1. Patient Related OuTcomes with Endeavor versus Cypher Stenting Trial:
4 Year Outcomes
Laura Mauri, MD
On Behalf of the PROTECT Investigators
Good evening, it is my pleasure , on behalf of my co-investigators, to present the PROTECT Trial 4 year outcomes

2. Disclosure Statement of Financial Interest Laura Mauri, MD
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
Grant/Research Support to institution
Consulting Fees/Honoraria
Major Stock Shareholder/Equity
Cordis, Medtronic, Abbott Vascular, Boston Scientific, Eli Lilly, Daiichi Sankyo, Bristol-Myers Squibb, and Sanofi-aventis
Medtronic, St. Jude Medical, Biotronik
None

3. Study Objective
The PROTECT trial is a broadly inclusive international randomized trial comparing the Endeavor Zotarolimus-eluting stent (E-ZES) with the Cypher Sirolimus-eluting stent (SES) with respect to definite or probable stent thrombosis at 3 years after coronary stent implantation.

4. Study Design
Largest RCT & First Trial Powered for Comparing ST with DES
Initialization Committee: E. Camenzind, G. Steg and W. Wijns
Real-world patients
Single and multiple coronary artery lesions
No limitations on number of lesions/vessels
N = 8800
1:1 Randomization
196 sites world wide
in 5 continents
Endeavor ZES
n = 4400
Cypher SES
n = 4400
Clinical endpoints
30d
6mo
12mo
18mo
24mo
30mo
3yr
4yr
5yr
Primary Endpoint: Composite of ARC Definite / Probable Stent Thrombosis at 3 years
Principle Secondary Endpoints at 3 years:
Total Death/Large MI
Total Death/Non-Fatal MI
Cardiac Death/Large MI
Cardiac Death/Non-Fatal MI
This was designed as a very inclusive study, the first study powered for a primary endpoint of stent thrombosis with 8800 subjects enrolled. Today I will present the 4 year outcomes.
The primary endpoint was x, there were several principle secondary endpoints, tested sequentially including death and large MI.
Camenzind E, et al. Am Heart J. 2009;158:902-9

5. Historic Perspective Definite / Probable Stent Thrombosis
ENDEAVOR Pooled
Bern - Rotterdam
PES 10.4% 5
Endeavor ZES 10
Driver BMS 4
P = 0.10 8
SES 7.6% 3 6
Cumulative Incidence of ARC
Def/Prob Stent Thrombosis (%) 2 4
1.5%
1.7%
The hypothesis to be tested was whether the difference in drug and polymer between endeavor and the first DES, such as Cypher would translate to differences in safety. This was conceived in the setting of observational analysis showing 1. the safety of the Endeavor stent over long term follow up, with low stent thrombosis rates, and the ongoing risk that appeared to be associated with the first DES, particularly in real work practice. 1
0.7%
0.9% 2 1 2 3 4 5 6 12 18 24 30 36 42 48
Time After Initial Procedure (Years)
Months After Index PCI
Mauri L., et al. JACC Cardiovasc Interv Dec;3(12):
Räber L., et al. Circulation. 2012;125: 5 5

6. Patient Eligibility Criteria
Inclusion of a Broad Patient Population
Inclusion Criteria
Clinically relevant coronary artery disease
Silent ischemia
Stable angina
Acute coronary syndrome including UA, NSTEMI and STEMI
Lesion characteristics
Number of lesions: max 4
Number of vessels: no limitation
Lesion length: no limitation
Qualify for implantation of DES
Eligible for both stent systems
Written informed consent
Exclusion Criteria
Pregnancy
Hypersensitivity / allergy to any of the drugs or components
Antiplatelet therapy
Contraindicated
Expected non-compliance
Planned elective surgery necessitating discontinuation
Warfarin
Medical condition
Previous brachytherapy
Previous implantation of DES
Implantation of BMS in past 12mo
Planned intervention of other non-cardiac vessels
Acute severe heart failure (Killip III-IV)
Life expectancy < 3yrs
Participation in another trial
Previous transplant
As such – the trial was designed with few exclusion criteria
Patients with ACS and STEMI were enrolled and there was no limit on number of vessels or lesion length.
Only patients unable to tolerate DAPT, with prior brachytherapy or stents, or severe heart failure were excluded.
Camenzind E, et al. Am Heart J. 2009;158:902-9

7. Australia & New Zealand
World-Wide Enrolment
8709 Patients from 196 Sites
Europe
Western – 3444 pts / 60 sites
Central – 1576 pts / 33 sites
Southern – 683 pts / 24 sites
Eastern – 392 pts / 9 sites
Northern – 264 pts / 6 sites
US & Canada
230 pts / 19 sites
Asia
1245 pts / 19 sites
Middle East
326 pts / 7 sites
Enrollment was global, and rapid spanning 5 continents and nearly 200 sites
South America
50 pts / 3 sites
Australia & New Zealand
499 pts / 16 sites
Camenzind E, et al. Am Heart J. 2009;158:902-9

8. Dual Anti-Platelet Therapy (DAPT)
Protocol Policy
Recommended DAPT therapy:
DAPT of Aspirin and Thienopyridine (clopidogrel)
Per instructions for use or guidelines: 3 – 12 months
At physician discretion
No precise duration mandated by the protocol
Consistent policy per site for both arms
Each site specified DAPT policy before site enrollment
Drugs, doses (loading, maintenance), duration
Site DAPT policy the same in both arms to ensure comparability
Was designed as a pragamatic study. The duration of therpay of DAPT was per site policy, with the request that each site use a uniform duration across the two treatment arms to ensure that the randomized comparison was one of stent type rather than drug-duration.
Camenzind E, et al. Am Heart J. 2009;158:902-9

9. Primary Endpoint Power Calculation1
Primary Endpoint: ARC Definite / Probable ST at 3 Years
Assumptions
Event rates at 3 years:
2.5% for C-SES2,3,4
1.5% for E-ZES5 (hazard ratio 0.60)
Two-sided type I error of 0.05
8800 patients yields 90% power to detect superiority
2 Spaulding C, et al. N Engl J Med. 2007;356:
SES ARC ST rates (N=878):
Early: 0.5%
Late: 0.3%
VLST: 2.8%
Def: 1.2%
Def/Prob: 1.5%
Def/Prob/Poss: 3.6%
3 Daemen J, et al. Lancet. 2007;369:
SES (N=3823) – angiographically confirmed ST (=ARC definite ST)
1yr: 1.7%
2yrs: 2.3%
3yrs: 2.9%
“Cumulative incidence curve between 30-days and 3 yrs was 0.6% per year”
4 Mauri L, et al. N Engl J Med. 2007; 356:
SES ARC Def/Prob ST rates (N=878):
Early: 0.6%
Late: 0.1%
VLST: 0.9%
“The incidence of definite or probable events occurring 1 to 4 years after implantation was 0.9% in the sirolimus-stent group”
5 Fajadet J, et al. EuroIntervention. 2010;6:
E-ZES ARC def/prob ST:
1yr: 0.7%
5yr: 0.9%
1 Camenzind E, et al. Am Heart J. 2009;158:902-9.
2 Spaulding C, et al. N Engl J Med. 2007;356:
3 Daemen J, et al. Lancet. 2007;369:
4 Mauri L, et al. N Engl J Med. 2007; 356:
5 Fajadet J, et al. EuroIntervention. 2010;6:562-7.

10. Patient Flow Chart Randomised 1:1 1 Yr Follow-up 2 Yr Follow-up
Patients Enrolled
N = 8709
Endeavor (E-ZES)
N = 4357
Cypher (SES)
N = 4352
Randomised 1:1
n = 4325
99.3%
n = 4305
98.9%
1 Yr Follow-up
n = 4305
98.8%
n = 4286
98.5%
2 Yr Follow-up
n = 4271
98.0%
n = 4261
97.9%
3 Yr Follow-up
n = 4217
96.8%
Follow has been excellent at >96% at 4 years.
It is ongoing for the final time point of 5 year.s
n = 4215
96.9%
4 Yr Follow-up 10

11. Patient Demographics Endeavor ZES N = 4357 Cypher SES N = 4352 P-value%
Endeavor ZES
N = 4357
Cypher SES
N = 4352
P-value
Age (yr)
62.3 ± 10.6
62.1 ± 10.7
0.50
Male
76.7
76.0
0.48
Diabetes mellitus
26.9
28.4
0.13
IDDM
6.5
7.4
0.11
Current smoker
24.9
25.2
0.71
Prior MI
20.3
20.8
0.53
Prior PCI
12.3
12.8
Prior CABG
4.6
5.1
0.21
Procedure indication
Silent ischemia
6.4
0.93
Stable angina
49.5
48.3
0.27
Unstable angina
18.3
19.3
Myocardial infarction (MI)
25.8
26.0
0.85
Acute MI within 72h
14.0
14.7
0.39
Patient characteristics were well-balanced and represent an all comers population with a relatively high frequency of MI, and acute MI.
Camenzind E, et al. Lancet. 2012; 380: 1396–405

12. Lesion / Procedure Characteristics%
Endeavor ZES
N = pts
6151 lesions
Cypher SES
N = 4352 pts
6140 lesions
P-value
RVD (mm)
2.98 ± 0.47
2.96 ± 0.47
0.03
Diameter stenosis (%)
82.8 ± 13.0
82.8 ± 12.8
0.80
Lesion length (mm)
17.7 ± 9.3
17.7 ± 9.0
0.73
B2/C lesions
53.7
55.7
0.02
Bifurcation
16.9
15.9
0.15
Thrombus
7.6
7.9
0.52
Multiple vessels treated
18.4
19.4
0.27
Multiple lesions treated
30.4
30.2
0.89
Number of lesions treated per patient
1.40 ± 0.71
1.39 ± 0.71
0.85
Number of stents per patient
1.63 ± 0.99
1.59 ± 0.96
0.06
Total stent length / patient (mm)
31.28 ± 20.80
31.20 ± 20.77
0.86
Elevated stent thrombosis risk present*
58.0
58.1
0.93
Complex lesions were well-represented, and 58% of subjects had at least on stent thrombosis risk factor.
*ST Risk Factors: bifurcation, bypass grafts, ISR, AMI <72 hr, LVEF <30%, unprotected LM, >2 vessels stented, renal insufficiency or failure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or total occlusion (preprocedure TIMI = 0).
Camenzind, et al. Lancet. 2012; 380: 1396–405

13. Time After Initial Procedure (months)
DAPT Usage
Endeavor ZES (N = 4357)
Cypher SES (N = 4352)
Patients on DAPT (%)
As intended, the duration of antiplatelet therapy did not differ between treatment arms. After the first year, a minority of patients remained on DAPT, with about 27% on DAPT at 4y.
Time After Initial Procedure (months)
P-value is not-significant between treatment arms at each time point.

14. Anticipated Event Rates at 3 Years
Primary Endpoint
Definite / Probable Stent Thrombosis
Anticipated Event Rates at 3 Years 3 2
Event Rate (%)
2.5
The primary endpoint results were presented at ESC in 2012 and published in the Lancet.
Compared with the projected rates, shown here… 1
1.5
Endeavor™ ZES
Cypher™ SES

15. Primary Endpoint Definite / Probable Stent Thrombosis 2.55 1.79 1.57
3 Year Outcomes
Log Rank P = 0.224
4 Year Outcomes
Log Rank P = 0.003 3
2.55 2
1.79
Event Rate (%)
1.57
1.42
2.5
…the 3 year event rates fell short of statistical significance.
However at 4 years, a prospectively planned annual follow up, there is a nearly 1% absolute difference in stent thrombosis rate, favoring Endeavor with a p value for difference of 0.003 1
1.5
67/4217
61/4357
106/4215
75/4352
Endeavor™ ZES
Cypher™ SES

16. Primary Endpoint Definite / Probable Stent Thrombosis 2.55% 1.57% 5%
Endeavor ZES (N = 4357)
Cypher SES (N = 4352)
P = 0.003
HR 0.63 (0.46 – 0.85) 4% 3%
Cumulative Incidence of
ARC Definite / Probable ST
2.55% 2%
1.57% 1%
You can see from the Kaplan Meier curve that there was separation of events at the three year time point; however it was not until an additional year of data was accrued that this reached statistical significance, and actually represents quite a change in the relative hazards. With a HR of 0.63, e.g. a 37% relative risk reduction associated with Endeavor, with a p value of 0% 1 2 3 4
Time After Initial Procedure (Years)
Patients at Risk
E-ZES
4357
4347
4230
4140
4025
C-SES
4352
4344
4212
4108
3979

17. Main Secondary Endpoints
Outcomes at 4 Years
All Death / Large MI
All Death / All MI 15 15
Cypher SES
Endeavor ZES
Cypher SES
Endeavor ZES
P = 0.017
HR 0.85 (0.74 – 0.97)
P = 0.024
HR 0.84 (0.71 – 0.98)
10.8
9.2 10 10
8.0
6.7
Cumulative Incidence of Events (%)
Cumulative Incidence of Events (%) 5 5 1 2 3 4 1 2 3 4
Time After Initial Procedure (years)
Time After Initial Procedure (years)
Cardiac Death / Large MI
Cardiac Death / All MI 15 15
This difference in very late st translated to a difference in very late death and MI. These were not periprocedural differences, as has been previously been shown for the thin strut Endeavor stent vs Cypher, but these are late large spontaneous MI.
Cypher SES
Endeavor ZES
Cypher SES
Endeavor ZES
P = 0.015
HR 0.78 (0.65 – 0.95)
P = 0.015
HR 0.83 (0.71 – 0.96) 10 10
8.4
6.9
Cumulative Incidence of Events (%)
Cumulative Incidence of Events (%)
5.4
4.2 5 5 1 2 3 4 1 2 3 4
Time After Initial Procedure (years)
Time After Initial Procedure (years)

18. Other Endpoints at 4 Years%
Endeavor ZES
n = 4217
Cypher SES
n = 4215
P-value
Death (all)
5.6
6.1
0.33
Cardiac death
2.9
3.4
0.24
MI (all)
4.6
5.8
0.015
Target vessel MI
4.0
5.0
0.027
Q-wave
1.2
1.9
0.013
Non Q-wave
3.5
4.1
0.14
Stroke
0.6
0.4
0.44
Bleeding (TIMI major/ minor/ minimal)
5.5
5.2
0.60
Major (TIMI)
2.2
2.0
0.65
TLR (clinically driven)
6.0
4.5
0.002
TVR
9.1
8.6
MACE (death, MI, TLR, emergent CABG)
14.3
14.0
0.68
MACCE (death, MI, TLR, eCABG, Stroke)
15.6
15.3
0.70
In fact you can see that there was a 1% absolute difference in TV MI, mostly driven by Q wmi.
There is a difference in TLR favoring Cypher, yet TVR was not different.

19. Events Associated with ST
Contribution of ST to Cardiac Death & MI
0 – 4 Yrs
1.57%
67/4217
106/4215
2.55% 54 89 45 80
Cardiac D
Stent Thrombosis
ARC Def/Prob
Total Number of
Associated Events MI 26 29
Cardiac D/MI
E-ZES
SES
The absolute number and the risk of stent thrombosis was higher for Cypher vs Endeavor.
We looked at the presentation and sequelae of stent thrombosis for each stent type, and according to the timing of presentation.
For both types of stents the majority of events were associated with cardiac death or MI, and the pattern of associated events was similar.
For both before one year, and very late (beyond one year) events, the presentation was similar.
Therefore, the difference in the 4 year primary endpoint of stent thrombosis translated directly to the difference in death and MI seen to favor Endeavor at 4 year.s
0 – 1 Yr
1 – 4 Yrs 15 59 62
Total Number of
Associated Events 18 32 39 14 21 27 8 13 15
E-ZES
SES
E-ZES
SES

20. Conclusion
The 4-year follow-up demonstrates a significantly lower rate of stent thrombosis in E-ZES (1.57%) compared with C-SES (2.55%), HR 0.63, p=0.003.
This translated to a difference in TVMI of 1% and a relative risk reduction in All death / Large MI of 16%, driven by a reduction in late, spontaneous Q wave MI
This is the first time any DES showed superiority over C- SES on hard clinical endpoints.
The reliable assessment of the efficacy and safety of any permanently implanted device such as a stent requires a well-powered, long-term study.