支架内血栓 in-stent thrombosis
DESCRIPTION
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 PresentationTRANSCRIPT
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– 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
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
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.
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?
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
(%
)
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
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-
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
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
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
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%
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
%
High Risk of ST in All-Comer Patient Population and STEMI Patients
%
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
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)
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
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
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
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
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
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
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
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)
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
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
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
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
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
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
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)
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
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)
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
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
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
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
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)
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)!
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