Association Between Intensity of Low-Density Lipoprotein Cholesterol Reduction With Statin-Based Therapies and Secondary Stroke Prevention: A Meta-analysis of Randomized Clinical Trials

IMPORTANCE: The benefits and risks associated with intensive low-density lipoprotein cholesterol (LDL-C)–lowering statin-based therapies to lessen the risk of recurrent stroke have not been established. OBJECTIVE: To conduct a meta-analysis of randomized clinical trials to evaluate the association of more intensive vs less intensive LDL-C–lowering statin-based therapies with outcomes for patients with ischemic stroke. DATA SOURCES: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from January 1, 1970, to July 31, 2021. STUDY SELECTION: This meta-analysis included randomized clinical trials that compared more intensive vs less intensive LDL-C–lowering statin-based therapies and recorded the outcome of recurrent stroke among patients with stroke. DATA EXTRACTION AND SYNTHESIS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was used for abstracting data and assessing data quality and validity. Relative risk (RR) with 95% CI was used as a measure of the association of more intensive vs less intensive LDL-C lowering with primary and secondary outcomes. MAIN OUTCOMES AND MEASURES: The primary outcome was recurrent stroke, and the secondary outcomes were major cardiovascular events and hemorrhagic stroke. RESULTS: The final analysis included 11 randomized clinical trials with 20 163 patients (13 518 men [67.0%]; mean [SD] age, 64.9 [3.7] years) with stroke. The mean follow-up was 4 years (range, 1-6.1 years). Pooled results showed that more intensive LDL-C–lowering statin-based therapies were associated with a reduced risk of recurrent stroke compared with less intensive LDL-C–lowering statin-based therapies (absolute risk, 8.1% vs 9.3%; RR, 0.88; 95% CI, 0.80-0.96) and that the benefit associated with these LDL-C–lowering therapies was not different among LDL-C–lowering strategies (statins vs no statins: RR, 0.90; 95% CI, 0.81-1.01; more statins or ezetimibe vs less statins or ezetimibe: RR, 0.77; 95% CI, 0.62-0.96; and proprotein convertase subtilisin/kexin type 9 inhibitors plus statins vs placebo plus statins: RR, 0.90; 95% CI, 0.71-1.15; P = .42 for interaction). More intensive LDL-C–lowering statin-based therapies were associated with a reduced risk of major cardiovascular events, but with an increased risk of hemorrhagic stroke, compared with less intensive LDL-C–lowering statin-based therapies. More intensive LDL-C–lowering statin-based therapies were associated with a reduced risk of recurrent stroke in trials with all patients having evidence of atherosclerosis (RR, 0.79; 95% CI, 0.69-0.91), but not in trials with most patients not having evidence of atherosclerosis (RR, 0.95; 95% CI, 0.85-1.07; P = .04 for interaction), compared with less intensive LDL-C–lowering statin-based therapies. CONCLUSIONS AND RELEVANCE: This study suggests that the benefits and risks of more intensive LDL-C–lowering statin-based therapies for recurrent stroke risk reduction might be more favorable than the benefits and risks of less intensive LDL-C–lowering statin-based therapies, especially for patients with evidence of atherosclerosis.