INtimal hyPerplasia evAluated by oCT in de novo COROnary lesions treated by drug-eluting balloon and bare-metal stent (IN-PACT CORO): study protocol for a randomized controlled trial.

Abstract

Neointimal hyperplasia plays a pivotal role in the pathogenesis of in-stent restenosis in patients undergoing percutaneous coronary interventions. Drug-eluting balloons are a promising tool to prevent restenosis after coronary angioplasty. Moreover, an increased knowledge of the pathophysiology of restenosis my help improve therapeutic strategies.
We present the design of an open-label, randomized three-arm clinical trial aimed to assess whether a strategy of bare-metal stent implantation with additional use of drug-eluting balloons, either before (pre-dilation) or after stenting (post-dilation), reduces the primary endpoint of in-stent neointimal hyperplasia area as compared with a strategy of bare-metal stent implantation alone. This primary endpoint will be assessed by optical coherence tomography at follow-up. Secondary endpoints will be the percentage of uncovered struts, and the percentage of struts with incomplete apposition. An ancillary study investigating the relation between systemic levels of endothelial progenitors cells and neointimal hyperplasia, and the interaction between endothelial progenitors cell levels and drug-eluting balloons has been planned. Thirty consecutive patients undergoing percutaneous coronary intervention will be randomized with a 1:1:1 design to bare-metal stent implantation alone (n = 10); bare-metal stent implantation after pre-dilation with a drug-eluting balloon (n = 10); or bare-metal stent implantation followed by post-dilation with a drug-eluting balloon (n = 10). Six-month follow-up coronary angiography with optical coherence tomography imaging of the stented segment will be performed in all patients. Blood samples for the assessment of endothelial progenitors cell levels will be collected on admission and at 6 months.
Experimental and early clinical data showed that inhibition of neointimal hyperplasia may be obtained by local administration of antiproliferative drugs loaded on the surface of angioplasty balloons. The INtimal hyPerplasia evAluated by oCT in de novo COROnary lesions treated by drug-eluting balloon and bare-metal stent (IN-PACT CORO) trial was conceived to test the superiority of a strategy of bare-metal stent implantation with additional drug-eluting balloon use (either before or after stenting) versus a strategy of bare-metal stent implantation alone for the reduction of neointimal hyperplasia. We also planned an ancillary study to assess the role of endothelial progenitors cells in the pathophysiology of neointimal hyperplasia.
Clinicaltrials.gov NCT01057563.

Full text

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STUDY PROTOCOLOpen Access
INtimal hyPerplasia evAluated by oCT in de novo
COROnary lesions treated by drug-eluting balloon
and bare-metal stent (IN-PACT CORO): study
protocol for a randomized controlled trial
Francesco Burzotta*, Marta Francesca Brancati, Carlo Trani, Italo Porto, Antonella Tommasino, Gianluigi De Maria,
Giampaolo Niccoli, Antonio Maria Leone, Valentina Coluccia, Giovanni Schiavoni and Filippo Crea
Abstract
Background: Neointimal hyperplasia plays a pivotal role in the pathogenesis of in-stent restenosis in patients
undergoing percutaneous coronary interventions. Drug-eluting balloons are a promising tool to prevent restenosis
after coronary angioplasty. Moreover, an increased knowledge of the pathophysiology of restenosis my help
improve therapeutic strategies.
Methods/Design: We present the design of an open-label, randomized three-arm clinical trial aimed to assess
whether a strategy of bare-metal stent implantation with additional use of drug-eluting balloons, either before
(pre-dilation) or after stenting (post-dilation), reduces the primary endpoint of in-stent neointimal hyperplasia area
as compared with a strategy of bare-metal stent implantation alone. This primary endpoint will be assessed by
optical coherence tomography at follow-up. Secondary endpoints will be the percentage of uncovered struts, and
the percentage of struts with incomplete apposition. An ancillary study investigating the relation between systemic
levels of endothelial progenitors cells and neointimal hyperplasia, and the interaction between endothelial
progenitors cell levels and drug-eluting balloons has been planned. Thirty consecutive patients undergoing
percutaneous coronary intervention will be randomized with a 1:1:1 design to bare-metal stent implantation alone
(n=10); bare-metal stent implantation after pre-dilation with a drug-eluting balloon (n=10); or bare-metal stent
implantation followed by post-dilation with a drug-eluting balloon (n=10). Six-month follow-up coronary
angiography with optical coherence tomography imaging of the stented segment will be performed in all patients.
Blood samples for the assessment of endothelial progenitors cell levels will be collected on admission and at
6 months.
Discussion: Experimental and early clinical data showed that inhibition of neointimal hyperplasia may be obtained
by local administration of antiproliferative drugs loaded on the surface of angioplasty balloons. The INtimal
hyPerplasia evAluated by oCT in de novo COROnary lesions treated by drug-eluting balloon and bare-metal stent
(IN-PACT CORO) trial was conceived to test the superiority of a strategy of bare-metal stent implantation with
additional drug-eluting balloon use (either before or after stenting) versus a strategy of bare-metal stent
implantation alone for the reduction of neointimal hyperplasia. We also planned an ancillary study to assess the role
of endothelial progenitors cells in the pathophysiology of neointimal hyperplasia.
Trial registration: Clinicaltrials.gov NCT01057563.
Keywords: Bare-metal stent, Drug-eluting balloon, Percutaneous coronary interventions
* Correspondence: f.burzotta@rm.unicatt.it
Institute of Cardiology, Catholic University of the Sacred Heart, L.go Gemelli,
8 00168 Rome, Italy
Full list of author information is available at the end of the article
© 2012 Burzotta et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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TRIALS

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Background
Restenosis due to neointimal hyperplasia causes repeat
target vessel revascularization in a relevant number of
patients undergoing percutaneous coronary interventions
(PCI).
Drug-eluting stents (DES) are currently widely adopted
to reduce the restenosis rate and repeat revasculariza-
tions [1]. However, DES technology is associated with a
profound inhibition of stent strut endothelialization,
which may lead to the presence of uncovered stent struts
and to the persistence of polymer inducing inflammatory
reactions in the vessel wall [2,3]. Such factors may in-
crease the risk of stent thrombosis so that prolonged
dual antiplatelet therapy is recommended after DES im-
plantation [4].
Experimental data [5] and early clinical experiences
showed that inhibition of neointimal hyperplasia may be
obtained by local administration of antiproliferative
drugs (like paclitaxel) loaded on the surface of angio-
plasty balloons [6-8]. Accordingly, drug-eluting balloons
(DEBs) are a promising tool to prevent restenosis and
avoid the undesirable persistence of DES polymers in the
vessel wall, thus potentially increasing the safety of PCI.
Most of the scientific evidence regarding DEB efficacy is
actually concentrated in the treatment of patients with
in-stent restenosis; there are some data about use of
DEBs for de novo lesions and for bifurcation lesions [9].
For de novo lesions the only registry available is the
Paclitaxel-Eluting PTCA-Balloon Catheter to Treat Small
Vessel Coronary Artery Disease (PEPCAD I), which con-
cluded that DEBs are associated with a high procedural
success rate in small de novo lesions, while DEBs in con-
junction with a bare-metal stent (BMS) remains a con-
cern because of high restenosis rate [10]. Until now,
DEBs failed to show equivalence to DES regarding angio-
graphic endpoints during PCI of small coronary arteries
[11].
Optical coherence tomography (OCT) is a novel im-
aging modality with high resolution to assess neointimal
coverage and stent strut apposition [12-14]. It was used
in a recent study [15] evaluating the effect of sequential
application of DEBs and BMS (for de novo coronary
lesions) on neointimal hyperplasia; the sequence of appli-
cation (DEB first versus BMS first) did not influence out-
come, except for better apposition when applying the
BMS first. However, in this study there was no control
group (that is, BMS alone).
Thus, we designed an open-label, single center, rando-
mized trial to evaluate whether additional DEB use in
patients undergoing BMS implantation, either before or
after the BMS implantation, improves neointimal forma-
tion assessed by OCT and affects the process of strut
coverage at follow-up, compared with BMS implantation
alone.
Moreover, recent clinical observations have suggested
that endothelial progenitor cells (EPC), may play a role
in the process of in-stent restenosis [16,17]. We therefore
planned an ancillary study, aiming at assessing the rela-
tion between levels of systemic EPC and neointimal
hyperplasia at follow-up.
Aims of the main study
To assess whether a strategy of BMS implantation with
additional DEB use, either at the time of pre-dilation or
of post-dilation:
1. reduces neointimal hyperplasia, as compared to a
strategy of BMS implantation alone;
2. affects strut coverage and strut malapposition.
Aims of endothelial progenitor cell ancillary study
To evaluate possible correlations of EPC levels with neoin-
timal hyperplasia, stent coverage and stent malapposition.
Methods/Design
Study design
The INtimal hyPerplasia evAluated by oCT in de novo
COROnary lesions treated by drug-eluting balloon and
bare-metal stent (IN-PACT CORO) trial is a single cen-
ter, open-label, randomized trial enrolling 30 consecutive
patientsundergoing PCI
Recruited patients will be randomized 1:1:1 to three
arms:
withBMSimplantation.
1. BMS implantation (BMS group).
2. BMS implantation after lesion pre-dilation with DEB
(PRE-DEB group).
3. BMS implantation followed by post-dilation with
DEB (POST-DEB group).
Clinical follow-up will be performed at 1, 6 and
12 months. Enrolled patients will undergo a 6-month fol-
low-up coronary angiography with OCT evaluation of
the stented segment using the C7-XRTMCoronary Im-
aging System (LightLab Imaging Inc., Westford, MA,
USA). OCT analysis will be performed off-line by expert
OCT analysts blinded to the treatment assignment.
The study protocol was conceived in March 2009, con-
formed to the Declaration of Helsinki, and was approved
by the Ethical Committee of our center. We prepared a
written informed consent which patients will be asked to
sign to be enrolled in the protocol.
The full study flow-chart is represented in Figure 1.
Study endpoints
The primary endpoint is 6-month in-stent neointimal
hyperplasia area assessed by OCT.
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Secondary endpoints are the 6-month percentage of
uncovered struts and the 6-month percentage of struts
with incomplete stent apposition.
Eligibility, inclusion and exclusion criteria
Eligible patients have to be at least 18 years old; both
genders are eligible but women with child-bearing poten-
tial are not accepted.
Since the study will recruit a small number of patients,
we selected a homogeneous population of stable non-
diabetic patients undergoing elective PCI with BMS and
already on statin at target dose for low-density lipopro-
tein cholesterol level <100 mg/dL. Since diabetes melli-
tusisknown todramatically
hyperplasia after BMS implantation (primary endpoint of
this study) and acute coronary syndromes may influence
acute stent apposition to the vessel wall (one of the sec-
ondary endpoints), we decided to exclude such clinical
conditions in order to reduce the possibility of any im-
balance of confounding factors.
We selected de novo, non-complex lesions with length
≥10 mm and≤25 mm, located in straight segments of
vessels whose size requires a single stent with diameter
of 3.0 to 3.5 mm. Clinical and angiographic inclusion cri-
teria are summarized in Table 1.
increaseneointimal
Clinical exclusion criteria
Clinical exclusion criteria are:
– age <18 years or impossibility to give informed
consent;
– women with child-bearing potential;
– diabetes mellitus;
– life expectancy less than 6 months or any condition
impeding clinical follow-up (for example, no fixed
address);
– significant platelet count alteration (<100,000
cells/mm3or >700,000 cells/mm3);
– gastrointestinal bleeding requiring surgery or blood
transfusions within the previous 4 weeks;
– participation to another study with any
investigational device or drug which is still in the
active phase;
– infective, neoplastic or autoimmune diseases;
– history of clotting pathology, known hypersensitivity
to aspirin, heparin, cobalt- chromium, paclitaxel or
contrast dye;
– renal failure with creatinine value >2.5 mg/dL;
– poor cardiac function as defined by left ventricular
global ejection fraction ≤30%;
– acute myocardial infarction within the past 48 hours;
– non ST-elevation acute coronary syndrome within
the past 48 hours.
Angiographic exclusion criteria
Angiographic exclusion criteria are:
– left main coronary artery disease;
– lesions in coronary artery bypass grafts;
– coronary anatomy not suitable for OCT scan;
– bifurcation lesions, chronic total occlusions, severe
calcifications or moderate-to-severe tortuosities;
Thirty patients undergoing PCI
prospectivelly enrolled and
randomized 1:1:1
10 patients treated by
BMS implantation
(BMS group)
10 patients treated by BMS after
lesion predilation with DEB
(PRE-DEB group)
10 patients treated by BMS followed
by postdilation with DEB
(POST-DEB group)
Six-month coronary angiography
with OCT evaluation
of stented segment
Clinical follow-up at
1, 6 and 12 months
Blood samples for EPCs assessment
on admission and after 6 months
(EPC IN-PACT ancillary study)
Figure 1 The study flow-chart.
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– presence of additional non-target lesions requiring
treatment, within and outside the target vessel,
which are not successfully treated (non-target lesions
should be treated prior to the target lesion).
Technical details of the percutaneous coronary
interventions procedure
General considerations on drug-eluting balloon usage
A DEB is mainly intended to serve as drug delivery to
the vessel wall and should therefore always cover the
stenotic area as well as adjacent vessel segments covered
by a stent or dilated by a balloon catheter, incidentally or
by intention.
DEB length and positioning within the target lesion
will therefore be carefully chosen to avoid geographic
miss between DEB and treated vessel segments.
Characteristics of the drug-eluting balloon used in the study
IN.PACTTMFalconTMis a paclitaxel-eluting PCI balloon
catheter manufactured by Invatec Technology Center
GmbH(Hungerbüelstrasse
Switzerland). Model mix includes Rapid Exchange (RX)
and, for some sizes, Over The Wire (OTW) design. The
balloon is coated with FreePacTM, a paclitaxel-eluting
formulation, at the dose of 3.0 μg per mm2of the bal-
loon surface.
The IN.PACTTMFalconTMRX dilatation balloon
catheter is composed of a proximal single-lumen
shaft, a dual-lumen distal shaft and a balloon close
to the catheter tip. The proximal shaft consists of a
stainless steel hypotube with a proximal end luer-
lock connector (hub) for balloon inflation. At the op-
posite side, a special transition construction guaran-
tees an optimal push-torque transmission through
the full catheter length. The first lumen of the distal
shaft is dedicated to guide wire passage while the
other, which continues through the proximal shaft up
to the hub, is dedicated to the inflation of the bal-
loon. Maximum guide wire diameter is 0.014 inches
(0.36 mm). A flushing needle with a luer port is pro-
vided in the sterile packaging to facilitate the flush-
ing of the guide wire lumen prior to usage.
The IN.PACTTMFalconTMOTW dilatation catheter
consists of a dual-lumen shaft ending proximally with a
12, 8500Frauenfeld
–
Y connector (hub) and distally with a balloon closed to
the catheter tip. The straight port of the Y connector is
the guide wire entrance and the side port is used to in-
flate and deflate the balloon. Both lumens run through
the entire shaft length. The guide wire lumen permits
the use of guide wires to facilitate advancement of the
catheter to and through the stenosis to be dilated and it
ends at the tip of the catheter. Maximum guide wire
diameter is 0.014 inches (0.36 mm).
The balloon is designed to reach specific diameters
at specific pressures. A single central radiopaque
marker and/or two radiopaque markers are available
in order to correctly position the balloon under
fluoroscopy. IN.PACTTMFalconTM is available in
different balloon sizes.
The majority of the drug is released within the first
30 seconds of balloon inflation. The duration of the
inflation should therefore be between 30 seconds and
1 minute for optimal drug release.
Percutaneous coronary interventions procedure
description according to randomization
1. BMS group procedure:
– Lesion pre-dilation with an undersized semi-
compliant balloon (balloon to artery ratio, 0.5:1).
– BMS implantation (stent to artery ratio, 1.1:1).
– Post-dilation of the stented segment with a non-
compliant balloon at high pressure (16 to 18 atm).
2. PRE-DEB group procedure:
a. Pre-dilation
– Pre-dilation of the target lesion with an
undersized semi-compliant standard
percutaneous transluminal coronary
angioplasty (PTCA) balloon (balloon to artery
ratio, 0.5:1).
b. DEB dilation
– DEB diameter and pressure: nominal DEB
diameter must be chosen to guarantee full
vessel wall contact at a pressure close to or
slightly higher than the DEB nominal pressure
(balloon to artery ratio, 1:1).
Table 1 Inclusion criteria
Clinical inclusion criteria
Non-diabetic patients with a stable coronary artery disease, undergoing elective PCI with BMS
patients already on statin, at target cholesterol level (low-density lipoprotein cholesterol <100 mg/dL)
Angiographic inclusion criteria
De novo non-complex lesions located in straight coronary segments
lesion length ≥10 mm and ≤25 mm
vessel size requiring a single stent with diameter between 3.0 and 3.5 mm
BMS: bare-metal stent; PCI: percutaneous coronary interventions.
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– DEB length: nominal DEB length must exceed
10 mm (5 mm per edge), the length of the
stent which is planned to be deployed.
– DEB inflation time: 45 seconds.
c. BMS implantation
d. Post-dilation
– Post-dilation of the stented segment must be
performed with a non-compliant PTCA
balloon.
– Balloon diameter: nominal PTCA balloon
diameter must be chosen to reach a balloon to
stent ratio of 1:1 at high pressure (16 to
18 atm).
– Balloon length and positioning: PTCA balloon
length should be shorter than the length of the
deployed stent. In case of post-stent edge
residual stenosis, post-dilation balloon must fall
within are outside the stent (5 mm per edge)
which was the previously dilated by the DEB.
3. POST-DEB group procedure:
a. Pre-dilation
– Pre-dilation of the target lesion must be
performed with an undersized semi-compliant
standard PTCA balloon (balloon to artery
ratio, 0.5:1).
b. BMS implantation
– Stent to artery ratio, 1.1:1.
– Stent length must allow full coverage of the
target lesion with a single stent as well as be
10 mm shorter than the DEB which the
operator is planning to use next.
c. Post-dilation
– Post-dilation of the stented segment must be
performed with a non-compliant PTCA
balloon.
– Balloon diameter: nominal PTCA balloon
diameter must be chosen to reach a balloon to
stent ratio of 1:1 at high pressure (16 to
18 atm).
d. DEB dilation
– DEB length and positioning: DEB length must
be 10 mm longer than the previously deployed
stent (or than the extended pre-treated area in
case of former post-dilation outside the stent
edges) and centered within such pre-treated
length (5 mm per edge).
– DEB inflation time: 45 seconds.
– Balloon to stent ratio: 1.1:1 at a pressure close
or slightly higher of the DEB nominal pressure.
The angiographic results of the procedure will be
assessed by three-dimensional quantitative coronary
angiography (QCA) using the Paieon Cardi-Op system
(Paieon, Inc., 747 Third Avenue, New York 10017-2803,
United States).
Post-procedural management
Cardiac damage markers (creatine-kinase-MB and tropo-
nin I) will be assessed before the procedure, and 6 hours
and 24 hours after PCI. Thereafter, further blood samples
will be performed only if clinically indicated.
After PCI, patients will be given aspirin (75 to
100 mg/d) and life-long clopidogrel (75 mg/d) for
≥3 months (according to the on-label prescription for
DEB-treated patients).
Follow-up
Clinical follow-up will take place at 1 month (±1 week),
6 months (±2 weeks) and 1 year (±30 days) by clinical
visit or phone interview.
At the 6-month (± 2 weeks) follow-up, all patients will
undergo a coronary angiography (with three-dimensional
QCA) and an OCT study.
We anticipate a patient drop-out rate of 10%.
Rationale for optical coherence tomography selection and
description of optical coherence tomography analysis
For many years, QCA has been used to assess regression
and progression of coronary obstructions in pharmaco-
logical interventions, to assess the efficacy of PCI and
stenting, and for vessel sizing. However, QCA late lumen
loss is the difference between two minimal lumen diam-
eter measurements at two different times, and the axial
location of this diameter is variable at each time point.
An angiogram only examines the lumen, while the dis-
ease is in the vessel wall. These limitations have spurred
the search for new intravascular diagnostic imaging tech-
niques. A meta-analysis of QCA versus intravascular
ultrasound (IVUS) parameters for assessing stent resten-
osis [18] showed by regression analysis that QCA late
lumen loss and percentage of diameter stenosis corre-
lates only moderately with IVUS evaluation of neointimal
hyperplasia. A recent work [19] evaluated the correlation
of angiographic late loss with the degree of in-stent
neointimal proliferation assessed by OCT, demonstrating
a poor correlation of angiographic late loss with OCT at
low degrees of neointimal proliferation (R=0.38).
The detection of the post-stent implantation intima by
OCT and IVUS has also been compared. After a median
follow-up time of 6 months, Matsumoto et al. examined
the reaction of the intima by OCT and found that 64% of
the struts had become covered with an intima <100 μm
thick (below the resolution of IVUS) [20]. The correl-
ation betweenOCTand
(r=0.980, P <0.001 for lumen area; r=0.978, P <0.001
for stent area; and r=0.961, P <0.001 for neointimal
area) was stronger than the correlation between IVUS
histologymeasurements
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and histology (r=0.803, P <0.001 for lumen area;
r=0.817, P <0.001 for stent area; and r=0.776, P <0.001
for neointimal area). In addition, the diagnostic accuracy
for detecting a small degree of neointimal proliferation
by OCT (area under the curve=0.967, 95% confidence
interval 0.914 to 1.019) was higher than that by IVUS
(area under the curve=0.781, 95% confidence interval
0.621 to 838) [21].
The frequency of detection of stent malapposition is
greater with OCT than with IVUS. In a recent in vivo
study by Kubo et al., the detection rate with OCT was
47% in a sample of 55 patients, while with IVUS it was
only 18% (P <0.001) [22]. Similar results were reported
by Bouma et al. five years earlier in a study involving ex-
perimental animals [23].
So OCT represents a useful clinical tool to study
endothelializationof stents
responses and to detect the presence of delayed healing
or incomplete apposition of stents to the arterial wall as
a possible mechanism of in stent thrombosis [24,25].
In our study, OCT will be performed with the imaging
system C7 XR (LightLab Imaging Inc.), using a non-
occlusive technique, with automated intracoronary injec-
tion of iso-osmolar contrast. This Fourier domain-OCT
system achieves 10 times higher resolution than IVUS, ap-
proximately 15 microns, with pullback speed of 2 cm/sec,
and an acquisition frame rate of 100 frames/sec.
The entire stent length will be assessed and cross-
sectional images will be analyzed every 0.4 mm.
The struts will be classified as uncovered if a tissue
layer on the endoluminal surface is not visible or covered
in the presence of visible tissue between the endoluminal
surface and the lumen.
The tissue coverage thickness will be measured in each
strut as the distance from the strut endoluminal surface
to the lumen. In each cross-section analyzed, a series of
parameters will be calculated.
andabnormal tissue
Endpoint assessment
The primary endpoint is in-stent neointimal hyperplasia
area, that is stent area minus lumen area [26] and its
percentage (tissue coverage area/stent area×100) evalu-
ated by OCT. The other related parameters of tissue
coverage thickness (μm), tissue volume coverage (tissue
coverage area×stent length) and its percentage (tissue
coverage volume/stent volume×100) will also be evalu-
ated. To assess the pattern of coverage, the ratio between
the difference of maximum and the minimum tissue
thickness coverage (minimum tissue thickness coverage/
maximum tissue thickness coverage) will be calculated in
each frame. A ratio close to 1 indicates an asymmetric
tissue coverage, on the opposite a ratio close to 0 indi-
cates a symmetric tissue coverage.
The secondary OCT endpoints are described in Table 2.
Incomplete strut apposition (ISA) will be defined as a dis-
tance between strut endoluminal surface and the vessel wall
higher than strut thickness. ISA will be considered present
if at least one single strut is incompletely apposed to the
vessel wall. In each OCT frame analyzed, the number of
struts with ISA and the maximum distance from the endo-
luminal stent strut to the vessel wall will be measured.
Sample size calculation and statistical analysis
The IN-PACT CORO trial is open-label, randomized
clinical trial in which patients will be randomly assigned,
with a 1:1:1 design, to BMS implantation alone, BMS im-
plantation with pre-DEB use, and BMS implantation
with post-DEB use. The primary aim is to test the super-
iority of a strategy of BMS implantation with pre- or
post-DEB use versus a strategy of BMS implantation
alone on the primary endpoint of in-stent neointimal
hyperplasia area, assessed by OCT at follow-up. Second-
ary endpoints will be the percentage of uncovered struts,
and the percentage of struts with ISA.
Little information is available on neointimal prolifera-
tion after BMS implantation: two small non-randomized
studies [13,27] reported maximal and minimal neointi-
mal thickness (mm) at 7.3 month follow-up (first study)
and mean neointimal thickness at 8 month follow-up
(latter study) being more than four-fold higher in the
BMS group compared with the sirolimus (rapamycin)-
eluting stent group, although data on neointimal area are
not available. In the Harmonizing Outcomes With
Revascularization and Stents in Acute Myocardial Infarc-
tion (HORIZONS-AMI) OCT sub-study, a mean neointi-
mal area of 2.8±1.4 was reported 13 months after a
BMS implantation [28].
A recent randomized study comparing 12 polymer-
coated rapamycin-eluting stents to 12 non- polymer
rapamycin-eluting stents [29] reported a neointimal area
of0.3±0.2mm2
inthe
1.2±0.8 mm2in the non-polymer stent, with a difference
of 0.9 mm2(95% confidence interval, 0.3 to 1.4).
We have hypothesized that additional DEB use (either
before or after BMS implantation) will yield a neointimal
area similar to that reported in the non-polymer rapamy-
cin-eluting stent (that is, 1.2 mm2) and that this value
corresponds to an approximately 50% reduction of mean
polymer stentversus
Table 2 Secondary endpoints
Percentage of uncovered struts
Number of uncovered struts/total number of struts
Percentage of struts with incomplete strut apposition (ISA)
Number of struts with ISA/total number of struts
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neointimal area in the group receiving BMS implantation
alone (hypothesizing a control group hyperplasia better
than that reported in the BMS arm of the HORIZONS-
AMI OCT sub-study). As two co-primary endpoints are
pre-specified: that is, either pre- or post-DEB use reduces
neointimal hyperplasia as compared to BMS alone, a
type I error of 2.5% will be allocated to each endpoint to
preserve the total type I error at the 5% level. Power is
set to 85% for each primary endpoint. To detect such
difference, 10 patients will be required in each group.
Since we anticipate a drop-out rate of 10%, we will re-
cruit another patient for each group in case of loss to fol-
low-up or unanalyzable studies.
Continuous variables will be reported as mean and
standard deviation or as median and interquartile range
(according to their distribution) and comparisons be-
tween two groups will be made with unpaired t-test or
Mann Whitney U-test, as appropriate. Categorical vari-
ables will be presented as numbers and frequencies
and comparisons will be made using Chi-square test or
Fisher’s exact test, as appropriate.
Endothelial progenitor cell ancillary study design
A correlation analysis will be performed to ascertain
whether EPC contribute to neointimal regrowth in such
patients.
Peripheral blood samples of all patients enrolled in the
IN-PACT CORO protocol will be obtained on admission
and after 6 months of follow-up (Figure 1).
Endothelial progenitor cells levels assessment for
endothelial progenitor cells ancillary study
The cytofluorimetric assays will be performed on admis-
sion and after 6 months’ follow-up. Peripheral blood will
be drawn and buffered using sodium citrate. One hundred
microliters of blood will be incubated with 5 μL of phyco-
erythrin-conjugated monoclonal antibody against CD34,
with 5 μL of fluorescein isothiocyanate-conjugated mono-
clonal antibody against kinase insert domain receptor
(KDR) and with 5 μL of monoclonal antibody against
CD45. Fluorescence-activated cell sorting assay will be
performed according to the specific log gain of forward
and side scatter. EPC will be detected as cells CD34+
KDR+CD45- The negativity for CD45 is fundamental to
distinguish EPC from other nucleated cells in peripheral
blood, represented by leukocytes [30].
Study limitations
The major anticipated limitation of the present study is
that it is an open-label and not a double-blinded trial. In
order to increase the feasibility of this spontaneous, non-
sponsored study, we decided to perform an open-label
trial. The treating physicians cannot be blinded since the
DEB device is fairly different from a standard balloon
due to its thick white covering material.
However, OCT analyses will be performed by an expert
OCT image analyzer who is not involved in patient re-
cruitment and blinded to patient randomization and
clinical status.
Trial status
Patient recruitment is ongoing.
Abbreviations
BMS: Bare-metal stent; DEB: Drug-eluting balloon; DES: Drug-eluting stent;
EPC: Endothelial progenitor cells; ISA: Incomplete strut apposition;
IVUS: Intravascular ultrasound; KDR: Kinase insert domain receptor;
OCT: Optical coherence tomography; OTW: Over The Wire; PCI: Percutaneous
coronary intervention; POST-DEB: Post-dilation with drug-eluting balloon;
PRE-DEB: Pre-dilation with drug-eluting balloon; PTCA: Percutaneous
transluminal coronary angioplasty; QCA: Quantitative coronary angiography;
RX: Rapid Exchange.
Competing interests
The authors declare that they have no competing interests.
Author details
Institute of Cardiology, Catholic University of the Sacred Heart, L.go Gemelli 8
00168 Rome, Italy.
Authors’ contributions
FB conceived the main study and drafted the manuscript. CT made
substantial contribution in study design and coordination. IP conceived the
EPC ancillary study and helped to draft the manuscript. MFB helped to draft
the manuscript and participated in study coordination and acquisition of
data. AT, GN and AML revised the manuscript with important intellectual
contribution. GDM and VC participated in acquisition of data. GS and FC
have given final approval of the version to be published. All authors read
and approved the final manuscript.
Funding
The authors declare that there is no funding source for this study.
Received: 8 May 2011 Accepted: 6 May 2012
Published: 6 May 2012
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doi:10.1186/1745-6215-13-55
Cite this article as: Burzotta et al.: INtimal hyPerplasia evAluated by oCT
in de novo COROnary lesions treated by drug-eluting balloon and
bare-metal stent (IN-PACT CORO): study protocol for a randomized
controlled trial. Trials 2012 13:55.
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