Angioscopic Comparison of Resolute and Endeavor Zotarolimus-Eluting Stents

Abstract

Background: Drug-eluting stents (DES) have reduced late loss and target lesion revascularization through the inhibition of neointimal hyperplasia, but instead increased the risk of very late stent failure due to incomplete neointimal coverage and neoatherosclerosis. Although newer DES are more effective and safer than the first-generation DES, the difference in the condition of the stented lesions between Resolute zotarolimus-eluting stents (R-ZES) and Endeavor zotarolimus-eluting stents (E-ZES) on angioscopy has not been reported.

Methods and Results: Consecutive patients who received R-ZES (n=46) or E-ZES (n=46) for de novo lesion of native coronary artery and had 1-year follow-up angioscopy were examined. Yellow color (grade 0–3), neointimal coverage (grade 0–2), heterogeneity score (maximum-minimum neointimal coverage grade) and thrombus (presence or absence) at stented lesion were evaluated. The maximum yellow color grade (1.2±0.9 vs. 0.7±1.0, P=0.005) was higher in R-ZES than in E-ZES. The maximum (1.9±0.3 vs. 1.5±0.5, P<0.001) and minimum (1.1±0.7 vs. 0.4±0.5, P<0.001) coverage grade was higher in E-ZES than in R-ZES. The heterogeneity score was higher in R-ZES than in E-ZES (1.0±0.5 vs. 0.7±0.7, P=0.007). Prevalence of thrombus was not different between the 2 stents (6.5% vs. 2.2%, P=0.4).

Conclusions: E-ZES had better neointimal coverage with less yellow plaque and lower heterogeneity score than R-ZES. The lesions with E-ZES appeared more stable than those with R-ZES. (Circ J 2016; 80: 650–656)

Drug-eluting stents (DES) have reduced late loss and target lesion revascularization (TLR) by the inhibition of neointimal hyperplasia but instead increased the risk of very late stent failure due to incomplete neointimal coverage and neoatherosclerosis.^1,2 Although newer DES are more effective and safer than the first-generation DES,^3–9 the difference in the condition of the stented lesions between Resolute zotarolimus-eluting stents (R-ZES) and Endeavor zotarolimus-eluting stents (E-ZES) on angioscopy has not been reported.

Editorial p 590

Methods

Study Design

This was a single-center study to compare the angioscopic characteristics of R-ZES (Resolute Integrity; Medtronic, Minneapolis, MN, USA) and E-ZES (Endeavor stent; Medtronic) at the stent-implanted segment at 1 year after implantation.

The 1-year follow-up catheterization was encouraged for all patients who received coronary intervention, but it was not performed when (1) the patient had renal dysfunction; or (2) informed consent was not obtained. In the 1-year follow-up catheterization, angioscopy was encouraged for all patients who received DES implantation, but it was not performed when (1) an angioscopy specialist was not available; (2) there was not adequate time for the examination; or (3) informed consent was not obtained. We have a registry of all patients who undergo angioscopy. From this registry, we retrospectively analyzed the consecutive patients who received R-ZES (between September 2012 and December 2013) or E-ZES (between May 2009 and July 2010) for de novo lesion of native coronary artery and had successful angioscopy at 1-year follow-up catheterization.

During this period, R-ZES was implanted in 198 patients and follow-up angioscopy was performed in 46 patients without reintervention before the follow-up; and E-ZES was implanted in 168 patients and follow-up angioscopy was performed in 46 patients without reintervention before the follow-up. The patients who had in-stent restenosis at follow-up (8 patients for R-ZES and 22 patients for E-ZES) were not included, because we focused on clarifying the angioscopic characteristics of the stented lesion in the patients without early stent failure before 1-year follow-up.

Catheterization was performed via the femoral, brachial, or radial artery approach using a 6-Fr or 7-Fr sheath and catheters. Coronary angiogram was recorded using the Innova Cardiovascular imaging system (GE Healthcare Japan, Tokyo, Japan); and quantitative coronary angiography was carried out with the system. All patients were taking aspirin 100 mg/day and ticlopidine 500 mg/day or clopidogrel 75 mg/day (dual antiplatelet therapy) throughout the study period. GPIIb/IIIa inhibitors were not used for any patient, because they were not approved in Japan for clinical use. Hypertension was defined as blood pressure >140/90 mmHg or the use of anti-hypertensive drugs. Diabetes mellitus was defined as fasting blood glucose >126 mg/dl or the use of oral drugs for diabetes mellitus or insulin therapy. Dyslipidemia was defined as low-density lipoprotein cholesterol >140 mg/dl or the use of statin. Acute coronary syndrome (ACS) includes acute myocardial infarction with/without ST elevation defined by the Joint European Society of Cardiology/American College of Cardiology Committee, and unstable angina defined according to the Braunwald classification. This study was approved by the Osaka Police Hospital Ethics Committee. Written informed consent was obtained from all enrolled patients.

Angioscopy

The non-obstructive coronary angioscope RX-3310A and MV-5010A (Machida, Tokyo, Japan) and the optic fiber DAG-2218LN (Machida) were used. Angioscopic observation of stented lesions was done while blood was cleared away from the field of view using injection of 3% dextran-40, as previously reported.¹⁰ Yellow color was classified into 4 grades (0, white; 1, slight yellow; 2, yellow; and 3, intensive yellow) compared with standard colors as previously reported.^11,12 Neointimal coverage was classified into 3 grades (0, no coverage; 1, poor coverage; 2, complete coverage) as previously reported.^13,14 Thrombus was defined as white or red material that had cotton-like or ragged appearance or that presented fragmentation with or without protrusion into the lumen or adherent to the lumen surface. Maximum and minimum neointimal coverage grade, maximum and minimum yellow color grade, and presence or absence of thrombus was determined for each stented lesion at follow-up. Heterogeneity score was defined as maximum-minimum neointimal coverage grade, to evaluate the heterogeneity of the coverage. Two angioscopy specialists blinded to patient characteristics evaluated the angioscopy images. In the case of disagreement, a third reviewer served as an arbitrator. The inter- and intra-observer reproducibility for the interpretation of angioscopy images was 95% and 95% for stent coverage, 85% and 95% for plaque color, and 90% and 100% for thrombus, respectively.¹³

Definition of Neoatherosclerosis on Angioscopy

Angioscopy cannot differentiate the yellow plaque inside the neointima and that under stent in the original vessel wall, therefore we defined atherosclerosis as including both, given that both the yellow plaque formed after stent implantation and that in the native coronary artery are similarly associated with thrombus formation. If a yellow plaque in the original vessel wall is covered by a thick neointima, it becomes white and stable; but if the yellow plaque is covered by a thin neointima, it remains yellow and vulnerable. We therefore defined angioscopic neoatherosclerosis as the yellow plaque formed, or that with increased yellow color intensity, after stent implantation; that is, progression of atherosclerosis after stent implantation regardless of whether the yellow plaque exists in the neointima or in the original vessel wall.

Statistical Analysis

Continuous data are given as mean±SD. Comparison of groups was done using unpaired Student’s t-test, chi-squared test, or Mann-Whitney test. Patient, lesion, and procedural characteristics were compared between R-ZES and E-ZES for the whole patient group, for ACS patients, and for non-ACS patients, respectively. To determine the contributing factors to maximum yellow color grade at 1 year, multivariate linear regression analysis was performed including stent type, stenting for ACS, gender, diabetes mellitus, hypertension, hypercholesterolemia, current smoking, chronic kidney disease, statin use, and eicosapentaenoic acid use as independent variables. P<0.05 was regarded as statistically significant. Statistical analysis was performed using SPSS (version 22.0 J for Windows, SPSS, Chicago, IL, USA).

Results

Patient and Lesion Characteristics

The 46 patients (46 lesions) for R-ZES and 46 patients (49 lesions) for E-ZES comprised the study group. Follow-up interval was 389±41 days for R-ZES and 379±59 days for E-ZES. The patient, lesion, and procedural characteristics are listed in Tables 1,2. Representative R-ZES and E-ZES are shown in Figure 1.

Table 1. Patient Characteristics

	All (n=92)			ACS (n=28)			Non-ACS (n=64)
	R-ZES	E-ZES	P-value	R-ZES	E-ZES	P-value	R-ZES	E-ZES	P-value
No. patients	46	46		18	10		28	36
Male	41 (89)	41 (89)	1.00	16 (89)	9 (90)	1.00	25 (89)	32 (89)	1.00
Age (years)	69±10	67±10	0.44	68±10	62±12	0.17	69±11	69±9	0.82
Risk factor
Diabetes mellitus	16 (35)	25 (54)	0.09	5 (28)	4 (40)	0.68	11 (39)	21 (58)	0.21
Hypertension	36 (78)	43 (93)	0.07	14 (78)	9 (90)	0.63	22 (79)	34 (94)	0.12
Hypercholesterolemia	33 (72)	41 (89)	0.06	13 (72)	10 (100)	0.13	20 (71)	31 (86)	0.21
Current smoker	6 (13)	6 (13)	1.00	2 (11)	2 (20)	0.60	4 (14)	4 (11)	0.72
Body mass index	25±3	24±3	0.02	25±3	26±4	0.60	25±3	23±2	0.004
CKD	18 (39)	22 (48)	0.53	9 (50)	3 (30)	0.43	9 (32)	19 (36)	0.13
Prior MI	6 (13)	13 (28)	0.12	0 (0)	1 (10)	0.36	6 (21)	12 (33)	0.40
Serum lipid profile (mg/dl)
Total cholesterol	158±25	171±25	0.02	170±26	171±15	0.89	151±21	171±27	0.002
LDL-C	86±23	93±23	0.13	89±26	89±19	0.99	84±21	94±25	0.07
HDL-C	43±12	48±12	0.03	45±14	51±13	0.27	42±10	48±11	0.04
Triglycerides	155±123	152±80	0.87	175±130	158±69	0.71	143±119	150±84	0.78
Medication
Statin	36 (78)	39 (85)	0.59	15 (83)	9 (90)	1.00	21 (75)	30 (83)	0.53
EPA	6 (13)	5 (11)	1.00	1 (6)	1 (10)	1.00	5 (18)	4 (11)	0.49
Aspirin	43 (93)	46 (100)	0.24	16 (89)	10 (100)	0.52	27 (96)	36 (100)	0.44
Ezetimibe	2 (4)	6 (13)	0.27	0 (0)	1 (10)	0.36	2 (7)	5 (14)	0.45
Clopidogrel/ticlopidine	46 (100)	46 (100)	NA	18 (100)	10 (100)	NA	28 (100)	36 (100)	NA
ARB/ACEI	34 (74)	27 (54)	0.19	12 (67)	7 (70)	1.00	22 (79)	20 (56)	0.07
β-blocker	27 (59)	25 (54)	0.83	11 (61)	5 (50)	0.70	16 (57)	20 (56)	1.00

Data given as mean±SD or n (%). ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; EPA, eicosapentaenoic acid; E-ZES, Endeavor zotarolimus-eluting stent; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NA, not applicable; R-ZES, Resolute zotarolimus-eluting stent.

Table 2. Lesion and Procedural Characteristics

	All (n=95)			ACS (n=28)			Non-ACS (n=67)
	R-ZES	E-ZES	P-value	R-ZES	E-ZES	P-value	R-ZES	E-ZES	P-value
No. lesions	46	49		18	10		28	39
Target vessel
LMT	2 (4)	4 (8)	0.68	1 (6)	0 (0)	1.00	1 (4)	4 (10)	0.39
LAD	21 (46)	20 (41)	0.68	10 (56)	6 (60)	1.00	11 (39)	14 (36)	0.80
LCX	12 (26)	6 (12)	0.12	5 (28)	1 (10)	0.38	7 (25)	4 (10)	0.18
RCA	13 (28)	21 (43)	0.14	3 (17)	3 (30)	0.63	10 (36)	19 (49)	0.33
IVUS use	46 (100)	49 (100)	NA	18 (100)	10 (100)	NA	28 (100)	39 (100)	NA
Rotational atherectomy use	2 (4)	2 (4)	1.00	0 (0)	0 (0)	NA	2 (7)	2 (5)	1.00
No. stents	1.2±0.5	1.4±0.6	0.18	1.2±0.4	1.3±0.7	0.51	1.2±0.5	1.4±0.6	0.18
Stent diameter (mm)	3.0±0.3	3.0±0.3	0.63	3.0±0.3	3.1±0.4	0.87	3.0±0.3	3.0±0.3	0.60
Total stent length (mm)	29±12	27±16	0.45	28±12	24±15	0.48	29±12	27±17	0.78
Maximum balloon size (mm)	3.3±0.6	3.3±0.5	0.84	3.3±0.7	3.4±0.6	0.95	3.2±0.6	3.3±0.4	0.78
Maximum inflation pressure (atm)	13±3.4	17±4.3	<0.001	12±2.5	18±3.7	0.001	14±3.6	17±4.4	0.02
QCA
Before procedure
Minimum lumen diameter (mm)	1.0±0.6	0.9±0.6	0.68	0.7±0.6	0.8±0.6	0.59	1.2±0.6	0.9±0.6	0.15
Diameter stenosis (%)	66±21	68±20	0.69	78±18	69±22	0.24	59±19	68±19	0.06
Lesion length	21±10	18±10	0.25	21±11	22±12	0.96	21±9.3	18±9.9	0.22
After procedure
Minimum lumen diameter (mm)	2.7±0.4	2.9±0.5	0.08	2.8±0.4	2.8±0.5	1.00	2.6±0.4	2.9±0.5	0.03
Diameter stenosis (%)	14±10	12±10	0.29	14±11	15±8	0.78	15±9.6	12±11	0.18
Acute luminal gain (mm)	1.7±0.7	1.9±0.8	0.15	2.1±0.7	2.0±0.6	0.63	1.5±0.6	1.9±0.8	0.01
1-year follow-up
Minimum lumen diameter (mm)	2.4±0.5	2.3±0.5	0.34	2.5±0.5	2.0±0.6	0.05	2.4±0.5	2.4±0.4	0.91
Diameter stenosis (%)	22±12	25±13	0.29	23±13	31±14	0.14	22±12	23±12	0.57
Late luminal loss (mm)	0.3±0.3	0.6±0.4	0.001	0.3±0.4	0.8±0.3	0.006	0.3±0.3	0.5±0.4	0.009

Data given as mean±SD or n (%). IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; LMT, left main trunk; QCA, quantitative coronary angiography; RCA, right coronary artery. Other abbreviations as in Table 1.

Figure 1.

Representative case of (A–F) Resolute zotarolimus-eluting stent (R-ZES) and (G–L) Endeavor zotarolimus-eluting stent (E-ZES). (A) An 86-year-old male patient with effort angina had severe stenosis in the mid-right coronary artery and (B) received R-ZES. At (C) 1-year follow-up catheterization, no in-stent restenosis was seen on angiography, but (D–F) grade 2 yellow plaque and grade 1 neointimal coverage was detected on angioscopy. (G) A 71-year-old male patient with silent myocardial ischemia had severe stenosis in the mid-right coronary artery and (H) underwent implantation of E-ZES. At (I) 1-year follow-up catheterization, no in-stent restenosis was seen on angiography, and (J–L) complete neointimal coverage (grade 2) without yellow plaque was seen on angioscopy. Yellow line with arrows, site of stent implantation; yellow arrowhead, site of angioscopy.

Angioscopy

The maximum yellow color grade (1.2±0.9 vs. 0.7±1.0, P=0.005) was higher in R-ZES than in E-ZES (Figure 2A) for the whole study group. It was also higher in R-ZES than in E-ZES for ACS patients, while it was not different for non-ACS patients.

Figure 2.

Angioscopy findings for Resolute zotarolimus-eluting stents (R-ZES) vs. Endeavor zotarolimus-eluting stents (E-ZES). (A) Maximum yellow color grade was significantly higher in R-ZES than in E-ZES. The minimum yellow color grade tended to be higher in R-ZES than in E-ZES. In the acute coronary syndrome (ACS) group, the maximum and minimum yellow color grade was significantly higher in R-ZES than in E-ZES, but in the non-ACS group, there was no significant difference. (B) The maximum and minimum neointimal coverage grade was significantly higher in E-ZES than in R-ZES, not only in the ACS group but also in the non-ACS group.

The maximum (1.9±0.3 vs. 1.5±0.5, P<0.001) and minimum (1.1±0.7 vs. 0.4±0.5, P<0.001) coverage grade was higher in E-ZES than in R-ZES (Figure 2B) for the whole study group. They were also higher in E-ZES than in R-ZES both for ACS patients and for non-ACS patients.

The heterogeneity score was higher in R-ZES than in E-ZES (1.0±0.5 vs. 0.7±0.7, P=0.007) for the whole study group. It was also higher in R-ZES than in E-ZES for the ACS patients (1.2±0.4 vs. 0.4±0.5, P=0.003), while it was not different for the non-ACS patients (1.0±0.6 vs. 0.8±0.7, P=0.3). Thrombus was detected only in 4 patients: 3 patients with R-ZES and 1 patient with E-ZES. Prevalence of thrombus was not different between R-ZES and E-ZES (6.5% vs. 2.2%, P=0.4) for the whole study group. The heterogeneity score was not different between the patients with and those without thrombus (1.3±1.0 vs. 0.9±0.6, P=0.4).

On multivariate linear regression analysis, stent type was the only significant contributing factor to maximum yellow color grade at 1 year among stent type, stenting for ACS, gender, diabetes mellitus, hypertension, hypercholesterolemia, current smoking, chronic kidney disease, statin use, and eicosapentaenoic acid use (Table 3).

Table 3. Multivariate Indicators of Maximum Yellow Grade at 1-Year Follow-up

	B	SE	β	t-test	P-value
Stent type (R-ZES or E-ZES)	0.51	0.21	0.27	2.45	0.02
ACS	0.13	0.21	0.06	0.60	0.55
Male	−0.41	0.31	−0.14	−1.31	0.20
Diabetes mellitus	0.18	0.20	0.10	0.92	0.36
Hypertension	−0.36	0.29	−0.13	−1.25	0.21
Hypercholesterolemia	0.08	0.27	0.03	0.28	0.78
Current smoker	−0.28	0.30	−0.10	−0.95	0.35
CKD	−0.07	0.20	−0.03	−0.32	0.75
Statin use	0.47	0.28	0.20	1.72	0.09
EPA use	−0.43	0.30	−0.15	−1.41	0.16

Abbreviations as in Table 1.

Discussion

This is the first report to compare condition of the stented lesions between E-ZES and R-ZES on angioscopy at 1 year after implantation. We have shown in the present study that E-ZES had better neointimal coverage with less yellow plaque and lower heterogeneity score than R-ZES. Therefore, the coronary lesions with E-ZES appeared to have a more stable condition than those with R-ZES.

Delayed Healing as a Cause of Late Stent Failure

In the first-generation DES, that is, Cypher sirolimus-eluting stents (C-SES) and Taxus paclitaxel-eluting stents (T-PES), the incidence of thrombus at follow-up was higher than that in bare metal stents (BMS).^13–20 This delayed healing with high frequency of thrombogenesis has been regarded as 1 possible mechanism for thrombotic occlusion or stenosis progression, that is, stent failure, in DES. In the newer DES, however (eg, E-ZES and Xience everolimus-eluting stents [X-EES]), the incidence of thrombus at follow-up is very low.^21–23 Both R-ZES and E-ZES had very low incidence of thrombus in the present study. Therefore, delayed healing would not be a major mechanism of late stent failure in those stents. Although heterogeneous neointima was associated with the presence of thrombus in the comparison of C-SES and T-PES used for stable angina patients,¹⁹ the incidence of thrombus in the present study was not significantly different between R-ZES and E-ZES, although the heterogeneity score was significantly higher in R-ZES than in E-ZES for the ACS patients. The heterogeneity score was not different between the stents for the non-ACS patients. This inconsistency may be due to the difference in the generation of DES or to the generally low incidence of thrombus in the present study. In any case, heterogeneity score is not associated with future cardiac events.²⁴

Neoatherosclerosis as a Cause of Late Stent Failure

Progression of neoatherosclerosis has been reported as a cause of very late stet thrombosis²⁵ and of restenosis after DES implantation.²⁶ Higo et al reported that C-SES had poor neointimal coverage and accelerated the formation of yellow plaque at 10-month follow-up, with thrombus being more frequently detected in the newly formed yellow lesions.¹⁴ Histopathologically, Nakazawa et al reported that the timing of atherosclerotic change, macrophage infiltration and/or necrotic core formation, was earlier in DES than in BMS.²⁷ R-ZES had the higher incidence of yellow plaque at 1 year after implantation than E-ZES in the present study.

R-ZES vs. E-ZES

E-ZES is covered by thick non-atherosclerotic fibrous white neointima, similar to BMS, but has a higher incidence of neointimal hyperplasia.^28–32 R-ZES is a new-generation ZES that uses the same metallic platform and the same dose of zotarolimus. The principal difference in R-ZES as compared with E-ZES is its durable polymer coating (BioLinx Polymer System) with slower drug release kinetics. The drug release is slower in R-ZES (50% and 85% drug release at 7 and 60 days after stent implantation) than in E-ZES (75% drug release at 2 days).³³ R-ZES has been found to have stronger suppression of neointimal hyperplasia with higher anti-restenotic efficacy than E-ZES in some clinical trials.^34–37 In the short-term comparison between R-ZES and E-ZES, R-ZES had better suppression of neointimal hyperplasia but higher incidence of uncovered and malapposed struts at 6-month follow-up.³⁸ According to the past clinical trials with long-term follow-up up to 5 years, TLR at 1 and 5 years were 3.9% and 10.2% in R-ZES,^39,40 and 5.9% and 7.5% in E-ZES,^41,42 respectively. Although these were not head-to-head comparison trials, the lesions with E-ZES appeared to be more stable during long-term follow-up than those with R-ZES.

Prediction of DES Failure on Angioscopy

We recently reported that in-stent atherosclerosis, as evaluated on the presence of yellow plaque at 1 year after the implantation of DES, is a risk factor for very late stent failure (in the Detect the Event of very late Stent failure from the drug-eluting stent NOT well covered by nEointima determined on angioscopy [DESNOTE] study).⁴³ Judging from this and the present result, R-ZES would have a higher risk of very late stent failure than E-ZES. In the DESNOTE study, the incidence of very late stent failure was 8.1% vs. 1.6% in the patients with vs. without yellow plaque (≥grade 2) during 4 years of follow-up. Yellow plaque (≥grade 2) was detected in 44% and 22% of the patients with R-ZES and E-ZES, respectively, in the present study. Therefore, the incidence of very late stent failure during 4 years of follow-up would be 4.5% vs. 3.0% in R-ZES vs. E-ZES, indicating that the difference would not be large enough to overcome the early difference of in-stent restenosis within 1 year, which was 4% vs. 13% in R-ZES vs. E-ZES. Very late stent failure, however, may not always be a benign event of restenosis but may be a life-threatening ACS. According to the DESNOTE study, very late stent failure may be prevented by the reduction of yellow plaque, for example with aggressive statin treatment; thus, aggressive statin treatment and other anti-atherosclerotic therapy should be more important after R-ZES implantation than after E-ZES implantation.

Study Limitations

The patient characteristics were generally similar but not completely matched between the R-ZES and E-ZES groups, because this was not a randomized trial. The R-ZES and E-ZES sample size was small, and selection bias may exist due to the fact that patients with renal dysfunction and those with small or tortuous coronary artery not suitable for angioscopy were not included in the present analysis.

Conclusions

E-ZES had better neointimal coverage with less yellow plaque and lower heterogeneity score than R-ZES at 1 year after implantation. The lesions with E-ZES appeared to be more stable than those with R-ZES.

Conflict of Interest / Financial Support

None.

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