Imaging data may predict best responders to evolocumab therapy: YELLOW III
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NEW ORLEANS — In adults with stable CAD on maximally tolerated statin therapy, more intensive lipid lowering with evolocumab was associated with favorable coronary plaque characteristics seen on multiple CV imaging modalities, data show.
For the YELLOW III trial, presented at the American College of Cardiology Scientific Session, patients with nonobstructive lesions prescribed evolocumab (Repatha, Amgen) underwent imaging via OCT, IVUS and near-infrared spectroscopy (NIRS).
“What we found was that [fibrous cap] thickness definitely improved, as well as plaque volume,” Annapoorna S. Kini, MD, director of The Mount Sinai Hospital’s cath lab, told Healio. “To understand what is going on, you need the three imaging modalities.”
Imaging to show treatment response
Despite high-intensity statin therapy, there is considerable residual risk for CV events among adults with CAD, Kini said during a featured clinical research presentation.
In YELLOW III, Kini and colleagues analyzed data from 137 adults with stable CAD with nonobstructive coronary lesions who underwent cardiac catheterization plus PCI; patients were prescribed maximally tolerated statin therapy for at least 4 weeks. The mean age of participants was 66 years; 71.5% were men and 129 were prescribed statins at baseline (71% high intensity; 29% moderate intensity). Recruitment took place between May 2021 and May 2022.
Participants underwent multimodality intracoronary imaging with OCT, IVUS and NIRS. After enrollment, all participants received evolocumab 140 mg every 2 weeks for 26 weeks.
Researchers reimaged the target lesion at 26 weeks to assess the change in plaque composition and morphology. Researchers also conducted gene expression analysis of peripheral blood mononuclear cells (PBMCs) using blood samples from baseline and follow-up for transcriptomic profile in PBMC by targeting 50 million reads per cell using conventional bulk RNA sequencing.
Primary endpoints were the nominal changes in OCT-defined minimal fibrous cap thickness and lipid core burden index at the maximal 4 mm segment by NIRS of the nonobstructive coronary lesion after 26 weeks. Secondary endpoints were the changes in lipid and macrophage content by OCT, percent atheroma volume and total atheroma volume by IVUS.
After 26 weeks of treatment, researchers observed a significant and substantial increase in minimum fibrous cap thickness, a reduction in the lipid core burden index and a reduction in percent atheroma volume. Minimal fibrous cap thickness increased from a mean baseline value of 70.9 µm to 97.7 µm (change, 26.8 µm; P < .001). Lipid core burden index fell from 306.8 to 213.1 (change, –93.7; P < .001). Total atheroma volume decreased from 137.2 mm3 to 131.2 mm3 (change, –6 mm3; P < .001).
At 6 months, 20% of participants did not demonstrate fibrous cap thickness thickening and 24% did not experience a reduction in lipid core burden index.
Researchers also found that observed changes in plaque morphology by OCT and NIRS were correlated with changes in PBMC gene expressions as a result of evolocumab therapy, Kini said.
The unique combination of IVUS and transcriptomic analysis of PBMC in YELLOW III will allow researchers to uncover molecular mechanisms responsible for the beneficial changes in atherosclerotic lesions of patients treated with evolocumab, Kini said. That data, in turn, can predict who will and will not likely respond to the therapy. Ongoing analysis from YELLOW III will include changes in PMBC gene expression after receiving evolocumab therapy.
“We still found that in about 20% of patients, their cap thickness did not improve,” Kini said in an interview. “That is why the genetic analysis, once it is completed, will give us an idea of why these patients did not respond. What is different? We may be able to figure that out soon.
“The goal is that we will have a predictive model for understanding who the responders to these therapies are,” Kini told Healio. “Then, we can have personalized medicine. I hope with this genetic analysis to come later, we can create personalized medicine, determining who needs a statin vs. who needs a PCSK9 inhibitor vs. who needs combination therapy.”
Perspective
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Manesh R. Patel, MD, FACC, FAHA, FSCAI
When I look at the findings from YELLOW III, it makes me feel confident that most of what we are trying to do — which is to get LDL as low as possible — has biologic plausibility. The LDL for this cohort was 96 mg/dL to start, and then after adding evolocumab, LDL could go down to 40 mg/dL. These data are valuable because both NIRS and OCT imaging show an improvement in fibrous cap thickness. This is also a novel study design because the researchers looked at nonobstructive lesions.
I always want to know of new ways to best determine who is and who is not a responder; however, I am cautious about making treatment decisions based on imaging response. That said, I do think this is an important study, as it gives me more biologic plausibility for lowering LDL to improve outcomes.
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Kini AS, et al. Featured Clinical Research I. Presented at: American College of Cardiology Scientific Session; March 4-6, 2023; New Orleans (hybrid meeting).
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