior statin group and 62,073 patients were included in the non-user group. Table 1

| Prior statin use and outcomes
The in-hospital mortality rates were similar between prior statin users and non-users (2.7% vs 2.3%). The evacuation rate of intracranial hematoma was also significantly reduced in prior statin users compared to non-users (7.2% vs. 10.3%).
Logistic regression analyses showed that prior statin use was not associated with in-hospital mortality in either the unadjusted  (Figure 1).

| Subgroup analyses
Subgroup analyses were conducted in patients with a history of stroke, ischemic stroke, and hemorrhagic stroke. Prior statin use was not associated with in-hospital mortality in the three subgroup analyses. Prior statin use was also associated with lower evacuation rates of intracranial hematoma among patients with a history of stroke  (Figures 2 and 3).

| Results after PSM
All covariates were well-balanced through the PSM (Table 2).
Additional logistic regression analyses were conducted based on the results of PSM and demonstrated that prior statin use was not associated with in-hospital mortality (p = 0.059) but was associated with a lower rate of intracranial hematoma evacuation (OR 0.69, 95% CI 0.58-0.81, p < 0.001) (Figure 1). Additional PSM revealed subgroup analysis results that were similar to the prior logistic regression analysis results (Figures 2 and 3).

| DISCUSS ION
Our study found that prior statin use was not associated with inhospital mortality but was associated with a significantly reduced To elucidate the relationship between ICH and statins, investigation of their pathophysiological mechanisms is warranted, given that these mechanisms remain unclear. A meta-analysis including 12 preclinical trials reported that statins were beneficial to significantly improve ICH recovery. 25 A rat model of ICH also showed that statin use suppressed neutrophil mobilization and invasion, attenuating brain edema and neurological deficits F I G U R E 3 Subgroup analysis of evacuation of intracranial hematoma. Adjusted: Adjusted for medical history of hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, myocardial infarction, heart failure, ischemic stroke, cerebral hemorrhage, mediation history of antiplatelet agents, anticoagulant agents, antihypertensive agents, antidiabetic agents, fasting plasma glucose, systolic blood pressure, diastolic blood pressure and INR. PSM, propensity score matching after ICH. 26 Statin use may also have neuroprotective antioxidant and BBB protective effects, including the acceleration of hematoma clean-up post-ICH by facilitating endogenous phagocytosis by erythrocytes. 26 PHE includes vasogenic and cytotoxic edema caused by BBB damage and inflammation. 27,28 Considering that statins decreased the PHE volumes, 12,15,19 statin use could reduce the severity and improve neurological recovery without increasing mortality in patients with ICH, 29-3 4 including in-hospital mortality. 35,36 Several pathways have been identified to regulate neuroinflammation process and brain edema after ICH. Receptor-interacting protein kinase-1, a master regulator of neuroinflammation, mediates programmed necrosis (necroptosis) via the mixed-lineage kinase-like protein and induces brain edema after ICH. 37 Irisin treatment has been shown to reduce brain edema through the integrin αVβ5/AMPK signaling pathway in mouse models. 38 Lithium has also been reported to attenuate brain edema through the Wnt/β-catenin signaling-dependent mechanism in ICH mouse models. 39 In addition, endogenously formed zinc TA B L E 2 Demographic and clinical characteristics between prior statins users and non-users after PSM Total cholesterol (Mean ± SD, mmol/L) 1.0 ± 1.9 1.0 ± 1.9 0.9 ± 1.9 5.3 Triglyceride (Mean ± SD, mmol/L) 0.5 ± 1.4 0.5 ± 1.3 0.5 ± 1.6 <0.1 Fasting plasma glucose (Mean ± SD, mmol/L) 6.9 ± 3.1 6.9 ± 3.2 6.9 ± 3.0 <0. protoporphyrin can induce ICH-related damage, including the lysis of red blood cells and brain edema. Hence, ferrochelatase, a catalyst that inserts zinc into protoporphyrin, may be beneficial for reducing brain edema. 40 Compared to the advances in therapeutic agents for ischemic stroke, [41][42][43] progress in ICH research is limited and drugs targeted to brain edema, including statins, may be promising.
In patients without a history of dyslipidemia, prior statin use was associated with reduced in-hospital mortality and intracranial hema- Fourth, we could not collect information on hematoma volume in our study, given that different methods are used to calculate hematoma volume in different sub-centers of CSCA (manually, semiautomatic software, or automatic software). However, we compared the GCS scores between statin users and non-users.
Comparable GCS scores suggested that hematoma volume may be similar between the groups with prior statin use and without prior statin use. Fifth, we failed to collect information on the frequency and dose of oral statin agents, and future studies should include information on the frequency and dose.
In conclusion, prior statin use is associated with reduced rates of evacuation of intracranial hematoma but is not related to in-hospital mortality in patients with ICH. Further randomized controlled trials are required to confirm these findings.

AUTH O R CO NTR I B UTI O N S
X.Z., Z.L., and Y.X. contributed to the conception and design of the study; H.G., K.X., X.Y., C.W., and C.W. contributed to the acquisition and analysis of data; G.L. and S.W. contributed to drafting the text and preparing the figures. Beijing Natural Science Foundation (Z200016).

CO N FLI C T O F I NTE R E S T
None.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data available on request from the authors.