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

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.

Keywords: ISMARDD study; cerebrovascular disorders; meta-analysis; post-stroke dementia; secondary prevention; statins; stroke.

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 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 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 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 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.