Serial Assessment of Coronary Artery Response to Paclitaxel

Serial Assessment of Coronary Artery Response to
Paclitaxel-Eluting Stents Using Optical
Coherence Tomography
Giulio Guagliumi, MD, FESC; Hiram G. Bezerra, MD, PhD; Vasile Sirbu, MD;
Hideyuki Ikejima, MD, PhD; Giuseppe Musumeci, MD; Giuseppe Biondi-Zoccai, MD;
Nikoloz Lortkipanidze, MD; Luigi Fiocca, MD; Davide Capodanno, MD, PhD; Wei Wang, MS;
Satoko Tahara, MD, PhD; Angelina Vassileva, MD; Aleksandre Matiashvili, MD;
Orazio Valsecchi, MD; Marco A. Costa, MD, PhD
Downloaded from http://circinterventions.ahajournals.org/ by guest on November 19, 2016
Background—The paucity of longitudinal, serial high-resolution imaging studies has limited our understanding of in vivo
arterial response to drug-eluting stents. We sought to investigate the human coronary response to paclitaxel-eluting stent
implantation, using serial optical coherence tomography assessments.
Methods and Results—Thirty patients with at least 2 significant coronary lesions in different vessels were treated with a
paclitaxel-eluting stent. The most severe stenosis (lesion A) was treated at the initial procedure, and the second target
vessel (lesion B) was stented 3 months later. Optical coherence tomography was performed at baseline, 3-, and 9-month
follow-up for lesions A and baseline and 6 months for lesions B. Prespecified end points were percent of uncovered and
malapposed struts over time. In lesions A, uncovered struts were 3.77⫾4.94% and 3.02⫾4.35% at 3 versus 9 months
(P⫽NS). Malapposed struts were 3.55⫾5.16% at post-procedure, 1.51⫾3.52% at 3 months, and 0.60⫾1.82% at 9
months (P⬍0.05, at 3 versus 9 months). Strut-level neointimal thickness was 0.19⫾0.09 mm and 0.20⫾0.11 mm
(P⫽NS) over time. Newly acquired malapposition was detected in 10.4% and 3.3% of 2.5-mm segments at 3- and
9-month follow-up. In lesions B, uncovered struts were 2.91⫾5.47% at 6-months. Malapposed struts were 4.94⫾6.70%
post-procedure and 1.01⫾3.11% at 6 months (P⬍0.01), with 0.19⫾0.09-mm neointimal thickness at follow-up.
Conclusions—Optical coherence tomography imaging suggested the first 3 months to be the period with most biological
activity after paclitaxel-eluting stent implantation, when the proliferative reaction mainly occurs and malapposition
resolves. A less active, yet continuous, dynamic arterial response, with resolution and development of malapposition,
occurs through 9 months post-treatment.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00704145.
(Circ Cardiovasc Interv. 2012;5:30-38.)
Key Words: percutaneous coronary intervention 䡲 drug-eluting stent 䡲 optical coherence tomography
䡲 malapposition 䡲 stent coverage
L
coherence tomography (OCT) has been established as an
accurate and reproducible high-resolution imaging method to
evaluate the in vivo vascular response to coronary stent
implantation6 –9; however, most OCT evaluations of stented
vessels have been focused on single time-point imaging
assessment.10 –13 The lack of prospective longitudinal studies
with sequential OCT image monitoring from the time of DES
implantation has hampered our understanding of the arterial
response to DES over time. We sought to investigate the in
vivo coronary artery reaction to paclitaxel-eluting stent (PES)
implantation using serial OCT evaluations.
ate stent thrombosis after drug-eluting stent (DES) implantation remains a major clinical concern.1 Delayed
arterial healing after DES implantation, revealed through
incomplete strut coverage and malapposition, has been associated with late stent thrombosis.2– 4 Early in the development
of DES, serial imaging using angiography and intravascular
ultrasound (IVUS) were performed to investigate vascular
response over time.5 These studies were designed to evaluate
the efficacy of DES to suppress neointimal proliferation and
did not have sufficient imaging resolution to assess arterial
wall response at the stent strut level. More recently, optical
Received August 6, 2011; accepted January 6, 2012.
From the Cardiovascular Department, Ospedali Riuniti, Bergamo, Italy (G.G., V.S., H.I., G.M., N.L., L.F., A.V., A.M., O.V.); University Hospitals
Case Medical Center, Case Western Reserve University, Cleveland, Ohio (H.G.B., W.W., S.T., M.A.C.); Division of Cardiology, University of Modena
and Reggio Emilia, Modena, Italy (G.B.-Z.); Cardiology Department, Ferrarotto Hospital, Catania, and University of Catania, Catania, Italy (D.C.).
Correspondence to Giulio Guagliumi, MD, Division of Cardiology, Cardiovascular Department, Ospedali Riuniti di Bergamo, Largo Barozzi 1, 24128
Bergamo, Italy. E-mail [email protected]
© 2012 American Heart Association, Inc.
Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org
30
DOI: 10.1161/CIRCINTERVENTIONS.111.965582
Guagliumi et al
WHAT IS KNOWN
●
●
●
Delayed arterial healing after drug-eluting stent implantation, revealed through incomplete strut coverage and malapposition, has been linked with late
stent thrombosis.
Optical coherence tomography is an accurate and
reproducible high-resolution imaging method to
evaluate the in vivo vascular response to coronary
stent implantation.
Temporal evolution of in vivo human coronary
artery response to paclitaxel-eluting stent implantation using serial optical coherence tomography imaging is poorly defined.
Downloaded from http://circinterventions.ahajournals.org/ by guest on November 19, 2016
WHAT THE STUDY ADDS
●
●
In paclitaxel eluting stents, ⬎90% of the proliferative response occurs, and ⬎85% of the postprocedure malapposition resolves in the first 3
months.
Between 3 and 9 months, the proliferative response
is less active, yet continuous, showing minimal
changes in the proportion of strut coverage and
resolution/development of new malapposition.
Serial OCT Assessment in PES
31
recommended indefinitely. All patients received clopidogrel (75 mg)
daily for a minimum of 6 months; recommended for 12 months.
Clinical follow-up (office visit or phone call) was planned at 1
month, 9 months (⫾2 weeks), 1 year, and 2 years.
Quantitative Coronary Angiography
Quantitative coronary angiography was performed at baseline, postindex percutaneous cardiac intervention, and at all follow-up time
points. Angiographic measurements were made in the same 2
orthogonal projections at each time point. Offline analysis of digital
coronary angiograms was performed by an independent core laboratory (Cardiovascular Imaging Core Laboratory, University Hospitals Case Medical Center, Cleveland, Ohio), using validated quantitative methods.14
Intravascular Ultrasound
IVUS imaging was performed on both treated lesions at the completion of each stent implant and at final follow-up, using the
Atlantis SR pro 40 MHz catheter and the iLab ultrasound console
(Boston Scientific). Automated motorized pullback at 0.5 mm/s was
used during all IVUS runs throughout the stent and at least 5 mm
distal and proximal to the stent. All IVUS data were digitally stored
for subsequent analysis. Quantitative volumetric IVUS analysis was
performed using a validated semi-automated detection algorithm
(Curad) and previously described methodology.15 The crosssectional areas and associated volumes were determined for the stent,
lumen, vessel, and neointimal area. Qualitative analysis included
stent malapposition, defined as blood speckle behind the struts,
categorized as persistent, resolved, and late acquired.
OCT Imaging Acquisition and Analyses
Methods
Study Design
This prospective, single-center study enrolled 30 consecutive patients with symptomatic multivessel coronary disease and at least 2
significant (ⱖ75% by visual estimation) angiographic stenoses in
different epicardial vessels suitable to stent implantation. All target
stenoses were treated with the implantation of PES (Boston Scientific, Natick, Mass) in staged procedures. The initial target lesion (A)
was selected and treated on the basis of stenosis severity and/or
extent of myocardial area in jeopardy, whereas the second lesion (B)
was stented 3 months after the initial intervention, when OCT
imaging was repeated for lesion A. A final follow-up assessment
(including coronary angiography, IVUS, and OCT of both treated
vessels) was performed 6 months after the second intervention (ie,
9-month follow-up of lesion A). This study design was adopted
(instead of imaging at consistent time-points [ie, 0, 3, 6, 9
months] for both lesion A and B) to avoid exposing patients to
unnecessary procedures for mere investigational purposes. The
study was conducted under Good Clinical Practice conditions and
in compliance with the Medical Device Regulations for Italy. The
Ethics Review Committee of Ospedali Riuniti di Bergamo approved
the protocol (www.clinicaltrial.gov NCT 00704145); all patients
provided written informed consent prior to enrollment.
Patient Selection, Procedure, and Follow-Up
Eligible subjects (ⱖ18 years) had multivessel coronary artery disease
(2- or 3-vessel disease) to be treated with percutaneous cardiac
intervention stent procedures. The study only included lesions in
native coronary arteries with diameter stenosis ⱖ75% and reference
vessel diameter between 2.5 to 3.5 mm per visual estimation.
Exclusion criteria were acute myocardial infarction; significant left
main disease; lesions in coronary artery bypass grafts; poor cardiac
function, as defined by left ventricular global ejection fraction
ⱕ30%; renal failure with creatinine value ⬎2.5 mg/dL; no suitable
anatomy for OCT (ostial lesions and extreme vessel tortuosity); and
inability to comply with dual antiplatelet therapy and follow-up
requirements. Intracoronary nitroglycerin (200 mg) was administered before all imaging procedures. Aspirin (100 mg daily) was
OCT images were obtained at all time points, according to a
previously described procedure.16 In brief, a time-domain OCT
system (LightLab Imaging) was used, and an occlusive technique
was adopted. Images were acquired with an automated pullback at a
rate of 1.0 mm/s, digitally stored, and submitted to the core
laboratory for offline analysis. Imaging analyses were performed by
an independent Core Laboratory (Cardiovascular Imaging Core
Laboratory, University Hospitals Case Medical Center, Cleveland,
Ohio). Dedicated software (LightLab) was used for measurements.
All cross-sectional images were initially screened for quality assessment and excluded from analysis if any portion of the stent was out
of the screen; if a side branch occupied ⬎45° of the cross-section; or
if the image had poor quality caused by residual blood, artifact, or
reverberation.9 Qualitative assessment was performed in every frame
(ie, every 0.06 mm), whereas quantitative strut level analysis and
morphometric analysis were performed at every 10 frames (ie,
0.6-mm interval) along the entire target segment. Strut-level intimal
thickness (SIT) was determined based on automated measurements
performed from the center of the luminal surface of each strut
blooming and its distance to the lumen contour.12 Struts covered by
tissue had positive SIT values, whereas uncovered or malapposed
struts had negative SIT. Strut malapposition was defined when the
negative value of SIT was higher than the sum of strut thickness plus
abluminal polymer thickness, according to stent manufacturer specifications, plus a compensation factor of 20 ␮m to correct for strut
blooming.16 Qualitative imaging assessment included detection of
embedded struts at post-procedure, defined as struts covered by
tissue and not otherwise interrupting the smooth lumen contour.
Tissue protrusion was defined as a tissue prolapse between stent
struts that directly correlates with the underlying plaque, without
abrupt transition and different optical properties.17
Serial OCT pullbacks were aligned based on fiducially points (end
of stent, branches). A similar length of the lesion, determined by the
shortest available common sequence, was analyzed at all time points.
After alignment of the serial OCT pullbacks, the stented segment
was automatically segmented in 2.5-mm intervals (subsegments),
and the number of subsegments was matched at different time points.
A subsegment with any malapposed struts was regarded as a
malapposed subsegment. If no malapposition was detected, the
32
Circ Cardiovasc Interv
February 2012
subsegment was counted as fully apposed. Newly acquired malapposition was defined as a fully apposed subsegment that developed
any malapposition at follow-up. In order to determine longitudinal
heterogeneity of uncovered or malapposed strut distribution, a
coefficient of variation (CV)18 was assessed for each 2.5-mm
subsegment and calculated dividing standard deviation by the mean
% of uncovered or malapposed struts. A low CV denotes homogeneous longitudinal distribution within the stented segment, and a
higher CV reveals heterogeneous distribution (clustering) of uncovered or malapposed struts, respectively.
Table 1.
Baseline Clinical Characteristics
Patients (n⫽30)
Age, y
67.8⫾9.6
Male sex
23 (76.0)
Hypertension
17 (56.6)
Hyperlipidemia
18 (60.0)
Current smoker
17 (56.6)
Diabetes
End Points and Data Management
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Primary imaging end points were the proportion of uncovered and
malapposed struts as assessed by OCT at different time points.
Secondary end points included neointimal hyperplasia (NIH) over
time (3, 6, 9 months). We also investigated the impact of postprocedure OCT findings on the rate of uncovered struts and NIH at
different time points. Data on clinical outcome, including major
adverse cardiac events (a composite of cardiac death, myocardial
infarction [MI], and target vessel revascularization, target lesion
revascularization, and stent thrombosis, as per the Academic Research Consortium definitions of definite/probable,19 were assessed
at 30 days, 1 year, and 2 years.
Statistical Methods
Given the exploratory study design and lack of previous data using
similar assessments, no formal sample size computation was performed.
Yet, in keeping with our prior works on this topic,11,12,16 a sample size
of 24 provides 80% power to detect a 3.0% uncovered struts’ percentage
reduction for 9-month versus 3-month follow-up, with an estimated
standard deviation of 5.0% and a significance level (␣) of 0.05, using a
2-sided 1-sample-test. Patient, lesion, and procedural characteristics and
event rates were analyzed using descriptive statistics with SAS version
9.1 or higher (SAS Institute Inc.), with statistical significance at the
2-tailed 0.05 level. Continuous variables were expressed as mean⫾SD,
and categorical variables were expressed as counts and percentages. The
generalized estimating equations model, with a first-order autoregressive covariance structure to account for the correlated data within each
subject, was used for the analysis of data sets arising from longitudinal
studies. The paired t test and generalized estimating equations model
were used for comparison of continuous and categorical variables,
respectively, between post-procedure and follow-up. The mixed effects
model was used to estimate the correlation coefficient between 2
variables, with repeated observations. Heterogeneity of uncovered or
malapposed struts was calculated by means of CV in subsegments, as
described above.
Results
Patient, Procedural, and
Angiographic Characteristics
Baseline clinical characteristics are reported in Table 1. All
patients underwent planned angiography, OCT, and IVUS imaging without clinical complications. Procedural and angiographic data are shown in Tables 2 and 3. There were no
differences in procedural characteristics between lesions A and
B, with the exception of a trend for larger stents used to treat
lesion B. This is probably because of the numerically, albeit
nonsignificantly larger reference vessel diameter in lesions B
compared with lesions A (2.49⫾0.48 versus 2.55⫾0.35,
P⫽0.61).
Optical Coherence Tomography
The incidences of tissue protrusion and embedded struts at
post-procedure, as detected by OCT, were 26.40⫾18.93% and
17.36⫾9.14%, respectively. These OCT findings were not
correlated with degree of NIH or uncovered struts over time.
7 (23.3)
Prior myocardial infarction
11 (36.7)
Prior percutaneous coronary intervention
5 (16.7)
Prior coronary artery bypass graft surgery
0 (0)
Unstable angina
14 (46.7)
Values are expressed as mean⫾SD or n (%).
Lumen and Neointimal Hyperplasia
Lumen volume and mean lumen area showed a slight, yet
statistically significant, decrease over time both in lesions A
and B (Table 4); however, neointimal proliferation only
partially explains the observed changes in lumen dimensions,
as there were no significant differences in mean NIH area,
NIH thickness, or % volume obstruction by OCT between 3
and 9 months. Malapposition resolution accounts for the
remaining lumen loss observed over time (Table 4).
Strut Coverage
At 3 months, 96.23⫾4.94% of PES struts were covered. The
rate of uncovered struts remained unchanged between 3 and
9 months (3.77⫾4.94% versus 3.02⫾4.35%, respectively,
P⫽0.35, Table 4). Similarly, the proportion of lesions with
complete stent coverage did not change significantly between
3- and 9-month follow-up (13.8% versus 18.5%, P⫽0.53).
Figure 1 shows strut coverage for individual PES implanted
in lesions A and B at different time points. The CV for % of
uncovered struts was high and not significantly different
between time points: 184.0⫾96.3% at 3 months,
162.0⫾107.4% at 9 months in lesions A, and 171.8⫾110.3%
at 6 months in lesions B, suggesting clustering of uncovered
struts, which remained unchanged over time.
Table 2.
Procedural Characteristics
Lesion A
(n⫽30)
Lesion B
(n⫽30)
Left anterior descending
16 (53.3)
8 (26.7)
Left circumflex
13 (43.3)
12 (40.0)
Procedural Characteristics
Lesion location
Right coronary artery
P Value
0.007
1 (3.3)
10 (33.3)
21.8⫾14.4
28.4⫾16.3
0.13
1.6⫾0.83
1.4⫾0.72
0.08
Stent diameter (mm)
2.77⫾0.25
2.93⫾0.24
0.052
Total stent length (mm)
28.1⫾14.0
33.1⫾16.5
Lesion length (mm)
No. of stents implanted
0.24
Pre-dilation, n (%)
22 (73)
21 (70)
0.77
Post-dilation, n (%)
15 (50)
18 (60)
0.44
18.7⫾2.6
19.0⫾2.6
0.66
Max inflation pressure (atm)
Values are expressed as mean⫾SD or n (%).
Guagliumi et al
Table 3.
Serial OCT Assessment in PES
33
Quantitative Coronary Angiography Over Time
Lesion A (n⫽30)
Pre-Procedure
Post-Procedure
Lesion B (n⫽30)
3 Mo
9 Mo¶
Pre-Procedure
Post-Procedure
6 mo¶
RVD (mm)
2.49⫾0.48
2.50⫾0.37
2.44⫾0.39
2.43⫾0.34
2.55⫾0.35
2.62⫾0.40
2.63⫾0.41
MLD (mm)
0.80⫾0.37§
2.22⫾0.34*†
1.87⫾0.54*
1.83⫾0.60†
1.11⫾0.36§
2.28⫾0.39‡
1.83⫾0.54‡
% DS
67.9⫾12.3§
11.0⫾6.9*
24.2⫾16.1*
26.1⫾18.6†
56.8⫾12.0§
13.0⫾8.2‡
30.7⫾15.5‡
0.36⫾0.40
0.39⫾0.49
...
...
0.45⫾0.37
LL (mm)
...
...
Values are expressed as mean⫾SD.
RVD indicates reference vessel diameter; MLD, minimum lumen diameter; DS, diameter stenosis; LL, late loss.
*P⬍0.01 between post-procedure vs 3 mo follow-up for lesion A.
†P⬍0.01 between post-procedure vs 9 mo follow-up for lesion A.
‡P⬍0.01 between post-procedure vs 6 mo follow-up for lesion B.
§P⬍0.01 between Lesion A vs Lesion B at pre-procedure.
¶Only 29 patients underwent elective assessment at 6 and 9 mo because of 1 patient death.
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Strut Malapposition
The number and frequency of malapposed struts decreased
over time, with its peak observed immediately postprocedure. Nevertheless, early acquired focal malapposition
with aneurismal formation led to increased volume of malapposition at 3-month follow-up (Table 4). Interestingly, resolution of aneurysms and associated malapposition were observed at 9-month follow-up (Figure 2).
Table 4.
Strut malapposition was also evaluated using a subsegmental analysis in order to better appreciate its temporal
evolution (Figure 3). Post-stent implantation, strut malapposition was observed in 32.7% (89/272) of subsegments
in lesions A and in 41.4% (137/331) in lesions B. Malapposition was resolved in 85.4% (76/89) of these subsegments at 3 months in lesions A. Similarly, 87.6% (120/
137) of malapposed subsegments post-stent implantation
OCT Findings at Different Time Points After PES Implantation
Lesion A (n⫽30)
Lesion B (n⫽30)
Post-Procedure
3 Mo
9 Mo**
Post-Procedure
6 Mo**
2995⫾1464*
2628⫾1315*¶
2929⫾1648¶
3423⫾1363
3471⫾1409
3.77⫾4.94
3.02⫾4.35
...
2.91⫾5.47
Strut-level analysis
No. of struts analyzed per lesion
Frequency of uncovered struts per lesion, %
...
Lesion with complete stent coverage, n (%)
...
4 (13.8)
5 (18.5)
...
6 (20.7)
Maximum length of segment with uncovered struts, mm
...
2.10⫾2.36¶
1.44⫾1.89¶
...
1.48⫾2.59
CV of uncovered struts in 2.5-mm subsegment, %
...
184.0⫾96.4
162.0⫾107.4
...
171.8⫾110.3
Neointimal thickness, mm
...
0.19⫾0.09
0.20⫾0.11
...
0.24⫾0.08
Frequency of malapposed struts per lesion, %
2.06⫾1.88†
1.51⫾3.52¶
0.60⫾1.82†¶
4.94⫾6.70§
1.01⫾3.11§
Maximum length of segment with malapposed struts, mm
1.03⫾1.19
0.93⫾1.82¶
0.50⫾1.19¶
1.69⫾2.36#
0.53⫾1.29#
...
69.2⫾121.5
75.2⫾137.5
...
100.7⫾152.9
CV of malapposed struts in 2.5-mm subsegment, %
Cross-section level analysis
No. of struts analyzed per cross-section
7.88⫾1.41*†
7.14⫾1.32*
7.18⫾1.43†
8.73⫾1.90§
7.79⫾1.55§
Mean stent area, mm2
6.47⫾1.55
6.50⫾1.56
6.48⫾1.48
7.03⫾1.58
7.14⫾1.49
Mean lumen area, mm2
6.60⫾1.54*†
5.13⫾1.61*‡
4.92⫾1.46†‡
7.21⫾1.58§
5.25⫾1.56§
1.45⫾0.70
1.59⫾0.77
...
1.93⫾0.64
Mean neointimal area, mm2
...
Mean malapposition area, mm2
0.02⫾0.02
Stent volume, mm3
173.5⫾77.4
0.04⫾0.06
0.02⫾0.06
177.6⫾78.6
0.06⫾0.15¶
177.3⫾74.4
0.02⫾0.06¶
216.3⫾122.6
222.3⫾108.6
Neointimal volume, mm3
...
39.4⫾22.5
42.7⫾22.7
...
59.8⫾32.0
Percentage net volume obstruction, %
...
23.0⫾10.1
24.9⫾10.9
...
27.8⫾10.2
0.51⫾0.60
1.90⫾4.73¶
0.55⫾1.63¶
1.31⫾2.01
0.72⫾2.14
3
Mean malapposition volume, mm
Values are expressed as mean⫾SD or n (%).
OCT indicates optical coherence tomography; PES, paclitaxel-eluting stent; AIT, abnormal intraluminal tissue; CV, coefficient of variation.
*P⬍0.01 between post-procedure vs 3 mo follow-up for lesion A.
†P⬍0.01 between post-procedure vs 9 mo follow-up for lesion A.
‡P⬍0.01 between 3 mo vs 9 mo follow-up for lesion A.
§P⬍0.01 between post-procedure vs 6 mo follow-up for lesion B.
¶P⬍0.05 between 3 mo vs 9 mo follow-up for lesion A.
#P⬍0.05 between post-procedure vs 6 mo follow-up for lesion B.
**Only 29 patients underwent elective assessment at 6 and 9 mo because of 1 patient death.
34
Circ Cardiovasc Interv
February 2012
Figure 1. Time course of uncovered and
malapposed struts after paclitaxel-eluting
stent (PES) implantation. Percentage of
uncovered and malapposed struts at
post-procedure, 3-, and 9-month
follow-up in (A, B) lesions A, and implant
and 6 months in (C, D) lesions B. Red
dashed lines represent mean⫾standard
deviation of uncovered and malapposed
struts percentage at each time point for
lesions A and B.
Downloaded from http://circinterventions.ahajournals.org/ by guest on November 19, 2016
in lesions B showed resolution at 6 months. Among
subsegments with fully apposed struts at post-procedure
(183 subsegments in lesions A and 194 in lesions B), new
malapposition appeared in 19 (10.4%) at 3-month (lesion
A) and 14 (7.2%) at 6-month follow-up (lesion B). Among
subsegments with fully apposed struts at 3 months (240
subsegments in Lesion A), newly acquired malapposition
developed at 9 months in 8 (3.3%).
Intravascular Ultrasound and Clinical Outcomes
IVUS results are reported in Table 5. Clinical follow-up at 1
and 2 years was 96.7% (29/30 patients), because of 1 death
(sudden death, probably cardiac in origin) that occurred at
204 days after enrollment. Overall target lesion revascularization rate per target vessel was 15.5% (9/58 lesions)
through 1 year, including 5 lesions A and 4 lesions B. One
year major adverse cardiac events rate was 26.7% (8/30
Figure 2. Serial optical coherence tomography (OCT) images, illustrating the dynamic nature of the vascular response after paclitaxeleluting stent (PES) implantation over time (upper panels indicate post-procedure; middle panels, 3-month follow-up; lower panels,
9-month follow-up). The target segment is shown in longitudinal views (left panels), which are divided in 2.5-mm subsegments (white
dashed lines and numbers). The right panels show corresponding cross-sectional OCT images at various subsegments. OCT image
post-procedure showed good stent expansion with a few malapposed struts in the proximal subsegment (arrowhead, subsegment 9).
At 3-month follow-up, almost all the struts were covered, and the malapposition in subsegment 9 was resolved. Interestingly, a newly
acquired malapposition area was observed, involving subsegments 5, 6, and 7 (asterisks in the longitudinal view). At 9-month followup, similar amount of coverage through the entire stent was measured, with complete resolution of the acquired malapposition
observed at 3 months.
Guagliumi et al
Serial OCT Assessment in PES
35
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Figure 3. Subsegmental optical coherence tomography (OCT) analysis of the temporal evolution of strut malapposition. Bar graphs
depict (left) number of subsegments with malapposition and (right) volumes of malapposition at different time points (white bars indicate
post-procedural strut malapposition; dashed bars, newly developed malapposition at 3-month follow-up; and solid black bars, new
malappositions developed at 9-month follow-up). A, B, Lesion A; (C, D), Lesion B. Both resolution and development of new strut
malapposition were observed at different periods.
patients). At 2 years follow-up, there was 1 additional acute
myocardial infarction because of definite very late stent
thrombosis (Figure 4).
Discussion
In the present study, we investigated the temporal evolution of in vivo human coronary artery response to PES
implantation, using serial OCT imaging. Sequential assessments of the arterial reaction to PES from the time of stent
implantation through 9-month follow-up provided the
following observations: (1) ⬎90% of the proliferative
Table 5.
response, depicted through the magnitude of neointimal
proliferation and strut coverage occurs in the first 3 months
after PES implantation; (2) thereafter, the proliferative
response subsides, showing minimal changes in the proportion of strut coverage and amount of neointimal hyperplasia between 3 and 9 months; (3) ⬎85% of the postprocedure malapposition resolves by 3-month follow-up;
and (4) newly acquired malapposition is a dynamic and
bidirectional biological phenomenon, illustrated by concomitant resolution and development of strut malapposition throughout the first 9 months post-stenting.
Intravascular Ultrasound Analysis at Implant and Final Follow-Up
Lesion A (n⫽28)
Mean EEM CSA, mm2
Mean lumen CSA, mm
2
Lesion B (n⫽27)
Post-Procedure
9 Mo Follow-Up
Post-Procedure
6 Mo Follow-Up
11.50⫾2.52*
12.53⫾3.36*
13.20⫾3.27†
14.17⫾3.35†
6.59⫾1.82†
6.58⫾1.44‡
6.06⫾1.94‡
7.35⫾1.78†
Mean stent CSA, mm2
6.56⫾1.44
6.69⫾1.71
7.35⫾1.78§
7.60⫾1.64§
Malapposition volume, mm3
0.62⫾1.38
4.67⫾19.43
0.09⫾0.48
2.62⫾10.90
...
11.58⫾11.27
...
Percent net volume obstruction, %
Stent malapposition per lesion, n (%)
14.79⫾8.41
7 (25.0)
3 (10.7)
1 (3.7)
3 (11.1)
Persistent malapposition, n (%)
...
0 (0.0)
...
0 (0.0)
Late acquired malapposition, n (%)
...
3 (10.7)
...
3 (11.1)
Values are expressed as mean⫾SD or n (%).
EEM indicates external elastic membrane; CSA, cross-sectional area.
*P⬍0.01 between post-procedure vs 9 mo follow-up for lesion A.
†P⬍0.01 between post-procedure vs 6 mo follow-up for lesion B.
‡P⬍0.05 between post-procedure vs 9 mo follow-up for lesion A.
§P⬍0.05 between post-procedure vs 6 mo follow-up for lesion B.
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February 2012
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Figure 4. Optical coherence tomography (OCT) findings of a definite, very-late stent thrombosis that occurred 639 days after implant.
A, OCT longitudinal and (B–F), cross-sectional images, obtained immediately after thrombus aspiration in a definite late stent thrombosis of a paclitaxel-eluting stent (PES) implanted in lesion A. Whereas (B, C) PES struts were fully covered, a (D–F) protruding intraluminal thrombus, attached to a (F) new ruptured plaque, was observed at the (A) proximal edge of the stent. In this stent, the observed
rates of uncovered and malapposed struts were 1.09% and 0.22% at 3 months and 0.75% and 0.00% at 9 months, with mean neointimal thickness of 0.19 mm at both time points.
The biological process that follows coronary artery stent
deployment is a response to vascular injury and has been
characterized by smooth muscle cell migration and proliferation.20 Intramural delivery of potent cell-cycle inhibitors via
DES was developed to block this proliferative process.21
Human pathology studies have observed the presence of
uncovered and malapposed stent struts in patients who died of
ST.3 Others using IVUS and, more recently, OCT have also
found malapposed and uncovered struts months after deployment of DES,4,22 although the frequency of these imaging
findings in vivo was much lower than those observed in
necropsy specimens. These findings led to the notion of a
delayed vascular response, also referred to as “healing,” after
DES implantation. Our recent OCT trials confirmed lower
degree of strut coverage and higher rate of malapposition in
PES compared with bare-metal stents at 6- and 13-month
follow-up.12,16 The present study provides unprecedented
detailed analysis of the temporal evolution of the arterial
reaction to PES. This study revealed that the proliferative
response after PES is an early process and follows the same
pattern as that observed with bare metal stents,23 with ⬎90%
of tissue response taking place within the first 3 months
post-vascular injury. The magnitude of the neointimal response is inhibited after PES deployment but not significantly
delayed.
The time period between DES deployment and early
follow-up has been largely unexplored by in vivo studies.
This OCT study revealed that strut penetration and tissue
protrusion through the stent struts had no relevant impact on
early vascular response after PES implantation. These results
are in line with recent OCT studies, showing that small
imaging findings at implant, such as tissue prolapse and
intrastent dissections after stenting, were not associated with
adverse outcomes.13,17
The very first clinical investigation to assess the vascular
response to DES implantation in humans over time used
serial IVUS imaging.5 These early studies were essentially
focused on overall neointimal proliferation and did not
address strut-level tissue coverage or malapposition. Recent
serial OCT imaging investigations have suggested a late
increase in neointimal proliferation in sirolimus-eluting stent
between 6 and 12 months.24 Whether these early observations
also apply to PES, which deliver a drug with different
properties and kinetics, remains to be determined. In the
present study, we could not detect significant growth in
neointimal proliferation or improvement in strut coverage
between 3 and 9 months in lesions A, and the degree of NIH
and uncovered struts at 6 months in lesion B was similarly
low. Indeed, in vivo vascular response to different DES varies
substantially.16 Whether our results can be applied to different
DES requires further investigations.
The temporal evolution of strut malapposition development and resolution after PES seems complex. Our data
suggest that both formation of new malapposition and resolution of “old” ones occur simultaneously in the same stented
vessel and that these opposing biological phenomena are
observed throughout the 9-month follow-up period. The time
frame from implantation to 3 months was the most active
period in the malapposition process (Figures 1 and 3), when
the largest number of malapposed struts resolved at the same
time that new malappositions and aneurysms were observed.
Interestingly, the subsequent period (3- to 9-month followup) was marked by an almost complete resolution of the early
acquired malapposition and appearance of late malapposition
at completely new sites. The overall rate and volume of
malapposition showed reduction beyond the 3-month
follow-up period in spite of a lower proliferative response
observed during the same time period. Apparently, malapposition and aneurysm resolution were important contributors of
Guagliumi et al
lumen loss over time. Whether strut malapposition will
continue to develop or completely resolve beyond 9-month
follow-up cannot be determined in the present study. Nevertheless, it is important to notice that new strut malappositions
observed at 9 months were less frequent than in previous
assessments and limited in size (Table 4).
Study Limitations
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The design of this study imposes several limitations on the
conclusions. Performing OCT imaging at consistent time
points (ie, 0, 3, 6, or 9 months) for both lesions A and B
would have been ideal. A less-than-ideal design was adopted
in the present study in keeping with clinical, technical, and
ethical considerations and recommendations from the Institutional Review Board, in order to limit patients’ exposure to
unnecessary procedures for mere investigational purposes.
Although serial OCT imaging demonstrated detailed repeatable arterial wall features inside PES, these imaging findings
were based on observations in a relatively small number of
patients. Small discrepancies between baseline and follow-up
OCT pullback lengths may affect comparative volumetric
analyses, whereas presence of artifacts necessitating rejection
of consecutive frames can introduce biases in comparative
segment evaluation. Current OCT cannot differentiate between different tissue types (whether cellular or not cellular
in nature) and, of course, cannot determine the endothelial
function. Moreover, the study was not designed and not
powered to investigate the clinical implications of OCT end
points. Future evaluations linking observed OCT findings to
clinical outcomes are needed.
Conclusions
The present study provides unique and potentially important
insights to understand the in vivo temporal evolution of
vascular response in patients undergoing PES implantation.
Serial OCT imaging revealed the first 3 months to be the
period with most biological activity after PES implantation,
when the proliferative reaction mainly occurs and malapposition resolves. The study also revealed a less active, yet
continuous, dynamic arterial response beyond 3 months, with
resolution and development of new malapposition and minimal
changes in the proportion of strut coverage through 9 months
post-treatment. Serial intravascular OCT is valuable to characterize the in vivo vascular response to DES implantation.
Sources of Funding
Ospedali Riuniti di Bergamo, Bergamo Italy with grant support from
Boston Scientific Corporation, Natick, MA.
Disclosures
Dr Guagliumi reports receiving grant/research support from Boston
Scientific Corporation (BSC), Medtronic Vascular, LightLab Imaging, and Labcoat and is a consultant for BSC, Cordis, and Volcano
Corporation. Dr Costa is on the Speaker Bureau and is a consultant
for BSC, Sanofi/Aventis, Eli Lilly, and Medtronic and is on the
Speaker Bureau and a member of the Scientific Advisory Board for
Abbott, Cordis, LightLab Imaging, and Scitech. Dr Sirbu reports
receiving grant/research support from LightLab Imaging. Dr Bezerra
reports receiving honoraria grants from St Jude Medical. Drs
Ikejima, Biondi Zoccai, Lortkipanidze, Capodanno, Matiashvili,
Serial OCT Assessment in PES
37
Vassileva, Musumeci, Fiocca, Wang, Tahara, and Valsecchi report
no conflicts.
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Serial Assessment of Coronary Artery Response to Paclitaxel-Eluting Stents Using Optical
Coherence Tomography
Giulio Guagliumi, Hiram G. Bezerra, Vasile Sirbu, Hideyuki Ikejima, Giuseppe Musumeci,
Giuseppe Biondi-Zoccai, Nikoloz Lortkipanidze, Luigi Fiocca, Davide Capodanno, Wei Wang,
Satoko Tahara, Angelina Vassileva, Aleksandre Matiashvili, Orazio Valsecchi and Marco A.
Costa
Circ Cardiovasc Interv. 2012;5:30-38; originally published online January 31, 2012;
doi: 10.1161/CIRCINTERVENTIONS.111.965582
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