Intensive lipid lowering with a regimen of statins plus a PCSK9 inhibitor in the 12 months after an acute coronary syndrome (ACS) appears to have benefits in modulating plaque phenotype, which is likely to lead to early reductions in cardiovascular risk, according to results from HUYGENS, presented Friday at the virtual European Society of Cardiology Congress 2021 by investigator Stephen J. Nicholls, MBBS, PhD.
The Amgen-sponsored study investigated the effects of treatment with its PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, evolocumab, with maximally tolerated statin therapy versus placebo and maximally tolerated statin fibrous cap thickness (FCT) in subjects with non-ST-elevation acute coronary syndrome (NSTE-ACS).
Many patients are not treated with intensive lipid-lowering agents, nor do they achieve low-density lipoprotein cholesterol (LDL-C) goals after an ACS, Nicholls, from Monash University, Melbourne, Australia, noted during his presentation.
This is despite established clinical benefits, including intravascular ultrasound (IVUS) trials showing that high intensity statins with or without PCSK9 inhibitors result in plaque regression, he said, adding that the degree of benefit is directly proportional to LCL-C lowering in these data.
Nevertheless, despite plaque vulnerability playing an important role in driving residual cardiovascular risk, the impact of lipid lowering is unknown, Nicholls said.
HUYGENS was, therefore, set-up to determine the impact on plaque phenotype post-ACS of adding the PCSK9 inhibitor evolocumab to statin therapy, with the primary endpoint of changing the minimum FCT. Secondary endpoints included percent change in minimum FCT, change in average minimum FCT and change in maximum lipid arc.
The study recruited 161 patients – of whom 135 were “completers,” undergoing OCT imaging at week 50 – with non-ST segment elevation myocardial infarction (NSTEMI), angiographic coronary artery disease (CAD), and qualifying LDL-C levels dependent on prior use of statin therapy (LDL-C of ≥60 mg/dL on high-intensity statins, ≥80 mg/dL on low or moderate statins, or ≥130 mg/dL on no statins at screening), at baseline.
Subjects also had a target segment on optical coherence tomography (OCT) imaging containing at least one image with a FCT less than 120 μm and one image with a lipid arc greater than 90°.
Mean age of the patients at baseline was 60 years, the majority were male and a high prevalence of risk factors was observed, said Nicholls, including diabetes and smoking. Nearly one quarter of patients had been treated with a statin at least 4 weeks prior to their NSTEMI, he added.
Patients were randomized in a 1:1 fashion to either 420 mg of evolocumab or matching placebo via monthly sub-cutaneous injection for 1 year, in addition to background lipid-lowering statin therapy. Most statin therapy during the 12 months of the trial was high-intensity, Nicholls said (82.7% of placebo group and 78.8% on trial drug).
After baseline imaging, the patients underwent OCT imaging at week 50 to evaluate changes in plaque phenotype, performed on cross-sectional images spaced 0.2 mm apart throughout a matched arterial segment.
It showed an absolute change in minimum FCT of +21.5 μm in placebo versus +42.7 μm in the evolocumab group (P=0.015). Percentage change in minimum FCT was +44.3% for placebo versus +81.8% in the study drug group (P = 0.04).
Mean minimum FCT was +29.8 μm for placebo, compared to +62.3 μm for evolocumab. “This reflects a greater generalized thickening of fibrous cab throughout the length of the vessel segment imaged,” said Nicholls.
Extended lipid arc was also measured in each image showing benefits over the addition of evolocumab to statin treatment, with a decrease of 57.5 degrees versus 31.4 degrees in placebo.
Meanwhile, LDL-C dropped from the average baseline measurement of 142.1 mg/dL for placebo and 140.4 mg/dL in the evolocumab group, to 87.2 mg/dL and 28.1 mg/dL, respectively (P<0.01).
“Together, these findings demonstrate a clear and unequivocal benefit of adding evolocumab to background statin therapy on plaque phenotype throughout the segment,” said Nicholls.
In an additional analysis, the investigators looked at the percentage of patients with any evidence of an image with a minimum FCT below 65 μm at the end of the study.
“We observed such images, known to be associated with an increased propensity to plaque rupture, in 30.2% of patients treated with statin plus placebo, but only 12.5% of patients treated with statin plus evolocumab,” Nicholls said.
“The findings suggest that vulnerable plaques can be stabilized after an ACS,” he noted, adding that they should “further motivate the use of intensive lipid lowering regiments in patients following an ACS.”
In a panel discussion following the session, Michael Joner, MD, of the Technical University of Munich, called the results “striking” as “for the first time, we see a direct effect of lipid lowering on plaque phenotype.”
Nicholls concluded that the results “really suggests to us that starting intensive lipid lowering early, and actually getting patients to continue that intensive lipid lowering throughout the 12 months, is what is going to maximize the potential to be able to stabilize plaques and we think that will ultimately lead to regression of disease and a reduction in cardiovascular risk.”