Author + information
- Received December 10, 2007
- Revision received February 14, 2008
- Accepted March 5, 2008
- Published online July 1, 2008.
- Takashi Kubo, MD, PhD,
- Toshio Imanishi, MD, PhD,
- Hironori Kitabata, MD,
- Akio Kuroi, MD,
- Satoshi Ueno, MD,
- Takashi Yamano, MD,
- Takashi Tanimoto, MD,
- Yoshiki Matsuo, MD, PhD,
- Takashi Masho, MD,
- Shigeho Takarada, MD, PhD,
- Atsushi Tanaka, MD, PhD,
- Nobuo Nakamura, MD,
- Masato Mizukoshi, MD, PhD,
- Yoshiaki Tomobuchi, MD, PhD and
- Takashi Akasaka, MD, PhD⁎ ()
Reprint requests and correspondence:
Dr. Takashi Akasaka, Department of Cardiovascular Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, 641-8509, Japan.
Objectives The aim of the present study was to compare lesion morphologies after sirolimus-eluting stent (SES) implantation between patients with unstable angina pectoris (UAP) and stable angina pectoris (SAP) with the use of optical coherence tomography (OCT).
Background The lesion morphologies before and after coronary stenting have been proposed as important predictors of clinical outcome. The high resolution of OCT provides detailed information of coronary vessel wall.
Methods We enrolled 55 patients (UAP: n = 24, SAP: n = 31), and examined lesion morphologies by using OCT at pre- and post-SES implantation and 9 months' follow-up.
Results The incidence of plaque rupture (42% vs. 3%, p < 0.001), intracoronary thrombus (67% vs. 3%, p ≤ 0.001) and thin-capped fibroatheroma (cap thickness <65 μm; 46% vs. 3%, p < 0.001) at pre-intervention was significantly greater in UAP than that in SAP. Although stent profiles and procedural characteristics were not different between the 2 groups, inadequate stent apposition (67% vs. 32%, p = 0.038) and tissue protrusion (79% vs. 42%, p = 0.005) after percutaneous coronary intervention were observed more frequently in patients with UAP. Plaque rupture was significantly increased after percutaneous coronary intervention in patients with UAP (42% to 75%, p = 0.018), and the persistence of core cavity after plaque rupture (28% vs. 4%, p = 0.031) at 9 months' follow-up was observed more frequently in UAP patients compared with SAP patients. At 9 months' follow-up, the incidence of inadequately apposed stent (33% vs. 4%, p = 0.012) and partially uncovered stent by neointima (72% vs. 37%, p = 0.019) was significantly greater in UAP patients than that in SAP patients. All patients took aspirin and ticlopidine during follow-up period, and no patients had stent thrombosis or adverse coronary events.
Conclusions Serial OCT examinations demonstrated markedly different vascular response up to 9 months after SES implantation between UAP and SAP patients. Although the inadequate lesion morphologies after stenting were observed more frequently in UAP patients, these findings were not associated with adverse outcomes in patients with antiplatelet therapy.
Percutaneous coronary intervention (PCI) with the use of sirolimus-eluting stent (SES) is an effective treatment for patients with acute coronary syndromes (ACS) (1). The main contribution of SES is to reduce the need for target-vessel revascularization (2). However, sirolimus has been reported to impair local vascular healing with delayed endothelization (3), and the patients with ACS, compared to those with stable angina pectoris (SAP), present a greater risk for thrombotic complication after SES implantation (4). Therefore, vascular response after SES implantation in the vulnerable lesion is a great concern. Recently, intravascular optical coherence tomography (OCT) has been developed as a high-resolution (10 to 20 μm) imaging modality (5). In the present study, we performed serial OCT examination before and after PCI and at 9 months' follow-up to compare lesion morphology after SES implantation between patients with unstable angina pectoris (UAP) and SAP.
The patients with UAP (Braunwald class III-B) or symptomatic SAP were enrolled. Angiographic inclusion criteria were: 1) an identifiable and de novo culprit lesion in a native coronary artery; and 2) good candidates for PCI. Exclusion criteria were as follows: 1) contraindications to SES implantation; 2) culprit lesion in the left main coronary artery or the osmium of the right, left anterior descending, or circumflex coronary artery; 3) bifurcation lesion; 4) chronic total occlusion; 5) making it difficult to advance the OCT catheter; 6) making the OCT examination difficult; 7) congestive heart failure with left ventricular ejection fraction <40%; and 8) renal insufficiency with baseline serum creatinine >1.5 mg/dl. Demographic and clinical data were prospectively collected. The institutional review board approved the study, and all patients provided informed consent before participation.
OCT image acquisition
Aspirin (100 mg), ticlopidine (200 mg), and intravenous heparin (100 U/kg) were administered before coronary catheterization. Coronary catheterization was performed by the conventional femoral approach using a 6-F sheath and catheters. The OCT evaluation was performed before and after PCI and at 9 months' follow-up. The technique of OCT imaging has been described previously (6,7). In brief, a 0.016-inch OCT catheter (Image Wire, Light Lab Imaging, Westford, Massachusetts) was advanced to the distal end of the culprit lesion through a 3-F occlusion balloon catheter. To remove the blood from the field of view, occlusion balloon was inflated to 0.6 atm at proximal site of the culprit lesion, and lactate Ringer's solution was infused into coronary artery from distal tip of the occlusion balloon catheter at 0.5 ml/s. The entire length of the culprit lesion was imaged with an automatic pullback device moving at 1 mm/s. During the pullback of OCT catheter, the images were captured at an acquisition rate of 15 frames/s and recorded digitally. Percutaneous coronary intervention was performed in a standard manner. The selections of balloon and SES (Cypher, Cordis Corp. Johnson & Johnson, Miami Lakes, Florida) size were based on intravascular ultrasound (IVUS) findings.
OCT image analysis
The OCT images were analyzed by 2 independent observers who were blinded to the clinical presentations. When there was discordance between the observers, a consensus reading was obtained. The corresponding images of serial OCT examination were identified by the distances from 2 landmarks, such as side branches and stent edges. The OCT images were analyzed with validated criteria for plaque characterization as reported previously (6,8). Before PCI, plaque rupture was identified by a presence of fibrous cap discontinuity and a cavity formation within the plaque (6,8). Fibrous cap thickness was measured at the thinnest part. Lipid was semiquantified as the number of involved quadrants on the cross-sectional image. When lipid was present in ≥2 quadrants within a plaque, it was considered a lipid-rich plaque. Thin-cap fibroatheroma (TCFA) was defined as a plaque with lipid content in ≥2 quadrants and the thinnest part of a fibrous cap measuring ≤65 μm. After PCI, inadequate stent apposition, tissue protrusion, intracoronary thrombus, stent edge dissection, and plaque rupture caused by PCI were evaluated by the use of OCT. The inadequate stent apposition was defined as 1 or more stent struts clearly separated from the vessel wall (7). When the distance between stent inner surface reflection and the vessel wall was >150 μm, the stent strut was identified as clearly separated (7). Tissue protrusion was defined as a tissue prolapse between stent struts extending inside a circular arc connecting adjacent struts (5). Thrombus was identified as an intraluminal mass discontinuing from the surface of the vessel wall that had a signal-free shadow in the OCT image (9). Stent edge dissection was defined as arterial disruption adjacent to the stent where a flap of tissue could be clearly differentiated from the underlying plaque (5).
Representative OCT images obtained after PCI were shown in Figure 1. At 9 months' follow-up, the stent struts were assessed every 1 mm within the stented segment and classified into 1 of the 3 categories (Fig. 2) as reported previously (7): 1) well-apposed to vessel wall with apparent neointimal coverage; 2) well-apposed to vessel wall without neointimal coverage; and 3) inadequately apposed to the vessel wall without neointimal coverage. Furthermore, residual ruptured plaque defined by the persistence of core cavity in the stented segment was evaluated (Fig. 3). The areas of stent, lumen, and neointimal hyperplasia were also measured every 1 mm within the stented segment; volumes were calculated with the use of Simpson's rule. Interobserver and intraobserver variabilities were assessed by the evaluation of all images.
IVUS image analysis
IVUS (Atlantis SR Pro 2.5F, 40-MHz, Boston Scientific, Natick, Massachusetts) examination was performed with an automatic pullback device at a rate of 0.5 mm/s. The corresponding images of OCT and IVUS were identified by the distances from 2 landmarks, such as side branches and stent edges. The IVUS analysis was performed according to the criteria of the American College of Cardiology Clinical Expert Consensus document on IVUS (10). Inadequate stent apposition, tissue protrusion, intracoronary thrombus, and stent edge dissection were noted in the qualitative analysis. Quantitative measurements included vessel area, lumen area, plaque area, lesion length, and remodeling index. Positive remodeling was defined as a remodeling index >1.0.
Quantitative coronary angiographic analysis
Quantitative coronary angiography was conducted with the Cardiovascular Measurement System (CMS-MEDIS Medical Imaging System, Leiden, the Netherlands). The reference diameter, minimal luminal diameter, and diameter stenosis were calculated by an independent operator. In addition, late lumen loss was calculated both in-stent and in the entire analysis segment, also including the 5-mm proximal and distal stent margins (also called in-segment).
Antiplatelet regimen and clinical follow-up
Aspirin 100 mg/day and ticlopidine 200 mg/day were administrated in all patients during follow-up period. Clinical status was assessed at hospital discharge and every month after the procedure. The 9 months' follow-up was an office visit together with exercise electrocardiogram testing.
Categorical data are presented as incidences and compared with chi-square statistics or the Fisher exact test. The Fisher exact test was used if there was an expected cell value <5. Continuous variables are presented as mean ± SD and compared with the use of an unpaired or paired t test. Intraobserver and interobserver variabilities were measured by κ test of concordance. All analysis required a p < 0.05 for statistical significance.
A total of 70 patients were consecutively enrolled in the study. Fifteen patients were excluded because the OCT imaging was not performed according to exclusion criteria (n = 12), the image quality precluded analysis (n = 2), or the equipment malfunctioned (n = 1). In the remaining 55 patients with successful OCT imaging, 24 patients presented with UAP, and 31 patients with SAP. Mean follow-up period was 9.2 ± 0.9 months. Ten patients refused the angiographic and OCT follow-up. Therefore, the follow-up OCT examination was performed in 18 patients with UAP and 27 patients with SAP.
Patient characteristics at baseline are demonstrated in Table 1. Minimum lumen diameter (0.5 ± 0.2 mm vs. 0.7 ± 0.3 mm, p = 0.015) and minimum lumen area (2.7 ± 0.7 mm2 vs. 3.0 ± 0.5 mm2, p = 0.034) were significantly smaller in UAP patients compared with SAP patients. The incidence of positive remodeling (67% vs. 31%, p = 0.021) was significantly greater in UAP patients. Coronary risk factors, distributions of the culprit vessel, and PCI procedures were comparable between the 2 groups.
The OCT findings before PCI are shown in Table 2. Incidence of plaque rupture (42% vs. 3%, p < 0.001), intracoronary thrombus (67% vs. 3%, p < 0.001), and lipid-rich plaque (71% vs. 42%, p = 0.031) in UAP was significantly greater than that in SAP. Fibrous cap thickness (73 ± 19 μm vs. 196 ± 58 μm, p < 0.001) was significantly thinner in UAP, and there was a significant difference in the incidence of TCFA (46% vs. 3%, p < 0.001) between 2 groups.
The comparison of lesion morphologies after PCI between patients with UAP and SAP is demonstrated in Figure 4. Although the incidence of stent edge dissection was similar in both groups, the incidence of inadequate stent apposition (67% vs. 32%, p = 0.038), tissue protrusion (79% vs. 42%, p = 0.005) and intracoronary thrombus (83% vs. 23%, p < 0.001) in patients with UAP was significantly greater than that in patients with SAP. In the assessment of the relationship between the pre-PCI lesion morphology with the post-PCI responses to stenting, the lesions with plaque rupture, thrombus, lipid-rich plaque, or TCFA (n = 18), compared with lesions without these OCT features (n = 37), showed high incidence of inadequate stent apposition (83% vs. 30%, p < 0.001), tissue protrusion (94% vs. 41%, p < 0.001), and intracoronary thrombus (100% vs. 24%, p < 0.001). In addition, using OCT, we were able to visualize these inadequate stent features more frequently than when using IVUS (Table 3).
The findings of serial OCT examination are summarized in Table 4. Plaque rupture was increased by PCI in UAP patients (42% to 75%, p = 0.018) but not changed in SAP patients. After PCI, the incidence of the ruptured plaque was significantly greater in patients with UAP compared to patients with SAP (75% vs. 13%, p < 0.001). Although the ruptured plaque decreased during follow-up in UAP (75% to 28%, p = 0.002), the incidence of the residual ruptured plaque at 9 months' follow-up was significantly greater in UAP patients than that in SAP patients (28% vs. 4%, p = 0.031) (Fig. 5). The inadequate stent apposition also decreased during follow-up period in UAP (67% to 33%, p = 0.032) and SAP (32% to 4%, p = 0.007) patients. At the follow-up, the incidence of inadequate stent apposition was significantly greater in UAP compared with SAP patients (33% vs. 4%, p = 0.012). The incidence of tissue protrusion at the follow-up was not different between the 2 groups. The stent edge dissection and intracoronary thrombus was not observed in both groups at 9 months' follow-up.
The OCT assessment of neointimal coverage of stent strut at 9 months' follow-up is demonstrated in Table 5. In 911 cross-sectional OCT images, 7,532 stent struts were evaluated. The mean number of struts with neointimal coverage in each stent was not different between UAP and SAP patients. The mean number of well-apposed struts without neointimal coverage (19.0 ± 18.1 vs. 6.6 ± 11.3, p = 0.007) and the mean number of inadequately apposed struts without neointimal coverage (4.0 ± 6.7 vs. 0.2 ± 1.2, p = 0.006) were significantly greater in UAP patients compared with SAP patients. In quantitative OCT analysis, percent volume of neointimal hyperplasia (10.9 ± 3.0 vs. 13.8 ± 4.5, p = 0.025) and percent mean area of neointimal hyperplasia (10.9 ± 3.0 vs. 13.6 ± 4.1, p = 0.029) were significantly smaller in UAP than those in SAP (Table 6). The incidence of SES featuring full coverage of every strut by neointima was significantly lower (28% vs. 63%, p = 0.019) in UAP, and the incidence of SES containing partially uncovered strut lesions was significantly greater (72% vs. 37%, p = 0.019) in UAP compared with SAP patients. The changes of the lesion findings from pre- to post-PCI to 9 months after SES implantation in UAP and SAP are diagramed in Figure 6.
Clinical and angiographical outcomes
PCI was successful in all patients. No complications occurred during OCT imaging. All patients took aspirin and ticlopidine during the follow-up period, and they did not have any adverse coronary events. None of patients had an evidence of ischemia in the exercise electrocardiogram testing at 9 months' follow-up. Furthermore, none of patients with follow-up coronary catheterization had angiographic restenosis and target vessel revascularization. In the follow-up angiography, in-stent percent diameter stenosis (6.4 ± 3.3% vs. 6.8 ± 3.9%, p = 0.765), in-segment % diameter stenosis (7.2 ± 2.8% vs. 7.4 ± 3.6%, p = 0.813), in-stent late loss (0.13 ± 0.33 vs. 0.14 ± 0.32, p = 0.957) and in-segment late loss (0.15 ± 0.35 vs. 0.14 ± 0.34, p = 0.935) were not different between UAP and SAP patients.
Intraobserver and interobserver variability
Intraobserver variability yielded acceptable concordance for inadequate stent apposition (κ = 0.90), tissue protrusion (κ = 0.92), intracoronary thrombus (κ = 0.94), stent edge dissection (κ = 0.96), and residual ruptured plaque (κ = 0.92). Interobserver variability showed relatively lower concordance for inadequate stent apposition (κ = 0.75), tissue protrusion (κ = 0.86), intracoronary thrombus (κ = 0.87), stent edge dissection (κ = 0.89), and residual ruptured plaque (κ = 0.86).
This is the first OCT study to compare vascular responses after SES implantation between UAP and SAP patients. The major findings of our analysis are as follows: 1) The incidence of plaque rupture, intracoronary thrombus, and TCFA in patients with UAP was significantly greater than that in patients with SAP. 2) Although the stent and procedural characteristics were not different between the 2 groups, the incidence of inadequate stent apposition and tissue protrusion after PCI was significantly greater in patients with UAP. 3) Plaque rupture was significantly increased by PCI in UAP patients, and the residual ruptured plaque at 9 months' follow-up was observed more frequently in UAP compared to SAP patients. 4) The incidence of inadequately-apposed stent and partially uncovered stent by neointima at 9 months' follow-up was significantly greater in UAP compared to SAP patients. 5) These OCT findings were not associated with adverse outcomes in patients with strict antiplatelet therapy during 9 months' follow-up.
Identification of vulnerable plaque by OCT
Vulnerable plaques constitute direct precursor lesions giving rise to coronary thrombosis. An autopsy study suggested that plaque rupture accounted for >60% of all intracoronary thrombi associated with sudden cardiac death (11). For plaque rupture, the morphology resembling vulnerable plaque has been described as TCFA. Recently, we reported that OCT allowed us to detect the fibrous cap disruption in 73% of acute myocardial infarction, which was similar to that in pathohistological examination (6). Jang et al. (8) demonstrated a greater prevalence of TCFA in patients with ACS (55%) compared with SAP (18%). The present OCT study showed that the frequency of intracoronary thrombus was also greater in UAP patients than that in SAP patients. These OCT findings supported our understanding of the pathophysiology of coronary artery disease. Although OCT is limited in the quantification of lipid-core, it might be a useful modality to evaluate the intrinsic features that determine plaque vulnerability in vivo.
Assessment of coronary stenting with OCT
Intravascular ultrasound is the gold standard for the assessment of coronary intervention. Cheneau et al. (12) showed that the post-intervention IVUS identified at least one of the abnormal findings, such as inadequate stent apposition, dissection, or thrombus, in 78% of patients with subacute stent thrombosis and identified multiple findings in 48% of the patients. Considering the high resolution of OCT, it is not surprising to observe an increased frequency and detail in the detection of small stent features. Bouma et al. (5) demonstrated that OCT, compared with IVUS, detected inadequate stent apposition (17% vs. 7%), tissue protrusion (69% vs. 29%), and dissection (19% vs. 5%) more frequently after stent implantation. However, these subtle findings by OCT may not be clinically relevant regardless of clinical presentation, lesion characteristics or stent type. The quantification or grading of the findings may be important to predict lesion outcomes after PCI.
SES implantation in the vulnerable lesion
The pivotal clinical registry demonstrated that the SES implantation were useful and safe in ACS (1). However, the ACS patients, compared to SAP patients, still have a greater risk for in-stent thrombosis, and this dreaded complication remains a major cause of death and morbidity (4). On the basis of the reliable IVUS reports, the large ulceration of the ruptured plaque might result in stent malapposition (12), and the soft plaque composition was thought to be high risk for tissue protrusion (13). A pathohistological study also demonstrated that breaching and penetration of a necrotic core might lead to the exposure of thrombogenic lipid content to flowing blood (14). Furthermore, the recent clinical studies suggested that SES could delay vascular healing. Matsumoto et al. (7) showed by OCT that almost 10% of the individual stent struts were not covered by neointima at 6 months after SES implantation. Awata et al. (15) demonstrated the presence of thrombi and yellow plaques even as much as 2 years after SES implantation by coronary angioscopy. These features can potentially increase the risk of thrombotic complications after SES implantation, especially in patients with ACS. The present OCT study demonstrated a greater incidence of inadequate stented lesion findings in UAP patients compared with SAP patients after SES implantation and 9 months' follow-up. These findings were not associated with adverse outcomes in patients with strict antiplatelet therapy. However, the withdrawal of antiplatelet therapy has been reported to be a significant risk factor for stent thrombosis in patients with SES implantation (16). The poorly healed sites of SES implantation may pose a significant risk for coronary thrombosis when antiplatelet therapy is abruptly discontinued. In addition, the vascular responses to SES versus bare-metal stents may differ according to clinical presentation or lesion characteristics. However, because the present study only included the lesions treated with SES, these observations can not be extrapolated to lesions in UAP or SAP patients treated with bare-metal stents.
There were several limitations in the present study. First, an inherent limitation of the present OCT system is need to remove the blood from the field of view for clear image acquisition, which was achieved through lactate Ringer's solution flushes during coronary occlusion by balloon catheter. Therefore, it was not able to observe ostial lesions of coronary artery. Second, a further limitation of OCT is the relatively shallow axial penetration. The vessels with reference diameter of ≥4 mm were excluded in this study. Third, the present study was a single-center OCT examination with a small sample size. Larger cohorts study with longer-term follow-up will be necessary to confirm our findings.
Serial OCT findings demonstrated markedly different vascular response up to 9 months after SES implantation between UAP and SAP patients. Although the inadequate lesion morphologies after stenting were observed more frequently in UAP compared with SAP patients, these findings were not associated with adverse outcomes in patients with antiplatelet therapy.
- Abbreviations and Acronyms
- acute coronary syndrome
- intravascular ultrasound
- optical coherence tomography
- percutaneous coronary intervention
- stable angina pectoris
- sirolimus-eluting stent
- thin-capped fibroatheroma
- unstable angina pectoris
- Received December 10, 2007.
- Revision received February 14, 2008.
- Accepted March 5, 2008.
- American College of Cardiology Foundation
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