Hidden Menace-Stent Thrombosis

in Drug Eluting Stent Era

Prof. Baogui SUNShanghai First People’s Hospital

What Are We Worrying About?

Stent Thrombosis

• Definite/Confirmed– Acute coronary syndrome AND– [Angiographic confirmation of thrombus

or occlusion OR– Pathologic confirmation of acute

thrombosis]

• Probable– Unexplained death within 30 days– Target vessel MI without angiographic

confirmation of thrombosis or other identified culprit lesion

• Possible– Unexplained death after 30 days

ARC Definition of Stent Thrombosis

Timing Classification of Stent Thrombosis

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.

DES definite ST incidence: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

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

between 30 days and 5 years

DES Definite ST Incidence:Bern-Cohort Study @ 5 Years

Wenaweser P et al. ESC 2008

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

%

Causes of Stent Thrombosis

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 Remodelling

Hypersensitivity ReactionDelayed Healing

Procedure and Lesion- related Parameters

• Use of multiple stents • Small vessel diameter • Residual dissection • Geographic miss • Slow flow • Long and/or bifurcation

lesions • Mal-apposition and/or under-

expansion of the stent

Patient Characteristics

• Diabetes • Acute Coronary Syndromes

(especially STEMI) • Left ventricular dysfunction • Renal failure • Advanced age • High platelet reactivity

Anti-platelet therapy

• Inadequate intensity of therapy (i.e. non-dual platelet inhibition or insufficient dose)

• Non-compliance • Premature cessation of anti-

platelet therapy

Reasons of ST in pts with anti-platelet therapyReasons of ST in pts with anti-platelet therapy

Antiplatelet therapy at time of ST occurrence

Bern-Rotterdam Cohort Study @ 5 YearsWenaweser P et al. ESC 2008

Impact of Platelet Reactivity after Clopidogrel Administration on Drug-Eluting Stent Thrombosis

Buonamici P et al JACC 2007

2.3 1.70.6

1.4

8.6

3.84.8

8.6

0

5

10

Definite/Probable ST

Early ST Late ST Mortality

Responders (n=699)

Non-Responders (n=105)p<0.001 p<0.001

p<0.001p=ns

Stent Characteristics

• Stent design and structure

• Strut profile or thickness

• Polymer nature and type

• Drug which stent coated

Triton TIMI 38 – Prasugrel vs.

Clopidogrel in ACS Patients With Stents

Wiviott SD et al. Lancet 2008;371:1353-63

Overall Stent Thrombosis

Early Stent Thrombosis

Late 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

ioPredictor: Length of Stent

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

Predictor: Bifurcated Lesion

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

ioPredictor: 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 Pts 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

ioPredictor: Diabetes

IijimaAm J Card 2007

HR=2.2(1.1-4.3)

HR=1.75(1.0-3.0)

De la TorreJACC 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 – 34.70

Wenaweser 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

Probable Causes of Late Stent Thrombosis

• Chronic inflammatory reaction to the polymer or drug

• Hypersensitivity to the polymer or drug

• Failure of stents to reendothelialize completely

• Late incomplete stent apposition• Disease progression

Late Incomplete Stent Apposition

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

Post-DES: Pathophysiologic Mechanism

Endothelialization

Clinical Outcomes of ST• Sudden Cardiac Death:

extremely dangerous• Non-fatal STEMI & NSTEMI:

most probably• Malignant Arrhythmias:

atypical• Chronic Total Occlusion:

gradually and asymptomatic

Treatment of Stent Thrombosis

Ⅰ. Repeated PCI:

most of pts

Ⅱ. Drug therapy:

all of pts

Ⅲ.Emergent CABG:

some of pts

Oral Medication

• Triple Antiplatelet Therapy: Clopidogrel & ASA & Cilostazol

• Double Dosage of Clopidogrel: 150mg per day.

• Prolonged Dual Antiplatelet Drug Therapy: >12 month ? longer is better?

• Dual Antiplatelet Drug Therapy & Oral Anticoagulation:

with warfarin ?

Prevention of Stent Thrombosis• Identification of High Risk Pts

modification of risks

• Avoidance of Abused Stent Deploymentlong stent, bifurcation stenting, stent overlapping

• Optimization of the Stent Deploymentno residual dissention,improve stent expansion

• Optimal anti-platelet therapyevaluate anti-platelet reactivity in high risk pts

• Prior to BMS in pts with low restenosis to the full extent possible

A Case of Very late ST

AMI for the First Time(22/Jun/2003)

• Female ， 55 years old

• Chest Pain for 13 hrs ， Medicine Treatment only in other Hospital, and to Our Hospital 1.5 Month later

• No History of Hypertension 、 DM 、 Dyslipidemia and Smoking

• ECG ： V1~V2→QS ， V3 → rS ， V1~V3 → inversed T wave

• UCG ： Slight Decreased Movement of Anterior Wall

CAG (7/Aug/2003) ：Total Occlusion of LAD

The Result ： Satisfied or Not ?

After PCI

• Clopidogrel was Stopped by the Pt 3-month after

PCI

• ASA 、 Statin 、 ACEI 、 Beta-blocker were kept

in using

• Symptom Free for 2 years, and Angina occurred 3

times in last 6 months before administration

AMI for the Second Time(11/Nov/2005)----27 Months Later

• Chest Pain for 4 hrs

• ECG: V2~V6→Elevated ST Segment for 0.1~0.6mV

• Markers of Myocardium ： Normal for TNI 、 CK-

MB 、 MYO

• Primary PCI ： 11/Nov/2005

CAG ： Stent Thrombosis with TIMI II Flow, LCX Affected

What to do?

10 days laterIncomplete Stent Apposition

Tirofiban and IABP

AMI for the Third Time(11/Aug/2006)----36 Months Later

• Chest Pain for 3 hrs

• ECG: V2~V6→Elevated ST Segment for 0.1~0.5mV

• Markers of Myocardium ： Normal for TNI、 CK-MB 、 MYO

• Primary PCI ： 11/Aug/2006

CAG ： LAD Occluded with In-stent Thrombosis, LCX AffectedWhat to do?

PTCA：Wire: ATW/BMWBallon: Sprinter 2.5*15mm