Trials of radiation to prevent or reduce in-stent restenosis

Clinical Trial Commentary

Dr Eric TopolChairman and Professor, Department of CardiologyDirector of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic

Dr Robert CaliffProfessor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

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

STents And Radiation Therapy

Dr Jeffrey Popma, 49th Annual Scientific Session of the ACC

START trial

34%

START trial 8-month outcomes

Placebo90Sr/90Y

Beta radiation reduced the need for target vessel revascularization (TVR) and the occurrence of major adverse cardiac events

perc

en

t

5

10

15

20

25

30

0

31%

TVR Major adversecardiac events

24.1

16.0

p=0.026

25.9

18.0

p=0.039

START trial Results

OutcomesPlacebo(n=232)

90Sr/90Y(n=244)

Reduced risk

p value

TVR 24.1% 16.0% 34% 0.026

TLR 25.9% 13.1% 42% 0.008

Major adverse cardiac events 22.4% 18.0% 31% 0.039

TLR = target lesion revascularization

START trial

START stands out as a great trial in its field

butit'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

120 very difficult patients from 2 centers 50% previous MI 40% previous CABG 40% with repeat in-stent restenosis 40% diabetic patients mean lesion length=31 mm

Most lesions pretreated with directional atherectomy, laser ablation or stent alone

Ron Waksman, MD, 49th Annual Scientific Session of the ACC

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

Lumen diameter (mm)

Iridium192 Placebo

Before treatment 0.78 0.68

After treatment 2.09 2.01

At 6-month follow-up 1.40 1.01*

*p=0.008

There was also a trend towards late thrombosis and total occlusion in the treatment group, 15% vs 6.7% in the placebo group

LONG WRIST trial Minimal lumen diameter

Results at 6-month follow-up

Iridium192

(n=60)Placebo(n=60)

Any major adverse cardiac event* 38.3% 61.7%†

Death 4.6% 6.1%

Q-wave MI 8.3% 0.0%‡

TLR 30.0% 60.0%

TVR 33.3% 60.7%

*includes death, Q-wave MI, bypass surgery, PTCA†p=0.01; ‡p=0.06

LONG WRIST trial

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 (4–8 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.

LONG WRIST trial Conclusions

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.

Radiation therapy Future effects

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.

Direct beta-vs-gamma trial neededBeta vs gamma

Teirstein et al. Circulation 2000;101:360-365

SCRIPPS trial

55 patients with previous restenosis randomized to receive an 800–3000 cGy dose of Iridium192 or placebo during stenting and angioplasty

ResultsRates 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

Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting

Iridium192

(n=26)Placebo(n=29)

pvalue

TLR 15.4% 48.3% <0.01

Death, MI or TLR 23.1% 55.2% 0.01Restenosis(50% stenosis)* 33.3% 63.6% <0.05

*12 patients (5 in the radiation group and 7 in the placebo group) refused the 3-year angiographic exam

Teirstein et al. Circulation 2000;101:360-365

SCRIPPS trial Results at 3-year follow-up

Late angiographic changes inpatients with no TLR at 6 months

Change in mean from 6 months to 3 years

Iridium192

(n=17)p

value

Placebo

(n=10)p

valueLumendiameter (mm) –0.37 0.15 0.00 0.98Stenosis (%) +12 0.25 +2 0.75

SCRIPPS trial

Teirstein et al. Circulation 2000;101:360-365

Radiation therapy should be used for patients with no other options, who can’t 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.

Radiation therapyTarget patients

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.

Radiation therapyObstacles to use

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.

Any center with money to invest and physicians willing to learn can use new technologies.

Technical 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.

New technologies Introduction and use

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

New technologiesRecording data

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

Radiation therapy Here to stay

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.

Therapy that worksRadiation therapy