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Article

Impact of Statin Therapy on the Risk of Stroke Recurrence, Mortality, and Dementia After Ischemic Stroke (ISMARDD Study): A Comprehensive Meta-Analysis

by
Muskaan Gupta
1,2,
Kevin J. Spring
2,3,4,5,
Roy G. Beran
1,2,3,5,6,7,8 and
Sonu Bhaskar
1,2,3,7,8,9,*
1
Global Health Neurology Lab, Sydney, NSW 2150, Australia
2
UNSW Medicine and Health, University of New South Wales (UNSW), South West Sydney Clinical Campuses, Sydney, NSW 2170, Australia
3
NSW Brain Clot Bank, NSW Health Pathology, Sydney, NSW 2170, Australia
4
Medical Oncology Group, Ingham Institute for Applied Medical Research, Sydney, NSW 2751, Australia
5
School of Medicine, Western Sydney University, Sydney, NSW 2000, Australia
6
Griffith Health, School of Medicine and Dentistry, Griffith University, Southport, QLD 4215, Australia
7
Ingham Institute for Applied Medical Research, Clinical Sciences Stream, Liverpool, NSW 2170, Australia
8
Department of Neurology & Neurophysiology, Liverpool Hospital and South West Sydney Local Health District, Liverpool, NSW 2150, Australia
9
Division of Cerebrovascular Medicine and Neurology, Department of Neurology, National Cerebral and Cardiovascular Center (NCVC), Suita 564-8565, Osaka, Japan
*
Author to whom correspondence should be addressed.
Neurol. Int. 2025, 17(11), 176; https://doi.org/10.3390/neurolint17110176
Submission received: 27 August 2025 / Revised: 9 October 2025 / Accepted: 20 October 2025 / Published: 1 November 2025
(This article belongs to the Special Issue Innovations in Acute Stroke Treatment, Neuroprotection, and Recovery)
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Versions Notes

Abstract

Background: Ischemic stroke (IS) remains a leading global cause of mortality, recurrence, and long-term disability, with survivors also at risk of post-stroke dementia (PSD) and cognitive impairment (PSCI). The precise impact of statin therapy across different IS populations, including those with cardioembolic/atrial fibrillation (CE/AF) strokes and patients with low-baseline low-density lipoprotein (LDL) cholesterol, remains unclear, as does the influence of statin timing, intensity, type, and solubility. Methods: We conducted the Impact of Statin Therapy on the Risk of Stroke Recurrence, Mortality, and Dementia After Ischemic Stroke (ISMARDD) meta-analysis, synthesizing evidence from 51 studies (n = 521,126), to evaluate the association between post-stroke statin therapy and key outcomes: all-cause mortality, stroke recurrence, cognition, and C-reactive protein (CRP). PSD was defined as new, persistent cognitive decline meeting standard diagnostic criteria, and PSCI as measurable but sub-threshold cognitive deficits. Random-effects models were used, and certainty was assessed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Results: Statin therapy significantly reduced all-cause mortality within 3 months (OR 0.32), at 1 year (OR 0.35), and beyond 1 year (OR 0.56). Stroke recurrence was modestly reduced both within 1 year (OR 0.77) and after 1 year (OR 0.76). Statin use was associated with a lower risk of PSD (OR 0.74) but not PSCI overall. Benefits extended to CE/AF-related strokes and patients with low-baseline LDL cholesterol, both showing significantly lower mortality with statin use. Early initiation (<24 h) was linked with reduced recurrence, though effects of statin intensity, type, and solubility were inconsistent. Statins also significantly reduced CRP levels, underscoring anti-inflammatory and pleiotropic mechanisms. Conclusions: The ISMARDD study demonstrates that statins confer survival benefit and selective cognitive protection (notably reduced PSD risk) after ischemic stroke, with modest recurrence benefit, supporting their broad use in secondary prevention. These findings highlight the need for precision-guided approaches tailored to stroke subtype, pharmacogenomics, and treatment timing to optimize therapeutic outcomes.

Graphical Abstract

1. Introduction

Ischemic stroke (IS) remains a leading global cause of death and long-term disability, with rising incidence particularly among ageing populations [1]. Despite advances in acute stroke interventions such as thrombolysis and mechanical thrombectomy, many survivors remain at elevated risk of recurrent stroke, cognitive impairments, and death [2,3]. While this epidemiological burden is well established, the critical question for clinical pharmacology is how pharmacological interventions, particularly statins, modify these risks beyond lipid lowering.
Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are central to cardiovascular and cerebrovascular risk reduction due to their low-density lipoprotein (LDL) cholesterol-lowering effects [4]. Beyond lipid modulation, accumulating evidence supports statins’ pleiotropic actions, including anti-inflammatory, endothelial-stabilizing, and neuroprotective effects [5], which may be especially relevant in the complex post-ischemic environment. Their ability to lower C-reactive protein (CRP) provides a biomarker-based link between statin exposure and anti-inflammatory benefit, suggesting mechanisms that could explain mortality and cognitive protection across diverse stroke subtypes.
The pivotal Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated the efficacy of high-dose atorvastatin (80 mg daily) in reducing stroke recurrence in non-cardioembolic IS patients [6]. However, the SPARCL trial excluded patients with atrial fibrillation (AF), cardioembolic strokes (CE), and coronary artery disease (CAD)—populations that constitute a large proportion of real-world IS cases [6,7,8]. Current guideline recommendations, derived largely from SPARCL, therefore fail to fully reflect the heterogeneity of IS subtypes and comorbidities seen in practice, including CE/AF-related strokes and patients with low baseline LDL-cholesterol [9,10,11,12,13,14,15,16].
While previous meta-analyses have investigated the impact of statin therapy on stroke recurrence and mortality, they often have inconsistent inclusion criteria, limited subtype representation, and a lack of stratification by pharmacological parameters such as statin intensity, solubility, or timing of initiation [17,18]. Moreover, few reviews have systematically integrated these drug-related factors with outcomes such as post-stroke cognitive impairment (PSCI) (referred to as measurable but sub-threshold cognitive deficits within 3–6 months of the stroke) or dementia (PSD) (defined as persistent cognitive decline meeting standard diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders [DSM] or International Classification of Diseases [ICD]) within 6 months of stroke) [19]—conditions increasingly recognized as critical long-term sequelae of IS [2,20]. Incorporating CRP and pharmacogenomic considerations provides a translational bridge between statin pharmacology and clinical outcomes, directly informing precision prescribing.
The Impact of Statin Therapy on the Risk of Stroke Recurrence, Mortality, and Dementia After Ischemic Stroke (ISMARDD) study was undertaken to address these critical gaps. We conducted a comprehensive systematic review and meta-analysis to evaluate the effects of post-stroke statin therapy on all-cause mortality, stroke recurrence, and cognitive outcomes across a broad range of IS populations. We further examined how these outcomes vary by statin intensity, type, solubility, and timing of initiation, and assessed the impact on CRP levels as a mechanistic marker, to provide insight into their pleiotropic and anti-inflammatory mechanisms. By synthesizing data from over 500,000 patients, the ISMARDD study provides an updated, evidence-based foundation for optimizing statin therapy in post-stroke management and advancing precision-based prevention strategies.

Objectives

This study aims to address the following research questions:
  • Primary Questions
(a)
In the broader IS cohort:
i.
What is the prevalence of all-cause mortality, stroke recurrence and PSD/PSCI in statin users, nonusers and overall?
ii.
Is post-stroke statin use associated with all-cause mortality, stroke recurrence and PSD/PSCI?
(b)
Variations in statin parameters:
i.
Is increasing statin intensity associated with all-cause mortality and stroke recurrence?
ii.
What is the prevalence of all-cause mortality and stroke recurrence by statin intensity, type, timing of initiation and solubility?
  • Secondary Questions
(a)
In CE/AF-related IS subgroups:
i.
What is the prevalence of all-cause mortality and stroke recurrence in statin users, nonusers and overall?
ii.
Is post-stroke statin use associated with all-cause mortality and stroke recurrence?
(b)
In IS patients with low baseline LDL-cholesterol:
i.
What is the prevalence of all-cause mortality in statin users, nonusers, and overall?
ii.
Is post-stroke statin use associated with all-cause mortality?
(c)
Is post-stroke statin use associated with changes in CRP levels in IS patients?

2. Materials and Methods

2.1. Literature Search and Study Selection

A comprehensive literature search for studies published between January 2005 to June 2025 was conducted in PubMed, EMBASE, Scopus, Web of Science and Cochrane Library databases. Key terms in the search strategy included: “stroke”, “brain infarction”, “cerebrovascular event”, “cerebrovascular accident”, “statin” and “hmg-coa reductase inhibitor”. Searches were limited to human studies and those published in or translated to English. A detailed search strategy is available in Supplemental Table S1.
All identified titles and abstracts were initially screened and filtered using EndNote Version 21.5 (Clarivate Analytics, London, UK). The eligibility of remaining articles was thoroughly examined against the inclusion and exclusion criteria outlined below. Additional relevant studies were identified by examining the reference list of systematic reviews and meta-analyses and via Google Scholar. These processes were conducted independently by two researchers, and any discrepancies were resolved through discussion.
The systematic flow of the literature search and study selection is depicted in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart (Figure 1). This report aligns with the PRISMA 2020 and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) checklists, which are presented in Supplemental Tables S2 and S3. This study was also registered in Open Science, registration number “mqnk5” (https://osf.io/mqnk5/ [accessed on 20 July 2025]).

2.2. Inclusion and Exclusion Criteria

Studies were included in this meta-analysis if they satisfied the following criteria:
(a)
participants aged 18 years or older;
(b)
patients receiving statin therapy after IS (either pre-stroke statin continued or newly initiated statin after stroke);
(c)
studies recruiting patients with all IS subtypes, or those focused on CE/AF-related strokes or patients with low baseline LDL-cholesterol;
(d)
included data on the outcomes of PSD/PSCI, stroke recurrence, all-cause mortality; or reported mean and standard deviation or median and interquartile ranges of CRP levels;
(e)
English language publications or translated to English; and
(f)
sample size of at least 20 patients.
Studies were excluded if:
(a)
included hemorrhagic stroke patients;
(b)
restricted to highly select cohorts, such as those with cancer or excluded key IS subtypes, such as those focused only on non-CE strokes;
(c)
did not contain raw data for outcomes;
(d)
only reported on pre-stroke statin use;
(e)
case reports, small case series, or studies with insufficient sample size;
(f)
systematic reviews and meta-analyses;
(g)
non-English or not translated.

2.3. Data Extraction

An Excel spreadsheet was utilized to extract the following key data from the selected studies:
  • Study demographics—author, publication year, country, study design, cohort size.
  • Control and intervention characteristics—statin type, dose, and timing of initiation.
  • Patient demographics—age, sex, National Institute of Health Stroke Scale (NIHSS) score, IS subtype according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, comorbidities (hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease, dyslipidemia, previous stroke) and lifestyle factors (smoking and alcohol consumption).
  • Clinical outcomes—all-cause mortality (within 3 months, 1 year and after 1 year), stroke recurrence (within and after 1 year), any PSD/PSCI diagnosis and CRP levels (within 3–7 days and after 7 days).
When required, Wan et al.’s method was employed to estimate means and standard deviations (SDs) from medians and interquartile ranges (IQR) [21]. Statin solubility was determined based on the statin characteristics defined by Climent et al. [22]. Statin intensity was based on the American College of Cardiology & American Heart Association (ACC/AHA) Classification of Intensity [23].

2.4. Methodological Quality Assessment of Included Studies

The methodological quality of the included studies was assessed using the Modified Jadad Analysis (Supplemental Table S4). We also assessed non-randomized studies with the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool and randomized controlled trials (RCTs) with the Risk of Bias (RoB 2) tool (Supplemental Tables S5 and S6); two reviewers assessed each study independently. The potential risk of bias due to funding was also evaluated based on the declaration of funding sources and conflicts of interest reported in each individual study (Supplemental Table S7).

2.5. Statistical Analyses

Statistical analyses were conducted using STATA version 13.0 (StataCorp, College Station, TX, USA). Summary analyses of patient characteristics were determined from the patient demographic data extracted from the included studies. In the analysis of statin parameter variations, any study that specified a statin parameter (such as timing of initiation, type or dose) was included in the analyses. In some instances, the number of patients included in the analysis were fewer than the initial total of patients due to missing data or lack of follow-up. Where possible, analyses were stratified by time-period, to determine both short-term and long-term effects of statin therapy, as well as by study design.

2.5.1. Prevalence Estimations

The “metaprop” package in STATA was used to perform a random-effects meta-analysis of proportions in studies to determine the pooled prevalence of the clinical outcomes in statin users and nonusers. The “cimethod(exact)” and “ftt” commands were used to obtain the 95% confidence intervals (CIs). Pooled prevalence estimates were calculated using all available studies, with no minimum number of studies required for inclusion in each analysis.

2.5.2. Outcome Associations

The “metan” package in STATA was used to perform a DerSimonian and Laird (DL) random-effects meta-analysis and construct forest plots to determine the association between post-stroke statin use and clinical outcomes. The DL model was selected given its ability to account for heterogeneity between and within studies. A minimum of three studies were required to conduct association analyses.
The analysis involved the calculation of odds ratios (ORs) between post-stroke statin exposure and outcomes such as all-cause mortality, stroke recurrence and PSD/PSCI. For zero-event studies, we used a continuity correction of 0.5. An OR < 1.0 indicated lower odds of the adverse outcome. Standardized mean differences (SMDs) were also calculated to determine the association between post-stroke statin use and changes CRP levels. A negative SMD indicated lower CRP levels in the statin exposed group.

2.5.3. Statistical Significance, Heterogeneity and Variance

Statistical significance was considered when the p-value was <0.05. Heterogeneity was quantified with τ2, I2, H2, and Cochran’s Q. Similarly to Shen et al., heterogeneity was considered low when I2 < 30%, moderate when I2 = 30–50%, substantial when I2 = 51–75%, and severe when I2 > 75% [24]. We explored heterogeneity sources through subgroup analyses by stroke subtype, statin parameters, and study design.

2.5.4. Bias and Sensitivity Analyses

The “metaninf” package in STATA was used to conduct sensitivity analyses which assessed the impact on the pooled OR when individual studies were excluded. We assessed small-study effects using Egger’s and Peters’ tests and inspected funnel plots.

2.6. Certainty of Evidence Assessment

We assessed certainty of evidence for each primary outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, considering risk of bias, inconsistency, indirectness, imprecision, and publication bias. Certainty ratings were presented as high, moderate, low, or very low. For each outcome, we provided the relative effect, assumed control risk, and calculated absolute effect estimates where baseline risk was available.

3. Results

3.1. Description of Included Studies

From 4052 identified articles, 206 full-text articles were assessed for eligibility. Of these, 144 were excluded for various reasons such as irrelevant study outcomes and highly selective or non-IS focused cohorts (Figure 1). A total number (N) of 51 studies, encompassing a total of (n) 521,126 patients, were included in this meta-analysis [25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75]. Among these, 31 studies were focused on all IS subtypes, of which 3 studies looked at PSD/PSCI [49,72,75], 21 looked at all-cause mortality [25,26,28,31,36,37,38,39,40,41,44,45,53,56,59,62,64,67,68,70,73], 12 looked at stroke recurrence [25,39,43,45,53,55,56,59,65,67,70,74], and 6 studies looked at CRP levels [26,29,57,61,65,74]. 10 studies were focused on CE/AF-related stroke, of which 8 looked at all-cause mortality [33,34,35,42,52,58,60,66] and 8 looked at stroke recurrence [33,34,35,54,58,60,66,69]. Three studies looked at all-cause mortality in IS patients with low baseline LDL-cholesterol [47,51,63]. Finally, 9 studies purely focused on statin parameters, including 6 studies on statin intensity [27,28,32,50,59,71], 2 on statin type [30,48], and 1 on statin timing of initiation [46]. Of the 51 studies included in the analysis, 22 studies provided data for multiple research questions.
Characteristics of the studies included in this meta-analysis—including study design, patient demographics as well as comorbidities and lifestyle factors—are detailed in Table 1 and Table 2, respectively. The meta-analysis incorporated studies from a diverse range of countries and age groups. Patients had high prevalence of cardiovascular risk factors and comorbidities such as hypertension, coronary artery disease and smoking. Variation in stroke treatment protocols was observed as the proportion of patients initiated on statin therapy after stroke ranged from 9.7% to 83.7%. A broad range of stroke severities were included, as evidenced by the wide spread of NIHSS scores.

3.2. Primary Analysis

3.2.1. Impact of Post-Stroke Statin Use on Clinical Outcomes in Broader Ischemic Stroke Cohorts

Prevalence Estimations
  • All-Cause Mortality
The overall prevalence of all-cause mortality was 12% within 3 months (95% CI: [0.09, 0.16]; z = 11.67; p < 0.01; n = 11,233; N = 10) [28,31,36,37,41,56,62,64,70,73], 14% within 1 year (95% CI: [0.08, 0.21]; z = 7.82; p < 0.01; n = 84,567; N = 14) [25,26,28,31,36,37,40,41,44,56,62,64,70,73] and 23% after 1 year (95% CI: [0.07, 0.44]; z = 4.20; p = 0.01; n = 163,348; N = 8) [37,38,39,45,53,59,67,68] of IS (Table 3; Supplemental Figure S1). There was severe heterogeneity among these studies (I2 = 94.83%, 99.73% and 99.98%, respectively, for each analysis).
In statin users, the prevalence of all-cause mortality within 3 months was 8% (95% CI: [0.05, 0.11]; z = 8.38; p < 0.01; n = 5052; N = 10) compared to 18% (95% CI: [0.13, 0.24]; z = 10.38, p < 0.01; n = 6181; N = 10) in statin non-users) [28,31,36,37,41,56,62,64,70,73]. Within 1 year after stroke, statin users had a prevalence of 9% (95% CI: [0.06, 0.14]; z = 7.30, p < 0.01; n = 55,421; N = 14) compared to nonusers who had a 21% prevalence (95% CI: [0.14, 0.30]; z = 8.49; p < 0.01; n = 29,146; N = 14) [25,26,28,31,36,37,40,41,44,56,62,64,70,73]. After 1 year statin users had a prevalence of 19% (95% CI: [0.05, 0.41]; z = 3.58; p < 0.01; n = 97,171; N = 8) compared to 30% (95% CI: [0.14, 0.50]; z = 5.30, p < 0.01; n = 66,177; N = 8) in nonusers [37,38,39,45,53,59,67,68] (Table 3; Supplemental Figure S2).
  • Stroke Recurrence
The overall prevalence of stroke recurrence was 4% (95% CI: [0.02, 0.08]; z = 4.38; p < 0.01; n = 60,026; N = 5) [25,56,65,70,74] within 1 year and 17% (95% CI: [0.11, 0.24]; z = 9.02; p < 0.01; n = 144,993; N = 8) [25,39,43,45,53,55,59,67] after 1 year of IS (Table 3; Supplemental Figure S3). There was severe heterogeneity among these studies, (I2 = 81.38% and 99.86%, respectively, for each analysis).
In statin users, the prevalence of stroke recurrence within 1 year was 3% (95% CI: [0.01, 0.07]; z = 3.41; p < 0.01; n = 43,631; N = 5) compared to 5% (95% CI: [0.02, 0.10]; z = 4.59; p < 0.01; n = 16,395; N = 5) in nonusers [25,56,65,70,74]. After 1 year of IS, statin users had a prevalence of 13% (95% CI: [0.08, 0.20]; z = 7.69; p < 0.01; n = 101,244; N = 8) compared to 20% (95% CI: [0.13, 0.28]; z = 9.31; p < 0.01; n = 43,749; N = 8) in nonusers [25,39,43,45,53,55,59,67] (Table 3; Supplemental Figure S4).
  • Post-Stroke Dementia/Cognitive Impairment
The overall prevalence of PSD/PSCI was 18% (95% CI: [0.09, 0.30]; z = 6.16; p < 0.01; n = 68,016; N = 3) [49,72,75] (Table 3; Supplemental Figure S5). There were insufficient studies to calculate heterogeneity between the studies.
The prevalence of PSD/PSCI was 19% in both statin users (95% CI: [0.09, 0.31]; z = 5.67, p < 0.01; n = 46,831; N = 3) and nonusers (95% CI: [0.09, 0.31]; z = 6.05; p < 0.01; n = 21,185; N = 3) [49,72,75] (Table 3; Supplemental Figure S6).
Outcome Associations
  • All-Cause Mortality
Statin use was associated with significantly decreased odds of all-cause mortality within 3 months with OR 0.32 (95% CI: [0.26, 0.39]; p < 0.01; z = −12.44; n = 11,233; N = 10) [28,31,36,37,41,56,62,64,70,73], within 1 year with OR 0.35 (95% CI: [0.28, 0.44]; p < 0.01; z = −9.30; n = 84,567; N = 14) [25,26,28,31,36,37,40,41,44,56,62,64,70,73] and after 1 year with OR 0.56 (95% CI: [0.44, 0.72]; p < 0.01; z = −4.51; n = 163,348; N = 8) [37,38,39,45,53,59,67,68] of IS (Table 4; Figure 2). The direction of effect remained consistent when stratified by study design, although was not significant for the RCT subgroups. Heterogeneity of studies was mixed, with low heterogeneity within the 3-month analysis (I2 = 19.4%), but severe heterogeneity for within 1-year (I2 = 86.8%) and after 1-year (I2 = 97.9%) analyses.
  • Stroke Recurrence
Statin use was associated with significantly decreased odds of stroke recurrence within 1 year with OR 0.77 (95% CI: [0.72, 0.82], z = −7.64; p < 0.01; n = 60,026; N = 5) [25,56,65,70,74] and after 1 year with OR 0.76 (95% CI: [0.66, 0.87], z = −3.88; p < 0.01; n = 144,993; N = 8) [25,39,43,45,53,55,59,67] of IS (Table 4; Figure 3). The direction of effect remained consistent when stratified by study design, although was not significant for the RCT subgroup in the within 1 year analysis. Heterogeneity of studies was mixed, with low heterogeneity for the within 1 year analysis (I2 = 0.0%) but severe heterogeneity (I2 = 85.1%) for the post 1-year analysis.
  • Dementia/Cognitive Impairment
Statin use was not significantly associated with decreased odds of overall PSD or PSCI after IS with OR 0.83 (95% CI: [0.66, 1.05]; z = −1.54; p = 0.12; n = 68,016; N = 3) [49,72,75] (Table 4; Figure 4). When looking at PSD alone, statin use was associated with significantly decreased odds with OR 0.74 (95% CI: [0.60, 0.90]; z = −2.94; p < 0.01; n = 67,666; N = 2) [49,72]. Heterogeneity was severe for the overall analysis (I2 = 90.9%) and the PSD subgroup (I2 = 92.1%).

3.2.2. Impact of Variations in Statin Parameters on Clinical Outcomes

  • Statin Timing
The prevalence of all-cause mortality in patients initiating statin within 24 h was 10% (95% CI: [0.06, 0.12]; z = 7.13; p < 0.01; n = 316; N = 3) [37,56,62] compared to 6% (95% CI: [0.03, 0.09]; z = 7.45; p < 0.01; n = 1169; N = 3) [31,32,36] in those initiating statin therapy after 24 h (Table 5; Supplemental Figure S7).
The prevalence of stroke recurrence, in patients initiating statin within 24 h, was 5% (95% CI: [0.01, 0.11]; z = 3.44; p < 0.01; n = 95; N = 2) [46,56] compared to 9% (95% CI: [0.06, 0.14]; z = 8.45; p < 0.01; n = 239; N = 2) [32,46] in those initiating statin therapy after 24 h (Table 5; Supplemental Figure S7).
  • Statin Type
The prevalence of all-cause mortality was lowest amongst rosuvastatin users (4%; 95% CI: [0.01, 0.07]; z = 4.55; p < 0.01; n = 6919; N = 2) [48,71] and highest amongst simvastatin users (10%; 95% CI: [0.06, 0.16]; z = 6.44; p < 0.01; n = 136; N = 2) [56,70] (Table 5; Supplemental Figure S8).
The prevalence of stroke recurrence was lowest amongst rosuvastatin users, though not statistically significant (2%; 95% CI: [0.00, 0.07]; z = 1.47; p = 0.14; n = 6681; N = 3) [30,48,65]. Stroke recurrence was highest amongst atorvastatin users (4%; 95% CI: [0.03, 0.05]; z = 10.93; p < 0.01; n = 37,080; N = 3) [30,32,48] (Table 5; Supplemental Figure S8).
  • Statin Solubility
The prevalence of all-cause mortality was similar between hydrophilic (6%, 95% CI: [0.05, 0.06]; z = 36.84; p < 0.01; n = 6919; N = 2) [48,71] and lipophilic (6%; 95% CI: [0.03, 0.10]; z = 5.88; p < 0.01; n = 37,181; N = 5) statin users [32,48,56,70,73] (Table 5; Supplemental Figure S9).
The prevalence of stroke recurrence was lower amongst hydrophilic statin users (2%; 95% CI: [0.00, 0.07]; z = 1.47; p < 0.01; n = 6681; N = 3) [30,48,65] compared to lipophilic (4%; 95% CI: [0.02, 0.06]; z = 6.37; p < 0.01; n = 37,216; N = 5) statin users [30,32,48,56,70] (Table 5; Supplemental Figure S9).
  • Statin Intensity
The prevalence of all-cause mortality was lowest in the moderate-high intensity statin group (4%; 95% CI: [0.02, 0.06]; z = 7.54; p < 0.01; n = 471; N = 2) [28,67] and was highest in the low-moderate intensity statin group (19%; 95% CI: [0.12, 0.28]; z = 8.31; p < 0.01; n = 21,001; N = 4) [28,37,38,59] (Table 5; Supplemental Figure S10).
The prevalence of stroke recurrence was lowest in the moderate intensity statin group (4%; 95% CI: [0.00, 0.10]; z = 2.40; p = 0.02; n = 205; N = 4) [32,56,65,70] and was highest in the moderate-high intensity statin group (17%; 95% CI: [0.13, 0.22]; z = 14.90; p < 0.01; n = 344; N = 1) [67]. The prevalence of stroke recurrence was similar between the low-moderate (10%; 95% CI: [0.10, 0.11]; z = 93.47; p = 0.01; n = 20,486; N = 1) [59] and high intensity (10%; 95% CI: [0.10, 0.11]; z = 55.10; p = 0.12; n = 9205; N = 2) [32,59] statin groups (Table 5; Supplemental Figure S10).
Increasing intensity of statin was not significantly associated with all-cause mortality with OR 0.92 (95% CI: [0.76, 1.12]; z = −0.80; p = 0.42; n = 103,236; N = 6) [27,28,32,50,59,71] or stroke recurrence with OR 1.10 (95% CI [0.88, 1.38]; z = −0.82; p = 0.41; n = 102,647; N = 4) [27,32,50,59] (Table 5; Supplemental Figure S11).

3.3. Secondary Analysis

3.3.1. Impact of Post-Stroke Statin Use in Cardioembolic/Atrial Fibrillation-Related Strokes

Prevalence Estimations
  • All-Cause Mortality
The overall prevalence of all-cause mortality was 23% (95% CI: [0.18, 0.28]; z = 15.74; p < 0.01; n = 51,280; N = 3) [42,52,60] within 1 year and 10% (95% CI: [0.04, 0.17]; z = 4.94; p < 0.01; n = 24,805; N = 5) [33,34,35,58,66] after 1 year of cardioembolic or AF-related stroke (Supplemental Table S8; Supplemental Figure S12).
In statin users, the prevalence of all-cause mortality within 1 year was 19% (95% CI: [0.14, 0.24]; z = 12.97; p < 0.01; n = 7107; N = 3) compared to 30% (95% CI: [0.19, 0.42]; z = 8.66, p < 0.01; n = 44,373; N = 3) in nonusers [42,52,60]. This was again observed after 1 year with a prevalence of 5% (95% CI: [0.02, 0.10]; z = 4.07, p < 0.01; n = 9497; N = 5) in statin users compared to 10% (95% CI: [0.03, 0.20]; z = 3.95, p < 0.01; n = 14,591; N = 5) in nonusers [33,34,35,58,66] (Supplemental Table S8; Supplemental Figure S13).
  • Stroke Recurrence
The overall prevalence of stroke recurrence was 6% (95% CI: [0.05, 0.06]; z = 31.22; p < 0.01; n = 4630; N = 2) [54,60] within 1 year and 13% (95% CI: [0.10, 0.18]; z = 11.60; p < 0.01; n = 28,723; N = 6) [33,34,35,58,66,69] after 1 year of cardioembolic or AF-related stroke (Supplemental Table S8; Supplemental Figure S14).
In statin users, the prevalence of stroke recurrence within 1 year was 5% (95% CI: [0.04, 0.06]; z = 22.78, p < 0.01; n = 2761; N = 2) compared to 6% (95% CI: [0.05, 0.07]; z = 20.53, p < 0.01; n = 1869; N = 2) in nonusers [54,60]. 1 year after stroke, prevalence of stroke recurrence was 12% (95% CI: [0.08, 0.17]; z = 8.94; p < 0.01; n = 11,040; N = 6) among statin users compared to 13% (95% CI: [0.10, 0.16]; z = 13.35; p < 0.01; n = 17,683; N = 6) in nonusers [33,34,35,58,66,69] (Supplemental Table S8; Supplemental Figure S15).
Outcome Associations
  • All-Cause Mortality
Statin use was associated with significantly decreased odds of all-cause mortality both within 1 year with OR 0.57 (95% CI: [0.42, 0.78]; z = −3.49; p < 0.01; n = 51,280; N = 3) [42,52,60] and after 1 year with OR 0.47 (95% CI: [0.25, 0.88]; z = −2.37; p = 0.02; n = 24,805; N = 5) [33,34,35,58,66] in CE/AF-related stroke patients (Supplemental Table S9; Supplemental Figure S16). Heterogeneity for both analyses was severe, (I2 = 88.5% and 90.5%, respectively).
  • Stroke Recurrence
Due to insufficient data, association analyses were unable to be conducted for stroke recurrence within 1 year. However, statin use was not significantly associated with decreased odds of stroke recurrence after 1 year with OR 0.84 (95% CI: [0.63, 1.12]; z = −1.23, p = 0.22; n = 28,723; N = 6) [33,34,35,58,66,69] in CE/AF-related stroke patients (Supplemental Table S9; Supplemental Figure S17). Heterogeneity of studies was severe (I2 = 82.3%).

3.3.2. Impact of Post-Stroke Statin Use in Ischemic Stroke Patients with Low Baseline LDL-Cholesterol Levels

  • Prevalence Estimations
The overall prevalence of all-cause mortality was 11% (95% CI: [0.07, 0.16]; z = 8.94; p < 0.01; n = 4824; N = 3) [47,51,63] (Supplemental Table S8; Supplemental Figure S12).
In statin users, the prevalence of all-cause mortality was 6% (95% CI: [0.04, 0.09]; z = 8.18; p < 0.01; n = 2799; N = 3) compared to 17% (95% CI: [0.11, 0.23]; z = 9.68; p < 0.01; n = 2025; N = 3) in statin non-users [47,51,63] (Supplemental Table S8; Supplemental Figure S13).
  • Outcome Associations
In patients with low baseline LDL-cholesterol, statin use was associated with significantly lower odds of all-cause mortality in IS patients with low baseline LDL-cholesterol levels with OR 0.32 (95% CI: [0.17, 0.58]; z = −3.708; p < 0.001; n = 4824; N = 3) [47,51,63] (Supplemental Table S9; Supplemental Figure S16). Heterogeneity of studies was severe (I2 = 85.6%).

3.3.3. Impact of Post-Stroke Statin Use on CRP Levels in Ischemic Stroke Patients

Statin use was associated with significantly lower CRP levels within 3–7 days after IS (SMD = −0.41, 95% CI: [−0.75, −0.06]; z = −2.33; p = 0.02; n = 157; N = 3) [29,57,61] and after 7 days of IS (SMD = −2.64, 95% CI: [−5.26, −0.03]; z = −1.98; p < 0.01; n = 410; N = 4) [26,29,65,74] (Table 4; Supplemental Figure S18). Heterogeneity of studies was mixed, with low heterogeneity for the 3–7-day analysis (I2 = 0.0%) and severe for the post 7-day analysis (I2 = 98.6%).

3.4. Bias & Sensitivity Analysis

Sensitivity analysis demonstrated that the exclusion of outliers and high-risk studies did not significantly alter the pooled estimates for most analyses (Supplemental Figure S19). The p-values in Egger’s and Peter’s tests were insignificant for most analyses (Supplemental Tables S10 and S11; Supplemental Figure S20). Inspection of funnel plots, however, revealed asymmetry, suggesting potential for publication bias (Supplemental Figure S21).

4. Discussion

This meta-analysis, the ISMARDD Study, significantly contributes to the evolving understanding of statin therapy’s role in secondary prevention following IS. Beyond confirming reduced mortality and recurrence risks, ISMARDD highlights the clinical pharmacology relevance of statin therapy. The mortality benefit likely reflects pleiotropic actions, anti-inflammatory, antioxidant, and endothelial-stabilizing, beyond LDL reduction. The observed reduction in CRP provides a biomarker-based link between statin exposure and anti-inflammatory benefit, strengthening mechanistic plausibility and translational relevance.
Pooled prevalence rates were 13–23% for all-cause mortality, 4–17% for stroke recurrence, and 19% for cognitive impairment or dementia. Statin users consistently experienced lower mortality and dementia risk compared to non-users, though effects on overall cognitive impairment were neutral. No consistent trends were identified concerning statin intensity, type, or solubility. Early initiation of statins (within 24 h) was linked with a lower prevalence of stroke recurrence. While early initiation of statin therapy (<24 h) demonstrated benefit for recurrence reduction, evidence regarding statin intensity, type, and solubility remains heterogeneous and should be interpreted with caution. These pharmacologic parameters warrant validation in controlled, phenotype-stratified cohorts. Pooled association analyses showed that statin use significantly reduced the odds of all-cause mortality by 44–68%, a benefit that extended across key subgroups, including patients with CE/AF-related strokes and those with low baseline LDL-cholesterol, who showed 43–53% and 68% lower odds of mortality, respectively. The effect on stroke recurrence was modest and mixed. While the broader IS group saw a 23–24% reduction in both short- and long-term recurrence, this effect did not reach significance in the CE/AF subgroup. Despite substantial heterogeneity (I2 > 75%), sensitivity analyses confirmed the robustness and consistency of the mortality and recurrence findings, underscoring the generalizability of the benefit across varied study populations and methods. No significant differences were observed for PSCI and composite cognitive impairment. However, statin use was associated with a 26% lower risk of post-stroke dementia. These findings extend the evidence base beyond the SPARCL trial [6], demonstrating benefit even in real-world populations excluded from that trial, including CE/AF-related strokes and patients with low baseline LDL-cholesterol, and align with prior meta-analyses reporting consistent mortality reductions but variable effects on recurrence [17,18,76,77]. Key clinical insights relating to post-stroke statin use, generated by the ISMARDD study and by previous studies, are summarized in Figure 5, and the certainty of the findings is summarized in Table 6. Substantial heterogeneity (I2 > 75%) across several analyses reflects the inclusion of diverse populations, study designs, and statin regimens. Nevertheless, sensitivity analyses confirmed the consistency of direction and robustness of pooled estimates.
To clarify the clinical guidance depicted in Figure 5, in accordance with the 2021 AHA/ASA secondary prevention guideline [12], high-intensity statin therapy (e.g., atorvastatin 80 mg or rosuvastatin 20 mg daily) is preferred for most ischemic stroke or TIA patients to reduce recurrent cardiovascular and cerebrovascular events. The recommendation for statin use in CE or AF-related ischemic stroke primarily addresses comorbid atherosclerotic and systemic vascular risk rather than the embolic mechanism itself. Moderate-intensity regimens may be considered only when high-intensity therapy is contraindicated or poorly tolerated. Evidence from trials such as SPARCL supports the long-term benefit of statin therapy for secondary prevention [6], though not specifically within the first 24–48 h post-onset. All patients should have lipid profiles reassessed 4–12 weeks after initiation, with ongoing monitoring for hepatic or muscle-related adverse effects.
  • Mechanistic Insights and Subgroup Effects
The mortality benefit, observed in post-stroke populations, likely reflects statin’s dual mechanism of action. While fatality after IS often arises from direct neurological damage, cardiovascular complications, or systemic infections [81], statins offer pleiotropic effects—anti-inflammatory, antioxidant, and endothelial-stabilizing—that extend beyond lipid lowering [81]. These effects may explain the consistent mortality benefit observed even in subgroups such as CE/AF-related stroke and patients with low baseline LDL-cholesterol, where hyperlipidemia is not central to pathophysiology. These findings are supported by our meta-analysis of CRP, a systemic inflammation marker, which was significantly lower among statin users compared to nonusers.
  • Stroke Recurrence and Etiology-Specific Effects
While statin use was associated with reduced stroke recurrence in the broader IS group, this benefit did not extend to the CE/AF subgroup. This may reflect etiological differences, especially since stroke recurrence tends to follow the same mechanism as the index event [82]. Patients with large artery atherosclerosis may benefit more from statin use due to their plaque-stabilizing effects [83], whereas CE/AF-related strokes, which are typically driven by cardiac dysrhythmia, may require alternative strategies [8]. Although statins exhibit antithrombotic properties, they likely do not modify the electrophysiological mechanisms of dysrhythmias [84].
  • Cognitive Outcomes: Differentiating PSD and PSCI
Statin therapy was associated with a 26% reduction in PSD risk but showed no clear effect on PSCI. This divergence may reflect underlying pathophysiological differences. While PSCI is often linked to neurodegeneration [85], PSD involves vascular injury, neuroinflammation, and possible acceleration of Alzheimer’s pathology [86,87,88]. Statins’ neuroprotective and anti-inflammatory properties may better align with the pathogenesis of PSD, explaining the differential benefit [89].
  • Optimizing Statin Therapy in Ischemic Stroke: Toward Precision Neurology
Statins are well established in the secondary prevention of IS and transient ischemic attack (TIA). Emerging evidence, including from this meta-analysis, suggests that statins may also confer mortality and cognitive benefits. The optimal regimen, including type, dose, and timing of initiation, remains to be clearly defined to inform evidence-based clinical guidelines. Given that the majority of included studies were observational, causality cannot be inferred. Nonetheless, the consistency of effect direction across study designs supports a strong associative signal warranting further randomized validation. Although our inclusion criteria focused on post-stroke statin therapy, several studies distinguished between pre-existing and newly initiated users. Evidence suggests that continuation of pre-stroke statins may further enhance survival and reduce early neurological deterioration, consistent with the concept of ‘statin preconditioning’ [90]. Future analyses differentiating continuation versus de novo initiation are warranted.
In our analysis, early statin initiation (within 24 h of stroke onset) was linked with a lower prevalence of stroke recurrence, though this was not seen with a reduction in all-cause mortality. This finding contrasts with several trials that reported no difference in outcomes between early and delayed initiation [91,92]. Similarly, no significant association was found between statin intensity and reduced adverse outcomes, mirroring mixed results in the literature. While some studies suggest high-intensity statins yield better outcomes, others report no clear advantage [93,94]. No consistent trends emerged regarding statin type or solubility. Lipophilic statins (such as atorvastatin, simvastatin) have greater blood–brain barrier penetration, which may enhance neuroprotective effects, though their use has also been linked to potential cognitive decline [95], underscoring the need for further clarification regarding their role in stroke recovery. The ISMARDD meta-analysis also revealed variable outcome profiles among individual statins. While simvastatin demonstrated higher prevalence of mortality and recurrence, rosuvastatin exhibited the most favorable outcomes, with atorvastatin showing intermediate or inconsistent effects. These apparent differences are likely attributable to variations in study design, sample sizes, and population characteristics rather than inherent pharmacologic disparities. In contrast to cardiology trials, where lipid-lowering and plaque-stabilizing effects dominate [23,96,97,98], post-stroke outcomes may be influenced by additional factors such as blood–brain barrier penetration [99,100,101], central nervous system distribution [102], and pleiotropic anti-inflammatory mechanisms [103]. Rosuvastatin’s higher hydrophilicity and potent CRP-lowering capacity may enhance cerebrovascular protection [104], whereas variability in atorvastatin findings may reflect differential inclusion of cardioembolic and mixed-etiology cohorts. These findings underscore the need for head-to-head, stroke-specific comparative studies to delineate the neurovascular effects of individual statins beyond their cardiovascular efficacy.
Responses to statin therapy vary depending on stroke subtype and individual patient characteristics such as age, ethnicity, comorbidities, and baseline LDL-cholesterol levels. The current study showed consistent mortality benefits across subgroups, but recurrence benefits differed by stroke etiology. CE/AF-related strokes showed less consistent recurrence benefit. Genetic variability further contributes to differential statin response [105,106]; Asian patients may achieve similar outcomes with lower doses due to altered metabolism [105], while some individuals exhibit pharmacogenomic resistance to statins [79,107]. These interindividual differences underscore the importance of pharmacogenomic modifiers of statin metabolism and transport, such as SLCO1B1 and ABCG2 variants, which alter bioavailability and treatment response. Patients with variations in SLCO1B1 gene have lower hepatic uptake of statins [108], or those with ABCG2 variants have impaired statin transport and lower bioavailability [109]. In such cases, adjunctive therapies (such as ezetimibe, PCSK9 inhibitors, bempedoic acid) warrant exploration. This highlights how precision-guided statin prescribing, integrating pharmacogenomics, solubility, and inflammatory markers, can optimize secondary prevention and cognitive protection after stroke.
These interindividual variations challenge the utility of a one-size-fits-all model, which is currently reflected in guidelines. A shift toward precision neurology, tailoring therapy to stroke subtype, pharmacogenomic profile, and inflammatory or lipid biomarkers, may enhance statin efficacy and safety [106]. This is particularly relevant for low- and middle-income countries (LMICs), where access to reperfusion therapies is limited and cost-effective interventions like statins may offer critical clinical value [110].

4.1. Strengths and Limitations

To our knowledge, this is the first meta-analysis to comprehensively evaluate the effects of post-stroke statin therapy on key clinical outcomes across short- and long-term time points. It is also the first to meta-analyze outcomes related to PSCI and PSD, as well as in patients with low baseline LDL-cholesterol levels—populations historically underrepresented in prior trials.
Nonetheless, several limitations warrant consideration. First, variability in treatment protocols across included studies may have influenced outcomes. Although only studies evaluating post-stroke statin use were included, differences in treatment duration, adherence, and concurrent use of thrombolysis, thrombectomy, or antiplatelet agents may introduce confounding. Second, the analysis primarily relied on observational data, inherently subject to selection bias and unmeasured confounders. Third, substantial statistical heterogeneity (I2 > 75%) was observed in most outcomes, likely reflecting differences in patient populations and local management practices, which may limit generalizability. Fourth, limited data were available on statin parameters (type, intensity, solubility), CE/AF-related stroke outcomes, and PSCI/PSD, restricting our ability to conduct association and robust subgroup analyses. Notably, data on lacunar strokes, an important etiology particularly in Asian populations [111], were insufficient for inclusion. Fifth, analyses involving statin-specific parameters were descriptive in nature and could not adjust for confounders, precluding causal inference. Lastly, evidence of publication bias may have inflated effect estimates, impacting the reliability of conclusions.

4.2. Future Directions

This meta-analysis highlights key gaps that should inform future research. First, RCTs are needed to evaluate the impact of statin regimen variations—including intensity, type, and timing—on clinical outcomes to support more tailored, evidence-based recommendations. Second, longitudinal studies assessing cognitive outcomes, particularly PSCI and PSD, are essential to better understand statins’ role in long-term brain health. Future longitudinal studies should employ standardized cognitive batteries, e.g., Montreal Cognitive Assessment (MoCA), Mini Mental State Examination (MMSE), or National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network (NINDS-CSN), to uniformly quantify post-stroke cognitive trajectories [112]. Third, focused research on the efficacy of statins in lacunar strokes is needed, especially given their prevalence in non-Western populations [111]. Fourth, meta-regression was limited by inadequate stratified data but will be considered in future pooled analyses. Fifth, exploring combination strategies involving statins and non-statin agents (e.g., PCSK9 inhibitors, ezetimibe) in statin-resistant individuals may help optimize outcomes in precision-guided, post-stroke lipid management. Serial measurement of CRP and related inflammatory mediators could clarify the temporal dynamics of statins’ pleiotropic effects and guide optimal initiation timing. Finally, future trials integrating genetic, lipidomic, and inflammatory biomarkers will enable precision-guided statin therapy tailored to stroke subtype and pharmacogenomic profile.

5. Conclusions

This comprehensive meta-analysis, the ISMARDD Study, demonstrates that post-stroke statin therapy is associated with significant reductions in all-cause mortality and PSD, with modest benefits on stroke recurrence. These effects were observed consistently across diverse IS populations, including patients with CE or AF-related strokes and those with low-baseline LDL cholesterol levels—subgroups historically excluded from key trials. Early initiation of statin therapy (within 24 h of stroke onset) was linked with reduced prevalence of recurrence, reinforcing the importance of timing in maximizing therapeutic outcomes. Although heterogeneity was present across included studies, sensitivity analyses confirmed the stability of key findings. No consistent variations were noted based on statin intensity, type, or solubility, suggesting that other biological and clinical factors may better guide individualized statin strategies. The reduction in CRP levels among statin users supports the role of anti-inflammatory and pleiotropic mechanisms in their neuroprotective effects. Taken together, these findings support a broad recommendation for statin use after IS. However, they also highlight the limitations of a one-size-fits-all approach. A shift toward precision neurology, where treatment is tailored to stroke subtype, comorbidities, LDL thresholds, cognitive risk, and inflammatory markers, may help unlock the full therapeutic potential of statins in post-stroke care [106]. Future trials should prioritize individualized treatment models and investigate optimal statin regimens for improving survival and long-term brain health in diverse stroke populations.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/neurolint17110176/s1, Supplemental Tables: Table S1. Search Strategy (Keywords/MeSH Terms); Table S2. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (2020) Checklist; Table S3. Meta-analysis of Observational Studies in Epidemiology (MOOSE) Checklist; Table S4. Modified Jadad Analysis for Methodological Quality; Table S5. ROBINS-I: Risk of Bias in Non-Randomized Studies of Interventions; Table S6. RoB-2: Risk of Bias in Randomized Trials; Table S7. Funding Bias Scores for Studies; Table S8. Pooled prevalence of clinical outcomes in ischemic stroke patient subgroups with post-stroke statin use vs. no post-stroke statin use; Table S9. Summary effects and heterogeneity obtained from meta-analysis of statin use and clinical outcomes after ischemic stroke in sub-groups; Table S10. Outputs of Peters’ test; Table S11. Outputs of Egger’s test; Supplemental Figures: Figure S1. Estimated prevalence of all-cause mortality within 3 months, 1 year and after 1 year of ischemic stroke; Figure S2. Estimated prevalence of all-cause mortality within 3 months, 1 year and after 1 year of ischemic stroke in statin users vs. nonusers, as shown in Figure S3. Estimated prevalence of stroke recurrence within 1 year and after 1 year of ischemic stroke; Figure S4. Estimated prevalence of stroke recurrence within 1 year and after 1 year of ischemic stroke in statin users vs. nonusers; Figure S5. Estimated prevalence of dementia/cognitive impairment after ischemic stroke; Figure S6. Estimated prevalence of dementia/cognitive impairment after ischemic stroke in statin users vs. nonusers; Figure S7. Estimated prevalence of all-cause mortality and stroke recurrence by statin timing of initiation; Figure S8. Estimated prevalence of all-cause mortality and stroke recurrence by statin type; Figure S9. Estimated prevalence of all-cause mortality and stroke recurrence by statin solubility; Figure S10. Estimated prevalence of all-cause mortality and stroke recurrence by statin intensity; Figure S11. Association between increasing statin intensity and all-cause mortality and stroke recurrence after ischemic stroke; Figure S12. Estimated prevalence of all-cause mortality within and after 1 year in cardioembolic/atrial fibrillation stroke patients and patients with low baseline low-density lipoprotein cholesterol; Figure S13. Estimated prevalence of all-cause mortality within and after 1 year in cardioembolic/atrial fibrillation stroke patients and patients with low baseline low-density lipoprotein cholesterol in statin users vs. nonusers; Figure S14. Estimated prevalence of stroke recurrence within and after 1 year in cardioembolic/atrial fibrillation stroke patients; Figure S15. Estimated prevalence of stroke recurrence within and after 1 year in cardioembolic/atrial fibrillation stroke patients in statin users vs. nonusers; Figure S16. Association between statin use and all-cause mortality within and after 1 year in cardioembolic and atrial-fibrillation related stroke patients and patients with low baseline low-density lipoprotein cholesterol; Figure S17. Association between statin use and stroke recurrence after 1 year in cardioembolic and atrial-fibrillation related stroke patients; Figure S18. Difference in CRP levels (mg/L) within 3–7 days and after 7 days of ischemic stroke between statin users and nonusers; Figure S19. Graphs of Sensitivity Analysis; Figure S20. Graphs of Egger’s Regression Test; Figure S21. Graphs of Funnel Plots.

Author Contributions

S.B. conceptualized and led the ISMARDD study, developing the overarching framework and supervising the Global Health Neurology Lab team. He provided intellectual leadership, validated key concepts, and oversaw all aspects of study design and manuscript development. S.B. encouraged M.G. to explore this topic and guided the synthesis and interpretation of findings. M.G. and S.B. jointly conducted the literature review, data collection, drafting of the manuscript, and critical revisions. R.G.B. and K.J.S. contributed to the discussion of the study design and provided critical feedback during the drafting and revision process. All authors have read and agreed to the published version of the manuscript.

Funding

This study received no direct funding. S.B. received separate financial support through the Grant-in-Aid for Scientific Research (KAKENHI) funded by the Japan Society for the Promotion of Science (JSPS), Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (Grant ID: 23KF0126). S.B. was also awarded the JSPS International Fellowship supported by MEXT and the Australian Academy of Science for the period 2023–2025 (Grant ID: P23712).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.

Conflicts of Interest

S.B. reports leadership or fiduciary roles with the following organizations: National Cerebral and Cardiovascular Center (Osaka, Japan) as Visiting Director (2023–2025); Rotary District 9675 (Sydney, Australia) as District Chair for Diversity, Equity, and Inclusion; the Global Health and Migration Hub Community, Global Health Hub Germany (Berlin, Germany) as Chair and Founding Member; and editorial board memberships at PLOS One, BMC Neurology, Frontiers in Neurology, Frontiers in Stroke, Frontiers in Public Health, Journal of Aging Research, Neurology International, Diagnostics, and BMC Medical Research Methodology. He also serves as a Member of the College of Reviewers for the Canadian Institutes of Health Research (CIHR), Government of Canada; Director of Research for the World Headache Society (Bengaluru, India); Scientific Review Committee Member at Cardiff University Biobank (UK); Chair of the Rotary Reconciliation Action Plan (RAP), Rotary District 9675 (NSW, Australia); Healthcare and Medical Adviser for Japan Connect (Osaka, Japan); and Expert Adviser/Reviewer for the Cariplo Foundation (Milan, Italy). These roles are unrelated to the submitted work. The other authors (M.G., R.G.B. and K.J.S.) declare no conflicts of interest. The funding bodies had no role in the design, data collection, interpretation, or preparation of this manuscript. The content is solely the responsibility of the authors and does not represent the official views of any affiliated or funding organizations.

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Figure 1. Preferred Reporting System for Systematic Reviews and Meta-Analyses (PRISMA) Flowchart showing the studies included in the meta-analysis. Abbreviations: N, number of studies; n, number of patients; CRP, C-reactive protein.
Figure 1. Preferred Reporting System for Systematic Reviews and Meta-Analyses (PRISMA) Flowchart showing the studies included in the meta-analysis. Abbreviations: N, number of studies; n, number of patients; CRP, C-reactive protein.
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Figure 2. Association between post-stroke statin use and all-cause mortality (A) within 3 months of ischemic stroke; (B) within 1 year of ischemic stroke; (C) after 1 year of ischemic stroke [25,26,28,31,36,37,38,39,40,41,44,45,53,59,56,62,64,67,68,70,73]. Abbreviations: CI, confidence interval; DL, DerSimonian and Laird; p, p-value.
Figure 2. Association between post-stroke statin use and all-cause mortality (A) within 3 months of ischemic stroke; (B) within 1 year of ischemic stroke; (C) after 1 year of ischemic stroke [25,26,28,31,36,37,38,39,40,41,44,45,53,59,56,62,64,67,68,70,73]. Abbreviations: CI, confidence interval; DL, DerSimonian and Laird; p, p-value.
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Figure 3. Association between post-stroke statin use and stroke recurrence: (A) within 1 year of ischemic stroke; (B) after 1 year of ischemic stroke [25,39,43,45,53,55,56,59,65,67,70,74]. Abbreviations: CI, confidence interval; DL, DerSimonian and Laird; p, p-value; Due to model limitations, studies with 0 events were replaced with 0.5 to allow for OR calculation.
Figure 3. Association between post-stroke statin use and stroke recurrence: (A) within 1 year of ischemic stroke; (B) after 1 year of ischemic stroke [25,39,43,45,53,55,56,59,65,67,70,74]. Abbreviations: CI, confidence interval; DL, DerSimonian and Laird; p, p-value; Due to model limitations, studies with 0 events were replaced with 0.5 to allow for OR calculation.
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Figure 4. Association between post-stroke statin use and incidence of dementia/cognitive impairment in ischemic stroke patients [49,72,75]. Abbreviations: CI, confidence interval; DL, DerSimonian and Laird; p, p-value.
Figure 4. Association between post-stroke statin use and incidence of dementia/cognitive impairment in ischemic stroke patients [49,72,75]. Abbreviations: CI, confidence interval; DL, DerSimonian and Laird; p, p-value.
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Figure 5. Clinical decision flow for post-stroke statin use (ISMARDD Decision Aid). This framework summarizes the recommended approach to post-stroke statin therapy based on stroke subtype, LDL-cholesterol (LDL-C) level, and timing of initiation. High-intensity statins (e.g., atorvastatin 80 mg or rosuvastatin 20 mg daily) are recommended for most patients with ischemic stroke or TIA to reduce recurrent vascular events, particularly in those with large-artery atherosclerosis (LAA) or mixed etiologies. In cardioembolic or AF-related stroke, statins may be considered to lower overall vascular risk but do not substitute for oral anticoagulation [78], which remains the cornerstone of secondary prevention. Lipid-lowering therapy should target LDL-C < 70 mg/dL or a ≥50% reduction from baseline, with lipid reassessment 4–12 weeks after initiation. Baseline liver enzyme testing is recommended, with repeat testing if clinically indicated; creatine kinase (CK) measurement is reserved for symptomatic cases. Statins are contraindicated in active liver disease or pregnancy, and dose adjustments may be required in renal impairment or when used with interacting medications [9,12,16,79,80]. Abbreviations: ISMARDD, Impact of Statin Therapy on the Risk of Stroke Recurrence, Mortality, and Dementia After Ischemic Stroke; LAA, large artery atherosclerosis; SVO, small vessel occlusion; LDL-C, low-density lipoprotein cholesterol; AF, atrial fibrillation; CE, cardioembolic; CRP, C-reactive protein.
Figure 5. Clinical decision flow for post-stroke statin use (ISMARDD Decision Aid). This framework summarizes the recommended approach to post-stroke statin therapy based on stroke subtype, LDL-cholesterol (LDL-C) level, and timing of initiation. High-intensity statins (e.g., atorvastatin 80 mg or rosuvastatin 20 mg daily) are recommended for most patients with ischemic stroke or TIA to reduce recurrent vascular events, particularly in those with large-artery atherosclerosis (LAA) or mixed etiologies. In cardioembolic or AF-related stroke, statins may be considered to lower overall vascular risk but do not substitute for oral anticoagulation [78], which remains the cornerstone of secondary prevention. Lipid-lowering therapy should target LDL-C < 70 mg/dL or a ≥50% reduction from baseline, with lipid reassessment 4–12 weeks after initiation. Baseline liver enzyme testing is recommended, with repeat testing if clinically indicated; creatine kinase (CK) measurement is reserved for symptomatic cases. Statins are contraindicated in active liver disease or pregnancy, and dose adjustments may be required in renal impairment or when used with interacting medications [9,12,16,79,80]. Abbreviations: ISMARDD, Impact of Statin Therapy on the Risk of Stroke Recurrence, Mortality, and Dementia After Ischemic Stroke; LAA, large artery atherosclerosis; SVO, small vessel occlusion; LDL-C, low-density lipoprotein cholesterol; AF, atrial fibrillation; CE, cardioembolic; CRP, C-reactive protein.
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Table 1. Clinical characteristics of studies included in meta-analysis of post-stroke statin use and clinical outcomes after ischemic stroke.
Table 1. Clinical characteristics of studies included in meta-analysis of post-stroke statin use and clinical outcomes after ischemic stroke.
Study IDAuthorYearCountryStudy DesignStudy CohortControlInterventionCohort Size
n (%)		Male
n (%)		Age
Mean (SD)		NIHSS Score
Mean (SD)		TOAST
n (%)		Outcomes Reported
LAACESVOOtherUndetermined
OverallC ^I ^Overall ^C *I +OverallCIOverallCIC *I +C *I +C *I +C *I +C *I +
All IS Subtypes
1Yakusevich et al. [70]2012RussiaRCTFirst acute cerebrovascular incidentStandard IS therapySimvastatin 40 mg + Standard IS therapy183
(100)		97
(53.0)		86
(47.0)		80
(44)		43
(44)		37
(43)		65.7
(8.3)		65.8 (9.3)65.6 (7.2)NR9.2 (3.7)8.9 (4.0)NRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
2Kim et al. [49]2024South KoreaRetrospectiveISNo statinDischarge statin37,553
(100)		8764
(23.3)		28,789
(76.7)		23,237
(61.9)		NRNR64.9 (12.4)NRNR3.0 (3.0)NRNRNRNRNRNRNRNRNRNRNRNRPSD
3Yang et al. [72]2022United KingdomRetrospectiveISNo statinStatin30,113
(100)		12,207
(40.5)		17,906
(59.5)		NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRPSD
4Huang et al. [75]2015ChinaRetrospectiveFirst-ever ISNo statinStatin350
(100)		214
(61.1)		136
(38.9)		244
(69.7)		NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRPSCI
5Beer et al. [29]2012AustraliaRCTAcute ISPlaceboAtorvastatin 80 mg40
(100)		23
(57.5)		17
(42.5)		NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRCRP Levels
6Muscari et al. [57]2011ItalyRCTISPlaceboAtorvastatin 80 mg62
(100)		31
(50.0)		31
(50.0)		20
(32.2)		12
(38.7)		8
(25.8)		75.3 (11.9)75.6 (12.2)74.9 (11.8)NR13.7 (10.1)13.7 (10.9)6 (19.4)6 (19.4)10 (32.3)10 (32.3)6
(19.4)		5
(16.1)		1
(3.2)		0
(0)		7 (22.6)10 (32.2)CRP Levels
7Zare et al. [73]2012IranRCTAcute moderate stroke in MCANo statinLovastatin 20 mg55
(100)		30
(54.5)		25
(45.5)		29
(52.7)		16
(53.3)		13
(52.0)		NR68.3 (10.7)63.3 (10.8)NR14.5 (4.3)16.0 (4.3)NRNRNRNRNRNRNRNRNRNRMortality
8Aivo et al. [25]2023FinlandRetrospectiveISNo statinStatin59,588
(100)		16,171
(27.1)		43,417
(72.9)		32,604
(54.5)		8377
(51.2)		24,227
(55.8)		NR71.7 (14.4)70.1 (11.4)NRNRNRNRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
9Flach et al. [39]2019EnglandProspectiveISNo statinStatin3061
(100)		2108
(68.9)		953
(31.1)		1536
(50.2)		1026
(48.7)		510
(53.5)		NRNRNRNRNRNR93
(4.4)		116
(12.2)		321
(15.2)		170
(17.8)		235
(11.1)		289
(30.3)		38
(1.8)		24
(2.5)		364
(17.3)		266
(27.9)		Mortality, Stroke Recurrence
10Han et al. [43]2021ChinaRetrospectiveNon-acute ISNo statinStatin466
(100)		279
(59.9)		187
(40.1)		NRNRNR71.5 (11.2)NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRStroke Recurrence
11Makihara et al. [53]2013JapanProspectiveFirst ever acute ISNo statinStatin2822
(100)		1829
(64.8)		993
(35.2)		1677
(59.4)		1137
(62.2)		540
(54.4)		NR71.2 (13.5)70.0 (10.9)NR4.0 (3.7)3.0 (3.0)316
(17.3)		239
(24.1)		475
(26.0)		139
(14.0)		452
(24.7)		260
(26.2)		NRNRNRNRMortality, Stroke Recurrence
12Milionis et al. [55]2009GreeceRetrospectiveFirst ever acute ISNo statinStatin794
(100)		596
(75.1)		198
(24.9)		543
(68.4)		404
(67.8)		139
(70.2)		NR68.8 (11.1)67.0 (10.3)NRNRNR177
(29.7)		62
(31.3)		146
(24.5)		49
(24.7)		166
(27.9)		53
(26.8)		NRNR107
(18.0)		34
(17.2)		Stroke Recurrence
13O’Brien et al. [59]2015United StatesRetrospectiveISNo statinStatin77,468
(100)		22,477
(29.0)		54,991
(71.0)		31,252
(40.3)		8541
(38.0)		22,711
(41.3)		NR81.2 (8.3)78.6 (8.2)NR6.0 (6.7)5.0 (5.2)NRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
14Zhang et al. [74]2018ChinaRCTISAspirinAspirin + Statin127
(100)		61
(48.0)		66
(52.0)		83
(65.4)		40
(65.6)		43
(65.2)		NR65.9 (1.8)64.6 (1.2)NRNRNRNRNRNRNRNRNRNRNRNRNRStroke Recurrence, CRP Levels
15Jia & Zhou [45]2013ChinaRetrospectiveIS with prior ICHNo statinAtorvastatin 20 mg354
(100)		193
(54.5)		161
(45.5)		212
(59.9)		117
(60.6)		95
(59.0)		NR62.4 (12.8)64.3 (12.0)NRNRNRNRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
16Arevalo-Lorido et al. [26]2014GermanyProspectiveISNo statinStatin313
(100)		108
(34.5)		205
(65.5)		150
(47.9)		34
(31.5)		116
(56.6)		NR77.5 (8.9)NRNR7.9 (5.1)NR39
(36.1)		59
(28.8)		29
(26.9)		44
(21.5)		34
(31.5)		84
(41.0)		3
(2.8)		5
(2.4)		3
(2.8)		13
(6.3)		Mortality, CRP levels
17Bao et al. [28]2023ChinaRetrospectiveAcute ISNo statinLow-to-moderate and high-dose statin327
(100)		48
(14.7)		279
(85.3)		181
(55.4)		25
(52.1)		156
(55.9)		70.0 (14.2)66.0 (17.8)NR9.7 (8.9)16.7 (7.6)NR12
(25.0)		100
(35.8)		26
(54.2)		117
(41.9)		0
(0.0)		26
(9.3)		2
(4.2)		8
(2.9)		8
(16.7)		28
(10.0)		Mortality
18Ni Chroinin et al. [36]2011IrelandProspectiveNew ISNo statinStatin301
(100)		112
(37.2)		189
(62.8)		153
(50.1)		52
(46.4)		101
(53.4)		NR73.4 (15.6)69.9 (13.1)NRNRNR1
(0.9)		23
(12.2)		51
(45.5)		56
(29.6)		12
(10.7)		33
(17.5)		4
(3.6)		4
(2.1)		44
(39.3)		72
(38.1)		Mortality
19Montaner et al. [56]2016SpainRCTISPlaceboSimvastatin 40 mg104
(100)		54
(51.9)		50
(48.1)		56
(53.8)		32
(59.3)		24
(48.0)		72.8 (14.7)71.3 (19.0)73.2 (13.7)8.2 (4.1)8.0 (5.3)8.0 (3.8)8
(14.8)		2
(4.0)		24
(44.4)		17
(34.0)		4
(7.4)		5
(10.0)		1
(1.9)		0
(0.0)		15
(2.8)		25
(50.0)		Mortality, Stroke Recurrence
20Cappellari et al. [31]2013ItalyRetrospectiveAcute IS with IVTNo statinStatin2072
(100)		1233
(59.5)		839
(40.5)		1210
(58.4)		705
(57.2)		505
(60.2)		66.6 (12.5)66.1 (13.7)67.3 (10.6)12.6 (6.0)13.3 (6.1)11.7 (5.9)NRNRNRNRNRNRNRNRNRNRMortality
21Cui et al. [37]2022ChinaProspectiveAcute IS with EVTNo statinLow-dose statin256
(100)		73
(28.5)		183
(71.5)		139
(54.3)		39
(53.4)		100
(54.6)		NR67.4 (13.1)67.1 (13.7)NR16.0 (6.1)15.0 (6.0)38
(52.1)		104
(56.8)		34
(46.6)		76
(41.5)		NRNRNRNRNRNRMortality
22Cui et al. [38]2021ChinaProspectiveAcute IS with IVTNo statinLow-dose statin215
(100)		35
(16.3)		180
(83.7)		102
(47.4)		17
(48.9)		85
(47.2)		NR72.2 (14.5)70.7 (12.1)NR14.0 (7.0)8.7 (7.5)NRNRNRNRNRNRNRNRNRNRMortality
23Scheitz et al. [62]2015GermanyRetrospectiveAcute IS with IVTNo statinStatin481
(100)		398
(82.7)		83
(17.3)		241
(50.1)		198
(49.7)		43
(51.8)		NR74.3 (12.6)75.7 (9.1)NR11.7 (8.9)10.7 (7.5)162
(40.7)		41
(49.4)		179
(45.0)		30
(36.1)		11
(2.8)		3
(3.6)		12
(3.0)		2
(2.4)		34
(8.5)		7
(8.4)		Mortality
24Furlan et al. [41]2020BrazilRetrospectiveISNo statinStatin97
(100)		34
(35.1)		63
(64.9)		NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRMortality
25Winardi et al. [68]2024TaiwanRetrospectiveISNo statinStatin78,732
(100)		39,366
(50.0)		39,366
(50.0)		42,936
(54.5)		21,468
(54.5)		21,468
(54.5)		NR67.7 (9.1)68.2 (9.2)NRNRNRNRNRNRNRNRNRNRNRNRNRMortality
26Song et al. [64]2014ChinaProspectiveFirst ISNo statinStatin7455
(100)		4224
(56.7)		3231
(43.3)		4584
(61.5)		2585
(61.2)		1999
(61.9)		NR64.5 (13.2)64.2 (12.3)NR5.7 (5.9)4.7 (4.4)NRNRNRNRNRNRNRNRNRNRMortality
27Hjalmarsson et al. [44]2012SwedenRetrospectiveAcute ISNo statinStatin744
(100)		291
(39.1)		453
(60.9)		358
(48.1)		117
(40.2)		241
(53.2)		NR80.8 (8.0)76.3 (7.6)NRNRNR50
(17.2)		139
(30.7)		134
(46.0)		115
(25.4)		64
(22.0)		125
(27.6)		4
(1.4)		5
(1.1)		39
(13.4)		69
(15.2)		Mortality
28Sakurai et al. [61]2011JapanProspectiveISNo statinStatin146
(100)		101
(69.2)		45
(30.8)		91
(62.3)		63
(62.4)		28
(62.2)		NR71.5 (13.6)69.9 (12.5)NR7.1 (7.4)5.0 (4.6)22
(21.8)		17
(37.8)		51
(50.5)		14
(31.1)		21
(20.8)		13
(28.9)		NRNRNRNRCRP Levels
29Ueno et al. [65]2015JapanRCTAcute ISNo statinRosuvastatin 5 mg24
(100)		12
(50.0)		12
(50.0)		23
(95.8)		12
(100.0)		11
(91.7)		71.3 (9.0)71.5 (10.6)71.0 (7.6)NRNRNRNRNRNRNRNRNRNRNRNRNRStroke Recurrence, CRP Levels
30Flint et al. [40]2011United StatesRetrospectiveISNo statinStatin12,689
(100)		6395
(50.4)		6294
(49.6)		5959
(47.0)		2800
(43.8)		3159
(50.2)		NR76.5 (NR)73.5 (NR)NRNRNRNRNRNRNRNRNRNRNRNRNRMortality
31Vitturi & Gagliardi [67]2020BrazilProspectiveFirst ever ISNo statinStatin440
(100)		96
(21.8)		344
(78.2)		189
(43.0)		NRNR58.3 (NR)NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
Cardioembolic or AF-related Stroke
32Choi et al. [34]2019South KoreaProspectiveAcute IS with AFNo statinLow-moderate- or high-intensity statin2153
(100)		574
(26.7)		1579
(73.3)		1120
(52.0)		322
(56.1)		798
(50.5)		73.2 (9.8)72.7 (11.0)NR7.7 (8.9)8.7 (10.4)NRN/AN/A499
(86.9)		1294
(82.0)		N/AN/AN/AN/A75
(13.1)		285
(18.0)		Mortality, Stroke Recurrence
33Lin et al. [52]2019TaiwanRetrospectiveAcute IS with AFNo statinStatin47,882
(100)		43,242
(90.3)		4640
(9.7)		27,177
(56.8)		24,553
(56.8)		2624
(56/6)		NR69.6 (14.2)65.6 (12.8)NRNRNRNRNRNRNRNRNRNRNRNRNRMortality
34Ntaios et al. [58]2014GreeceRetrospectiveAcute IS with AFNo statinStatin404
(100)		302
(74.8)		102
(25.2)		NRNRNR67.2 (12.3)74.6 (11.5)73.7 (9.8)NRNRNRNRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
35Choi et al. [33]2014South KoreaRetrospectiveCardioembolic strokeNo statinStatin535
(100)		295
(55.1)		240
(44.9)		295
(55.1)		163
(55.3)		132
(55.0)		NR68.6 (13.3)NRNRNRNRN/AN/A295
(100)		240
(100)		N/AN/AN/AN/AN/AN/AMortality, Stroke Recurrence
36Choi et al. [35]2024VariousRetrospectiveAcute IS with AFNo statinStatin20,902
(100)		13,402
(64.1)		7500
(35.9)		10,947
(52.4)		6941
(51.8)		4006
(53.4)		NR73.5 (12.2)73.8 (11.1)NRNRNRNRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
37Vitturi & Gagliardi [66]2019BrazilProspectiveCardioembolic strokeNo statinStatin91
(100)		18
(19.8)		73
(80.2)		47
(51.6)		7
(38.9)		40
(85.1)		NR55.9
(13)		NRNRNRNRNRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
38Gong et al. [42]2023ChinaRetrospectiveCardioembolic strokeNo statinStatin510
(100)		106
(20.8)		404
(79.2)		227
(44.5)		47
(44.3)		180
(44.6)		70.7 (10.4)70.7 (10.5)70.7 (10.4)16.3 (5.2)17.0 (4.5)16.3 (5.2)N/AN/A106
(20.8)		404
(79.2)		N/AN/AN/AN/AN/AN/AMortality
39Park et al. [60]2020South KoreaProspectiveCardioembolic strokeNo statinStatin2888
(100)		1025
(35.5)		1863
(64.5)		1289
(44.6)		469
(45.8)		820
(44.0)		75.3 (NR)75.2 (1.2)75.4 (0.9)NR12.3 (10.4)8.7 (8.9)N/AN/A10251863N/AN/AN/AN/AN/AN/AMortality, Stroke Recurrence
40Marvardi et al. [54]2025VariousProspectiveAcute IS with AFNo statinStatin1742
(100)		844
(48.5)		898
(51.5)		811
(46.6)		357
(42.3)		454
(50.6)		NR77.2 (10.5)74.3 (9.1)NR9.2 (7.2)7.6 (6.5)NRNRNRNRNRNRNRNRNRNRStroke Recurrence
41Wu et al. [69]2017TaiwanRetrospectiveAcute IS with AFNo statinStatin4638
(100)		3092
(66.7)		1546
(33.3)		2277
(49.1)		1518
(49.1)		759
(49.1)		NR75.6 (7.4)75.6 (7.4)NRNRNRNRNRNRNRNRNRNRNRNRNRStroke Recurrence
Low Baseline LDL-C Levels
42Kim et al. [47]2023South KoreaProspectiveAcute IS with LDL-C <70 mg/dLNo statinStatin2850
(100)		735
(25.8)		2115
(74.2)		1810
(63.5)		448
(61.0)		1362
(64.4)		69.5 (13.4)70.1 (13.9)69.3 (13.2)5.7 (6.7)7.7 (9.7)4.7 (5.9)229
(31.2)		903
(42.7)		400
(54.4)		775
(36.6)		106
(14.4)		437
(20.7)		NRNRNRNRMortality
43Lee et al. [51]2024TaiwanRetrospectiveAcute IS with LDL-C <70 mg/dLNo statinStatin956
(100)		631
(66.0)		325
(34.0)		NRNRNR76.6 (13.7)NRNRNR11.8 (9.6)NRNRNRNRNRNRNRNRNRNRNRMortality
44Song et al. [63]2015ChinaProspectiveAcute IS with LDL-C <1.8 mmol/LNo statinStatin1018
(100)		659
(64.7)		359
(35.3)		687
(67.5)		440
(66.8)		247
(68.8)		NR65.0 (13.8)65.6 (12.1)NR6.0 (6.7)5.0 (5.2)236
(35.8)		176
(49.0)		121
(18.4)		59
(16.4)		55
(8.3)		23
(6.4)		12
(1.8)		6
(1.7)		235
(35.7)		95
(26.5)		Mortality
Statin Intensity
17Bao et al. [28]2023ChinaRetrospectiveAcute ISLow-moderate intensity statinHigh-intensity statin279
(100)		152
(54.5)		127
(45.5)		156
(55.9)		76
(50.0)		80
(63.0)		NR71.1 (13.4)67.6 (13.5)NR8.3 (8.2)8.7 (9.0)43
(28.3)		57
(44.9)		72
(47.4)		45
(35.4)		22
(14.5)		4
(3.1)		1
(0.7)		7
(5.5)		14
(9.2)		14
(11.0)		Mortality
45Yang et al. [71]2021ChinaRCTAcute ISRosuvastatin 5 mgRosuvastatin 20 mg310
(100)		155
(50.0)		155
(50.0)		228
(73.5)		116
(74.8)		112
(72.3)		NR66.6 (12.0)65.0 (11.8)NR7.7 (6.0)6.0 (4.5)NRNRNRNRNRNRNRNRNRNRMortality
46Chen et al. [32]2018ChinaRCTAnterior circulation infarctAtorvastatin 20 mgAtorvastatin 60 mg117
(100)		57
(48.7)		60
(51.3)		73
(62.4)		34
(59.6)		39
(65.0)		NR60.9 (11.9)62.4 (11.5)NRNRNRNRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
13O’Brien et al. [59]2015United StatesRetrospectiveISLow-moderate intensity statinHigh-intensity statin29,631
(100)		20,486
(69.1)		9145
(30.9)		12,462
(42.1)		8502
(41.5)		3960
(43.3)		NR78.9 (8.3)77.9 (8.2)NR4.7 (4.4)5.3 (5.9)NRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
47Bach et al. [27]2023DenmarkRetrospectiveFirst ISModerate intensity statinHigh-intensity statin27,387 (100)14,355
(52.4)		13,032
(47.6)		15,495 (56.6)7905
(55.1)		7590
(58.2)		NR68.7 (14.1)68.3 (13.3)NRNRNRNRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
48Kyto et al. [50]2024FinlandRetrospectiveAcute ISLow-moderate intensity statinHigh-intensity statin45,512
(100)		38,228
(84.0)		7284
(16.0)		25,293
(55.6)		20,762
(54.3)		4531
(62.2)		NRNR68.4
(10.7)		NRNRNRNRNRNRNRNRNRNRNRNRNRMortality, Stroke Recurrence
Statin Timing
49Kang et al. [46]2015South KoreaRetrospectiveAcute ISDelayed statin (after 24 h)Early statin (within 24 h)167
(100)		122
(73.1)		45
(26.9)		107
(64.1)		67
(54.9)		30
(66.7)		NRNR67.7 (11.6)NRNR13.3 (8.4)48
(39.3)		20
(44.4)		61
(50.0)		13
(28.9)		NRNRNRNRNRNRStroke Recurrence
Statin Type
50Kim et al. [48]2025South KoreaProspectiveAcute ISAtorvastatinRosuvastatin43,512
(100)		36,903
(84.8)		6609
(15.2)		26,001
(59.8)		21,992
(59.6)		4009
(60.7)		69.2 (12.5)69.2 (12.5)69.7 (12.8)3.7 (4.4)3.7 (4.4)3.3 (3.7)13,976
(37.9)		2436
(36.9)		7087
(19.2)		1314
(19.9)		6609
(17.9)		1542
(23.3)		NRNR9231
(25.0)		1317
(19.9)		Mortality, Stroke Recurrence
51Cao et al. [30]2017ChinaRCTCerebral infarctionAtorvastatin 20 mgRosuvastatin 10 mg120
(100)		60
(50.0)		60
(50.0)		65
(54.2)		35
(58.3)		30
(50.0)		NR45.8
(7.5)		46.8
(7.5)		NRNRNRNRNRNRNRNRNRNRNRNRNRStroke Recurrence
Abbreviations: n, number of patients; SD, standard deviation; NIHSS, National Institute of Health Stroke Scale; RCT, randomized controlled trials; IS, ischemic stroke; C, control; I, intervention; TOAST, Trial of Org 10172 in Acute Stroke Treatment; LAA, large artery atherosclerosis; CE, cardioembolic; SVO, small vessel occlusion; MCA, middle cerebral artery; ICH, intracerebral hemorrhage; IVT, intravenous thrombolysis; EVT, endovascular thrombectomy; AF, atrial fibrillation; LDL-C, low-density lipoprotein cholesterol; PSD, post-stroke dementia; PSCI, post-stroke cognitive impairment; NR, not reported; N/A; not applicable. ^ Percentage of total cohort size; * Percentage of control cohort size; + Percentage of intervention cohort size.
Table 2. Comorbidities and lifestyle factors in cohorts of ischemic stroke patients included in meta-analysis of post-stroke statin use and clinical outcomes.
Table 2. Comorbidities and lifestyle factors in cohorts of ischemic stroke patients included in meta-analysis of post-stroke statin use and clinical outcomes.
AuthorYearHypertension
n (%)		Baseline Systolic Blood Pressure
Mean (SD)		Diabetes Mellitus
n (%)		Atrial Fibrillation
n (%)		Coronary Artery Disease
n (%)		Dyslipidaemia ^
n (%)		Previous Stroke
n (%)		Smoking
n (%)		Alcohol Use
n (%)
C *I +CIC *I +C *I +C *I +C *I +C *I +C *I +C *I +
All IS Subtypes
Yakusevich et al. [70]201274
(76.3)		36
(41.9)		156.4 (15.8)156.4 (15.3)10
(10.3)		8
(9.3)		12
(12.4)		14
(16.3)		8
(8.2)		10
(11.6)		NRNRNRNRNRNRNRNR
Kim et al. [49]2024NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR
Yang et al. [72]2022NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR
Huang et al. [75]2015NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR
Beer et al. [29]2012NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR
Muscari et al. [57]201130
(96.8)		27
(87.1)		NRNR5
(16.1)		8
(25.8)		NRNRNRNRNRNR3
(9.7)		5
(16.1)		6
(19.4)		4
(12.9)		NRNR
Zare et al. [73]201220
(66.7)		13
(52.0)		NRNR5
(16.7)		4
(16.0)		NRNRNRNR6
(20.0)		4
(16.0)		NRNR8
(26.7)		9
(36.0)		NRNR
Aivo et al. [25]201595
(55.9)		102
(61.1)		NRNR30
(17.6)		32
(19.2)		54
(31.8)		64
(38.3)		NRNRNRNR46
(27.1)		30
(18.0)		NRNRNRNR
Flach et al. [39]20238894
(55.0)		26,614
(61.3)		NRNR3250
(20.1)		9639
(22.2)		4964
(30.7)		9421
(21.7)		1326
(8.2)		4211
(9.7)		NRNRNRNRNRNRNRNR
Han et al. [43]2019749
(35.5)		377
(39.6)		NRNR1649
(78.2)		800
(83.9)		1562
(74.1)		833
(87.4)		1654
(78.5)		829
(87.0)		118
(5.6)		764
(80.2)		NRNR1255
(59.5)		629
(66.0)		NRNR
Makihara et al. [53]2021NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR
Milionis et al. [55]20131327
(72.3)		836
(84.2)		NRNR429
(23.5)		388
(39.1)		506
(27.7)		147
(14.8)		207
(11.3)		185
(18.6)		NRNRNRNR935
(51.1)		476
(47.9)		NRNR
O’Brien et al. [59]2009440
(73.8)		135
(68.2)		159.0 (29.0)158.0 (26.0)211
(35.4)		55
(27.8)		77
(12.9)		24
(12.1)		144
(24.2)		45
(22.7)		151
(25.3)		57
(28.8)		NRNR233
(39.1)		80
(40.4)		NRNR
Zhang et al. [74]201517,397
(77.4)		41,518
(75.5)		NRNR5147
(22.9)		12,648
(23.0)		NRNR5237
(23.3)		11,163
(20.3)		4046
(18.0)		13,858
(25.2)		NRNR2113
(9.4)		7259
(13.7)		NRNR
Jia & Zhou [45]201822
(36.1)		24
(36.4)		NRNR25
(41.0)		28
(42.4)		NRNRNRNRNRNRNRNRNRNRNRNR
Arevalo-Lorido et al. [26]2013137
(71.0)		109
(67.7)		NRNR94
(48.7)		83
(51.6)		27
(14.0)		26
(16.1)		93
(48.2)		81
(50.3)		NRNRNRNR80
(41.5)		73
(45.3)		NRNR
Bao et al. [28]201492
(85.2)		168
(82.0)		160.4 (27.4)NR29
(26.9)		64
(31.2)		NRNRNRNRNRNRNRNR16
(14.8)		45
(22.0)		NRNR
Ni Chroinin et al. [36]202322
(45.8)		158
(56.6)		139.0 (23.8)NR7
(14.6)		44
(15.8)		17
(35.4)		77
(27.6)		3
(6.3)		39
(14.0)		0
(0.0)		10
(3.6)		12
(25.0)		53
(19.0)		13
(27.1)		103
(36.9)		NRNR
Montaner et al. [56]201159
(52.7)		84
(44.4)		NRNR6
(5.4)		11
(5.8)		44
(39.3)		52
(27.5)		17
(15.2)		21
(11.1)		18
(16.1)		37
(19.6)		12
(10.7)		16
(8.5)		23
(20.5)		70
(37.0)		NRNR
Cappellari et al. [31]201635
(64.8)		29
(58.0)		NRNR7
(13.0)		10
(20.0)		3
(5.6)		12
(24.0)		1
(1.9)		2
(4.0)		8
(14.8)		7
(14.0)		3
(5.6)		4
(8.0)		13
(24.1)		10
(20.0)		NRNR
Cui et al. [37]2013706
(57.3)		595
(70.9)		146.6 (20.7)146.6 (19.6)197
(16.0)		147
(17.5)		316
(25.6)		146
(17.4)		NRNR308
(25.0)		478
(57.0)		113
(9.2)		65
(7.7)		294
(23.8)		209
(24.9)		NRNR
Cui et al. [38]202234
(46.6)		92
(50.3)		135.8 (24.0)141.4 (25.1)12
(16.4)		32
(17.5)		NRNR10
(13.7)		31
(16.9)		NRNRNRNR13
(17.8)		57
(31.1)		NRNR
Scheitz et al. [62]202118
(51.4)		85
(47.2)		153.2 (32.2)148.5 (24.7)8
(22.9)		34
(18.9)		17
(48.6)		46
(25.6)		4
(11.4)		22
(12.2)		NRNRNRNR10
(28.6)		59
(32.8)		NRNR
Furlan et al. [41]2015320
(80.4)		79
(95.2)		NRNR87
(21.9)		30
(36.1)		169
(42.5)		32
(38.6)		63
(15.8)		33
(39.8)		148
(37.2)		60
(72.3)		83
(20.9)		29
(34.9)		94
(23.6)		19
(22.9)		NRNR
Winardi et al. [68]2020NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR
Song et al. [64]2024NRNRNRNR17,275
(43.9)		17,524
(44.5)		NRNRNRNRNRNRNRNRNRNRNRNR
Hjalmarsson et al. [44]20142300
(54.5)		1961
(60.7)		NRNR692
(16.4)		646
(20.0)		333
(7.9)		156
(4.8)		540
(12.8)		358
(11.1)		NRNRNRNR1651
(39.1)		1304
(40.4)		431
(10.2)		379
(11.7)
Sakurai et al. [61]2012162
(55.7)		262
(57.8)		142.9 (22.5)141.4 (21.3)30
(10.3)		69
(26.3)		115
(39.5)		101
(38.5)		NRNR10
(3.4)		108
(41.2)		123
(42.3)		90
(34.4)		NRNRNRNR
Ueno et al. [65]201177
(76.2)		37
(82.2)		NRNR22
(21.8)		12
(26.7)		43
(42.6)		8
(17.8)		19
(18.8)		10
(22.2)		7
(6.9)		45
(100.0)		NRNR33
(32.7)		18
(40.0)		NRNR
Flint et al. [40]20159
(75.0)		11
(91.7)		NRNR6
(50.0)		3
(25.0)		1
(8.3)		2
(16.7)		NRNR12
(100.0)		12
(100.0)		3
(25.0)		3
(25.0)		5
(41.7)		6
(50.0)		NRNR
Vitturi & Gagliardi [67]20114816
(75.3)		5363
(85.2)		NRNR1769
(27.7)		2449
(38.9)		1771
(27.7)		1403
(22.3)		1154
(18.0)		1914
(30.4)		NRNR654
(10.2)		475
(7.5)		NRNRNRNR
Yakusevich et al. [70]2020NRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNRNR
Cardioembolic or AF-related stroke
Choi et al. [34]2019395
(68.8)		1109
(70.2)		NRNR156
(27.2)		434
(27.5)		574
(100.0)		1579
(100.0)		61
(10.6)		206
(13.0)		98
(17.1)		404
(25.6)		NRNR94
(16.4)		219
(13.9)		NRNR
Lin et al. [52]201931,698
(73.3)		3579
(77.1)		NRNR15,951
(36.9)		1857
(40.0)		NRNRNRNRNRNRNRNRNRNRNRNR
Ntaios et al. [58]2014224
(74.2)		83
(81.4)		NRNR63
(20.9)		20
(19.6)		262
(86.8)		86
(84.3)		NRNR83
(27.5)		53
(52.0)		NRNR52
(17.2)		21
(20.6)		NRNR
Choi et al. [33]2014199
(67.5)		171
(71.3)		NRNR56
(19.0)		67
(27.9)		NRNR30
(10.2)		43
(17.9)		NRNRNRNR76
(25.8)		67
(27.9)		NRNR
Choi et al. [35]20249424
(70.3)		3693
(49.2)		NRNR1305
(9.7)		1597
(21.3)		11,298
(84.3)		4219
(56.3)		NRNR5468
(40.8)		2420
(32.3)		NRNRNRNRNRNR
Vitturi & Gagliardi [66]201912
(66.7)		58
(79.5)		NRNR4
(22.2)		21
(28.8)		9
(50.0)		40
(54.8)		2
(11.1)		18
(24.7)		2
(11.1)		14
(19.2)		4
(22.2)		16
(21.9)		6
(33.3)		18
(24.7)		NRNR
Gong et al. [42]202352
(49.1)		207
(51.2)		144.0 (25.4)144.0 (24.4)18
(17.0)		65
(16.1)		77
(72.6)		276
(68.3)		14
(13.2)		84
(20.8)		12
(11.3)		43
(10.6)		23
(21.7)		73
(18.1)		13
(12.3)		50
(12.4)		NRNR
Park et al. [60]2020708
(69.1)		1297
(69.6)		142.0
(2.6)		140.5
(1.7)		267
(26.0)		460
(24.7)		940
(91.7)		1615
(86.7)		NRNR153
(14.9)		569
(30.5)		NRNR114
(11.1)		215
(11.5)		NRNR
Marvardi et al. [54]2025623
(73.8)		720
(80.2)		NRNR165
(19.5)		231
(25.7)		312
(37.0)		420
(46.8)		92
(10.9)		163
(18.2)		130
(15.4)		445
(49.6)		199
(23.6)		257
(28.6)		NRNR51
(6.0)		70
(7.8)
Wu et al. [69]20172986
(96.6)		1493
(96.6)		NRNR1036
(33.5)		518
(33.5)		NRNR2028
(65.6)		1014
(65.6)		NRNRNRNRNRNRNRNR
Low Baseline LDL-C Levels
Kim et al. [47]2023437
(59.5)		1365
(64.5)		NRNR240
(32.7)		807
(38.2)		325
(44.2)		627
(29.6)		NRNR37
(5.0)		239
(11.3)		NRNR173
(23.5)		604
(28.6)		NRNR
Lee et al. [51]2024476
(75.4)		NRNRNR254
(40.3)		NR192
(30.4)		NR132
(20.9)		NRNRNR202
(32.0)		NR143
(22.7)		NRNRNR
Song et al. [63]2015373
(56.6)		230
(70.8)		NRNR121
(18.4)		71
(21.8)		95
(14.4)		38
(11.7)		87
(13.2)		47
(14.5)		NRNR215
(32.6)		115
(35.4)		294
(44.6)		151
(46.5)		71
(10.8)		34
(10.5)
Statin Intensity
Bao et al. [28]202393
(61.2)		65
(51.2)		146.5 (24.2)151.1 (26.1)28
(18.4)		16
(12.6)		53
(34.9)		24
(18.9)		24
(15.8)		15
(11.8)		5
(3.3)		5
(3.9)		36
(23.7)		17
(13.4)		55
(36.2)		48
(37.8)		NRNR
Yang et al. [71]202185
(54.8)		85
(54.8)		NRNR21
(13.5)		19
(12.3)		25
(16.1)		9
(5.8)		21
(13.5)		11
(7.1)		9
(5.8)		7
(4.5)		28
(18.1)		25
(16.1)		NRNRNRNR
Chen et al. [32]201841
(71.9)		45
(75.0)		144.0 (22.6)143.5 (22.1)17
(29.8)		21
(35.0)		NRNR3
(5.3)		5
(8.3)		18
(31.6)		23
(38.3)		5
(8.8)		7
(11.7)		25
(43.9)		28
(46.7)		25
(43.9)		22
(36.7)
O’Brien et al. [59]201515,201
(74.2)		6850
(74.9)		NRNR4650
(22.7)		2268
(24.8)		NRNR4261
(20.8)		2094
(22.9)		5183
(25.3)		2405
(26.3)		NRNR2684
(13.1)		1244
(13.6)		NRNR
Bach et al. [27]20238100
(56.4)		7387
(56.7)		NRNR1147
(8.0)		1078
(8.3)		NRNRNRNRNRNRNRNR4688
(32.7)		3862
(29.6)		13,528
(94.2)		11,667
(89.5)
Kyto et al. [50]202423,107
(50.8)		4786
(10.5)		NRNR8625
(19.0)		1981
(4.4)		8410
(18.5)		1508
(3.3)		NRNRNRNRNRNRNRNRNRNR
Statin Timing
Kang et al. [46]201574
(60.7)		28
(62.2)		NRNR22
(18.0)		10
(22.2)		49
(40.2)		15
(33.3)		NRNRNRNR18
(14.8)		12
(26.7)		NRNRNRNR
Statin Type
Kim et al. [48]202524,562
(66.6)		4550
(68.8)		146.1 (27.7)152.4 (27.7)12,426
(33.7)		2372
(35.9)		7214
(19.5)		1275
(19.3)		3146
(8.5)		625
(9.5)		12,656
(34.3)		2519
(38.1)		7274
(19.7)		1543
(23.3)		9010
(24.4)		1490
(22.5)		NRNR
Cao et al. [30]201728
(46.7)		25
(41.7)		NRNR10
(16.7)		11
(18.3)		NRNRNRNR15
(25.0)		16
(26.7)		NRNR7
(11.7)		8
(13.3)		NRNR
Abbreviations: n, number of patients; SD, standard deviation; C, control; I, intervention; NR, not reported; AF, atrial fibrillation; LDL-C, low-density lipoprotein-cholesterol; ^ Includes any reported hyperlipidemia and hypercholesterolemia. * Percentage of control cohort size; + Percentage of intervention cohort size.
Table 3. Pooled prevalence of clinical outcomes in all ischemic stroke subtypes.
Table 3. Pooled prevalence of clinical outcomes in all ischemic stroke subtypes.
OutcomeTime FrameAnalysis SubgroupOverallStatin NonusersStatin Users
Summary EffectsHeterogeneityHeterogeneity Variance EstimatesSummary EffectsHeterogeneityHeterogeneity Variance EstimatesSummary EffectsHeterogeneityHeterogeneity Variance Estimates
Pooled Prevalence (95% CI)Test of ES = 0Chi-SquaredHI2 (%)p-Valueτ2 ≤ ΦPooled Prevalence (95% CI)Test of ES = 0Chi-SquaredHI2 (%)p-Valueτ2 ≤ ΦPooled Prevalence (95% CI)Test of ES = 0Chi-squaredHI2 (%)p-Valueτ2 ≤ Φ
Dementia or Cognitive Impairment Dementia-------0.12 [0.11, 0.12]z = 98.99,
p < 0.01		-----0.11 [0.11, 0.11]z = 144.13,
p < 0.01		-----
Cognitive Impairment-------0.36 [0.29, 0.42]z = 17.72,
p < 0.01		-----0.46 [0.37, 0.54]z = 16.33,
p < 0.01		-----
Overall0.18 [0.09, 0.30]z = 6.16,
p < 0.01		1939.56-99.90<0.010.060.19 [0.09, 0.31]z = 6.05,
p < 0.01		619.12-99.68<0.010.060.19 [0.09, 0.31]z = 5.67,
p < 0.01		1444.50-99.86<0.010.06
All-Cause Mortality≤3 monthsRetrospective0.18 [0.12, 0.24]z = 9.75,
p < 0.01		-36.1491.70<0.01-0.25 [0.16, 0.34]z = 8.93,
p < 0.01		-27.1588.95<0.01-0.11 [0.06, 0.19]z = 5.77,
p < 0.01		-26.2188.55<0.01-
Prospective0.13 [0.07, 0.21]z = 6.34,
p < 0.01		-----0.25 [0.08, 0.47]z = 4.13,
p < 0.01		-----0.07 [0.03, 0.13]z = 5.14,
p < 0.01		-----
RCT0.04 [0.02, 0.07]z = 6.17,
p < 0.01		-----0.04 [0.01, 0.09]z = 3.28,
p < 0.01		-----0.03 [0.01, 0.07]z = 3.50,
p < 0.01		-----
Overall0.12 [0.09, 0.16]z = 11.67,
p < 0.01		-160.0494.38<0.010.030.18 [0.13, 0.24]z = 10.38,
p < 0.01		-140.8193.61<0.010.040.08 [0.05, 0.11]z = 8.38,
p < 0.01		-77.5688.40<0.010.02
≤1 yearRetrospective0.17 [0.08, 0.30]z = 5.31,
p < 0.01		-4303.9899.86<0.01-0.26 [0.13, 0.42]z = 5.86,
p < 0.01		-2321.2799.74<0.01-0.11 [0.05, 0.19]z = 5.01,
p < 0.01		-1364.3199.56<0.01-
Prospective0.14 [0.07, 0.24]z = 5.86,
p < 0.01		-113.2797.35<0.01-0.26 [0.10, 0.45]z = 4.76,
p < 0.01		-97.9196.94<0.01-0.08 [0.03, 0.16]z = 4.32,
p < 0.01		-73.5695.92<0.01-
RCT0.07 [0.01, 0.17]z = 2.82,
p < 0.01		-----0.06 [0.00, 0.18]z = 2.08,
p < 0.01		-----0.08 [0.02, 0.17]z = 3.37,
p < 0.01		-----
Overall0.14 [0.08, 0.21]z = 7.82
p < 0.01		-4436.6599.71<0.010.110.21 [0.14, 0.30]z = 8.49,
p < 0.01		-2445.1299.47<0.010.130.09 [0.06, 0.14]z = 7.30,
p < 0.01		-1453.1199.11<0.010.07
>1 yearRetrospective0.35 [0.07, 0.71]z = 3.28,
p < 0.01		-----0.38 [0.12, 0.69]z = 4.01,
p < 0.01		-----0.34 [0.05, 0.72]z = 3.04,
p < 0.01		-----
Prospective0.17 [0.06, 0.31]z = 4.79,
p < 0.01		-576.4799.31<0.01-0.26 [0.13, 0.42]z = 5.73,
p < 0.01		-305.3898.69<0.01-0.12 [0.04, 0.24]z = 4.26,
p < 0.01		-223.2498.21<0.01-
Overall0.23 [0.07, 0.44]z = 4.20,
p = 0.01		-36,960.4499.98<0.010.420.30 [0.14, 0.50]z = 5.30,
p < 0.01		-11,553.8899.94<0.010.330.19 [0.05, 0.41]z = 3.58,
p < 0.01		-23,089.7899.97<0.010.46
Stroke Recurrence≤1 yearRetrospective0.03 [0.00, 0.09]z = 2.53,
p = 0.01		-14.2678.97<0.01-0.08 [0.08, 0.09]z = 73.79,
p < 0.01		-----0.07 [0.06, 0.07]z = 107.27,
p < 0.01		-----
RCT0.07 [0.07, 0.07]z = 130.56, p < 0.01-----0.04 [0.00, 0.11]z = 2.43,
p = 0.02		-8.5765.010.04-0.02 [0.00, 0.06]z = 1.84,
p = 0.07		-5.9049.130.12-
Overall0.04 [0.02, 0.08]z = 4.38,
p < 0.01		-21.4881.38<0.010.020.05 [0.02, 0.10]z = 4.59,
p < 0.01		-11.3464.740.020.020.03 [0.01, 0.07]z = 3.41,
p < 0.01		-10.9163.320.030.02
>1 yearRetrospective0.20 [0.12, 0.30]z = 7.62,
p < 0.01		-4717.4999.92<0.01-0.23 [0.13, 0.34]z = 7.58,
p < 0.01		-1566.5899.74<0.01-0.15 [0.08, 0.25]z = 6.47,
p < 0.01		-3191.4899.87<0.01-
Prospective0.12 [0.07, 0.18]z = 7.99,
p < 0.01		-----0.14 [0.08, 0.22]z = 7.28,
p < 0.01		-----0.10 [0.05, 0.16]z = 6.92,
p < 0.01		-----
Overall0.17 [0.11, 0.24]z = 9.02,
p < 0.01		-5040.6799.86<0.010.060.20 [0.13, 0.28]z = 9.31,
p < 0.01		-1761.8299.60<0.010.070.13 [0.08, 0.20]z = 7.69,
p < 0.01		-3338.9499.79<0.010.06
Abbreviations: CI, confidence interval; ES, effect size; H, heterogeneity statistic; RCT, randomized controlled trial. Note: Φ represents the heterogeneity variance threshold used to assess model convergence. τ2 ≤ Φ denotes that the estimated between-study variance lies within the acceptable tolerance range for random-effects meta-analysis.
Table 4. Summary effects and heterogeneity obtained from meta-analysis of statin use and clinical outcomes after ischemic stroke.
Table 4. Summary effects and heterogeneity obtained from meta-analysis of statin use and clinical outcomes after ischemic stroke.
OutcomeTime FrameNnEffect MeasureAnalysis SubgroupSummary EffectsHeterogeneityHeterogeneity Variance Estimates
OR (95% CI)SMD (95% CI)Test of Overall EffectCochran’s QHI2 (%)p-Valueτ2 ≤ Φ
Post-Stroke Dementia or Cognitive Decline-267,666ORPost-Stroke Dementia0.74 [0.60, 0.90]-z = −2.94, p < 0.0112.69-92.1<0.010.02
1350Post-Stroke Cognitive Impairment1.52 [0.98, 2.36]z = 1.886, p = 0.060.00---
368,016Overall0.83 [0.66, 1.05]z = −1.54, p = 0.1221.953.3190.9<0.010.03
All-Cause Mortality≤3 months42749ORRetrospective0.36 [0.27, 0.47]-z = −7.41, p < 0.012.36-0.00.50-
38142Prospective0.26 [0.18, 0.39]z = −7.09, p < 0.014.1051.20.130.06
3342RCT0.73 [0.25, 2.11]z = −0.58, p = 0.571.130.00.57-
1011,233Overall0.32 [0.26, 0.39]z = −12.438, p < 0.0111.161.1119.40.270.02
≤1 year775,770ORRetrospective0.37 [0.28, 0.47]-z = −7.554, p < 0.0163.30-90.5<0.010.08
48455Prospective0.31 [0.26, 0.36]z = −13.26, p < 0.012.620.00.45-
3342RCT0.93 [0.46, 1.90]z = −0.20, p = 0.840.800.00.81-
1484,567Overall0.35 [0.28, 0.44]z = −9.30, p < 0.0196.312.7586.8<0.010.09
>1 year3156,554ORRetrospective0.78 [0.54, 1.12]-z = −1.36, p = 0.17292.93-99.3<0.010.08
56794Prospective0.41 [0.27, 0.62]z = −4.20, p < 0.0118.5678.40.010.14
8163,348Overall0.56 [0.44, 0.72]z = −4.51, p < 0.01326.916.8397.9<0.010.08
Stroke Recurrence≤1 year159,588ORRetrospective0.77 [0.72, 0.82]-z = −7.59, p < 0.010.00----
4 *438RCT0.62 [0.24, 1.60]z = −0.99, p = 0.321.680.00.64-
5 *60,026Overall0.77 [0.72, 0.82]z = −7.64, p < 0.011.880.690.00.76<0.01
>1 year5138,670ORRetrospective0.82 [0.70, 0.95]-z = −2.60, p = 0.0132.50-87.1<0.0010.02
36323Prospective0.68 [0.51, 0.89]z = −2.79, p = 0.013.8147.50.150.03
8144,993Overall0.76 [0.66, 0.87]z = −3.88, p < 0.0146.862.5985.1<0.010.02
CRP Levels3–7 days3248SMD--−0.41 [−0.75, −0.06]z = −2.33, p = 0.020.010.080.00.993<0.01
>7 days4504SMD--−2.64 [−5.26, −0.03]z = −1.98, p < 0.01207.978.3398.6< 0.016.96
Abbreviations: N, number of studies; n, number of patients; RCT, randomized controlled trial; OR, odds ratio; SMD, standardized mean difference; CI, confidence interval; CRP, C-reactive protein; * Due to model limitations, studies with 0 events were replaced with 0.5 to allow for OR calculation. Note: Φ represents the heterogeneity variance threshold used to assess model convergence. τ2 ≤ Φ denotes that the estimated between-study variance lies within the acceptable tolerance range for random-effects meta-analysis.
Table 5. Pooled prevalence and summary effects of clinical outcomes after ischemic stroke by statin parameters.
Table 5. Pooled prevalence and summary effects of clinical outcomes after ischemic stroke by statin parameters.
ParameterOutcomeTimeframeNnEffect MeasureVariation/
Comparison		Effect Size
Pooled Prevalence (95% CI)Test of ES = 0OR (95% CI)Test of Overall Effect
Statin TypeAll-Cause Mortality≤1 year2136PrevalenceSimvastatin0.10 [0.06, 0.16]z = 6.44, p < 0.01N/AN/A
125Lovastatin0.04 [0.00, 0.20]z = 1.42, p = 0.16N/AN/A
337,020Atorvastatin0.05 [0.02, 0.08]z = 5.18, p < 0.01N/AN/A
36919Rosuvastatin0.04 [0.01, 0.07]z = 4.55, p < 0.01N/AN/A
Stroke Recurrence≤1 year2136PrevalenceSimvastatin0.03 [0.00, 0.06]z = 2.89, p < 0.01N/AN/A
437,080Atorvastatin0.04 [0.03, 0.05]z = 10.93, p < 0.01N/AN/A
36681Rosuvastatin0.02 [0.00, 0.07]z = 1.47, p = 0.14N/AN/A
Statin SolubilityAll-Cause Mortality≤1 year26919PrevalenceHydrophilic0.06 [0.05, 0.06]z = 36.84, p < 0.01N/AN/A
537,181Lipophilic0.06 [0.03, 0.10]z = 5.88, p < 0.01N/AN/A
Stroke Recurrence≤1 year36681PrevalenceHydrophilic0.02 [0.00, 0.07]z = 1.47, p = 0.14N/AN/A
537,216Lipophilic0.04 [0.02, 0.06]z = 6.37, p < 0.01N/AN/A
Statin TimingAll-Cause Mortality90-day3316Prevalence≤1 day0.10 [0.06, 0.12]z = 7.13, p < 0.01N/AN/A
31169>1 day0.06 [0.03, 0.09]z = 7.45, p < 0.01N/AN/A
Stroke Recurrence90-day295Prevalence≤1 day0.05 [0.01, 0.11]z = 3.44, p < 0.01N/AN/A
2239>1 day0.09 [0.06, 0.14]z = 8.45, p < 0.01N/AN/A
Statin IntensityAll-Cause Mortality≤2 years125PrevalenceLow0.04 [0.00, 0.20]z = 1.42, p = 0.16N/AN/A
421,001Low-moderate0.19 [0.12, 0.28]z = 8.31, p < 0.01N/AN/A
4348Moderate0.05 [0.01, 0.13]z = 2.68, p = 0.01N/AN/A
2471Moderate-high0.04 [0.02, 0.06]z = 7.54, p < 0.01N/AN/A
39360High0.09 [0.00, 0.32]z = 1.48, p = 0.14N/AN/A
N/A6103,028ORLower intensity vs. higher intensityN/AN/A0.92 [0.76, 1.12]z = −0.80, p = 0.42
Stroke Recurrence≤2 years120,486PrevalenceLow-moderate0.10 [0.10, 0.11]z = 93.47, p = 0.01N/AN/A
4205Moderate0.04 [0.00, 0.10]z = 2.40, p = 0.02N/AN/A
1344Moderate-high0.17 [0.13, 0.22]z = 14.90, p < 0.01N/AN/A
29205High0.10 [0.10, 0.11]z = 55.10, p = 0.12N/AN/A
N/A4102,647ORLower intensity vs. higher intensityN/AN/A1.10 [0.88, 1.38]z = −0.82, p = 0.41
Abbreviations: N, number of studies; n, number of patients; CI, confidence interval; ES, effect size; OR, odds ratio; N/A, not available.
Table 6. Grading of Recommendations Assessment, Development and Evaluation (GRADE) Summary of Findings: Statin Therapy After Ischemic Stroke.
Table 6. Grading of Recommendations Assessment, Development and Evaluation (GRADE) Summary of Findings: Statin Therapy After Ischemic Stroke.
OutcomeNo. of Studies (Participants)Study DesignRelative Effect (95% CI)Assumed Risk (Control)Risk with StatinAbsolute EffectCertainty of EvidenceReasons
All-cause mortality, ≤1 year14 (n = 84,567)Observational and RCTs
(adjusted estimates pooled via random-effects)		OR 0.35 (0.28–0.44)210 per 100090 per 1000120 fewer per 1000⊕⊕◯◯ Low to Moderate−1 risk of bias; −1 inconsistency; +1 large effect
Stroke recurrence,
≤1 year		5 (n = 60,026)Observational and RCTs
(random-effects)		OR 0.77 (0.72–0.82)———⊕⊕◯◯ Low−1 risk of bias; −1 inconsistency; −1 zero-event handling
Post-stroke dementia (any time)2 (subset)Observational
(random-effects)		OR 0.74 (0.60–0.90)———⊕⊕◯◯ Low−1 risk of bias; −1 imprecision; −1 inconsistency likely
CRP (3–7 d/>7 d)3/4; n = 248/504Observational and RCTs; continuous outcome
(SMD)		SMD −0.41 (−0.75 to −0.06) at 3–7 d; SMD −2.64 (−5.26 to −0.03) at >7 d———⊕◯◯◯ Very low−1 risk of bias; −1 inconsistency; −1 indirectness
GRADE Working Group grades of evidence: ⊕⊕⊕⊕ High: We are very confident that the true effect lies close to that of the estimate of the effect. ⊕⊕⊕◯ Moderate: We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. ⊕⊕◯◯ Low: Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. ⊕◯◯◯ Very low: We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate; The Assumed Risk comes from control group event rates in the included studies. The Relative Effect (OR) is applied to this baseline to estimate the risk under statin therapy. The Absolute Effect is simply the difference between assumed control risk and the estimated statin risk, expressed per 1000 patients for clarity. Abbreviations: n, number of participants; RCTs, randomized controlled trial; SMD, standardized mean difference; OR, odds ratio.
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Gupta, M.; Spring, K.J.; Beran, R.G.; Bhaskar, S. Impact of Statin Therapy on the Risk of Stroke Recurrence, Mortality, and Dementia After Ischemic Stroke (ISMARDD Study): A Comprehensive Meta-Analysis. Neurol. Int. 2025, 17, 176. https://doi.org/10.3390/neurolint17110176

AMA Style

Gupta M, Spring KJ, Beran RG, Bhaskar S. Impact of Statin Therapy on the Risk of Stroke Recurrence, Mortality, and Dementia After Ischemic Stroke (ISMARDD Study): A Comprehensive Meta-Analysis. Neurology International. 2025; 17(11):176. https://doi.org/10.3390/neurolint17110176

Chicago/Turabian Style

Gupta, Muskaan, Kevin J. Spring, Roy G. Beran, and Sonu Bhaskar. 2025. "Impact of Statin Therapy on the Risk of Stroke Recurrence, Mortality, and Dementia After Ischemic Stroke (ISMARDD Study): A Comprehensive Meta-Analysis" Neurology International 17, no. 11: 176. https://doi.org/10.3390/neurolint17110176

APA Style

Gupta, M., Spring, K. J., Beran, R. G., & Bhaskar, S. (2025). Impact of Statin Therapy on the Risk of Stroke Recurrence, Mortality, and Dementia After Ischemic Stroke (ISMARDD Study): A Comprehensive Meta-Analysis. Neurology International, 17(11), 176. https://doi.org/10.3390/neurolint17110176

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