650 NISHIMOTO Y et al.

Circulation Journal
Official Journal of the Japanese Circulation Society
ORIGINAL ARTICLE
http://www. j-circ.or.jp Cardiovascular Intervention

Angioscopic Comparison of Resolute and Endeavor

Zotarolimus-Eluting Stents
Yuji Nishimoto, MD; Koshi Matsuo, MD; Yasunori Ueda, MD, PhD; Ryuta Sugihara, MD;
Akio Hirata, MD, PhD; Ayaka Murakami, BSc; Kazunori Kashiwase, MD, PhD;
Yoshiharu Higuchi, MD, PhD; Yoshio Yasumura, MD, PhD

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 neo-
intimal 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 (pres-
ence 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)

Key Words: Angioscopy; Drug-eluting stent (DES); Neointima; Thrombus; Vulnerable plaque

D
rug-eluting stents (DES) have reduced late loss and
target lesion revascularization (TLR) by the inhibi-
tion 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 retrospec-
tively 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 with-
out reintervention before the follow-up; and E-ZES was

Received October 21, 2015; revised manuscript received December 7, 2015; accepted December 23, 2015; released online January 20,
2016   Time for primary review: 14 days
Cardiovascular Division, Osaka Police Hospital, Osaka (Y.N., K.M., R.S., A.H., A.M., K.K., Y.H., Y.Y.); Cardiovascular Division, Osaka
National Hospital, Osaka (Y.U.), Japan
Mailing address:  Yasunori Ueda, MD, PhD, FACC, FESC, FJCC, Cardiovascular Division, Osaka National Hospital, 2-1-14 Hoenzaka,
Chuo-ku, Osaka 540-0006, Japan.   E-mail: yellowplaque@gmail.com
ISSN-1346-9843  doi: 10.1253/circj.CJ-15-1119
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.80, March 2016

Angioscopy of R-ZES vs. E-ZES 651

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 lipopro-
tein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NA, not applicable; R-ZES, Resolute zotarolimus-eluting
stent.

implanted in 168 patients and follow-up angioscopy was per- Angioscopy

formed 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 cathe-
ters. Coronary angiogram was recorded using the Innova Car-
diovascular 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-hyperten-
sive drugs. Diabetes mellitus was defined as fasting blood
glucose >126 mg/dl or the use of oral drugs for diabetes mel-
litus 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 Cardi-
ology 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.
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 previ-
ously 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 cover-
age; 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 neo-
intimal 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

Circulation Journal  Vol.80, March 2016

652 NISHIMOTO Y et al.

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.

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 neo-
intima, 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, stent-
ing for ACS, gender, diabetes mellitus, hypertension, hyper-
cholesterolemia, 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.
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.
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 dif-
ferent 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%,

Circulation Journal  Vol.80, March 2016

Angioscopy of R-ZES vs. E-ZES
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 eicos-
apentaenoic acid use (Table 3).
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.
Circulation Journal  Vol.80, March 2016
653
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 ste-
nosis 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 neointi-
mal coverage was detected on
angioscopy. (G) A 71-year-old male
patient with silent myocardial isch-
emia had severe stenosis in the
mid-right coronary artery and (H)
underwent implantation of E-ZES.
At (I) 1-year follow-up catheteriza-
tion, no in-stent restenosis was seen
on angiography, and (J–L) com-
plete neointimal coverage (grade
2) without yellow plaque was seen
on angioscopy. Yellow line with
arrows, site of stent implantation;
yellow arrowhead, site of angios-
copy.
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 pres-
ent 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
654 NISHIMOTO Y et al.

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.

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.

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, het-
erogeneity 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 neo-
intimal coverage and accelerated the formation of yellow
plaque at 10-month follow-up, with thrombus being more

Circulation Journal  Vol.80, March 2016

Angioscopy of R-ZES vs. E-ZES
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 neo-
intimal hyperplasia.28–32 R-ZES is a new-generation ZES that
uses the same metallic platform and the same dose of zotaro-
limus. 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 com-
parison between R-ZES and E-ZES, R-ZES had better sup-
pression 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 implanta-
tion 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 inci-
dence 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, respec-
tively, 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 ther-
apy should be more important after R-ZES implantation than
after E-ZES implantation.
Study Limitations
The patient characteristics were generally similar but not com-
pletely 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 tortu-
ous coronary artery not suitable for angioscopy were not
included in the present analysis.
Circulation Journal  Vol.80, March 2016
655
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.
References
  1. Kastrati A, Mehilli J, Pache J, Kaiser C, Valgimigli M, Kelbaek H,
et al. Analysis of 14 trials comparing sirolimus-eluting stents with
bare-metal stents. N Engl J Med 2007; 356: 1030 – 1039.
  2. Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger
C, et al. Early and late coronary stent thrombosis of sirolimus-eluting
and paclitaxel-eluting stents in routine clinical practice. Lancet 2007;
369: 667 – 678.
  3. Eisenstein EL, Wijns W, Fajadet J, Mauri L, Edwards R, Cowper
PA, et al. Long-term clinical and economic analysis of the Endeavor
drug-eluting stent versus the Driver bare-metal stent: 4-year results
from the ENDEAVOR II trial (Randomized Controlled Trial to
Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578
Eluting Driver Coronary Stent in De Novo Native Coronary Artery
Lesions). JACC Cardiovasc Interv 2009; 2: 1178 – 1187.
  4. Kandzari DE, Mauri L, Popma JJ, Turco MA, Gurbel PA, Fitzgerald
PJ, et al. Late-term clinical outcomes with zotarolimus- and siroli-
mus eluting stents: 5-year follow-up of the ENDEAVOR III (A
Randomized Controlled Trial of the Medtronic Endeavor Drug
[ABT-578] Eluting Coronary Stent System Versus the Cypher
Sirolimus-Eluting Coronary Stent System in De Novo Native Coro-
nary Artery Lesions). JACC Cardiovasc Interv 2011; 4: 543 – 550.
 5. Leon MB, Kandzari DE, Eisenstein EL, Anstrom KJ, Mauri L,
Cutlip DE, et al. Late safety, efficacy, and cost-effectiveness of a
zotarolimus eluting stent compared with a paclitaxel-eluting stent in
patients with de novo coronary lesions: 2-year follow-up from the
ENDEAVOR IV trial (Randomized, Controlled Trial of the
Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent Sys-
tem Versus the Taxus Paclitaxel-Eluting Coronary Stent System in
De Novo Native Coronary Artery Lesions). JACC Cardiovasc Interv
2009; 2: 1208 – 1218.
  6. Garg S, Serruys P, Onuma Y, Dorange C, Veldhof S, Miquel-Hébert
K, et al. 3-year clinical follow-up of the XIENCE V everolimus-
eluting coronary stent system in the treatment of patients with de
novo coronary artery lesions: The SPIRIT II trial (Clinical Evalua-
tion of the Xience V Everolimus Eluting Coronary Stent System in
the Treatment of Patients with de novo Native Coronary Artery
Lesions). JACC Cardiovasc Interv 2009; 2: 1190 – 1198.
  7. Stone GW, Midei M, Newman W, Sanz M, Hermiller JB, Williams
J, et al. Randomized comparison of everolimus-eluting and pacli-
taxel-eluting stents: Two-year clinical follow-up from the Clinical
Evaluation of the Xience V Everolimus Eluting Coronary Stent
System in the Treatment of Patients with de novo Native Coronary
Artery Lesions (SPIRIT) III trial. Circulation 2009; 119: 680 – 686.
  8. Stone GW, Rizvi A, Sudhir K, Newman W, Applegate RJ, Cannon
LA, et al. Randomized comparison of everolimus- and paclitaxel-
eluting stents. 2-year follow-up from the SPIRIT (Clinical Evalua-
tion of the XIENCE V Everolimus Eluting Coronary Stent System)
IV trial. J Am Coll Cardiol 2011; 58: 19 – 25.
  9. Onuma Y, Miquel-Hebert K, Serruys PW; SPIRIT II Investigators.
Five-year long-term clinical follow-up of the XIENCE V everoli-
mus-eluting coronary stent system in the treatment of patients with
de novo coronary artery disease: The SPIRIT II trial. EuroInterven-
tion 2013; 8: 1047 – 1051.
10. Ueda Y, Nanto S, Komamura K, Kodama K. Neointimal coverage
of stents in human coronary arteries observed by angioscopy. J Am
Coll Cardiol 1994; 23: 341 – 346.
11. Ueda Y, Ohtani T, Shimizu M, Hirayama A, Kodama K. Assessment
of plaque vulnerability by angioscopic classification of plaque color.
Am Heart J 2004; 148: 333 – 335.
12. Ueda Y, Asakura M, Yamaguchi O, Hirayama A, Hori M, Kodama
K. The healing process of infarct-related plaques. Insights from 18
months of serial angioscopic follow-up. J Am Coll Cardiol 2001; 38:
1916 – 1922.
13. Oyabu J, Ueda Y, Ogasawara N, Okada K, Hirayama A, Kodama K.
Angioscopic evaluation of neointima coverage: Sirolimus drug-
eluting stent versus bare metal stent. Am Heart J 2006; 152:
656
1168 – 1174.
14. Higo T, Ueda Y, Oyabu J, Okada K, Nishio M, Hirata A, et al. Ath-
erosclerotic and thrombogenic neointima formed over sirolimus drug
eluting stent: An angioscopic study. JACC Cardiovasc Imaging
2009; 2: 616 – 624.
15. Kotani J, Awata M, Nanto S, Uematsu M, Oshima F, Minamiguchi
H, et al. Incomplete neointimal coverage of sirolimus-eluting stents:
Angioscopic findings. J Am Coll Cardiol 2006; 47: 2108 – 2111.
16. Awata M, Kotani J, Uematsu M, Morozumi T, Watanabe T, Onishi
T, et al. Serial angioscopic evidence of incomplete neointimal cover-
age after sirolimus-eluting stent implantation: Comparison with bare
metal stents. Circulation 2007; 116: 910 – 916.
17. Takano M, Yamamoto M, Xie Y, Murakami D, Inami S, Okamatsu
K, et al. Serial long-term evaluation of neointimal stent coverage and
thrombus after sirolimus-eluting stent implantation by use of coro-
nary angioscopy. Heart 2007; 93: 1533 – 1536.
18. Takano M, Yamamoto M, Murakami D, Inami S, Okamatsu K,
Seimiya K, et al. Lack of association between large angiographic late
loss and low risk of in-stent thrombus: Angioscopic comparison
between paclitaxel- and sirolimus-eluting stents. Circ Cardiovasc
Interv 2008; 1: 20 – 27.
19. Awata M, Nanto S, Uematsu M, Morozumi T, Watanabe T, Onishi
T, et al. Heterogeneous arterial healing in patients following pacli-
taxel-eluting stent implantation: Comparison with sirolimus-eluting
stents. JACC Cardiovasc Interv 2009; 2: 453 – 458.
20. Hara M, Nishino M, Taniike M, Makino N, Kato H, Egami Y, et al.
High incidence of thrombus formation at 18 months after paclitaxel-
eluting stent implantation: Angioscopic comparison with sirolimus-
eluting stent. Am Heart J 2010; 159: 905 – 910.
21. Awata M, Nanto S, Uematsu M, Morozumi T, Watanabe T, Onishi
T, et al. Angioscopic comparison of neointimal coverage between
zotarolimus- and sirolimus-eluting stents. J Am Coll Cardiol 2008;
52: 789 – 790.
22. Akazawa Y, Matsuo K, Ueda Y, Nishio M, Hirata A, Asai M, et al.
Atherosclerotic change at one year after implantation of Endeavor
zotarolimus-eluting stent vs. everolimus-eluting stent. Circ J 2014;
78: 1428 – 1436.
23. Ichikawa M, Takei Y, Hamasaki T, Kijima Y. Characterization of
patients with angioscopically-detected in-stent mural thrombi:
Genetics of clopidogrel responsiveness and generations of drug-
eluting stents. Circ J 2015; 79: 85 – 90.
24. Nishino M, Yoshimura T, Nakamura D, Lee Y, Taniike M, Makino
N, et al. Comparison of angioscopic findings and three-year cardiac
events between sirolimus-eluting stent and bare-metal stent in acute
myocardial infarction. Am J Cardiol 2011; 108: 1238 – 1243.
25. Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC, et
al. Pathological correlates of late drug-eluting stent thrombosis: Strut
coverage as a marker of endothelialization. Circulation 2007; 115:
2435 – 2441.
26. Liistro F, Stankovic G, Di Mario C, Takagi T, Chieffo A, Moshiri S,
et al. First clinical experience with a paclitaxel derivate-eluting
polymer stent system implantation for in-stent restenosis: Immediate
and long-term clinical and angiographic outcome. Circulation 2002;
105: 1883 – 1886.
27. Nakazawa G, Vorpahl M, Finn AV, Narula J, Virmani R. One step
forward and two steps back with drug-eluting-stents: From prevent-
ing restenosis to causing late thrombosis and nouveau atherosclero-
sis. JACC Cardiovasc Imaging 2009; 2: 625 – 628.
28. Leon MB, Nikolsky E, Cutlip DE, Mauri L, Liberman H, Wilson H,
et al. Improved late clinical safety with zotarolimus-eluting stents
compared with paclitaxel-eluting stents in patients with de novo
coronary lesions: 3-year follow-up from the ENDEAVOR IV (Ran-
domized Comparison of Zotarolimus- and Paclitaxel-Eluting Stents
in Patients With Coronary Artery Disease) trial. JACC Cardiovasc
Interv 2010; 3: 1043 – 1050.
29. Kim JS, Jang IK, Kim JS, Kim TH, Takano M, Kume T, et al. Opti-
cal coherence tomography evaluation of zotarolimus-eluting stents
at 9-month follow-up: Comparison with sirolimus-eluting stents.
Circulation Journal  Vol.80, March 2016
NISHIMOTO Y et al.
Heart 2009; 95: 1907 – 1912.
30. Guagliumi G, Sirbu V, Bezerra H, Biondi-Zoccai G, Fiocca L,
Musumeci G, et al. Strut coverage and vessel wall response to
zotarolimus-eluting and bare-metal stents implanted in patients with
ST-segment elevation myocardial infarction: The OCTAMI (Optical
Coherence Tomography in Acute Myocardial Infarction) study.
JACC Cardiovasc Interv 2010; 3: 680 – 687.
31. Guagliumi G, Musumeci G, Sirbu V, Bezerra HG, Suzuki N, Fiocca
L, et al. Optical coherence tomography assessment of in vivo vascu-
lar response after implantation of overlapping bare-metal and drug-
eluting stents. JACC Cardiovasc Interv 2010; 3: 531 – 539.
32. Kim JS, Jang IK, Fan C, Kim TH, Kim JS, Park SM, et al. Evaluation
in 3 months duration of neointimal coverage after zotarolimus-
eluting stent implantation by optical coherence tomography: The
ENDEAVOR OCT trial. JACC Cardiovasc Interv 2009; 2: 1240 – 
1247.
33. Udipi K, Chen M, Cheng P, Jiang K, Judd D, Caceres A, et al. Devel-
opment of a novel biocompatible polymer system for extended drug
release in a next-generation drug-eluting stent. J Biomed Mater Res
A 2008; 85: 1064 – 1071.
34. Meredith IT, Worthley S, Whitbourn R, Walters DL, McClean D,
Horrigan M, et al. Clinical and angiographic results with the next-
generation resolute stent system: A prospective, multicenter, first-in-
human trial. JACC Cardiovasc Interv 2009; 2: 977 – 985.
35. Serruys PW, Silber S, Garg S, van Geuns RJ, Richardt G, Buszman
PE, et al. Comparison of zotarolimus-eluting and everolimus-eluting
coronary stents. N Engl J Med 2010; 363: 136 – 146.
36. Yeung AC, Leon MB, Jain A, Tolleson TR, Spriggs DJ, Mc Laurin
BT, et al. Clinical evaluation of the Resolute zotarolimus-eluting
coronary stent system in the treatment of de novo lesions in native
coronary arteries: The RESOLUTE US clinical trial. J Am Coll
Cardiol 2011; 57: 1778 – 1783.
37. Saito S, Maehara A, Vlachojannis GJ, Parise H, Mehran R;
RESOLUTE Japan Investigators. Clinical and angiographic evalua-
tion of the resolute zotarolimus-eluting coronary stent in Japanese
patients: Long-term outcome in the RESOLUTE Japan and
RESOLUTE Japan small vessel study. Circ J 2015; 79: 96 – 103.
38. Guagliumi G, Ikejima H, Sirbu V, Bezerra H, Musumeci G,
Lortkipanidze N, et al. Impact of drug release kinetics on vascular
response to different zotarolimus-eluting stents implanted in patients
with long coronary stenoses: The LongOCT study (Optical Coher-
ence Tomography in Long Lesions). JACC Cardiovasc Interv 2011;
4: 778 – 785.
39. Serruys PW, Silber S, Garg S, van Geuns RJ, Richardt G, Buszman
PE, et al. Comparison of zotarolimus-eluting and everolimus-eluting
coronary stents. N Engl J Med 2010; 8: 136 – 146.
40. Iqbal J, Serruys PW, Silber S, Kelbaek H, Richardt G, Morel MA,
et al. Comparison of Zotarolimus- and everolimus-eluting coro-
nary stents: Final 5-year report of the RESOLUTE All-Comers
Trial. Circ Cardivasc Interv 2015; 8: e002230, doi:10.1161/
CIRCINTERVENTIONS.114.002230.
41. Fajadet J, Wijns W, Laarman GJ, Kuck KH, Ormiston J, Münzel T,
et al. Randomized, double-blind, multicenter study of the Endeavor
zotarolimus-eluting phosphorylcholine-encapsulated stent for treat-
ment of native coronary artery lesions: Clinical and angiographic
results of the ENDEAVOR II trial. Circulation 2006; 114: 798 – 806.
42. Fajadet J, Wijns W, Laarman GJ, Kuck KH, Ormiston J, Baldus S,
et al. Long-term follow-up of the randomised controlled trial to
evaluate the safety and efficacy of the zotarolimus-eluting driver
coronary stent in de novo native coronary artery lesions: Five year
outcomes in the ENDEAVOR II study. EuroIntervention 2010; 6:
562 – 567.
43. Ueda Y, Matsuo K, Nishimoto Y, Sugihara R, Hirata A, Nemoto T,
et al. In-stent yellow plaque at 1 year after implantation is associated
with future event of very late stent failure: The DESNOTE Study
(Detect the Event of Very late Stent Failure From the Drug-Eluting
Stent Not Well Covered by Neointima Determined by Angioscopy).
JACC Cardiovasc Interv 2015; 8: 814 – 821.