Beyond low-density lipoprotein cholesterol levels: Impact of prior statin treatment on ischemic stroke outcomes

Abstract

Although essential for cardiovascular therapy, the pleiotropic effects of statins on ischemic stroke lack clinical evidence. This study examined the effects of statins beyond low-density lipoprotein cholesterol (LDL-C) levels on mortality and stroke severity. A total of 825,874 patients with ischemic stroke were included in this study, of whom 125,650 statin users were 1:1 matched with non-users based on their LDL-C levels (±0.05 mmol/L), forming the LDL-C-matched cohort. Associations between preceding statin treatment, in-hospital mortality, and stroke severity (National Institutes of Health Stroke Scale score ≥16) were estimated by multivariate and conditional logistic regression models in overall cohort and LDL-C-matched cohort, respectively. The overall statin effects reduced in-hospital mortality (odds ratio [OR]: 0.72, 95% confidence interval [CI]: 0.65-0.79, p < 0.001) and moderate-to-severe stroke (OR: 0.93, 95% CI: 0.90-0.96, p < 0.001). After matching for LDL-C levels, the reduction in mortality persisted (OR: 0.63, 95% CI: 0.52-0.77, p < 0.001) but not for moderate-to-severe stroke (OR: 0.96, 95% CI: 0.90-1.02, p = 0.215). Stratified by LDL-C levels, the effects of statin beyond LDL-C in reducing mortality remained consistent across all LDL-C ranges but increased with LDL-C reduction for stroke severity and achieved statistical significance at LDL-C <2.60 mmol/L. Mediation analyses showed that LDL-C reduction explained 0.35% (95% CI: 0.23-0.93, p = 0.235) of the statin treatment-mortality relationship and 12.47% (95% CI: 6.78-18.16, p < 0.001) for moderate-to-severe stroke. When examining the overall statin efficacy, LDL-C <2.60 mmol/L was not necessary for mortality reduction but for reducing stroke severity. The efficacy of statins in ischemic stroke outcomes is primarily derived from their effects beyond the LDL-C levels, suggesting that their neuroprotective effects should be considered in addition to their lipid-lowering effects.

Graphical abstract

Figure 1

The overall effect and the effect beyond LDL-C levels of preceding statin treatment on in-hospital mortality and stroke severity The analyses were performed using logistic regression models and conditional logistic regression models in the overall and LDL-C-matched cohorts, respectively, after adjusting for age, sex, body mass index, smoking status, alcohol intake, history of hypertension, diabetes mellitus, ischemic stroke, myocardial infarction, atrial fibrillation and heart failure, IV thrombolytic therapy, and antithrombotic treatment. LDL-C, low-density lipoprotein cholesterol; IV, intravenous; OR, odds ratio; CI, confidence interval.

Figure 2

Subgroup analyses of the overall effect and the effect beyond LDL-C levels of preceding statin treatment on in-hospital mortality The analyses were performed using logistic regression models and conditional logistic regression models in the overall (indicating the overall effect of the preceding statin treatment) and LDL-C-matched (indicating the effect beyond LDL-C of the preceding statin treatment) cohorts, respectively, after adjusting for age, sex, body mass index, smoking status, alcohol intake, history of hypertension, diabetes mellitus, ischemic stroke, myocardial infarction, atrial fibrillation and heart failure, IV thrombolytic therapy, and antithrombotic treatment. LDL-C, low-density lipoprotein cholesterol; IV, intravenous; OR, odds ratio; CI, confidence interval.

Figure 3

Subgroup analyses of the overall effect and the effect beyond LDL-C levels of preceding statin treatment on stroke severity The analyses were performed using logistic regression models and conditional logistic regression models in the overall (indicating the overall effect of the preceding statin treatment) and LDL-C-matched (indicating the effect beyond LDL-C of the preceding statin treatment) cohorts, respectively, after adjusting for age, sex, body mass index, smoking status, alcohol intake, history of hypertension, diabetes mellitus, ischemic stroke, myocardial infarction, atrial fibrillation and heart failure, IV thrombolytic therapy, and antithrombotic treatment. LDL-C, low-density lipoprotein cholesterol; IV, intravenous; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; CI, confidence interval.

Figure 4

Associations between the effects beyond LDL-C levels and LDL-C reduction with the preceding statin treatment All analyses were performed in the LDL-C-matched cohort using conditional logistic regression models after adjusting for age, sex, body mass index, smoking status, alcohol intake, history of hypertension, diabetes mellitus, ischemic stroke, myocardial infarction, atrial fibrillation and heart failure, IV thrombolytic therapy, and antithrombotic treatment. LDL-C, low-density lipoprotein cholesterol; IV, intravenous; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; CI, confidence interval.

Figure 5

Significance of low LDL-C levels in the overall efficacy of preceding statin treatment (A) The overall effect of preceding statin treatment on all-cause mortality and moderate-to-severe stroke, at different LDL-C levels. (B) Interaction effects between preceding statin treatment and LDL-C levels on all-cause mortality and moderate-to-severe stroke. All analyses were performed in the overall cohort using logistic regression models after adjusting for age, sex, body mass index, smoking status, alcohol intake, history of hypertension, diabetes mellitus, ischemic stroke, myocardial infarction, atrial fibrillation and heart failure, IV thrombolytic therapy, and antithrombotic treatment. LDL-C, low-density lipoprotein cholesterol; IV, intravenous; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; CI, confidence interval.