Association of Ezetimibe and Statin Combinations With Recurrent Ischemic Stroke: A Nationwide Study With Dual Design

Statin is recommended for patients with ischemic stroke (IS) to lower low-density lipoprotein cholesterol. Although combining statin with ezetimibe further reduced low-density lipoprotein cholesterol, its impact on IS recurrence has varied by statin type. We used 2 study designs-a retrospective cohort and a case-control study-using the Korean Health Insurance Review and Assessment database. Patients hospitalized for IS between July 2017 and July 2021 who were treated with atorvastatin or rosuvastatin were included. The cohort study compared recurrent IS risk between ezetimibe users and nonusers, using 1:1 propensity score matching for baseline characteristics. The case-control study assessed ezetimibe use between recurrent cases with IS and age-, sex-, index year-matched controls. Cox proportional hazards and logistic regression models were used to calculate hazard ratios (HRs) and adjusted HRs (aHRs) for the cohort study, as well as odds ratios (ORs) and adjusted ORs (aORs) for the case-control study. We conducted several sensitivity analyses. Among 26 937 patients with IS (16 215 atorvastatin, 10 722 rosuvastatin), the cohort study showed ezetimibe combined with atorvastatin significantly reduced recurrent IS incidence (aHR, 0.73 95% CI, 0.55-0.98, P=0.037), whereas rosuvastatin showed no significant difference (aHR, 1.00 95% CI, 0.80-1.24, P=0.985). The case-control study confirmed ezetimibe's protective effect with atorvastatin (aOR, 0.74 95% CI, 0.58-0.93, P=0.012) but not with rosuvastatin (aOR, 1.01 95% CI, 0.83-1.24, P=0.903). Sensitivity analyses supported these findings. Ezetimibe combined with atorvastatin was associated with lower recurrent IS rates compared with atorvastatin alone, whereas its addition to rosuvastatin showed no significant association.