(Circulation. 2000;102:2915.)
© 2000 American Heart Association, Inc.
Brief Rapid Communications |
Effect of Intracoronary 
-Radiation Therapy on In-Stent Restenosis
An Intravascular Ultrasound Analysis from the Gamma-1 Study
From the Intravascular Ultrasound Imaging Laboratory, Washington Hospital Center, Washington, DC (G.S.M., N.J.W., R.W., C.P.); Scripps Clinic, La Jolla, Calif (P.S.T., R.J.R., P.T., S.J.); Cleveland Clinic, Cleveland, Ohio (S.G.E.); Lenox Hill Hospital, New York, NY (I.M., Y.K., J.M., M.B.L.); Cordis (J.G.); and Brigham and Women’s Hospital, Boston, Mass (R.A.K.).
Correspondence to Neil J. Weissman, MD, 110 Irving St, NW - 4B1, Washington, DC 20010. E-mail gsm1{at}mhg.edu
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionConclusionsReferences |
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Background—The aim of this study was to use serial volumetric intravascular ultrasound to evaluate the effect of
-radiation on recurrent in-stent
restenosis. Methods and Results—After successful reintervention, patients were randomized to receive either 192Ir or placebo. Intravascular ultrasound studies with motorized pullback (0.5 mm/s) were performed immediately after irradiation and at 8-month follow-up in 70 patients. Paired volumetric analysis of the stented segment and of 5-mm proximal and distal reference segments was performed; this included measurements of the external elastic membrane, lumen, plaque and media (external elastic membrane minus lumen), stent, and intimal hyperplasia (stent minus lumen). Baseline proximal reference, stent, and distal reference measurements were similar in both groups. The changes in proximal and distal reference measurements of the external elastic membrane, plaque and media, and lumen areas were similar in both groups. However, the decrease in stented segment lumen volume was less in the 192Ir patients than the placebo patients (–25±34 mm3 versus –48±42 mm3; P=0.0225), and the increase in the volume of intimal hyperplasia in the stented segment was less in the 192Ir patients than in the placebo patients (28±37 mm3 versus 50±40 mm3; P=0.0352). When averaged over the length of the stented segment (32±13 mm versus 33±14 mm; P=0.9), the increase in mean area of intimal hyperplasia was 0.8±1.0 mm2 in the 192Ir group and 1.6±1.2 mm2 in the control group (P=0.0065). Late stent-vessel wall malapposition was noted in one placebo patient and no 192Ir patients.
Conclusions—-Radiation
therapy can effectively prevent recurrent in-stent restenosis
by inhibiting neointimal formation within the stent. At the
stent edge, there were no significant differences between
192Ir and placebo
patients.
Key Words: catheters • stents • restenosis • imaging
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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In-stent restenosis (ISR) remains the major limitation of coronary stenting. The primary mechanism of ISR is neointimal hyperplasia.1 Despite aggressive interventional strategies to treat ISR, angiographic recurrence and late clinical outcomes have been disappointing.2 Recently, adjunct brachytherapy using 192Ir was shown to reduce recurrent ISR after primary catheter-based intervention.3 4 We report the results of the intravascular ultrasound (IVUS) substudy of Gamma-1, a multicenter, randomized, placebo control trial of
-irradiation to reduce ISR. |
Methods |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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After primary catheter-based intervention, 252 patients with ISR in a native coronary artery (angiographic reference, 2.75 to 4.00 mm) were randomized (double-blinded) to receive either 192Ir (Best Industries) or placebo. The following 4 of the 12 Gamma-1 sites were selected for the IVUS substudy: Washington Hospital Center, Scripps Clinic and Research Foundation, Cleveland Clinic Foundation, and Lennox Hill Hospital. These 4 centers enrolled 139 patients; paired (immediately after irradiation and at 8-month follow-up) IVUS images were available in 70 patients. No differences existed in baseline patient and lesion characteristics or primary treatment when comparing (1) patients in the IVUS substudy versus the total cohort and (2) treated versus untreated (placebo) patients in the IVUS substudy (including diabetes and frequency of diffuse or proliferative ISR5 ).
Sources were inserted into a noncentered, blind lumen catheter (Cordis). The ISR lesion was treated at the operator’s discretion using conventional techniques, which were typically balloon angioplasty, atheroblation (rotational atherectomy or excimer laser angioplasty), and/or additional stent implantation (>80% of the lesions in both groups were restented). Dosimetry was calculated as follows. A series of IVUS images after reintervention was analyzed. The distance from the center of the IVUS catheter to the external elastic membrane (EEM) was measured over the length of the stent, and maximum and minimum source-to-target distances were determined. The dwell time was calculated to deliver 800 cGy to the target farthest from the radiation source, provided no more than 3000 cGy was delivered to the target closest to the source. Source lengths included 6 seeds (23-mm ribbon) for lesions <15 mm, 10 seeds (39-mm ribbon) for lesions 15 to 30 mm, and 14 seeds (55-mm ribbon) for lesions 30 to 45 mm.
Paried IVUS Imaging and
Analysis
IVUS imaging was performed after the administration
of intracoronary nitroglycerine (150 to 200
µg) using a commercial scanner (SCIMED) consisting of a
single-element, 30- or 40-MHz transducer mounted on the tip of a
flexible shaft rotated at 1800 rpm within either a 3.2 or 2.6 F short
monorail polyethylene imaging sheath. Motorized transducer pullback
(0.5 mm/s) was performed to ensure a constant interval between
slices, allowing accurate volumetric analysis. Ultrasound
images were recorded on half-inch, high-resolution, s-VHS videotape
for off-line analysis. According to validated and published
protocols6 7 8 9
and using computerized planimetry (TapeMeasure, Indec Systems), the
reference segment EEM, lumen, and plaque and media (P&M; EEM minus
lumen) areas were measured every 1 mm over a 5-mm length adjacent
to the stent edge. Stent, lumen, and intimal hyperplasia (IH; stent
minus lumen) areas were measured every 1 mm within the stented
segment. Mean reference and stent areas and stent volumes were
calculated. Minimum lumen area (MLA) and maximum area stenosis
(mean reference lumen minus MLA divided by mean reference lumen) were
reported.
Statistical Analysis
Continuous data are presented as mean±1SD.
Statistical analysis was performed with Statview 4.5 (Abacus
Concepts). Continuous variables were compared using paired or
unpaired Student’s t tests or
factorial ANOVA with post hoc comparisons using the Bonferroni
correction.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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The Figure
shows the postintervention versus follow-up IVUS analysis of
the proximal reference, stented, and distal vessel segments. Both
192Ir and placebo groups experienced a
decrease in proximal and distal reference lumen areas that was more the
result of a decrease in EEM area than an increase in P&M area. Changes
in proximal reference measurements were similar to changes in distal
reference measurements in both groups; however, all of the changes were
small.
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The
Figure
also shows that in both the 192Ir and
placebo groups there was a decrease in lumen area within the stented
segment that was almost entirely the result of an increase in IH area.
In control patients, there was a larger decrease in stent lumen area
compared with both proximal reference
(P=0.0202) and distal reference
(P=0.0115) vessel segments.
Conversely, in 192Ir patients, the decrease
in stent lumen area was similar to the decrease in proximal reference
and distal reference lumen areas
(P=0.9 for both
comparisons).
The
Table
shows the IVUS analysis of the 192Ir
versus the placebo group. Baseline proximal reference, stented segment,
and distal reference measurements were similar in the 2 groups. The
changes in proximal and distal reference segment EEM, P&M, and lumen
areas were also similar. However, the decrease in stented segment lumen
volume and the increase in stented segment IH volume was less in
192Ir patients compared with placebo
patients. When averaged over the length of the stent, the increase in
IH area was 0.8±1.0 mm2 in the
192Ir group and 1.6±1.2
mm2 in the control group
(P=0.0065).
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The
Table
also shows the IVUS MLA and area stenosis. Baseline
measurements were similar between the 2 groups. The follow-up MLA was
larger, the area stenosis was smaller, and the change in MLA
was less in the 192Ir patients compared with
placebo patients.
Late malapposition (not present postintervention) was noted in one placebo patient and no 192Ir patients.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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The current study demonstrated a reduction in late lumen loss and neointimal hyperplasia in patients with ISR treated with
-radiation. These data are consistent with the
results of the Scripps Coronary Radiation to Inhibit
Proliferation Post-Stenting (SCRIPPS)
Trial.3 In the SCRIPPS trial,
IH volume measured 45.1 mm3 in
control patients and 15.5 mm3 in
192Ir patients
(P=0.01). When normalized for
ISR length, IH area in the 192Ir group in
the SCRIPPS study measured 0.7 mm2
(identical to the current study) and 2.2
mm2 in controls (greater than in the current
study). Nevertheless, there were several differences between the
SCRIPPS trial and the current study. (1) SCRIPPS included vein graft
lesions; the current study did not. (2) Mean lesion length was shorter
in SCRIPPS. Lesion length is a predictor for recurrence after
conventional therapies and brachytherapy. (3) Only 62% of the patients
in SCRIPPS had ISR. Previous ISR is a risk factor for
recurrence after conventional
therapies.5 (4) A total of
27% of the 192Ir group and 41% of the
control group in SCRIPPS were diabetic. Diabetes may be a risk factor
for recurrence after conventional therapies.
The data in the current study are also consistent
with the result of the Washington Radiation for In-Stent
Restenosis Trial (WRIST). In WRIST, IH volume measured
55.0 mm3 in control patients and
3.1 mm3 in treated patients
(P<0.0001). There were also
several differences between WRIST and the current study. (1) WRIST
included vein graft lesions. (2) WRIST used a fixed dose
prescription.4 (3) A total of
39% of the 192Ir group and 45% of the
control group in SCRIPPS were diabetic.
The current study also indicated an absence of edge effect
after -radiation. Changes in segments 5 mm proximal and distal
to the stent were similar in the -radiation and control groups. Edge
effects have been most noticeable with the
32P-emitting
stent.10 11 IVUS
studies of edge restenosis with the
32P-emitting stent have indicated that this
is predominately the result of exaggerated neointimal
hyperplasia.
IVUS End Points in Brachytherapy
Studies
Most current brachytherapy studies include IVUS
analysis or at least an IVUS substudy. In SCRIPPS, only 65% of
the 55 patients had paired (postintervention and follow-up) IVUS;
nevertheless, IVUS end points were markedly positive. Similarly, in
Gamma-1, only 28% of the 252 patients had paired IVUS imaging;
however, the IVUS end points were still positive. Because of the
sensitivity of this modality, IVUS end points may require fewer
patients to be enrolled; however, this may be offset by
attrition from inadequate IVUS studies or lack of follow-up
IVUS.
Study Limitations
Serial (postintervention and follow-up) IVUS imaging
was performed in only a subset of the 252 patients enrolled in the
Gamma-1 trial. Total occlusions were typically not imaged at follow-up;
these could represent exaggerated neointimal
hyperplasia or late stent thrombosis. It has been suggested that IVUS
can underestimate neointimal volume, especially in subtotal
lesions.
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Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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-Radiation significantly reduces recurrent ISR by
inhibiting neointimal tissue growth within the stent; it
does not have a significant impact on the adjacent reference
segments.
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Acknowledgments |
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Supported by Cordis.
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Footnotes |
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J. Giorgianni is an employee of Cordis. Dr Teirstein receives research funding from Cordis, Guidant, Boston Scientific, Novoste, and Isostent; he also serves as a consultant to Guidant and Cordis. He owns patents on radiation devices and may receive royalties on the sale of these devices. Dr Waksman is a consultant to Guidant, Nucletron, and Radiance; Dr Tripuraneni is a consultant to Best, Cordis, Novoste, Guidant, and Nucletron; and Dr Jani is a consultant to Cordis and Best.
Received August 17, 2000; revision received October 11, 2000; accepted October 16, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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