Laura Mauri, MD, MSc Brigham and Women ’s Hospital Harvard Clinical Research Institute Boston, Massachusetts October 24, 2007 TCT Late Breaking Clinical Trial Disclosures: Advisory Board Member Medtronic
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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

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

P for Non-Inferiority < 0.001
Δ=3.8%
6.8% 7.4%
Endeavor (n=50/740) Taxus (n=54/734)
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Endeavor Safety Analysis ENDEAVOR I Registry 48 months n=97/100 (97%) ENDEAVOR II ENDEAVOR II CA Registry ENDEAVOR III ENDEAVOR IV ENDEAVOR PK 360day follow up 720day follow up 1080day follow up Double-blind Randomized Trial 36 months n=577/598 (97%) Continued Access Registry 24 months n=288/296 (97%) Confirmatory Trial vs. Cypher 24 months n=313/323 (97%) Confirmatory Trial vs. Taxus 12 months n=749/773 (97%) Pharmacokinetic Trial 9 months n=42/43 (98%) n=2050 n=1287 n=675
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Endeavor Safety Analysis
Patient Demographics n = 2132 Endeavor treated patients
Diabetes (%) RVD (mm) Lesion Length (mm) Recommended Clopidogrel Duration Clinical F/U 12m (%) 2y (%) 3y (%) *9 months EI n = 100 EII n = 598 EII CA n = 296 EIII n = 323 EIV n = 773 EPK n = 43 16.0
18.2
25.8
29.7
31.2
41.9
E2 Driver N = 599 22.2
2.96
2.73
2.63
2.75
2.73
2.54
2.76
10.94
3m 14.04
16.49
3m 3m 14.96
3m 13.41
6m 15.02
3m 14.38
3m 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
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Endeavor Safety Analysis
Patient Characteristics
RVD (mm) Lesion length (mm) Diabetes Mellitus (%) Insulin Dependent Diabetes Age – yrs Male (%) History of Smoking (%) Prior PCI (%) Hyperlipidemia (%) Hypertension (%) Endeavor (n = 2132) 2.73
14.16
26.1
8.3
62.5±10.7
71.5 49.2
26.0
81.2
73.0
Driver (n = 596) 2.76
14.38
22.2
7.4
61.9±10.5
75.3 35.2
18.0
76.9
68.2
p value 0.128
0.446
0.054
0.49
0.23
0.06
<0.001
<0.001
0.02
0.02
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Endeavor Safety Analysis
Patient Characteristics
EF % Angina Category % Stable Angina Unstable Angina MI Number of Diseased Vessels % 1 2 3 Endeavor (n = 2132) 58.9±10.9
49.3
40.8
9.9
58.8
26.7
14.5
Driver (n = 596) 60.8±11.8
p value 0.002
0.514
50.8 33.3
15.8
0.030
62.9
26.3
10.7
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Endeavor Pooled Safety Analysis
Percent of Patients on DAPT at:
1 Year Endeavor
(EI, EII, EIICA)
29.1% (279/958) 2 Years 11.2% (106/943) Driver
(EII)
29.0% (166/572) 13.5% (76/562)
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Endeavor Safety Analysis
Cumulative Incidence of Death to 1080 Days
10% 8% 6% 4% 2% 0% 0 Endeavor Driver 90 180 270 360 450 540 630 720 810 Time after Initial Procedure (days) 900 990 1080 Death Endeavor
# Events % CI
Driver
# Events % CI
0 2132
0 0.0%
596
0 0.0%
30 2122
4 0.2%
594
0 0.0%
270 2094
14 0.9%
588
3 0.5%
360 2058
4 1.1%
583
1 1.0%
720 1251
10 1.8%
568
9 2.2%
1080 651
9 3.2%
551
13 4.5%
4.5% 3.2%
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Endeavor Safety Analysis
Cumulative Incidence of Cardiac Death to 1080 Days
10% Endeavor Driver 8% 6% 4% 2% 0% 0
2.4% 1.0%
90 180 270 360 450 540 630 720 810 Time after Initial Procedure (days) 900 990 1080 Cardiac Death Endeavor
# Events % CI
Driver
# Events % CI
0 2132
0 0.0%
596
0 0.0%
30 2122
3 0.1%
594
0 0.0%
270 2094
9 0.6%
588
3 0.5%
360 2058
2 0.7%
583
1 0.7%
720 1251
2 0.8%
568
7 1.9%
1080 651
1 1.0%
551
3 2.4% 11

Endeavor Safety Analysis
Cumulative Incidence of MI to 1080 Days
10% 8% 6% 4% 2% 0% 0 Endeavor Driver 90 180 270 360 450 540 630 720 810 Time after Initial Procedure (days) 900 990 1080 MI Endeavor
# Events % CI
Driver
# Events % CI
0 2132
30 1.4%
596
15 2.5%
30 2063
10 1.9%
571
6 3.5%
270 2052
6 2.2%
566
2 3.9%
360 2014
2 2.3%
560
0 3.9%
720 1219
2 2.4%
545
0 3.9%
1080 634
2 2.7%
528
2 4.2%
4.2% 2.7%
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Endeavor Safety Analysis
Cumulative Incidence of Cardiac Death and MI to 1080 Days
10% Endeavor Driver 8% 6% 4% 2% 0% 0 90 180 270 360 450 540 630 720 810 Time after Initial Procedure (days) 900 990 1080
6.6% 3.5%
Cardiac Death or MI Endeavor
# Events % CI
Driver
# Events % CI
0 2132
30 1.4%
596
15 2.5%
30 2083
12 2.0%
573
6 3.5%
270 2052
14 2.6%
566
5 4.4%
360 2014
4 2.8%
560
1 4.5%
720 1219
3 3.1%
545
7 5.8%
1080 634
3 3.5%
528
5 6.6% 13

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)
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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)
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Endeavor Safety Analysis
Cumulative Incidence of Stent Thrombosis (Protocol) to 1080 Days
10% Endeavor Driver 8% 6% 4% 2% 0% 0 90 180 270 360 450 540 630 720 810 Time after Initial Procedure (days) 900
1.2%
990 1080
0.5%
Days Endeavor
# Events % CI
Driver
# Events % CI
0 2132
1 0.0%
596
1 0.2%
30 2117
6 0.3%
587
6 1.2%
270 2086
3 0.5%
581
0 1.2%
360 2050
0 0.5%
576
0 1.2%
720 1248
0 0.5%
561
0 1.2%
1080 648
0 0.5%
544
0 1.2% 16

Endeavor Safety Analysis
Cumulative Incidence of ARC Definite/Probable ST to 1080 Days
10% Endeavor Driver 8% 6% 4% 2% 0% 0 90 180 270 360 450 540 630 720 810 Time after Initial Procedure (days) 900
1.5%
990 1080
0.7%
Def/Prob Thrombosis Endeavor
# Events % CI
Driver
# Events % CI
0 2132
1 0.0%
596
1 0.2%
30 2117
6 0.3%
585
6 1.2%
270 2085
4 0.5%
581
1 1.3%
360 2049
2 0.6%
575
0 1.3%
720 1247
1 0.7%
560
0 1.3%
1080 648
0 0.7%
542
1 1.5% 17

Endeavor Safety Analysis
(ARC definite and probable)
Early (0-30d) Late (31-360d) Very Late (361d-3y) Cumulative (to 3y) Cumulative Incidence -% Endeavor n=2132 0.3%
[95% CI]
[0.09,0.57] Driver n=596 1.2% 0.3% 0.1% 0.7% [0.04,0.55] [0.00,0.32] [0.00,1.41] 0.2% 0.2% 1.5%
[95% CI]
[0.03,2.04] [0.00,0.51] [0.00,0.59] [0.35,2.71]
Standard error was estimated by Peto formula 18

Endeavor Safety Analysis
Death Cardiac Death MI Cumulative Incidence -% Endeavor n=2132 3.2
1.0
2.7
3.5
[95% CI]
[1.71,4.65] [0.14,1.81] [1.35,4.12] [1.97,5.10] Driver n=596 4.5
2.4
4.2
6.6
Cardiac Death/MI Thrombosis (protocol) Thrombosis (Def/Prob) 0.5
0.7
[0.00, 1.06] [0.00,1.41]
Standard error was estimated by Peto formula
1.2
1.5
[95% CI]
[2.59,6.49] [0.96,3.88] [2.30,6.15] [4.28,8.99] [0.14,2.21] [0.35,2.71]
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ENDEAVOR Safety Analysis
Cumulative Incidence of Safety Endpoints to 1080 Days
Endeavor
n=2132
Driver
n=596
6.6% 4.5% 3.2% 2.4% 2.7% 1.0% Death Cardiac Death Error bars represent 95% confidence intervals MI 4.2% 3.5% Cardiac Death/MI 1.2% 0.5% Protocol ST Definition 1.5% 0.7% ARC Def/Prob ST Definition
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ARC Definite/Probable ST
0-1080 Days
Endeavor Driver
Cardiac Death and MI
0-1080 Days
P=0.098
6.6% 4.4% 6.6%
P=0.280
1.5% 0.8% Endeavor II 1.5% 0.7% Endeavor Pooled 3.5% Endeavor II Endeavor Pooled
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Endeavor Safety Summary: Diabetics
Cumulative Incidence of Safety Endpoints to 1080 Days
Endeavor
n=555
Driver
n=132 9.2% 7.8% 4.7% 4.2%
Death
1.1%
Cardiac Death
2.7%
MI
4.6% 3.2%
Cardiac Death/MI
2.3% 0.5%
Protocol ST Definition
3.1% 1.3%
ARC Def/Prob ST Definition
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Endeavor Clinical Program: Small Vessels
Cumulative Incidence of Safety Endpoints to 1080 Days (RVD<2.5mm)
Endeavor
n=733
Driver
n=195 9.3% 3.5% 4.7%
Death
3.6% 1.4%
Cardiac Death
1.7%
MI
5.7% 2.9%
Cardiac Death/MI
2.6% 0.3%
Protocol ST Definition
3.6% 0.5%
ARC Def/Prob ST Definition
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Endeavor Clinical Program: Long Lesions
Cumulative Incidence of Safety Endpoints to 1080 Days (>15mm)
Endeavor
n=805
Driver
n=232 10.9% 6.6% 3.5% 3.8% 2.6%
Death
0.9%
Cardiac Death MI
7.4% 4.5% 2.6%
Cardiac Death/MI
1.7% 0.5%
Protocol ST Definition
0.8%
ARC Def/Prob ST Definition
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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
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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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