PACMAN-AMI: Addition of Alirocumab Lacks Benefit for Endothelial Function

Alirocumab did not further improve flow-mediated dilation (FMD) among patients with acute myocardial infarction (AMI), compared with 52-week secondary preventative medical therapy, according to a recent substudy of the PACMAN-AMI randomized clinical trial.¹

Improvement in endothelial function, as assessed by brachial artery FMD, throughout 1 year, was achieved with high-intensity statin therapy, but the addition of the protein convertase subtilisin/kexin type 9 (PCSK9) inhibitor did not further the benefits in patients with AMI.

“The results of our trial suggest that improvement in endothelial function can be achieved throughout 1 year after AMI by guideline-based secondary preventative medical therapy, including a high-intensity statin,” wrote the investigative team, led by Lorenz Räber, MD, PhD, department of cardiology at Bern University Hospital Inselspital. “However, we did not observe a direct additional benefit on FMD by adding the PCSK9 inhibitor alirocumab to rosuvastatin.”

Evidence has shown the beneficial effect of PSCK9 inhibitors on cardiovascular outcomes, lowering low-density lipoprotein cholesterol (LDL-C) by upregulation of hepatic LDL-C receptors.² The available literature is growing on the potential pleiotropic effects of PSCK9, particularly its involvement in inflammatory and oxidative processes.³

However, Räber and colleagues pointed to a lack of investigation into the effect of PCSK9 inhibition on FMD among patients with AMI, and its association with the extent and stability of coronary atherosclerosis in multimodality intracoronary imaging.

PACMAN-AMI compared the effects of biweekly alirocumab 150 mg versus placebo added to rosuvastatin between May 2017 and October 2020. This pre-specified substudy of PACMAN-AMI was performed among patients enrolled at Bern University Hospital (n = 173), with brachial artery FMD measured at 4 and 52 weeks after AMI, and intracoronary imaging at baseline and 52 weeks.

For the analysis, the pre-specified primary endpoint was the absolute difference in FMD between the placebo and alirocumab groups at 52 weeks. Among the total enrolled population, 139 (80%) underwent serial FMD measurement. Patients had a mean age of 58.1 years, 16% were female, and the baseline LDL-C level was 155.9 mg/dL.

Upon analysis, at 52 weeks, investigators found no difference in FMD between the alirocumab (5.44 ± 2.24%) and placebo (5.45 ± 2.19%) groups (between-group difference, –0.21% [95% CI, –0.77 to 0.35; P = .47). Compared with FMD at 4 weeks, 52-week FMD was similarly significantly improved in both groups (P < .001).

Intracoronary imaging endpoints revealed a significant association between baseline plaque burden, assessed by intracoronary intravascular ultrasound, and FMD at 4 weeks (slope, –1.00 [95% CI, –1.70 to –0.30]; P = .006), with a trend toward a significant association throughout 52 weeks (P = .08). However, there were no significant associations with lipid pool, measured by near-infrared spectroscopy (slope, –7.36; P = .32) or fibrous cap thickness, measured by optical coherence tomography (slope, –1.57; P = .62).

Another substudy of the PACMAN-AMI trial revealed no overall improvement in coronary hemodynamics with alirocumab in non-obstructive non-infarct related arteries, as evaluated by Quantitative Flow Ratio, remaining in line with the current findings.⁴

“Further functional and morphological effects of PCSK9 inhibitors in the evolution of atherosclerosis should be subject to future studies,” Räber and colleagues wrote.

References

1. _{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;392:117504. doi:10.1016/j.atherosclerosis.2024.117504}
2. _{Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174}
3. _{Punch E, Klein J, Diaba-Nuhoho P, Morawietz H, Garelnabi M. Effects of PCSK9 Targeting: Alleviating Oxidation, Inflammation, and Atherosclerosis. J Am Heart Assoc. 2022;11(3):e023328. doi:10.1161/JAHA.121.023328}
4. _{Bär S, Kavaliauskaite R, Otsuka T, et al. Impact of alirocumab on plaque regression and haemodynamics of non-culprit arteries in patients with acute myocardial infarction: a prespecified substudy of the PACMAN-AMI trial. EuroIntervention. 2023;19(4):e286-e296. Published 2023 Jul 17. doi:10.4244/EIJ-D-23-00201}