eluting Stents The SPIRIT Trials

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1 Everolimus-eluting eluting Stents The SPIRIT Trials Gregg W. Stone, MD Columbia University Medical Center Cardiovascular Research Foundation

2 Abbott XIENCE V Everolimus-eluting eluting Stent Everolimus Durable Fluoropolymer ML VISION Stent Platform ML VISION Stent Delivery System SPIRIT Clinical Trials

3 Everolimus A Sirolimus Analog Sirolimus (Rapamycin) Everolimus H O HO O FKBP Binding domain O O N H O O O H O O O O O O O O O HO N O O O O O HO O O O Formula C H 79 NO ; MW: C H 83 NO ; MW: Original Indications Approvals Acute Rejection Kidney, Liver OUS & US Acute & Chronic Rejection Heart, Kidney, Lung OUS; US approvable

4 Coating Integrity XIENCE V Fluoropolymer (7.8 um thick) Dilated to 3.5 mm Uniform, consistent coating integrity upon deployment Good adhesion to stent no bonding, webbing, tearing Non-tacky drug matrix prevents unwanted adhesions Photos taken by and on file at Abbott Vascular

5 DES Strut and Polymer Thickness 3.0 mm diameter stents,, 500x magnification CYPHER TAXUS ENDEAVOR XIENCE V Strut Thickness: Strut Thickness: Strut Thickness: Strut Thickness: 140 µm Polymer Thickness: 12.6 µm Total: um 132 µm Polymer Thickness: 16 µm Total: 148 um 91 µm Polymer Thickness: 5.3 µm Total: 96.3 um 81 µm Polymer Thickness: 7.8 µm Total: 88.8 um Strut thickness per manufacturer s s published specifications. Data on file at Abbott

6 14 Day Endothelialization: Rabbit Iliac Model XIENCE V CYPHER TAXUS ENDEAVOR c/o R. Virmani,, submitted

7 SPIRIT Family of Trials (N=10,430) SPIRIT First RCT Safety and performance, Europe N = 60 2 year F/U completed SPIRIT II RCT Clinical support for CE launch N = year F/U completed SPIRIT III RCT Pivotal RCT with parallel registries, US & Japan N = 1,380 9 month RCT F/U completed SPIRIT IV RCT SPIRIT V RCT and Reg SPIRIT Women RCT and Reg Continued safety and performance RCT, US N = 3,690 Enrollment started Q3 06 OUS Registry N = 2700 Diabetic RCT N = 300 pts randomized 2:1 vs Taxus Enrollment started: Q4 06 OUS Registry + RCT N = 1550 pt registry RCT 450 pts randomized 2:1 vs Cypher Spirit VI US post market approval registry all comers (n=5000)

8 SPIRIT First: Study Design SPIRIT First Single de novo Lesions mm, 12 mm length n = 60 1 : 1 XIENCE V Everolimus Eluting Coronary Stent (n=28) ML VISION Control (n=32) Prospective, randomized, single-blind trial Stent Size: 3.0 x 18 mm Clinical follow-up: 1, 6, 9, and 12 months, 2, 3, 4, 5 years Angio and IVUS follow-up: 6 & 12 months Clopidogrel: 3 months Bailout only with BMS Only animal data on single stent available at the onset of the study Angiographic and IVUS core lab: Cardialysis Enrollment Complete: April 1, 2004 PI: Patrick Serruys,, MD, PhD Serruys PW et al. EuroInt 2005; 1:58-65

9 SPIRIT First: In-Stent LL at 6 and 12 Mos Cumulative Frequency (%) XIENCE V (n=22) 6 Mo 12 Mo Control (n=25) 6 Mo 12 Mo XIENCE V 6Mo: XIENCE V 12Mo: Control 6Mo: Control 12Mo: 0.10 ± ± ± ± Late Loss (mm)

10 SPIRIT II Trial (N=300) A maximum of two de novo lesions (1 lsn/artery) mm 28 mm N = : 1 XIENCE V N = 223 TAXUS Control N = 77 Prospective, single blind, randomized trial Stent sizes: mm; Stent lengths: 8, 18, 28 mm Angio FU: 6 months in all pts; 2 years in 152 pts IVUS FU: 6 months and 2 years in 152 pts Clinical follow-up at 1, 6, 9 months, 1 and 2 years 6 months clopidogrel for both arms Primary endpoint: In-stent late loss at 6 months (NI) Serruys PW. EuroInterv 2006;2:

11 Primary Endpoint: In-stent LL (Analysis lesion, 6 months) % of lesions XIENCE V TAXUS 0.11 ± 0.27 (n = 201) 0.36 ± 0.39 (n = 73) Non-inferiority p< Superiority p< In-stent late loss (mm) Angiographic 6-mo 6 FU: XIENCE V: 91%; TAXUS: 95%

12 Clinical Results at 12 Months P=0.04 Event rate (%) P=0.11 P=0.053 MACE = cardiac death, MI, ischemia-driven TLR Ruygrok P et al. ACC2007

13 SPIRIT III Study Algorithm 1002 pts enrolled at 65 U.S sites RVD 2.5 mm mm; Lesion length 28 mm Max. 2 lesions each in a different epicardial vessel Pre-rand: rand: ASA 300 mg, clopidogrel 300 mg load unless on chronic Rx Randomized 2:1 XIENCE V:TAXUS Stratified by diabetes and intent for 1 vs. 2 lesion treatment Pre-dilatation mandatory Everolimus-eluting eluting XIENCE V Paclitaxel-eluting eluting TAXUS Aspirin 80 mg QD for 5 years; Clopidogrel 75mg QD for 6 6 months Clinical f/u: : 1, 6, 9 months and yearly for years Angio f/u 8 mos; ; IVUS f/u 8 mos

14 Patient Flow - Clinical Randomized (N=1,002) XIENCE V (N=669) Lost to f/u = 8 Patient withdrawal = 3 TAXUS (N=333) 7 = Lost to f/u 4 = Patient withdrawal 9 month follow-up * (N=980; 98%) XIENCE V (N=658) TAXUS (N=322) *F/U window ±14 days

15 Patient Flow - Angiographic Randomized (N=564) XIENCE V (N=376) Lost to f/u = 3 Patient withdrawal = 2 Death = 2 No qualifying angio = 67 TAXUS (N=188) 3 = Lost to f/u 3 = Patient withdrawal 1 = Death 37 = No qualifying angio 8 month angio F/U * (N=436; 77%) XIENCE V (N=302) TAXUS (N=134) *F/U window: ± 28 days

16 Baseline Demographics XIENCE V 669 pts TAXUS 333 pts P value Age (in years) 63.2 ± ± Male (%) Hypertension (%) Hypercholesterolemia (%) Diabetes mellitus (%) Insulin requiring (%) Current smoker (%) Prior MI (%) Unstable angina (%)

17 Baseline Angiography XIENCE V 767 lesions TAXUS 382 lesions P value Lesion location LAD 41.3% 42.9% 0.61 LCX 27.6% 28.3% 0.83 RCA 31.0% 28.5% 0.41 LMCA 0.1% 0.3% 0.55 QCA RVD (mm) 2.77 ± ± MLD (mm) 0.82 ± ± % DS 70.0 ± ± Lsn length (mm) 14.7 ± ±

18 Procedural Results XIENCE V 669 pts 768 lesions TAXUS 332 pts 382 lesions P value # lesions/pt* 1.2 ± ± lesion pts* 15.4% 15.4% 1.0 # stents/pt 1.3 ± ± # stents/lesion 1.2 ± ± Max. stent diameter/lesion (mm) 3.0 ± ± Max. stent diameter/rvd 1.1 ± ± Total stent length/lesion 22.8 ± ± Total stent length/lesion length 1.6 ± ± Maximum pressure (atm.) 14.8 ± ± 2.6 <0.05 * All vessels had a single lesion except 5 pts in whom a single vessel had two lesions Of 1,322 total stents implanted, 8 were non study stents

19 % of Lesions 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% *F/U window ±28 days. Primary Endpoint: In-segment LL at 8 Months* (Analysis Lesion) TAXUS: 0.28 ± 0.48 (n=134) XIENCE V: 0.14 ± 0.41 (n=301) In-segment Late Loss (mm) P NI < P SUP = 0.004

20 Late Loss at 8 Months* XIENCE V 301 patients TAXUS 134 patients P value Analysis lesion 301 lesions 134 lesions In-segment 0.14 ± ± In-stent 0.16 ± ± All lesions 343 lesions 158 lesions In-segment 0.14 ± ± In-stent 0.16 ± ± *F/U window ±28 days.

21 Binary Restenosis at 8 Months* P=0.07 P=1.0 P=0.06 P= /344 14/158 9/315 4/143 8/343 9/158 3/334 2/155 *F/U window ±28 days.

22 IVUS In-stent Measures at 8 Months* P=0.04 ±31.3 P=0.01 ±9.9% ±11.4 ±6.4% *F/U window ±28 days.

23 IVUS Incomplete Apposition (Paired lesion serial analysis) XIENCE V 90 lesions TAXUS 43 lesions P value Post procedure 34.4% 25.6% months 25.6% 16.3% 0.27 Resolved 8.9% 9.3% 1.0 Persisting 24.4% 14.0% 0.18 Late acquired 1.1% 2.3% 0.54 IVUS performed in only 1 pt with stent thrombosis, showing no incomplete apposition either post procedure or at FU

24 TVF and MACE Through 270 Days* RR [95% CI] = 0.79 [0.51, 1.23] P NI < SUP =0.31 P SUP RR [95% CI] = 0.56 [0.34, 0.94] SUP = P SUP Rate (%) XIENCE V (657 pts) TAXUS (321 pts) 47/657 29/321 30/657 26/321 TVF MACE *F/U window ±14 days. TVF = Cardiac death, MI, ischemia-driven TVR. MACE = Cardiac death, MI, ischemia-driven TLR.

25 TVF Through 284 Days HR=0.79 [ ] P logrank = % 7.2% TVF (%) Days

26 MACE Through 284 Days MACE (%) HR=0.56 [ ] P logrank = % 4.6% Days

27 TVF Components Through 270 Days* P=0.67 P=0.64 P=0.053 P=0.45 P=0.47 *F/U window ±14 days.

28 Ischemia-driven TLR Through 284 Days Rate (%) HR=0.52 [ ] P logrank = % 2.6% Days

29 Safety Endpoints at 270 Days* XIENCE V (658 pts) TAXUS (322 pts) P=0.55 P=1.0 P=0.64 P= % 2.5% 2.7% 2.0% Q=0 Q= % 0.9% 0.46% L=0.15 E= C=0.5 C=0.6 NC=0.5 NC=0.3 NQ=1.8 NQ=2.5 Stent thrombosis Death MI Death or MI *F/U window ±14 days. E = early ( 30d);( L = late (>30d-9mo); C = cardiac; NC = non cardiac; Q = Q-wave; Q NQ = non Q-waveQ

30 SPIRIT II and SPIRIT III RCTs: MACE 12 months 9 months P=0.04 P=0.03 P=0.003 MACE rate (%) N=220 N=76 N=658 N=322 N=878 N=398 MACE = cardiac death, MI, ischemia-driven TLR

31 SPIRIT II and SPIRIT III RCTs: Safety 12 months 9 months Event rate (%) P=1.0 P=0.38 P=0.34

32 SPIRIT II and SPIRIT III: Ischemic TLR 12 months 9 months Ischemic TLR rate (%) P=0.053 P=0.053 P=0.01 N=220 N=76 N=658 N=322 N=878 N=398

33 SPIRIT II and SPIRIT III: All TLR 12 months 9 months All TLR rate (%) P=0.065 P=0.004 P< N=220 N=76 N=658 N=322 N=878 N=398

34 SPIRIT II and SPIRIT III Pooled: Restenosis 6 months 8 months Binary restenosis rate (%) P=0.02 P=0.03

35 SPIRIT IV Trial Expansion* Proposal for expansion submitted to FDA Randomized (N=3,690) *Previously 1,125 pts XIENCE V (N=2,460) 2 1 Single blind No angiographic FU TAXUS (N=1,230) Up to 3 lesions in 1, 2 or 3 separate vessels (2 max per vessel) Primary endpoint: MACE at 9 months (cardiac death, MI, ischemia-driven TLR) Sequential noninferiority and superiority testing Noninferiority power analysis: 8.2% common event rate, δ = 2.7%, 1-sided α = % power (allowing for 2.5% drop-out) out) If primarily powered for superiority : 8.2% rate with TAXUS, 4.8% rate with XIENCE V (absolute 3.4% reduction, relative 41.5% reduction), 2-sided α = % power (allowing for 2.5% drop-out) out)

36 Everolimus-eluting eluting XIENCE V stents Conclusions A polymer-based, 2 nd generation DES with optimal characteristics - Thin, robust, durable, non-adhesive polymer - Everolimus low late loss and %VO CoCr struts excellent deliverability Extensive animal testing excellent safety profile Extensive clinical investigation safe and effective for typical on-label DES lesions