Efficacy of Evolocumab Therapy in Patients with Acute Coronary Syndrome in the Very Early Phase for Reducing Plaque Vulnerability Assessed by Optical Coherence Tomography

Research Article

Austin J Clin Cardiolog. 2022; 8(1): 1089.

Efficacy of Evolocumab Therapy in Patients with Acute Coronary Syndrome in the Very Early Phase for Reducing Plaque Vulnerability Assessed by Optical Coherence Tomography

Yano H¹*, Horinaka S², Fukushi T¹, Miyaishi Y¹, Kuribara J¹, Kawaguchi R¹ and Naito S¹

¹Department of Cardiology, Gunma Prefectural Cardiovascular Center, Maebashi, Gunma, Japan

²Department of Cardiology and Nephrology, Dokkyo Medical University, Mibu, Tochigi, Japan

*Corresponding author: Hideki Yano, Department of Cardiology, Gunma Prefectural Cardiovascular Center, Maebashi, Gunma, 371-0004, Japan

Received: February 23, 2022; Accepted: March 15, 2022; Published: March 22, 2022


Background: Proprotein convertase subtilisin/kexin type 9 inhibitor, evolocumab, has been demonstrated to produce significantly greater reduction in LDL cholesterol levels and cardiovascular events than standard statin therapy in patients with coronary artery disease. Whereas, effect on fibrouscup thickness or extension of the atherosclerotic plaque with early therapy with PCSK9-inhibitor within 1-week after onset of Acute Coronary Syndrome (ACS) has never been reported.

Methods: Patients were non-randomly allocated to either the early evolocumab group (received evolocumab 140 mg every 2 weeks within 1-week after onset of ACS) or the late evolocumab group (from 4-week after onset of ACS). Optical Coherence Tomography (OCT) was performed to assess intermediate, non-culprit lesions just 4 and 36 weeks after emergent percutaneous coronary intervention.

Results: The decrease in Low-Density Lipoprotein Cholesterol (LDL-C) was greater in the early than in the late group between baseline and 4-week followup (reduction rate: -69.4% vs. -32.5%). However, the percentage of decrease in LDL-C was comparable in the two groups between baseline and 36-week follow-up. OCT analysis revealed that the increase in fibrous-cap thickness was greater in the early than in the late group between baseline and 4-week followup (early evolocumabgroup: +32μm, late evolocumab group: +18um). However, the percentage of increase in fibrous-cap thickness increased comparably in the 2 groups between baseline and 36-week follow-up.

Conclusions: Evolocumab therapy in the very early phase produced incremental growth in fibrous-cap thickness, which was associated with greater reduction of LDL-C even in the short term in the early phase of ACS compared to the late evolocumab group.

Keywords: Evolocumab; Optical coherence tomography; Fibrous cap thickness; Plaque stabilization


LDL-C: Low-Density Lipoprotein Cholesterol; ACS: Acute Coronary Syndrome; IVUS: Intravascular Ultrasound; OCT: Optical Coherence Tomography; PCSK9: Proprotein Convertase Subtilisin/ Kexin Type 9; PCI: Percutaneously Coronary Intervention; STEMI: ST-segment Elevation Myocardial Infarction; NSTEMI: Non-STSegment Elevation Myocardial Infarction; TCFA: Thin-Cap Fibro Atheroma


Several large-scale, multicenter, randomized trials have shown the importance of Low-Density Lipoprotein Cholesterol (LDL-C) regulation with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, on the risk of cardiovascular events or death [1,2].

Previous clinical trials have shown that although patients experience the highest risk of death and recurrent is chaemic events in the early Post-Acute Coronary Syndrome (ACS) period, these early events can be reduced by early onset of statin therapy [3,4].

The imaging studies using grayscale Intravascular Ultrasound (IVUS) have reported that statin therapy results in major suppression [5], or even regression, of Atheroma volume in the atherosclerotic coronary arteries [6]. However the grayscale IVUS is appropriate for plaque volume evaluation, it does not have the spatial resolution to accurately measure the thickness of the fibrous cap. Unlike other imaging modalities, intravascular Optical Coherence Tomography (OCT) is a high-resolution imaging technique for plaque characterization. OCT can evaluate the measurement of fibrouscap thickness, thought to be a major factor in plaque vulnerability [7]. Previous study demonstrated that more potent lipid-lowering therapy by statin in patients induces significant plaque regression and, by decreasing plaque lipid content and increasing plaque fibrous cap thickness, induces plaque stabilization [8]. Besides, the fibrouscap thickness was demonstrated to be increased by the aggressive ipid-lowering therapy with statin after acute myocardial infarction [9]. However, in a high CV risk population in a routine care setting in Japan, a previous study reported that guideline recommended LDL-C goal attainment was low. In addition, physicians should emphasize the need for more potent lipid-lowering therapy in this population [10].

Therefore, a beneficial increase in fibrous-cap thickness after statin treatment may be established to translate into substantial decreases in clinical events as a benchmark for future investigational agents that target plaque instability.

Then evolocumab, a fully human monoclonal antibody that inhibits Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) from binding to LDL receptors on the liver surface, significantly have emerged as a novel treatment option for effectively lowering LDL-C levels by approximately 60% [11]. Further research data reported that PCSK9 might also accelerate atherosclerosis by promoting inflammation, endothelial dysfunction, and hypertension by mechanisms beyond degradation of hepatic LDL receptors [12,13].

In the Global Assessment of plaque regression with a PCSK9 antibody as measured by an intravascular ultrasound (GLAGOV) trial, among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in percent atheroma volume [14]. Additionally, recent randomized multicenter trials clearly demonstrated that use of a PCSK9 inhibitor was associated with a significantly reduced incidence of adverse clinical events in patients with high-risk stable coronary artery disease [15] or ACS [16]. Recently, we reported that adding the PCSK9-inhibitor evolocumab to statin therapy might produce incremental growth in fibrous cap thickness and regression of the lipid-rich plaque after ACS [17]. However, as mentioned above, the risk of death and recurrent ischaemic events in ACS patients is highest in the early post-onset period. Then it is still unclear whether the timing of the introduction of evolocumab will have an effect on plaque regression. In particular, the effect of very early PCSK9- inhibitor evolocumab therapy on plaque vulnerability in patients with ACS remains unknown compared to the late evolocumab group. Because of that, the aim of the present study was to assess the effect of very early PCSK9 inhibitor evolocumab therapy on fibrous-cap thickness in coronary atherosclerotic plaques of patients with ACS by using OCT.

Materials and Methods

Study patients and design

This study was a retrospective, non-randomized, observational, two centers (Dokkyo Medical University Hospital and Gunma Prefectural Cardiovascular Center) study. From March 2017 to 2021 Apr, June, all consecutive patients with multivessel disease who had untreated dyslipidemia (defined as serum LDL-C level >100mg/dL) and received emergent Percutaneously Coronary Intervention (PCI) after ACS and OCT imaging were evaluated. Of these, data from 56 patients using OCT to compare the effect of PCSK9 inhibitor evolocumab therapy on fibrous-cap thickness in coronary atherosclerotic plaque between an early evolocumaband late evolocumab groups were extracted. All patients were treated with rosuvastatin 5mg once daily from baseline (within 24h after the OCT examination) for aggressive lipid-lowering therapy, which is a secondary prevention of ACS. Patients in the early evolocumab group received evolocumab (140mg every 2 weeks) within 1 week after onset of ACS, whereas patients in the late evolocumab group received evolocumab (140mg every 2 weeks) from 4 weeks after baseline.

After receiving informed consent, we performed staged PCI for the residual lesion 4 weeks after emergent PCI and conducted follow-up coronary angiography 36 weeks thereafter. The follow-up target lesions of the OCT analysis were de novo, intermediate, and nonculpritcoronary lesion in patients with ACS. Five patients were excluded (one patient refused, and four patients failed OCT analysis), and the remaining 51 patients were fully examined in this study (Figure 1).

In this study, ACS is defined as ST-Segment Elevation Myocardialinfarction (STEMI), Non-ST-Segment Elevation Myocardial Infarction (NSTEMI), or unstable angina. The follow-up target lesion of the OCT analysis had a diameter stenos is percentage of 30% - 70% by visual estimation on angiogram. If more than two de novo, intermediate, or non-culprit lesions were recognized, the most severely stenotic lesion was selected as the target lesion in the OCT analysis. The target lesion could be in both the PCI-treated and non-PCI-treated coronary arteries, where the target lesion was >10mm apart. Exclusion criteria included left main trunk lesions, cardiogenic shock, recommended coronary artery bypass grafting, severechronic kidney disease, unsuccessful PCI, and current use of any lipid-lowering therapy.

OCT image protocol and analysis

OCT was performed using the ILUMIEN OCT imaging system (Abbott Vascular, Santa Clara, CA, USA) with a motorized pullback system at 20mm/s and a rotation speed of 100frames/s, using a non-occlusive technique. The OCT images were digitally stored for offline analysis. The OCT images were obtained and reviewed side by side at baseline, 4-week follow-up, and 36-week follow-up. Target lesions between baseline and follow-up OCT were matched based on their distances from landmarks, such as branches and calcifications. Independent, experienced OCT investigators, blinded to the patient groups, measured fibrous-cap thickness using a dedicated offline review system (St. Jude Medical Inc., St. Paul, MN, USA) at the laboratory. The calibration was adjusted before the OCT analysis. The minimum lumen area in each target lesion was determined using an automated measurement algorithm and additional manual corrections. The plaque tissue was characterized using previously validated criteria [18]. The fibrous cap was identified as a lesion with high back scattering and a relatively homogeneous OCT signal. The lipid or necrotic core was identified as a signal-poor region with poorly delineated borders, little or no signal backscattering, and an overlying signal-rich layer, the fibrous cap. The minimum fibrous cap thickness was calculated using a previously reported method [19]. In brief, the fibrous cap thickness of each lipid-rich plaque was measured, first at 1mm intervals over the lipid plaque then three times at its thinnest part at each cross-section, and the average value was calculated. Minimum fibrous cap thickness was determined as the smallest fibrous cap thickness in the three candidate frames selected by manual screening (Figure 2). The maximum lipid arc was defined as the largest lipid arc from the center of the lumen in the three candidate frames selected by visual screening (Figure 2). Although the fluctuation by the OCT catheter position could be influenced by the largest lipid arc, a frame was selected to be as similar as possible to the side branch and the lesion morphology, and the center of the lumen was determined to measure the largest lipid arc. Lipid length was calculated from the number of frames with lipid cores.