Author + information
- Received March 23, 2018
- Revision received April 13, 2018
- Accepted April 16, 2018
- Published online October 1, 2018.
- Sang-Eun Lee, MD, PhDa,b,
- Hyuk-Jae Chang, MD, PhDa,b,∗ (, )
- Ji Min Sung, PhDa,b,
- Hyung-Bok Park, MDb,c,
- Ran Heo, MDb,d,
- Asim Rizvi, MDe,
- Fay Y. Lin, MDe,
- Amit Kumar, MSce,
- Martin Hadamitzky, MDf,
- Yong Jin Kim, MD, PhDg,
- Edoardo Conte, MDh,
- Daniele Andreini, MD, PhDh,
- Gianluca Pontone, MD, PhDh,
- Matthew J. Budoff, MDi,
- Ilan Gottlieb, MD, PhDj,
- Byoung Kwon Lee, MD, PhDk,
- Eun Ju Chun, MD, PhDl,
- Filippo Cademartiri, MD, PhDm,
- Erica Maffei, MDn,
- Hugo Marques, MDo,
- Jonathon A. Leipsic, MDp,
- Sanghoon Shin, MDq,
- Jung Hyun Choi, MD, PhDr,
- Kavitha Chinnaiyan, MDs,
- Gilbert Raff, MDs,
- Renu Virmani, MDt,
- Habib Samady, MDu,
- Peter H. Stone, MDv,
- Daniel S. Berman, MDw,
- Jagat Narula, MD, PhDx,
- Leslee J. Shaw, PhDu,
- Jeroen J. Bax, MD, PhDy and
- James K. Min, MDe
- aDivision of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei University Health System, Seoul, South Korea
- bYonsei-Cedars-Sinai Integrative Cardiovascular Imaging Research Center, Yonsei University College of Medicine, Yonsei University Health System, Seoul, South Korea
- cDepartment of Internal Medicine, Division of Cardiology, Catholic Kwandong University International St. Mary's Hospital, Incheon, South Korea
- dDivision of Cardiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
- eDalio Institute of Cardiovascular Imaging, New York-Presbyterian Hospital and Weill Cornell Medical College, New York, New York
- fDepartment of Radiology and Nuclear Medicine, German Heart Center Munich, Munich, Germany
- gSeoul National University College of Medicine, Seoul National University Hospital, South Korea
- hCentro Cardiologico Monzino, IRCCS, Milan, Italy
- iDepartment of Medicine, Los Angeles Biomedical Research Institute, Torrance, California
- jDepartment of Radiology, Casa de Saude São Jose, Rio de Janeiro, Brazil
- kGangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
- lSeoul National University Bundang Hospital, Seoul, South Korea
- mCardiovascular Imaging Center, SDN Foundation IRCCS, Naples, Italy
- nDepartment of Radiology, Area Vasta 1/ASUR Marche, Urbino, Italy
- oUNICA, Unit of Cardiovascular Imaging, Hospital da Luz, Lisbon, Portugal
- pDepartment of Medicine and Radiology, University of British Columbia, Vancouver, British Columbia, Canada
- qNational Health Insurance Service Ilsan Hospital, Goyang, South Korea
- rBusan University Hospital, Busan, South Korea
- sDepartment of Cardiology, William Beaumont Hospital, Royal Oak, Michigan
- tDepartment of Pathology, CVPath Institute, Gaithersburg, Maryland
- uDivision of Cardiology, Emory University School of Medicine, Atlanta, Georgia
- vDivision of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- wDepartment of Imaging and Medicine, Cedars-Sinai Medical Center, Los Angeles, California
- xIcahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, New York
- yDepartment of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
- ↵∗Address for correspondence:
Dr. Hyuk-Jae Chang, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei-Cedars-Sinai Integrative Cardiovascular Imaging Research Center, Yonsei University College of Medicine, Yonsei University Health System 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea.
Objectives This study sought to describe the impact of statins on individual coronary atherosclerotic plaques.
Background Although statins reduce the risk of major adverse cardiovascular events, their long-term effects on coronary atherosclerosis remain unclear.
Methods We performed a prospective, multinational study consisting of a registry of consecutive patients without history of coronary artery disease who underwent serial coronary computed tomography angiography at an interscan interval of ≥2 years. Atherosclerotic plaques were quantitatively analyzed for percent diameter stenosis (%DS), percent atheroma volume (PAV), plaque composition, and presence of high-risk plaque (HRP), defined by the presence of ≥2 features of low-attenuation plaque, positive arterial remodeling, or spotty calcifications.
Results Among 1,255 patients (60 ± 9 years of age; 57% men), 1,079 coronary artery lesions were evaluated in statin-naive patients (n = 474), and 2,496 coronary artery lesions were evaluated in statin-taking patients (n = 781). Compared with lesions in statin-naive patients, those in statin-taking patients displayed a slower rate of overall PAV progression (1.76 ± 2.40% per year vs. 2.04 ± 2.37% per year, respectively; p = 0.002) but more rapid progression of calcified PAV (1.27 ± 1.54% per year vs. 0.98 ± 1.27% per year, respectively; p < 0.001). Progression of noncalcified PAV and annual incidence of new HRP features were lower in lesions in statin-taking patients (0.49 ± 2.39% per year vs. 1.06 ± 2.42% per year and 0.9% per year vs. 1.6% per year, respectively; all p < 0.001). The rates of progression to >50% DS were not different (1.0% vs. 1.4%, respectively; p > 0.05). Statins were associated with a 21% reduction in annualized total PAV progression above the median and 35% reduction in HRP development.
Conclusions Statins were associated with slower progression of overall coronary atherosclerosis volume, with increased plaque calcification and reduction of high-risk plaque features. Statins did not affect the progression of percentage of stenosis severity of coronary artery lesions but induced phenotypic plaque transformation. (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging [PARADIGM]; NCT02803411)
- coronary artery atherosclerosis
- coronary artery disease
- coronary computed tomography angiography
In numerous randomized controlled trials in patients eligible for primary and secondary prevention therapies, statins have been effective in reducing the risk of major adverse cardiac events (1–3). A recent pooled analysis of patients from 8 randomized clinical trials undergoing serial intravascular ultrasonography examinations over 18 to 24 months demonstrated the insight that may be afforded by serial plaque evaluation, finding that statins exhibit pro-calcific effects independently of their effects on reducing plaque progression (4). These findings may unify the paradox of increased coronary artery calcium progression seen in statin trials, despite reduced events.
However, intravascular techniques are subject to calcium shadowing and thus must rely on semiquantitative indices (5). Additionally, the generalizability of intravascular ultrasonography data to a lower risk population beyond secondary prevention population or advanced coronary disease (CAD), or beyond 24-months, is unknown because the invasiveness of the method applied has limited the study population to those patients who are at relatively high risk or who already have advanced CAD (6–8). Prior serial coronary computed tomography angiography (CTA) studies are limited to their number and qualitative methods (4,9).
To address this knowledge gap, we prospectively enrolled a large multinational cohort of consecutive patients with suspected CAD who underwent serial coronary CTA at a minimum of 2-year interscan intervals to determine the long-term effects of statins on plaque progression and calcification in a low-risk patient population.
The PARADIGM (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging) study was a dynamic, multinational observational registry that prospectively collected clinical, procedural, and follow-up data for patients who underwent clinically indicated serial coronary CTA (10). The study protocol was approved by the institutional review boards of all participating centers.
The PARADIGM study consisted of 2,252 patients managed at 13 sites in 7 countries (Brazil, Canada, Germany, Italy, Portugal, South Korea, and the United States), who were enrolled between 2003 and 2015. The study included consecutive patients with suspected or known CAD undergoing serial coronary CTA at an interscan interval of ≥2 years and excluded patients with complete absence of clinical data at baseline (coronary CTA-1) or follow-up (coronary CTA-2) (10).
For this analysis, further exclusion criteria included documented prior CAD (defined as myocardial infarction or revascularization before coronary CTA-1 (n = 227), patients without information on statin use at the time of both coronary CTAs (n = 192), patients who discontinued statin use after coronary CTA-1 (n = 86), and patients with either coronary CTA results uninterpretable for quantitative coronary CTA measurement (n = 492); 1,255 patients were included in the final analysis. Patients were divided into a statin-naive group (n = 474), if they were not taking a statin at the time of coronary CTA-1 and follow-up coronary CTA (coronary CTA-2), and a statin-taking group (n = 781), if they were taking a statin at the time of coronary CTA-2 (Figure 1). In case of patients with ≥3 coronary CTA scans, the first and last coronary CTAs were analyzed. Patients who experienced a clinical event between the 2 coronary CTAs were not omitted.
Coronary CTA analysis protocol
All coronary CTAs were performed in accordance with Society of Cardiovascular Computed Tomography guidelines (11,12). Datasets from each participating site were transferred to a core laboratory for blinded image analysis. Coronary atherosclerosis was evaluated on multiplanar and cross-sectional coronary CTA images. All evaluations were performed by level III experienced readers masked to clinical results, using semiautomated plaque analysis software (QAngioCT Research Edition v22.214.171.124, Medis Medical Imaging Systems, Leiden, the Netherlands) with manual correction (13).
Briefly, all coronary arteries with a diameter ≥2 mm were evaluated on every coronary artery and its branches (Online Methods, Online Figure 1). The presence of atherosclerosis was defined as any tissue ≥1 mm2 within or adjacent to the lumen that could be discriminated from surrounding pericardial tissue, epicardial fat, or lumen, and identified in >2 planes (12,14). Plaque volume (PV) (mm3) and vessel volume (mm3) measurements were obtained for all coronary lesions (15). Percent atheroma volume (PAV) was defined as: [(PV/vessel volume) × 100] (%) (15). To determine progression and/or regression of the lesion, annual change in PAV (△PAV/year, %/year) was defined as follows: (△PAV)/(interval between coronary CTA examinations). Atherosclerotic PAV was subclassified by composition, using predefined intensity cutoff values in Hounsfield units (HU) that have been validated relative to intravascular ultrasonography studies, into noncalcified plaque (−30 to 350 HU); encompassing low-attenuation plaque (−30 to 30 HU); fibro-fatty plaque (30 to 130 HU); fibrous PAV (131 to 350 HU); and calcified PAV (≥351 HU) (16,17). The interobserver and intraobserver intraclass correlation for total PV was 0.992 and 0.996 (p < 0.001), respectively, and ranged between 0.95 and 0.99 for PV by composition (Online Table 1, Online Figures 2 and 3).
Additionally, measurements for each lesion included length, volume, and plaque composition, as well as percent diameter stenosis (%DS). A cutpoint of ≥50%DS was used for obstructive CAD (18).
We evaluated atherosclerotic plaque features previously which have been reported as being associated with incident major adverse cardiac events and coronary ischemia and which have been termed high-risk plaque(s) (HRP) (14,19). HRP were defined as coronary lesions with ≥2 of the following features: positive arterial remodeling, low-attenuation plaque, or spotty calcification (19). Low-attenuation plaque, previously correlated with low attenuation, was defined as any plaque containing ≥1 voxels with HU ≤30 (14,20). Spotty calcification was defined as presence of calcification <3 mm in any direction within a plaque (19,21).
For longitudinal comparisons of coronary CTAs, coronary segments and lesions were co-registered between the coronary CTA-1 and coronary CTA-2 evaluations by using fiduciary landmarks including the distance from the ostium and the branch vessels (Online Figures 4 and 5).
The primary study objective was to compare the annualized within-lesion change in PAV between coronary CTA-1 and coronary CTA-2 by statin exposure. Secondary endpoints included annualized changes in PAV by plaque composition and development of HRP and its constituent features, increased percent diameter of stenosis, and development of obstructive lesion.
Continuous variables are expressed as mean ± SD, whereas categorical variables are presented as absolute counts and percentages. Differences between categorical variables were analyzed using the chi-square or Fisher exact test, as appropriate, and those between continuous variables using Student’s t-test. Changes between coronary CTA-1 and coronary CTA-2 were assessed using paired t-tests.
To account for the effect of common factors in clustered lesions within a single patient, marginal Cox models for multivariate failure times were used to determine the association between statin use and progression of coronary atherosclerosis and reported in terms of hazard ratios (HRs) and 95% confidence intervals (CI) (22). Multivariate adjustment was performed for known CAD risk factors, for example, age, sex, hypertension, diabetes mellitus, family history of CAD, history of smoking, and blood pressure (23). The analysis also accounted for total PAV and low-density lipoprotein level at baseline, use of antiplatelet therapy and beta-blocker, and location of each lesion within the 3 major coronary vessels (left anterior descending, left circumflex, and right coronary artery).
To investigate whether the results of marginal Cox models would remain consistent if the differences in baseline characteristics between the statin-naive and statin-taking group was compensated, marginal Cox models were repeated after patients were matched in 1:1 manner using propensity score method (Online Methods).
A two-tailed p value <0.05 was considered statistically significant. All analyses were performed using SAS version 9.4 software (SAS Institute Inc., Cary, North Carolina) and R version 3.3.0 software (R Development Core Team, Vienna, Austria).
Study population and baseline characteristics
The study population consisted of 1,255 patients (60 ± 9 years of age; 56.7% men) (Table 1). At coronary CTA-1, patients presented mainly for 1 or more cardiac symptoms (97%), and the major reason for undergoing coronary CTA-2 was persistent or worsening cardiac symptoms (64%) (Online Table 2). The interscan interval between coronary CTAs was 3.8 ± 1.6 years (median 3.4 years; interquartile range: 2.6 to 4.8 years). Both the tube voltage and the tube current decreased at coronary CTA-2 compared with those at coronary CTA-1 (Online Table 2).
Between coronary CTA-1 and coronary CTA-2, 102 patients (8.1%) experienced revascularization (11 surgical and 92 percutaneous coronary interventions); 6 statin-naive patients and 96 statin-taking patients (p < 0.001).
Most statin-taking patients (94%) were taking moderate to high-intensity statins, which consisted of atorvastatin or rosuvastatin (24). At coronary CTA-1, statin-taking patients were older and had higher prevalence of hypertension and diabetes mellitus than statin-naive patients (p < 0.05 for all), with higher total cholesterol and similar low-density and high-density lipoprotein levels. At coronary CTA-2, total cholesterol and low-density lipoprotein levels were lower in statin-taking patients with no differences in high-density lipoprotein levels.
Changes in stenosis severity according to statin use
Overall, 3,575 coronary lesions (2.9 lesions per patient) were analyzed, with 2,496 lesions in statin-taking patients (3.2 lesions per patient) and 1,079 lesions in statin-naive patients (2.3 lesions per patient) (Table 2, Online Table 3). The average stenosis severity per lesion was low (13.6 ± 13.6%), with only 52 lesions (1.6%) showing diameter stenosis ≥50% at baseline. Over time, statin therapy slowed the increase in %DS (1.5 ± 3.8% per year vs. 1.9 ± 3.8% per year, respectively; p = 0.009), although not enough to observe an impact in the binary progression of nonobstructive coronary lesion to ≥50%DS (1.0% vs. 1.4%, respectively; p > 0.05).
Changes in PV and plaque composition according to statin use
Compared with statin-taking patients, statin-naive patients exhibited higher PAV per lesion at coronary CTA-1 (14.4 ± 13.1 mm3 vs. 10.9 ± 11.2 mm3, respectively; p < 0.001) and calcified and noncalcified PAV (5.2 ± 7.4 mm3 vs. 3.2 ± 5.6 mm3 and 9.1 ± 10.0 mm3 vs. 7.6 ± 9.4 mm3, respectively; both p < 0.05).
Over time, the atherosclerotic lesion composition changes in statin-taking patients differed from those in statin-naive patients. Annualized progression of coronary lesion PAV was slower in statin-taking patients than in statin-naive patients (1.76 ± 2.40 mm3 per year vs. 2.04 ± 2.37 mm3 per year, respectively; p = 0.002) (Figure 2). Furthermore, lesions in statin-taking patients experienced higher annualized progression of calcified PAV (1.27 ± 1.54 mm3 per year vs. 0.98 ± 1.27 mm3 per year, respectively; p < 0.001) but slower progression of noncalcified PAV than lesions in statin-naive patients (0.49 ± 2.39 mm3 per year vs. 1.06 ± 2.42 mm3 per year, respectively; p < 0.001).
Within noncalcified PAV, the progression rates of fibrous and fibro-fatty PAVs were slower in statin-taking patients than in statin-naive patients (0.53 ± 1.81 mm3 per year vs. 0.89 ± 1.78 mm3 per year and −0.03 ± 1.18 mm3 per year vs. 0.16 ± 1.28 mm3 per year, respectively; both p < 0.001), with no significant differences for low-attenuation PAV (p = 0.202) (Figure 2).
Changes in high-risk plaque features according to statin use
At coronary CTA-1, statin-taking patients exhibited a higher prevalence of HRP, positive remodeling, and spotty calcification (13.7% vs. 10.0%; 56.0% vs. 47.6%; and 10.2% vs. 6.8%, respectively; all p < 0.05), with no differences in low-attenuation plaque (8.5% vs. 8.4%, respectively; p = 0.95). The annualized incidence of HRP, positive remodeling, spotty calcification, and low-attenuation plaques were lower in statin-taking patients (0.9% per year vs. 1.6% per year; 5.2% per year vs. 7.2% per year; 0.2% per year vs. 0.5% per year; and 0.8% per year vs. 1.0% per year, respectively; p < 0.001 for all).
Impact of statins on progression of coronary atherosclerosis
Multivariate Cox proportional hazards model adjusted for baseline PAV, low-density lipoprotein level at baseline, lesion location, use of antiplatelets and beta-blockers, and clinical risk factors for CAD indicated that statins exerted no effect on the rate of progression to ≥50%DS at the time of coronary CTA-2 (p = 0.225) (Table 3). Statins reduced the risk of annualized total PAV increase above the median of the study population (HR: 0.796; 95% CI: 0.687 to 0.925; p = 0.003).
Upon stratification by plaque composition, statins also reduced the risk of annualized increase in noncalcified PV above the median (HR: 0.703; 95% CI: 0.605 to 0.820; p < 0.001), which held true for each of the 3 noncalcified components (fibrous PAV HR: 0.701; 95% CI: 0.603 to 0.817; fibro-fatty PAV HR: 0.745; 95% CI: 0.633 to 0.879; and low-attenuation PV HR: 0.644; 95% CI: 0.522 to 0.798; all p < 0.001) but not for calcified PV (p = 0.365).
Statin therapy was associated with lower rates of formation of lesions possessing positive arterial remodeling at the time of coronary CTA-2 (HR: 0.764; 95% CI: 0.596 to 0.983; p = 0.034), which was associated with a reduced risk of new high-risk plaque lesions (HR: 0.670; 95% CI: 0.473 to 0.960; p = 0.026). No effect of statins was observed regarding the development of low-attenuation plaque or spotty calcification (all p > 0.05).
These findings remained consistent when the statin-naive and statin-taking patients were matched using propensity scores (Online Tables 4 to 6). Statins continued to be associated with the reduced risk of annualized total and noncalcified PAV increase above the median and also reduced the risk of developing HRP and positive arterial remodeling.
In the analysis of this large, prospective observational cohort evaluating temporal changes in plaque characteristics by using quantitative assessment, statin therapy was associated with slower rates of progression of overall coronary atherosclerosis volumes with differential effects on different plaque types. Statins were also associated with the increase of calcified plaque components and reduced progression of noncalcified portions of atherosclerotic lesions. Moreover, although statins did not have a protective effect against the development of high-grade coronary stenoses, they successfully reduced the risk of positive remodeling and HRPs. Furthermore, we can generalize observations of the pro-calcific effects of statins, independent of their reduction in plaque progression, to a multiethnic, multinational, low-risk cohort outside of a clinical trial setting. Our study provides a context and data that have not been available previously for interpretation of serial coronary CTA and that provide insight into the natural history of both vulnerable and calcific plaque. Importantly, coronary CTA was able to effectively measure the impact of statin use on decreased progression of subclinical atherosclerosis.
Corresponding with early serial angiographic statin trials, we demonstrated slower coronary artery luminal narrowing, without affecting the binary development of obstructive CAD (25,26). In line with both prior landmark studies of serial invasive imaging (7,27) and more recent small coronary CTA studies (8,9), we demonstrated that statins slow the progression of coronary atherosclerosis in whole-heart evaluations by coronary CTA, beyond the proximal arterial segments interrogated by intravascular ultrasonography. These prior studies preferentially used either invasive modalities focusing on a single culprit plaque or noninvasive modalities assessing the change in atherosclerosis on a per-patient level (4,9).
However, neither approach can fully evaluate the impact of statin therapy on coronary atherosclerotic lesions, as evaluating only a single plaque will neglect the interactions between coexisting plaques, and per-patient analysis will aggregate the findings of individual plaques (28). Moreover, previous invasive studies have enrolled mainly patients undergoing clinically indicated invasive coronary angiography, meaning patients not indicated for invasive assessment, most of whom were at an earlier stage of CAD and possibly exhibited a different pattern of disease progression, and who accounted for much a greater portion of the population, were omitted. Therefore, the strengths of the current study include not only the large sample size and long follow-up duration but also the methodology of examining lesion-specific changes over time in a population with relatively lower risk, by quantitatively analyzing the entire coronary tree, using a noninvasive imaging modality.
Coronary artery calcium scoring is a robust tool for prognostication of future adverse cardiovascular events (29); and elevated coronary artery calcium score progression portends worse prognosis (5). However, a randomized controlled trial of statin therapy demonstrated no impact on slowing the progression of coronary artery calcium score (30–32). Given the present findings, it remains unknown whether an increasing calcium score in a patient who is being treated with statins represents a malignant or benign process, and uncertainty exists as to the utility of serial coronary calcium scoring for monitoring therapeutic efficacy in patients being treated with statins (5,28).
Taken together, our results suggest that interpretation of calcium progression should be stratified by statin treatment, as increasing coronary calcification in statin-taking patients may represent stabilization of atherosclerotic lesions. Even furthermore, inducing calcification of plaques may be one of the mechanisms by which statins exert a positive effect in reducing the risk of major adverse cardiovascular events. This hypothesis, although attractive, remains to be proven; and future large-scale trials evaluating atherosclerosis treatment by targeting specific atherosclerotic characteristics based upon plaque composition and other high-risk plaque features now seem warranted.
Our results complement those of the ICONIC (Incident COroNary Syndromes Identified by Computed Tomography) trial, a nested case control study of atherosclerotic plaque precursors to acute coronary syndrome. In the ICONIC study, we observed that lesion characteristics and plaque burden by composition had predictive value for acute coronary syndrome, independent of clinical risk factors and total plaque burden. There was a continuum of risk of acute coronary syndromes by plaque composition, with greater weight for lower attenuation plaque burden. In the PARADIGM study, we observed that plaque composition and characteristics can be decoupled from plaque burden due to treatment effects. Increased calcification with statins, coherent with its known impact on reducing clinical events, support the concept of increased HU attenuation as evidence of plaque stabilization. Together, the results of these 2 studies demonstrate the applicability and insight of noninvasive plaque evaluation in the ranges of high and low risk.
First, our results did not attempt to distinguish between the impact of high- and low-intensity statins, and we cannot exclude confounding by indication or unmeasured and time-varying confounders. Among the statin-taking group, 303 patients began statin therapy during the interval (38.8%). However, the coherence of our study with findings in a large, pooled, high-risk intravascular ultrasonography cohort randomized to statins supports the validity of our finding. Second, although the HU thresholds for plaque composition were validated by using virtual histology-intravascular ultrasonography, the HU thresholds of low-attenuation and fibrous plaque demonstrate significant overlap relative to histopathology, and the spatial resolution of coronary CTA may result in partial volume effects within a pixel (17). Thus, the categories of plaque composition described should not be taken as discrete histopathological entities but rather as gradations of risk in plaques. Third, because of the observational design of the study, patients were not randomized, and there is a major difference in baseline characteristics between groups. However, the main findings of this study remained consistent even after propensity score matching. Additionally, because only patients who had 2 coronary CTA scans were eligible, patients had a relatively low prevalence of obstructive CAD and event rate. Patients who progress more rapidly and, hence, who more likely to experience clinical events may not attend for a second coronary CTA. Thus, selection bias is inevitable, and the generalizability of our results to high-risk populations is not known, and our study was not powered to estimate the coronary event risk of plaque progression. To overcome these limitations, prediction models will require large, ideally, population-based prospective cohorts of serial coronary CTA or randomized study that may be economically feasible only with completely automated coronary CTA measurements. However, as there are no current professional society recommendations endorsing the routine use of serial coronary CTA for evaluation of CAD (18), an observational registry such as the present study provides a unique opportunity to assess the natural history of CAD.
Our findings suggest that, over a longer term and among lower-risk patients undergoing serial coronary CTA, statins are associated with slower progression of overall coronary atherosclerosis volume, with increased plaque calcification and reduction of high-risk plaque features.
COMPETENCY IN MEDICAL KNOWLEDGE: Statins change the composition of intraplaque constituents by increasing calcification and reducing the noncalcified portion within plaques. Although statins do not have protective effect against the progression of coronary lesions to high-grade stenoses, statins reduce the risk of developing adverse plaque characteristics, including high-risk plaques and positive remodeling.
TRANSLATIONAL OUTLOOK: Prospective clinical trials targeting specific coronary atherosclerotic phenotypes based upon high-risk plaque features and plaque constituents are necessary to delineate the impact of statin-induced plaque calcification on clinical outcomes.
The authors acknowledge PARADIGM investigators in the U.S. Coordinating Center: Patricia Dunham, BA; Kimberly Elmore, MHA; Dan Gebow, PhD; Alexander van Rosendael, MD; and Wijnand Stuijfzand, MD; and additional PARADIGM site investigators: Ralph Gentry; Taekyeong Kim, MD; Hanna Nieberler, MD; and Mark Pica, BS.
Supported in part by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation (NRF) of Korea, funded by Ministry of Science and ICT (MSIT) grant 2012027176 and by gifts from the Dalio Institute of Cardiovascular Imaging and the Michael Wolk Foundation. Funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Dr. Chang had full access to all data in the study and final responsibility for the decision to submit the manuscript for publication. Dr. Chang has received funding from Leading Foreign Research Institute Recruitment Program through NRF of Korea funded by MSIT grant 2012027176). Dr. Min has received funding from U.S. National Institutes of Health (NIH) grants R01 HL111141, R01 HL115150, R01 118019, and U01 HL 105907, Qatar National Priorities Research Program grant 09-370-3-089, and GE Healthcare. Dr. Min has consulted for HeartFlow; has served on the scientific advisory board of Arineta; and holds equity interest in MDDX. Dr. Bax has received unrestricted research grants from Biotronik, Medtronic, Boston Scientific, and Edwards Lifesciences. Dr. Chun has received funding from NRF grant NRF-2015R1D1A1A01059717, funded by the Korean Government (Ministry of Education, Science and Technology). Dr. Leipsic has consulted for and holds stock in HeartFlow and Circle Cardiovascular Imaging; and has received speakers fees from GE Healthcare. Dr. Budoff has received grants from NIH and GE Healthcare. Dr. Samady has received grant support from Phillips/Volcano and St. Jude and Abbott, Medtronic, and Gilead. Dr. Andreini is a member of the Speakers Bureau for GE Healthcare; and has received grant support from GE Healthcare and Bracco. Dr. Pontone has received institutional research grants from GE Healthcare, HeartFlow, Medtronic, Bracco, and Bayer. Dr. Berman has received royalties from Cedars-Sinai. Dr. Virmani has received institutional research support from 480 Biomedical, Abbott Vascular, Arterial Remodeling Technologies BioSensors International, Biotronik, Boston Scientific, Celonova, Claret Medical, Cook Medical, Cordis, Edwards Lifesciences, Medtronic, MicroVention, OrbusNeich, ReCord, SINO Medical Technology, Spectranetics, Surmodics, Terumo Corporation, W.L. Gore, and Xeltis; and has received honoraria from 480 Biomedical, Abbott Vascular, Boston Scientific, Cook Medical, Lutonix, Medtronic, Terumo Corporation, and W.L. Gore; and has consulted for 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Todd Villines, MD, served as the Guest Editor for this paper.
- Abbreviations and Acronyms
- percent diameter stenosis
- coronary artery disease
- computed tomography angiography
- baseline computed tomography angiography
- follow-up computed tomography angiography
- high-risk plaque
- percent atheroma volume
- plaque volume
- Received March 23, 2018.
- Revision received April 13, 2018.
- Accepted April 16, 2018.
- 2018 American College of Cardiology Foundation
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