Evolocumab Effect on Plaque Characteristics in Stable CAD Patients

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By Jair Basantes de la Calle on

Key Points

  • The YELLOW III study aimed to assess the effect of 26 weeks of evolocumab on plaque morphology using intravascular imaging (OCT and NIRS/IVUS) and peripheral blood mononuclear cell (PBMC) gene expression analysis in patients with stable CAD on maximally tolerated statin therapy.
  • In patients with stable CAD on maximally tolerated statins, more intensive lipid lowering with addition of evolocumab for 26 weeks resulted in significant and substantial increase in the minimum FCT by OCT, reduction in NIRS maxLCBI4mm and reduction in atheroma volume by IVUS in angiographically non-obstructive lesions.
  • The prevalence of high-risk vulnerable TCFA lesions was reduced from 48% to 13%.
  • This is the first multimodality imaging report in stable patients with non-obstructive lesions and lower levels of LDL-C at baseline.

PCSK9 inhibitors have been effectively demonstrated to lower the risk of cardiovascular disease in individuals experiencing hypercholesterolemia.1 These drugs function by inhibiting PCSK9, an enzyme that reduces LDL receptors in liver cells, thus decreasing the LDL cholesterol levels in the body. Recent research on PCSK9 inhibitors (PCSK9i) suggests that they might have a plaque-stabilizing impact 2, and theoretically reduce the incidence of cardiovascular events in individuals with atherosclerosis. The Yellow III study presented at the ACC 2023 conference further supports this hypothesis and highlights the potential of PCSK9i in the management of patients with stable CAD. The trial, led by Dr. Annapoorna Kini from the Icahn School of Medicine at Mount Sinai, was a phase 4, single-center clinical trial that aimed to investigate the effect of evolocumab on coronary plaque characteristics in patients with stable coronary artery disease (CAD) on maximum tolerated doses of statins.  Patients with CAD undergoing cardiac cathetehrization or elective PCI with a non-obstructive lesion and optimal background statin therapy were included. Non-obstructive lesions (30-50% stenosis) identified by angiography in a non-culprit vessel with lipid-rich plaque were studied.

 

Out of 329 patients screened, 137 were enrolled, and 110 completed 26-week follow up. The trial lasted for 26 weeks, during which patients received 140 mg of evolocumab subcutaneously every 2 weeks. The patients were evaluated to see if there were any changes in plaque morphology using intravascular imaging as well as genomic studies. The primary endpoints of the study were changes in the minimal fibrous cap thickness (FCT), assessed by optical coherence tomography (OCT), and changes in maximum lipid core burden index within 4 mm (maxLCBI 4 mm), assessed by near-infrared spectroscopy (NIRS) after 26 weeks of treatment. The secondary endpoints included changes in the maximal lipid arc, lipid length, lipid volume index, macrophage accumulation, and calcification by OCT, as well as changes in percent atheroma volume (PAV) and total atheroma volume (TAV) by intravascular ultrasound (IVUS). The researchers also investigated changes in gene expression.

Results from the Yellow III trial show that patients treated with evolocumab for 26 weeks had an increased FCT by OCT with an absolute change of 26.8 (p < 0.001), reduced NIRS maxLCBI 4 mm (306.8 vs. 213.1; p < 0.001), and an increased cap thickness (70.9 µm vs. 97.7; p < 0.001). Thus, after six months of follow-up, there is evidence of atherosclerotic plaque stabilization in the coronary arteries. Overall, the Yellow III study provides important insights into the potential impact of evolocumab on coronary plaque characteristics in patients with nonobstructive coronary lesions already treated with statins. These findings could have significant implications for the management of patients with CAD and highlight the importance of secondary prevention measures for patients. Looking into the future, and from a molecular point of view, data from the trial will help to develop a tailored profile designed for patients with elevated cholesterol levels who are non-responders to other drugs and interventions targeted to decrease cholesterol levels. Clinically, the outcomes from the YELLOW III trial support the use of PCSK9i, especially in patients who are already treated with statins but do not achieve an optimal LDL value.

 

References 

  1. O’Donoghue, Michelle L., et al. “Long-term evolocumab in patients with established atherosclerotic cardiovascular disease.” Circulation 146.15 (2022): 1109-1119.
  2. Räber, L., Ueki, Y., Otsuka, T., Losdat, S., Häner, J. D., Lonborg, J., … & Ten Cate, T. (2022). Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial. Jama, 327(18), 1771-1781.