支架内血栓 in-stent thrombosis

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支架内血栓 In-Stent Thrombosis. 北京大学第一医院 李建平. Definite/Confirmed (肯定的) Acute coronary syndrome AND [Angiographic confirmation of thrombus or occlusion OR Pathologic confirmation of acute thrombosis] Probable (可能的) Unexplained death within 30 days - PowerPoint PPT Presentation

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Page 1: 支架内血栓 In-Stent Thrombosis

支架内血栓In-Stent Thrombosis

北京大学第一医院 李建平

Page 2: 支架内血栓 In-Stent Thrombosis

• Definite/Confirmed (肯定的)– Acute coronary syndrome AND– [Angiographic confirmation of thrombus or occlusion

OR– Pathologic confirmation of acute thrombosis]

• Probable (可能的)– Unexplained death within 30 days– Target vessel MI without angiographic confirmation of

thrombosis or other identified culprit lesion

• Possible (不能排除的)– Unexplained death after 30 days

ARC 支架内血栓定义

Page 3: 支架内血栓 In-Stent Thrombosis

支架内血栓的预后

SES (N=13)

BMS (N=15

)

Death 4 5

Myocardial Infarction 13 13

Fatal MI 4 4

Q Wave MI 8 5

Non-Q Wave MI 5 8Similar mortality observed for SES and BMS thrombosisSimilar mortality observed for SES and BMS thrombosis

Pooled Data from RAVEL, SIRIUS, C-SIRIUS, E-SIRIUSPooled Data from RAVEL, SIRIUS, C-SIRIUS, E-SIRIUS

Page 4: 支架内血栓 In-Stent Thrombosis

支架内血栓发生时间

ST = stent thrombosis; SAT = subacute stent thrombosis;LST = late stent thrombosis; VLST = very late stent thrombosis.Adapted from Bhatt. J Invasive Cardiol. 2003;15(suppl B):3B.

Page 5: 支架内血栓 In-Stent Thrombosis

Ste

n t T

h rom

bos i

s (%

)

支架内血栓与抗凝、抗血小板治疗

ASA und Ticlopidine

ASA und Anticoagulation

ASA und Clopidogrel

DES

ASA = Acetylsalicylic acidDES: Drug-eluting stentASA = Acetylsalicylic acidDES: Drug-eluting stent

Bare Metal Stent Bare Metal Stent

Prasugrel?

Page 6: 支架内血栓 In-Stent Thrombosis

BMS 支架内血栓发生率

Days

10

8

6

4

2

00 30 60 120 600

N

Early1.2%

(N=71)

Late0.4%

(N=24)

Study population 1995-2002

-6,058 patients undergoing PCI with BMS

Wenaweser P et al. EHJ 2005

N=1,191 N=1,855 N=361 N=6,058Ste

nt

Th

rom

bo

si s

(%

)

Page 7: 支架内血栓 In-Stent Thrombosis

DES 肯定的 ST 发生率 :Bern - Rotterdam Cohort Study

Daemen, Wenaweser et al. Lancet 2007;369:667-78

0.6% / yearEarly ST 91 pts(60%)

Late ST 61 pts (40%)

Incidence density:

1.3 / 100 patient years

N=8146

Page 8: 支架内血栓 In-Stent Thrombosis

0 1 2 3 4

Time since PCI in years

0

1

2

3

4

5C

um

ula

tiv

e i

nc

ide

nc

e,

%

Months 1 12 24 36 48

Cumulative incidence, % 1.2 1.6 2.1 2.7 3.3

Patients at risk 7538 7210 5164 2790 1051

Incidence density

1.0 / 100 pt years

3.3%

3.5

0.53% (95% CI=0.44-0.64)/ year

192 definite ST cases

DES 肯定的 ST 发生率 :Bern-Rotterdam Cohort Study @ 4 Years

Wenaweser P et al. J Am Coll Cardiol 2008, 52, 1134-

Page 9: 支架内血栓 In-Stent Thrombosis

0.52% (95% CI=0.42-0.62)/ year

between 30 days and 5 years

DES 肯定的支架内血栓发生率 :Bern-Cohort Study @ 5 Years

Wenaweser P et al. ESC 2008

Page 10: 支架内血栓 In-Stent Thrombosis

Favours DES Favours BMS

>18

0 d

ays 3

1-1

80 d

ays0

-30

day

sT

ime

aft

er P

CI

.1 .2 .5 1 2 5 10 20 50 100

Odds Ratio

Favors DES Favors BMS

.1 .2 .5 1 2 5 10 20 50 100

Odds Ratio

Adjusted Resultswith interaction terms for time since PCI

Early period: 0-30 daysOR 0.59, 95% CI .35 - 1.01

Late period: 31-180 daysOR 0.52, 95% CI .16 – 1.75

Very late period: > 180 daysOR 9.4, 95% CI 2.56 – 34.70Wenaweser et al. ACC 2007

DES vs BMSA cohort of 9,175 patients treated with either BMS or DES (SES or PES), all

patients with angiographically documented ST were identified as cases

Page 11: 支架内血栓 In-Stent Thrombosis

Very Late ST > 1 Year (Per Protocol)

P=0.75

P=0.02

% P=0.30

P=0.03

%

Stone G et al. NEJM 2007;356:998-1008Kastrati A et al. NEJM 2007;356:1030-9

Sirolimus-Eluting Stent Paclitaxel-Eluting Stent

Page 12: 支架内血栓 In-Stent Thrombosis

SIRTAX – Definite ST @ 4 YearsWindecker S et al ESC 2008

2.0%

1.8%

2.8%

2.4%

3.7%

3.4%0.00

0.05

0.10

0.15

0.20C

umula

tive

Inci

denc

e of

ST

(%

)

0 .25 .5 .75 1 1.25 1.5 1.75 2 2.25 2.5 2.75 3 3.25 3.5 3.75 4Follow-up (years)

Sirolimus Stent Paclitaxel Stent

1-year HR1.12 [0.46, 2.76]

P = 0.01

2-year HR0.86 [0.40, 1.87]

P = 0.71

3-year HR0.90 [0.47, 1.73]

P = 0.75

4-year HR1.06 [0.57, 1.95]

P = 0.86

SES 4.2%

PES 3.9%

Page 13: 支架内血栓 In-Stent Thrombosis

Overall Incidence of ST with DES

CYPHER

TAXUS ENDEAVOR XIENCE

BIOMATRIX

0.4 0.3

0.70.5

1.61.4

0.8

TAXUS II

TAXUS IV

TAXUS V

TAXUS VI

REALITY

SIRTAX

ISAR-D

M

1

0.5

0.8

1.9

Endea

vor I

Endea

vor I

I

Spirit I

II

Lead

ers

0.2

1.1

2

0.6

1.8

0.8

00

1

2

3

SIRIU

S

E-SIR

IUS

C-SIR

IUS

REALITY

SIRTAX

ARTS II

ISAR-D

M

%

Page 14: 支架内血栓 In-Stent Thrombosis

High Risk of ST in All-Comer Patient Population and STEMI Patients

%

Page 15: 支架内血栓 In-Stent Thrombosis

支架内血栓的病因

STENT THROMBOSIS

StentDesign/Length

PolymerSurfaceDrugs

LesionVessel SizeThrombus

InterventionResidual Dissection

Incomplete Stent AppositionAntithromobotic Medication

PatientGenetic Polymorphism

Reduced LV-EFAcute Coronary Syndrome

Hematology Disorder

DrugsResistance

Drug-drug InteractionDuration of Antiplatelet

Treatement

Vessel ReactionVessel Remodeling

Hypersensitivity ReactionDelayed Healing

Page 16: 支架内血栓 In-Stent Thrombosis
Page 17: 支架内血栓 In-Stent Thrombosis

早期支架内血栓的预测因素 :残留夹层 / 撕裂

Bare Metal StentsMACE @ 30 days

Schühlen H et al. Circulation 1998

N=2,894

Drug-Eluting StentsMACE @ 30 days

Biondi-Zoccai G et al. EHJ 2006

N=2,418

%P=0.01

P=0.01

Residual Dissectio

n: Independent P

redictor of M

ACE (OR=2.9)

Page 18: 支架内血栓 In-Stent Thrombosis

早期支架内血栓 IVUS 预测因素 With the Use of Sirolimus-Eluting Stents

Fujii K et al. J Am Coll Cardiol 2005;45:995-8

Minimal Stent CSA

P<0.001

mm2

Stent Expansion Residual Stenosis

%P<0.001

Stent Underexpansion and Residual R

eference Segment Stenosis:

Independent Predictors of E

arly Stent Thrombosis!

P<0.001

Page 19: 支架内血栓 In-Stent Thrombosis

支架内血栓预测因素药物反应异常

Wenaweser P et al. JACC 2005; 45(11):1748-52

Page 20: 支架内血栓 In-Stent Thrombosis

服药后血小板活性与 DES ST 的关系Buonamici P et al JACC 2007

p<0.001 p<0.001

p<0.001p=ns

Page 21: 支架内血栓 In-Stent Thrombosis

Iakovou et alJAMA 2005

Park et alAm J Card 2006

Airoldi et alCirculation 2007

Kuchulakanti et alCirculation 2006

OR=89.8(29.9-270)

HR=19.2(5.6-65.5)

HR=13.7(4.0-46.7)

OR=4.8(2.0-11.1)

Odd

s/H

azar

d R

atio

过早停用抗血小板药物是支架内血栓的重要预测因素

Page 22: 支架内血栓 In-Stent Thrombosis

支架内血栓发生时的抗血小板治疗 Bern-Rotterdam Cohort Study @ 5 Years

Wenaweser P et al. ESC 2008

Page 23: 支架内血栓 In-Stent Thrombosis

Park et alAm J Card 2006

Airoldi et alCirculation 2007

Iakovou et alJAMA 2005

Machecourt et alJACC 2007

OR=1.03(1.00-1.05)

OR=1.01(1.00-1.03)

OR=2.75(1.55-4.88)

Od

ds

Rat

io

支架内血栓的预测因素 - 支架长度OR=1.02

(1.00-1.04)OR=1.08(1.06-1.1)

De la Torre et alJACC 2008

Page 24: 支架内血栓 In-Stent Thrombosis

Roy et alJ Interv Card 2007

Kuchulakanti et alCirculation 2006

OR=4.4(2.0-10.0)

Odd

s R

atio

支架内血栓的预测因素 - 分叉病变

OR=2.4(1.1-5.6)

Iakovou et alJAMA 2005

OR=6.4(2.9-14.1)

Ong et alJACC 2005*

OR=12.9(4.7-35.8)

*in setting of AMIJoner et al JACC 2006

Page 25: 支架内血栓 In-Stent Thrombosis

Park et alAm J Card 2006

Daemen et alLancet 2007

Urban et alCirculation 2006

OR=12.4(1.7-89.7)

OR=2.3(1.3-4.0)

OR=1.8(1.1-2.7)

Od

ds/

Haz

ard

Rat

io

支架内血栓的预测因素 -ACS

De la Torre et alJACC 2008

HR=2.6(1.3-4.9)

Page 26: 支架内血栓 In-Stent Thrombosis

Impact of Thrombus Burden on Risk of ST With DES in Patients With STEMI

Sianos G et al. J Am Coll Cardiol 2007;50:573-83

Variable Hazard Ratio 95% CI

Age 0.6 0.4-0.8

Index ST 6.2 2.1-18.9

Bifurcation 4.1 1.6-10.0

Thrombectomy 0.1 0.01-0.8

Large thrombus 8.7 3.4-22.5

Independent Predictors of ST

Page 27: 支架内血栓 In-Stent Thrombosis

Kuchulakanti Circ 2006

Urban Circ 2006

IakovouJAMA 2005

DaemenLancet 2007

Machecourt JACC 2007

OR=2.0(0.8-4.9)

OR=2.8(1.7-4.3)

HR=3.7(1.7-7.9)

HR=2.0(1.1-3.8)

OR=2.7(1.4-5.2)

Od

ds/

Haz

ard

Rat

io

支架内血栓的预测因素 - 糖尿病

IijimaAm J Card 2007

HR=2.2(1.1-4.3)

HR=1.75(1.0-3.0)

De la TorreJACC 2008

Page 28: 支架内血栓 In-Stent Thrombosis

晚期支架内血栓的可能原因

• Chronic inflammatory reaction to the polymer or drug

• Hypersensitivity to the polymer or drug

• Failure of stents to completely reendothelialize completely

• Late incomplete stent apposition

• Disease progression

Page 29: 支架内血栓 In-Stent Thrombosis

获得性晚期支架贴壁不良

Baseline 8 mo follow-up

SIRIUS Trial: 7/80 (8.7%) patients, no 12-month MACE

Ako J. et al. JACC 2005;46:1002-5

Page 30: 支架内血栓 In-Stent Thrombosis

Cook et al. Circulation 2007Kotani et al. JACC 2006

Joner et al. JACC 2006Togni et al. JACC 2005

Abnormal Vasomotion Delayed Healing

Delayed Endothelialization Vessel Remodeling

DES 后病生理机制

Endothelialization

Page 31: 支架内血栓 In-Stent Thrombosis

支架内血栓的预防

• 高危病人的辨认• 避免过度支架

– 长支架 , 分叉支架 , 支架重叠

• 支架植入的理想结果 – 无残留撕裂 / 夹层– 支架膨胀良好

• 增加抗血小板治疗的有效性– 高危病人评估抗血小板药物的反应性

• 再狭窄低危病人中使用 BMS

Page 32: 支架内血栓 In-Stent Thrombosis

专家共识专家共识专家共识专家共识FDA DES Panel Meeting

There is an increase in “very late” (>1 yr) stent There is an increase in “very late” (>1 yr) stent thrombosis associated with current DESthrombosis associated with current DES

• ~2-4 per 1000 pts per year (? continous hazard, ~2-4 per 1000 pts per year (? continous hazard, ? patient and lesion predictors) ? patient and lesion predictors)

• Data from multiple sources indicate thatData from multiple sources indicate thatDES are associated with delayed healingDES are associated with delayed healingresponses and increased inflammationresponses and increased inflammation

• The causes of late DES thrombosis are multi-The causes of late DES thrombosis are multi-factorial; device, procedural, and patientfactorial; device, procedural, and patientfactors (often multiple = perfect storm) factors (often multiple = perfect storm)

Page 33: 支架内血栓 In-Stent Thrombosis

专家共识专家共识专家共识专家共识FDA DES Panel Meeting

• There may be a link between post-DES reduced There may be a link between post-DES reduced neo-intimal hyperplasia (late loss) and delayed neo-intimal hyperplasia (late loss) and delayed late healing responses which contributes to late late healing responses which contributes to late stent thrombosisstent thrombosis

• DES stent thrombosis is highly definition DES stent thrombosis is highly definition dependent; need for revised standardizeddependent; need for revised standardizeddefinitions and adjudication methods (ARC) definitions and adjudication methods (ARC) to facilitate inter-study comparisonsto facilitate inter-study comparisons

Page 34: 支架内血栓 In-Stent Thrombosis

专家共识专家共识专家共识专家共识““Off-label DES use – increased incidence of late Off-label DES use – increased incidence of late

DES thrombosis and death/MI cw “on-label”, butDES thrombosis and death/MI cw “on-label”, butinadequate controls; results inconsistent!inadequate controls; results inconsistent!

• Few RCTs (underpowered); FDA sanctioned Few RCTs (underpowered); FDA sanctioned registries = insufficient sample size and FU, registries = insufficient sample size and FU, represents major data gap and source of represents major data gap and source of concernconcern

• Large population studies (SCAAR) fraught Large population studies (SCAAR) fraught with methodologic flaws (e.g. risk adjustment with methodologic flaws (e.g. risk adjustment issues) issues)

Page 35: 支架内血栓 In-Stent Thrombosis

专家共识专家共识专家共识专家共识Duration of dual anti-platelet therapy should Duration of dual anti-platelet therapy should

extend beyond the present product labelsextend beyond the present product labels

• OOne year is reasonable compromise (esp. forne year is reasonable compromise (esp. for“off-label” DES use)“off-label” DES use)

• Must balance against the increased risk ofMust balance against the increased risk ofbleeding with dual anti-platelet therapybleeding with dual anti-platelet therapy

• Additional studies immediately required toAdditional studies immediately required tobetter clarify optimal anti-platelet therapybetter clarify optimal anti-platelet therapy

Page 36: 支架内血栓 In-Stent Thrombosis

专家共识专家共识专家共识专家共识Assess patient and lesion characteristics to Assess patient and lesion characteristics to

establish restenosis risk profileestablish restenosis risk profile

• Determine relative value of DES vs. BMS inDetermine relative value of DES vs. BMS inevery patient (no more “unrestricted” use) every patient (no more “unrestricted” use)

• Consider both on-label and off-label Consider both on-label and off-label situations (ironically, off-label use scenarios situations (ironically, off-label use scenarios may be more compelling)may be more compelling)

• Increased restenosis risk = favor DESIncreased restenosis risk = favor DES

• Increased safety concerns = favor No DES Increased safety concerns = favor No DES

Page 37: 支架内血栓 In-Stent Thrombosis

专家共识专家共识专家共识专家共识Assess patient factors which may preclude long-Assess patient factors which may preclude long-

term (at least one year) dual AP therapyterm (at least one year) dual AP therapy

• Planned or possible intercurrent surgeryPlanned or possible intercurrent surgery

• Bleeding Hx or tendenciesBleeding Hx or tendencies

• Other concomitant medications (e.g. Other concomitant medications (e.g. coumadin)coumadin)

• Socio-economic factors which may affect Socio-economic factors which may affect Plavix compliance Plavix compliance

Page 38: 支架内血栓 In-Stent Thrombosis

专家共识专家共识专家共识专家共识Consider alternatives to DES, if risk-benefit Consider alternatives to DES, if risk-benefit

assessments prove unfavorableassessments prove unfavorable

• CABG – unprotected LM disease, complex CABG – unprotected LM disease, complex MVD (esp. diabetics), recurrent ISR (esp. VBT) MVD (esp. diabetics), recurrent ISR (esp. VBT)

• BMS – Plavix dependence concerns, large BMS – Plavix dependence concerns, large (>4mm diameter) vessels, ? AMI pts, ? low (>4mm diameter) vessels, ? AMI pts, ? low restenosis risk lesionsrestenosis risk lesions

• Balloon PCI – sidebranch in bifurcations Balloon PCI – sidebranch in bifurcations (provisional stent only), small vessels in distal (provisional stent only), small vessels in distal locations locations

Page 39: 支架内血栓 In-Stent Thrombosis

专家共识专家共识专家共识专家共识Optimize DES implantation techniquesOptimize DES implantation techniques

• Adequate lesion preparation (pre-dilatation)Adequate lesion preparation (pre-dilatation)

• High pressure implantation methodologies High pressure implantation methodologies (like previous BMS strategies)(like previous BMS strategies)

• Avoid undersizing and inflow/outflow Avoid undersizing and inflow/outflow obstruction (mod stenoses or dissections)obstruction (mod stenoses or dissections)

• Implant stent edges into normal references Implant stent edges into normal references segmentssegments

• Consider IVUS guidance (esp. LAD) Consider IVUS guidance (esp. LAD)

Page 40: 支架内血栓 In-Stent Thrombosis

专家共识专家共识专家共识专家共识Careful explanations and open communication Careful explanations and open communication

with patients and familieswith patients and families

• Careful pre-treatment historyCareful pre-treatment history

• Discussion with EVERY pt re: risks and Discussion with EVERY pt re: risks and benefits of DES vs. alternative therapiesbenefits of DES vs. alternative therapies

• Ongoing (post-Rx) communication and careful Ongoing (post-Rx) communication and careful FU re: dual AP compliance (instructions = NO FU re: dual AP compliance (instructions = NO Plavix discontinuation without MD approval)! Plavix discontinuation without MD approval)!

Page 41: 支架内血栓 In-Stent Thrombosis

DES 风险 & 获益• 治疗 1000 个病人可以预防 100 个再狭窄• 同时可以预防 10 个再狭窄相关的心肌梗

死• 可能会因为晚期支架内血栓增加 5 个心

肌梗死• 获益 > 风险