Virtual histology does not reveal PCSK9 inhibition-induced changes in plaque composition

Effect of Evolocumab on Coronary Plaque Composition

Literature - Nicholls SJ, Puri R, Anderson T et al. - J Am Coll Cardiol. 2018; 72. DOI: 10.1016/j.jacc.2018.06.078

Introduction and methods

PCSK9 regulates cholesterol homeostasis by inhibiting recycling of LDL receptors to the hepatocyte surface [1-3]. It has recently been demonstrated that incremental lowering of LDL-c with the PCSK9 antibody evolocumab resulted in regression of coronary atherosclerosis in statin-treated patients on serial intravascular ultrasound (IVUS)[4].

Plaques associated with acute coronary syndromes often contain lipid, inflammatory and necrotic material [5], a phenomenon that is referred to as vulnerable plaques. Efforts are made to identify high-risk plaques and to search for therapies that can induce phenotypic changes in plaques towards stabilization [6]. Ultrasound-determined virtual histology (VH) has been validated for use to assess necrotic, fibrofatty, fibrous and dense calcium components of plaque, as in conventional histology [7].

This prespecified sub-analysis of the GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured By Intravascular Ultrasound) [4,8] study was to use VH analysis to characterize the effects of treatment with evolocumab on the composition of coronary atherosclerosis in patients on optimal statin therapy, in order to determine if VH imaging gives incremental information as compared with volumetric intravascular ultrasound (IVUS). Eligible patients had >20% stenosis on IVUS in a target, nonculprit coronary artery at the time of clinically indicated coronary angiogram, LDL-c ≥80 mg/dL or 60-80 mg/dL if they had either 1 major or 3 minor risk factors for disease progression. Patients were randomized to evolocumab 420 mg SC monthly or placebo for 76 weeks. Two weeks after end of study treatment, an end-of-study IVUS examination was done in the same coronary artery.

Main results

  • LDL-c was lowered by 62.8% (from 90.9 to 33.5 mg/dL) in the evolocumab group, as compared with no change in the placebo-treated patients. More favorable significant changes were also seen with evolocumab vs placebo for HDL-c (+11.6% vs. +7.5%), triglycerides (-11.5% vs. +2.7%) and lipoprotein(a) (-22.7% vs. -2.5%)
  • A significant reduction in percent atheroma volume (PAV) was seen with evolocumab vs. placebo (-1.20% vs. +0.17%, P<0.0001). Total atheroma volume (TAV) also decreased with the PCSK9 inhibitor (-3.6mm³ vs. -0.8mm³, P=0.04).
  • More evolocumab-treated patients showed regression of PAV (68.3% vs. 46.1%, P<0.0001) and TAV (64.6% VS. 53.3%, p=0.04).
  • No significant differences were seen between treatment groups with regard to changes in dense calcium, fibrous, fibrofatty and necrotic core volumes.
  • No significant differences were seen between treatment groups with regard to nominal changes in the percentage of plaque occupied by dense calcium, fibrous, fibrofatty, and necrotic core.
  • In the primary GLAGOV analysis, patients with baseline LDL-c <70 mg/dL showed nominally greater plaque regression upon treatment with evolocumab. Exploratory analyses in this subgroup showed no significant difference between treatment groups in change in necrotic core volume, although a significant reduction was seen with evolocumab (-2.9 mm³, vs. +0.4 mm³ with placebo, P=0.08 for comparison of groups). The volume of fibrofatty or fibrous material did not significantly differ between groups either.


This study confirmed that treatment with evolocumab to statin-treated patients yielded robust LDL-c lowering and regression of coronary atherosclerosis. No significant differences in plaque composition were detected by VH imaging between treatment groups. This is the largest serial VH analysis performed to date, and the lack of detected differences in plaque composition suggests that the VH imaging technique fails to characterize any potential additional benefits of lipid-lowering therapies.

Editorial comment

In an editorial comment [8], Stone et al. discuss the utility of radio-frequency (RF) IVUS for detection of vulnerable plaques and for guidance of treatment of these plaques and vulnerable patients, both on the study by Nicholls and colleagues, and on a study by Schuurman et al. on the 5-year outcomes of AtheroRemo-IVUS (The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis–Intravascular Ultrasound) [9]. We refer to the editorial comment for a critical appraisal of this technique and arguments for why it may not be of sufficient added value for named purposes.


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