Cardiovascular Disease, Imaging
Watch Time: 7 mins

Annapoorna Kini, ACC 2023: Evolocumab in patients with stable coronary artery disease, the Yellow III study

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Published Online: Mar 30th 2023

The Yellow III study aimed to assess the effect of evolocumab in combination with statins on plaque morphology in patients with stable coronary artery disease. In this touchCARDIO interview, we speak with Dr Annapoorna Kini (Cardiac Catheterization Laboratory, Mount Sinai Medical Centre, New York, NY, USA) to discuss the Yellow series, with focus on the Yellow III aim, results and clinical impact. 

The abstract entitled ‘Effect Of Evolocumab On Coronary Plaque Characteristics In Stable Coronary Artery Disease: A Multimodality Imaging Study (the Yellow III Study)’ (Abstract number 403-14) was presented at ACC.23 Together With WCC (ACC.23/WCC) in New Orleans, 4–6 March 2023. 


  1. What are the aims, design, and eligibility criteria of the Yellow III study? (0:24)
  2. What were the primary and secondary endpoints and how well were they achieved? (4:22)
  3. What was unique about the methodology of this study and what is the clinical benefit? (5:44)

Disclosures: Annapoorna Kini has received grant/research support from Amgen for the YELLOW III study.

Support: Interview and filming supported by Touch Medical Media. Interview conducted by Danielle Crosby.

Filmed as a highlight of ACC 2023

Access more content on Imaging here and Cardiovascular Disease here



Good morning. I’m Dr Annapoorna Kini. I’m director of the Cath lab at Mount Sinai Medical Center in New York City. I’m also Professor of Medicine in the Icahn School of Medicine here in New York.

Q. What are the aims, design, and eligibility criteria of the Yellow III study?

We did have a yellow series. In the yellow one, we randomized to different statins. We started with low statin compared with high statin, which was rosuvastatin. We showed that rosuvastatin, a higher dose statin, was much better in reducing the lipid core burden index (LCBI), which is a test that we do in the arteries. 

Then in the yellow two, we wanted to exactly understand how the so-called LCBI, or the lipid in the plaque, is removed. There is a good cholesterol called HDL. HDL works like a suction. Cholesterol efflux, takes cholesterol out of the plaque. So we studied that. Then also we studied the gene expression on these patients that when given statins, what exactly happens, why, what happens to their genetic profile? We found that cholesterol efflux goes up in patients when they take statins, the lipid in the plaque reduces. Also we found the genes that regulate the cholesterol mechanism, which I just mentioned all the various steps of the cholesterol mechanism (video 1), the genes related to that cholesterol, genes related to cholesterol efflux. That is a plaque and on top of that, what is called a fibrous cap. Gene related to the fibrous cap improvement, all those were upregulated. So that was yellow two. 

In yellow three, we already knew statins work by which time PCSK9 has been introduced into the market. How does PCSK9 work on stable patients? So that is what’s different. Why we started on a stable patient was because the so-called acute coronary syndrome population is very small. The majority of the patients are stable coronary artery disease patients. What exactly happens in their plaque when they take PCSK9? That was the aim of the yellow three study. 

The design was that we included patients who were coming for an angiogram. After the angiogram, we wanted to make sure they do have some disease, like a plaque 30%–50% disease. Once we found that, then they had to be on statin for 4 weeks to make sure that LDL was controlled on statin. That is the current guidelines, that before you give PCSK9, you have to make sure you give statin. If on statin and the LDL is still high, only then you can give PCSK9. Then we made sure we did another imaging, which is called an optical coherence tomography (OCT) scan to understand – as I was talking about the plaque is covered by a cap that is called a fibrous cap – how the fibrous cap is and how much lipid is there? We have certain criteria, if they met the criteria, then the patient got enrolled. Then we give evolocumab, which is 140 milligrams subcutaneously every 2 weeks for 26 weeks. They came back and we just did the imaging inside their body. So that was the design. 

So to say who were eligible, we wanted to make sure that they were on statin. They still had to have certain high level of LDL on statin. Once we knew that was a number, they were the one that we consented and then did this imaging work. By that imaging we had, again, some inclusion exclusion criteria. They had to meet the inclusion criteria and then only they got evolocumab. It was a very intense study. About 137 patients were enrolled and about 110 patients actually came back. So we did the imaging when they came back after 26 weeks.

Q. What were the primary and secondary endpoints and how well were they achieved?

The primary endpoint was the imaging endpoint, which was based on the OCT. We wanted to make sure that the fibrous cap was thick, that was one. The other was that the near-infrared spectroscopy (NIRS) LCBI had to go down. The secondary endpoints were intravascular ultrasound (IVUS) endpoints and other OCT imaging endpoints that were part of the trial. All imaging endpoints were met in this trial, which was good. We were happy when we presented that and we showed that the fibrous cap, which was about 70.9 at the baseline improved, meaning it became thick. Once the fibrous cap becomes thick, the plaque becomes stable, which means it will not rupture and cause a myocardial infarction. So it became like 97.7, which was an absolute change of 26.8 micron. That was a big number. About 20% of the patients did not change the fibrous cap and we called them ‘non-responders’. Even in the NIRS, we saw a big decrease. But about 24% of the patients did not respond to PCSK9, termed ‘non-responders’.

Q. What was unique about the methodology of this study and what is the clinical benefit?

We did it on stable patients. As I mentioned in the yellow one and yellow two, we used statin, so we do have the gene expression data on the starting patients. Now from this study, the genetic expression we have just done by using the microRNA, which comes from the DNA expression and is always changing in people as opposed to the DNA of the body that cannot be changed. That microRNA analysis is ongoing. 

What is unique about this is we did it on stable patients, and we did it on statin and now we are doing it on PCSK9. We are the only ones that have this kind of gene expression data on these patients with statin and PCSK9. We will understand who exactly are the responders to statin, who are responders to PCSK9 and who are non-responders. Our goal is that if we can actually come up with a biomarker, then we can potentially come up with some kind of indication saying who should get statin and who should get PCSK9 directly. That can help the scientific community and that is the clinical benefit. That can also change into what is called ‘precision medicine’ or ‘personalized medicine’ that we talk about. It is not a one size fits all. Therefore, when you see a doctor, maybe we can come up with a blood test on a biomarker, that when we do that, then we can personalize the medicine for that particular patient.

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