Remain J-aded: LDL-C levels below 70 mg/dL associated with increased risk of intracranial hemorrhage

EBM Focus - Volume 14, Issue 17

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Reference: Neurology 2019 Jul 30;93(5):e445

Driving low density lipoprotein cholesterol (LDL-C) as low as possible seems to be the mindset of many clinicians and patients these days. But how low is too low? Studies examining the risks of low LDL-C levels have found mixed results, with some demonstrating an association between low levels of LDL-C and an increased risk of intracerebral hemorrhage (ICH). Additionally, statin therapy for secondary prevention may increase the risk of ICH.

This prospective cohort study followed over 96,000 Chinese adults for nine years, excluding those with myocardial infarction, stroke, or cancer. Fasting lipid profiles, blood pressure, and other health endpoints were collected at baseline and biennially thereafter. Most participants were men (80%) with a normal or overweight body mass index. Participants with LDL >100 mg/dL were more likely to smoke and use anti-hypertensives, aspirin, and cholesterol-lowering agents. During follow-up, 753 cases of ICH were identified (0.78%) through survey data, medical records, and death certificates. Average LDL-C levels between 70-90 mg/dL and levels of 100 mg/dL or greater had a similar risk of ICH, while lower levels were associated with an increased risk of ICH, even after adjusting for smoking, statin use, hypertension, antiplatelet and anticoagulant use (LDL <50 mg/dL, multivariate-adjusted hazard ratio [aHR] 2.69 [95% CI 2.03-3.57] and LDL 50-69 mg/dL, aHR 1.65 [95%CI 1.32-2.05]). In sensitivity analyses, a similar risk was demonstrated when excluding participants using anticoagulants and statins at follow-up and those with hypertension. Lower total cholesterol concentrations were also associated with a higher risk of ICH (TC <120 mg/dL, aHR 2.24 [95% CI 1.48-3.4]), whereas high density lipoprotein cholesterol and triglycerides were not associated with ICH.

Clinicians have to navigate the J-shaped curve of relative harms and benefits in many clinical scenarios. Elevated LDL-C >190 mg/dL has been consistently associated with cardiovascular death. It appears an LDL-C value below 70 mg/dL may increase the risk of ICH. Some studies have demonstrated an associated increased risk of statin therapy with hemorrhagic stroke, yet the same association has not been demonstrated with proprotein convertase subtilisin/kexin type 9 inhibitor therapy. The LDL-C value at which the number needed to treat to prevent cardiovascular events outweighs the number needed to harm to prevent adverse events such as ICH has not been identified. While the current guidelines recommend aggressive LDL-C lowering with multiple agents, this is yet another study questioning the safety of driving down LDL-C as low as possible. With regard to statin therapy for patients, the event rate for cardiovascular disease is considerably higher ( 2% in the same population over 4 years) than for intracerebral hemorrhage (< 1% over 9 years). Finding the perfect LDL-C number at the base of the J-shaped curve may be difficult and likely varies across different cohorts. Thus it offers yet another important opportunity for shared decision-making.

For more information, see the topic Intracerebral Hemorrhage in DynaMed.

DynaMed EBM Focus Editorial Team

This EBM Focus was written by Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School and Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed.