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

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?

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

Procedure

Stent ThrombosisStent ThrombosisPatient, Procedure, DevicePatient, Procedure, Device

StentStentThrombosisThrombosis

• Stent apposition• Flow/Runoff

Patient• Higher Risk• AP Compliance

Device•• Polymer Polymer • Drug

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

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

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

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

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

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.

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.

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

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

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

Late Incomplete Apposition After DES Placement

Drug Eluting Stent Group

Struts may be potentially vulnerableBaseline Follow-up

Clinical Impact of Stent Clinical Impact of Stent ThrombosisThrombosis

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

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

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

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

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%

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

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)

• 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

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

Treatment and prevention Treatment and prevention StrategiesStrategies

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

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

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

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

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

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

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

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

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%

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

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

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

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?