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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