The Clinical Spectrum of DES Thrombosis ... · Lymphocytes Neutrophils Eosinophils Very late...
Transcript of The Clinical Spectrum of DES Thrombosis ... · Lymphocytes Neutrophils Eosinophils Very late...
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The Clinical Spectrum of DES The Clinical Spectrum of DES Thrombosis: Thrombosis: multifactorialmultifactorial Causes, Causes, clinical Presentation, and clinical Presentation, and Recommended Treatment StrategiesRecommended Treatment Strategies
Ron Waksman MD, FACC, FSCAIProfessor of Medicine (Cardiology) Georgetown UniversityAssociate Chief of Cardiology Washington Hospital CenterWashington DC
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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 ThrombosisTime Frame of Stent ThrombosisHow did we get here?How did we get here?
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History of Stent Thrombosis MeasurementHistory of Stent Thrombosis MeasurementFrom Acute to Very LateFrom Acute to Very Late
1991
Acute < 24 hr
Palmaz SchatzBenestentSTRESS
1995 2000
Early < 30 days
DAPT STARSIVUS, High Pressure Balloon
2006
Late < 1 year
DES EraProlonged antiplatelet therapy
Present
VLST ≥ 1 year
FDA PanelARC Definitions
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Procedure
Stent ThrombosisStent ThrombosisPatient, Procedure, DevicePatient, Procedure, Device
StentStentThrombosisThrombosis
• Stent apposition• Flow/Runoff
Patient• Higher Risk• AP Compliance
Device•• Polymer Polymer • Drug
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Stent Thrombosis is Multi-Factorial
Stent Thrombosis
LesionComplexity, disease• Long lesions• Small vessels• Multi-vessel• AMI/ ACS• Diabetics• Bifurcations
Technical
Operator:•Under expansion• Incomplete wall apposition•Poor technique
PatientPremature AntiplateletDiscontinuation
•Plavix® compliance•Upcoming surgery•Plavix®resistance/intolerance
DES Injury & healing:• Strut thickness• Stent design
(scaffolding/conformability)• Polymer• Drug and elution profile• Stent delivery system• Adequate or proper stent
expansionModified from Honda and Fitzgerald, Circulation 2003:108, 2Kereiakes D., et. al Rev Cardiovasc Med: 2004; 5 (1): 9-15
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Impact of premature thienopyridinediscontinuation: The PREMIER registry
500 pts with AMI undergoing primary PCI with DES at 19 U.S. medical centers, alive and well at 30 days
Spertus JA et al. Circulation 2006;113:2803-9.SpertusSpertus JA et al. Circulation 2006;113:2803JA et al. Circulation 2006;113:2803--9.9.
68 (13.6%) were no longer taking 68 (13.6%) were no longer taking prescribed prescribed thienopyridinesthienopyridines at 30 daysat 30 days
P
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Milan/Siegburg ExperienceStent thrombosis after DES (SES or PES) occurred Stent thrombosis after DES (SES or PES) occurred
in 29/2229 pts (1.3%) at 9 in 29/2229 pts (1.3%) at 9 mosmos (45% mortality)(45% mortality)
CentroCentroCuoreCuoreColumbusColumbus
UnstableUnstableanginaangina
PriorPriorbrachyRxbrachyRx
ThrombusThrombus DiabetesDiabetes UnprotUnprot..left mainleft main
BifurcationBifurcation RenalRenalfailurefailure
PrematurePrematurePlavixPlavix d/cd/c
Several patient and lesion Several patient and lesion subgroups have an subgroups have an
unacceptably high stent unacceptably high stent thrombosis rate! thrombosis rate!
IakovouIakovou I et al. JAMA 2005;293:2126I et al. JAMA 2005;293:2126--21302130
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Platelet Responsiveness and Thrombosis804 patients, 25 def/prob thromboses
Variable Hazard Ratio(95% CI)P
ClopidogrelNonresponsiveness 3.08 (1.32–7.16) 0.009
Acute myocardial infarction 2.41 (1.04–5.63) 0.041
Total stent length, mm 1.01 (1.00–1.02) 0.010
LVEF per 1% increase 0.95 (0.92–0.98) 0.001
Buonamici et al, JACC 2007
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Predictors of Stent Thrombosis
Up to 30 days SubacuteStent Technique
Lesion complexity
Long lesions
Small vessels
Bifurcations
Pharmacologic
Clopidogrel resistance
Early discontinuation
After 1 M late ST:Less based upon lesion complexity?
Pharmacologic role less well-defined
Largely off clopidogrel
? Slow endothelialization
Genetics
Polymer inflammation
Athero Vulnerable Plaque
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The Role of Stent Properties In Thrombosis
Modular designMetal coverageStrut thicknessStrut shapeSurface smoothnessCoating materialsDrug properties
Hara H et al. Adv Drug Deliv Rev. 2006;58:377-386.
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Potential Inflammatory Reaction
Suggested by early preclinical dataMay be related to the polymers, the drug coatings themselves, or perhaps both. Heightened activity of:Macrophages Multinucleated giant cells
Lymphocytes NeutrophilsEosinophils
Very late inflammatory response in animal models may, in and of itself, create thrombosis.
Inflammation can cause positive remodeling of the artery, which results in stent malapposition
Hara H et al. Adv Drug Deliv Rev. 2006;58:377-386.
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Localized Hypersensitivity and Late DES Thrombosis
Postmortem radio- and photomicrographs (A and B) showing 2 LCxsirolimus-eluting stents with dense surrounding inflammation
VirmaniVirmani, R. et al. , R. et al. CirculationCirculation 2004;109:7012004;109:701--705705
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Healing After Stent Implantation in HumansDifferences Between BMS and DES
Joner M et al. J Am Coll Cardiol. 2006;48:193-202.Colombo A, Corbett SJ. J Am Coll Cardiol. 2006;48:203-205.
P=0.001P=0.001
P
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Healing After DES Implantation in HumansImportance of Strut Coverage
DES Lesions With Thrombus
(n=28)
DES Lesions Without Thrombus
(n=34) P
Duration, days 173 127 NS
EEM (mm2) 17.2±4.6 13.2±5.2 0.002
Stent area, mm2 7.5±2.0 6.7±3.2 0.02
Plaque area, mm2 9.7±3.9 6.5±3.7 0.003
Neointimal thickness, mm 0.074 0.11 0.05
Fibrin score 2.4±1.3 1.2±1.1 0.002
Endothelialization, % 40.5±29.8 80.0±25.2
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Late Incomplete Apposition After DES Placement
Drug Eluting Stent Group
Struts may be potentially vulnerableBaseline Follow-up
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Clinical Impact of Stent Clinical Impact of Stent ThrombosisThrombosis
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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. DESDefinite Stent Thrombosis: BMS vs. DESThe Bern Experience 1995The Bern Experience 1995--20052005
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Very Late Stent Thrombosis Very Late Stent Thrombosis Initial Cases and Discussion: Lancet 2004Initial Cases and Discussion: Lancet 2004
McFadden EP et al. Lancet 2004; 364:1519–21
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Day 4002001000 500300
CYPHER
TAXUS
335 343 375 442
Very Late Stent Thrombosis Very Late Stent Thrombosis Initial Cases and Discussion: DAPT PriorInitial Cases and Discussion: DAPT Prior
McFadden EP et al. Lancet 2004; 364:1519–21
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ARC Stent Thrombosis ARC Stent Thrombosis Impact of Impact of BrachytherapyBrachytherapy
Mauri et al. N Engl J Med. 2007;356:1020-1029. *Includes intervening TLR
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Clinical Importance of Stent Thrombosis: Death and MI
Author/Year BMS/DES ST Def Death or MI Death
Cutlip 2001 BMS Angio or Clinical 70% 21%
Heller 2001 BMS Angio + AMI 100% 17%
Iakovou 2005 DES Angio or Clinical 45%
Ong 2005 DES Angio & Clinical 100 25%
Kuchulakanti 2006 DES Angio 31%
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Clinical Outcome and Prognosis Clinical Outcome and Prognosis of Patients who Present with of Patients who Present with
Early versus Late Stent ThrombosisEarly versus Late Stent Thrombosis
Gilles Gilles LemesleLemesle, Laurent , Laurent BonelloBonello, Axel de , Axel de LabriolleLabriolle, Tina Pinto , Tina Pinto SlottowSlottow, , Rebecca Rebecca TorgusonTorguson, Kimberly , Kimberly KaneshigeKaneshige, , ZhenyiZhenyi XueXue, William O , William O SuddathSuddath, ,
Lowell F Lowell F SatlerSatler, Kenneth M Kent, Joseph Lindsay, Augusto D , Kenneth M Kent, Joseph Lindsay, Augusto D PichardPichard, and Ron Waksman., and Ron Waksman.
Washington Hospital Center, Washington DC, USAWashington Hospital Center, Washington DC, USA
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Methods: Retrospective study
Between 2003 and 2007 91 patients
with definite ST
Early ST(n=51)
Late or Very Late ST(n=40)
Follow-up at 1 year after the first ST episodePrimary endpoint: composite criterion of
Death - Recurrent MI - Recurrent ST
Late ST (n=14)Very late ST (n=26)
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• The median [interquartiles] occurrence time of ST after the initial PCI was:
– 6 days [3-9.5] in the early ST group
– 494.5 days [241-763.5] in the late ST group.
Median occurrence time of ST
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Primary endpoint Death-Recurrent MI-Recurrent ST At 1 year after the first ST episode
Log Rank, p=0.029
30%
52.9%
Early ST groupLate ST group
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Treatment and prevention Treatment and prevention StrategiesStrategies
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Impact of thrombus aspiration use for Impact of thrombus aspiration use for the treatment of stent thrombosis the treatment of stent thrombosis on early patient outcome.on early patient outcome.
Between 2003 and 2008, 91 consecutive Between 2003 and 2008, 91 consecutive patients presenting with a definite ST were patients presenting with a definite ST were included in this analysis included in this analysis
Angiographic Success Event free survival:Death-MI-Recurrent ST
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Independent predictors of the Independent predictors of the composite criteria Deathcomposite criteria Death--MIMI--Recurrent Recurrent ST at 30 days.ST at 30 days.
Hazard RatioHR 95% CI
p value
Clinical presentation as acute MI
2.5 1.4 - 4.40.002
Cardiogenicshock
4.8 2.0 - 11.3
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HighHigh--Pressure Balloons Pressure Balloons Early work showed ST after 30 daysEarly work showed ST after 30 days
Colombo et al. Circulation.1995;91:1676;
1.4% (n=5) ST rate with in 6 months with n=2 1.4% (n=5) ST rate with in 6 months with n=2 after 2 months after 2 months
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Early Stent ThrombosisEarly Stent ThrombosisEarly BMS Experience: With and Without AnticoagulationEarly BMS Experience: With and Without Anticoagulation
.6% stent thrombosis rate by 30 days .6% stent thrombosis rate by 30 days combination of combination of ticlopidineticlopidine and aspirinand aspirin
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Balancing ST and TLR Balancing ST and TLR Threshold for Risk of VLSTThreshold for Risk of VLST
0.14% Absolute 0.14% Absolute DifferenceDifference
Not every patient should get DES
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Independent Angiographic and Procedural Predictors of Stent Thrombosis by Multivariate
AnalysisWashington Hospital Center Study
Procedural Predictor Odds ratio Confidence interval P-value
Left anterior descending artery 1.65 1.0-2.8 0.08
Proximal 1.74 1.0-3.0 0.05
Reference vessel diameter 0.51 0.2-1.1 0.08
Drug Eluting Stent 1.86 1.0-3.5 0.06
Intravascular Ultrasound Guidance
0.42 0.2-0.7 0.002
Pre-dilatation 1.5 0.9-2.6 0.16
Ron Waksman, MD, Presented at CRT 2007
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12 Months Outcomes
IVUS(n=884)
No IVUS(n=884)
p
Major adverse cardiac events 128 (14.5%) 143 (16.2%) 0.32
Death 50 (5.7%) 62 (7.1%) 0.23
Cardiac death 16 (1.9%) 24 (2.8%) 0.18
Q-wave myocardial infarction 18 (2.1%) 26 (3.1%) 0.21
Target vessel revascularization 73 (8.5%) 77 (9.1%) 0.69
Target lesion revascularization 43 (5.1%) 61 (7.2%) 0.06
Definite stent thrombosis 6 (0.7%) 18 (2.0%) 0.014
Probable stent thrombosis 35 (4.0%) 51 (5.8%) 0.08
Late definite stent thrombosis 2 (0.2%) 6 (0.7%) 0.29
Roy et al European heart Journal 2008
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ARC Stent ThrombosisARC Stent Thrombosis SPIRIT IISPIRIT II
Definite and Probable XIENCE V
223 patientsn (%)
TAXUS 77 patients
n (%)
Acute stent thrombosis (%) (1Y) 2 (1.0) 1 (1.5)
Total stent thrombosis (%) 2 (1.0) 2 (2.9)
p=NS * Same patient
One new stent thrombosis in the TAXUS arm between 2 years and 3 years, none in the XIENCE V arm
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Cumulative Incidence Rates of ARC Stent Cumulative Incidence Rates of ARC Stent Thromboses (Definite/Probable)Thromboses (Definite/Probable) SPIRIT IISPIRIT II
1-year HRNA [NA]p=0.089
2-year HR0.68 [0.06, 7.55]
p=0.76
3-year HR0.35 [0.05, 2.46]
p=0.27
XIENCE VTAXUS
ARC
Ste
nt T
hrom
bosi
s (%
)
0
1
2
3
4
5
6
Time Post Index Procedure (Months)0 3 6 9 12 15 18 21 24 27 30 33 36
1.3%
0.0% 1.3%
0.4%1.3%
0.9%
2.8%
0.9%
1.9%
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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 AnalysisEndeavor Safety AnalysisARC Definite and Probable ST to 4 yearsARC Definite and Probable ST to 4 years
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DES Safety: Lessons LearnedDES Safety: Lessons Learned
1 year data not sufficient to evaluate DES1 year data not sufficient to evaluate DESDivergence with BMS appeared at 2 yearsDivergence with BMS appeared at 2 years
BMS assumption of no very late ST was BMS assumption of no very late ST was incorrectincorrect
RCT in simple subjects may not be sufficient RCT in simple subjects may not be sufficient to evaluate safetyto evaluate safety
Sample sizes of 1Sample sizes of 1--2000 subjects not 2000 subjects not sufficient to detect small relative differencessufficient to detect small relative differences
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All ComerDual APT >3 to 200 International Sites
Randomization 1:1
EndeavorN=4400
Clinical Follow-up30d 6mo 4 yr3yr3yr30mo24mo 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 PROTECT International RCT Designed to Estimate VLST (>1 year)International RCT Designed to Estimate VLST (>1 year)
Over 3500 Patients Currently EnrolledOver 3500 Patients Currently EnrolledOver 3500 Patients Currently Enrolled
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Recommended Treatment StrategiesRecommended Treatment StrategiesAspiration avoid a new DESAspiration avoid a new DES
Increase use of IVUS guided PCI Increase use of IVUS guided PCI
High pressure, avoid geographic missHigh pressure, avoid geographic miss
Improve patient Compliance for DAPTImprove patient Compliance for DAPT
Never stop aspirinNever stop aspirin
Check responsiveness to DAPTCheck responsiveness to DAPT
Selective use of DES / New Generations?Selective use of DES / New Generations?