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)

Abstract

Introduction The impact of 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 drugs (LLAs, RCTs) on the different types of stroke. Material and methods PubMed, SCOPUS, Web of Science and Google Scholar were searched up to 1st 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 at highest category of LDL-C had a lower risk for of hemorrhagic stroke (RR: 0.91, 95%CI 0.85-0.98, I2:0%) 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, I2:0%) 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, I2:53%, n=13). Statin therapy decreased the risk of all strokes (RR=0.88, 95% CI 0.80-0.97, ARR: 0.6 %, NNT: 167, I2:56%). 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, I2:0%); the same was observed for statins (RR= 0.76, 95%CI:0.69-0.84, ARR: 1.3%, NNT: 77, I2:32%). TSA indicated that both benefit boundaries and optimal sample size was reached. There was no significant effect of LLAs regardless of the achieved level of the LDL-C on the risk of hemorrhagic stroke; however, TSA indicated that further studies were needed to settle the question and most of 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 LLAs studies.

Keywords

• low-density lipoprotein cholesterol
• systematic review
• meta-analysis
• stroke