Evolocumab improves endothelial function in high-risk ASCVD
In the EVAS trial, evolocumab improved endothelial function at 8 weeks in ASCVD patients with elevated LDL-c levels despite high-intensity statin therapy, compared with placebo.
This summary is based on the publication of Kannenkeril D, Bosch A, Kolwelter J, et al. - PCSK-9-inhibitor therapy improves endothelial function in high-risk patients with cardiovascular disease. Clin Res Cardiol. 2024 Nov 20 [Online ahead of print]. doi: 10.1007/s00392-024-02556-6
Introduction and methods
Background
The PCSK9 inhibitor evolocumab reduced LDL-c levels and the risk of CV events in patients with high CVD risk who were already being treated with optimized lipid-lowering therapy (LLT), including a statin, as was shown by the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial [1]. The mechanism behind this reduction in CV outcomes is unclear, but perhaps improvement of an impaired endothelial function plays a role.
Aim of the study
The study aim was to examine the effect of evolocumab on endothelial function in high-risk ASCVD patients who were on optimized LLT.
Methods
The EVAS trial was a double-blind, placebo-controlled, parallel-group, phase 4 RCT conducted at the University Hospital Erlangen-Nuremberg, Germany. In this trial, 103 patients with clinically evident ASCVD and fasting LDL-c ≥70 mg/dL (≥1.8 mmol/L) or non–HDL-c ≥100 mg/dL (≥2.6 mmol/L) despite high-intensity statin therapy, were randomized to 2 subcutaneous injections of evolocumab 420 mg every 4 weeks or placebo. Endothelial function was assessed using a semiautomatic high-resolution ultrasound system (UNEX EF 18G) at baseline, 1, 4, and 8 weeks.
Outcomes
The primary endpoint was the change in vasoactive range (VAR) from baseline to 8 weeks. Secondary endpoints included changes from baseline to 8 weeks in other endothelial function parameters, i.e., flow-mediated vasodilation (FMD) and low flow-mediated vasoconstriction (L-FMC). Safety assessment at 10 weeks included the frequencies of adverse events, serious adverse events, and adverse events considered to be related to the study drug.
Main results
• The change in VAR from baseline to 8 weeks was 2.2 ± 7.0 mm (P=0.034) in patients treated with evolocumab (n=53) and −0.24 ± 4.1 mm (P=0.698) in those treated with placebo (n=50) (P for difference between groups=0.045).
• There were no significant differences in the change in FMD (P for group difference=0.422) or L-FMC (P for group difference=0.280) after 8 weeks of treatment with evolocumab versus placebo.
• In the overall study population (n=103), the change in LDL-c level was related to the change in VAR at 8 weeks (r=−0.222; P=0.0386). No such relationships were observed between LDL-c change and the other endothelial function parameters.
• Subgroup analyses demonstrated the VAR improved after 8 weeks of evolocumab treatment in patients aged ≤67 years (P=0.006), participants with baseline LDL-c >95 mg/dL (P=0.042), and those with baseline systolic blood pressure ≤125 mmHg (P=0.049).
• The rates of adverse events were similar in the evolocumab and placebo groups, and none of the 4 serious adverse events were considered to be related to the study drug.
Conclusion
In the single-center EVAS trial, treatment with evolocumab for 8 weeks improved endothelial function, as assessed by the VAR, in high-risk ASCVD patients on optimized LLT, compared with placebo. The authors believe their “results contribute to the mechanistic explanation why lower incidence of the CV composite endpoint has been demonstrated in the FOURIER study.”
Reference
1. Sabatine MS et al (2017) Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 376(18):1713–1722