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ORIGINAL PAPER
Randomized comparison of biolimus-eluting stentswith biodegradable polymer versus everolimus-eluting stentswith permanent polymer coatings assessed by optical coherencetomography
Tomohisa Tada • Adnan Kastrati • Robert A. Byrne • Tibor Schuster •
Rezarta Cuni • Lamin A. King • Salvatore Cassese • Michael Joner •
Jurgen Pache • Steffen Massberg • Albert Schomig • Julinda Mehilli
Received: 2 June 2013 / Accepted: 16 January 2014 / Published online: 23 January 2014
� Springer Science+Business Media Dordrecht 2014
Abstract We sought to compare the healing patterns of
biolimus-eluting stents with biodegradable polymer (BP-
BES, Nobori) versus everolimus-eluting stents with per-
manent polymer (PP-EES, Xience) using intravascular
optical coherence tomography (OCT). A total of 34
patients undergoing treatment of de novo coronary lesions
were randomly assigned to receive BP-BES (n = 15) or
PP-EES (n = 19). Stent tissue coverage and apposition as
well as the incidence of peri-strut low intensity area (PLIA)
were assessed by OCT at 6–8 months. Generalized linear
mixed models were used to account for clustered data.
OCT imaging was available for 17 lesions with 2,805 struts
in the BP-BES group and 22 lesions with 3,890 struts in the
PP-EES group. BP-BES as compared to PP-EES showed
similar rates of uncovered struts (479 vs. 588, odds ratio
(OR) 1.54 (95 % CI 0.63–3.79), P = 0.34) and malap-
posed struts (46 vs. 32 struts, OR 1.64 [95 % CI
0.21–12.5], P = 0.64). Three lesions with BP-BES
(17.6 %) versus 5 lesions with PP-EES (22.7 %) had
[30 % uncovered struts (P = 0.78). The proportion of
patients with PLIA was similar in both groups (BP-BES
41.2 % vs. PP-EES 36.4 %, OR 1.11 [95 % CI 0.43–2.87],
P = 0.83). New generation BP-BES as compared to PP-
EES showed similar stent coverage and apposition as
assessed by OCT at 6–8 months. In addition, PLIA—pos-
sible markers of delayed arterial healing—were observed
with similar frequency in both groups.
Keywords Biodegradable polymer � Drug-eluting stent �Optical coherence tomography � Vascular healing
Introduction
The high efficacy of first generation drug-eluting stents
(DES) in suppressing neointimal growth after stent
implantation represented a significant victory in the battle
against coronary restenosis. However the cost to be borne
was a slight increase in the incidence of very late stent
thrombosis (VLST) in comparison with bare metal stents
[1]. Pathological studies have suggested that the absence of
stent strut tissue coverage and the persistence of fibrin
deposition are the pathological hallmarks of delayed arte-
rial healing and mechanistically underlie the slight excess
of stent thrombosis seen with these devices [2–4].
Against this background, newer generation DES have
been developed with thinner stent struts, lower drug dos-
ages and improved biocompatibility polymers. The com-
bination of biodegradable polymer and asymmetric
abluminal coating on the biolimus-eluting stent (BP-BES;
T. Tada (&) � A. Kastrati � R. A. Byrne � R. Cuni �L. A. King � S. Cassese � M. Joner � J. Pache � A. Schomig
Deutsches Herzzentrum, Technische Universitat, Lazarettstrasse
36, 80636 Munich, Germany
e-mail: tomohisa@kuhp.kyoto-u.ac.jp
T. Tada � A. Kastrati � R. A. Byrne � L. A. King � S. Cassese �M. Joner � J. Pache � S. Massberg � A. Schomig � J. Mehilli
DZHK (German Centre for Cardiovascular Research), Partner
Site Munich Heart Alliance, Munich, Germany
T. Schuster
Institut fur Medizinische Statistik und Epidemiologie,
Technische Universitat, Munich, Germany
S. Massberg � J. Mehilli
Munich University Clinic, Department of Cardiology,
Ludwig-Maximilian University, Munich, Germany
A. Schomig
1. Medizinische Klinik, Klinikum Rechts der Isar, Technische
Universitat, Munich, Germany
123
Int J Cardiovasc Imaging (2014) 30:495–504
DOI 10.1007/s10554-014-0376-1
Nobori, Terumo, Japan) is designed to improve the vas-
cular healing response after stent implantation. Indeed,
9-month optical coherence tomography (OCT) follow-up
with a similar stent technology—the Biomatrix BES
(Biosensors, Switzerland)—showed improved stent strut
coverage when compared with permanent polymer-based
sirolimus-eluting stents (SES) [5]. This may underlie the
significant reduction in VLST observed with these stents in
clinical trials [6, 7]. In addition, the new generation thin-
strut permanent polymer everolimus-eluting stent (PP-EES,
Xience, Abbott Vascular, Santa Rosa, CA, USA), also
demonstrates signs of improved vascular healing in pre-
clinical studies [3], as well as a reduced incidence of def-
inite stent thrombosis in comparison with the leading first
generation DES [8, 9].
Direct comparison of these 2 new generation technolo-
gies in terms of vascular healing patterns has remained
outstanding to date. Accordingly, in the ISAR-TEST 6
(intracoronary stenting and angiographic results: test safety
of biodegradable and permanent limus-eluting stents) OCT
trial, we aimed to compare the patterns of neointimal
coverage and stent apposition between the BP-BES and the
PP-EES using OCT surveillance at 6–8 months after
stenting.
Methods
Patient selection, study procedure and follow-up
ISAR-TEST 6 OCT was a prospective randomized trial
enrolling patients at 2 centers in Munich, Germany. Eli-
gible patients (age C 18 years) were those who had angina
pectoris and/or objective signs of ischemia, in the presence
of a C50 % diameter stenosis de novo native coronary
artery lesion and accepted to undergo follow-up OCT. Key
exclusion criteria were patients with ST-segment elevation
myocardial infarction, cardiogenic shock, left main stem
disease, malignancies or other comorbid conditions with
life expectancy less than 12 months, known hypersensi-
tivity or allergy or contra-indication to contrast agents. The
study complied with the declaration of Helsinki, was
approved by institutional ethics committee and registered
at clinicaltrials.gov (study identifier: NCT01097434). All
patients provided written informed consent for participa-
tion in the trial.
After successful wiring of the index stenosis, patients
were randomly assigned to receive either BP-BES or
PP-EES. Balloon angioplasty and stent implantation were
performed according to standard techniques. Maximal
balloon pressure was defined as the highest balloon pres-
sure performed with the largest balloon during index PCI.
Follow-up OCT surveillance was scheduled for all patients
at 6–8 months. Data were collected and entered into a
computer database by specialized personnel of the Clinical
Data Management Centre (ISAR Center, Munich, Ger-
many). All events were adjudicated and classified by an
event adjudication committee blinded to the treatment
groups.
Quantitative coronary angiography (QCA) was per-
formed at baseline and immediately after PCI. Digital an-
giograms were analyzed offline at the core laboratory
(ISAR Center, Munich, Germany) with a validated auto-
mated edge detection system (QAngio XA v7.1, Medis
medical imaging systems, Leiden, The Netherlands).
Study devices
The Nobori BP-BES system (Terumo Corporation, Tokyo,
Japan) is a new generation DES made of stainless steel
(120 lm stent strut thickness) that elutes biolimus A9, an
analog of sirolimus. Biodegradable polymer (polylactid
acid) is applied only on the abluminal stent surface (10 lm
polymer thickness), and is designed to allow for rapid
initial elution of *40 % of drug from the stent. The initial
burst is followed by sustained drug release and polymer
degradation over the period of 6–9 months. The design of
the Nobori stent system has been described in details pre-
viously [10]. The Xience PP-EES (Abbot Vascular, Santa
Clara, CA, USA) is a thin cobalt-chromium stent coated
with everolimus at a dose of 100 lg/cm2 of stent surface
(81 lm stent strut thickness and 8 lm polymer thickness)
and a non-biodegradable fluoropolymer, designed to
release 80 % of the everolimus in the first 30 days after
deployment.
Optical coherence tomography analysis
End point definitions
The primary endpoint of the study was the difference in
percentage of uncovered struts between BP-BES and PP-
EES assessed by OCT at 6–8 months post index inter-
vention. Secondary endpoints were percentage of malap-
posed struts and strut-level intimal thickness (SIT).
Image acquisition and offline analysis
The methods of OCT image acquisition were described in a
previous report [11]. Following administration of intrave-
nous heparin and intracoronary nitrates OCT was per-
formed using frequency domain OCT (C7XR system,
LightLab Imaging, Westford, MA, USA) allowing acqui-
sition at 100 frames per second with non-occlusive imaging
technique. A standard guide wire was advanced distally in
the target vessel and the OCT companion C7 DragonflyTM
496 Int J Cardiovasc Imaging (2014) 30:495–504
123
catheter was advanced over the wire using rapid exchange
technology. OCT imaging was performed at a pullback of
20 mm/s, during flush of 2–4 mL/s of iso-osmolar contrast
through the guiding catheter to replace blood flow and
permit visualization of the stented segment and intima-
lumen interface. If the stented segment was too long to be
safely imaged in a single pullback, image acquisition was
stopped and an additional pullback performed during a
second contrast injection using anatomic landmarks such as
side branches, calcifications for longitudinal view
orientation.
Offline data analysis was performed in the core labora-
tory (ISAR Center, Munich, Germany) by personnel blin-
ded to stent-type allocation and clinical and procedural
characteristics of the patients. Analysis of contiguous
cross-sections at 1 mm longitudinal intervals within the
stented segment was performed using proprietary software
(LightLab imaging, Westford, MA, USA). Metallic stent
struts typically appear as bright, signal-intense structures
(blooming) with dorsal shadowing. A strut was considered
suitable for analysis only if it had (1) well defined bright
‘blooming’ appearance, and (2) characteristic shadow
perpendicular to the light source. The number of stent
struts was determined in each cross-section. Thickness of
the tissue coverage on the luminal side of each strut was
measured at the middle of the long axis of the strut. The
inner contours of each strut reflection were delineated for
each strut and its distance to the lumen contour was cal-
culated automatically to determine SIT. Because the bio-
logical and clinical significance of stent coverage thickness
that is measured to be less than the axial resolution of the
OCT is debatable, struts were adjudicated as covered by
tissue only if they had positive SIT values C minimal axial
resolution of OCT (20 lm) [11]. Struts were classified as
malapposed if protruding into the lumen at a distance
greater than the sum of the strut and polymer thickness
(120 lm for the BP-BES and 89 lm for the PP-EES) plus
the minimal axial resolution of OCT (20 lm). Malapposed
struts were classified as uncovered, since tissue surround-
ing the malapposed struts is not well understood. Lumen
area and stent area were drawn in each cross-section and
neointimal area, percent area stenosis, and neointimal
hyperplasia volume were calculated, as appropriate [12]. If
any cavities outside the implanted stent were observed,
area of extrastent cavity was calculated as: lumen area—
stent area. The extra stent cavity volume was estimated for
each stented lesion and normalized per stent volume. In
addition we also developed novel ‘‘spread-out neointimal
topographies’’ to visualize the distribution of the neointi-
mal growth in the stented segment using a circumferential
measurement of the thickness by means of an automated
contour detection algorithm available in the Light Lab
proprietary software. The graphics represented the stented
vessel, as if it had been cut longitudinally along the ref-
erence angle 0� and spread out on a flat surface. Non-
analyzable frames were defined as frames in which greater
than 45� of the lumen border was not visualized (e.g. due to
presence of side branch) or with severe artifacts (e.g. due to
inadequate blood clearance or non-uniform rotation dis-
tortion). In case of non-analyzable frames, an alternative
frame of appropriate image quality within the next fol-
lowing or preceding two frames was analyzed. Qualitative
analysis of peri-strut low intensity area (PLIA) was
assessed in frames with more than 5 % neointimal hyper-
plasia. PLIA was defined as a region around stent struts
with a homogenous lower intensity appearance than sur-
rounding tissue on OCT images without significant signal
attenuation behind the area. [13, 14] Only PLIA inside the
inner contours of the stent reflections was included in this
analysis.
Statistical analysis
The objective of this study was to compare the BP-BES
and PP-EES regarding stent strut coverage at 6–8 months
follow-up as assessed by OCT. Designed as a superiority
study, the following assumptions were used to calculate the
sample size: a percentage of the evaluable strut segments
not covered by neointima of 5 % for the PP-EES, a relative
reduction of 20 % with BP-BES, a 2-sided a-level of 0.017
and power of 90 %. On this basis, a total number of 15
patients had to provide the necessary number of struts for
the analysis. The analysis of primary and secondary end-
points was planned on an intention-to-treat basis. To
account for the clustered nature of the data, a generalized
linear mixed model was conducted for strut-level and
frame-level analysis for comparison between patients with
BP-BES and patients with PP-EES with patient indicator
(patient, lesion, and frame for strut-level analysis, patient
and lesion for frame-level analysis) as a random effect and
type of stent (for strut-level analysis) and existence of
PLIA (for frame-level analysis) as a fixed effect. Data are
presented as values and percentages or mean
value ± standard deviation or median and interquartile
range (IQR). Categorical variables were compared with the
Fisher’s exact test. Continuous variables were compared
using the Welch’s t test and Mann–Whitney U test based
on the distribution. All analyses were performed with the R
2.15.1 (The R foundation for Statistical Computing,
Vienna, Austria) and JMP 9.0.2 (SAS Institute Inc, Cary,
NC, USA) programs. All statistical analyses were two-
tailed and P values \0.05 were considered statistically
significant.
Int J Cardiovasc Imaging (2014) 30:495–504 497
123
Results
Baseline patient, lesion and procedural characteristics
In total 34 patients (41 lesions) were enrolled in the ISAR-
TEST 6 OCT study. Of these 15 patients (19 lesions) were
randomly assigned to receive BP-BES and 19 patients (22
lesions) to receive PP-EES. Patient study flow is shown in
Fig. 1. Both groups were well matched according to
baseline clinical, angiographic and procedural characteris-
tics as shown in Table 1.
Clinical outcomes
At 12 months, 3 patients in BP-BES group and 4 patients in
PP-EES group underwent revascularization (17.7 % in BP-
BES vs. 18.2 % in PP-EES, P = 0.67). Otherwise there were
no clinical events in either group at 12 months follow-up.
OCT and QCA measurements
Lesion-level OCT and QCA analysis results at 6–8-month
surveillance are shown in Table 2. One patient (2 lesions)
in the BP-BES group was excluded due to unwillingness to
consent to invasive follow-up. The median follow-up
duration was 203 ± 19 days in BP-BES group and
194 ± 37 days in PP-EES group (P = 0.45).
A total of 2,805 struts (17 lesions) in BP-BES group and
a total of 3,890 struts (22 lesions) in PP-EES group were
assessed strut-by-strut in off-line OCT analyses. Coverage
and malapposition of the stent struts were analyzed at strut-
and lesion-level. The spread-out neointimal topography
showing the spatial distribution of the neointimal growth of
individual analyzed stent is shown in Fig. 2.
Regarding the primary endpoint 479 uncovered struts in
BP-BES and 588 uncovered struts in PP-EES were
observed. After adjustment for clustering, there was no
difference between BP-BES and PP-EES in terms of the
percentage of uncovered struts (10.7 % [95 % CI 2.1–39.9]
versus 4.9 % [95 % CI 1.7–13.4], odds ratio (OR) 1.54
(95 % CI 0.63–3.79), P = 0.34, Fig. 3) The percentage of
malapposed struts was similar in both groups (BP-BES 46
struts versus PP-EES 32 struts, OR 1.64 [95 % CI
0.21–12.5], P = 0.64). Strut-level intimal thickness was
also similar in both groups 50 lm (20–90 lm) versus
70 lm (30–130 lm) (estimated difference -21.5 lm,
95 % CI [-49.7 to 6.7], P = 0.17) (Fig. 4). No correlations
between the frame-level percentage of uncovered struts and
lumen area (R2 = 0.13, P \ 0.001) or neointimal area
(R2 = 0.05, P \ 0.001) were observed (Fig. 5a, b).
In lesion-level analysis, 3 lesions with BP-BES (17.6 %)
versus 5 lesions with PP-EES (22.7 %) had [30 %
uncovered struts (P = 0.78). There were no significant
differences in area and volumetric analyses between the
groups regarding any of the assessed parameters (Table 2).
No evidence of thrombus was observed in any of the
stented segments.
OCT qualitative analysis was assessed frame-by-frame
with a total of 372 frames in the BP-BES group and a total
of 424 frames in the PP-EES group. The qualitative
assessment of PLIA was highly reproducible: the intra-
observer and inter-observer reproducibility (R2) were 0.84
and 0.83, respectively. The proportion of patients who had
any frames with PLIA (Fig. 6a) was similar in both groups
(41.2 % in BP-BES and 36.4 % in PP-EES, OR 1.11, 95 %
CI [0.43–2.87], P = 0.83). Frames with PLIA as compared
to those without had higher percent hyperplasia obstruction
(Fig. 6b).
Discussion
The main findings of the ISAR-TEST 6 OCT randomized
study are: (1) in terms of OCT markers of vascular healing
including strut coverage and malapposition there was no
difference observed between the patients treated with BP-
BES and PP-EES at 6–8 months surveillance; (2) both BP-
BES and PP-EES showed similar high antirestenotic effi-
cacy as assessed by strut-level intimal thickness and OCT
volumetric analysis; and (3) the incidence of peri-strut low
intensity area within the stented segments was similar in
both groups.
The comparable efficacy and safety profile of both stents
as assessed by OCT imaging in our study is consistent with
Fig. 1 Study flow chart. BP-BES biodegradable polymer biolimus-
eluting stents, OCT optical coherence tomography, PP-EES perma-
nent polymer everolimus-eluting stents
498 Int J Cardiovasc Imaging (2014) 30:495–504
123
the hypothesized design advantages of both devices in
comparison with first generation DES and in agreement
with accumulating clinical outcome data with both BP-
BES and PP-EES [6–9, 15]. Notably, in a previous OCT
study investigators were able to show an improvement in
stent strut coverage with BP-BES in comparison with the
first generation sirolimus-eluting stent (SES) [5], whereas
no such difference could be seen in our study. It seems
Table 1 Biodegradable polymer biolimus-eluting stents versus permanent polymer everolimus-eluting stents: characteristics of patients and
lesions at baseline
Patients BP-BES PP-EES P value
n = 15 n = 19
Age (year) 65.5 ± 11.0 70.1 ± 8.2 0.34
Male sex [no. (%)] 13 (86.7) 16 (84.2) 0.81
Body mass index (kg/m2) 27.1 ± 3.6 27.0 ± 3.2 0.93
Diabetes Mellitus [no. (%)] 3 (20.0) 7 (36.8) 0.28
Arterial hypertension [no. (%)] 10 (66.7) 16 (84.2) 0.43
Hyperlipidemia [no. (%)] 13 (86.7) 14 (73.7) 0.66
Current smoker [no. (%)] 2 (13.3) 2 (10.5) 0.83
Prior myocardial infarction [no. (%)] 3 (20.0) 4 (21.1) [0.99
Prior coronary artery bypass grafting [no. (%)] 2 (13.3) 2 (10.5) [0.99
Prior percutaneous coronary intervention [no. (%)] 5(33.3) 12 (63.2) 0.17
Clinical presentation [no. (%)] 0.58
NSTEMI 1 (6.7) 3 (15.8)
Unstable angina 4 (26.7) 3 (15.8)
Stable angina 10 (66.7) 12 (63.2)
Multivessel disease [no. (%)] 14 (93.3) 16 (84.2) [0.99
Lesions n = 19 n = 22
Target-vessel location [no (%)] 0.58
Left anterior descending artery 4 (21.1) 7 (31.8)
Left circumflex artery 7 (36.8) 8 (36.4)
Right coronary artery 8 (42.1) 6 (27.3)
Complex morphology (B2/C) [no (%)] 11 (57.9) 13 (59.1) [0.99
Procedural characteristics
Predilatation 15 (83.3) 18 (81.8) 0.89
Stent length 18 [18-24] 18 [18] 0.32*
Mean stent diameter 2.96 ± 0.31 3.06 ± 0.57 0.28
Mean balloon diameter 2.89 ± 1.03 3.24 ± 0.65 0.73
Maximal balloon pressure 13.7 ± 5.1 13.8 ± 3.1 [0.99
QCA characteristics
Lesion length (mm) 12.0 [10.3-15.3] 10.7 [8.7-15.0] 0.30*
Vessel size (mm) 2.81 ± 0.39 2.89 ± 0.56 0.81
Minimum lumen diameter (mm)
Before procedure 1.00 ± 0.43 1.11 ± 0.36 0.50
Post procedure 2.63 ± 0.40 2.65 ± 0.47 0.96
Percent stenosis (%)
Before procedure 64.9 ± 13.3 61.2 ± 11.2 0.33
Post procedure 10.3 ± 3.5 11.4 ± 6.4 0.43
Data is shown as n (%), mean ± SD or median [IQR]
Categorical variables were compared with the Fisher’s exact test
If not indicated otherwise, Continuous variables were compared with the two-sided Welch’s t test for independent samples
BP-BES biodegradable polymer biolimus-eluting stents, NSTEMI non ST-segment elevation myocardial infarction, PP-EES permanent polymer
everolimus-eluting stents, QCA quantitative coronary angiography
* Mann–Whitney U test for non-parametric comparison of the stent type groups (BP-BES vs. PP-EES)
Int J Cardiovasc Imaging (2014) 30:495–504 499
123
Table 2 Lesion-level OCT and QCA analysis at 6–8 months
BP-BES 17 lesions PP-EES 22 lesions P value
OCT outcomes
Lesion with at least 30 % uncovered struts (%) 3 (17.6) 5 (22.7) 0.78
Lesion with at least 10 % uncovered struts (%) 11 (64.7) 11 (50.0) 0.28
Lesion with any uncovered struts (%) 16 (94.1) 20 (90.9) 0.60
Lesion with at least 5 % malapposed struts (%) 2 (11.8) 1 (4.6) 0.40
Lesion with any malapposed struts (%) 8 (47.1) 7 (31.8) 0.26
Mean lumen area (mm2) 5.8 [4.5–6.7] 5.1 [4.3–7.3] 0.64
Lumen volume (mm3) 117.8 [90.0–163.4] 94.8 [74.6–145.8] 0.28
Mean stent area (mm2) 6.1 [5.0–7.6] 6.6 [5.2–7.9] 0.44
Stent Volume (mm3) 122.0 [93.1–188.8] 117.3 [94.3–137.3] 0.56
Neointimal hyperplasia volume (mm3) 6.5 [2.6–27.0] 17.1 [9.1–35.0] 0.18
% Hyperplasia obstruction—corrected by stent volume 9.8 [3.1–21.8] 15.3 [7.8–29.4] 0.07
Extrastent cavity volume, mm3 7.1 [2.5–14.9] 4.6 [0.3–18.9] 0.70
% Extrastent cavity volume—corrected by stent volume 4.7 [2.8–10.2] 4.3 [0.3–12.2] 0.64
QCA outcomes
Minimum lumen diameter (mm) 2.35 ± 0.82
2.49 [2.05–2.97]
2.51 ± 0.54
2.58 [2.09–2.83]
0.95*
Percent stenosis (%) 21.5 ± 24.3
13.1 [7.7–16.6]
12.8 ± 6.3
12.0 [7.6–17.7]
0.91*
Recurrent binary restenosis (%) 3 (15.8) 1 (4.6) 0.50
Late lumen loss (in-stent) (mm) 0.31 ± 0.62
0.10 [-0.05–0.28]
0.11 ± 0.24
0.06 [-0.05–0.35]
0.22
Data is shown as n (%), mean ± SD or median [IQR]
Categorical variables were compared with the Fisher’s exact test
Continuous variables were compared with Mann–Whitney U test for non-parametric comparison of the stent type groups (BP-BES vs. PP-EES)
BP-BES biodegradable polymer biolimus-eluting stents, OCT optical coherence tomography, PP-EES permanent polymer everolimus-eluting
stents, QCA quantitative coronary angiography
Fig. 2 Spread-out neointimal
topography. The distribution of
the neointimal growth in the
stented segment is displayed
using a circumferential
measurement of the thickness
by means of an automated
contour detection algorithm
available in the Light Lab
proprietary software. The
graphics represented the stented
vessel, as if it had been cut
longitudinally along the
reference angle 0� and spread
out on a flat surface. BP-BES
biodegradable polymer
biolimus-eluting stents, PP-EES
permanent polymer everolimus-
eluting stents
500 Int J Cardiovasc Imaging (2014) 30:495–504
123
most likely that this is related to the use of a superior
comparator in the PP-EES. Indeed, tighter confidence
intervals in the rate of uncovered struts in PP-EES as
compared to BP-BES in the current study may suggest
more homogenous neointimal growth patterns after PP-
EES implantation. Moreover, although there were no sta-
tistical differences, there was a tendency towards higher
mean neointimal thickness by OCT as well as lower late
luminal loss by QCA in PP-EES in comparison with BP-
BES. Nevertheless there are some methodological differ-
ences between the 2 studies which should be considered.
As an example, the percentage of lesions with any
uncovered struts in patients treated with BP-BES in the
LEADERS-OCT sub-study was notably lower at 63.3 %,
in comparison with 94.1 % in the current ISAR-TEST 6
OCT study and such differences may be accounted for by
two reasons. First, instead of a qualitative assessment of
strut coverage, we used a quantitative definition. In addi-
tion, the more conservative definition of coverage used in
Fig. 3 Stent strut coverage at 6–8 months. BP-BES biodegradable
polymer biolimus-eluting stents, CI confidence interval, OR odds
ratio, PP-EES permanent polymer everolimus-eluting stents
Fig. 4 Histograms showing the
distribution of the neointimal
thickness on the stent struts at
6–8 months. BP-BES
biodegradable polymer
biolimus-eluting stents, PP-EES
permanent polymer everolimus-
eluting stents
Fig. 5 Correlation between the frame-level percentage of uncovered struts and lumen area or neointimal area. a Uncovered struts (%) versus
lumen area. b Uncovered struts (%) versus area stenosis (%)
Int J Cardiovasc Imaging (2014) 30:495–504 501
123
the current study takes into account the minimal axial
resolution of OCT (20 lm). In view of reported wide inter-
and intra-observer variability during qualitative analysis
[16], we believe that quantitative assessment of the OCT
strut coverage should be the preferred approach. Second,
the time interval between OCT examination and stent
implantation in our study—at approximately 200 days after
stenting—is somewhat shorter than previous studies and
may account for some of the excess of uncovered struts [5,
17]. However, the optimal timing for evaluating vessel wall
healing after stenting is still unknown. Indeed 2-year
LEADERS-OCT data showed that the difference in rate of
stent coverage between BP-BES and SES disappeared over
time [5, 18].
Regardless of whether qualitative or quantitative ana-
lysis is used for adjudication of strut coverage, the majority
of stents will have uncovered struts. As we know that the
incidence of stent thrombosis is low, this raises the ques-
tion of what percentage of uncovered struts is likely to
confer a significant risk of adverse clinical events. In this
respect pathological data has suggested that levels of
uncovered struts greater than 30 % is associated with
clinically relevant long-term events [2]. In our study, the
percentage of lesions with at least 30 % uncovered strut
was 17.7 % with BP-BES and 23.8 % with PP-EES. The
hypothesis that these patients may benefit from prolonged
dual antiplatelet therapy for more than 6 months after
stenting should be tested in future specifically-designed
trials.
The percentage of stent strut malapposition in the cur-
rent study was low and similar to the rates seen in previous
trials [5, 11, 18]. However as in other trials to date,
assessment of stent malapposition in our study is limited by
the lack of an OCT examination immediately following
the index intervention. This could have facilitated
differentiation between late acquired stent malapposition
caused by positive remodeling of the stented vessel wall
and persisting procedure-related acute stent malapposition.
Indeed late acquired vessel wall remodeling is well rec-
ognized as an important predictor of VLST [19, 20].
Finally, we also assessed for peri-strut low intensity
areas—potential markers of delayed arterial healing—in
our report and found similar rates in both treatment groups.
However the clinical significance of these findings remain
to be fully elucidated. A preclinical study using a porcine
stent implantation model reported the incidence of PLIA on
OCT images was three times higher in DES than in bare
metal stents [13]. Comparative histological observations
suggested that these areas may represent fibrin accumula-
tions surrounded by proteoglycans extracellular matrix and
inflammatory cell infiltrate [13]. Moreover, a positive
correlation was seen between the incidence of stent struts
with PLIA and the degree of neointimal thickening after
stent implantation in animal and human studies [13, 14]. In
the present study, the incidence of PLIA was approxi-
mately 40 % in both groups, somewhat lower than that
observed in a previous report with first generation DES
comparing sirolimus- and paclitaxel-eluting stents (58.1
and 86.5 % respectively) [14] Although OCT and histo-
pathological correlation data remains scant it could be
speculated that the lower incidence of PLIA in both BP-
BES and PP-EES might be interpreted as further evidence
of improved vascular healing with these stents.
Study limitations
There were several important limitations in this study.
First, the sample size calculation was limited by the lack of
preceding studies and assumption of 20 % difference
between BP-BES and PP-EES in the percentage of
Fig. 6 a Representative example (PP-EES) of peri-strut low intensity
area. Peri-strut low intensity area (PLIA) was defined as a region
around stent struts with a homogenous lower intensity appearance
than surrounding tissue on OCT images without significant signal
attenuation behind the area (white arrows). Asterisk indicates a dorsal
shadow behind the guide-wire. b Relation between percent neointimal
obstruction and the presence of peri-strut low intensity area. PLIA
peri-strut low intensity area
502 Int J Cardiovasc Imaging (2014) 30:495–504
123
uncovered struts was necessarily arbitrary. Moreover this
was not performed with adjustment for data clustering. In
addition the study is not powered or designed to investigate
the clinical implications of OCT endpoints. Second, the
absence of longitudinal follow-up correlating intimal cov-
erage of stent struts and subsequent late clinical events
such as stent thrombosis is an important issue both in our
trial and in other OCT studies. Third, the time point of
OCT assessment was 6–8 months after stenting. Intracor-
onary imaging assessment at longer follow-up period may
provide additional relevant information. Fourth, while
qualitative evaluation of in-stent neointimal tissue might be
important to investigate the risk of future thrombus for-
mation, conventional OCT technology cannot distinguish
between neointima and other materials such as fibrin, and
cannot detect thin layers of endothelium below the limit of
its axial resolution. Finally, although it is the standard used
by many investigators, OCT measurements at 1 mm lon-
gitudinal intervals might impact the accuracy of the OCT
analysis.
Conclusions
Biodegradable polymer biolimus-eluting stents as com-
pared to durable polymer everolimus-eluting stents were
associated with similar strut coverage and malapposition
using OCT surveillance at 6–8 months follow-up. More-
over peri-strut low intensity areas were observed with
similar frequency with both platforms. The clinical sig-
nificance of these findings requires further specific longer-
term studies.
Acknowledgments This work was founted by the European Com-
mission under the Seventh Framework Program (PRESTIGE project
grant 260309) and supported by a research Grant for supplying OCT
catheters from Terumo Europe.
Conflict of interest Dr. Kastrati reports received lecture fees from
Abbott, Astra-Zeneca, Biotronik, Biosensors, MSD, The Medicines
and St. Jude Medical. Dr. Mehilli reports received lecture fees form
Abbott, Biotronik and Terumo. The remaining authors report no
conflicts of interest.
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