CLINICAL RESEARCH: CARDIAC IMAGING
Long-term safety of intravascular ultrasound in nontransplant, nonintervened, atherosclerotic coronary arteries
Antoine Guédès, MD,
Pierre-Frédéric Keller, MD,
Philippe L. L'Allier, MD,
Jacques Lespérance, MD,
Jean Grégoire, MD and
Jean-Claude Tardif, MD*
Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
Manuscript received September 15, 2004;
revised manuscript received October 25, 2004,
accepted October 26, 2004.
* Reprint requests and correspondence: Dr. Jean-Claude Tardif, MHI Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, Canada, H1T 1C8 (Email: jean-claude.tardif{at}icm-mhi.org).
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Abstract
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OBJECTIVES: The goal of this study was to demonstrate that intravascular ultrasound (IVUS) examination of native coronary arteries does not result in an acceleration of the atherosclerotic process.
BACKGROUND: Intravascular ultrasound is increasingly used to assess the effects of pharmacologic agents on atherosclerosis.
METHODS: Intravascular ultrasound examinations of one coronary artery and coronary angiography were performed in 525 patients at baseline. Patients then underwent a follow-up angiogram 18 to 24 months later. All end points were evaluated in IVUS-related and non-IVUS arteries using quantitative coronary analysis. The study end points were the coronary change score (per-patient mean of minimum lumen diameter changes for all lesions measured), occurrence of new coronary lesions, and progression of preexistent lesions at follow-up. Acute angiographic and clinical complications were also analyzed.
RESULTS: Coronary change score was –0.06 ± 0.23 mm and –0.05 ± 0.21 mm for IVUS-related and non-IVUS arteries, respectively (p = 0.35). The increase in percent diameter stenosis from baseline to follow-up was 0.8 ± 6.7% and 1.2 ± 7.0% in the IVUS-related and non-IVUS arteries (p = 0.29). New lesions occurred in 3.6% and 3.9% of IVUS-related and non-IVUS arteries, respectively (p = 0.84). When all coronary lesions were considered, the incidence of lesion progression was not significantly different between IVUS-related (11.6%) and non-IVUS (9.8%) arteries. Coronary spasm occurred in 1.9% of IVUS procedures, and there was one case of acute occlusion with no long-term sequelae.
CONCLUSIONS: Intravascular ultrasound does not significantly accelerate atherosclerosis in native coronary arteries and can be used safely to assess progression/regression in clinical trials.
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Abbreviations and Acronyms
| | IVUS = intravascular ultrasound | | MLD = minimum lumen diameter | | PCI = percutaneous coronary intervention | | QCA = quantitative coronary analysis |
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Atherosclerosis imaging has taken on increasing importance in the understanding of the natural history of coronary artery disease and the processes leading to luminal narrowing, as well as the assessment of therapy efficacy (1). Intravascular ultrasound (IVUS) is an imaging method that uses miniaturized ultrasound transducers at the tip of catheters to provide cross-sectional images of both the coronary arterial lumen and wall with excellent resolution. The precise assessment of both plaque burden and vascular remodeling has resulted in the increasing use of IVUS as the primary efficacy assessment measure of several antiatherosclerotic approaches in randomized clinical trials (2–5). Advantages of IVUS include its ability to reveal antiatherosclerotic effects within a relatively short period of time and with a reasonable sample size, in contrast to trials assessing clinical events; IVUS can also help to determine dose-response relationships in the development of novel pharmacologic agents (5).
Because of these advantages of IVUS, it is imperative to demonstrate the safety of this catheter-based imaging modality, especially when used strictly for research purposes in native coronary arteries. Although the short-term safety of IVUS has been shown in large multicenter registries (6,7), the data on long-term safety after coronary imaging are much more limited. Indeed, while three studies have reported follow-up after initial IVUS examination of transplant coronary arteries (8–10), there are presently no published data on long-term safety in nontransplant, native atherosclerotic coronary arteries that have never been treated by percutaneous coronary intervention (PCI). In addition, there is a concern that catheter-induced endothelial damage may lead to an acceleration of the atherosclerotic process in instrumented vessels (11). Therefore, we assessed in this study the long-term safety of IVUS up to two years after the initial examination of atherosclerotic native coronary arteries.
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Methods
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Patient population.
The study population consisted of 525 patients of the Avasimibe and Progression of coronary Lesions assessed by intravascular UltraSound (A-PLUS) trial from 25 centers in Canada, the U.S., Europe, Australia, and South Africa (3). Patients needed to have suspected or proven coronary artery disease and be scheduled for clinically indicated coronary angiography. All patients underwent a baseline coronary angiogram and IVUS after giving written informed consent, and a second coronary angiogram was done after 18 to 24 months of follow-up.
The target coronary artery for IVUS needed to have a 20% to 50% diameter stenosis in a vessel  2.5 mm by visual angiographic assessment to facilitate the IVUS examination. The target coronary artery also had to be free of filling defects suggestive of thrombus and should not have been influenced by prior or present therapeutic PCI. Patients undergoing PCI of a nontarget artery at the time of screening catheterization could be included.
IVUS procedure.
Intravascular ultrasound studies were performed using 3.2-F or 2.9-F 30-MHz IVUS catheters (Boston Scientific, Natick, Massachusetts). 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 using the same guidelines to ensure high-quality imaging (12). To ensure each center was initially capable of proper collection of IVUS data, the core laboratory reviewed two test-run examinations before approving the clinical site.
Angiographic procedure.
Attention was paid to have identical conditions during both 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. All patients had intracoronary contrast injections after the IVUS examination was performed to allow detection of coronary spasm, thrombus, dissection, or any other angiographically visible acute complication.
Quantitative coronary analysis (QCA) of angiograms.
All coronary angiograms were analyzed at our QCA core laboratory by means of the Clinical Measurements Solutions system (QCA-CMS, Version 5.1; MEDIS Imaging Systems, Leiden, the Netherlands) (13). The automatic edge detection program determines the vessel contours by assessing brightness along scanlines perpendicular to the vessel center (14). To provide absolute numbers for vessel sizes, a calibration factor expressed in mm/pixel is determined by applying the edge-detection procedure for parallel boundaries on a non-tapering section (of known size) of the contrast-filled catheter. The computer automatically calculates the minimum lumen diameter (MLD), reference diameter, percentage diameter stenosis, and stenosis length.
The QCA was performed by technicians supervised by an experienced physician (14–16) in matched projections from the baseline and follow-up coronary angiograms. For each lesion in the study end point segments, an end-diastolic frame from both angiograms (baseline and follow-up) was selected with identical angulation that best showed the stenosis at its most severe degree with minimal foreshortening and branch overlap. The study end point segments included all those of a diameter 2.0 mm with stenosis 20% at baseline and those with new lesions at follow-up. All coronary arteries intervened with PCI were excluded from the analysis (from the aorto-ostial junction to the distal segment, and its branches).
Among study end point segments, IVUS-related (instrumented) and non-IVUS (non-instrumented, control) arteries were identified. All coronary segments from the aorto-ostial junction to the distal segment reached by the tip of the IVUS guidewire were considered as IVUS-related segments. The non-IVUS (control) segments were defined as all coronary artery segments without any instrumentation for IVUS or past or present PCI. The number of coronary segments measured by QCA in the IVUS-related (instrumented) and non-IVUS (control) coronary arteries was dependent on the criteria described above.
Comparison between IVUS-related and control coronary arteries from baseline to follow-up coronary angiography using QCA.
The coronary change score was defined as the per-patient mean of the MLD changes of all coronary segments analyzed by QCA between baseline and follow-up (16). A change in MLD 0.4 mm represents approximately twice the SD of repeat measurements of lesions filmed at one- to six-month intervals in previous studies (14,15) and was, therefore, taken to represent a true change, either progression or regression. 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. Lesion progression was considered present when at least one lesion at baseline (20%) showed a worsening of MLD 0.4 mm at the follow-up angiogram. For each patient, these end points were evaluated in the IVUS-related segments and the non-IVUS (control) coronary artery segments.
Acute angiographic and clinical complications.
All IVUS examinations performed at baseline were analyzed for acute clinical complications. A total of 475 IVUS examinations were suitable for the analysis of acute angiographic complications. For the remaining 50 patients, there was no adequate angiographic recording to assess the presence or absence of spasm or other complications after IVUS instrumentation. Such patients were excluded from the statistical analysis of acute angiographic complications, although they were all reported as normal by the operators who performed the coronary angiograms. Acute angiographic complications were considered along the entire IVUS-related artery from the aortocoronary ostial junction to the tip of the guidewire. Detailed clinical manifestation of any angiographic complication was reported for each patient.
Statistical analysis.
Continuous data are presented as mean ± SD. For each patient, the study end points were evaluated in the IVUS-related coronary segments and the non-IVUS (control) coronary segments. Comparisons between IVUS-related arteries and control arteries were done using a repeated measures analysis of variance for coronary change score, lesion length and reference diameter at baseline, and using McNemar tests for new coronary lesions and progression of coronary lesions. Paired t tests were used for baseline lesion length and baseline reference diameter for the patients with both IVUS-related arteries and non-IVUS arteries (n = 387). All analyses were done with SAS (version 8.2, SAS Institute, Cary, North Carolina). A value of p < 0.05 was considered significant.
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Results
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Patients' characteristics at baseline are summarized in Table 1. The mean age of the patients was 58 years, and 55% of them had hypertension. The vast majority (88%) of patients were treated with statins: 48% of patients were treated with atorvastatin, 27% with simvastatin, and 13% with pravastatin. Mean low-density lipoprotein cholesterol was 92 mg/dl (2.42 mmol/l), and mean high-density lipoprotein cholesterol was 44 mg/dl (1.20 mmol/l). Mean plaque volume on IVUS was 199 ± 71 mm3 (Table 2). Mean duration of follow-up was 19 months. Quantitative coronary analysis results at baseline and follow-up are summarized in Table 3.
Coronary change score.
The coronary change score, defined as the per-patient mean of MLD changes for all lesions measured, was available in 499 patients for IVUS-related (instrumented) arteries and in 400 patients for non-IVUS (non-instrumented, control) arteries. The lipid profiles were similar in both groups of patients (Table 4). The distribution of coronary arteries was as follows: left anterior descending, circumflex, and right coronary arteries represented 35%, 23%, and 42%, respectively, of IVUS-related arteries and 28%, 41%, and 31%, respectively, of non-IVUS arteries. There were 1,068 lesions studied in IVUS-related arteries and 1,024 lesions in non-IVUS arteries. The coronary change score was –0.06 ± 0.23 mm for the IVUS-related arteries and –0.05 ± 0.21 mm for the non-IVUS coronary arteries (p = 0.35) (Fig. 1). Among the 387 patients in whom both IVUS-related and non-IVUS arteries were assessed, the coronary change score was –0.05 ± 0.21 mm and –0.04 ± 0.21 mm for IVUS-related arteries and non-IVUS arteries, respectively (p = 0.50) (Table 5).
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Figure 1 Bar graphs for the coronary change score (left panel) and for the categorical end points (right panel) for all lesions in the intravascular ultrasound (IVUS)-related (instrumented) and non-IVUS (control) coronary arteries. *To assess statistical significance for the rates of categorical end points, patients with both evaluable IVUS-related coronary arteries and evaluable non-IVUS arteries were taken and McNemar tests were done (see text). Solid bars = IVUS-related arteries (instrumented); ruled bars = non-IVUS arteries (control).
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New coronary lesions.
New coronary lesions were present in 18 of 499 (3.6%) of patients for IVUS-related arteries and in 17 of 400 (4.3%) of patients for non–IVUS-related arteries. Among the 387 patients in whom both IVUS-related and non-IVUS arteries were assessed, new coronary lesions were present in 14 of 387 (3.6%) and 15 of 387 (3.9%) of patients for IVUS-related and non-IVUS (control) arteries, respectively (p = 0.84) (Fig. 1). Among the 14 patients with new coronary lesions in IVUS-related arteries at follow-up, 2 of 14 (14%) also had new coronary lesions in non-IVUS coronary arteries and 12 of 14 (86%) had not. Among the 373 patients without new lesions in IVUS-related coronary arteries at follow-up, 13 of 373 (3%) had new lesions in non-IVUS coronary arteries and 360 of 373 (97%) had not.
Progression of coronary lesions.
Lesion progression occurred in 58 of 499 (11.6%) patients for IVUS-related arteries and in 39 of 400 (9.8%) patients for non-IVUS (control) arteries. To assess statistical significance of these rates, patients with both evaluable IVUS-related arteries and evaluable non-IVUS coronary arteries were taken (n = 387). Lesion progression was present in 45 of 387 (11.6%) of patients in IVUS-related coronary arteries and in 36 of 387 (9.3%) of patients in non-IVUS coronary arteries (p = 0.27) (Fig. 1). Among the 45 patients with lesion progression in IVUS-related coronary arteries at follow-up, 7 of 45 (16%) also had lesion progression in non-IVUS coronary arteries and 38 of 45 (84%) had not. Among the 342 patients without progression of coronary lesions in IVUS-related arteries at follow-up, 29 of 342 (8%) had lesion progression in non-IVUS coronary arteries and 313 of 342 (92%) had not.
Acute angiographic complications and clinical events.
The most frequent side effect was coronary spasm, which occurred in nine procedures out of a total of 475 IVUS examinations for an incidence of 1.9%. Coronary spasm was relieved in all cases by the intracoronary injection of nitroglycerin.
Only one major complication occurred during these IVUS examinations performed at baseline, which was an occlusion at the site of a preexisting 50% diameter stenosis of the second left posterolateral coronary artery. This was successfully treated by balloon angioplasty, and the artery was angiographically normal at 24-month follow-up. There were no episodes of guidewire entrapment, embolism, thrombus, unstable angina, myocardial infarction, or death related to the IVUS examinations.
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Discussion
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This is the first clinical study that demonstrates that IVUS examination of native atherosclerotic coronary arteries does not accelerate disease progression evaluated after up to 24 months of follow-up. The coronary change score as well as the incidence of new coronary lesions and disease progression were similar in IVUS-related and non-IVUS coronary arteries. Intravascular ultrasound is increasingly used as the primary efficacy assessment measure of several antiatherosclerotic approaches in randomized clinical trials (2–5). The precise evaluation of plaque burden and vascular remodeling with IVUS indeed makes it an excellent imaging modality for clinical trials of atherosclerosis progression/regression (1). It is, however, extremely important to demonstrate the safety of this invasive diagnostic procedure, especially when performed for research purposes. Although its short-term safety has been well demonstrated (6,7), the data on the long-term safety of IVUS was much more limited.
Disease progression in coronary arteries.
The one-year safety of IVUS imaging has been assessed by serial QCA of angiograms in three studies involving only cardiac transplant recipients (8–10). The first two studies were small and involved 38 and 86 heart transplant patients and did not show any significant difference between instrumented and non-instrumented vessels in terms of percentage or absolute change in angiographic lumen diameter one year after the initial IVUS examination (8,9). Ramasubbu et al. (10) compared vessel diameter, frequency, and severity of coronary stenosis between instrumented and non-instrumented coronary arteries in 226 heart transplant recipients one to two years after IVUS examination. In that study, a comparison with 130 control coronary arteries allowed the demonstration of the absence of disease acceleration in the 548 IVUS-related vessels in these transplant patients, but QCA measurements of matched angiograms were actually performed in only 31 patients (10).
Although these data in heart transplant recipients were reassuring, transplant arteriopathy is, in part, an immune-mediated disease that is not identical to atherosclerosis (17). In addition, stenosis at the time of IVUS examination was less severe in these cardiac transplant patients than in our study of native coronary arteries. To our knowledge, our study is the first one to evaluate prospectively the effect of IVUS examination on disease progression in nontransplant, nonintervened, atherosclerotic native coronary arteries.
Acute angiographic complication and clinical events.
The most frequently encountered complication in previous reports was coronary spasm, which occurred in approximately 2% to 3% of patients during interventional and diagnostic IVUS procedures and usually responded rapidly to administration of intracoronary nitroglycerin (1,6,7). Major and acute procedural complications potentially associated with IVUS imaging were rare and occurred during interventional cases (6). In one large multicenter registry involving more than 2,200 patients assessing its short-term safety, there was no occurrence of myocardial infarction associated with IVUS imaging performed for diagnostic indications (6). In our study, the incidence of coronary spasm was 1.9%, and there was one case of acute occlusion requiring balloon angioplasty that did not result in myocardial infarction or long-term sequelae.
Study limitations.
Quantitative coronary analysis has limitations when used for the assessment of atherosclerosis progression, the most important one being its inability to allow direct visualization of the coronary arterial wall; QCA nevertheless remains the best imaging method currently available to evaluate the long-term safety of IVUS. However, atherosclerotic changes that would not result in luminal changes could not be analyzed. Because there was 80% power to detect a difference of 0.04 mm in coronary change score, minimal changes in lumen dimensions might not have been detected. The long-term follow-up without significant deleterious angiographic effects clearly supports the safety of IVUS imaging. The safety of the procedure as demonstrated in this study may be dependent on the characteristics of the patients. Performing IVUS examination on severely stenotic and calcified coronary arteries in patients with comorbidities may not necessarily be as safe. The IVUS arteries were indeed larger at baseline than non-IVUS arteries in our study.
Conclusions.
This study has shown that diagnostic IVUS imaging does not significantly accelerate atherosclerosis in native human coronary arteries and can be used safely to assess disease progression/regression in clinical trials.
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Acknowledgments
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The authors gratefully acknowledge the expert work of the QCA core laboratory technicians (France Belanger, Colette Desjardins, Marie-Josee Dussault), IVUS core laboratory technicians (Joanne Vincent, Ginette Grenier, Francine Duval, and Colombe Roy), and biostatisticians (Sylvie Levesque, MSc, and Marie-Claude Guertin, PhD) who have contributed to this study.
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Footnotes
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This research was financed by the Pfizer and Canadian Institutes of Health Research chair in atherosclerosis. Drs. Guédès and Keller contributed equally to this work.
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References
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Abstract
Methods