PCSK9 inhibitor does not improve endothelial function after MI


In a PACMAN-AMI substudy among patients with acute MI, alirocumab added to high-intensity statin therapy did not result in further improvement of flow-mediated dilation at 52 weeks compared with placebo.

This summary is based on the publication of Rexhaj E, Bär S, Soria R, et al - Effects of alirocumab on endothelial function and coronary atherosclerosis in myocardial infarction: A PACMAN-AMI randomized clinical trial substudy. Atherosclerosis. 2024 Mar 6:392:117504 [Online ahead of print]. doi: 10.1016/j.atherosclerosis.2024.117504

Introduction and methods


Flow-mediated dilation (FMD) is considered to be the “gold standard” for the noninvasive evaluation of endothelial function [1,2]. While several small studies have shown that short-term treatment with the PCSK9 inhibitor evolocumab improved FMD in chronic coronary syndrome, diabetes mellitus, and familial hypercholesterolemia [3-7], the effect of PCSK9 inhibition on FMD in patients with acute MI (AMI) has not been investigated.

Aim of the study

In a prespecified substudy of the PACMAN-AMI trial, the authors examined the effects of alirocumab, in addition to high-intensity statin therapy, on FMD in AMI patients, as well as the association between FMD and the extent and stability of coronary atherosclerosis as assessed with multimodality intracoronary imaging.


The PACMAN-AMI (PCSK9 antibody AliroCuMab on coronary Atherosclerosis in patieNts with Acute Myocardial Infarction) study was a European, multicenter, investigator-initiated, double-blind, placebo-controlled, phase 3 RCT in which 300 AMI patients undergoing PCI were randomized to subcutaneous alirocumab 150 mg biweekly or placebo, in addition to high-intensity statin therapy with rosuvastatin 20 mg [8,9]. Participants underwent serial coronary angiography and intracoronary imaging (intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT)) of 2 non–infarct-related arteries at baseline and 52 weeks.

In the current substudy, 139 patients recruited at the Bern University Hospital in Bern, Switzerland were included. Brachial artery FMD was measured at 4 weeks (i.e., baseline measurement) and 52 weeks post-MI.


The prespecified primary endpoint was the absolute difference in FMD between the placebo and alirocumab groups at 52 weeks. Secondary endpoints were the absolute between-group difference in FMD at 4 weeks and the between-group difference in absolute FMD change from 4 to 52 weeks.

Prespecified intracoronary imaging endpoints were the associations between FMD at 4 weeks and IVUS-derived percent atheroma volume, NIRS-derived maximum lipid core burden index (4 mm), and OCT-derived minimum fibrous cap thickness at baseline and the associations between change in FMD from 4 to 52 weeks and changes in the 3 aforementioned parameters from baseline to 52 weeks.

Main results

Primary and secondary endpoints

  • The mean ± SD FMD at 52 weeks was 5.44 ± 2.24% in patients treated with alirocumab (n=68) and 5.45 ± 2.19% in placebo-treated patients (n=71) (between-group difference: –0.21%; 95%CI: –0.77% to 0.35%; P=0.47).
  • At 4 weeks, the mean ± SD FMD was 4.52 ± 1.87% in the alirocumab group and 4.32 ± 1.62% in the placebo group (between-group difference: 0.20%; 95%CI: –0.47% to 0.87%; P=0.56).
  • In both groups, FMD improved from 4 to 52 weeks (P<0.001).

Intracoronary imaging endpoints

  • There was a significant association of 4-week FMD with IVUS-derived percent atheroma volume at baseline (slope: –1.00; 95%CI: –1.70 to –0.30; P=0.006) but not with NIRS-derived maximum lipid core burden index (4 mm) (slope: –7.36; P=0.32) or OCT-derived minimum fibrous cap thickness (n=81; slope: –1.57; P=0.62).
  • There were no significant associations between FMD change and changes in percent atheroma volume (slope: −0.19; 95%CI: –0.40 to 0.02; P=0.08), maximum lipid core burden index (4 mm), and minimum fibrous cap thickness.


In this prespecified substudy of the PACMAN-AMI trial among patients with AMI, addition of alirocumab to high-intensity statin therapy (rosuvastatin 20 mg) did not result in further improvement of endothelial function as assessed by brachial artery FMD at 52 weeks, compared with placebo. FMD at 4 weeks was inversely related to coronary plaque burden in non–infarct-related arteries at baseline but not to the lipid core burden index or fibrous cap thickness. Furthermore, there was a trend toward an inverse association between change in FMD from 4 to 52 weeks and change in coronary plaque burden over 1 year.

The authors offer the following explanation for the negative results: “[...], it appears possible that in PACMAN-AMI, rosuvastatin initiation at trial enrollment induced its established effects on FMD and may have attenuated a potential added benefit of alirocumab on FMD.” They doubt the difference in effects on FMD between alirocumab and evolocumab are related to the type of PCSK9 inhibitor. “[These discrepancies] may rather be explained by differences in patient population, study design, timepoint of FMD assessment, comedication, and treatment duration.”

Find this article online at Atherosclerosis.


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