Dimitrios Alexopoulos 30.10medicalrecords.gr/hcs2008/slides/slides_aithousa_a/013... · 2018. 2....

126
DES και θρόμβωση Dimitrios Alexopoulos 30.10.2008

Transcript of Dimitrios Alexopoulos 30.10medicalrecords.gr/hcs2008/slides/slides_aithousa_a/013... · 2018. 2....

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DES και θρόμβωση

Dimitrios Alexopoulos30.10.2008

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60

70

80

90

100

60

70

80

90

100

Time after Initial Procedure (years)

0 1 2 3 4Time after Initial Procedure (years)

TAXUS I, II, IV, V, VI(n=3,506)

RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS(n=1,748)

P<0.000176.4% (202)92.2% (66)

CYPHER stent (n=870) Bare metal stent (n=878)

0 1 2 3 4

P<0.000180.0% (337)89.9% (164)

TAXUS stent (n=1,749) Bare metal stent (n=1,757)

9 Prospective, Double-Blind, Randomized TrialsFreedom From Ischemic TLR

Independent CRF patient-level meta-analysis from TCT 2006

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Very Late Stent Thrombosis Initial Cases and Discussion: Lancet 2004

McFadden EP et al. Lancet 2004; 364:1519–21

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1 month 1 year

Acute≤1d

Late > 1 mo < 1year

Subacute>1d - ≤1mo

Early < 1 mo Very Late > 1year

0 day to 1 day Acute stent thrombosis>1 day to 1 month Subacute stent thrombosis>1 month to 1 year Late stent thrombosis

> 1 year Very late stent thrombosis

Time Frame of Stent ThrombosisHow did we get here?

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We conclude that a high delivery success rate can be expected with this device and that clinical thrombosis is

less frequent in anticoagulated patients than in nonanticoagulated patients.

Acute Stent ThrombosisEarly BMS Experience

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02468

1012141618

PS1991

Sten

t thr

ombo

sis

(%)

16%

0.6%

Coumadin

Schatz et al. Circulation.1991;83:148; Fischman et al. N Engl J Med. 1994;331496;

Acute Stent ThrombosisEarly BMS Experience: With and Without Anticoagulation

PS1991

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Early Stent Thrombosis BMS Era Analysis: Trials Included

Cutlip et al: Circulation 2001;103;1967-1971

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Cutlip et al: Circulation 2001;103;1967-1971

Early Stent Thrombosis BMS Era: Results to 30 days

6186 pts, 0.9% 30-day ST

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Conclusions—Stent thrombosis occurred in ,1.0% of patients undergoing stenting of native coronary artery lesions and receiving routine antiplatelet therapy with aspirin plus ticlopidine. Procedure-related variables of persistent dissection,total stent length, and final lumen diameter were significantly associated with the probability of stent thrombosis.

Procedure-related variables ofpersistent dissection,total stent length, and final lumen diameter weresignificantly associated with the probability of stent thrombosis.

Early Stent Thrombosis BMS Era:

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Late Stent Thrombosis—Factors to Consider

Discontinuation of Anti-Platelet Therapy

DelayedEndothelialization

Late IncompleteApposition

Polymer Hypersensitivity/Inflammation

Late StentThrombosis

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Carter, AJ et al. Cardiovas Res. 2004;63:617.Lafont, A. Cardiovas Res. 2004;63:575.

Polymer Biocompatibility Issues

Once the drug is eluted from the stent, theremaining polymer if not biocompatible, may stimulate

inflammation and late intimal development.

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SES vs BMS

Conclusion:• BMS SES implantation may have an adverse effect on local

endothelium-dependent vasomotor responses six months after SES compared to BS implantation

S.H. Hofma et al. EHJ. 2005.

Functional EndotheliumM

ean

vess

el d

iam

eter

(mm

)

0.5Baseline

01

1.5

2

2.5

3

Ach Baseline Ach

Bare stentsn = 5

SESn = 7

-40-8

20

-7 -6 Nitrates

10

0

-10

-20

-30 SESBare

Mea

n lu

min

al d

iam

eter

cha

nge

(%)

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Late Stent Thrombosis 18 Months Post-SRL Stent Due to Hypersensitivity

Late DES thrombosis with aneurysm

Marked chronic inflamm + eos

Impaired healing+

Hypersensitivity(most likely to polymer)

Iatrogenic SRL-Stent Induced Hypersensitivity,Aneurysm Formation, & Thrombosis

Virmani, Guagliumi, FarbCirc 2004;109:701

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Overlapping SES vs PESBMS PESSESBMS

Overlap Overlap

Conclusions:• BMS showed far greater endothelialization than DES

• Lack of coverage highlighted in areas of overlap

• Less surface coverage by endothelial cells in PES than SES

Delayed Endothelialization

Finn et al. (Circulation. 2005;112:270-278.)

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Kotani et al. JACC Vol. 47, No. 10, 2006.

>80% Cypher Struts Exposed vs. BMS StrutsExposed Stent Struts at 6 Months

0255075

100

Incomplete coverage Complete coverage

Sirolimus-eluting stent

Bare-metal stent

Grade 0 Grade 1 Grade 2 Grade 3

250

5075

100

Perc

ent

Perc

ent

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Distal OLP Prox

Ospedali Riuniti di Bergamo

Six Month OCT: 75/76 eligible patientsAnalyzed: 250 stented segments every 0.3 mm (6968 cross-sections) , 53.047

struts

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0%

1.8%

98.2% 94.6%

2.7%

2.7%

“Vulnerable Struts”

p=0.081

Primary Endpoint: OverlapProportion of uncovered and/or malapposed struts in BMS vs DES

1.8±4.0 5.4±14.3

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Late-Incomplete AppositionPotential for Stent Thrombosis

Baseline

PositiveRemodeling

No Remodeling

Follow-up

In a Taxus and Cypher study of patients with late incomplete apposition upon clopidogrel discontinuation:

20% had stent thrombosis*

* Study by Dr. Abizaid, presented at TCT 2005.

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Conclusion:• LIA occurs in 12% of cases after DES implantation

• The predictors of LSM are total stent length, primary stenting in acute myocardial infarction, and chronic total occlusion lesions

Incomplete Late Stent Apposition

*Hong M.K. et al. Circulation. 2006;113:414-419.

Frequency and Implications13.2

8.4

Cypher Taxus

Perc

ent o

f Pat

ient

s

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Moreno, JACC 45:954, 2005N=5030 (10 RCT)

• Number of stents/patient• Total stent length

Iakovou and Colombo, JAMA 293:2126, 2005N=2229 (3 Centers)

• Premature antiplatelet rx d/c• Renal failure• Bifurcation lesion• Diabetes• ↓ LVEF

Correlates of DES Thrombosis

Kuchulakanti, Circulation 113:1108, 2006• Discontinuation of clopidogrel• Renal failure• Bifurcation lesions• In-stent restenosis

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Pinto Slottow, TL et al. Incidence and Correlates of Stent Thrombosis

Clopidogrel Compliance

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WHC Experience DES with and without IVUS

4082 unselected DESpatients

4/03-5/06 at WHC

2801 patientsIVUS guided DES

Implantation in all lesions

1281 patientsAngiographic guided

DES implantation

884 patients (1312 lesions)Patient propensity-score matched884 patients (1296 lesions)

All patients completed 12 month clinical follow up

Both Taxus and Cypher stents

were used

Probal Roy et al.EHJ 2008

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30 Day and 12 Months OutcomesIVUS

(n=884)No IVUS(n=884)

p Value

30-day Outcomes, n (%)

Major adverse cardiac events 25 (2.8%) 46 (5.2%) 0.01

Death 15 (1.7%) 29 (3.3%) 0.03

Cardiac death 6 (0.7%) 14 (1.6%) 0.07

Q-wave myocardial infarction 6 (0.7%) 12 (1.4%) 0.15

Target vessel revascularization 10 (1.1%) 17 (2.0%) 0.17

Target lesion revascularization 6 (0.7%) 15 (1.7%) 0.045

Cumulative stent thrombosis 4 (0.5%) 12 (1.4%) 0.045

12-month Outcomes, n (%)Major adverse cardiac events 128 (14.5%) 143 (16.2%) 0.32

Death 50 (5.7%) 62 (7.1%) 0.23

Cardiac death 0.18

Q-wave myocardial infarction 0.21

Target vessel revascularization 0.69

Target lesion revascularization 0.06

Definite stent thrombosis 0.014Probable stent thrombosis 0 08

Probal Roy, et al. EHJ 2008

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Stent Thrombosis is Multi-Factorial

Stent Thrombosis

LesionComplexity, disease, healing:• Long lesions• Small vessels• Multi-vessel, Multi stent• AMI• Diabetics• Bifurcations

Technical

Operator Dependent:•Under expansion•Incomplete wall apposition•Crush technique•Vessel Preparation

Patient

Premature Antiplatelet Discontinuation

• Plavix® compliance• Upcoming surgery• Plavix® non responsive• Plavix allergy /intolerance

DES

Injury & healing:• Strut thickness• Stent design (scaffolding/conformability)

• Polymer• Drug and elution profile• Stent delivery system• Adequate or proper stent expansion

Modified from Honda and Fitzgerald, Circulation 2003:108, 2Kereiakes D., et. al Rev Cardiovasc Med: 2004; 5 (1): 9-15

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Presentation with DES Thrombosis

Iakovou: JAMA 2005; 293: 2126-30

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Stent thrombosis

Time (years)210

Cum

ulat

ive

risk

of s

tent

thro

mbo

sis

%

2

1

0

DES n=21 717BMS n=20 058

Stent typTotal cohort

N=41 775 stents

0.5% per year

Unadjusted

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All-Cause Mortality: RCTs (On-Label)

I-V Overall (I-squared = 0.0%, p = 0.927)

Ortolani et al

TAXUS V - Simple

D+L Overall

TAXUS IV

Pache et al

C-SIRIUS

E-SIRIUS

SIRIUS

TAXUS II

RAVEL

SCORPIUS

1.05 (0.84, 1.30)

2.00 (0.19, 21.38)

1.09 (0.53, 2.22)

1.05 (0.84, 1.30)

0.89 (0.63, 1.25)

1.40 (0.45, 4.35)

0.68 (0.11, 4.04)

1.08 (0.25, 2.24)

1.02 (0.67, 1.54)

1.61 (0.57, 4.53)

1.75 (0.73, 4.16)

1.28 (0.35, 4.61)

100.00

0.85

9.20

40.20

3.67

1.45

3.93

27.25

4.39

6.23

2.84

1.1 1 10

4,818 patients, 10 trials

Favors DES Favors BMS

Estimate (95% CI) Weight (%)

1.05 (0.84,1.30)1.05 (0.84,1.30), p=0.69

Random Effects*Fixed Effects (I2=0.0%)

Mean f/u 4.0 yrs

Ajay J. Kirtane and Gregg W. Stone, 2008

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All-Cause Mortality: RCT’s (Off-Label)

I-V Overall (I-squared = 0.0%, p = 0.798)

HAAMU-STENT

Passion

PRISON IIMISSION!

DIABETES

BASKET (SES only)

Seville

D+L Overall

SES-SMARTSTRATEGY

TAXUS V - complex

SESAMITyphoon

0.84 (0.62, 1.13)

2.00 (0.63, 6.38)

0.70 (0.36, 1.36)

0.50 (0.09, 2.67)0.48 (0.09, 2.59)

1.44 (0.48, 4.33)

0.82 (0.37, 1.84)

1.35 (0.23, 7.78)

0.84 (0.62, 1.13)

0.21 (0.02, 1.71)0.84 (0.36, 1.96)

0.84 (0.38, 1.84)

0.43 (0.11, 1.63)1.01 (0.38, 2.65)

100.00

6.64

20.16

3.103.16

7.36

13.84

2.871.8012.40

14.32

4.909.44

1.1 1 10

4,049 patients, 12 trials

Favors DES Favors BMS

Estimate (95% CI) Weight (%)

0.84 (0.62,1.13)0.84 (0.62,1.13), p=0.24

Random Effects*Fixed Effects (I2=0.0%)

Mean f/u 1.5 yrs

Ajay J. Kirtane and Gregg W. Stone, 2008

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All-Cause Mortality: All Registries

NOTE: Weights are from random effects analysis

D+L Overall (I-squared = 70.1%, p = 0.000)

Ontario (matched)Germany Metabolic Syndrome

GHOST (adjusted)

RESTEMARTS 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)

Melbourne

McMaster STEMI (adjusted)

REAL (adjusted)

Mayo FFR SubstudyItalian 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)

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

5.981.15

3.09

3.631.92

4.87

6.29

5.256.80

1.20

2.31

4.66

3.13

0.76

6.80

1.78

1.25

6.984.70

0.73

0.29

6.10

0.360.57

3.216.44

3.40

6.35

1.1 1 10

161,232 patients, 28 registries

Favors BMS

Estimate (95% CI) Weight (%)

0.80 (0.72,0.88), p<0.0010.83 (0.79,0.86)

Favors DES

*Random Effects (I2=70.1%)Fixed Effects

Mean f/u 2.5 yrsAjay J. Kirtane and Gregg W. Stone, 2008

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MI: RCTs (On Label)

I-V Overall (I-squared = 0.0%, p = 0.761)

RAVEL

D+L Overall

SIRIUS

E-SIRIUS

TAXUS II

TAXUS IV

C-SIRIUS

TAXUS V - Simple

SCORPIUS

Ortolani et al

1.03 (0.81, 1.30)

1.24 (0.49, 3.14)

1.03 (0.81, 1.30)

0.96 (0.59, 1.55)

1.94 (0.93, 4.02)

0.63 (0.23, 1.72)

0.99 (0.66, 1.48)

0.59 (0.14, 2.47)

0.98 (0.52, 1.81)

0.82 (0.23, 2.95)

1.50 (0.26, 8.61)

100.00

6.29

23.26

10.13

5.36

33.28

2.63

13.95

3.33

1.77

1.1 1 10

4,318 patients, 9 trials

Favors DES Favors BMS

Estimate (95% CI) Weight (%)

1.03 (0.81,1.30)1.03 (0.81,1.30), p=0.82

Random Effects*Fixed Effects (I2=0.0%)

Ajay J. Kirtane and Gregg W. Stone, 2008

Mean f/u 4.4 yrs

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MI: RCT’s (Off Label)4,532 patients, 12 trials

1.1 1 10

SCANDSTENT

HAAMU-STENT

Typhoon

SES-SMART

PRISON II

TAXUS V - complex

Passion

STRATEGY

MISSION!

SESAMI

BASKET (All)

DIABETES

Estimate (95% CI) Weight (%)

0.33 (0.09, 1.18)

0.25 (0.03, 2.19)

0.80 (0.22, 2.97)

0.16 (0.04, 0.67)

0.83 (0.26, 2.64)

1.84 (0.86, 3.94)

0.83 (0.26, 2.69)

0.82 (0.31, 2.40)

0.62 (0.28, 1.39)

1.00 (0.20, 4.88)

1.15 (0.64, 2.08)

0.60 (0.20, 1.50)5.08

1.83

4.97

4.24

6.26

14.52

6.16

8.03

13.11

3.30

24.22

8.29

Favors DES Favors BMS

0.77 (0.54,1.10)0.83 (0.62,1.10), p=0.19

Random Effects*Fixed Effects (I2=25.5%)

Ajay J. Kirtane and Gregg W. Stone, 2008

Mean f/u 1.5 yrs

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MI: All Registries

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)

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)

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

8.901.10

3.09

3.55

8.26

4.21

2.69

6.10

1.11

5.15

0.70

5.01

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)

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

8.901.10

3.09

3.55

8.26

4.21

2.69

6.10

1.11

5.15

0.70

5.01

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

129,955 patients, 24 registries

Favors DES Favors BMS

Estimate (95% CI) Weight (%)

0.89 (0.80,0.98), p=0.023 0.96 (0.91,1.01)

*Random Effects (I2=57.9%)Fixed Effects

*MI is QWMI in Washington Hospital Center, RESTEM

Ajay J. Kirtane and Gregg W. Stone, 2008Mean f/u 2.5 yrs

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3 yr

Freedom from Stent Thrombosis out to 3-Years

Meta-Analysis: TAXUS II, IV, V, VI

Days Since Index Procedure

Free

dom

from

Ste

nt T

hrom

bosi

s

100%

90%

80%

12m 2 yr

10950

6m

500 600 700 800 900 1000100 200 300 400

TAXUSN = 1718

ControlN = 1727

98.7% (T)99.2% (C)

p = 0.36

Stent ThrombosisBetween 2 and 3 Years0.0% (0/922) TAXUS0.1% (1/921) Control

Stable early and very late rates

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Ellis: ACC 2006

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0 1 2 3 4

Time since PCI in years

0

1

2

3

4

5C

umul

ativ

e in

cide

nce,

%

Months 1 12 24 36 48Cumulative incidence, % 1.2 1.6 2.1 2.7 3.3Patients at risk 7538 7210 5164 2790 1051

3.3%

3.5

192 definite ST cases

Definite Stent Thrombosis: DESPatients Followed to 4 years

Incidence density1.0 / 100 pt years

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Months 1 12 24 36 42

Cumulative incidence SES, % 1.0 1.2 1.7 2.4 2.7Cumulative incidence PES, % 1.3 1.9 2.5 3.1 3.6

0

1

2

3

4

5

0 1 2 3

Cum

ulat

ive

inci

denc

e, %

3.5

PES Rotterdam

PES BernSES BernSES Rotterdam

PES: 3.6%

SES: 2.7%

HR=0.71(0.53-0.95)

P=0.019

192 Definite ST Cases

Definite Stent Thrombosis: DES Stent TypePatients Followed to 4 years

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Endeavor Safety AnalysisARC Definite/Probable ST to 1440 Days

Endeavor Pooled Safety Analysis: I Meredith et al. PCR. 2008.

Def/Prob Thrombosis 0 30 270 360 720 1080 1440

Endeavor 2132 2117 2085 2049 1247 1216 636# Events 1 6 4 2 1 0 0

% CI 0.0% 0.3% 0.5% 0.6% 0.7% 0.7% 0.7%Driver 596 585 581 575 560 549 539

# Events 1 6 1 0 0 1 0% CI 0 2% 1 2% 1 3% 1 3% 1 3% 1 5% 1 5%

0%

2%

4%

6%

8%

10%

0 90 360 720 1440Time After Initial Procedure (days)

Cum

ulat

ive

Inci

denc

e of

Def

/Pro

bTh

rom

bosi

s (A

RC

)

180 270 450 540 630 810 900 990 1080 1170 13501260

Endeavor Driver

1.5%0.7%

Before 1 yearEndeavor: 0.7%Driver: 1.2%

After 1 yearEndeavor: 0.08%Driver: 0.3%

Log rank p= 0.059

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0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

0 360 720 1080 1440

AR

C (D

ef/P

rob

Endeavor 2064 1251 1216 636

No. at Risk

Cypher 863 848 823 788 Taxus 1351 1300 1117 715

1 Year 2 Years 3 YearsPooled Data

Xience 959 868 NA NA

4 Years

Mauri et al. N Engl J Med. 2007;356:1020-1029.Endeavor: Mauri et al. TCT. 2007.Xience: Spirit II at ACC and Spirt III at PCR

Days

Endeavor Safety AnalysisARC Definite and Probable ST to 4 years

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All ComerDual APT >3 to <12 months

N = 8800>200 International Sites

Randomization 1:1

EndeavorN=4400

Clinical Follow-up30d 6mo 4 yr3yr30mo24mo 5 yr

Primary Endpoint: ARC Definite or Probable Stent Thrombosis at 3 years

Main Secondary Endpoints:Death or Cardiac death combined all non-fatal MI as well as the number of patients with large non-fatal MIClinical Follow up and Dual Antiplatelet Monitoring:At 30 days, and every 6 months until 3 years, than each year until 5 years

CypherN=4400

12mo 18mo

PROTECT International RCT Designed to Estimate VLST

(>1 year)

Over 3500 Patients Currently Enrolled

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% o

f Pat

ient

sXience

ARC Definite and Probable ST before and after 1 year

Endeavor: Fajadet et al. PCR 2008

0.9%0.7%

0.3%0.5%

0.6%0.8%

1.0%0.8%

0.0%

0.5%

1.0%

1.5%

2.0%

Sprit III Pooled Spirit III Pooled

XienceTaxus

TaxusXience TaxusXience TaxusXience TaxusXience2/3216/655 3/3986/878 3/3092/642 3/3824/853

≤1 year ≥1 year to 2 years

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11/11/2008 Schömig, Dibra, Spaulding et al Eur H J (in press)

Meta-analysis of DES vs. BMS RCTs in AMI:

Stent Thrombosis

1

3

5

Prob

abili

ty o

f Ste

nt T

hrom

bosi

s (%

)

4

2

0

DES BMS

Months After Randomisation0 2 41 53 7 96 108 11 12

29/1,31225/1,474Overall

1/1602/160SESAMI2/880/87STRATEGY

13/35712/355TYPHOON.

3/3093/310PASSION

3/1522/158MISSION

5/822/82HAAMU-STENT

1/901/180Di Lorenzo

1/743/142BASKET-AMI

BMS group

DES groupTrial

No. of events/Total No. of patients

I2 = 0%; P (heterogeneity) =0.88; P (Overall Effect) =0.43

-1 101

0.80 (0.46 TO 1.39)

Favours DES

Favours BMS

Hazard Ratio

1.7%

2.2%

Kastrati A, et al. Eur Heart J. 2007;28:2706-13.

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Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Cilostazol) Significantly Reduces Ischemic Events

after Drug-Eluting Stent Implantation

Division of Cardiology, Asan Medical CenterUniversity of Ulsan College of Medicine, Seoul, Korea

Seong-Wook Park, MD, PhD, FACC

:Drug-Eluting stenting followed by Cilostazol treatment REduces Adverse Serious cardiac Events

The DECREASE Registry

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Timing of stent thrombosis and use of antiplatelet therapy

0

21

23

7

0

2

4

6

8

10

Acute Subacute Late

Num

ber o

f pat

ient

s

Triple antiplatelet therapy (n=3)

Dual antiplatelet therapy (n=12)

1 aspirin alone

1 dual therapy

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A “Rare” Adverse Event Could Have Major Consequences

45% of ST leads to death60% of ST leads to MI

~2.5 million stents implanted

1.2% stent thrombosis rate

~30,000 people affected

*Lakovou et al. JAMA. May 2005.*Results are from 2005 US, www.devicelink.com.

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Endeavor Pooled Safety Analysis

Dual Antiplatelet Therapy (DAPT) Usage

Percent of patients on DAPT at: 1 year 2 years 3 years 4 years

ENDEAVOR (I, II, IICA)29.1%(279/958)

11.2%(106/943)

8.5%(79/926)

8.3%(75/908)

Driver (II) 29.0%(166/572)

13.5%(76/562)

9.1%(50/548)

9.2%(50/945)

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0.00%

0.20%

0.40%

0.60%

0.80%

1.00%

1.20%

1.40%

ST Rate 0.60% 0.80% 0.40% 0.80% 0.50% 1.30% 0.46% 0.00% 1.00% 0.50% 1.20% 0.00% 0.00% 0.80% 0.10%

Taxus -Taxus IV

Express -Taxus IV

Cypher -Sirius

BX Velocity -

Sirius

Xience V -Spirit II

Taxus -Spirit II

Xience V -Spirit III

Taxus -Spirit III

Endeavor -Endeavor

I

Endeavor -Endeavor

II

Driver -Endeavor

II

Endeavor -Endeavor

III

Cypher -Endeavor

III

Endeavor -Endeavor

IV

Taxus -Endeavor

IV

Timing 9M 9M 9M 9M 6M 6M 9M 9M 12M 9M 9M 9M 9M 9M 9M

Late Stent Thrombosis: Total ST Rates in key trials before 1 year

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Late DES Thrombosis

• Late DES thrombosis is uncommon but associated with high morbidity

• LST (beyond 1-2 yrs) is more frequent with DES than BMS

• LST is associated with D/C of antiplatelet Rx • Etiology not well understood (likely related to

delayed healing / hypersensitivity)• Prolong dual antiplatelet Rx advisable in high

risk pts

Conclusions

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ENDEAVOR IIENDEAVOR II Clopidogrel Therapy for ≥3 months

Days Post Procedure

1.2% (7)Driver

1 2 303 12 13 14

0.5% (3)

Endeavor

100 200 360270

1 year720500 600

2 years

Defined as angiographic thrombus or subacute closure within the stented vessel at the time of the clinically driven angiographic re-study for documented ischemia (chest pain and ECG changes). Any death not attributed to a non-cardiac cause within the first 30 days is considered a surrogate for stent thrombosis in the absence of documented angiographic stent patency.

Safety Profile

Fajadet et al. Circulation. 2006;114:98-806.

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Conclusions• Healing delay is inherent in the mechanism of

benefit of DES’s• SAT rates appear to be similar to BMS for simple

lesions– But the time window for risk is longer for DES’s (i.e. late

DES thrombosis)– Premature discontinuation of anti-platelet therapy

increases risk of thrombosis• Thrombosis rates likely increased for complex

lesion and patient subsets– Major side branches, bifurcations, overlapped stents,

thrombus containing lesions, poor distal runoff– Renal failure, diabetics

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Endeavor Safety AnalysisCumulative Incidence of Cardiac Death and

MI to 1440 Days

Endeavor Pooled Safety Analysis: I Meredith et al. PCR. 2008.

Cardiac Death or MI 0 30 270 360 720 1080 1440Endeavor 2132 2083 2052 2014 1219 1186 622# Events 30 12 14 4 3 5 5

% CI 1.4% 2.0% 2.6% 2.8% 3.1% 3.5% 4.3%Driver 596 573 566 560 545 535 525

# Events 15 6 5 1 7 5 2% CI 2.5% 3.5% 4.4% 4.5% 5.8% 6.6% 7.0%

0%

2%

4%

6%

8%

10%

0 90 360 720 1440Time After Initial Procedure (days)

Car

diac

Dea

th o

r MI

180 270 450 540 630 810 900 990 1080 1170 13501260

Endeavor Driver

7.0%

4.3%

Log rank p= 0.005

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11/11/2008 Lagerqvist B, et al. Oral Presentation. ESC 2007.

…no more overall significant difference in mortality”

Total cohort n=35,262 One stent cohort n=18,9372003 – 2005 Adjusted Risk

RR: 1.03 (0.94 - 1.14)

BMS DES

Cum

ulat

ive

risk

of d

eath

0.05

0.10

0.15

Time (years)1 32 40

BMS 18,769 18,136 17,948 16,109 13,401 10,326 7,158 3,970 1,179

DES 12,015 11,705 11,559 9,020 6,181 3,844 2,153 847 115

2003 – 2005 Adjusted Risk

RR: 0.95 (0.83 - 1.1)

BMS DES

Time (years)1 32 4

Cum

ulat

ive

risk

of d

eath

0.05

0.10

0.15

0

Slope 2.5% / yr

BMS 12,556 12,185 12,061 10,837 9,001 6,920 4,824 2,697 783

DES 6,381 6,237 6,161 4,844 3,280 2,038 1,140 462 58

“During 4 years follow-up …

SCAAR 2007 ReportComposite of Death up to 4 years Post-

Procedure

James S. Oral Presentation. TCT 2007

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11/11/2008 James S, et al. Oral Presentation. ESC 2007

SCAAR 2007 ReportLandmark Analyses per Year

BMS

DES

6,448 5,713 2,9346,037 5,918 5,820 5,5205,612 7

1,799 1,568 5351,685 1,644 1,607 1,4961,539 0

6,737 5,883 06,228 6,090 5,983 33,143 0

3,880 3,388 03,638 3,550 3,468 21,523 0

5,584 0 05,061 4,949 2,611 00 0

6,336 0 05,963 5,809 2,573 00 0

Total cohort (Death or MI: risk adjusted )Prespecified landmarks at 6 months

2003

0

0.05

0.10

0.25

0 21 3 4Time (years)

Cum

ulat

ive

risk

of d

eath

or M

I

RR: 1.06 (0.86-1.32)

RR: 1.31 (1.12-1.53)

BMS DES

0.15

0.20DES 21.8 %

2004

0

0.10

0.20

0.25

0 21 3 4Time (years)

RR: 0.98 (0.83-1.17)

RR: 1.22 (1.05-1.43)0.05

0.15

BMS DES

DES 36.5 %

2005

Time (years)

0

0.05

0.20

0.25

0 21 3 4

RR: 0.69 (0.59-0.81)

RR: 0.93 (0.76-1.13)

0.15

0.10

BMS DES

DES 53.1 %

James S. Oral Presentation. TCT 2007

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81 cases

010

2030

4050

Freq

uenc

y

0 1 2 3Years

76 cases

010

2030

4050

Freq

uenc

y

0 1 2 3Years

Bare Metal Stents Drug-Eluting Stents

Definite Stent Thrombosis: BMS vs. DESThe Bern Experience 1995-2005

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Endeavorn = 2132 [95% CI]

Drivern = 596 [95% CI]

Early (0-30d)

0.3% [0.09,0.57] 1.2% [0.31,2.04]

Late (31-360d)

0.3% [0.04,0.52] 0.2% [0.00,0.51]

Very Late (361d-4y)

0.1% [0.00,0.32] 0.2% [0.00,0.56]

Cumulative(to 4y)

0.7% [0.13,1.30] 1.5% [0.41,2.64]

Cumulative Incidence -%

Cumulative Incidence of Stent Thrombosis byTime Interval (ARC definite and probable)

Endeavor Safety Analysis

Standard error was estimated by Peto formula

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71.7%

59.4%

71.7%63.9%

0%

20%

40%

60%

80%

100%

Per

cent

Adh

eren

ce to

DA

PT

1 year 2 year

Spirit IIIAdherence to DAPT

TaxusXience TaxusXience

XienceTaxus

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Day 4002001000 500300

CYPHER

TAXUS

335 343 375 442

Very Late Stent Thrombosis Initial Cases and Discussion: DAPT Prior

McFadden EP et al. Lancet 2004; 364:1519–21

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TAXUS I, II, IV, V, VI(n=3,506)

RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS(n=1,748)

Stent Thrombosis Freedom From (ARC Definite/Probable) Stent Thrombosis

Kirtane et al. TCT. 2007. *Includes intervening TLR

9 of 11 BMS patients who had an ST due to intervening TLR received brachytherapy

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0 1 2 3 4

0.00

0.05

0.10

0.15

2003-2005, Adjusted

Time (years)

Cum

ulat

ive

risk

of d

eath

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Death/MI-

total cohortYear by year

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Impact on Cardiac Death and MI

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Delayed Endothelialization

Conclusions:• 86.7% of Cypher

stents had incomplete coverage (Grades 0-1)

• 0% of BMS had incomplete coverage(Grades 0-1)

Cypher vs BMS

Grade 0 was defined as stent struts that were fully visible, similar to immediately after implantation.Grade 1 was defined as stent struts that bulged into the lumen and, although covered, were still transparently visible.Grade 2 was defined as stent struts that were visible, but not clearly seen (ie, they were translucent). Grade 3 was defined as stent struts that were not visible by angioscopy (ie, they were embedded in the neointima).Kotani et al. JACC Vol. 47, No. 10, 2006.

0255075

100

Incomplete coverage Complete coverage

Sirolimus-eluting stent

Bare-metal stent

Grade 0 Grade 1 Grade 2 Grade 3

250

5075

100

Perc

ent

Perc

ent

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TAXUS I, II, IV, V, VI(n=3,506)

RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS(n=1,748)

Cardiac Death and MI Freedom from Cardiac Death and MI

Kirtane et al. TCT. 2007.

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Ellis: ACC 2006

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2007:Stone et al Circulation 2007;115;2842-2847

Pooled Analysis Taxus II, IV, V, VI, Trials Stent Thrombosis Related Events

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2007:Stone et al Circulation 2007;115;2842-2847

Pooled Analysis Taxus II, IV, V, VI, Trials TLR Related Events

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PlateletAggregation

VesselPermeability

Vessel Tone and Vascular Remodeling

Smooth MuscleProliferation

Wound Healing

Angiogenesis

Nitric Oxide (NO)Roles in Vasculature

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Stent Thrombosis:Procedure, Product, Patient

Procedure

StentThrombosis

Post DilationFull Apposition

PatientHigher Risk

AP Compliance

Product

PolymerDrug

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Procedure

Stent ThrombosisProcedure, Product, Patient

StentThrombosis

• Post Dilation• Flush apposition

Patient• Higher Risk• AP Compliance and

Resistance

Product• Polymer integrity

and reactions• Drug effects

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Causes of DES Thrombosis

• The polymer (hypersensitivity reactions, inflammatory and thrombogenic)!!!

• The drug (delayed healing and incomplete late stent apposition)

• The procedure (suboptimal stent deployment and inflow/outflow problems)

• The patient (anti-platelet resistance, intrinsic thrombogenicity and more complex lesions)

= increased sensitivity to obligatory prolonged dual antiplatelet regimens

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Lack of Endothelial Strut CoverageDES vs BMS >3 years in Humans

P = .0001

Perc

enta

ge E

ndot

helia

lizat

ion

Duration in months

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 11 15 16 17 20 >40

Taxus and CypherBMS

Joner, Virmani et al. Circulation. 2005;112:3210.

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Correlates with Definite DES Thrombosis

Definite ST Multivariate Logistic Regression Analysis

Characteristic Odds Ratio

Confidence Interval

p value

Diabetes mellitus 1.9 1.2-3.1 0.006MI this admission 2.0 1.3-3.3 0.003Number of stents 1.3 1.1-1.5 <0.001Restenosis lesion 4.1 2.3-7.5 <0.001

Pinto T, Waksman R, et al. AHA 2007

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Pts 2900 939 2833 6186 1001 215 7484 1205

Yrs 92-95 95-96 92-97 95-99 93-95 95-96 93-02 2001

1.81.5

2.3

0.9

1.9 1.9

0.4

2.8

0

1

2

3

4

5

Karrillon De Servi Schuhlen Cutlip Moussa Werner Cheneau Serruys

Stent Thrombosis in Bare Metal Stents

1.2% in 22,763 pts

%

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2.9

5.8

5.5

2.7

0.040.02

1.8

%

8.7±13.3 8.3±20.90.05±0.19

1.8±4.0

p<0.001

p=0.04

p<0.001

p<0.001

Secondary Endpoint: Overlap Proportion of uncovered and/or malapposed struts by stent type

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Predictors of Stent Thrombosis Change with Time:

Up to 6 months:

Patient & Lesion complexity

Diabetes

Renal Failure

Long lesions

Small vessels

Bifurcations

Pharmacologic

Plavix® resistance

Early discontinuation

After 6 months:

Apparently not lesion complexity

Number of Stents ??

Apparently Not pharmacologic

Largely off Plavix

But will capture all meds.

Slow endothelialization

Genetics

Rupture Plaque ?

EPC levels

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WHC Predictors of Stent Thrombosis in DES Era

OR 95% CI P valueAge 0.97 0.94-1.0 0.06Male 0.66 0.31-10.4 0.27CABG History

0.15 0.01-1.2 0.07

Renal failure

3.75 1.2-11.3 0.02

IDDM 2.0 0.84-4.9 0.12Bifurcation 4.4 1.96-10.0 0.0004ISR 4.5 1.8-11.4 0.0013Lack of clopidogrel

0.21 0.09-0.49 0.0003Washington Hospital Center

Kuchulakanti, Waksman. Circulation 2005;113:1108-13

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