Add-on evolocumab improves plaque characteristics in statin-treated CAD patients

In individuals with stable coronary artery disease (CAD), intensifying their lipid-lowering regimen with evolocumab, a PCSK9* inhibitor, led to improvements in coronary plaque characteristics on intravascular imaging, findings from the YELLOW III trial have shown.

“[Our study showed that] in patients with stable CAD on maximally tolerated statins, more intensive lipid-lowering with the addition of evolocumab for 26 weeks resulted in significant and substantial increase in minimum fibrous cap thickness (FCT) by OCT** and reductions in maxLCBI_4mm*** by NIRS** and in atheroma volume by IVUS** in angiographically nonobstructive lesions,” said Dr Annapoorna Kini from Mount Sinai Hospital, New York, New York, US, at ACC.23/WCC.

OCT-related minimum FCT increased from 70.9 µm at baseline to 97.7 µm at the week-26 follow-up, yielding a significant absolute change of 26.8 µm (p<0.001). Fibrous cap increased in 80 percent of patients. About half of the cohort (n=53) had FCT <65 µm at baseline; by week 26, this number was down to 14 (p<0.001). [ACC.23, abstract 403-14]

Further FCT stratification revealed that 61 percent of participants had FCT >84 µm, 33 percent had FCT 55–84 µm, while only 6 percent had FCT <54 µm.

NIRS maxLCBI_4mm, another important imaging endpoint, dropped substantially from baseline to week 26 (-93.7; p<0.001). Three-quarters of participants had a decreased maxLCBI_4mm.

Regarding secondary imaging endpoints, all lipid and macrophage parameters^# by OCT dropped from baseline to follow-up (p<0.001 for all), which denote improvement, said Kini. Absolute change in total atheroma volume by IVUS between the two timepoints was significant (-6.0 mm³; p<0.001), as was absolute change in lesion LCBI by NIRS (-49.6; p<0.001).

Apart from the imaging improvements, there was a significant reduction in LDL-C^## from baseline to follow-up (from 96.8 to 39.1 mg/dL; p<0.001). For total cholesterol and HDL-C^##, the respective absolute changes were -64.0 mg/dL (p<0.001) and 1.8 mg/dL (p=0.05).

From YELLOW I to III

There remains a considerable residual risk of cardiovascular events in patients with stable CAD despite high-intensity statin therapy, Kini stressed. “PCSK9 inhibitors have reduced this risk.”

In YELLOW I, Kini and team randomized patients with obstructive coronary disease to standard of care or rosuvastatin 40 mg daily for 6–8 weeks. “We saw a reduction in LCBI with aggressive lipid therapy, [but there were] no changes in FFR^### or IVUS parameters on follow-up.”

“We wanted to understand how plaque morphology changes, so we proceeded with YELLOW II, wherein we again evaluated patients with obstructive coronary lesions,” she continued. This cohort included patients with LCBI ≥150, and they were all given daily rosuvastatin 40 mg for 8–12 weeks. “We found an increase in FCT by OCT, which correlated with an increase in cholesterol efflux and a decrease in [C-reactive protein].”

The team then moved on to YELLOW III to determine the effect of 26 weeks of evolocumab on coronary plaque morphology using multimodality imaging. They enrolled patients with stable CAD undergoing cardiac catheterization or angioplasty who were at least 4 weeks on maximally tolerated statins. Nonobstructive coronary lesions were identified on angiogram in a non-culprit vessel.

Lipid-rich plaque was a very important criteria, underscored Kini. “Maximum lipid arc had to be >90° and minimal FCT had to be ≤120 µm. If [they met these criteria], patients were included in the trial, and they underwent OCT and NIRS/IVUS of the study lesion.” Participants were instructed to take evolocumab 140 mg Q2W on top of their statins for 26 weeks. Of the 137 enrolees (mean age 66 years, 72 percent male), 110 completed follow-up.

“We had a very high-risk patient population,” said Kini. Most (n=69) had single-vessel disease. Fifteen patients had nonobstructive coronary disease.

“[YELLOW III is the] first multimodality imaging report in stable patients with nonobstructive lesions and lower levels of LDL-C at baseline (compared with previous trials) that further supports aggressive lipid-lowering in this patient population,” Kini concluded.