Effect Of Evolocumab On Coronary Plaque Characteristics In Stable Coronary Artery Disease: A Multimodality Imaging Study (The Yellow III Study)

Dr. Numan Kılıç

Introduction
It is known that the risk of recurrent cardiovascular events continues in patients with coronary artery disease despite high-dose statin therapy.

Intention
It was aimed to investigate the effects of 26-week evolucumab treatment on coronary plaque morphology in stable coronary artery patients receiving maximally tolerated statin therapy, by intravascular imaging methods such as OCT, NIRS/IVUS, and gene expression analysis of peripheral blood mononuclear cells.

1. Endpoint:

• Evaluation of minimal fibrous head thickness change with OCT.
• Evaluation of the maximal lipid core damage index (maxLCBI4mm) change at 4 mm depth by NIRS.

2. Endpoint:

• Evaluation of maximal lipid angle, length, volume index, macrophage accumulation and calcification change with OCT
• Evaluation of percent atheroma volume (PAV) and total atheroma volume (TAV) with IVUS
• Evaluation of variation of PBMC gene expression

Methods:
Stable coronary artery patients with or without PCI taken to the catheter laboratory, after taking the highest tolerated dose of statins for at least 4 weeks, 30-50% (non-responsible lesions) stenosis was evaluated with OCT. Patients with a maximum lipid angle greater than 90 degrees and a Minimal FCT less than 120 μm were included in the study and their baseline evaluations were made with NIRS/IVUS. 140 mg of Evolocumab added to statin therapy every other week for 26 weeks. At the end of 26 weeks, the lesions were reevaluated with OCT, NIRS/IVUS. The patients were clinically evaluated at the first, sixth, and twelfth months. PBMC transcriptomic analysis was performed at baseline and follow-up of the study.

Results:
Screening was performed by including 329 patients in the study. 192 were excluded, 94 did not meet criteria for LDL-C, 84 did not have a suitable coronary angiographic lesion , 14 had lipid plaque FCT <120. In the follow-up of 137 patients, 27 patients were excluded from the study for various reasons(death, non-prosecution, drug non-compliance, withdrawal of consent). 110 patients were followed for 26 weeks and 7 statin intolerances were observed during this period. The decrease in LDL-C and total cholesterol was significant in the follow-up of the patients, p <0.01. Minimal FCT, maxLCBI4mm change was significant, p<0.01. Among the secondary endpoints, maximum lipid angle, lipid length, lipid volume index, maximum macrophage angle, macrophage length were observed to change significantly, p<0.01.

Outcome
Significant increase in minimum FCT in OCT with the addition of evolocumab for 26 weeks to maximum dose statin therapy in stable coronary artery patients; NIRS max was LCBI4mm and angiographically non-occlusive lesions showed a decrease in atheroma plaque volume as assessed by IVUS.

Initial multiple imaging evaluations of non-obstructive lesions in patients with low baseline LDL-C were supportive of aggressive lipid-lowering therapy in the general population. FCT thickening was not observed in 20% of the patients at 6-month clinical follow-up, and LCBI decrease was not observed in 24%. PBMC transcriptomic data will reveal subjective data to generate predictive models about the effect of treatment based on PCSK9 inhibition on plaque morphology.

Comment
Evolocumab treatment for 26 weeks added to intensive statin therapy in stable coronary artery patients with non-obstructive lesions was evaluated. This treatment regresses the atheroma plaque, increases the fibrous cap thickness, decreases LDL-C and total cholesterol values. In addition, it provides a decrease in maximum lipid angle, decrease in lipid length, decrease in lipid volume index, maximum macrophage angle, macrophage length and decrease in macrophage volume index. With these effects, it reduces unstable sensitive plaques from 48% to 13%.