(Circulation. 2000;101:2227.)
© 2000 American Heart Association, Inc.
Brief Rapid Communication |
Safety of Intracoronary 
-Radiation on Uninjured Reference Segments During the First 6 Months After Treatment of In-Stent Restenosis
A Serial Intravascular Ultrasound Study
From the Intravascular Ultrasound Imaging and Cardiac Catheterization Laboratories, Washington Hospital Center, Washington, DC.
Correspondence to Gary S. Mintz, MD, 110 Irving St, NW, 4B1, Washington, DC 20010. E-mail gsm1{at}mhg.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—The effects of endovascular irradiation on uninjured reference segments during the treatment of in-stent restenosis are unknown.
Methods and Results—In the Washington Radiation for In-Stent
restenosis Trial (WRIST), patients with in-stent
restenosis were first treated with conventional catheter-based
techniques and then randomized (blinded) to receive either
-irradiation (192Ir) or a placebo (dummy seeds). We
identified all patients in whom the active (n=19) or dummy seeds (n=19)
extended >10 mm proximal and distal to the in-stent
restenosis lesion. Serial (postirradiation and follow-up)
external elastic membrane (EEM), lumen, and plaque and media
(EEM-lumen) areas were measured (using intravascular ultrasound) every
1 mm over 5-mm-long reference segments that were 6 to 10 mm
proximal and distal to the in-stent restenosis lesion. During
follow-up, a similar small increase occurred in the plaque and media
area in the proximal and distal reference segments in both
192Ir and placebo patients. However, in the
192Ir patients, an increase in both proximal and distal EEM
area occurred; as a result, no change in lumen area occurred.
Conversely, in the placebo patients, the proximal reference EEM area
decreased, and no change occurred in the distal reference EEM area;
this contributed to a decrease in lumen area.
Conclusions—There was no evidence of a deleterious effect of
-irradiation on angiographically normal uninjured reference segments
in the first 6 months after the treatment of in-stent
restenosis.
Key Words: restenosis • ultrasonics • radioisotopes
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Randomized, placebo-controlled clinical trials have shown that adjunct brachytherapy reduces recurrent in-stent restenosis after primary catheter-based intervention.1 2 However, concerns about brachytherapy still include late thrombosis, edge effects, aneurysm formation, and the occurrence of premature atherosclerosis.3 4 The need to cover the entire treated area to avoid "geographical miss" and edge effects and the limited selection of 192Ir source lengths has resulted in the use of longer radioactive seed trains. As a result, angiographically normal (and unintervened) reference segments are often exposed to
-irradiation. The safety of this approach is not
known. The current report used serial (postirradiation and follow-up) intravascular ultrasound (IVUS) to assess the response to ionizing radiation of the angiographically normal but (by IVUS) "pathologically abnormal" reference segments that were not injured during the primary catheter-based treatment of in-stent restenosis.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patient Population
In the Washington Radiation In-Stent restenosis Trial (WRIST), patients with in-stent restenosis were first treated with conventional catheter-based techniques and then randomized (blinded) to receive either
-irradiation
(192Ir, Best Industries) or a placebo (dummy
seeds). All index angiograms and serial IVUS from native artery WRIST
patients were screened. We identified all patients in whom active
(n=19) or dummy seeds (n=19) extended >10 mm proximal and distal
to the in-stent restenosis lesion to cover arterial
reference segments that were 
5 mm long and that were not injured
during the intervention. Initial interventions included rotational
atherectomy (SciMed/Boston Scientific Corporation, n=24),
excimer laser angioplasty (Spectranetics, n=4), additional stent
implantation (n=10), balloon angioplasty (n=3), or a combination of the
techniques. Sites of intervention at each step were documented
angiographically. The seeds were delivered through 5-French closed-end, noncentering catheters. Dwell time (22.4±4.2 minutes) was calculated to deliver 15 Gy at 2 mm from the source. Angiographic and IVUS studies were performed after the administration of 200 µg of intracoronary nitroglycerin. IVUS imaging was performed after the dwell time and at follow-up using a commercial scanner (SciMed/Boston Scientific) and motorized pullback (at 0.5 mm/s) of a mechanically rotating transducer (40 or 30 MHz) through a stationary imaging sheath.
IVUS Analysis
External elastic membrane (EEM), lumen, and plaque and media
(P&M=EEM-lumen) areas and the plaque burden (P&M area/EEM area) were
measured using computerized planimetry (TapeMeasure, Indec Systems)
according to validated and published protocols.5 6 7 8 IVUS
analysis was limited to 5-mm-long reference segments that were
6 to 10 mm proximal and 6 to 10 mm distal to the in-stent
restenosis lesion. The first 5 mm were skipped to ensure
that only the uninjured reference segment was analyzed.
Measurements were made every 1 mm and averaged.
Statistical Analysis
Statistical analysis was performed using StatView 4.5
(SAS Institute). Data are presented as mean±1SD. Continuous
variables were compared using a paired or unpaired Student’s
t test or ANOVA for repeated measures.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Baseline Findings
None of the reference segments were normal; the minimal plaque burden was 0.37. Proximal reference postintervention EEM, lumen, and P&M areas were larger in 192Ir versus control arteries; however, because of the small numbers, these differences did not reach significance (Table
:
P=0.056, P=0.18, and P=0.16,
respectively). Distal reference postintervention EEM, lumen, and P&M
areas were similar in both groups (Table: P=0.9,
P=0.8, P=0.8, respectively). Plaque burdens were
also similar (Table).
|
Serial Findings
During follow-up, a similar small increase occurred in P&M area in
the proximal and distal reference segments in both
192Ir and control patients (Table
and
Figure 1). However, changes in EEM
differed significantly. In 192Ir patients, both
the proximal and distal EEM areas increased; as a result, no change
occurred in proximal or distal lumen area. Conversely, in the control
patients, proximal reference EEM area decreased, but no change occurred
in distal reference EEM area; as a result, both proximal and distal
reference lumen areas decreased (Table and Figure 1).
|
When the individual image slices were compared, these changes did not
vary along the length of the reference segment (Figure 2). No difference existed in IVUS
measurements according to the primary device used.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The current study failed to detect a deleterious effect of
-irradiation on uninjured, reference segments in the first 6 months
after irradiation. Mild progression of disease (increased P&M area)
occurred in both irradiated and placebo arteries. However, the
increased P&M area in the controls was not accompanied by positive
remodeling (increase in EEM); as a result, lumen dimensions decreased.
Conversely, -irradiation seemed to induce positive remodeling, so
the increase in P&M area had little impact on lumen dimensions. Angiographic reference segments in the current study were not normal. Histopathologic studies have indicated that an enlargement of the diseased arterial wall occurs to compensate for atherosclerotic plaque accumulation.9 10 Previous IVUS studies of reference segments after catheter-based interventions have shown a combination of increased P&M area (after nonstent intervention), intimal hyperplasia (after stent implantation), and either negative or an absence of positive remodeling.2 8 Conversely, other studies have demonstrated positive remodeling after brachytherapy.11 12 13 14 In the Beta Energy Restenosis Trial (BERT), as in the current study, ß-irradiation prevented lumen loss, not by reducing neointimal hyperplasia, but by promoting positive remodeling.13
Limitations
Follow-up was limited to 6 months. Atherosclerosis
as a complication of external irradiation has been reported >5 years
after treatment.15 16 17 18 Thus, longer follow-up of
brachytherapy patients will be necessary. However, external-beam
irradiation delivers larger doses of radiation than brachytherapy, and
most of the patients in this report were treated at an age when their
coronary arteries were probably not atherosclerotic.
Reference segments in the current study were diseased. The impact of brachytherapy on normal reference segments cannot be determined. The increase in P&M area was small.
Although the current report includes all patients with native artery WRIST lesions in whom seeds extended >10 mm proximal and distal to the in-stent restenosis lesion, only 38 of 100 lesions fit this criterion, which might have introduced selection bias. The number studied may have been too few to detect an effect; we calculated a 12.7% possibility of not detecting a decrease in lumen area in the 192Ir group (P<0.05).
Conclusions
In the first 6 months after the treatment of in-stent
restenosis, -irradiation does not seem to injure
angiographically normal reference segments. Instead, -irradiation
seems to promote positive remodeling.
|
Acknowledgments |
|---|
This study was supported by a grant from the Cardiovascular Research Foundation.
Received December 31, 1999; revision received March 23, 2000; accepted March 27, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med. 1997;336:1697–1703.
2. Waksman R, White RL, Chan RC, et al. Intracoronary gamma radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation. In press.
3.
Costa MA, Sabat M, van der Giessen WJ, et al. Late
coronary occlusion after intracoronary brachytherapy.
Circulation. 1999;100:789–792.
4.
Condado JA, Waksman R, Gurdiel O, et al. Long-term
angiographic and clinical outcome after percutaneous
transluminal coronary angioplasty and intracoronary
radiation therapy in humans. Circulation. 1997;96:727–732.
5.
Mintz GS, Popma JJ, Pichard AD, et al.
Arterial remodeling after coronary angioplasty: a
serial intravascular ultrasound study. Circulation. 1996;94:35–43.
6.
Kimura T, Kaburagi S, Tamura T, et al. Remodeling of
human coronary arteries undergoing coronary angioplasty
or atherectomy. Circulation. 1997;96:475–483.
7.
Lansky AJ, Mintz GS, Popma JJ, et al. Remodeling after
directional coronary atherectomy (±adjunct PTCA): a serial
angiographic and intravascular ultrasound analysis from the
Optimal Atherectomy Restenosis Study (OARS). J Am
Coll Cardiol. 1998;32:329–337.
8.
Hoffmann R, Mintz GS, Dussaillant GR, et al. Patterns
and mechanisms of in-stent restenosis: a serial intravascular
ultrasound study. Circulation. 1996;94:1247–1254.
9. Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1371–1375.[Abstract]
10.
Stiel GM, Stiel LSG, Schofer J, et al. Impact of
compensatory enlargement of atherosclerotic coronary arteries
on angiographic assessment of coronary heart disease.
Circulation. 1989;80:1603–1609.
11.
Waksman R, Rodriguez JC, Robinson KA, et al. Effect of
intravascular radiation on cell proliferation, apoptosis, and
vascular remodeling after balloon overstretch injury of porcine
coronary arteries. Circulation. 1997;96:1944–1952.
12.
Meerkin D, Tardiff J, Crocker IR, et al. Effects of
intracoronary ß-radiation therapy after coronary
angioplasty: an intravascular ultrasound study. Circulation. 1999;99:1660–1665.
13.
Sabate M, Serruys PW, van der Giessen WJ, et al.
Geometric vascular remodeling after balloon angioplasty and
beta-radiation therapy: a three-dimensional intravascular ultrasound
study. Circulation. 1999;100:1182–1188.
14.
Sabate M, Kay IP, van der Giessen WJ, et al. Preserved
endothelium-dependent vasodilation in coronary
segments previously treated with balloon angioplasty and
intracoronary irradiation. Circulation. 1999;100:1623–1629.
15.
Hancock SL, Tucker M, Hoppe RT. Factors affecting late
mortality from heart disease after treatment of Hodgkin’s disease.
JAMA. 1993;270:1949–1955.
16.
Hancock S, Donaldson S, Hoppe R. Cardiac disease
following treatment of Hodgkin’s disease in children and adolescents.
J Clin Oncol. 1993;11:1208–1215.
17. Brosius FC, Waller BF, Roberts WG. Radiation heart disease: analysis of 16 young (aged 15 to 33 years) necropsy patients who received over 3500 rads to the heart. Am J Med. 1981;70:519–530.[Medline] [Order article via Infotrieve]
18. McEneiry PT, Dorosti K, Schiavone WA, et al. Clinical and angiographic features of coronary artery disease after chest irradiation. Am J Cardiol. 1987;60:1020–1024.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  E. Cheneau, R. Waksman, H. Yazdi, R. Chan, J. Fourdnadjiev, C. Berzingi, V. Shah, A. E. Ajani, L. Leborgne, and F. O. Tio How to Fix the Edge Effect of Catheter-Based Radiation Therapy in Stented Arteries Circulation, October 22, 2002; 106(17): 2271 - 2277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.W. Serruys, G. Sianos, W. van der Giessen, H.J.R.M. Bonnier, P. Urban, W. Wijns, E. Benit, M. Vandormael, R. Dorr, C. Disco, et al. Intracoronary {beta}-radiation to reduce restenosis after balloon angioplasty and stenting. The Beta Radiation In Europe (BRIE) study Eur. Heart J., September 1, 2002; 23(17): 1351 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Mintz, N. J. Weissman, and P. J. Fitzgerald Intravascular Ultrasound Assessment of the Mechanisms and Results of Brachytherapy Circulation, September 11, 2001; 104(11): 1320 - 1325. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Sianos, I. P. Kay, M. A. Costa, E. Regar, K. Kozuma, P. J. de Feyter, E. Boersma, C. Disco, and P. W. Serruys Geographical miss during catheter-based intracoronary beta-radiation: incidence and implications in the BRIE study J. Am. Coll. Cardiol., August 1, 2001; 38(2): 415 - 420. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||