safety of drug eluting stents nd generation des have a ... · meta-analysis des vs bms in 22 rcts...
TRANSCRIPT
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Safety of Drug Eluting Stents
Do 2nd generation DES have a lower risk of stent thrombosis?
Keith G Oldroyd
West of Scotland Regional Heart & Lung Centre
Golden Jubilee National Hospital
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Conflicts of Interest Advisory boards for Biosensors; Cordis; BSCI
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Safety of Drug Eluting Stents
Cypher/Taxus vs BMS
Cypher/Taxus vs Endeavor
Cypher/Taxus vs Xience/Promus
Cypher vs Biomatrix
Cypher vs Yukon
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Safety and Efficacy of Sirolimus Eluting Stents (NEJM 2007; 356: 998-1008)
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Safety and Efficacy of Paclitaxel Eluting Stents (NEJM 2007; 356: 998-1008)
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Scottish Coronary Revascularisation Register All-cause mortality for “off-label” use of DES
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HORIZONS - Stent Thrombosis (ARC Definite or Probable)
2238 2122 2098 2078 1884
744 701 694 683 629
Number at risk
TAXUS DES
EXPRESS BMS
Ste
nt
Th
rom
bo
sis
(%
)
0
1
2
3
4
Time in Months
0 1 2 3 4 5 6 7 8 9 10 11 12
TAXUS DES (n=2238)
EXPRESS BMS (n=744) 3.4% 3.1%
HR [95%CI]
0.92 [0.58,1.45]
p=0.72
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DES
( n=1476)
%
BMS
(n=1476)
%
Rate
difference
p
Death 17.5 20.7 -3.2 0.02
MI 13.8 16.9 -3.0 0.02
TVR 18.4 23.7 -5.4 <0.001
Garg P et al. Circulation 2008
MASS Registry: PS matched risks and risk differences at 3 years in diabetic patients
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Meta-analysis DES vs BMS
In 22 RCTs involving 9,470 patients randomized to DES or
BMS and followed for ≥1 year, DES resulted in:
• A non-significant 3% reduction in mortality - HR 0.97 (0.81,1.15)
• A non-significant 6% reduction in MI - HR 0.94 (0.79,1.13)
• A significant 55% reduction in TVR – HR 0.45 (0.37,0.54)
In 30 Registries with 174,302 patients treated with either
DES or BMS and followed for ≥1 year, DES resulted in:
• A significant 20% reduction in mortality - HR 0.80 (0.72,0.88)
• A significant 11% reduction in MI – HR 0.89 (0.80-0.98)
• A significant 47% reduction in TVR – HR 0.53 (0.47-0.61)
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This is not a class effect for “drug-eluting stents”. The
sirolimus-eluting CYPHER stent has a wide therapeutic
window and does not have a problem with either early
or late thromboses
Jeff Moses. TCT 04
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Study name Statistics for each study Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value p-Value
TAXI 0.417 0.105 1.660 -1.241 0.215
TAXUS Meta / Cypher Meta 0.905 0.651 1.257 -0.597 0.550
CORPAL 1.298 0.683 2.470 0.796 0.426
REALITY 1.000 0.555 1.801 0.000 1.000
SIRTAX 0.979 0.555 1.728 -0.073 0.942
I-DIABETES 1.058 0.548 2.041 0.168 0.867
I-SMART3 1.308 0.559 3.061 0.619 0.536
I-DESIRE 0.734 0.245 2.198 -0.552 0.581
DIABETES I, II (C. Death) 0.320 0.013 7.903 -0.696 0.487
BASKET 1.027 0.429 2.461 0.061 0.952
Cervinka 0.363 0.014 9.234 -0.613 0.540
Di Lorenzo 1.349 0.291 6.252 0.382 0.702
Han 1.364 0.297 6.268 0.399 0.690
Long DES II 0.198 0.009 4.154 -1.042 0.297
Petronio 2.042 0.179 23.266 0.575 0.565
Prosit 1.234 0.516 2.951 0.472 0.637
SORT OUT II 1.000 0.525 1.904 0.000 1.000
Zhang 1.031 0.367 2.895 0.059 0.953
SOLACI 0.232 0.036 1.514 -1.527 0.127
MILAN 1.043 0.345 3.150 0.074 0.941
DEScover 0.844 0.631 1.129 -1.142 0.254
NY State 0.924 0.765 1.116 -0.820 0.412
RESEARCH / T-SEARCH 1.590 0.870 2.905 1.509 0.131
STENT 0.877 0.678 1.135 -0.997 0.319
ACUITY 0.963 0.642 1.446 -0.181 0.857
REWARDS 1.216 0.919 1.609 1.365 0.172
Prarie Heart 0.518 0.226 1.189 -1.552 0.121
Thoraxcenter Real World 1.456 1.104 1.919 2.664 0.008
TC-WYRE (C. Death) 0.696 0.185 2.618 -0.537 0.592
Aoki - Full Metal Jacket 3.071 0.503 18.753 1.216 0.224
Chu- SVG 1.246 0.177 8.768 0.221 0.825
Airoldi- ISR 1.369 0.087 21.643 0.223 0.823
Western Denmark 1.256 0.955 1.652 1.629 0.103
1.029 0.945 1.121 0.664 0.507
0.01 0.1 1 10 100
PES Better SES Better
Mortality PES vs. SES - Random Effects Model
Pooled Odds Ratio
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Driver
Endeavor
1 2 270 30 50 100 125 150 200 225 3 4 5 6 7 8 9 10 11 12 13 14
1.2% (7) 1.2% (7)
0.5%(3) 0.5%(3)
Days
Endeavor II Stent thrombosis
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“Does even distribution of neointima explain the
unsurpassed stent thrombosis rates with Endeavor?”
Professor Martin Rothman 2005
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ENDEAVOR IV – 2 year outcomes
TCT 08
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SORTOUT-III Definite Stent Thrombosis
Hazard Ratio (95% CI) 4.62 (1.33 – 16.1) p=0.02
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SORTOUT-III Myocardial Infarction
Hazard Ratio (95% CI) 3.47 (1.14 – 10.5) p=0.03
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SORTOUT-III Clinically Significant Restenosis
Hazard Ratio (95% CI) 6.59 (2.57 – 16.9) p<0.0001
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Western Denmark Heart Registry Endeavor vs Cypher
Thuesen L. TCT 2008
Hazard ratio
(95% CI)
Sortout 3
All-cause mortality 1.34 (1.04–1.71)*
Cardiac mortality 1.83 (0.99–3.41)
MI >28 days 1.01 (0.88–1.16)
Definite stent thrombosis 1.78 (1.06–3.00)* 4.62
TLR 2.39 (1.82–3.13)*
In-segment restenosis
(lesion)
2.44 (1.76–3.37)*
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XIENCE/PROMUS N=669
TAXUS Express2 N=333
Total Thrombosis 1.3% 1.7%
Early (0 - 30 days) 0.4% 0.0%
Late (31 days – 1 year*) 0.5% 0.6%
Very Late (1-2 years*) 0.3% 1.0%
P=0.77
P=0.34
P=NR
P=NR
SPIRIT III Presentation, Gregg W. Stone, MD, PCR 2008.
SPIRIT III - 2 Year Results ARC Definite / Probable Stent Thrombosis
Refer to glossary
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*ACS with thrombus or unexplained death or AMI in the target lesion distribution within 30 days.
SPIRIT III - 2 Year Results Protocol* Stent Thrombosis
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Xience/Promus vs Cypher ?
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LEADERS Cardiac Death & Myocardial Infarction
6.7%
6.6%
Biolimus Stent
Sirolimus Stent
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LEADERS Definite Stent Thrombosis
2.0%
2.0%
Biolimus Stent
Sirolimus Stent
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ISAR-TEST 3
Yukon
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Conclusion
There is as yet no convincing evidence of any important safety differences between any of the currently available DES.
It may never be possible to convincingly demonstrate such differences even if they exist.
Any differences that do exist in the risk of stent thrombosis between DES are very small and less important than several other potential causative factors including the patient
the lesion
the operator
response to and premature discontinuation of DAPT
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ISAR-TEST 3
Yukon
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Future Studies on DES Safety - DAPT
• Designed to enroll more than 15 000 patients being treated with one of the four DES currently approved in the US and more than 5000 patients treated with a BMS.
•All patients will receive DAPT - clopidogrel or prasugrel for 12 months.
•At 12 months, after the exclusion of any patients with MACCE or major bleeding patients will be randomised to either placebo or ongoing DAPT out to 30 months.
•Follow-up will end at 33 months, to include a possible "rebound period.“
•The co-primary end points will be stent thrombosis and MACCE, and the major safety end point will be major bleeding.
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DES and BMS for Acute Myocardial Infarction
N=4,016 patients with DES for MI
N=3,200 patients with BMS for MI
2,453 (61.1%) DES for NSTEMI
1,563 (38.9%) DES for STEMI
1,382 (43.2%) BMS for NSTEMI
1,818 (56.8%) BMS for STEMI
Propensity score matched pairs
2629 MI
1,221 NSTEMI
1,302 STEMI
1,221 NSTEMI
1,302 STEMI
2629 MI
matched pairs
matched pairs
Mauri L et al. N Engl J Med 2008; 359:1330-1342.
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-6% -3% 0% 3% 6%
DES and BMS for Acute Myocardial Infarction
Risk Differences in Matched MI Patient Groups at 2 years
Risk Difference (95% CI), DES v. BMS
Death Recurrent MI
NSTEMI
MI
STEMI
n=2629
pairs
n=1221
pairs
n=1302
pairs
-6% -3% 0% 3% 6%
Favors
DES
Favors
BMS
-2.7% [-4.5%, 0%] P=0.002
-1.9% [-4.6%, 0.9%] P=0.18
-3.1% [-5.4%, -0.8%] P=0.009
Favors
DES
Favors
BMS
-1.5% [-3.1%, 0.2%] P=0.08
-2.4% [-5.0%, 0.3%] P=0.07
-1.6% [-3.7%, 0.5%] P=0.127
Mauri L et al. N Engl J Med 2008; 359:1330-1342.
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E-PCR 2008
SPIRIT III – 2 year outcomes
Xience/Promus
n=669 (%)
Taxus Exp2
n=333 (%)
p
MACE 7.3 12.8 0.004
TVF 10.7 15.4 0.04
TLR 4.6 7.5 0.07
Definite/probable
stent thrombosis
0.3 1.0 NS
Among patients who stopped DAPT @ 6 months there were
fewer stent thrombosis "episodes" in Xience V-treated patients
compared to Taxus-treated patients but ……………….
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SORTOUT-III Cardiac Mortality
Hazard Ratio (95% CI) 2.17 (0.75 – 6.24) p=0.14
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Mortality: All RCTs 8,867 patients, 21 trials**
Mortality: All Registries
161,232 patients, 28 registries** Estimate
(95% CI)
Weight
(%)
I-V Overall (I-squared = 0.0%, p = 0.918)
BASKET (SES only)
TAXUS II
HAAMU-STENT
Seville
Ortolani et al
TAXUS IV
E-SIRIUS
Study ID
DIABETES
PRISON II
STRATEGY
RAVEL
SES-SMART
TAXUS V
Typhoon
MISSION!
SCORPIUS
SESAMI
D+L Overall
Passion
C-SIRIUS
Pache et al
SIRIUS
0.97 (0.81, 1.15)
0.82 (0.37, 1.84)
1.61 (0.57, 4.53)
2.00 (0.63, 6.38)
1.35 (0.23, 7.78)
2.00 (0.19, 21.38)
0.89 (0.63, 1.25)
1.08 (0.25, 2.24)
ES (95% CI)
1.44 (0.48, 4.33)
0.50 (0.09, 2.67)
0.84 (0.36, 1.96)
1.75 (0.73, 4.16)
0.21 (0.02, 1.71)
0.97 (0.57, 1.65)
1.01 (0.38, 2.65)
0.48 (0.09, 2.59)
1.28 (0.35, 4.61)
0.43 (0.11, 1.63)
0.97 (0.81, 1.15)
0.70 (0.36, 1.36)
0.68 (0.11, 4.04)
1.40 (0.45, 4.35)
1.02 (0.67, 1.54)
100.00
4.80
2.87
2.30
1.00
0.55
26.29
2.57
(I-V)
2.55
1.07
4.30
4.08
0.62
10.92
3.27
1.09
Weight
1.86
1.70
6.99
0.95
2.40
17.82
%
0.97 (0.81, 1.15)
0.82 (0.37, 1.84)
1.61 (0.57, 4.53)
2.00 (0.63, 6.38)
1.35 (0.23, 7.78)
2.00 (0.19, 21.38)
0.89 (0.63, 1.25)
1.08 (0.25, 2.24)
ES (95% CI)
1.44 (0.48, 4.33)
0.50 (0.09, 2.67)
0.84 (0.36, 1.96)
1.75 (0.73, 4.16)
0.21 (0.02, 1.71)
0.97 (0.57, 1.65)
1.01 (0.38, 2.65)
0.48 (0.09, 2.59)
1.28 (0.35, 4.61)
0.43 (0.11, 1.63)
0.97 (0.81, 1.15)
0.70 (0.36, 1.36)
0.68 (0.11, 4.04)
1.40 (0.45, 4.35)
1.02 (0.67, 1.54)
100.00
4.80
2.87
2.30
1.00
0.55
26.29
2.57
(I-V)
2.55
1.07
4.30
4.08
0.62
10.92
3.27
1.09
Weight
1.86
1.70
6.99
0.95
2.40
17.82
%
1.1 1 10
Favors DES Favors BMS
Estimate
(95% CI)
Weight
(%)
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 70.1%, p = 0.000)
Ontario (matched)
Germany Metabolic Syndrome
GHOST (adjusted)
RESTEM
ARTS II (from RCT)
ACUITY (from RCT)
Western Denmark (adjusted)
STENT (adjusted)
Massachusetts (matched)
Cedars Acute MI
I-V Overall
NHLBI (on label, adjusted)
Wake Forest (adjusted)
DEScover (unadjusted)
Multicenter SVG (adjusted)
MIDAS (adjusted)
Liverpool (matched)
ERACI III (from RCT)
SCAAR (adjusted)
Asan Korea (adjusted)
Study ID
Melbourne
McMaster STEMI (adjusted)
REAL (adjusted)
Mayo FFR Substudy
Italian Diabetic Multivessel (adjusted)
Washington Hosp Center (matched)
Rotterdam Off-Label
NHLBI (off label, adjusted)
NY State (adjusted, unmatched)
0.80 (0.72, 0.88)
0.71 (0.59, 0.84)
1.47 (0.65, 3.35)
0.55 (0.36, 0.83)
0.73 (0.51, 1.05)
0.74 (0.41, 1.35)
0.63 (0.49, 0.82)
1.00 (0.86, 1.17)
0.69 (0.55, 0.87)
0.79 (0.71, 0.89)
0.82 (0.37, 1.83)
0.83 (0.79, 0.86)
1.47 (0.87, 2.48)
0.72 (0.55, 0.95)
0.53 (0.35, 0.80)
1.33 (0.47, 3.76)
0.66 (0.59, 0.74)
0.45 (0.24, 0.84)
1.18 (0.54, 2.58)
1.03 (0.94, 1.14)
0.60 (0.46, 0.79)
ES (95% CI)
0.67 (0.23, 1.94)
0.17 (0.03, 0.97)
0.83 (0.70, 0.98)
1.00 (0.21, 4.75)
1.22 (0.36, 4.10)
1.16 (0.78, 1.75)
0.98 (0.85, 1.13)
0.94 (0.64, 1.38)
0.84 (0.72, 0.97)
100.00
5.98
1.15
3.09
3.63
1.92
Weight
4.87
6.29
5.25
6.80
1.20
2.31
4.66
3.13
0.76
6.80
1.78
%
1.25
6.98
4.70
(D+L)
0.73
0.29
6.10
0.36
0.57
3.21
6.44
3.40
6.35
1.1 1 10
Favors DES Favors BMS
0.97 (0.81,1.15)
0.97 (0.81,1.15), p=0.72
Random Effects
*Fixed Effects (I2=0.0%)
*Random Effects (I2=70.1%)
Fixed Effects
0.80 (0.72,0.88), p<0.001
0.83 (0.79,0.86)
<1.0 Favors DES; * = significant
Meta-analysis DES vs. BMS Mortality RCT and Registry Analysis
**All-cause mortality data was available in 21 of 22 RCTs and 28 of 30 Registries.
Presented by Gregg W. Stone MD and Ajay Kirtane MD, ACC 2008. Point estimates are represented by red circles; Confidence intervals by red lines and Weight by yellow boxes (based on
primary model); No significant effect of number of patients (total or DES patients) or diabetic patients by meta-regression; Random effects used except if I2<25.
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MI: All RCTs
8,850 patients, 20 trials**
I-V Overall (I-squared = 3.0%, p = 0.420)
SESAMI
Passion
C-SIRIUS
RAVEL
TAXUS IV
TAXUS V
SCORPIUS
SIRIUS
DIABETES
MISSION!
E-SIRIUS
SCANDSTENT
Study ID
Ortolani et al
SES-SMART
STRATEGY
HAAMU-STENT
BASKET (All)
Typhoon
TAXUS II
PRISON II
D+L Overall
0.94 (0.79, 1.13)
1.00 (0.20, 4.88)
0.83 (0.26, 2.69)
0.59 (0.14, 2.47)
1.24 (0.49, 3.14)
0.99 (0.66, 1.48)
1.27 (0.79, 2.04)
0.82 (0.23, 2.95)
0.96 (0.59, 1.55)
0.60 (0.20, 1.50)
0.62 (0.28, 1.39)
1.94 (0.93, 4.02)
0.33 (0.09, 1.18)
ES (95% CI)
1.50 (0.26, 8.61)
0.16 (0.04, 0.67)
0.82 (0.31, 2.40)
0.25 (0.03, 2.19)
1.15 (0.64, 2.08)
0.80 (0.22, 2.97)
0.63 (0.23, 1.72)
0.83 (0.26, 2.64)
0.94 (0.78, 1.13)
100.00
1.29
2.40
1.59
3.80
20.13
Weight
14.59
2.02
14.07
3.23
5.11
6.13
%
1.98
(I-V)
1.07
1.65
3.13
0.71
9.45
1.94
3.24
2.44
1.1 1 10
Estimate
(95% CI)
Weight
(%)
Favors DES Favors BMS
MI: All Registries
129,955 patients, 24 registries**
Estimate
(95% CI)
Weight
(%)
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 57.9%, p = 0.000)
ACUITY (from RCT)
Melbourne
ARTS II (from RCT)
Asan Korea (adjusted)
Ontario (matched)
Study ID
NHLBI (on label, adjusted)
Washington Hosp Center (matched)
STENT (adjusted)
ERACI III (from RCT)
Wake Forest (adjusted)
Germany Metabolic Syndrome
NHLBI (off label, adjusted)
Western Denmark (adjusted)
GHOST (adjusted)
SCAAR (adjusted)
REAL (adjusted)
RESTEM
DEScover (unadjusted)
Brazil Large Vessels
Cedars Acute MI
Massachusetts (matched)
Italian Diabetic Multivessel (adjusted)
I-V Overall
Mayo FFR Substudy
McMaster STEMI (adjusted)
0.89 (0.80, 0.98)
1.07 (0.91, 1.25)
1.00 (0.39, 2.58)
0.53 (0.32, 0.88)
0.66 (0.42, 1.05)
1.10 (0.91, 1.32)
ES (95% CI)
0.71 (0.47, 1.05)
0.51 (0.29, 0.88)
0.69 (0.52, 0.92)
2.30 (0.91, 5.96)
0.84 (0.60, 1.18)
0.23 (0.07, 0.78)
0.71 (0.50, 1.00)
1.29 (1.06, 1.57)
1.12 (0.74, 1.70)
1.01 (0.91, 1.11)
0.92 (0.76, 1.11)
0.80 (0.52, 1.23)
0.69 (0.40, 1.18)
1.50 (0.25, 8.90)
0.25 (0.06, 1.16)
0.92 (0.83, 1.02)
1.02 (0.46, 2.25)
0.96 (0.91, 1.01)
0.67 (0.12, 3.84)
0.28 (0.04, 1.71)
100.00
8.90
1.10
3.09
3.55
8.26
(D+L)
4.21
2.69
6.10
1.11
5.15
0.70
5.01
Weight
%
8.02
4.03
10.17
8.18
3.86
2.80
0.33
0.48
10.10
1.50
0.35
0.30
0.89 (0.80, 0.98)
1.07 (0.91, 1.25)
1.00 (0.39, 2.58)
0.53 (0.32, 0.88)
0.66 (0.42, 1.05)
1.10 (0.91, 1.32)
ES (95% CI)
0.71 (0.47, 1.05)
0.51 (0.29, 0.88)
0.69 (0.52, 0.92)
2.30 (0.91, 5.96)
0.84 (0.60, 1.18)
0.23 (0.07, 0.78)
0.71 (0.50, 1.00)
1.29 (1.06, 1.57)
1.12 (0.74, 1.70)
1.01 (0.91, 1.11)
0.92 (0.76, 1.11)
0.80 (0.52, 1.23)
0.69 (0.40, 1.18)
1.50 (0.25, 8.90)
0.25 (0.06, 1.16)
0.92 (0.83, 1.02)
1.02 (0.46, 2.25)
0.96 (0.91, 1.01)
0.67 (0.12, 3.84)
0.28 (0.04, 1.71)
100.00
8.90
1.10
3.09
3.55
8.26
(D+L)
4.21
2.69
6.10
1.11
5.15
0.70
5.01
Weight
%
8.02
4.03
10.17
8.18
3.86
2.80
0.33
0.48
10.10
1.50
0.35
0.30
1.1 1 10
Favors DES Favors BMS
0.94 (0.78,1.13)
0.94 (0.79,1.13), p=0.54
Random Effects
*Fixed Effects (I2=3.0%) 0.89 (0.80,0.98), p=0.023
0.96 (0.91,1.01) *Random Effects (I2=57.9%)
Fixed Effects
<1.0 Favors DES; * = significant
Meta-analysis DES vs. BMS MI RCT and Registry Analysis
***MI data was available in 20 of 22 RCTs and 24 of 30 Registries
Presented by Gregg W. Stone MD and Ajay Kirtane MD, ACC 2008. Point estimates are represented by red circles; Confidence intervals by red lines and Weight by yellow boxes (based on primary
model); No significant effect of number of patients (total or DES patients) or diabetic patients by meta-regression; Random effects used except if I2<25%.
Refer to glossary
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Drug-Eluting and Bare Metal Stenting for Acute Myocardial Infarction Patient Characteristics after Match
DES
(n = 2629)
BMS
(n =2629) % SD
Age – yrs 64.7 64.2 0.0
Female (%) 33.7 33.4 0.8
Diabetes Mellitus (%) 22.4 22.9 -1.3
Hyperlipidemia (%) 62.1 63.6 -3.2
Hypertension (%) 66.1 66.7 -1.3
Current Smoker (%) 31.0 30.8 0.3
Prior PCI (%) 12.6 12.8 -0.9
Prior MI (%) 24.0 23.0 2.4
Prior CABG (%) 9.0 8.8 0.5
*%SD = Percent Standardized Difference
Values <10% reflect well-matched
characteristics
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Drug-Eluting and Bare Metal Stenting for Acute Myocardial Infarction Patient Characteristics after Match
DES
(n = 2629)
BMS
(n =2629) %SD
Congestive Heart Failure (NYHA 3-4) 9.2 8.3 3.1
Chronic Lung Disease (%) 12.9 12.0 2.9
History of Neoplasm (%) 2.9 2.7 1.4
History of GI Bleeding (%) 3.2 3.2 0.2
Chronic Renal Insufficiency (%) 6.6 6.5 0.3
Dialysis (%) 1.4 1.5 -1.0
Clopidogrel Preadminstered (%) 29.6 31.2 -3.5
GPIIb/IIIa Inhibitor Preadminstered (%) 38.8 37.7 2.4
*%SD = Percent Standardized Difference
Values <10% reflect well-matched
characteristics
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Drug-Eluting and Bare Metal Stenting for Acute Myocardial Infarction Procedure Indications after Match
DES
(n = 2629)
BMS
(n =2629)
MI type
STEMI 55.4 50.5
NSTEMI 44.6 49.5
Procedure status
Urgent (%) 37.6 40.2
Emergency/Salvage (%) 51.8 47.8
Thrombectomy 9.1 8.8
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Drug-Eluting and Bare Metal Stenting for Acute Myocardial Infarction Procedural Characteristics after Match
DES
(n = 2629)
BMS
(n =2629) %SD
Multilesion treatment
2 lesions 20.0 21.3 -3.3
3 lesions 3.7 4.7 -4.9
4 lesions 0.7 0.8 -1.8
Target vessel
Left circumflex 26.4 28.2 -3.9
Right coronary 44.8 43.6 2.5
Left main 1.5 1.4 1.0
Saphenous vein graft 5.1 5.0 0.5
Arterial graft 0.2 0.2 0.0
*%SD = Percent Standardized Difference
Values <10% reflect well-matched
characteristics
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Drug-Eluting & Bare Metal Stenting in Massachusetts
Risk Differences in Matched MI Patient Groups at 2 years Risk Difference (95% CI), DES v. BMS
Revascularizati
on
TVR
-10% -5% 0% 5% 10%
Favors
DES
Favors
BMS
-5.3% [-7.4%, -3.2%] P<0.001
-5.3% [-8.4%, -2.3%] P<0.001
-6.0% [-9.0%, -3.0%] P<0.001
-10% -5% 0% 5% 10%
Favors
DES
Favors
BMS
-3.6% [-5.2%, -2.0%] P<0.001
-2.9% [-5.4%, -0.5%] P=0.02
-3.5% [-5.8%, -1.3%] P=0.002
NSTEMI
MI
STEMI
n=2629
pairs
n=1221
pairs
n=1302
pairs
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Han Y. American College of Cardiology 2008 Scientific Sessions/
i2 Summit-SCAI Annual Meeting; March 31, 2008; Chicago, IL.
Angiographic results, accounting for 32% of treated lesions, in CREATE
Parameter (mean) Baseline After
stenting
9 mo
Reference vessel
diameter (mm)
2.77 3.19 3.13
%-stenosis 73.5 25.0 30.0
Minimum lumen diameter
(mm)
0.74 2.34 2.13
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Han Y. American College of Cardiology 2008 Scientific Sessions/
i2 Summit-SCAI Annual Meeting; March 31, 2008; Chicago, IL.
Clinical outcomes in CREATE
Parameter (mean) 6 mo, n=2068
(%)
12 mo, n=2063
(%)
MACE 1.8 2.7*
Cardiac death 0.9 1.1
Nonfatal MI 0.3 0.4
TLR 0.8 1.6 *Primary end point
MACE=major adverse cardiac events
TLR=target-lesion revascularization
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Angiographic outcomes at six months and two years in SPIRIT-2*: Xience-V vs Taxus
End point
Xience-V,
97 lesions
Taxus,
35 lesions p
In-stent late loss
• 6 mo (mm) 0.17 0.33 0.004
• 2 y (mm) 0.33 0.34 0.603
In-stent %-diameter stenosis
• 6 mo (%) 16.00 18.3 0.062
• 2 y (%) 19.20 18.8 0.959
In-stent binary restenosis rate
• 6 mo (%) 1.00 2.90 0.461
• 2 y (%) 2.10 2.90 1.000 *Includes lesions for which there were data at both six months and two years
Serruys PW, et al. March 31, 2008; Chicago, IL.
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Intravascular ultrasound measurements at six months and two years in SPIRIT-2*: Xience-V vs Taxus
End point
Xience-V,
69 lesions
Taxus,
32 lesions p
Neointimal hyperplasia
• 6 mo (mm3) 4.1 12.6 <0.001
• 2 y (mm3) 8.4 11.6 0.253
Stent obstruction volume
• 6 mo (%) 2.8 6.5 <0.001
• 2 y (%) 5.2 5.8 0.403 *Includes lesions for which there were data at both six months and two years
Serruys PW, et al. March 31, 2008; Chicago, IL.
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Clinical outcomes at six months and two years in SPIRIT-2: Xience-V vs Taxus
End point
Xience-V,
n=211 (%)
Taxus,
n=73 (%) p
Cardiac death
• 6 mo 0.0 1.3 0.257
• 2 y 0.5 1.4 0.449
MI
• 6 mo 0.9 3.9 0.110
• 2 y 2.8 5.5 0.286
TLR (ischemia driven)
• 6 mo 1.8 3.9 0.379
• 2 y 3.8 6.8 0.330
Total MACE
• 6 mo 2.7 6.5 0.158
• 2 y 6.6 11.0 0.308 TLR=target-lesion revascularization
MACE=major adverse cardiac events
Serruys PW, et al. March 31, 2008; Chicago, IL.
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SES PES (n=2282) (n=1476)
n % n % p
Death 61 2.7 31 2.1 0.26
MI 50 2.2 27 1.8 0.44
TVR 95 4.2 50 3.4 0.23
CABG Target Vessel 12 0.5 11 0.7 0.40
Re-PCI Target Vessel 84 3.7 41 2.8 0.13
MACE 180 7.9 100 6.8 0.20
Stent Thrombosis 15 0.7 7 0.5 0.52
< 24 hours 1 2
24 hours to 30 days 11 1
> 30 days 3 4
S.T.E.N.T. Registry
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Future Studies on DES Safety DAPT
No stent-stent or drug-drug comparisons
• Only the FDA and the DSMB will have access to all the device- and drug-level data
• This is “fully appropriate” given the lack of any statistical power in a study this size to make comparisons between devices or drugs.
Dr William Maisel (Beth Israel Deaconess Medical Center) commented… "I find it ironic that after months and years of hearing about how stents are different and that one company's stent, for biologic or platform or endothelialisation reasons, has different rates of stent thrombosis, we're suddenly lumping them all together."
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DES
(%)
BMS
(%)
p
Mortality, all AMI 10.7 12.8 0.02
Mortality, STEMI 8.5 11.6 0.008
Mortality, non-STEMI 12.8 15.6 0.04
Recurrent MI, all AMI 8.8 10.2 0.09
Recurrent MI, STEMI 7.0 8.0 0.34
Recurrent MI, non-STEMI 10.3 13.3 0.02
Mauri L et al. N Engl J Med 2008; 359:1330-1342.
Massachusetts Registry -2 year risk-adjusted outcomes
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P Value from Log Rank test
TAXUSTM Express2TM Stent n=333 XIENCE™ V (PROMUS™) Stent n=669
Inci
denc
e R
ate
(%)
1.3%
0.9%
1.7%
0.6%
0%
1%
2%
3%
1 Year 2 Years
P= NR P= 0.77
SPIRIT III Clinical Trial 2-Year Results ARC Definite / Probable Stent Thrombosis
Adapted from SPIRIT III Presentation, Gregg W. Stone, MD, PCR 2008.
Refer to glossary
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*ACS with thrombus or unexplained death or AMI in the target lesion distribution within 30 days.
Adapted from SPIRIT III Presentation, Gregg W. Stone, MD, PCR 2008.
P Value from Log Rank test
TAXUSTM Express2TM Stent n=333 XIENCE™ V (PROMUS™) Stent n=669
Inci
denc
e R
ate
(%)
1.0%
0.7%
1.7%
0.6%
0%
1%
2%
3%
1 Year 2 Years
P= NR P= 0.35
SPIRIT III Clinical Trial 2-Year Results Protocol* Stent Thrombosis
Refer to glossary
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0.7%0.6%
1.2%
0.8%
0.0%
0.5%
0%
1%
2%
ENDEAVOR II ENDEAVOR III ENDEAVOR IV
0.3%
0.0%
0.3%
0.1%0.0%
0.9%
0%
1%
2%
ENDEAVOR II ENDEAVOR III ENDEAVOR IV
ENDEAVOR II, III, and IV Studies 9-month Safety Results
DriverTM Stent n = 591
EndeavorTM Stent n = 592
Death
(%
)
QW
MI (%
)
ENDEAVOR II
CypherTM Stent n = 113
EndeavorTM Stent n = 323
ENDEAVOR III
TAXUSTM Stent n = 734
EndeavorTM Stent n = 740
ENDEAVOR IV
p=0.342 p=1.00 p=0.772
0.8%
0.0%
0.5%
0.1%0.0%
1.2%
0%
1%
2%
ENDEAVOR II ENDEAVOR III ENDEAVOR IV
Pro
toco
l S
T (
%)
p=0.287 p=NA p=1.00
p=0.224 p=NA p=0.124
0.9%
0.0%
0.5%
0.1%0.0%
1.4%
0%
1%
2%
ENDEAVOR II ENDEAVOR III ENDEAVOR IV
AR
C (
Def
+ P
rob
) S
T (
%)
p=NR p=NR 95% CI
[0.1%, 1.6%]
92.3% of EndeavorTM Stent patients were on DAPT through 6 months
ENDEAVOR II Fajadet et al, Circulation, August 22, 2006. ENDEAVOR III Kandzari et al., JACC, December 19, 2006. ENDEAVOR IV www.fda.gov.
All ARC (def+prob) stent thrombosis rates www.fda.gov. Refer to glossary
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9 months
Hazard ratio
(95% CI)
All-cause mortality 1.45 (0.75–2.79)
Cardiac mortality 2.17 (0.75–6.24)
MI 3.47 (1.14–10.5)
Definite stent thrombosis 4.62 (1.33–16.1)
TLR 4.19 (2.10–8.35)
Clinical restenosis 6.59 (2.57–16.9)
Lassen JF. TCT 2008
SORT-OUT III (Danish) RCT: Endeavor vs Cypher
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ENDEAVOR IV – 2 year outcomes
TCT 08
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REALITY:12 MONTH OUTCOMES
CYPHER (684 patients; 970 lesions)
TAXUS (669 patients; 941 lesions)
P-value
MACE,% (n) 10.7% (73) 11.4% (76) 0.73
Death, % (n) 2.3% (16) 1.3% (9) 0.23
Cardiac Death 1.5% (10) 1.0% (7) 0.63
MI (all), % (n) 5.1% (35) 6.0% (40) 0.55
Q-wave 0.1% (1) 1.2% (8) 0.02
Non–Q-wave 5.0% (34) 4.8% (32) 0.90
TLR (all),% (n) 6.0% (41) 6.1% (41) >0.99
TVR (non-TL) 2.0% (14) 1.8% (12) 0.84
TVF, % (n) 12.0% (82) 12.9% (86) 0.68
Morice et al. JAMA 2006, 295: 895-904.
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2.4%2.0%
1.8%
3.8%
5.1%
6.2%
7.8%
1.8%
4.5%
5.8%
7.1%
8.6%
0%
2%
4%
6%
8%
10%
12%
MACE TVF TVR TLR Death AMI
P=NS P=NS
Incid
en
ce R
ate
(%
)
P=NS P=NS P=NS
SORTOUT II: 9 MONTH OUTCOMES
TAXUS
N = 1033 Cypher
N = 1065
P=NS
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Meta-analysis of Stent Thrombosis SES vs PES
Moreno et al. Br J Clin Pharmacol. 2007 July; 64(1): 110–112. Risk of stent thrombosis after sirolimus or paclitaxel
eluting coronary stent implantation
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Study name Statistics for each study Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value p-Value
SOLACI 0.232 0.036 1.514 -1.527 0.127
MILAN 1.043 0.345 3.150 0.074 0.941
DEScover 0.844 0.631 1.129 -1.142 0.254
NY State 0.924 0.765 1.116 -0.820 0.412
RESEARCH / T-SEARCH 1.590 0.870 2.905 1.509 0.131
STENT 0.877 0.678 1.135 -0.997 0.319
ACUITY 0.963 0.642 1.446 -0.181 0.857
REWARDS 1.216 0.919 1.609 1.365 0.172
Prarie Heart 0.518 0.226 1.189 -1.552 0.121
Thoraxcenter Real World 1.456 1.104 1.919 2.664 0.008
TC-WYRE (C. Death) 0.696 0.185 2.618 -0.537 0.592
Aoki - Full Metal Jacket 3.071 0.503 18.753 1.216 0.224
Chu- SVG 1.246 0.177 8.768 0.221 0.825
Airoldi- ISR 1.369 0.087 21.643 0.223 0.823
Western Denmark 1.256 0.955 1.652 1.629 0.103
1.048 0.904 1.215 0.623 0.533
0.01 0.1 1 10 100
PES Better SES Better
Mortality PES vs. SES in Registries - Random Effects Model
Pooled odds ratio
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Study name Statistics for each study Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value p-Value
TAXI 0.417 0.105 1.660 -1.241 0.215
TAXUS Meta / Cypher Meta 0.905 0.651 1.257 -0.597 0.550
CORPAL 1.298 0.683 2.470 0.796 0.426
REALITY 1.000 0.555 1.801 0.000 1.000
SIRTAX 0.979 0.555 1.728 -0.073 0.942
I-DIABETES 1.058 0.548 2.041 0.168 0.867
I-SMART3 1.308 0.559 3.061 0.619 0.536
I-DESIRE 0.734 0.245 2.198 -0.552 0.581
DIABETES I, II (C. Death) 0.320 0.013 7.903 -0.696 0.487
BASKET 1.027 0.429 2.461 0.061 0.952
Cervinka 0.363 0.014 9.234 -0.613 0.540
Di Lorenzo 1.349 0.291 6.252 0.382 0.702
Han 1.364 0.297 6.268 0.399 0.690
Long DES II 0.198 0.009 4.154 -1.042 0.297
Petronio 2.042 0.179 23.266 0.575 0.565
Prosit 1.234 0.516 2.951 0.472 0.637
SORT OUT II 1.000 0.525 1.904 0.000 1.000
Zhang 1.031 0.367 2.895 0.059 0.953
0.992 0.827 1.191 -0.084 0.933
0.01 0.1 1 10 100
PES Better SES Better
Mortality PES vs. SES in RCT - Random Effects Model
Pooled odds ratio
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BES n=857
(%)
SES n=850
(%)
OR
(95% CI)
Cardiac death, MI, or
clinically indicated TVR
9.2 10.5 0.88
(0.64–1.19)
Death 2.6 2.8 0.91
(0.51–1.62)
Cardiac death 1.6 2.5 0.66
(0.34–1.30)
MI 5.7 4.6 1.25
(0.82–1.92)
Clinically indicated
TVR
4.4 5.5 0.79
(0.52–1.22)
Any TVR 5.7 7.3 0.77
(0.53–1.13)
Windecker S et al. Lancet 2008
LEADERS: Clinical outcomes at nine months
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“Does even distribution of (MORE) neointima explain
the unsurpassed stent thrombosis rates with
Endeavor?”
Professor Martin Rothman 2005