Relationship between low-density lipoprotein cholesterol, lipid-lowering agents and risk of stroke: a meta-analysis of observational studies (n = 355,591) and randomized controlled trials (n = 165,988)

INTRODUCTION: The impact of low-density lipoprotein cholesterol (LDL-C) on the risk of different types of strokes is unclear. Therefore, we systematically evaluated the impact of LDL-C levels (cohort studies) and lipid-lowering agents (LLAs) (randomized controlled trials) on the different types of stroke. MATERIAL AND METHODS: PubMed, SCOPUS, Web of Science and Google Scholar were searched up to 1(st) September 2019. The DerSimonian-Laird method and generic inverse variance methods were used for quantitative data synthesis. The leave-one-out method was performed as sensitivity analysis. Trial sequential analysis (TSA) was used to evaluate the optimal sample size to detect a 35% reduction in outcomes after administration of LLAs. RESULTS: Participants in the highest category of LDL-C had a lower risk of hemorrhagic stroke (RR = 0.91, 95% CI: 0.85–0.98, I(2) = 0%) compared with the lowest category of LDL-C. Subjects with the highest category of LDL-C had a higher risk of ischemic stroke (RR = 1.11, 95% CI: 1.07–1.14, I(2) = 0%) compared to the lowest LDL-C category. LLAs decreased the risk of all types of strokes for those who achieved LDL-C < 1.8 mmol/l (< 70 mg/dl; RR = 0.88, 95% CI: 0.80–0.96, absolute risk reduction (ARR): 0.7%, number needed to treat (NNT): 143, I(2) = 53%, n = 13). Statin therapy decreased the risk of all strokes (RR = 0.88, 95% CI: 0.80–0.97, ARR = 0.6%, NNT = 167, I(2) = 56%). With regard to ischemic stroke only, LLAs decreased the risk of ischemic stroke for those who achieved LDL-C < 1.8 mmol/l (< 70 mg/dl; RR = 0.75, 95% CI: 0.67–0.83, ARR = 1.3%, NNT = 77, I(2) = 0%); the same was observed for statins (RR = 0.76, 95% CI: 0.69–0.84, ARR = 1.3%, NNT = 77, I(2) = 32%). TSA indicated that both benefit boundaries and optimal sample size were reached. There was no significant effect of LLAs regardless of the achieved level of LDL-C on the risk of hemorrhagic stroke; however, TSA indicated that further studies are needed to settle the question and most of the effects were subject to high levels of heterogeneity. CONCLUSIONS: Our study sheds light on the debatable association between low LDL-C and different type of strokes. This information can help determine the optimal LDL-C range for stroke prevention, and help plan future LLA studies.