Clinical Trial Commentary

1
Clinical Trial Commentary
Trials of radiation to prevent or reduce
in-stent restenosis

• Dr Eric Topol
• Chairman and Professor, Department of Cardiology
• Director of the Joseph J Jacobs Center for
  Thrombosis and Vascular Biology at the Cleveland
  Clinic
• Dr Robert Califf
• Professor of Cardiology
• Associate Vice Chancellor for
• Clinical Research at Duke University

2
START trial
STents And Radiation Therapy

• Largest randomized trial of in-stent restenosis
  performed to date
• 476 patients with in-stent restenosis
• 50 centers in Europe and North America
• Double-blind randomization to beta-source
  radiation or placebo
• radiation arm vascular brachytherapy using a
  90strontium/90yttrium source train

Dr Jeffrey Popma, 49th Annual Scientific Session
of the ACC
3
START trial
8-month outcomes
Beta radiation reduced the need for target vessel
revascularization (TVR) and the occurrence of
major adverse cardiac events
25.9
24.1
?31
?34
percent
18.0
16.0
p0.026
p0.039
TVR
Major adversecardiac events
4
START trial
Results
5
START trial
START stands out as a great trial in its field
but it's way too small and the follow-up is way
too short to draw definitive conclusions

• Concerns
• idealized patient groups are not representative
  of what happens in the general population
• the technology may not actually be effective
• too much may be extrapolated from this 1 trial

6
LONG WRIST trial
Washington Radiation for In-Stent Restenosis
Trial for Long Lesions

• 120 very difficult patients from 2 centers
• 50 previous MI
• 40 previous CABG
• 40 with repeat in-stent restenosis
• 40 diabetic patients
• mean lesion length31 mm
• Most lesions pretreated with directional
  atherectomy, laser ablation or stent alone

Ron Waksman, MD, 49th Annual Scientific Session
of the ACC
7
LONG WRIST trial
Minimal lumen diameter
There was also a trend towards late thrombosis
and total occlusion in the treatment group, 15
vs 6.7 in the placebo group
8
LONG WRIST trial
Results at 6-month follow-up
9
LONG WRIST trial
Conclusions
Gamma radiation is feasible and generally
safe. Gamma radiation reduces restenosis and
major adverse cardiac events among patients with
in-stent restenosis with very long lesions (48
cm). Gamma radiation reduces angiographic and
clinical recurrences at 6 months by 37 to
54. In-stent restenosis, especially in a diffuse
pattern, has a malignant course despite all
available treatments.
10
Radiation therapy
Future effects
A study of radiation for breast cancer is
expected to show a dramatic increase in cardiac
deaths in the second decade. With any sort of
radiation to the coronary arteries, the concern
is not what's going to happen this year or next,
but 5 years down the line.
11
Beta vs gamma
Direct beta-vs-gamma trial needed
Beta radiation therapy takes 3 to 5 minutes
gamma takes 20 to 30 minutes. There are much
more data are available on gamma
radiation. Larger trials with extended follow-up
are needed to confirm whether beta radiation is
safer than gamma radiation.
12
SCRIPPS trial
Scripps Coronary Radiation to Inhibit
Proliferation Post-Stenting
55 patients with previous restenosis randomized
to receive an 8003000 cGy dose of Iridium192 or
placebo during stenting and angioplasty Results Ra
tes of restenosis, TLR, and combined endpoint
(death, MI, and TLR) were significantly lower No
specific adverse effects of radiation therapy 1
death occurred following a stent thrombosis, but
the 100 occlusion of the vessel at the 6-month
follow-up angiograph means it was unlikely to be
related to the radiation exposure
Teirstein et al. Circulation 2000101360-365
13
SCRIPPS trial
Results at 3-year follow-up
Teirstein et al. Circulation 2000101360-365
14
SCRIPPS trial
Late angiographic changes inpatients with no TLR
at 6 months
Teirstein et al. Circulation 2000101360-365
15
Radiation therapy
Target patients
Radiation therapy should be used for patients
with no other options, who cant worry about
effects that may arise 5 or 10 years later. But,
when new techniques are put into practice, they
are sometimes used to treat patients other than
the intended recipients.
16
Radiation therapy
Obstacles to use
Both beta and gamma require a radiation
oncologists in the cath lab. Beta is very
expensive, projected to be more than a few
thousand dollars. Trial limitations Entry to
trials should be restricted to patients for whom
there is no other alternative. But, trials have
not included patients who have had the 2 or 3
bypass operations and multiple attempts at
balloon angioplasty.
17
Radiation therapy
Safety profile
Experience wide-field mediastinal radiation
cannot be compared with the micro-point source
directed only at the atheroma. It will take years
and thousands of patients before radiation
therapy can be used with complete confidence.
18
New technologies
Introduction and use
Any center with money to invest and physicians
willing to learn can use new technologies. Technic
al barriers may restrict the use of new
technologies to large centers with many in-stent
restenosis patients. A center of excellence
program would restrict the use of a new
technology to a nucleus of sites that have
experience and expertise.
19
New technologies
Recording data
Cardiac surgeons use the Society of Thoracic
Surgeons database to record data and develop
quality-improvement models. Cardiologists should
take more responsibility for their data
Complicated technologies such as beta radiation
should be very closely monitored
20
Radiation therapy
Here to stay
Even the increase in death and infarct
late-thrombosis in the gamma trials has not
slowed the enthusiasm for radiation
therapy. Gamma, beta, or both radiation therapies
may soon be approved for commercial use. When
any such therapy is initiated, long-term
follow-up should be part of the treatment
plan With the internet, technology is no longer
an impediment to large studies with long
follow-ups
21
Radiation therapy
Therapy that works
Radiation trials have shown that we can inhibit
the tissue response that leads to in-stent
restenosis. Radiation therapy inhibits the lesion
in in-stent restenosis patients when everything
else fails.