Comparison of Intravascular Ultrasound and Quantitative Coronary Angiography for the Assessment of Coronary Artery Disease Progression
Background— The relative merits of quantitative coronary analysis (QCA) and intravascular ultrasound (IVUS) for the assessment of progression/regression in coronary artery disease are uncertain. To explore this subject further, we analyzed the angiographic and IVUS data derived from a contemporary clinical trial population.
Methods and Results— We investigated the relationships between QCA and IVUS at single time points (n=525) and also for the changes over time (n=432). QCA and IVUS data underwent central laboratory analyses. Statistically significant correlations were observed between the QCA coronary artery score and the IVUS-derived lumen volume (r=0.65, P<0.0001) and total vessel volume (r=0.55, P<0.0001) and between the QCA cumulative coronary stenosis score and percent atheroma volume on IVUS (r=0.32, P<0.0001) at baseline for matched segments. A similar pattern of correlations was observed for global (all segments) QCA-derived and single-vessel IVUS-derived data. There were statistically significant but weak correlations between the changes over time in lumen dimensions on QCA and IVUS (P=0.005) and between the change in cumulative coronary stenosis score on QCA and percent atheroma volume on IVUS (r=0.14, P=0.01). Nevertheless, patients with and without angiographic progression had changes in plaque volume on IVUS of 9.13 and 0.20 mm3, respectively (P=0.028).
Conclusions— QCA- and IVUS-derived measures of lumen dimensions are correlated at single time points and for changes over time. Although the change in percent atheroma volume is only weakly correlated with QCA changes as continuous variables, disease progression on QCA is associated with significant increases in plaque volume on IVUS compared with no angiographic progression.
Received July 31, 2006; accepted January 5, 2007.
Historically, quantitative coronary analysis (QCA) has been the reference method for the angiographic assessment of coronary artery disease (CAD) severity and progression.1–6 The limitations of coronary angiography, particularly with respect to underestimation of disease severity, however, are well described.7–10 In recent years, intravascular ultrasound (IVUS) has emerged as a more sensitive tool for the assessment of plaque severity and morphology compared with other methods, such as QCA.11–16 Unlike QCA, IVUS allows direct visualization of the arterial wall and plaque. Positive artery remodeling, which is known to be associated with plaque rupture,17,18 can be detected more accurately by IVUS than by QCA.16 Serial IVUS follow-up provides an opportunity to assess change in the nature and severity of coronary atheroma with time, and the safety of this approach has been confirmed.19 For these reasons, IVUS has become the reference method for quantification of plaque volume and evaluation of plaque progression/regression in trials of antiatherosclerosis drug therapies.20,21
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IVUS assessments, however, are usually restricted to 1 instrumented coronary artery; thus, whether or not information derived from a few segments of 1 artery may be correlated with disease in other coronary arteries is uncertain. Furthermore, there are presently no comparative data for the relationships between atherosclerosis progression or regression as assessed by QCA and IVUS. To explore this subject further, we analyzed the angiographic and IVUS data derived from a contemporary clinical trial population.21 We therefore investigated the relationships between QCA- and IVUS-derived measures of CAD severity at single points in time and also compared the changes in QCA and IVUS data over time. Given the fact that QCA has been accepted as a surrogate end point,22 comparison with coronary angiography is important to further validate IVUS and raise the status of this imaging biomarker.
The population in the present study included patients who were randomized in the Avasimibe and Progression of Coronary Lesions Assessed by Intravascular Ultrasound (A-PLUS) trial, a multicenter placebo-controlled study of the acyl coenzyme A:cholesterol acyltransferase enzyme inhibitor avasimibe.23 Five hundred twenty-five patients from 25 centers in Canada, the United States, Europe, Australia, and South Africa had a baseline IVUS assessment,23 and 432 patients had an evaluable repeat IVUS examination.21 These patients needed to have suspected or proven coronary artery disease and be scheduled for clinically indicated coronary angiography. The target coronary artery for IVUS needed to have a 20% to 50% diameter stenosis in a coronary artery ≥2.5 mm in diameter by visual angiographic assessment to facilitate the IVUS examination. In addition, this target artery should not have been the subject of previous or present revascularization and had to be free of radiographic contrast filling defects. Patients undergoing percutaneous coronary intervention of a non-IVUS target artery could be included. All patients gave written informed consent.
Meticulous care was taken to ensure identical conditions during the angiographic examinations at baseline and follow-up (catheters, contrast media, projections, recordings). In particular, intracoronary nitroglycerin (150 μg) was administered into each coronary artery before angiographic injection. The segments of interest were visualized in multiple transverse and sagittal views to clearly separate stenoses from branches, minimize foreshortening, and obtain views as perpendicular as possible to the long axis of the segments to be analyzed.
Quantitative Coronary Analysis
All coronary angiograms were analyzed at the Montreal Heart Institute QCA Core Laboratory by means of the Clinical Measurements Solutions system (QCA-CMS, version 5.1; MEDIS Imaging Systems, Leiden, the Netherlands).23 The automatic edge detection program determines the vessel contours by assessing brightness along scan lines perpendicular to the vessel center. QCA was performed by experienced technicians supervised by an expert physician in matched projections from the baseline and follow-up coronary angiograms.4,24 For each lesion, an end-diastolic frame from both angiograms (baseline and follow-up) was selected with identical angulations that best showed the stenosis at its most severe degree with minimal foreshortening and branch overlap. The coronary artery segments analyzed included all those with a reference diameter ≥1.5 mm and a stenosis ≥20% at baseline and those with new lesions at follow-up. All coronary arteries intervened with percutaneous coronary intervention were excluded from the analysis (from the aorto-ostial junction to the distal segment and its branches) to exclude neointima/restenosis from the analysis of atherosclerosis progression. The quantification system has been shown to measure coronary dimensions from different end-diastolic cine frames with an average SD of the measurement differences of ±0.13 mm.24 Computer software automatically calculates the minimum lumen diameter (MLD), reference diameter, percent diameter stenosis, and stenosis length.
QCA Measures of CAD Severity
The QCA variables were determined at baseline and follow-up: (1) The coronary artery score represents the per-patient average of the MLD of all the measured segments4,25; a higher score reflects less obstructed coronary artery lumen. (2) The cumulative coronary stenosis score was calculated by adding all percent diameter stenoses in SI units (50%=0.50); the cumulative coronary stenosis score is an index of the anatomic extension and severity of CAD, and a higher value reflects more severe disease.26 (3) The mean plaque area was calculated by averaging all of the plaque area values in the segments studied27; the plaque area by QCA is represented by the area between the estimated interpolated reference and luminal contours within the obstruction boundaries. (4) The mean lesion diameter was calculated as the mean lumen diameter within the obstruction boundaries of each lesion and then averaged for all segments studied.
To assess disease progression and regression with the use of continuous QCA data, the changes in coronary artery score, cumulative coronary stenosis score, mean plaque area, and mean lesion diameter were calculated. To assess disease change as a categorical variable by QCA, the following approach was taken. A change in MLD ≥0.4 mm represents approximately twice the SD of repeat measurements of lesions filmed at 1- to 6-month intervals in previous studies24 and was taken to represent a true change, either progression or regression. Lesion progression or regression was therefore considered present when a lesion at baseline showed a worsening or improvement, respectively, of MLD ≥0.4 mm at the follow-up angiogram.24 Disease progression by QCA in the IVUS-related artery was defined as ≥1 lesion with a worsening of MLD ≥0.4 mm with no lesion having an improvement of MLD ≥0.4 mm. A new coronary lesion was defined as a stenosis that was not apparent on the first angiogram or was <20% in diameter stenosis but that narrowed by ≥0.4 mm in MLD at the follow-up angiogram on QCA.
IVUS Image Acquisition
The methods of the IVUS procedure have been detailed previously.23 In brief, single-vessel IVUS studies were performed at baseline and follow-up with the use of 30-MHz IVUS catheters (Boston Scientific, Natick, Mass).23 Intracoronary nitroglycerin (150 μg) was administered before the IVUS examination. The IVUS catheter was advanced distally, at least 40 mm beyond the coronary artery ostium, to a recognizable landmark (arterial branch). The guiding catheter was disengaged before imaging to allow visualization of the aorto-ostial junction. The transducer was then pulled back automatically at a speed of 0.5 mm/s up to the guiding catheter with the use of a validated motorized device. A detailed running audio commentary was recorded during the pullback. A second pullback was then performed in the same coronary artery with the use of the same guidelines to ensure high-quality imaging.28 To ensure that each center was initially capable of proper collection of IVUS data, the core laboratory reviewed 2 test-run examinations before approving the clinical site.
IVUS Image Analyses
IVUS images were analyzed by side-by-side viewing of baseline and follow-up studies, review of landmarks and pullback speed, frame-by-frame comparison for matching segments, and digitization of images. Distal and proximal branches were used as fiduciary sites to allow matching of the coronary segment to be traced. The lumen and external elastic membrane borders were traced manually on 1 of every 4 digitized cross sections with a custom-developed system (INDEC). Contours were interpolated for all the digitized cross sections between the manually drawn ones, but the segmentation was assessed visually in all cases on each cross section and always corrected manually if necessary. Interpolation of the lumen and external elastic membrane contours was performed according to an acoustic quantification method and a nonlinear algorithm, respectively, as described previously.23 A total of 900 cross sections were analyzed in the 30-mm segment of interest at both baseline and follow-up. Plaque, lumen, and total vessel volumes were computed for the entire length of the analyzed segments by multiplying the corresponding areas of each of the cross sections by the distance between the neighboring slices and then adding all the products. The intraclass coefficients for interobserver variability of measurement of plaque and vessel volumes in our laboratory are 0.98 and 0.99, respectively.
IVUS End Points and Definitions
The variables determined at both baseline and follow-up by analyses of IVUS images included (1) total plaque volume (mm3); (2) total lumen volume (mm3); (3) total vessel volume (mm3); and (4) percent atheroma volume. Percent atheroma (plaque) volume was computed by dividing plaque volume by total vessel volume and then multiplying by 100%. Comparisons were made between IVUS data and the 4 QCA measures of CAD severity for all coronary artery segments (global) and for IVUS-instrumented (matched) segments at baseline and at follow-up and for the change from baseline to follow-up.
Continuous data are presented as mean±SD. Relationships between IVUS results and the QCA indices for all segments (global) or for the segments corresponding to the IVUS-related artery were assessed with Pearson correlation coefficients. Comparisons of continuous data between groups at baseline and follow-up (eg, QCA: progression versus no progression) were performed with Student t tests, and comparison of the change from baseline to follow-up between groups was done with an ANCOVA with the baseline value as the covariate. After a significant group-by-baseline value interaction, groups were compared at 3 different values of the baseline covariate (the 25th, 50th, and 75th percentiles). A 2-sided probability level of <0.05 was taken as significant. All analyses were done with SAS (versions 8.2 and 9.1.3; SAS Institute, Cary, NC).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
IVUS Versus QCA Results at 1 Time Point
Five hundred twenty-five patients were included in this analysis, and their baseline characteristics are shown in Table 1. Of these, 432 subjects had paired IVUS data. Total vessel, lumen, and plaque volumes were 438.3±127.6, 239.0±84.0, and 199.3±71.2 mm3, respectively, at baseline and 435.0±131.9, 234.4±85.1, and 200.6±72.3 mm3, respectively, at follow-up. Percent atheroma volume was 45.2±9.9% at baseline and 46.1±9.5% at follow-up. The correlations between QCA parameters at baseline for the IVUS-related artery and for all coronary artery segments and IVUS results at baseline are shown in Tables 2 and 3⇓, respectively. In the IVUS-related artery, significant correlations were observed between the QCA coronary artery score and the IVUS-derived total lumen volume (r=0.65, P<0.0001; Figure) and total vessel volume (r=0.55, P<0.0001) at baseline (Table 2). There were statistically significant but relatively weak correlations between QCA-derived measures and IVUS indices of plaque burden (r=0.32, P<0.0001 for percent atheroma volume on IVUS versus cumulative coronary stenosis score on QCA).
A similar pattern of correlations was observed when we compared QCA performed in all coronary arteries and IVUS-derived data (Table 3). The coronary artery score for all arteries assessed by QCA correlated with total lumen volume on IVUS (r=0.54, P<0.0001). There were statistically significant correlations between QCA parameters and IVUS indices of plaque burden; these correlations tended to be better for percent atheroma volume than for plaque volume (r=0.30, P<0.0001 for percent atheroma volume versus cumulative coronary stenosis score). The results comparing QCA parameters at follow-up and IVUS results at follow-up were similar to those described at baseline.
Changes on IVUS Versus Changes on QCA
Although the change in coronary artery score on QCA correlated weakly with the change in IVUS-derived total lumen volume (r=0.14, P=0.005) and the change in minimal lumen area (r=0.17, P=0.0006) over time in the IVUS-related artery, no significant correlations were observed between the change in QCA indices and change in IVUS-derived plaque volume for all coronary segments or for matched segments (Tables 4 and 5⇓). However, there were statistically significant but weak correlations between the change in QCA measures and the change in percent atheroma volume on IVUS (r=0.14, P=0.01 for change in cumulative coronary stenosis score in all vessels on QCA versus percent atheroma volume on IVUS; Tables 6 and 7⇓). In contrast, no significant correlations were observed between changes in QCA measures (global and matched segments) and changes in IVUS-derived plaque volume when baseline and follow-up IVUS examinations were matched for 5-mm subsegments centered on either the largest plaque area, the least plaque area, the largest lumen area, or the smallest lumen area at either baseline or follow-up (data not shown).
The comparison of IVUS results between subjects with QCA evidence of disease progression in the IVUS-related artery and subjects with no progression of disease is shown in Table 8. Compared with subjects with no disease progression by QCA, subjects with angiographic progression had greater plaque volume on IVUS at baseline (P=0.0495) and a mean increase of plaque volume of 9.13 mm3 between both examinations (versus a mean increase of 0.20 mm3 in those without angiographic progression; P=0.0283 for interaction between progression [yes/no] and baseline plaque volume). This significant interaction indicates that the difference between patients with angiographic progression and patients with no progression on QCA depends on the baseline status of plaque volume. Therefore, patients with and without progression on QCA were compared at different values of plaque volume at baseline (Table 9). Patients with angiographic progression had greater increases in plaque volume from baseline to follow-up on IVUS for baseline plaque volumes of 146 mm3 (P<0.005), 190 mm3 (P<0.005), and 239 mm3 (P=0.1349).
The major findings of the present study can be summarized as follows: (1) QCA (coronary artery score and mean lumen diameter) and IVUS measures of lumen dimensions correlate fairly well at a given point in time. (2) There are statistically significant but relatively weak correlations between QCA measure of plaque burden (cumulative coronary stenosis score) and percent atheroma volume on IVUS. (3) Changes in lumen dimensions over time (change in coronary artery score on QCA versus change in lumen volume on IVUS) correlate weakly and less well than at a given point in time. (4) There are statistically significant but weak correlations between the change in QCA measures and the change in percent atheroma volume on IVUS. (5) Although there is no correlation between changes in QCA measures and changes in plaque volume on IVUS as continuous variables, patients with angiographic progression have both greater plaque volume at baseline on IVUS and significantly higher increases in plaque volume over time compared with patients with no angiographic progression.
The significant albeit imperfect correlations between the standard approaches to measure lumen dimensions with QCA (coronary artery score) and IVUS (total lumen volume) demonstrate the relationship between these imaging modalities, despite angiography depicting the lumen as a longitudinal silhouette and IVUS providing cross-sectional images of the true architecture of the lumen. Similarly, despite the fact that angiography does not allow direct visualization of the arterial wall and atherosclerotic plaque, there were statistically significant but weak correlations between QCA and measures of plaque burden on IVUS. When QCA performed in all vessels and IVUS of a single artery were compared, the correlations of plaque volume on IVUS tended to be better with QCA measures attempting to evaluate plaque burden (cumulative coronary stenosis score and mean plaque area) than with QCA indices focusing on the most severe lumen obstruction (coronary artery score and mean lesion diameter). Interestingly, in this comparison of QCA in all vessels and IVUS in 1 coronary artery, the correlations with QCA were better (although still relatively weak) for IVUS-determined percent atheroma volume than for plaque volume. The possible reasons for the latter finding are discussed below.
To our knowledge, the present study is the first that evaluates angiographic progression over time in the 3 coronary arteries and change in plaque burden by IVUS. Although changes in lumen dimensions over time on QCA and IVUS were correlated weakly in the present study, there was no correlation between the change in QCA measures and the change in plaque volume on IVUS as continuous variables. Of note, no correlation was found between the change in any QCA measures and the change in plaque volume in the 5-mm subsegment with greatest disease severity at baseline on IVUS. Nevertheless, when QCA results were analyzed as a dichotomous variable, patients with evidence of angiographic progression had both larger plaque volumes on the initial IVUS examination and a significant increase in plaque volume (9 mm3) from baseline to follow-up. In contrast, patients without angiographic evidence of disease progression had no increase (a mean change of 0.20 mm3) in plaque volume on IVUS. Dichotomous progression on QCA was probably associated with greater increase in plaque volume on IVUS in part because outward remodeling had already been utilized in these patients entering the study with angiographic stenoses. In contrast, the lack of correlation when these measurements were analyzed as continuous variables is probably explained by the variable (bidirectional) accompanying vascular remodeling29 that occurred. This confusing issue was clarified by the analysis of the change over time of percent atheroma volume on IVUS, which revealed statistically significant (albeit weak) correlations with QCA measures. This is probably because both percent atheroma volume on IVUS and QCA parameters take into account changes in plaque burden as well as vascular remodeling. In contrast to percent atheroma volume, plaque volume provides information only on plaque burden and not on remodeling, and its change over time did not correlate with changes in QCA indices as continuous variables. Although the correlations between the change in percent atheroma volume on IVUS and changes in cumulative coronary stenosis score and mean plaque area were weak, they were similar in the analysis of all segments and that limited to the IVUS-related artery, which suggests that interrogation of 1 coronary artery provides information similar to that obtained in the other vessels. When it is considered that coronary angiography has been recognized as a surrogate marker and used to broaden claims of several lipid-lowering agents,22 our findings linking changes on QCA with changes in percent atheroma volume on IVUS may contribute to some extent to the validation of the latter as a useful biomarker. However, these correlations are not sufficiently strong to represent definitive validation with an established surrogate end point. Therefore, data linking changes on IVUS with long-term clinical outcomes are also needed to validate the clinical significance of the information provided by IVUS.
In conclusion, QCA- and IVUS-derived measures of lumen dimensions are correlated at single time points and for changes over time. Although the change in percent atheroma volume is only weakly correlated with QCA changes as continuous variables, disease progression on QCA is associated with significant increase in plaque volume on IVUS compared with no angiographic progression.
We gratefully acknowledge the expert work of the personnel of the intravascular ultrasound core laboratory (Joanne Vincent, Francine Duval, Ginette Grenier, Colombe Roy, Claudette Léger-Gauthier) and of the QCA core laboratory (France Bélanger, Colette Desjardins, Marie-Josée Dussault).
Sources of Funding
The present study was supported by the Pfizer and Canadian Institutes of Health Research Chair in Atherosclerosis held by Dr Tardif. Dr Berry was supported by a British Heart Foundation International Fellowship. Dr Lespérance received a research grant as QCA core laboratory director for the A-PLUS Study.
Dr Tardif holds the Pfizer and Canadian Institutes of Health Research Chair in Atherosclerosis. The remaining authors report no conflicts.
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Intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA) provide different assessments of coronary disease. In contrast to QCA, IVUS allows direct visualization of the arterial wall and plaque, which is highly desirable in the evaluation of atherosclerosis. Before the present study, however, there were no comparative data for the relationships between atherosclerotic changes assessed by both methods. Our present study, conducted in 525 patients, shows that QCA and IVUS measures of lumen dimensions are correlated at single time points and for changes over time. Although there was no correlation between changes in QCA measures and changes in plaque volume on IVUS as continuous variables, patients with angiographic progression had both greater plaque volume at baseline IVUS examination and significantly higher increases in plaque volume over time compared with patients without angiographic progression. We also found statistically significant but weak correlations between the change in QCA measures and the change in percent atheroma volume on IVUS. When it is considered that coronary angiography has been recognized as a surrogate marker and used to broaden claims of several lipid-lowering agents, our findings linking changes on QCA with changes in percent atheroma volume on IVUS (an index that takes into account both plaque burden and remodeling) may contribute to some extent to the validation of the latter as a useful biomarker. However, these correlations are not sufficiently strong to represent definitive validation with an established surrogate end point. Therefore, data linking changes on IVUS with clinical outcomes are also needed to validate the clinical significance of the information provided by IVUS.
↵*The first 2 authors contributed equally to this work.