Apolipoprotein E Plasma Concentrations Are Predictive of Recurrent Strokes: Insights From the SPARCL Trial

Abstract

Background: In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, atorvastatin (80 mg per day) was compared with placebo in patients with recent stroke or transient ischemic attack and no known coronary artery disease. Given the central role of apoE (apolipoprotein E) in lipoprotein metabolism and in the central nervous system, we assessed the contribution of apoE to subsequent cerebrovascular and cardiovascular events in this trial.

Methods and results: ApoE concentrations and major isoforms (E2/E3/E4) were determined by liquid-chromatography high resolution mass-spectrometry in plasma samples collected at baseline from 4348 SPARCL participants. Patients in the lowest quartile were compared with those in the highest quartiles of apoE concentrations. Multivariable-adjusted hazard-ratios (HR) and 95% CIs were calculated using Cox proportional hazards regression models. We found a significant association between low apoE concentrations and the risk of recurrent strokes or cerebrovascular events (HR, 1.401 [95% CI, 1.154-1.701], P<0.001 and 1.467 [95% CI, 1.260-1.708], P<0.001) driven by a higher incidence of ischemic strokes and transient ischemic attacks in the entire cohort as well as separately in each treatment arm of SPARCL. In contrast, apoE concentrations did not significantly associate with the incidence of hemorrhagic strokes in SPARCL. We also found a significant association between reduced apoE concentrations and the risk of subsequent coronary events (HR, 1.373 ([95% CI, 1.064-1.772], P=0.015) in the entire cohort that was, however, significant only in the placebo arm of SPARCL.

Conclusions: Low apoE concentrations are predictive of recurring cerebrovascular events in patients with a history of stroke or transient ischemic attack.

Registration: URL: https://www.clinicaltrials.gov; Identifier: NTC00147602.

Keywords: apolipoprotein E; atorvastatin; secondary prevention; stroke.

Figure 1. Cumulative incidence and hazard ratios of cerebrovascular events by levels of apoE plasma concentrations at baseline during 6 years following randomization.

Kaplan–Meier estimates for cerebrovascular events in all patients (A), in patients randomized to atorvastatin 80 mg (B), or placebo (C), with apoE concentrations below (Quartile 1) or above (Quartiles 2–4) 3.62 mg/dL at baseline. Insets show the same data on an enlarged y axis. D, Hazard ratios for composite cerebrovascular events and each major type of cerebrovascular event by levels of apoE concentrations at baseline in all patients and each treatment arms. Kaplan–Meier estimates and hazard ratios were adjusted for age, sex, type of entry event, time since entry event, body mass index, triglycerides, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, smoking, hypertension, and diabetes at baseline. apoE indicates apolipoprotein E; and HR, hazard ratio.

Figure 2. Cumulative incidence and hazard ratios of coronary events by levels of apoE plasma concentrations at baseline during 6 years following randomization.

Kaplan–Meier estimates for cerebrovascular events in all patients (A), in patients randomized to atorvastatin 80 mg (B), or placebo (C) with ApoE concentrations below (Quartile 1) or above (Quartiles 2–4) 3.62 mg/dL at baseline. Insets show the same data on an enlarged y axis. D, Hazard ratios for composite coronary events and each major type of coronary event by levels of apoE concentrations at baseline in all patients and each treatment arms. Kaplan–Meier estimates and hazard ratios were adjusted for age, sex, type of entry event, time to entry event, body mass index, triglycerides, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, smoking, hypertension, and diabetes at baseline apoE indicates apolipoprotein E; CABG, coronary artery bypass graft; HR, hazard ratio; and PCI, percutaneous coronary intervention.