De Novo and Restenotic Coronary Lesions Clinical and Angiographic Outcomes After Use of Sr-90 Beta Radiation for the Treatment of De Novo and Restenotic Coronary Lesions Richard E. Kuntz Burton Speiser, Michel Joyal/Raoul Bonan & Andre Arseneault, Gary Neiss/David Cox & Mark Kirsch, Warren Laskey & Mohan Suntharalingham, Charles Wilmer/Charles Brown & Frederick Schwaibold, Sigmund Silber & Peter von Rottkay, David Fischman & Michael Savage, and Stuart Pocock & Mona Abdalla for the Beta-Cath System Trial Investigators This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle)

Background Beta radiation using 90Strontium/ 90Yttrium (Sr-90), and Phosphorous-32 significantly reduced angiographic and clinical recurrence after PTCA for in-stent restenosis in two randomized trials (START and INHIBIT), confirming earlier beneficial effects shown with gamma radiation, Iridium-192 (SCRIPPS, WRIST, GAMMA-I). This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle)

Purpose To assess the safety and effectiveness of beta radiation in patients with de novo coronary lesions using a 30mm 90Sr/90Y source train in conjunction with: Stand alone balloon angioplasty, or Provisional stent placement in which balloon angioplasty was suboptimal This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle)

“Radiation Source Train” The Beta-Cath System Transfer Device Containing “Radiation Source Train” Coronary Artery “Delivery Catheter”

Patient undergoes PTCA (n=1100) Suboptimal PTCA result Original Trial Design – July ‘97 Patient undergoes PTCA (n=1100) Optimal PTCA result Stand-alone PTCA Branch Suboptimal PTCA result Provisional Stent arm Randomize Randomize Placebo Sr-90 Placebo Sr-90 Stent as needed No planned intervention Stent deployment

Trial Design Primary Efficacy Endpoint: 8-Month TVF (Target Vessel Failure : death, MI, TVR) Secondary Efficacy Endpoints: 8-Month angiographic restenosis, MLD and late loss at target site Safety Endpoints: 8-Month MACE (Major Adverse Cardiac Events : Death, MI, emergent CABG, TVR) and aneurysm formation

Sample Size Determination Clinical Restenosis: Designed to show a 32% treatment effect in the overall trial, assuming a 22% 8-month TVF rate in the placebo group and a 15% 8-month TVF rate in the treatment group (a = 0.05; b = 0.20) with a study enrollment of 1100 patients Angiographic Restenosis: Designed to detect 0.2 mm difference between active and placebo arms in each branch (balloon angioplasty and stent branches, a = 0.05; b = 0.20), assuming an 80% angiographic follow-up rate, with a minimum enrollment of 480 patients per branch This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle)

Trial Design Trial Initiated: July 1997 Enrollment: 1,100 patients Enrollment Completion: September 1999 Site Participation: 59 (US & Europe) Trial Design: Randomized, Triple-Masked Principal Investigators: R. Kuntz, MD (Cardiology) B. Speiser, MD (Rad Onc)

Sample Size Expansion NOV 98 - DSMB reported an unexpectedly high level of late stent thrombosis. Sponsor recommended minimum 60 days antiplatelet therapy (APT) MAR 99 - DSMB recommended extension of trial with a new branch to replicate the Provisional Stent Branch with extended APT, minimum of 90 days. N = 1455 This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Stand Alone PTCA Branch (n=504) Provisional Stent Branch (n= 499) Provisional Stent Branch >60/90 days APT (n=452)

Trial Design Data Coordinating and Statistical Analysis Center CDAC / Harvard Clinical Research Institute London School of Hygiene/Tropical Medicine: Stuart Pocock and Mona Abdalla Angiographic Laboratory Thomas Jefferson University: David Fischman, MD; Michael Savage, MD IVUS Core Laboratory CRI: Neil Weismann, MD EKG Core Laboratory CDAC: Peter Zimetbaum, MD DSMB Committee Chairman: Thomas Ryan, MD Clinical Events Committee Chairman: David Cohen, MD Sponsor Novoste Corporation

INCLUSION CRITERIA EXCLUSION CRITERIA Single lesion, single vessel intervention De novo or restenotic > 50% (by visual assessment) Target lesion in vessels between 2.7 and 4.0 mm RVD Target lesion length treatable with 20 mm balloon with the 30 mm Source Train PTCA Stand-alone Enrollment Stable lumen <30% DS Absence of thrombus, spasm, or dissection EXCLUSION CRITERIA Multi-vessel coronary intervention Unprotected left main disease Prior Chest Radiotherapy Provisional Stent Enrollment Stable lumen  30 to 50% DS Absence of thrombus, spasm, or significant dissection Stent mounted on balloon  24mm This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle)

Dose Prescription Reference vessel diameter (RVD) was determined visually after completion of coronary intervention Dose prescription point calculated @ 2 mm from center of source axis: 16.1 Gy* in RVD > 2.7 - < 3.3 mm 20.7 Gy* in RVD > 3.3 - <4.0mm 90Sr/90Y has a 28 year half-life, and short treatment time of 3-5 minutes This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) *NIST dose recalibration, March 2000

Overall Baseline Demographics Total cohort Sr-90 n = 744 Placebo n = 711 Age, yrs. 61.0 60.7 Men, % 73.3 73.7 Diabetes, % 22.2 23.2 Smoking, % 27.0 26.8 Restenotic, % 8.2 7.5 Prior CABG, % 9.8 9.0 LVEF, % 57.4 57.5

Baseline Angiographic Findings PTCA Sr-90 Placebo Stent Sr-90 Placebo Stent (>60d) RVD, mm 2.98 3.00 3.09 3.05 3.07 3.01 Pre - MLD, mm 0.85 0.84 0.86 0.88 0.89 Pre – DS, % 71.3 72.3 71.7 71.2 71.5 70.8 Lesion Length, mm 11.9 12.3 12.6 12.7 12.5 12.8

Follow-up Percent Compliance Sr-90 Placebo PTCA 264 240 Clinical 95.8% 95.4% Angiographic 81.8% 87.9% Stent 252 247 97.2% 97.6% 79.8% 82.2% Stent  60d 228 224 93.4% 93.8% 81.1% 82.1%

Major Adverse Events – In-Hospital % PTCA Sr-90 Placebo n=264 n=240 Stent Sr-90 Placebo n=264 n=240 Stent (>60d) Sr-90 Placebo n=264 n=240 Death 0.0 0.4 0.5 Q Wave MI 0.8 Non-Q Wave MI 1.1 1.7 3.2 2.0 1.3 3.6 Emerg. CABG TVR 0.9 2.2 Any MACE 1.5 2.5 2.8 4.9 Abrupt Closure -- Stent Occlusion

Late Treatment Site Thrombosis (thrombosis >30 days) Placebo Sr-90 % p=0.18 p<0.001 p=0.98 Both were bailout stents This is the Sample Column Chart slide. To create this particular slide, copy and paste the sample in the Slide Sorter view as follows: Select View / Slide Sorter Highlight the Sample Column Chart page and select Edit / Copy Place the courser where you want the new slide to be and select Edit / Paste Double-click on the pasted-in slide to return to Slide view To access the column chart, right/click on the chart and select chart object / open from the menu. This will open the chart in Microsoft Graph. You can make any changes to the chart and spreadsheet here. When you are finished making your changes, select File / Exit and return to… from the menu bar. THIS METHOD IS PREFERRED TO DOUBLE-CLICKING THE GRAPH AND OPENING IT IN POWERPOINT. Double-clicking the graph can sometimes reformat the sizes, colors, animations and fonts in your graph. n = 2 n = 17 n = 3 n = 3

Clinical Outcome Analysis – New Cohort following DSMB recommendation PTCA (n=504) Stent (n= 499) Stent >60d APT (n=452) This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) New Cohort

8 Mo Clinical Outcomes – New Cohort n=956 (%) This is the Sample Column Chart slide. To create this particular slide, copy and paste the sample in the Slide Sorter view as follows: Select View / Slide Sorter Highlight the Sample Column Chart page and select Edit / Copy Place the courser where you want the new slide to be and select Edit / Paste Double-click on the pasted-in slide to return to Slide view To access the column chart, right/click on the chart and select chart object / open from the menu. This will open the chart in Microsoft Graph. You can make any changes to the chart and spreadsheet here. When you are finished making your changes, select File / Exit and return to… from the menu bar. THIS METHOD IS PREFERRED TO DOUBLE-CLICKING THE GRAPH AND OPENING IT IN POWERPOINT. Double-clicking the graph can sometimes reformat the sizes, colors, animations and fonts in your graph.  12 % p=0.37  10 % p=0.41  9 % p=0.40 Heterogeneity test p=0.09 p=0.19 p=0.08

8 Month Angiographic Outcomes (%) Sr-90 Placebo This is the Sample Column Chart slide. To create this particular slide, copy and paste the sample in the Slide Sorter view as follows: Select View / Slide Sorter Highlight the Sample Column Chart page and select Edit / Copy Place the courser where you want the new slide to be and select Edit / Paste Double-click on the pasted-in slide to return to Slide view To access the column chart, right/click on the chart and select chart object / open from the menu. This will open the chart in Microsoft Graph. You can make any changes to the chart and spreadsheet here. When you are finished making your changes, select File / Exit and return to… from the menu bar. THIS METHOD IS PREFERRED TO DOUBLE-CLICKING THE GRAPH AND OPENING IT IN POWERPOINT. Double-clicking the graph can sometimes reformat the sizes, colors, animations and fonts in your graph.  38% p=0.003  14% p=0.27  36% p=0.01  21% p=0.06 Note: No late aneurysms detected PTCA Group Stent (>60d) Group

Secondary Analysis

Clinical Outcome Analysis – All Stent Cohort PTCA (n=504) Stent (n= 499) Stent >60d APT (n=452) This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) All Stent Cohort

8 Mo Angiographic Outcomes – All Stent (%) Sr-90, n=380 Placebo, n=384 This is the Sample Column Chart slide. To create this particular slide, copy and paste the sample in the Slide Sorter view as follows: Select View / Slide Sorter Highlight the Sample Column Chart page and select Edit / Copy Place the courser where you want the new slide to be and select Edit / Paste Double-click on the pasted-in slide to return to Slide view To access the column chart, right/click on the chart and select chart object / open from the menu. This will open the chart in Microsoft Graph. You can make any changes to the chart and spreadsheet here. When you are finished making your changes, select File / Exit and return to… from the menu bar. THIS METHOD IS PREFERRED TO DOUBLE-CLICKING THE GRAPH AND OPENING IT IN POWERPOINT. Double-clicking the graph can sometimes reformat the sizes, colors, animations and fonts in your graph.  29% p=0.004  30% p=0.004

8 Mo Clinical Outcomes – All Stent (%) This is the Sample Column Chart slide. To create this particular slide, copy and paste the sample in the Slide Sorter view as follows: Select View / Slide Sorter Highlight the Sample Column Chart page and select Edit / Copy Place the courser where you want the new slide to be and select Edit / Paste Double-click on the pasted-in slide to return to Slide view To access the column chart, right/click on the chart and select chart object / open from the menu. This will open the chart in Microsoft Graph. You can make any changes to the chart and spreadsheet here. When you are finished making your changes, select File / Exit and return to… from the menu bar. THIS METHOD IS PREFERRED TO DOUBLE-CLICKING THE GRAPH AND OPENING IT IN POWERPOINT. Double-clicking the graph can sometimes reformat the sizes, colors, animations and fonts in your graph.  59 % p=0.001  54 % p=0.001  60 % p=0.001 Heterogeneity test p=0.06 p=0.02 p=0.01

Clinical Outcome Analysis – PTCA Stent (n= 499) Stent >60d APT (n=452) This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle)

8 Mo Clinical Outcomes – PTCA (%) This is the Sample Column Chart slide. To create this particular slide, copy and paste the sample in the Slide Sorter view as follows: Select View / Slide Sorter Highlight the Sample Column Chart page and select Edit / Copy Place the courser where you want the new slide to be and select Edit / Paste Double-click on the pasted-in slide to return to Slide view To access the column chart, right/click on the chart and select chart object / open from the menu. This will open the chart in Microsoft Graph. You can make any changes to the chart and spreadsheet here. When you are finished making your changes, select File / Exit and return to… from the menu bar. THIS METHOD IS PREFERRED TO DOUBLE-CLICKING THE GRAPH AND OPENING IT IN POWERPOINT. Double-clicking the graph can sometimes reformat the sizes, colors, animations and fonts in your graph.  35% p=0.07  28% p=0.12  30% p=0.06

Conclusions The Beta-Cath™ System trial is the first and largest prospective, randomized, blinded placebo-controlled multi-center trial that investigated the use of vascular brachytherapy (VBT) for the prevention of restenosis in de novo lesions. This study was the first to identify the higher-than- expected rate of late stent thrombosis when radiation was used with new stent implantation, and was the first to solve it with extension of adjunctive anti-platelet therapy.

Conclusions The primary clinical endpoint, Target Vessel Failure (TVF), was not shown to be significantly lower in the combined radiation arms compared with combined placebo arms. Secondary analyses: Beta radiation in the PTCA branch: 34.6% reduction for Sr-90 in TVF/MACE rate, p=0.06 37.6% reduction for Sr-90 in lesion segment restenosis rate, p=0.003 Disparate results in angiographic restenosis in the combined Stent branches: 28.9% reduction for Sr-90 in lesion segment restenosis rate, p=0.004 30% increase for Sr-90 in the analysis segment, p=0.004

Conclusions The paradox of positive treatment effect for Sr-90 seen in ALL lesion segment analysis and the negative treatment effect of Sr-90 seen in the Stent analysis segment likely explains the negative treatment effect of Sr-90 on clinical restenosis in stents, and merits further investigation. Geographic Miss (inadequate radiation coverage of the interventional injury) may have contributed to the negative results of Sr-90. The overall positive results in the lesion segment analysis and the strong trends in the clinical outcomes in the PTCA branch suggests a potential role for Sr-90 radiation in the treatment of de novo coronary lesions if the increase in restenosis in the “analysis segment” can be solved.