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

Conflicts of Interest Advisory boards for Biosensors; Cordis; BSCI

Safety of Drug Eluting Stents

Cypher/Taxus vs BMS

Cypher/Taxus vs Endeavor

Cypher/Taxus vs Xience/Promus

Cypher vs Biomatrix

Cypher vs Yukon

Safety and Efficacy of Sirolimus Eluting Stents (NEJM 2007; 356: 998-1008)

Safety and Efficacy of Paclitaxel Eluting Stents (NEJM 2007; 356: 998-1008)

Scottish Coronary Revascularisation Register All-cause mortality for “off-label” use of DES

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

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

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)

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

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

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

“Does even distribution of neointima explain the

unsurpassed stent thrombosis rates with Endeavor?”

Professor Martin Rothman 2005

ENDEAVOR IV – 2 year outcomes

TCT 08

SORTOUT-III Definite Stent Thrombosis

Hazard Ratio (95% CI) 4.62 (1.33 – 16.1) p=0.02

SORTOUT-III Myocardial Infarction

Hazard Ratio (95% CI) 3.47 (1.14 – 10.5) p=0.03

SORTOUT-III Clinically Significant Restenosis

Hazard Ratio (95% CI) 6.59 (2.57 – 16.9) p<0.0001

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)*

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

*ACS with thrombus or unexplained death or AMI in the target lesion distribution within 30 days.

SPIRIT III - 2 Year Results Protocol* Stent Thrombosis

Xience/Promus vs Cypher ?

LEADERS Cardiac Death & Myocardial Infarction

6.7%

6.6%

Biolimus Stent

Sirolimus Stent

LEADERS Definite Stent Thrombosis

2.0%

2.0%

Biolimus Stent

Sirolimus Stent

ISAR-TEST 3

Yukon

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

ISAR-TEST 3

Yukon

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.

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.

-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.

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 ……………….

SORTOUT-III Cardiac Mortality

Hazard Ratio (95% CI) 2.17 (0.75 – 6.24) p=0.14

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.

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

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

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

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

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

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

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

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

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.

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.

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.

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

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."

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

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

*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

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

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

ENDEAVOR IV – 2 year outcomes

TCT 08

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.

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

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

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

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

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

“Does even distribution of (MORE) neointima explain

the unsurpassed stent thrombosis rates with

Endeavor?”

Professor Martin Rothman 2005