Association of Subclinical Intrastent Thrombus Detected 9 Months After Implantation of 2nd-Generation Drug-Eluting Stent With Future Major Adverse Cardiac Events　― A Coronary Angioscopic Study ―

Abstract

Background: Detection of yellow plaques (YP) by coronary angioscopy (CAS) 1 year after 1st-generation drug-eluting stent (DES) implantation has been related to future coronary events. However, the association between CAS findings and clinical outcomes following 2nd-generation DES implantation has not been investigated.

Methods and Results: This study included a total of 248 2nd-generation DES in 179 patients, who were examined by CAS 9±2 months after implantation. Angioscopic evaluation included dominant neointimal coverage (NIC) grade, heterogeneity of NIC, presences of YP and intrastent thrombus. The outcome measure was major adverse cardiac events (MACE) defined as a composite of cardiac death, acute myocardial infarction and any coronary revascularization. The association between the CAS findings and MACE was evaluated using the Kaplan-Meier method. A Cox proportional hazards model was used to assess the predictors of MACE. The mean follow-up duration was 1,367±843 days. Dominant NIC grade (P=0.98), heterogeneity of NIC (P=0.20) and YP (P=0.53) were not associated with the incidence of MACE. However, intrastent thrombus was significantly associated with MACE (P=0.033). Intrastent thrombus (adjusted hazard ratio: 2.22; 95% confidence interval [CI]: 1.12–4.39), acute coronary syndrome (2.83; 95% CI: 1.42–5.67) and B2/C lesion (2.13; CI: 1.12–4.05) were independent predictors of MACE.

Conclusions: Subclinical intrastent thrombus observed by CAS at 9 months after 2nd-generation DES implantation was independently associated with poor clinical outcome.

The use of drug-eluting stents (DES) has dramatically decreased the rate of restenosis at 1 year after implantation compared with bare-metal stents,¹ but late stent-related events such as restenosis or stent thrombosis (ST) have been reported beyond 1 year after implantation of DES.^2,3

Second-generation DES were developed with a thinner strut platform coated with a biocompatible polymer and drugs. These stents demonstrated superiority in reducing ST compared with 1st-generation DES.⁴ In-stent neoatherosclerosis, delayed arterial healing, and other abnormal vascular responses are important contributing factors for very late stent failure after implantation of DES.^5,6

Coronary angioscopy (CAS) can observe the stent in situ under direct, full-color vision, and evaluate arterial healing after stent implantation.^7–14 Detection of yellow plaque (YP) by CAS at 1 year after implantation of DES has been reported as a pathologic sign of in-stent neoatherosclerosis. It was also reported that the presence of in-stent YP, detected by CAS at 1 year after implantation, is associated with future coronary events.⁷ However, the vast majority (81%) of the stents investigated in that study were 1st-generation DES. Thus far, no study has evaluated the association between the CAS findings of 2nd-generation DES and future clinical events.

Methods

Study Design

We performed a single-center observational study that included patients who underwent CAS as well as angiography at 9±2 months after 2nd-generation DES implantation for coronary artery disease (CAD) caused by de novo lesions in native coronary arteries. We excluded patients who had any event of earlier stent failure such as in-stent restenosis or who could not undergo successful angioscopic evaluation. Although angioscopic evaluation at follow-up angiography was encouraged for all the patients, it was not performed when the informed consent was not given or when a specialist in angioscopic evaluation was not available. A total of 248 2nd-generation DES implanted in 179 patients (mean age: 68±10 years; 81% males) were enrolled in this study. All patients received ticlopidine (200 mg/day) or clopidogrel (75 mg/day) in addition to aspirin (100 mg/day) immediately after percutaneous coronary intervention. Most patients continued to receive dual antiplatelet therapy during the follow-up period. The Medical Ethics Committee of Kansai Rosai Hospital approved the study, and all patients provided written informed consent.

Angiographic and Angioscopic Follow-up

Coronary angiography was performed after administration of unfractionated heparin (5,000 IU) into the radial or femoral artery via the inserted sheath, and isosorbide dinitrate (2.5 mg) into the coronary artery. Angioscopy was subsequently performed using a Fullview NEO angioscope catheter (FiberTech, Tokyo, Japan), as previously described.^8,9 Briefly, the optical fiber was placed in the distal segment of the coronary artery and manually pulled back from the distal edge of the stent to the proximal edge under careful angioscopic and angiographic guidance. Angioscopic images consisted of 3,000 pixels with full color and were digitally stored for off-line analysis.

Angioscopic Analysis Angioscopic images were analyzed to determine the following: (1) the dominant degree of neointimal coverage (NIC) over the stent; (2) heterogeneity of NIC; (3) the presence of YP underneath the stent; and (4) the presence of intrastent thrombus. NIC over the stent was classified into 4 grades as previously described: grade 0, stent struts fully visible, similar to immediately after implantation; grade 1, stent struts bulging into the lumen and, although covered, still transparently visible; grade 2, stent struts embedded in the neointima, but translucently visible; grade 3, stent struts fully embedded and invisible on angioscopy.¹⁰ In this study, grades 0 and 1 were termed incomplete coverage, and grades 2 and 3 were termed complete coverage. Heterogeneity of NIC has been defined previously.¹¹ NIC was evaluated throughout the entire stented segment, and judged as heterogeneous when differences in the NIC grade became apparent. Struts crossing the side branch and located in the overlapping segment were excluded from grading. In addition, stent edges were excluded from the heterogeneity analysis. The severity of YP was graded as follows: grade 0, white; grade 1, light yellow; grade 2, yellow; grade 3, intense yellow. In the current investigation, the presence of YP was defined as maximum YP grade ≥2, in accordance with the previous study.⁷ Thrombus was defined by the criteria adopted by the European Working Group on Coronary Angioscopy.¹²

Outcome Measures

The outcome measure was major adverse cardiac events (MACE), defined as a composite of cardiac death, myocardial infarction and any coronary revascularization. The study evaluated the association between CAS findings and MACE, and assessed the predictors of MACE by multivariate analysis.

Statistical Analysis

All results are expressed as mean±SD unless otherwise stated. Freedom from MACE was measured by Kaplan-Meier analysis, and comparison between groups was performed by log-rank test. Multivariate analysis was performed using a Cox proportional hazard model. Variables in the univariate analysis with P<0.05 were selected for the multivariate analysis. Statistical significance was defined as P<0.05. All calculations were performed using the IBM SPSS Statistics Version 20 (IBM Corp., Armonk, NY, USA).

Results

Patients

Baseline patient characteristics at the time of DES implantation and medication characteristics at the time of CAS evaluation are shown in Table 1. At angioscopic evaluation, statins and β-blockers were prescribed for 168 (68%) patients and 98 (40%) patients, respectively. Lesion and procedural characteristics are shown in Table 2. Biolimus-eluting stents (Nobori, Terumo, Tokyo, Japan), cobalt-chromium everolimus-eluting stents (Xience, Abbot Vascular, Santa Clara, CA, USA), platinum-chromium everolimus-eluting stents (Promus, Boston Scientific, Natick, MA, USA) and slow-release zotarolimus-eluting stents (Resolute, Medtronic, Minneapolis, MN, USA) were implanted in 17%, 50%, 17% and 16% of cases, respectively.

Table 1. Patient and Medication Characteristics

	Overall (n=248)
Age, years	68±10
Male, n (%)	201 (81)
Coronary risk factors, n (%)
Hypertension,* n (%)	221 (89)
Dyslipidemia,† n (%)	191 (77)
Diabetes mellitus,‡ n (%)	95 (38)
Current smoking, n (%)	56 (23)
Serum profile
Total cholesterol, mg/dL	185±33
LDL-C, mg/dL	111±28
HDL-C, mg/dL	49±13
Triglycerides, mg/dL	120±60
HbA1c, %	6.4±1.1
ACS, n (%)	59 (24)
Medications (at angioscopic examination), n (%)
Aspirin	242 (98)
P2Y12 inhibitor	218 (88)
Statins	168 (68)
β-blockers	98 (40)

Data are mean±SD or n (%). *Receiving antihypertensive medication, systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg. ^†Treatment with medication, total cholesterol ≥220 mg/dL, LDL-C ≥140 mg/dL, HDL-C ≤40 mg/dL, or triglycerides ≥150 mg/dL. ^‡Oral agent or insulin treatment or HbA_1c ≥6.5%. ACS, acute coronary syndrome; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Table 2. Lesion and Procedural Characteristics

	Overall (n=248)
Target vessel, n (%)
LAD	107 (43)
LCX	40 (16)
RCA	101 (41)
Type B2/C lesions*, n (%)	162 (65)
QCA
Pre-MLD, mm	0.83±0.55
Lesion length, mm	19±12
Pre-%DS, %	69±19
RD, mm	2.70±0.78
Post-MLD, mm	2.53±0.53
Post-%DS, %	15±9
Stent type, n (%)
BES	41 (17)
Cobalt-chromium EES	125 (50)
Platinum-chromium EES	43 (17)
Slow-release ZES	39 (16)
Stent diameter, mm	3.09±0.38
Total stent lengths, mm	22±7
Post dilation, n (%)	168 (68)
Post balloon size, mm	3.14±0.44

Data are mean±SD or n (%). *Based on the American College of Cardiology/American Heart Association Classification. BES, biolimus-eluting stent; %DS, percent diameter stenosis; EES, everolimus-eluting stent; LAD, left anterior descending artery; LCX, left circumflex artery; MLD, minimum lumen diameter; QCA, quantitative coronary angiography; RCA, right coronary artery; RD, reference diameter; ZES, zotarolimus-eluting stent.

Association Between CAS Findings and MACE

The mean follow-up duration was 1,367±843 days. The details of the CAS findings are shown in Table 3. Complete coverage was obtained in 107 (43%) patients. Heterogeneity of NIC was detected in half of the patients. YP and intrastent thrombus were detected in 65 (26%) and 61 (25%) patients, respectively. The results showed the dominant NIC grade, heterogeneity of NIC and the presence of YP were not associated with MACE (Figure 1A–C). In contrast, the presence of intrastent thrombus was associated with MACE, and freedom from MACE was lower in cases of intrastent thrombus (Figure 1D). Particularly, freedom from target lesion revascularization was significantly lower in cases of intrastent thrombus than in those without intrastent thrombus (Table 4, Figure 2). Multivariate analysis revealed that intrastent thrombus (adjusted hazard ratio: 2.22; 95% confidence interval [CI]: 1.12–4.39), acute coronary syndrome (2.83; CI: 1.42–5.67) and B2/C lesion (2.13; CI: 1.12–4.05) were independent predictors of MACE (Table 5).

Table 3. Coronary Angioscopy Findings at Follow-up

	Overall (n=248)
Dominant NIC grade
0	10 (4)
1	131 (53)
2	62 (25)
3	45 (18)
Complete coverage	107 (43)
Heterogeneity of NIC	124 (50)
Yellow grade
0	87 (35)
1	96 (39)
2	45 (18)
3	20 (8)
Yellow plaque	65 (26)
Intrastent thrombus	61 (25)

Data are n (%). NIC, neointimal coverage.

Figure 1.

Kaplan-Meier curves for major adverse cardiac events (MACE). Freedom from MACE was similar between (A) groups with complete and incomplete neointimal coverage (67.8% vs. 74.3%, 5 years after stent implantation, P=0.98), (B) groups with and without heterogeneous neointimal coverage (68.6% vs. 73.6%, 5 years after stent implantation, P=0.20) and (C) groups with and without yellow plaques (74.5% vs. 67.5%, 5 years after stent implantation, P=0.82). (D) Freedom from MACE was significantly lower in cases of intrastent thrombus than in those without intrastent thrombus (68.7% vs. 71.8%, 5 years after stent implantation, P=0.033).

Table 4. Cumulative Incidence of MACEs Between Intrastent Thrombus and No Thrombus Groups by Kaplan-Meier Analysis

	Intrastent thrombus	No thrombus	P value
MACE, n (%)	11 (31.3)	26 (28.2)	0.033
CD, n (%)	0 (0)	1 (1.4)	0.63
AMI, n (%)	0 (0)	0 (0)	–
TLR, n (%)	3 (12.7)	3 (3.9)	0.039
TVR, n (%)	3 (12.7)	8 (8.8)	0.60
Non-TVR, n (%)	6 (22.4)	16 (17.1)	0.068

Data are n (%). AMI, acute myocardial infarction; CD, cardiac death; MACE, major adverse cardiac event; TLR, target lesion revascularization; TVR, target vessel revascularization.

Figure 2.

Kaplan-Meier curves for events with and without intrastent thrombus. (A) Freedom from cardiac death was similar between groups with and without intrastent thrombus (100% vs. 98.6%, five years after stent implantation, P=0.63). (B) Freedom from target lesion revascularization was significantly lower in cases of intrastent thrombus than in those without intrastent thrombus (87.3% vs. 96.1%, 5 years after stent implantation, P=0.039). (C) Freedom from target vessel revascularization was similar between groups with and without intrastent thrombus (87.3% vs. 91.2%, 5 years after stent implantation, P=0.60). (D) Freedom from non-target vessel revascularization tended to be lower in cases of intrastent thrombus than in those without intrastent thrombus (77.6% vs. 82.9%, five years after stent implantation, P=0.068).

Table 5. Multivariate Analysis for Predictors of MACE

	Univariate		Multivariate
	HR [95% CI]	P value	HR [95% CI]	P value
Age	1.03 [0.99–1.07]	0.139
Male	0.64 [0.33–1.23]	0.179
Hypertension	2.95 [0.71–12.2]	0.117
Dyslipidemia	0.81 [0.43–1.52]	0.513
Diabetes mellitus	1.61 [0.91–2.86]	0.105
Hyperuricemia	2.42 [1.15–5.11]	0.002	1.86 [0.85–4.06]	0.120
Smoking	1.28 [0.61–2.67]	0.509
ACS	2.89 [1.48–5.62]	0.002	2.83 [1.42–5.67]	0.003
Statin	0.66 [0.37–1.19]	0.167	1.67 [0.94–2.95]	0.776
B2/C lesion	2.11 [1.12–3.99]	0.021	2.13 [1.12–4.05]	0.022
Intrastent thrombus	1.98 [1.04–3.75]	0.037	2.22 [1.12–4.39]	0.023

Variables with P<0.05 in the univariate analysis were selected for multivariate analysis. HR, hazard ratio. Other abbreviations as in Tables 1,4.

We also performed landmark Kaplan-Meier analysis from the CAS evaluation (Figure S1) and subanalysis of patients with stable CAD (Figure S2), and these demonstrated similar results to the main outcomes.

Discussion

The results of this study demonstrated that dominant NIC, heterogeneity of NIC and the presence of YP were not associated with MACE. However, the presence of intrastent thrombus was significantly associated with MACE and freedom from MACE was significantly lower in cases of intrastent thrombus mainly because of a higher rate of target lesion revascularization. Moreover, multivariate analysis revealed that intrastent thrombus, acute coronary syndrome and B2/C lesion were independent predictors of MACE. To the best of our knowledge, this is the first study to assess the relationship between CAS findings and future prognosis for patients with CAD treated with 2nd-generation DES.

The association between CAS findings and future events has been previously reported. Furthermore, the presence of YP, observed by CAS at 1 year after the implantation of DES, has predicted future MACE.⁷ However, the DES included in that study were mainly 1st-generation DES. In the present study, intrastent thrombus was a predictor of future MACE, unlike the presence of YP. Presence of YP at 1 year after implantation of DES is indicative of neoatherosclerosis, which is one of the phenomena of an abnormal vascular response. However, delayed arterial healing and other abnormal vascular responses, together with neoatherosclerosis, are necessary to induce late stent failure.^5,6 Neoatherosclerosis can occur after implantation of either a 1st- or 2nd-generation DES.¹⁵ However, delayed arterial healing and other abnormal vascular responses are less frequently observed after implantation of 2nd-generation DES than after implantation of 1st-generation DES.¹⁵ Therefore, the risk of future MACE, as a result of neoatherosclerosis, is low after implantation of 2nd-generation DES, which differentiates the results of the current study from the previously reported findings.⁷

Studies using optical coherence tomography (OCT) have reported that the presence of neoatherosclerosis is independently associated with MACE after stent implantation.¹⁶ However, this method of assessment has not previously reported an association between the presence of intrastent thrombus and future MACE after implantation of DES. CAS is superior to OCT in detecting thrombus, thus enabling detection of intrastent thrombi that are not be detectable by OCT.¹⁷ Thus, CAS contributed to the novel findings reported here, associating intrastent thrombus with future MACE.

A previous pathologic report stated that poorly covered struts are a risk factor for ST.¹⁸ Furthermore, an OCT study showed an independent association of uncovered struts with late ST.¹⁹ However, in the current study, NIC was not associated with future clinical outcomes, a discrepancy between the studies that was caused by differences in the outcome measures. The present study evaluated future MACE, including cardiac death, myocardial infarction and any coronary revascularization, rather than ST. Furthermore, late and very late ST were not reported in this study population.

Clinical Implications

Thrombus adhesion occurs in the initial phase of arterial healing and rarely occurs where arterial repair is sufficient.^13,20 Mitsutake et al reported that patients with intrastent thrombus at approximately 1 year after implantation of DES had endothelial dysfunction.¹⁴ Therefore, it may be posited that patients with intrastent thrombus at 1 year after stent implantation have endothelial dysfunction globally in the coronary arteries as well as in the treated artery. This corroborates our finding that intrastent thrombus 9 months after implantation may predict the occurrence of future MACE. Therefore, close follow-up is warranted for patients in whom CAS detects intrastent thrombus.

Study Limitations

Firstly, this was a single-center, non-randomized observational study. Secondly, only subclinical intrastent thrombi were observed, so no conclusions can be derived regarding the continuation of dual antiplatelet therapy. Thirdly, evaluation of the entire stented segment was not possible because CAS evaluates the intravascular status in a forward-looking manner. Fourth, although MACE were significantly greater in intrastent thrombus group, the difference between groups decreased in the last phase of the study period (Figure 1D). A longer follow-up is needed to investigate the effect of intrastent thrombus on long-term outcomes. Finally, late and very ST did not occur in this population; thus, the current study did not provide data regarding ST. However, as previously demonstrated, the incidence of ST is low after implantation of 2nd-generation DES.⁴

Conclusions

Subclinical intrastent thrombus observed by CAS nine-month after implantation of 2nd-generation DES was independently associated with MACE. Intrastent thrombus, which is indicative of incomplete arterial healing, may predict future MACE.

Acknowledgments / Name of Grant

None.

Supplementary Files

Supplementary File 1

Figure S1. Landmark Kaplan-Meier curves from coronary angioscopy evaluation for major adverse cardiac events (MACE).

Figure S2. Kaplan-Meier curves for major adverse cardiac events (MACE) in patients with stable coronary artery disease.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-0098

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