Saqib Chowdhary Wythenshawe Hospital STENT THROMBOSIS How Do IVUS & OCT Help.
Stent Thrombosis
Transcript of Stent Thrombosis
StentThrombo
sisDr. Surinder SinghDr. Surinder Singh
Time Frame Classification Time Frame Classification
Suggested Risk FactorsSuggested Risk Factors Procedure - Related
Smaller final lumen dimensions (malapposition/ underexpansion),
Persistent slow coronary blood flow
Placement of multiple stents Overlapping stents Dissections Geographic miss Late stent malapposition Stent length Residual stenosis SB occlusion
Patient - Related Male Low ejection fraction Diabetes mellitus Advanced age Renal failure Smoker Antiplatelet therapy compliance
Lesion - Related Setting of an ACS Complex PCI (bifurcation, ISR,
graft, CTO)
Predictors of DES Predictors of DES ThrombosisThrombosis
Moreno, JACC 2005:45;954Moreno, JACC 2005:45;954N=5030 (10 RCT)N=5030 (10 RCT) Number of stents/patientNumber of stents/patient Total stent lengthTotal stent length
Iakovou and Colombo, JAMA 2005:293;2126Iakovou and Colombo, JAMA 2005:293;2126N=2229 (3 Centers)N=2229 (3 Centers) Premature antiplatelet rx d/cPremature antiplatelet rx d/c Renal failureRenal failure Bifurcation lesionBifurcation lesion DiabetesDiabetes ↓ ↓ LVEFLVEF
Kuchulakanti, Circulation 2006:113;1108Kuchulakanti, Circulation 2006:113;1108 Discontinuation of clopidogrelDiscontinuation of clopidogrel Renal failureRenal failure Bifurcation lesionsBifurcation lesions In-stent restenosisIn-stent restenosis
Independent Predictors of Late STIakovou I et al JAMA. 2005;293:2126-2130
Late Incomplete AppositionDrug-eluting stent
Dante Pazzanese Experience - 5% at 6 mths (20% had ST)
Predictorsof ST after DES (SES or PES)Predictorsof ST after DES (SES or PES)29/2229 pts (1.3%) at 9.3 ± 5.6 mos29/2229 pts (1.3%) at 9.3 ± 5.6 mos
Iakovou et al. JAMA 2005;293:2126-2130Iakovou et al. JAMA 2005;293:2126-2130
1.71.4
0.0
3.7
1.4 1.3
0
1
2
3
4
5
SmallVessel
MediumVessel
LargeVessel
AR
C D
ef/P
rob-
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ined
ST
(%)
CYPHER® Bx VELOCITY
Stent Thrombosis Through 4 Years:
Subgroup Analysis by Vessel Size
p = NS for all
Diabetes, ARC Def/Probable
n = 60 81 71 70 62 79
3.2
0.6 0.7
2.7
0.7
1.7
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3
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5
SmallVessel
MediumVessel
LargeVessel
CYPHER® Bx VELOCITY
Mean RVD: 2.25 2.22 2.68 2.68 3.22 3.24 n = 280 296 308 268 283 184
p = NS for all
Total Population, ARC Def/Probable
AR
C D
ef/P
rob-
Def
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ST
(%)
Thrombogenicity of the StentThrombogenicity of the Stent The majority of studies with BMS reported ST only within the first 30 days. In a
cumulative analysis of 8 clinical series involving almost 20,000 patients, an averageincidence of ST of 1.2% (range 0.4% to 2.8%)
Stent design Platelet activation was greater during the 30 days after implantation of an open-
cell versus a closed-cell stent. J Invasive Cardiol 2002
Stent strut thickness and polymer type and thickness Nonerodable polymers of the Cypher and Taxus DES provoke chronic
eosinophilic infiltration of the arterial wall in a small number of cases. All cases of hypersensitivity occur 4 months after DES implantation after the
complete release of the drug and is likely related to the polymer. In SES, 80% of the rapamycin is eluted by 30 days, whereas PES have a
biphasic drug release profile in vitro with an initial burst during the first 48 hrs after implantation followed by a sustained low-level release for at least 2 weeks. However, both rapamycin and paclitaxel easily penetrate into cells of the vessel wall owing to their lipophilic properties, which leads to chronic retention of the drug in the arterial tissue.
Tanner C and Virmani R Circulation 2007;115;1051-1058
AntiplateletsAntiplatelets 4% to 30% of patients treated with conventional doses of clopidogrel do
not display adequate antiplatelet response
5% to 45% of patients treated with conventional doses of aspirin do not display adequate antiplatelet response
Nguyen TA et al. JACC 2005; 45:1157-1164.Gum PA Stone et al. JACC. 2003; 41:961-965
Triple Versus Dual Antiplatelet TherapyJ. Am. Coll. Cardiol. 2005;46;1833-1837
Biological Mechanisms
J Am Coll Cardiol 2006
Impaired Re-endothelializationImpaired Re-endothelializationAutopsy study: Autopsy study: 23 DES patients, 14 LST, 13 died
J Am Coll Cardiol. 2006;48:193–202
Clinical importance of stent thrombosisClinical importance of stent thrombosis
Incidence of ST DES - Early ST
Rate of stent thrombosisJACC 2005:954–9
9 Prospective, Double-Blind, Randomized 9 Prospective, Double-Blind, Randomized TrialsTrials
Freedom From Stent ThrombosisFreedom From Stent ThrombosisStone GW et al. NEJM 2007;356:998-1008
Incidence of Late Stent Thrombosis DESMcFadden E et al. Lancet 2004;364:1519
Rate of Late stent thrombosisRate of Late stent thrombosis JACC 2005:954–9
BASKET-LATEn = 743, 6 – 18 months
Pfisterer M. JACC 2006
Incidence of Late stent Thrombosis >30 daysmeta--analysis of 14 randomized clinical trials 6675 pts
Am J of Medicine 2006;119, 1056-1061
Very Late DES Thrombosis On-Label Very Late DES Thrombosis On-Label UseUse
>1 Year Post Implant Pooled RCTs>1 Year Post Implant Pooled RCTs
Primary PCIPrimary PCITyphoon - Stent Thrombosis @12 months
SESAMI : ST 3.1% of SES versus 3.7% of BMSPASSION : Acute ST 0.3% in PES
Subacute ST in 0.3% in PES and 1% in BMS Late ST in 1 patient in the PES group and none in the BMS group.
Reference Year Patients Stents FU ST RateST Rate
Moreno 2005 5,030 BMS 48%SES 17%PES 34%
6–12 mn SAT: 0.35% (BMS = DES)LST: 0.23% (BMS = DES)
Bavry 2005 3,817 BMS 48%PES 52%
6–12 mn SAT + LST: 0.76% (PES = BMS)
Morice (REALITY)
2006 1,386 SES 51%PES 49%
12 mn SAT: SES 0.4%, PES 1.0%LST: SES 0%, PES 0.3%
Kastrati 2005 3,669 SES 50%PES 50%
6–13 mn SAT + LST: 1.0% (PES = SES)
Spalding 2007 1,748 BMS 50%SES 50%
48 mn SAT: SES 0.5%, BMS 0.5%LST: SES 0.3%, BMS 1.3%VLST: SES 2.8%, PES 1.7
Mauri 2007 4,545 SES 19%PES 31%BMS 50%
48 mn SAT: SES 0.5%, BMS 0.3%LST: SES 0.1%, BMS 1.0%
VLST: SES 0.9%, BMS 0.4%SAT: PES 0.5%, BMS 0.5%LST: PES 0.4%, BMS 0.3%
VLST: PES 0.9%, BMS 0.6%
Rates of Stent Thrombosis in Meta-analysis
Kastrati 2007 4,958 SES 50%BMS 50%
12.1–58.9Mn
SAT LST VLST:SES 1.4%, BMS 1.26%
VLST: SES 0.6%, BMS 0.05%
Pfisterer (BASKETLATE)
2006 746 SES 34%PES 38%BMS 38%
12 mn Definite: DES 1.4%, BMS 0.8%Definite + possible:
DES 2.6%, BMS 1.3%
Ellis 2007 3,445 PES 50%BMS 50%
14–41mn
SAT: PES: 0.5%, BMS: 0.5%LST + VLST: PES 0.5%,
BMS 0.06%
Stone 2007 5,261 SES 17%PES 33%BMS 50%
48 mn SAT: SES 0.5%, BMS 0.1%LST: SES 0.1%, BMS 0.5%
VLST: SES 0.6%, BMS 0%SAT: PES 0.5%, BMS 0.6%LST: PES 0.2%, BMS 0.1%
VLST: PES 0.7%, BMS 0.2%
Bavry 2006 6,675 SES 24%PES 26%BMS 50%
12–36 mn DES 0.5%, BMS 0%SES 0.36%, BMS 0% PES 0.59%, BMS 0%
CYPHER Thrombosis Rates Across 6 Registries
‘‘Real-world’ outcomes through 1 yearReal-world’ outcomes through 1 yearCYPHER (n=2067)CYPHER (n=2067)
e-CYPHERe-CYPHERTAXUS (n=7393)TAXUS (n=7393)
ARRIVE 1& 2ARRIVE 1& 2
Stent Thrombosis
P value Stent Thrombosis
P value
Diabetes vs. No Diabetes 1.12 vs. 0.75 0.44 2.87 vs. 2.03 0.10
2.5 mm vs. >2.5 mm 1.02 vs. 0.73 0.47 3.06 vs. 1.95 0.03
>28 mm vs. 28 mm 1.90 vs. 0.76 0.22 4.49 vs. 1.96 <0.0001
Multiple vs. Single stents 1.35 vs. 0.73 0.22 4.20 vs. 1.43 <0.0001
Multiple vs. Single Vessel 1.16 vs. 0.59 0.04 3.53 vs. 2.05 0.01
Acute MI vs. Non-AMI 0.67 vs. 0.88 1.00 3.49 vs. 2.12 0.07
Coronary Stent Thrombosis Protocol Definitions Differ across
Programs
Academic Research ConsortiumARC Definitions
Cutlip et. al.: Circulation; 2007 Rationale
Variability in definitions of key clinical endpoints across DES Trials
Inappropriate comparisons and conclusions based on different definitions
Potential to bias results by choosing definitions most favorable to those conducting analyses
ARC Proposed Standard ARC Proposed Standard Definitions Definitions
DEFINITE (Angiographic or pathologic confirmation): Angiographic confirmation:
TIMI 0 with occlusion originating in or within 5 mm of stent in the presence of a thrombus
TIMI flow grade 1, 2, or 3 originating in or within 5 mm of stent in the presence of a thrombus
AND 1 of the following criteria < 48 hours: New acute onset of ischemic symptoms at rest (typical chest pain
with duration >20 minutes) New ischemic ECG changes suggestive of acute ischemia Typical rise and fall in cardiac biomarkers
Pathologic confirmation: Evidence of recent thrombus within the stent determined at autopsy
or via examination of tissue retrieved following thrombectomy
PROBABLE: Any unexplained death within the first 30 days Any MI (related to documented acute ischemia and without another
obvious cause) in the territory of the stent
POSSIBLE: Any unexplained death >30 days
Cumulative Incidence of CYPHER Thrombosis at 4 Yrs Cumulative Incidence of CYPHER Thrombosis at 4 Yrs (ARC Definite or Probable)(ARC Definite or Probable)
Mauri L, et al. Mauri L, et al. NEJM NEJM 2007; 356: 1020- 292007; 356: 1020- 29
Cumulative Incidence of TAXUS Thrombosis at 4 Years Cumulative Incidence of TAXUS Thrombosis at 4 Years (ARC Definite or Probable)(ARC Definite or Probable)
4-Year Follow-Up of Randomized Trials of DES Versus BMS
Long term Mortality: SES vs. PES9 RCTs
Kastrati A et al. NEJM 2007;356:1030-9
Preventive Strategies Optimizing stent implantation
Selection of the appropriate diameter and length of stent. Placement of excessively long DES (overstenting) should be avoided. Residual stent marginal dissections or significant stenoses should be treated. Suboptimal under- or overdeployment of stent diameter should be avoided. IVUS may be useful in optimizing deployment results. Some specific techniques may be associated with higher rates of ST.
Adjunctive therapy Dual antiplatelet therapy after DES implantation is crucial. Recently, the recommendation has been to extend this therapy for up to 12
months in patients at low risk for bleeding events. Preliminary data suggest that “triple” antiplatelet therapy may be associated
witha reduction in MACE, including ST, and may be a therapeutic option for
patients at high risk for ST.
Design of Future DES Simple chemical coating
Titanium-nitride-oxide diminishes platelet adhesion and fibrinogen. Dimethyl sulfoxide prevents vascular SMC and migration and at the same time
inhibits TF upregulation in endothelial cells, vascular smooth muscle, andmonocytes and prevents thrombotic occlusion in a mouse carotid injury model.
Coating of stents with substances that potentially facilitate re-endothelialization e.g.coating of stents with CD34 antibodies designed to “capture” EPCs.
Stents loaded with an integrin-binding cyclic Arg-Gly-Asp peptide acceleratedendothelialization by attracting EPCs in a porcine model.
A combination of “prohealing” substances (such as VEGF) with established“antirestenosis” drugs.
Prohealing strategies such as the use of peroxisome proliferator–activated receptor-agonists, which not only diminish inflammation but also enhance endothelialization
What have we learned… for DES?
Timing of stent thrombosis events is different than for BMS Is overall incidence different? Represents a device failure
Mechanism of stent thrombosis may be different than for BMS Likely related to delayed healing Does this explain all late events?
Dual antiplatelet therapy is crucial for a longer duration than for BMS How long is enough? What are the concomitant bleeding risks? Events will occur despite dual APT
Risks of complications (death, MI, ST) are higher for patients receiving DES off label vs. on label
How do these risks compare with alternative therapies (medical Rx, BMS, CABG)?