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

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.

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.

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.

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].

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].

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].

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.

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.

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.

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

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.

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).