COBRA Trial C ryoplasty o r Conventional B alloon Post-dilation of Nitinol Stents For R evascularization of Periph

1. ClinicalTrial.gov Identifier: NCT00827853 COBRA TrialCryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For Revascularization of Peripheral Arterial Segments Subhash Banerjee, MD Chief, Division of Cardiology, VA North Texas Health Care Associate Prof. of Medicine, UT Southwestern Medical Center Dallas, TX On behalf of COBRA investigators:

2. Grant/Research Support Consulting Fees/Honoraria Major Stock Shareholder/Equity Ownership/Founder Intellectual Property Rights Boston Scientific Corporation, Medicines Company, Gilead, Relypsa Medtronic, Cordis, St Jude, Gilead, Boehinger, Sanofi Mdcare Global (spouse) Mdcare Global (spouse) Mdcare Global (spouse) Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company

3. COBRA TrialCryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For Revascularization of Peripheral Arterial Segments Investigators: Subhash Banerjee, MD VA North Texas HCS/UTSW Emmanouil S. Brilakis, MD, PhD VA North Texas HCS/UTSW Tony Das, MD Presbyterian Hospital of Dallas Kenneth Saland, MD Presbyterian Hospital of Dallas Mazen Abu-Fadel, MD Oklahoma City VAMC/OU Faisal Latif, MD Oklahoma City VAMC/OU Eric Dipple, MD Midwest CV Research Foundation Nicholas Shammas, MD Midwest CV Research Foundation *UTSW: University of Texas Southwestern Medical Center ±VAMC: VA Medical Center ¥ OU: Oklahoma University

4. COBRA TrialCryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For Revascularization of Peripheral Arterial Segments Cryoplasty • PolarCath® peripheral dilatation system simultaneously dilates & cools the vessel wall • Cooling (-10oC) is achieved by inflating the balloon with nitrous oxide instead of saline and contrast N2O Refrigerant Cylinder Balloon Catheter • Mechanisms of Action • Induces smooth muscle cell (SMC) apoptosis1 • Minimizes SMC necrosis (-5 to -15oC)2 • Reduces in-stent restenosis (ISR) Microprocessor-Controlled Inflation Unit PolarCath is a trademark of Boston Scientific Corporation and its affiliates. Image property of Boston Scientific Corporation 1Isner et al, Circulation; 1995 2Virmani et al, CryoLetters; 2005

5. COBRA TrialCryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For Revascularization of Peripheral Arterial Segments Background: Diabetes mellitus is associated with increased risk of in-stent restenosis after superficial femoral artery (SFA) stenting with nitinol self-expanding stents (nSES)1 Hypothesis: When compared to conventional balloon angioplasty, cryoplasty post-dilation decreases the risk of SFA nSES in-stent restenosis 1Bakken et al, Journal of Vasc Surgery; 2007

6. COBRA Trial Design 121 patients with DM consented between August 2008 and December 2010 in 4 clinical sites in U.S. • DESIGN: Prospective, randomized, multi-center clinical evaluation of the PolarCath® system vs. conventional balloon post-dilation of nSES implanted in the SFA of patients with DM, presenting with life-style limiting claudication • OBJECTIVE: To compare the rates of binary restenosis, at 12 months, as determined by duplex ultrasound (DUS) 4 (8.9%) Deaths* 47 (39%) patients not stented 90 SFA nSES implanted (74 patients/16 B/L) nSES Post-dilation Randomization 1:1 Conventional Balloon Group or CBA (N=45) Cryoplasty Group (N=45) 2 (4.4%) Deaths* ≥2.5 times increase in Doppler peak systolic velocity (PSV) in the stented segment and 10mm beyond its proximal and distal edges DUS and clinical follow-up at 12 months in 95.5% (N=43) DUS and clinical follow-up at 12 months in 91.1% (N=41) nSES: nitinol self-expanding stents *Excluded from stent based primary analysis

7. COBRA Trial Inclusion Criteria Exclusion Criteria • Diabetics, insulin or non-insulin dependent above 21 years of age • Severe intermittent claudication (RB stage 3), chronic critical limb ischemia with rest pain (RB stage 4), or chronic critical limb ischemia with ischemic ulcers (RB stage 5) • SFA nSES length ≥ 60 mm • SFA nSES diameter ≥ 5 mm • Serum creatinine ≥ 2.0 mg/dl • Absence of at least 1 vessel brisk infra-popliteal run-off to the foot • LV ejection fraction ≤ 25% • Allergy to iodinated contrast • Allergy to aspirin or clopidogrel • Relative or absolute contraindication to anticoagulation • WBC < 3,000K/UL; platelet count < 100,000K/UL; Hgb < 10 g/dl Sample size calculation: assuming 65% and 35% restenosis with conventional balloon and cryoplasty treatments and 10% attrition, for an alpha = 0.05 and power =80%, 43 vascular segments would be needed in each treatment arm1 1Banerjee et al, Am J of Cardiology; 2009

8. COBRA Trial Baseline Characteristics MI: myocardial infarction

9. COBRA Trial Baseline Characteristics ACEI: angiotensin converting enzyme inhibitor ARB: angiotensin receptor blocker

10. COBRA Trial Procedural Characteristics ABI: ankle-brachial index

11. COBRA Trial PolarCath® Post-dilation of nSES CTO crossing Mid SFA CTO Confirmation 2v run-off Polarcath® postdil Final result Procedural success 100% Mean fluoroscopy time 31.82 ± 20.30 min Mean ACT 238.21 ± 32.31 UFH 79% Procedural adverse events 8.9% (Cryo.) 6.7% (Conv.) ACT: activated clotting time UFH: unfractionated heparin

12. COBRA Trial Primary endpoint: 12m binary restenosis 60% p=0.01 55.8% 40% 29.3% 20% Cryoplasty Balloon Post-dilation n=41 Conventional Balloon Post-dilation n=43

13. COBRA Trial Cumulative hazard of restenosis HR=2.39, 95% CI 1.19 – 4.78 p<0.01 Conventional Cryoplasty Cumulative hazard of restenosis Time (in days) Cryoplasty 45 45 45 43 39 35 33 Conventional 45 44 42 36 32 29 21 ACT: activated clotting time UFH: unfractionated heparin

14. COBRA Trial Change in ABI from baseline at 12m p=0.66 Baseline 12m Baseline 12m Conventional Balloon Post-dilation Cryoplasty Balloon Post-dilation ABI: ankle-brachial index

15. COBRA Trial Change in WIQ* from baseline at 12m p=0.005 p=0.002 Baseline 12m Baseline 12m Conventional Balloon Post-dilation Cryoplasty Balloon Post-dilation *Walking impairment questionnaire score

16. COBRA Trial SFA Chronic total occlusion 12m binary restenosis 90% p=0.06 60% 70.0% 36.0% 30% Cryoplasty Balloon Post-dilation n=25 Conventional Balloon Post-dilation n=20

17. COBRA Trial Cumulative hazard of restenosis (Non-CTO vs. CTO) HR=3.61, 95% CI 0.99 –13.18; p= 0.05* Conventional CTO Conventional non-CTO Cryoplasty CTO Cryoplasty non-CTO HR=2.69, 95% CI 0.74 – 9.85; p=0.13* Cumulative hazard of restenosis HR=2.65, 95% CI 0.72 – 9.80; p=0.15* Reference Group Time (in days) *Comparedtoreferencegroup

18. COBRA Trial Bilateral SFA nSES Implants 12m binary restenosis 90% p=0.03 60% 66.7% 26.7% 30% Cryoplasty Balloon Post-dilation n=15 Conventional Balloon Post-dilation n=15 Analysis excludes 1 patient with same treatment to B/L LE

19. COBRA TrialCryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For Revascularization of Peripheral Arterial Segments Conclusions In patients with diabetes mellitus presenting with life-style limiting claudication, post-dilation of nitinol self-expanding stents in the SFA using PolarCath®cryoplasty significantly reduced 12-month in-stent restenosis compared to conventional balloon post-dilation These results indicate the potential impact of stent post-dilation strategies on endovascular treatment of symptomatic peripheral arterial disease

20. COBRA TrialCryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For Revascularization of Peripheral Arterial Segments Acknowledgements: Tayo Addo, MD DSMB chair Bertis Little, PhD DSMB member Kevin Kelly, PharmD DSMB member Rick Weideman, PharmD DSMB member Ravi Sarode, MD DSMB member Christopher Lichtenwalter, MD Core laboratory analysis Lorenza Makke, RVT Core laboratory analysis Preeti Kamath, BDS, MHALead study coordinator Daniel Tran, MSc Data manager Boston Scientific Corporation Research grant support Dallas VA Research Corp. Research administration