From the Intravascular Ultrasound Imaging and Cardiac Catheterization
Laboratories, Washington Hospital Center, Washington, DC.
Correspondence to Martin B. Leon, MD, Cardiology Research Foundation, 110 Irving St, NW, 4B1, Washington, DC 20010.
Abstract
Background—Mechanisms of
recurrence after treatment of in-stent restenosis
are unknown.
Methods and Results—We prospectively performed quantitative
coronary angiography (QCA) and intravascular ultrasound (IVUS)
in 37 lesions with Palmaz-Schatz stents enrolled in a study of
intracoronary radiation for in-stent restenosis.
Primary treatment was at the discretion of the operator: PTCA (n=8) or
ablation+adjunct PTCA (n=29). Lesions were studied before intervention,
immediately after primary intervention, and 42±8 minutes later. QCA
measurements included minimal luminal diameter and diameter
stenosis. Planar IVUS measurements included
arterial, stent, lumen, and in-stent tissue areas. Stent,
lumen, and in-stent tissue volumes were calculated by use of Simpson's
rule. Compared with immediately after intervention, the delayed (42±8
minutes) minimal lumen area decreased by 20% (5.8±1.9 to
4.5±1.3 mm2, P<0.0001) and the lumen
volume by 12% (58±41 to 52±37 mm3,
P=0.0001). Ten lesions (27%) had a
Conclusions—There is significant tissue reintrusion shortly after
catheter-based treatment of in-stent restenosis. This was
greater in longer lesions and those with a larger in-stent tissue
burden, was not reflected in the QCA measurements, and may contribute
to recurrence.
Stents have a lower
restenosis rate than balloon angioplasty
(PTCA).1 2 However, in-stent restenosis
rates of 20% to 30% persist, in-stent restenosis results from
intimal hyperplasia,3 4 and treatment remains
unsatisfactory.5 6 7 8 9 During initial experiences
with intracoronary gamma radiation for in-stent
restenosis, we observed significant lumen loss between
completion of the intervention and the end of the dwell time. The
present study used intravascular ultrasound (IVUS) and quantitative
coronary angiography (QCA) prospectively to assess early lumen
loss after transcatheter treatment of in-stent
restenosis.
Methods
Patient Population
Primary treatment strategy was determined by the operator: PTCA (n=8),
excimer laser coronary angioplasty (ELCA; Spectranetics; n=12)
+ adjunct PTCA, or rotational atherectomy (RA; SCIMED/Boston Scientific
Corp; n=17) + adjunct PTCA. The largest laser fiber was 1.9±0.2
mm; the largest burr, 2.0±0.1 mm. Primary or adjunct
balloon/artery ratio was 1.26±0.21; maximal pressure was 15±3
atm.
After intervention, patients were randomized to catheter-based gamma
irradiation or placebo. A 5F closed-end catheter was positioned at the
angioplasty site, and a nylon ribbon with active
(192Ir) or dummy seeds was introduced. The
radiation dose was 15 Gy at 2 mm radially from the source; the
dwell time averaged 24±5 minutes. IVUS imaging was then repeated,
42±8 minutes after the postintervention study.
QCA Analysis
IVUS Image Acquisition and Analysis
Reproducibility of IVUS in studies of stented lesions has been
reported.10 Automatic transducer pullback length
measurements have been validated.11 External
elastic membrane (EEM, visible through the stent in 12 lesions),
stent, and lumen CSAs were measured (TapeMeasure, Indec Systems).
In-stent tissue CSA was calculated as stent minus lumen CSA. EEM
corresponded to the media-adventitia border, a reproducible measure of
total arterial CSA. When tissue encompassed the catheter,
the lumen was assumed to be 0.9 mm2. The
length where in-stent tissue CSA was
Measurements were made every 1 mm. Stent, lumen, and in-stent
tissue volumes were calculated by Simpson's rule and were measured on
the first 20 lesions imaged before intervention.
Planar analysis was performed on all lesions. The delayed IVUS
study was analyzed first to identify the smallest lumen CSA.
Corresponding image slices were then identified and measured on the
preintervention and postintervention studies.
Statistical Analysis
Results
QCA Results
IVUS Results
Volumetric Analysis
Planar Analysis
Correlates of Early Lumen Loss
Volumetric analysis was similar. The lumen volume decrease
correlated with (1) preintervention stent volume (r=0.662,
P=0.0015), lumen volume (r=0.674,
P=0.0011), and in-stent tissue volume
(r=0.650, P=0.0019); (2) lesion length
measured by QCA (r=0.531, P=0.0418) or IVUS
(r=0.671, P=0.0012); and (3) lumen volume
increase (r=0.656, P=0.0017) and in-stent tissue
volume decrease (r=0.662, P=0.0015) during the
intervention.
The decreases in lumen CSA and volume were similar for vein graft
versus native lesions, ablative devices+adjunct PTCA versus PTCA alone,
and prior versus first episode of in-stent restenosis, and did
not correlate with the interval between IVUS studies or ablation
catheter size.
Discussion
By both planar and volumetric IVUS analysis, there was a
significant and consistent early lumen loss after
"successful" treatment of in-stent restenosis; 27% of
lesions had a
The reported recurrence rate after treatment of in-stent
restenosis varies but may be greater in diffuse
lesions.6 14 The present study found the
greatest early lumen loss in lesions with the worst in-stent
restenosis (longer lesions, more in-stent tissue).
Previous IVUS studies of in-stent restenosis have indicated
that neointimal tissue ablation/extrusion and additional
stent expansion are both important mechanisms of lumen
recovery.7 8 9 15 This was confirmed in the
present study.
Early lumen loss resulted from tissue reintrusion (decreased EEM and
increased in-stent tissue). Despite additional stent expansion during
the intervention, there was only a tendency for early stent recoil
(decreased stent dimensions).
Early lumen loss correlated with lumen increase and tissue decrease
during the intervention, not with additional stent expansion. However,
(1) IVUS imaging was not performed after ablation and after
adjunct PTCA, (2) ablation using ELCA or RA to treat in-stent
restenosis tends to be modest,9 16 and
(3) directional coronary atherectomy was not permitted. The
present study cannot separate the impact of ablation versus
extrusion or determine whether more aggressive tissue removal will
limit early lumen loss.
Study Limitations
Conclusions
Acknowledgments
This study was supported in part by Cardiology
Research Foundation, Washington, DC.
Received February 16, 1998;
revision received May 27, 1998;
accepted May 29, 1998.
References
© 1998 American Heart Association, Inc.
Brief Rapid Communication
Early Lumen Loss After Treatment of In-Stent Restenosis
An Intravascular Ultrasound Study
2.0-mm2 decrease in minimum lumen area. Lumen loss (1)
resulted from increased tissue with the stent, (2) correlated with
lesion length and preintervention in-stent tissue, and (3) was not seen
angiographically.
Key Words: restenosis • stents • ultrasonics
From February to August 1997, 64 patients were enrolled in a
study of intracoronary gamma radiation for in-stent
restenosis. In the present study, we analyzed 37
lesions (31 native coronary and 6 vein graft) in 36 patients
(age, 62±10 years; 24 men) previously treated with Palmaz-Schatz
stents (Cordis). Reasons for exclusion were restenting of the lesions
(n=13), no delayed (n=6) or inadequate IVUS (n=1), in-stent tissue
<75% of stent cross-sectional area (CSA; n=2), restenosis
localized to stent margin(s) (n=1), or presence of non–Palmaz-Schatz
stents (n=5). (One patient had 2 lesions; per protocol, only 1 was
enrolled in the radiation trial.) There were 65 stents (1.8 per
lesion), implanted 9.6±8.3 months previously. Fifteen patients (40%)
had prior in-stent restenosis; the last episode was 5.5±3.3
months previously.
By use of an automated edge-detection algorithm (CMS-GFT, Medis)
and the outer diameter of contrast-filled catheters for calibration,
lesion length ("shoulder to shoulder"), minimal luminal diameter
(MLD), reference diameter, and percent diameter stenosis (DS)
were measured in the same view before intervention, after intervention,
and 42±8 minutes later.
All IVUS studies were performed after 200 mg
intracoronary nitroglycerin. IVUS was performed
before intervention in 27 lesions and after intervention and 42±8
minutes later in all 37 lesions. Studies were performed with
single-element 30-MHz transducers rotating at 1800 rpm and withdrawn
automatically at 0.5 mm/s within a 3.2F short monorail imaging
catheter (CardioVascular Imaging Systems, Inc). Complete imaging runs
were performed from beyond the stent to the aorto-ostial junction.
Studies were recorded on 1/2-in high-resolution s-VHS tapes. 75% of stent CSA (or was packed
around the catheter) defined the in-stent restenotic
lesion.
Statistical analysis was performed with StatView 4.5
(Abacus Concepts) or SAS (SAS Institute). Continuous variables were
compared by linear regression analysis, unpaired Student's
t test, or ANOVA for repeated measures. Post hoc,
postintervention, and delayed measurements were compared by paired
t test with the Bonferroni correction for multiple
comparisons. A value of P<0.05 was considered significant
except for post hoc comparisons in which P<0.017 was
required (0.05 divided by 3).12 13
Before intervention, lesion length measured 17.0±8.6 mm
(range, 5.0 to 33.4 mm), reference diameter 2.82±0.61 mm,
MLD 0.70±0.24 mm, and DS 75±9%. Postintervention MLD increased
to 2.16±0.56 mm, and DS decreased to 26±15% (both
P<0.0001). After the delay, there was no significant change
in MLD (2.09±0.48 mm, P=0.25) or DS (26±17%,
P=0.79).
The length of in-stent tissue occupying 75% stent CSA was
9.8±8.0
mm.
Stent volume increased from 84±63 mm3
before intervention to 102±73 mm3 after
intervention, lumen volume increased from 16±11 to 58±41
mm3, and in-stent tissue volume decreased from
68±52 to 44±33 mm3 (all
P<0.0001; Figure 1
). After the delay, lumen volume
decreased to 52±37 mm3, and in-stent tissue
volume increased to 51±38 mm3 (both
P=0.0001); there was no change in stent volume (102±73
mm3, P=0.50).
View larger version (33K):
[in a new window]
Figure 1. Volumetric preintervention (Pre),
postintervention (Post), and delayed (after 42±8 minutes) IVUS
results. All were statistically different (ANOVA for repeated measures,
P<0.0001). Post hoc analysis showed delayed
lumen significantly smaller and in-stent tissue significantly greater
than after intervention (both P=0.0001 vs threshold of
P<0.017 for statistical significance).
Stent CSA increased from 8.3±2.7 mm2
before intervention to 10.4±3.0 mm2 after
intervention, lumen CSA increased from 1.5±0.4 to 5.8±1.9
mm2, and in-stent tissue CSA decreased from
6.7±2.6 to 4.6±1.8 mm2 (all
P<0.0001; Figure 2). After the delay, EEM CSA decreased
from 17.6±3.9 to 16.6±3.9 mm2
(P=0.001), lumen CSA decreased to 4.5± 1.3
mm2 (P<0.0001), in-stent tissue CSA
increased to 5.6±2.2 mm2
(P<0.0001), and stent CSA tended to decrease (to
10.2±3.1 mm2, P=0.0625). Ten
lesions (27%) had a 2.0-mm2 decrease in lumen
CSA (38±3% of acute lumen gain). An example is shown in Figure 3.
Nine lesions underwent additional intervention (stent or PTCA). Early
lumen loss was not preferentially localized to the articulation.
View larger version (42K):
[in a new window]
Figure 2. Planar preintervention (Pre), postintervention
(Post), and delayed (after 42±8 minutes) IVUS results. All were
statistically different (ANOVA for repeated measures, all
P<0.0001). Post hoc analysis showed delayed
lumen significantly smaller and in-stent tissue significantly greater
than after intervention (both P<0.0001 vs threshold of
P<0.017 for statistical significance).
View larger version (121K):
[in a new window]
Figure 3. In-stent restenotic lesion in right
coronary artery (white arrows). Post-PTCA, an increase in lumen
CSA (1.0 to 7.7 mm2) was a result of an increase in
stent CSA (9.2 to 12.0 mm2) and a decrease in in-stent
tissue (8.2 to 4.3 mm2). Between post-PTCA and delayed
studies, there was a reduction in lumen CSA (to 4.4
mm2), an increase in tissue (to 7.6 mm2,
white arrows), but no change in stent CSA (12.0
mm2).
The lumen CSA decrease correlated with the preintervention stent
CSA (r=0.480, P=0.0113), in-stent tissue CSA
(r=0.488, P=0.0098), and QCA lesion length
(r=0.354, P=0.0504:
1.7±1.4-mm2 decrease in lesions 20 mm in
length versus 1.0±0.6-mm2 in lesions <20
mm in length, P=0.0669). It also correlated with lumen CSA
increase (r=0.711) and in-stent tissue CSA decrease
(r=0.749, both P<0.0001) during the intervention
but not with stent CSA increase. 2.0-mm2 decrease in
lumen CSA that was not detected angiographically. The mechanism
appeared to be tissue reintrusion back into the stent.
Only Palmaz-Schatz stents were included; the frequency and
magnitude of these findings in other stents are unknown. Only 8 lesions
were treated with PTCA alone, and 3 different treatment strategies were
used (PTCA, ELCA+PTCA, and RA+PTCA). ELCA and RA device sizes tended to
be modest. Not all of the lesions were imaged before intervention.
In-stent tissue reintrusion could not be separated from thrombus
formation. The EEM was visible through the stent in only 12 lesions.
Because this is a randomized, double-blinded study (not yet unblinded),
the impact of radiation versus placebo cannot be determined.
Early tissue reintrusion into the stent after treatment of
in-stent restenosis is common and often significant
(2.0-mm2 decrease in lumen CSA in
27%). This was greater in longer lesions and those with a larger
in-stent tissue burden, was not reflected in the QCA measurements, and
may contribute to recurrence.
2.0-mm2 decrease in minimum lumen area.
There is significant tissue reintrusion shortly after catheter-based
treatment of in-stent restenosis.
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