Author + information
- Received May 18, 2018
- Revision received June 25, 2018
- Accepted June 27, 2018
- Published online October 15, 2018.
- Stephen J. Nicholls, MBBS, PhDa,b,∗ (, )@sahmriau@SAHMRI_Heart,
- Rishi Puri, MBBS, PhDb,
- Todd Anderson, MDc,
- Christie M. Ballantyne, MDd,
- Leslie Cho, MDb,
- John J.P. Kastelein, MD, PhDe,
- Wolfgang Koenig, MDf,
- Ransi Somaratne, MDg,
- Helina Kassahun, MDg,
- Jingyuan Yang, PhDg,
- Scott M. Wasserman, MDg,
- Satoshi Honda, MDa,
- Daisuke Shishikura, MD, PhDa,
- Daniel J. Scherer, MBBSa,
- Marilyn Borgman, RN, BSNb,
- Danielle M. Brennan, MSb,
- Kathy Wolski, MPHb and
- Steven E. Nissen, MDb
- aSouth Australian Health and Medical Research Institute, University of Adelaide, Adelaide, South Australia, Australia
- bDepartment of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio
- cLibin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- dSection of Cardiovascular Research, Baylor College of Medicine and the Methodist DeBakey Heart and Vascular Center, Houston, Texas
- eDepartment of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- fDeutsches Herzzentrum München, Technische Universität München, Munich, DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Department of Internal Medicine, University of Ulm Medical Center, Ulm, Germany
- gAmgen Inc., Thousand Oaks, California
- ↵∗Address for correspondence:
Dr. Stephen J. Nicholls, South Australian Health and Medical Research Institute, P.O. Box 11060, Adelaide, South Australia 5001, Australia.
Background Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated patients.
Objectives The purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition.
Methods A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal.
Results Compared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (−1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (−3.6 mm3 vs. −0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (−3.0 ± 0.6 mm3 vs. −2.4 ± 0.6 mm3; p = 0.49), fibrofatty (−5.0 ± 1.0 mm3 vs. −3.0 ± 1.0 mm3; p = 0.49), and necrotic (−0.6 ± 0.5 mm3 vs. −0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = −0.15; p < 0.001).
Conclusions The addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422)
Proprotein convertase subtilisin kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis by inhibiting recycling of the low-density lipoprotein (LDL) receptor to the hepatocyte surface (1–3). The monoclonal anti-PCSK9 antibody evolocumab substantially lower LDL cholesterol when administered as monotherapy or combined with statins (4,5). Serial intravascular ultrasound (IVUS) imaging has recently demonstrated that incremental lowering of LDL cholesterol to very low levels with the PCSK9 inhibitor evolocumab produces regression of coronary atherosclerosis in statin-treated patients (6). This finding extends prior observations that LDL lowering reduces the burden of coronary atherosclerosis in proportion to achieved LDL cholesterol levels (7–10).
The favorable effects of LDL cholesterol-lowering agents on coronary atheroma volume are supported by observations that the burden and progression of coronary atherosclerosis are associated with adverse cardiovascular outcomes (11,12). There remains considerable interest in characterizing the effect of medical therapies on plaque composition, based on necropsy findings that plaques associated with acute coronary syndromes contain lipid, inflammatory, and necrotic material (13). This phenomenon, termed the vulnerable plaque hypothesis, has led to efforts to identify high-risk plaques and to determine if medical therapies can promote phenotypic changes in plaques that are associated with stabilization (14).
Spectral tissue analysis of the radiofrequency ultrasound backscatter signal acquired during IVUS imaging has been postulated as an approach to distinguish and quantify individual plaque components. Validation studies from ex vivo arterial imaging have demonstrated that ultrasound-determined virtual histology (VH) correlates with necrotic, fibrofatty, fibrous, and dense calcium components of plaque assessed by conventional histology (15). This technique has been used to characterize the clinical features consistent with high-risk plaque phenotypes. In particular, observational studies, but not randomized controlled trials, have suggested that the presence of a thin cap fibroatheroma, identified by VH imaging, is associated with a greater likelihood of adverse cardiovascular outcomes (16). The objective of this analysis 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. This would provide the opportunity to determine if use of VH imaging would provide incremental information in addition to volumetric intravascular ultrasound, a well-validated approach to serial evaluation of antiatherosclerotic agents.
The details of the GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured By Intravascular Ultrasound) trial have been described in detail previously (6,17). Patients were eligible for recruitment if they were age >18 years; were treated with a stable dose of statin therapy for at least 4 weeks; had acceptable IVUS imaging within a target, nonculprit coronary artery at the time of a clinically indicated coronary angiogram demonstrating at least 1 epicardial coronary artery stenosis >20%; and had an LDL cholesterol that was ≥80 mg/dl or between 60 and 80 mg/dl provided that they had either 1 major (noncoronary atherosclerotic cardiovascular disease, acute coronary syndrome or type 2 diabetes) or 3 minor (current smoking, hypertension, low high-density lipoprotein cholesterol, family history of premature cardiovascular disease, age [men ≥50 years, women ≥55 years] or C-reactive protein [CRP] ≥2 mg/l) risk factors for disease progression. All patients underwent IVUS imaging at the time of their clinically indicated coronary angiogram. Patients were randomized to be treated with placebo or evolocumab 420 mg administered subcutaneously monthly for 76 weeks. An end-of-study IVUS examination was performed within the same coronary artery at the 78-week time point of the study (i.e., 2 weeks following the final administration of study drug).
Image acquisition and analysis
The details of image intravascular ultrasound imaging acquisition and analysis have been described in detail previously (6,7,9,10,18–23). Imaging was performed within a single coronary artery at baseline and following 78 weeks of treatment. Core laboratory analysts at the Cleveland Clinic, blinded to treatment status and sequencing of imaging studies (baseline vs. follow-up) defined the leading edges of the lumen and outer vessel wall by manual planimetry in images spaced 1-mm apart and where there is no artifact obscuring >90° of contiguous outer vessel wall, with reproducibility as previously reported (7,9,10,18–23). A number of measures of plaque burden were determined. Percent atheroma volume (PAV) was calculated as follows:where EEMarea is the cross-sectional area of the external elastic membrane and Lumenarea is the cross-sectional area of the lumen. The change in PAV was calculated as the PAV at 78 weeks minus the PAV at baseline. Normalized total atheroma volume (TAV) was calculated as follows:where the average plaque area in each image was multiplied by the median number of images analyzed in the entire cohort to compensate for differences in segment length between patients. Change in normalized TAV was calculated as the TAV at 78 weeks minus the TAV at baseline. Regression of PAV or TAV was defined in any reduction in that parameter from baseline.
VH-IVUS analysis was possible in arteries studied with the 45 MHz rotational catheter (Revolution, Volcano Corporation, Rancho Cordova, California). The radiofrequency signal, captured at the peak of the R-wave, enabled reconstruction of a color coded map distinguishing necrotic core, dense calcium, fibrofatty and fibrotic plaque components. Off-line grayscale and radiofrequency IVUS analysis was performed using echoPlaque 4.0 (Indec Medical Systems, Santa Clara, California). External elastic membrane and lumen borders were contoured for each image gated at the time of the peak of the R-wave, and the acoustic shadow due to the catheter was excluded from plaque analysis. Absolute and percentage plaque measures of each VH parameter was performed using the trapezoidal rule (24–28).
A full statistical analysis plan was written prior to the completion of the image analysis (Online Appendix). Continuous variables were expressed as mean ± SD or median (interquartile range) when not normally distributed. Categorical parameters were expressed as percentage. Biochemical measurements are reported as least-square means (95% confidence intervals) calculated from analysis of covariance models adjusting for region and treatment group. The absolute change in normalized dense calcium volume from baseline to week 78 is the primary VH endpoint. Secondary endpoints included absolute changes in normalized volume for necrotic core, fibrofatty, and fibrous VH measures and nominal changes in percent of plaque based on volume for the 4 VH components.
An analysis of covariance model was used to assess the absolute change in normalized dense calcium volume between treatment groups. The model includes terms for treatment, region, and baseline volume as covariates. Least-square means and corresponding 95% confidence intervals are provided for each treatment (evolocumab and placebo) and for the difference between the treatment groups. Analysis of the secondary endpoints followed a similar methodology as the primary endpoint analysis. The superiority of evolocumab to placebo was assessed for the 4 changes in normalized atheroma volume composition endpoints. Nominal p values were generated and adjusted for multiplicity using the Hochberg method. An additional exploratory analysis was conducted in patients with baseline LDL-C level <70 or >70 mg/dl.
The sample size for the VH substudy was defined by the number of subjects who had evaluable imaging at both time points that enabled analysis of both grayscale and VH data. A sample size of 150 patients/group provides 80% power to detect a change of 0.81 mm3 in normalized dense calcium between the treatment groups, assuming an SD of 2.5 and a 2-sided alpha of 0.05. Of the 342 patients with VH imaging acquired at both time points, 11 were excluded due to imaging quality issues that precluded accurate definition of plaque borders, resulting in 331 patients available for serial analysis. All p values are 2-sided, and p < 0.05 was considered statistically significant. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina).
Patient characteristics and concomitant medication use
The clinical characteristics and concomitant medication use of the 331 patients with evaluable VH images are summarized in Table 1. Patients had a mean age of 59 years, were predominantly male and Caucasian, and had a high prevalence of cardiovascular risk factors. Both groups demonstrated a high rate of use of established medical therapies. In particular, 99% of patients were treated with a statin, of which 59% were high intensity at baseline. No differences were observed between patients with evaluable serial VH imaging and the entire GLAGOV cohort (data not shown).
Biochemical measures throughout the study are summarized in Table 2. There were no significant differences between the groups at baseline. LDL cholesterol decreased by 62.8% from 90.9 to 33.5 mg/dl in the evolocumab group (p < 0.0001 for comparison from baseline), but did not change in the placebo group (p < 0.0001 for comparison between groups). The evolocumab group demonstrated more favorable effects on the change in high-density lipoprotein cholesterol (+11.6% vs. +7.5%; p = 0.02), triglycerides (−11.5% vs. +2.7%; p = 0.0002), and lipoprotein(a) (−22.7% vs. −2.5%; p < 0.0001) compared with placebo. Although CRP decreased in both groups, a lower on-treatment level was demonstrated in the placebo group (1.1 mg/l vs. 1.5 mg/l; p = 0.04).
IVUS-derived measures of plaque burden are summarized in Table 3. A significant reduction in percent atheroma volume was observed with evolocumab (−1.20%) but not placebo (+0.17%; p < 0.0001 for comparison between groups). Similarly, total atheroma volume decreased with evolocumab (−3.6 mm3) but not placebo (−0.8 mm3; p = 0.04 for comparison between groups). A greater percentage of patients treated with evolocumab demonstrated regression of percent atheroma volume (68.3% vs. 46.1%; p < 0.0001) and total atheroma volume (64.6% vs. 53.3%; p = 0.04).
Measures of plaque composition, expressed as normalized volumes and as a percentage of the whole plaque burden, are summarized in Table 4. No significant differences were observed between the placebo and evolocumab groups, respectively, with regards to changes in dense calcium (+0.6 ± 0.3 mm3 vs. +1.0 ± 0.3 mm3; p = 0.49), fibrous (−2.4 ± 0.6 mm3 vs. −3.0 ± 0.6 mm3; p = 0.49), fibrofatty (−3.0 ± 1.0 vs. −5.0 ± 1.0 mm3; p = 0.49) and necrotic core (−0.1 ± 0.5 mm3 vs. −0.6 ± 0.5 mm3; p = 0.49) volumes.
Similarly, no significant difference was observed between the placebo and evolocumab groups with regard to nominal changes in the percentage of plaque occupied by dense calcium (+1.0 ± 0.4% vs. +2.2 ± 0.4%; p = 0.10), fibrous (−0.6 ± 0.8% vs. −1.4 ± 0.8%; p = 0.67), fibrofatty (−0.9 ± 1.1% vs. −1.6 ± 1.1%; p = 0.67), and necrotic core (+0.4 ± 0.5% vs. +0.9 ± 0.6%; p = 0.67).
An exploratory analysis of changes in both the normalized volume and percentage of plaque burden occupied by the different components in patients with a baseline LDL cholesterol <70 mg/dl was performed. In the primary GLAGOV analysis, this subgroup demonstrated nominally greater plaque regression with evolocumab. A significant reduction in necrotic core volume was observed in the evolocumab (−2.9 mm3), but not placebo group (+0.4 mm3), although the difference between the groups just failed to meet statistical significance (p = 0.08). The volume of plaque occupied by fibrofatty material decreased by 6.0 mm3 with placebo and by 6.7 mm3 with evolocumab. Fibrous tissue decreased with evolocumab (−3.4 mm3), but not placebo (−0.8 mm3) (Table 5).
In the overall population studied in this analysis, stronger correlations were observed between changes in plaque burden and both necrotic core (PAV: r = 0.32; p < 0.001; TAV: r = 0.42; p < 0.001) and fibrous (PAV: r = 0.43; p < 0.001; TAV: r = 0.43; p < 0.001) volume than for changes in fibrofatty (PAV: r = 0.20; p < 0.001; TAV: r = 0.22; p < 0.001) and dense calcium (PAV: r = 0.10; p = 0.07; TAV: r = 0.18; p < 0.001) components (Table 6). A significant, albeit predictable, relationship was observed between increasing tertiles of changes in either measure of plaque burden with changes in necrotic core (p < 0.001), fibrofatty (p = 0.03), and fibrous (p < 0.001) tissue, but not dense calcium (Table 7).
Only very weak correlations were observed between changes in either LDL cholesterol or high sensitivity CRP with changes in necrotic core or dense calcium components (Table 8). Of note, the inverse correlation between changes in LDL cholesterol and changes in percent of plaque occupied by calcium (r = −0.15; p < 0.001) was of a similar magnitude to previously reported direct correlations between changes in LDL cholesterol and plaque burden with other lipid-lowering therapies (Central Illustration).
The ability to perform VH imaging within a serial IVUS study provides the potential to characterize the effects of medical therapies on the composition of coronary atheroma for treatments with established effects on disease burden. This pre-specified substudy of the GLAGOV trial included patients who had concomitant VH imaging, demonstrating that administration of evolocumab to statin-treated patients with coronary artery disease produced robust reductions in LDL cholesterol and regression of coronary atherosclerosis, but did not produce any significant difference in plaque composition compared with statin monotherapy using this technique. Additional, non–pre-specified analyses revealed an increase in plaque calcification in association with LDL cholesterol lowering, whereas marked atheroma regression was predictably accompanied by reductions in the size of all other plaque components.
The lack of any demonstrable differences between the treatment groups in changes in VH parameters raises questions about the utility of this approach to plaque imaging in assessing the effects of lipid-modifying therapies. In the main trial and in this substudy, evolocumab produced robust effects on lipid parameters and promoted highly significant atheroma regression. Yet, despite these effects, the current study, the largest serial VH analysis performed to date, was unable to delineate any difference between the treatment groups. This likely represents a failure of this investigational imaging modality to characterize any potential additional benefits of lipid-lowering therapies.
A large body of published data involving VH has focused on the potential role of the necrotic core in plaque vulnerability. Some observational reports suggest that the presence of a thin cap fibroatheroma, defined by a large plaque burden in association with a large content of necrotic material, predicts a greater likelihood of future cardiovascular events (16). However, to date no prospective randomized trial has demonstrated that application of such imaging and detection of necrotic material changes clinical practice or influences clinical outcome. Necrotic core imaging has been proposed as an alternative approach to evaluation of novel antiatherosclerotic therapies. However, statins have been reported to have variable effects on necrotic material (26,27), and the only experimental therapy to exert favorable effects on the necrotic core, the lipoprotein-associated phospholipase A2 inhibitor darapladib (28), did not subsequently prove to reduce cardiovascular events in 2 large clinical outcome trials (29,30). In fact, our analysis demonstrated that favorable reductions in necrotic core were only observed in patients demonstrating a marked degree of plaque regression. This would seem intuitive, as a reduction in plaque volume would be expected to be accompanied by reductions in all of its components. Although this finding supports the concept that plaque regression will reduce the components likely to promote plaque instability, it suggests that VH imaging provides no incremental information beyond evaluating changes in plaque burden in this trial of evolocumab.
We observed small increases in plaque calcification in both treatment groups. The lack of statistical difference between the groups may reflect the relatively limited power of the imaging technique and potential challenges with measurement due to changes in catheter position and generation of acoustic shadows. Nevertheless, the increase in calcification in the statin monotherapy group supports previous reports (26,31), while the finding of a greater degree of plaque calcification with evolocumab extends this observation to an additional LDL cholesterol-lowering agent. The finding that changes in plaque calcification correlated inversely with changes in LDL cholesterol, but not with a reduction in plaque burden, suggests that a reduction in plaque lipid decreases the stimuli promoting activation of molecular mediators of calcium production within plaque. The extent and change in plaque calcification were relatively small, and the clinical impact of these changes has not been determined. Whether similar changes would be observed in the presence of more calcified atherosclerosis is unknown.
Demonstrating an increase in plaque calcification with both statins and evolocumab further calls into question the role of serial calcium scoring to monitor therapeutic responses. Increasing calcium scores and their progression independently predict cardiovascular outcomes in large cohort studies (32). It is likely that this reflects an ongoing accumulation of vulnerable plaque elsewhere within the coronary vasculature, which is likely to promote ongoing cardiovascular risk. However, the increase in calcification with lipid-lowering therapies that is observed in the presence of plaque regression would suggest that this is more likely to reflect a favorable effect on plaque stability. Accordingly, this provides further evidence to question the utility of serial calcium scoring to monitor patients treated with lipid-lowering agents.
We observed no meaningful reduction in CRP with evolocumab. Similarly, the increase in plaque calcium in this study correlated with changes in LDL cholesterol, but not CRP. These findings provide additional evidence suggesting that the effects of PCSK9 inhibition are exclusively due to favorable effects on lipids. Although statins have been reported to possess non–lipid-lowering properties and CRP lowering associated with their benefit on plaque progression (33,34) and cardiovascular events (35), PCSK9 inhibitors have not yet demonstrated a similar effect. The current findings extend the effects of lowering LDL cholesterol to very low levels to suggest a potential role in promoting a more stable plaque phenotype; however, this requires further investigation.
The lack of any demonstrable differences between the treatment groups in changes in VH parameters raises questions about the utility of this type of plaque imaging in assessing the effects of antiatherosclerotic therapies. Conversely, evolocumab produced robust effects on lipid parameters and promoted highly significant atheroma regression. Yet, despite these effects, the current study, the largest serial VH analysis performed to date, was unable to delineate any difference between the treatment groups. On the basis of the findings of this analysis and associated variability in measurements, the study had limited power to detect changes in any of the VH parameters (9% to 21%) between the treatment groups. The greater power to detect a difference in terms of percentage of plaque containing calcium (62%) may reflect a greater ability to detect a relationship between changes in LDL-C and plaque calcium. This suggests that serial VH imaging is inferior to plaque burden measurements in evaluating effects of lipid-lowering therapies. In addition, potential issues related to changes in catheter position within the lumen may influence image acquisition, and it remains uncertain whether VH truly reflects the plaque components it is purported to measure. It is important to note that despite this, VH analysis has been validated to detect compositional features on histology with the rotational catheter used in this study (36,37). In fact, it is interesting to note that a modest correlation was observed between changes in plaque burden with changes in necrotic, fibrous, and fibrofatty material. This was evidenced by the intuitive observation that the greatest reductions in these parameters were observed in the setting of the greatest degree of plaque regression. Although this is of potential interest, whether it reflects incremental information or change is unknown. This may, therefore, represent a failure of an emerging imaging modality to characterize any potential benefits of novel antiatherosclerotic therapies.
A number of additional limitations to this trial should be noted. The study was performed in patients undergoing a clinically indicated coronary angiogram. Whether the findings can be extrapolated to asymptomatic patients with subclinical atherosclerosis is unknown. The changes in VH parameters observed with evolocumab occurred in the setting of prior statin treatment; whether differences are found with evolocumab monotherapy are unknown. Similarly, the effect of prior statin therapy in the presence or absence of concomitant ezetimibe on the findings is unknown. Although the findings reaffirm that intensive lipid lowering has a favorable effect on coronary atherosclerosis, how it influences clinical outcome remains to be established. It is also unknown whether similar effects will be observed with alternative approaches to PCSK9 inhibition. Although this analysis comprised the largest serial VH imaging dataset established, it is possible that a much larger cohort may have been required to demonstrate any difference between the groups. VH imaging represents one of a number of novel modalities with the potential to visualize individual plaque factors that may play a role in the transition of atherosclerotic plaque to ischemic events. Whether additional modalities such as near-infrared spectroscopy or optical coherence tomography will demonstrate additional plaque benefits of PCSK9 inhibition has not been investigated. Similarly, whether this tool would be of utility in the evaluation of novel non–lipid-lowering, antiatherosclerotic agents remains to be determined.
Administration of the PCSK9 inhibitor evolocumab to statin-treated patients with coronary artery disease produced robust lowering of LDL cholesterol and plaque regression; yet, VH imaging was unable to detect any plaque composition differences between the groups. As a result, the mechanistic factors that link lipid lowering with plaque regression in the setting of PCSK9 inhibition requires further investigation. Although serial VH imaging does not appear to be a useful tool to characterize additional effects of evolocumab beyond changes in plaque burden, it remains to be determined what utility will be provided by alternative approaches to assessing plaque morphology.
COMPETENCY IN MEDICAL KNOWLEDGE: Combined therapy with a statin and the PCSK9 inhibitor evolocumab lowers serum LDL cholesterol and promotes plaque regression while increasing plaque calcification, suggesting plaque stabilization.
TRANSLATIONAL OUTLOOK: Further studies are needed to define the role of vascular ultrasound imaging for quantification of the calcific, necrotic, fibrofatty, and fibrous components of coronary atheromatous plaque in relation to the pathogenesis of ischemic events and the effect of various to lipid-lowering therapies.
Plaque measurements were made by the members of the Atherosclerosis Imaging Core Laboratory at the Cleveland Clinic.
The GLAGOV trial was sponsored by Amgen. Dr. Nicholls has received research support from AstraZeneca, Amgen Inc., Anthera, Eli Lilly, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience; and has received consulting fees and honoraria from AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr. Puri has received consulting fees from Cerenis, Sanofi, and Amgen. Dr. Anderson has received honoraria for speaking from Amgen Inc., Bayer, and Sanofi; and was the local principle investigator on clinical research studies for Amgen, Merck, and Dalcor. Dr. Ballantyne has received grant/research support (paid to institution, not individual) from Abbott Diagnostic, Amarin, Amgen, Esperion, Ionis, Novartis, Pfizer, Regeneron, Roche Diagnostics, Sanofi-Synthelabo, National Institutes of Health, American Heart Association, and American Diabetes Association; and has served as a consultant for Abbott Diagnostics, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, Ionis, Matinas BioPharma Inc., Merck, Novartis, Pfizer, Regeneron, Roche Diagnostics, and Sanofi-Synthelabo. Dr. Cho has conducted research with Amgen. Dr. Kastelein has received personal consulting fees from Amgen, CiVi Biopharma, Sanofi, Affiris, Akarna Therapeutics, Amgen, CSL Behring, Regeneron, Staten Biotech, Madrigal, The Medicines Company, Kowa, Lilly, Esperion, Gemphire, Ionis Pharmaceuticals, and Akcea Pharmaceuticals. Dr. Koenig has received personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, GlaxoSmithKline, DalCor, Sanofi, Berlin-Chemie, Kowa, and Amgen; and has received grants and nonfinancial support from Roche Diagnostics, Beckmann, Singulex, and Abbott. Dr. Somaratne is an employee of and stockholder in Amgen; and is an inventor on at least 1 patent application owned by Amgen relating to evolocumab. Dr. Kassahun is an employee of and stockholder in Amgen. Dr. Yang is a former employee of and stockholder in Amgen. Dr. Wasserman is an employee of Amgen. Dr. Nissen’s institution (Cleveland Clinic Center for Clinical Research) has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Cerenis, Eli Lilly, Esperion, Pfizer, The Medicines Company, Takeda, and Orexigen; he is involved in these clinical trials, but receives no personal remuneration for his participation; and consults for many pharmaceutical companies, but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- C-reactive protein
- intravascular ultrasound
- low-density lipoprotein
- percent atheroma volume
- proprotein convertase subtilisin kexin type 9
- total atheroma volume
- virtual histology
- Received May 18, 2018.
- Revision received June 25, 2018.
- Accepted June 27, 2018.
- 2018 American College of Cardiology Foundation
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