R elated O u T comes with E ndeavor versus C ypher Stenting T rial 4 Year Outcomes Laura Mauri MD On Behalf of the PROTECT Investigators Disclosure Statement of Financial Interest ID: 534520
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Slide1
Patient Related OuTcomes with Endeavor versus Cypher Stenting Trial: 4 Year OutcomesLaura Mauri, MDOn Behalf of the PROTECT InvestigatorsSlide2
Disclosure Statement of Financial Interest Laura Mauri, MDWithin the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
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, BiotronikNone
Affiliation/Financial Relationship
CompanySlide3
Study ObjectiveThe 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.Slide4
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
Endeavor
ZES
n = 4400
Study Design
Largest RCT & First Trial Powered for Comparing ST with DES
Initialization Committee: E. Camenzind, G.
Steg
and W.
Wijns
Cypher
SES
n = 4400
6mo
4yr
3yr
30mo
18mo
24mo
12mo
Clinical endpoints
5yr
30d
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
Camenzind E, et al.
Am Heart J
. 2009;158:902-9Slide5
Historic Perspective0
2
4
6
8
10
0
6
12
18
24
30
36
42
48
Months
After Index PCI
PES 10.4
%
SES 7.6
%
Cumulative Incidence
of ARC
Def
/
Prob
Stent Thrombosis (%)
5
3
0
0
1
2
3
4
5
Time After Initial Procedure (Years)
4
2
1
P
= 0.10
1.7%
0.9%
Driver BMS
Endeavor ZES
0.7%
1.5%
Definite / Probable Stent Thrombosis
ENDEAVOR Pooled
Bern - Rotterdam
Räber
L., et al.
Circulation
. 2012;125:1110-1121.
Mauri L., et al.
JACC
Cardiovasc
Interv
.
2010 Dec;3(12):1240-9.Slide6
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 limitationLesion length: no limitationQualify for implantation of DES Eligible for both stent systems
Written informed consent
Exclusion CriteriaPregnancy
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 vesselsAcute severe heart failure (Killip III-IV)Life expectancy < 3yrsParticipation in another trialPrevious transplantPatient Eligibility Criteria
Inclusion of a Broad Patient Population
Camenzind E, et al.
Am Heart J
. 2009;158:902-9Slide7
World-Wide Enrolment8709 Patients from 196 Sites
Camenzind E, et al.
Am Heart
J
. 2009;158:902-9
South America
50
pts
/ 3
sites
US & Canada
230
pts
/ 19
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
Asia
1245
pts
/ 19
sites
Middle East
326
pts
/ 7 sites
Australia & New Zealand
499
pts
/ 16
sitesSlide8
Dual Anti-Platelet Therapy (DAPT)Recommended DAPT therapy:DAPT of Aspirin and Thienopyridine (clopidogrel)Per instructions for use or guidelines: 3 – 12 monthsAt physician discretionNo precise duration mandated by the protocolConsistent policy per site for both armsEach site specified DAPT policy before site enrollmentDrugs, doses (loading, maintenance), duration Site DAPT policy the same in both arms to ensure comparability
Protocol Policy
Camenzind E, et al.
Am Heart J
. 2009;158:902-9Slide9
Primary EndpointPower Calculation1
1
Camenzind
E, et al.
Am Heart J
. 2009;158:902-9.2 Spaulding C, et al.
N Engl J Med. 2007;356:989-97.3 Daemen J, et al. Lancet. 2007;369:667-78.4 Mauri L, et al. N Engl J Med. 2007; 356:1020-9.5 Fajadet J, et al. EuroIntervention. 2010;6:562-7.
Primary Endpoint: ARC Definite / Probable ST at 3 YearsAssumptionsEvent rates at 3 years:
2.5% for C-SES
2,3,4
1.5% for E-ZES
5
(hazard ratio 0.60)
Two-sided type I error of 0.05
8800 patients
yields 90% power to detect superioritySlide10
Randomised 1:1
Endeavor (E-ZES)
N = 4357
n =
4325
99.3%
n =
4305
98.8%
Patients EnrolledN = 8709
Cypher (SES)
N = 4352
n =
4305
98.9%
n =
4286
98.5%
n =
4271
98.0
%
n =
4261
97.9%
1 Yr Follow-up
2
Yr
Follow-up
3
Yr
Follow-up
Patient Flow Chart
n =
4217
96.8%
n =
421596.9%
4 Yr Follow-upSlide11
Patient Demographics%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
0.48
Prior CABG
4.6
5.1
0.21
Procedure indication
Silent ischemia
6.5
6.4
0.93
Stable angina
49.5
48.3
0.27
Unstable angina
18.3
19.3
0.21
Myocardial infarction (MI)
25.8
26.0
0.85
Acute MI within 72h
14.0
14.7
0.39
Camenzind E, et al.
Lancet.
2012; 380: 1396–405Slide12
Lesion / Procedure Characteristics%Endeavor
ZES
N = 4357
pts
6151 lesions
Cypher SES
N = 4352 pts
6140 lesionsP-valueRVD (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 ± 20.8031.20 ± 20.770.86Elevated stent thrombosis risk present
*
58.0
58.1
0.93
*
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: 1396–405Slide13
Time After Initial Procedure (months)DAPT UsagePatients on DAPT (%)Endeavor ZES (N = 4357)
Cypher SES (N = 4352)
P-value is not-significant between treatment arms at each time point.Slide14
Primary EndpointAnticipated Event Rates at 3 YearsEvent Rate (%)
1.5
2.5
0
1
2
3
Endeavor
™
ZES
Cypher
™
SES
Definite / Probable
Stent
ThrombosisSlide15
Event Rate (%)Endeavor™ ZESCypher™ SES
1.5
2.5
0
1
2
3
1.42
1.79
Primary Endpoint
Log
Rank
P
=
0.224
Definite / Probable
Stent
Thrombosis
61/4357
75/4352
1.57
Log
Rank
P
=
0.003
67/4217
2.55
106/4215
3 Year Outcomes
4 Year OutcomesSlide16
Definite / Probable Stent Thrombosis
Time After Initial Procedure (Years)
Cumulative
Incidence
of
ARC
Definite / Probable
ST
0%
0
1
4
5%
2%
2
P
=
0.003
HR 0.63
(
0.46
–
0.85)
1%
Primary Endpoint
1.57%
2.55%
Endeavor ZES (N = 4357)
Cypher SES (N = 4352)
3%
4%
3
Patients at Risk
E-ZES
4357
4347
4230
4140
4025
C-SES
4352
4344
4212
4108
3979Slide17
All Death / Large MI
All Death / All MI
Cardiac Death / Large MI
Cardiac Death / All MI
Cumulative Incidence of
Events (%)
Time After Initial Procedure
(years)0
4015
5
1
2
3
Cumulative Incidence of Events (%)
Time After Initial Procedure
(years)
0
4
0
15
5
1
2
3
Cumulative Incidence of Events (%)
Time After Initial Procedure
(years)
0
4
0
15
5
1
2
3
Cumulative Incidence of Events (%)
Time After Initial Procedure
(years)
0
4
0
15
5
1
2
3
P
= 0.024
HR 0.84 (0.71 – 0.98)
P =
0.017
HR 0.85 (0.74 – 0.97)
P =
0.015
HR 0.78 (0.65 – 0.95)
P =
0.015
HR 0.83 (0.71 – 0.96)
Cypher
SES
Endeavor ZES
Cypher
SES
Endeavor ZES
Cypher
SES
Endeavor ZES
Cypher
SES
Endeavor ZES
Main Secondary Endpoints
10
8.0
6.7
10
10.89.2
10
5.4
4.2
10
8.4
6.9
Outcomes at 4 YearsSlide18
%
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
0.44
MACE (
death, MI, TLR, emergent CABG)
14.3
14.0
0.68
MACCE (
death, MI, TLR,
eCABG
, Stroke)
15.6
15.3
0.70
Other Endpoints at 4 YearsSlide19
1.57%
67/4217
106/4215
2.55%
Events Associated with ST
Contribution of ST to Cardiac Death & MI
Total Number of
Associated Events
26
29
45
80
54
89
Cardiac D
MI
Cardiac D/MI
0 – 1 Yr
Total Number of
Associated Events
E-ZES
SES
18
32
39
14
21
27
E-ZES
SES
1 – 4
Yrs
8
13
15
15
59
62
E-ZES
SES
0 – 4
Yrs
ARC
Def
/
Prob
Stent ThrombosisSlide20
ConclusionThe 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 MIThis 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.