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Endeavor Safety: Pooled Analysis of Early and Late Safety of a Zotarolimus-Eluting Stent

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Endeavor Safety: Pooled Analysis of Early and Late Safety of a Zotarolimus-Eluting Stent Laura Mauri, MD, MSc Brigham and Women s Hospital Harvard Clinical Research ... – PowerPoint PPT presentation

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Title: Endeavor Safety: Pooled Analysis of Early and Late Safety of a Zotarolimus-Eluting Stent


1
Endeavor Safety Pooled Analysis of Early and
Late Safety of a Zotarolimus-Eluting Stent
  • Laura Mauri, MD, MSc
  • Brigham and Womens Hospital
  • Harvard Clinical Research Institute
  • Boston, Massachusetts
  • October 24, 2007
  • TCT Late Breaking Clinical Trial
  • Disclosures
  • Advisory Board Member Medtronic

1
2
Endeavor Safety Analysis
  • The data reported for available DES in the US
    indicate that these devices are important
    advancements
  • by reducing the need for revascularization
  • without a statistical increase in the incidence
    of MI and death
  • Any small increase in LST appears to be offset by
    a reduction in downstream revascularization
    events prevented by DES

3
Endeavor Safety Analysis
  • An ideal DES would
  • 1) Reduce the incidence of
    revascularization and its downstream events and
  • 2) Provide equivalent or better safety results
    compared with BMS
  • Single randomized trials have been sufficient to
    show efficacy, but not to show safety

4
ENDEAVOR IV
Primary Endpoint Result at 9 months
Target Vessel Failure P for Non-Inferiority lt
0.001 ?3.8
7.4
6.8
Taxus (n54/734)
Endeavor (n50/740)
5
Endeavor Safety Analysis
ENDEAVOR I
Registry 48 months n97/100 (97)
ENDEAVOR II
Double-blind Randomized Trial 36 months n577/598
(97)
ENDEAVOR II CA Registry
Continued Access Registry 24 months n288/296
(97)
Confirmatory Trial vs. Cypher 24 months
n313/323 (97)
ENDEAVOR III
ENDEAVOR IV
Confirmatory Trial vs. Taxus 12 months n749/773
(97)
ENDEAVOR PK
Pharmacokinetic Trial 9 months n42/43 (98)
360day follow up n2050
720day follow up n1287
1080day follow up n675
6
Endeavor Safety Analysis
Patient Demographics n 2132 Endeavor treated
patients
EI n 100 EII n 598 EII CA n 296 EIII n 323 EIV n 773 EPK n 43 E2 Driver N 599
Diabetes () 16.0 18.2 25.8 29.7 31.2 41.9 22.2
RVD (mm) 2.96 2.73 2.63 2.75 2.73 2.54 2.76
Lesion Length (mm) 10.94 14.04 16.49 14.96 13.41 15.02 14.38
Recommended Clopidogrel Duration 3m 3m 3m 3m 6m 3m 3m
Clinical F/U 12m () 2y () 3y () 99 99 98 98.7 98.2 96.5 98.6 97.3 99.1 96.9 96.9 97.7 98.3 97.8 96.7
9 months
7
Endeavor Safety Analysis
Patient Characteristics
Endeavor (n 2132) Driver (n 596) p value
RVD (mm) 2.73 2.76 0.128
Lesion length (mm) 14.16 14.38 0.446
Diabetes Mellitus () 26.1 22.2 0.054
Insulin Dependent Diabetes 8.3 7.4 0.49
Age yrs 62.510.7 61.910.5 0.23
Male () 71.5 75.3 0.06
History of Smoking () 49.2 35.2 lt0.001
Prior PCI () 26.0 18.0 lt0.001
Hyperlipidemia () 81.2 76.9 0.02
Hypertension () 73.0 68.2 0.02
8
Endeavor Safety Analysis
Patient Characteristics
Endeavor (n 2132) Driver (n 596) p value
EF 58.910.9 60.811.8 0.002
Angina Category 0.514
Stable Angina 49.3 50.8
Unstable Angina 40.8 33.3
MI 9.9 15.8
Number of Diseased Vessels 0.030
1 58.8 62.9
2 26.7 26.3
3 14.5 10.7
9
Endeavor Pooled Safety Analysis
Dual Antiplatelet Therapy (DAPT) Usage
1 Year 2 Years 2 Years
Endeavor (EI, EII, EIICA) 29.1 (279/958) 29.1 (279/958) 11.2 (106/943)
Driver (EII) 29.0 (166/572) 29.0 (166/572) 13.5 (76/562)
Percent of Patients on DAPT at
10
Endeavor Safety Analysis
Cumulative Incidence of Death to 1080 Days
10
8
6
Cumulative Incidence of Death
4.5
4
3.2
2
0
0
90
180
270
360
450
540
630
720
810
900
990
1080
Time after Initial Procedure (days)
Death 0 30 270 360 720 1080
Endeavor 2132 2122 2094 2058 1251 651
Events 0 4 14 4 10 9
CI 0.0 0.2 0.9 1.1 1.8 3.2
Driver 596 594 588 583 568 551
Events 0 0 3 1 9 13
CI 0.0 0.0 0.5 1.0 2.2 4.5
11
Endeavor Safety Analysis
Cumulative Incidence of Cardiac Death to 1080
Days
10
8
6
Cumulative Incidence of Cardiac Death
4
2.4
2
1.0
0
0
90
180
270
360
450
540
630
720
810
900
990
1080
Time after Initial Procedure (days)
Cardiac Death 0 30 270 360 720 1080
Endeavor 2132 2122 2094 2058 1251 651
Events 0 3 9 2 2 1
CI 0.0 0.1 0.6 0.7 0.8 1.0
Driver 596 594 588 583 568 551
Events 0 0 3 1 7 3
CI 0.0 0.0 0.5 0.7 1.9 2.4
12
Endeavor Safety Analysis
Cumulative Incidence of MI to 1080 Days
10
8
6
Cumulative Incidence of MI
4.2
4
2.7
2
0
0
90
180
270
360
450
540
630
720
810
900
990
1080
Time after Initial Procedure (days)
MI 0 30 270 360 720 1080
Endeavor 2132 2063 2052 2014 1219 634
Events 30 10 6 2 2 2
CI 1.4 1.9 2.2 2.3 2.4 2.7
Driver 596 571 566 560 545 528
Events 15 6 2 0 0 2
CI 2.5 3.5 3.9 3.9 3.9 4.2
13
Endeavor Safety Analysis
Cumulative Incidence of Cardiac Death and MI to
1080 Days
10
8
6.6
6
Cumulative Incidence of Cardiac Death or MI
4
3.5
2
0
0
90
180
270
360
450
540
630
720
810
900
990
1080
Time after Initial Procedure (days)
Cardiac Death or MI 0 30 270 360 720 1080
Endeavor 2132 2083 2052 2014 1219 634
Events 30 12 14 4 3 3
CI 1.4 2.0 2.6 2.8 3.1 3.5
Driver 596 573 566 560 545 528
Events 15 6 5 1 7 5
CI 2.5 3.5 4.4 4.5 5.8 6.6
14
Stent Thrombosis Protocol Definition
  • Coronary symptoms AND
  • Angiographic confirmation of thrombus or
    occlusion OR
  • Pathologic confirmation of acute thrombosis
  • Unexplained death within 30 days
  • Target vessel MI without angiographic
    confirmation of thrombosis or other identified
    culprit lesion within 30 days
  • Patients with intervening TLR were excluded
  • Timing
  • Acute (within first 24 hours)
  • Sub-Acute (within first 30 days)
  • Late (past 30 days)

15
Stent Thrombosis Academic Research Consortium
(ARC)
  • Definite/Confirmed
  • Coronary symptoms AND
  • Angiographic confirmation of thrombus or
    occlusion OR
  • Pathologic confirmation of acute thrombosis
  • Probable
  • Unexplained death within 30 days
  • Target vessel MI without angiographic
    confirmation of thrombosis or other identified
    culprit lesion
  • Possible
  • Unexplained death after 30 days
  • Timing
  • Early (within first 30 days)
  • Late (30 days to 1 year)
  • Very Late (past 1 year)

16
Endeavor Safety Analysis
Cumulative Incidence of Stent Thrombosis
(Protocol) to 1080 Days
10
8
6
Cumulative Incidence of Thrombosis
4
2
1.2
0.5
0
0
90
180
270
360
450
540
630
720
810
900
990
1080
Time after Initial Procedure (days)
Days 0 30 270 360 720 1080
Endeavor 2132 2117 2086 2050 1248 648
Events 1 6 3 0 0 0
CI 0.0 0.3 0.5 0.5 0.5 0.5
Driver 596 587 581 576 561 544
Events 1 6 0 0 0 0
CI 0.2 1.2 1.2 1.2 1.2 1.2
17
Endeavor Safety Analysis
Cumulative Incidence of ARC Definite/Probable
ST to 1080 Days
10
8
6
Cumulative Incidence of ARC Definite/Probable
4
2
1.5
0.7
0
0
90
180
270
360
450
540
630
720
810
900
990
1080
Time after Initial Procedure (days)
Def/Prob Thrombosis 0 30 270 360 720 1080
Endeavor 2132 2117 2085 2049 1247 648
Events 1 6 4 2 1 0
CI 0.0 0.3 0.5 0.6 0.7 0.7
Driver 596 585 581 575 560 542
Events 1 6 1 0 0 1
CI 0.2 1.2 1.3 1.3 1.3 1.5
18
Endeavor Safety Analysis
Cumulative Incidence of Stent Thrombosis by Time
Interval (ARC definite and probable)
Cumulative Incidence -
Endeavor n2132 95 CI Driver n596 95 CI
Early (0-30d) 0.3 0.09,0.57 1.2 0.03,2.04
Late (31-360d) 0.3 0.04,0.55 0.2 0.00,0.51
Very Late (361d-3y) 0.1 0.00,0.32 0.2 0.00,0.59
Cumulative (to 3y) 0.7 0.00,1.41 1.5 0.35,2.71
Standard error was estimated by Peto formula
19
Endeavor Safety Analysis
Cumulative Incidence of Safety Endpoints to 1080
days
Cumulative Incidence -
Endeavor n2132 95 CI Driver n596 95 CI
Death 3.2 1.71,4.65 4.5 2.59,6.49
Cardiac Death 1.0 0.14,1.81 2.4 0.96,3.88
MI 2.7 1.35,4.12 4.2 2.30,6.15
Cardiac Death/MI 3.5 1.97,5.10 6.6 4.28,8.99
Thrombosis (protocol) 0.5 0.00, 1.06 1.2 0.14,2.21
Thrombosis (Def/Prob) 0.7 0.00,1.41 1.5 0.35,2.71
Standard error was estimated by Peto formula
20
ENDEAVOR Safety Analysis
Cumulative Incidence of Safety Endpoints to 1080
Days
n2132
n596
6.6
Clinical Event ()
4.5
4.2
3.5
3.2
2.7
2.4
1.5
1.2
1.0
0.7
0.5
Death
Cardiac Death
MI
Cardiac Death/MI
Protocol ST Definition
ARC Def/Prob ST Definition
Error bars represent 95 confidence intervals
21
Endeavor Safety Summary Randomized Trial and
Pooled Data to 3 years
22
Endeavor Safety Summary Diabetics
Cumulative Incidence of Safety Endpoints to 1080
Days
n132
n555
9.2
7.8
Clinical Event ()
4.7
4.6
4.2
3.2
3.1
2.7
2.3
1.3
1.1
0.5
Death
Cardiac Death
MI
Cardiac Death/MI
Protocol ST Definition
ARC Def/Prob ST Definition
23
Endeavor Clinical Program Small Vessels
Cumulative Incidence of Safety Endpoints to 1080
Days (RVDlt2.5mm)
n195
n733
9.3
Clinical Event ()
4.7
5.7
3.6
3.5
2.9
3.6
2.6
1.7
1.4
0.5
0.3
Death
Cardiac Death
MI
Cardiac Death/MI
Protocol ST Definition
ARC Def/Prob ST Definition
24
Endeavor Clinical Program Long Lesions
Cumulative Incidence of Safety Endpoints to 1080
Days (gt15mm)
n232
n805
10.9
7.4
6.6
Clinical Event ()
4.5
3.8
3.5
2.6
2.6
1.7
0.8
0.9
0.5
Death
Cardiac Death
MI
Cardiac Death/MI
Protocol ST Definition
ARC Def/Prob ST Definition
25
ENDEAVOR Safety Analysis
Conclusions 1
  • From the ENDEAVOR clinical program dataset of
  • 2132 patients treated with Endeavor and
  • 596 patients treated with Driver
  • There was no evidence of increased rates of
    death, cardiac death, or myocardial infarction
    in patients treated with the Endeavor stent
    compared with Driver BMS to 3 years follow up
  • There was no evidence of increased stent
    thrombosis risk within 1 year (0.7 vs 1.3 ARC
    definite/probable) or in years 1-3 (0.1 vs 0.2)
    in patients treated with the Endeavor stent
    compared with those treated with the Driver BMS

26
ENDEAVOR Safety Analysis
Conclusions 2
  • The observed excellent safety profile should be
    considered in the context of the density of
    clinical follow up and concomitant antiplatelet
    therapy
  • 1287 Endeavor stent patients followed to 2 years,
    675 patients to 3 years
  • 71 of Endeavor stent patients dual antiplatelet
    therapy at 1 year and 89 off dual antiplatelet
    therapy at 2 years
  • High risk subgroups (diabetic, small vessel, long
    lesions) had similarly good safety profile
    consistent with the overall results
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