(Circulation. 2000;101:2130.)
© 2000 American Heart Association, Inc.
Editorials |
Prevention of Coronary Restenosis
The Evolving Evidence Base for Radiation Therapy
From the Cardiovascular Divisions of the Brigham and Women’s Hospital (R.E.K.) and the Beth Israel Deaconess Medical Center (D.S.B.) and Harvard Medical School (R.E.K., D.S.B.), Boston, Mass.
Correspondence to Donald S. Baim, MD, Cardiovascular Division, Beth Israel Deaconess Medical Center, East Campus, 330 Brookline Avenue, Boston, MA 02215. E-mail dbaim{at}bidmc.harvard.edu
Key Words: Editorials • restenosis • radiation • brachytherapy
Restenosis, the time-limited renarrowing of the lumen of a coronary artery, affects 20% to 40% of patients in the months after an initially successful intervention.1 2 As such, it represents the extreme form of the healing response that produces a normally distributed amount of late loss in lumen diameter at all interventional sites.3 To some extent, the percentage of patients who develop renarrowing can be reduced by acutely achieving the largest possible lumen diameter (as by stenting) via the "bigger is better" principle. Stenting can also prevent any late loss caused by vascular contraction,4 although it does not reduce (and, in fact, increases) the amount of late loss due to excessive intimal hyperplasia. To lower the restenosis rate further and to provide durable treatment for in-stent restenosis when it occurs, potent treatments to blunt this late loss are thus required.
Although a number of pharmacological approaches have been tried to limit late loss, only a few have shown even preliminary efficacy. However, radiation therapy seems to provide an interesting, nonpharmacological approach to controlling this excessive response to injury response that is analogous to its role in limiting the growth of many rapidly proliferating neoplasms and non-neoplastic conditions of excessive proliferation (eg, exophthalmos of Grave’s disease or keloid scar formation).
There are some concerns with this hypothesis. First, the number of proliferating cells in an active restenosis lesion is generally small, and such cells are virtually absent in a de novo lesion that might undergo prophylactic radiation at the time of original intervention. Because the main effect of vascular radiotherapy is breaking single- and double-stranded DNA and, thereby, killing actively dividing cells in the media and intima,5 the paucity of such actively dividing cells in the target tissue is of concern. Hopefully, radiation can also injure the dormant cells located in the media and adventitia that will be called on to migrate, proliferate, and synthesize matrix after the coronary intervention in a manner similar to the radiotherapy inhibition of the infiltration by inflammatory cells and fibroblasts after initial keloid excision.6 Otherwise, the radiation of de novo lesions may have to wait until active cell division has begun.
Other theoretical problems include dosing, paradoxical stimulation,
late failure, as well as dosimetry and other practical issues. The
minimum radiation dose that will prevent excessive hyperplasia in
aggressive proliferators who would have restenosed, without interfering
with the healing required to repair dissections and to cover the
surface of stents in the majority of patients who would not have
restenosed, has yet to be determined. Paradoxical stimulation is the
potential for subtherapeutic (sublethal) doses to injure some cellular
populations and cause paradoxical excessive tissue proliferation. Late
failure, the potential for late aneurysm formation or very late
term (>5 years) coronary renarrowing like that seen after
higher-dose (
50 Gy) treatments for Hodgkin’s disease,7
is also a concern. Dosimetry issues relate to lack of centering the
source within the vessel (which may lead to a extreme differences in
dose to the near and far vessel walls) and the penetration distances of
ß- and 
-radiation (which may lead to the shielding of deeper
tissue from ß rays or the irradiation of deeper, perivascular tissue
by rays). Finally, practical issues are related to the need to
accurately treat long segments and bifurcation lesions or to retreat
segments when new disease arises, as well as the need to have a
radiation oncologist administer the brachytherapy treatment. Despite
these obstacles, both and ß radiotherapy have demonstrated
efficacy in porcine models.8 9 10 This efficacy is now
being confirmed in early human studies.
The early clinical trials have demonstrated that many of these theoretical problems are clinical realities. (1) A greater demonstrated benefit of radiation therapy exists in patients with aggressive in-stent proliferation11 compared with de novo lesions, possibly suggesting the importance of matching the timing of therapy to the presence of actively dividing cells. (2) Unusually late (months, rather than days) stent thrombosis occurs in patients who undergo radiation therapy, suggesting that radiation has the potential to inhibit even the minimum healing response required to cover the stent struts. (3) The effects of treatment are inconsistent among the ß-brachytherapy12 13 and ß-radioactive stent trials (with the occurrence of "candy wrapper" restenosis at the ends of the treatment zone), which suggests a stimulatory effect of subtherapeutic radiation doses or the failure to deliver the prescribed radiation dose to an appropriate target depth in the iatrogenically-injured target vessel segment (so-called geographical miss).
In light of these considerations, our understanding of coronary
radiation therapy and its effect on vascular renarrowing is far more
limited than our now relatively mature understanding of the vascular
renarrowing process after conventional therapy (nonradiation) with
coronary devices, and each subsequent trial adds importantly to
our understanding of, and comfort with, radiation therapy. The
-Washington Radiation for In-Stent restenosis Trial (WRIST)
reported in this issue of Circulation14 is one
such trial, and it provides strong evidence supporting the use of
-radiation in the treatment of in-stent coronary
restenosis. This cohort of patients is ideal for study because
they have a high (50% to 80%) restenosis rate when treated
with other modalities, they are in the midst of a proliferative process
(greater radiation sensitivity), and excessive proliferation is the
only mechanism for in-stent restenosis.
Current Evidence for In-Stent Radiation Efficacy
The 130-patient -WRIST by Waksman et al14 is 1 of
3 small-to-moderate sized (but each markedly positive) randomized
trials that have demonstrated the efficacy of
192Ir -radiation in the prevention of
restenosis in patients with in-stent restenosis. The
other 2 trials were the 55-patient Scripps Coronary Radiation
to Inhibit Proliferation Post Stenting (SCRIPPS) trial15
and the 252-patient, multicenter GAMMA-I trial.16
The -WRIST trial had an efficacy similar to that of the SCRIPPS
trial against binary angiographic restenosis (treatment effect,
67% and 69%, respectively), which was larger than the 41% treatment
effect reported in the larger multicenter GAMMA-I trial. Although it is
typical for the best results to be seen in smaller, pioneering,
single-center studies, with a lower efficacy seen in subsequent larger
multicenter trials, we need to be observant for slight differences in
treatment technique (particularly dosing) that may also explain the
observed differential efficacy.
Evidence for Radiation Efficacy Outside In-Stent Restenosis
Trials to demonstrate the usefulness of radiation therapy for
non–in-stent coronary obstructions must be larger and more
complex than the simple in-stent restenosis trials. The reasons
include (1) the more complex mechanisms of initial narrowing
(variable proportions of chronic plaque build-up and vascular
contraction as well as the variable contributions of radiotherapy
on neointimal proliferation versus vessel wall remodeling)
and (2) the larger sample sized needed due to the low expected
control-arm clinical restenosis rate compared with that seen in
a study of in-stent restenosis. To illustrate this point, the
BETA-CATH trial, a multicenter pivotal trial of adjunctive
90Sr/90Y ß-therapy for
non-stented obstructions that is currently in the follow-up phase, has
randomized 1455 patients to measure the radiation efficacy for both
stent and non-stent coronary interventions. Given these
limitations, it is not surprising that currently, no pivotal data
demonstrate any efficacy for - or ß-radiation therapy in
non-stented coronary obstructions. However, many promising
small, single-arm studies have reported low restenosis rates
and low loss indexes under these conditions for both
ß-13 and -brachytherapy,17 as well as
with ß-radioactive stents. More interesting are the
intravascular ultrasound findings suggesting favorable (expansion)
vascular remodeling with ß-brachytherapy,13 although
such small, single-arm studies require further confirmatory imaging
from randomized datasets.
ß Versus Radiation
Currently, randomized evidence for a beneficial effect of
radiotherapy on the prevention of restenosis in patients with
in-stent restenosis is limited to the -source
192Ir, although Waksman et al have reported a
promising recent single-arm study that uses ß-radiation
(32P wire). ß-radiation therapy may
prove to be equally efficacious as that with -radiation, and it has
several practical advantages, including fewer changes in policy and
catheterization laboratory equipment and the reduced
potential for radiation exposure to patients and staff.18
However, ß-radiation also has potential shortcomings, including its
relative lack of adventitial penetrance.18 19 At least one
small, uncontrolled ß-radiation pilot study using 90Y
showed no effect of radiation in the prevention of
restenosis12 with a calculated 2-mm deep tissue
dose <3 Gy, despite a prescribed dose of 18 Gy at the lumen
surface.20 Potential solutions for improving uniform
ß-penetrance include the use of higher energy ß sources (such as
90Sr) and radioactive liquid-filled balloons to
place the source closer to the vessel wall.21 Until
comparable trials are available, it would be premature to conclude
decisively that the current evidence base supports the efficacy of
sources other than 192Ir or of radiation therapy
for non-stented coronary obstructions or stented de novo
lesions.
Dosing
Formal, definitive, randomized, dose-finding studies have not been
performed for either - or ß-radiation in the treatment of human
intracoronary lesions. The prescribed doses, which are
determined largely on the basis of porcine studies, have generally
involved a prescription of a mean dose of 12 to 18 Gy at a depth of
2 mm. Because of geometrical factors, actual delivered doses may
be significantly higher or lower in different parts of the vessel. A
retrospective analysis of calculated delivered doses, however,
suggests a dose-response relationship for 192Ir.
Because of a lack of centering, most -radiation trials have
prescribed at least 8 Gy to the far wall, with no more than 30 Gy to
the near wall. Finally, the importance of finding the optimal dose is
underscored by the suggestion that doses <10 Gy may be stimulatory, as
was found in one porcine study10 but not in a
second.22 These low doses may also affect vascular
contraction adversely, which is important because current systems
administer such sublethal dosing to deeper vascular structures and just
beyond the end of the indwelling source in every intracoronary
radiation treatment. If such areas were exposed to the mechanical
trauma of an intervention, such as a balloon injury beyond the edge of
the radiation source, this might explain the intense candy wrapper
effect seen at the ends of some radioactive stents.
Late Stent Thrombosis
The problem of late stent thrombosis was first raised in the
public forum when the data and safety monitoring board for the
multicenter BETA-CATH trial recognized an unusually high (6%) rate
of late acute thromboses in patients with de novo lesions who were
randomized to stenting but not in those randomized to balloon
angioplasty. Both the magnitude of the thrombosis rate (6%) and the
timing (30 to 90 days) of the thrombosis were unusual compared with
other stent experiences.23 Presumably, the same mechanism
of action intended to reduce restenosis (namely, the inhibition
of neointimal formation) might also have affected the
neointimal and endothelial regrowth
required to cover the stent struts by 2 weeks after non-radiation
stenting. In November 1998, the Food and Drug Administration was
notified, and a 400-patient randomized stent branch with extended (>3
months, compared with 4 weeks in the initial stent branch)
antiplatelet (ticlopidine or clopidogrel) therapy was added to the
BETA-CATH Trial. Only after this attention to the problem did the
occurrence of late stent thrombosis with other and ß systems come
to light.24 Interestingly, no reports of late thrombosis
were seen in the IsoStent radiation stent registries, suggesting a
potential mitigating effect of dose fractionation over a longer time
compared with the near-instantaneous delivery in the brachytherapy
trials.
The -WRIST Trial has a 7% late stent thrombosis rate, which was a
major contributor to the combined end point of late major adverse
cardiac events. A pooled analysis of the SCRIPPS, GAMMA-I, and
-WRIST studies suggests that patients treated with -brachytherapy
for in-stent restenosis are at a much higher risk of late
thrombosis when a new stent is deployed when compared with a non-stent
treatment. Because none of these trials required extended (>2 months)
antiplatelet therapy, it is not currently known whether extended
antiplatelet therapy will mitigate the late stent thrombosis
problem after radiation.
Do We Need a New Restenosis Model for Radiation Therapy
The prevalent model for restenosis looks at the size of the coronary lumen at 6 months; after this point, the model assumes that lumen size remains stable.1 2 3 The past 5 years of experience with radiation therapy have demonstrated that we must expand our views of restenosis, or at least look well beyond the 6-month time described by Nobuyoshi et al1 and Serruys et al2 for balloon angioplasty, which was confirmed for stents.25 Recent 3-year angiographic follow-up data from the SCRIPPS trial demonstrate that the renarrowing process continues well beyond the traditional 6-month boundary; thus, longer follow-up is appropriate.26 Also, a simple analysis of the luminogram within the stented segment will not suffice.27 Different mechanisms of postradiation restenosis may operate in the original lesion segment, the stented segment, the ballooned segment, and the actual irradiated segment, and they may also relate to the changing doses via source-specific axial fall-off. Only a combination of intravascular ultrasound and careful angiography, which documents balloon, stent, and radiation source positioning, can fully describe the contributions of contraction (or negative remodeling), expansion (or favorable remodeling), and geographical miss to the restenosis process.
Coronary Radiation Therapy Today
Coronary radiation therapy is still far from being a
panacea, but it continues to gather momentum as the first potent
therapy for in-stent restenosis. Only when the problem of late
stent thrombosis is controlled, the precise anatomical prescription and
optimum dose are fully determined, and the relative places of the
radiation types ( versus ß) and sources are established will we be
able to put this potent new therapy in its correct clinical
perspective. However, given the high risk of recurrent
restenosis in patients who present with in-stent
restenosis, the absence of other effective interventional
treatments, the simple pathophysiological model of
pure proliferation that is ideal for radiation, and the unprecedented
efficacy demonstrated for -radiation in 3 randomized trials,
intracoronary brachytherapy does seem to be a breakthrough
treatment for patients with in-stent restenosis.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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