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

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 90 strontium/ 90 yttrium source train STents And Radiation Therapy Dr Jeffrey Popma, 49th Annual Scientific Session of the ACC START trial

34% START trial 8-month outcomes Placebo 90 Sr/ 90 Y Beta radiation reduced the need for target vessel revascularization (TVR) and the occurrence of major adverse cardiac events percent 31% TVR Major adverse cardiac events p= p=0.039

START trial Results Outcomes Placebo (n=232) 90 Sr/ 90 Y (n=244) Reduced risk p value TVR24.1%16.0%34%0.026 TLR25.9%13.1%42%0.008 Major adverse cardiac events22.4%18.0%31%0.039 TLR = target lesion revascularization

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

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) Iridium 192 Placebo Before treatment After treatment At 6-month follow-up * *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 Iridium 192 (n=60) Placebo (n=60) Any major adverse cardiac event*38.3%61.7%† Death4.6%6.1% Q-wave MI8.3%0.0%‡ TLR30.0%60.0% TVR33.3%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 needed Beta vs gamma

Teirstein et al. Circulation 2000;101: SCRIPPS trial 55 patients with previous restenosis randomized to receive an 800–3000 cGy dose of Iridium 192 or placebo during stenting and angioplasty Results Rates 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

Iridium 192 (n=26) Placebo (n=29) p value TLR15.4%48.3%<0.01 Death, MI or TLR23.1%55.2%0.01 Restenosis (  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: SCRIPPS trial Results at 3-year follow-up

Late angiographic changes in patients with no TLR at 6 months Change in mean from 6 months to 3 years Iridium 192 (n=17) p value Placebo (n=10) p value Lumen diameter (mm)– Stenosis (%) SCRIPPS trial Teirstein et al. Circulation 2000;101:

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 therapy Target 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 therapy Obstacles 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 technologies Recording 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 works Radiation therapy