DEV PAHLAJANI MD,FACC,FSCAICHIEF OF INTERVENTIONAL CARDIOLOGY,

BREACH CANDY HOSPITAL,MUMBAI

TREATMENT OF LATE AND VERY LATE STENT THROMBOSIS

DES increased thrombogenicity

• According to the Euro PCR-06 Daily; a 1.2% rate of late stent thrombosis means around 30,000 people were affected, accounting for a 45% mortality rate.

BMS VS DES –ADVERSE EVENTSIncidences of serious adverse events (Death or MI)

N=870N=878

N=1675 N=1685

Study Design: BASKET LATE trial

743 patients randomized in the BASKET trial and without an event during the 6 month Clopidogrel phase

Bare metalVISION stents (BMS)

N=244

Drug eluting stents(DES)(pooled paclitaxel and sirolimus DES groups)

n=499

Followed for 1 year off clopidogrel

• Primary Endpoint: Composite cardiac death or nonfatal MI• Other Endpoints: “Thrombosis-related events”

Ref: Pfisterer M et al.ACC 2006

BASKET LATE Trial

• “For every 100 patients treated with DES,3.3 cases of cardiac death or MI are induced for reduction of 5 cases of TLR”

BASKET-LATEn = 743, 6 – 18 months

Pfisterer M. JACC 2006

ARC Proposed Standard Definitions DEFINITE (Angiographic or pathologic confirmation): Angiographic confirmation:

1. TIMI 0 with occlusion originating in or within 5 mm of stent in the presence of a thrombus

2. TIMI flow grade 1, 2, or 3 originating in or within 5 mm of stent in the presence of a thrombus

3. AND 1 of the following criteria < 48 hours:4. New acute onset of ischemic symptoms at rest (typical chest pain

with duration >20 minutes)5. New ischemic ECG changes suggestive of acute ischemia6. Typical rise and fall in cardiac biomarkers

Pathologic confirmation:1. Evidence of recent thrombus within the stent determined at autopsy

or via examination of tissue retrieved following thrombectomy

PROBABLE: 1. Any unexplained death within the first 30 days2. Any MI (related to documented acute ischemia and without another obvious

cause) in the territory of the stent

POSSIBLE: Any unexplained death >30 days

Definite

Too Narrow

Misses people who have an MI but don’t have an angiogram

Definite

Probable

Possible

Too Broad

Includes natural history events (equal

in both arms) that dilute out true ST

signal*Definite

Probable

Best Balance

Includes MI with or without angio, but

not 1.5%/year natural history deaths

* Worse if you include post TLR events• Restenotic stent can’t really develop ST• Brachytherapy or new DES certainly can• More such events occur in the BMS arm

ARC Definitions of Stent Thrombosis - Gaps

Dr. Don Baim, TCT 2006.

Thrombosis Can Occur Any Time Post-Stent Implantation

Very Late ST

Late ST

SAT

Acute ST

Time Frame Classification

30 days

90 days

365 days

Very Late> 1 year

0 days

Ear

ly1-

30 d

ays

Acu

te1

Day

Sub-A

cute

2- 3

0 D

ays

Late

>30 days- 1 year

Occurrence of Stent ThrombosisEVASTENT REGISTRY

JACC 2007, 50, 501

2.5

2.0

1.5

1.0

0.5

0.0Cum

ulati

ve p

roba

bilit

y of

ste

nt

thro

mbo

sis

(%)

Follow-up (days)

0 30 90 180 365

ST+ (n=) 23 26 36 41

ST- (n=) 1692 1679 1669 1664

Stent ThrombosisP

erc

en

t S

ten

t Th

rom

bosis

Days

Bern-Rotterdam

0

0.5

1

1.5

2

2.5

3

3.5

0 10 30 365 730 1095

1.6

3.22.7

2.51.9

Wenaweser P. et al: EHJ 2005 26 1180-1187.Wenaweser P. et al: ESC 2006.Bern-Rotterdam and HCRI CEC ST definitions both require angiographic confirmation.

Bern TaxusBern BMS

Bern Cypher

LATE STENT THROMBOSIS

STEMI ACUTE CORONARY SYNDROME

LEFT VENTRICULAR FAILURE CARDIOGENIC SHOCK

TREATMENT OF LST

MANAGE LIKE PRIMARY PCI

BALLOON DILATATION

SUPPORTIVE MEASURES

IABP IF SHOCK OR LVF

LIBERAL USE OF GPIIB/IIIA BLOCKERS

ASPIRIN AND CLOPIDOGREL IF NOT ON

THROMBUS ASPIRATION

AVOID DES PREFER BMS

Clinical importance of stent thrombosis

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 %

‘Real-world’ outcomes through 1 yearCYPHER (n=2067)

e-CYPHERTAXUS (n=7393)

ARRIVE 1& 2

Stent Thrombosis

P value Stent Thrombosis

P value

Diabetes vs. No Diabetes 1.12 vs. 0.75 0.442.87 vs. 2.03 0.10

2.5 mm vs. >2.5 mm 1.02 vs. 0.73 0.473.06 vs. 1.95 0.03

>28 mm vs. 28 mm 1.90 vs. 0.76 0.224.49 vs. 1.96 <0.0001

Multiple vs. Single stents 1.35 vs. 0.73 0.224.20 vs. 1.43 <0.0001

Multiple vs. Single Vessel 1.16 vs. 0.59 0.043.53 vs. 2.05 0.01

Acute MI vs. Non-AMI 0.67 vs. 0.88 1.003.49 vs. 2.12 0.07

Incidence of Late stent Thrombosis >30 daysmeta-analysis of 14 randomized clinical trials 6675 pts

Am J of Medicine 2006;119, 1056-1061

The data suggest that late stent thrombosis occurs at a steady rate during follow-up up to three years, tends to be more frequent with PES than with SES, and can unpredictably occur at any time point despite antiplatelet therapy.

Late stent thrombosis complicating the use of DES seems to be a distinct entity with pathophysiological factors that differ from those of early stent thrombosis.

The data suggest that late stent thrombosis occurs at a steady rate during follow-up up to three years, tends to be more frequent with PES than with SES, and can unpredictably occur at any time point despite antiplatelet therapy.

Late stent thrombosis complicating the use of DES seems to be a distinct entity with pathophysiological factors that differ from those of early stent thrombosis.

Daemen et al. Lancet. 2007 Feb 24; 369: 667 – 78.Daemen et al. Lancet. 2007 Feb 24; 369: 667 – 78.

Bern-Rotterdam Analysis: SummaryBern-Rotterdam Analysis: Summary

Late Stent Thrombosis—Factors to Consider

Late StentThrombosis

Late IncompleteApposition

DelayedEndothelialization

Discontinuation of Anti-Platelet

TherapyPolymer Hypersensitivity/

Inflammation

Incidence of Late Stent Thrombosis DESMcFadden E et al. Lancet 2004;364:1519

Incidence of Thrombosis in 40 autopsy cases of DES

STENT THROMBOSIS DES

Predictors of late stent thrombosis

2229 consecutive patients at 3 centers

Independent predictors of late ST (>30 days < 9 mo)-premature antiplatelet therapy d/c HR=161-renal failure HR=10.1-bifurcation lesion HR=6.0-diabetes HR=5.8

Independent Predictors of Late ST

Iakovou I et al JAMA. 2005;293:2126-2130

Predictors of ST after DES (SES or PES)29/2229 pts (1.3%) at 9.3 ± 5.6 mos

Iakovou et al. JAMA 2005;293:2126-2130

Iakovou I et al JAMA. 2005;293:2126-2130

Multivariate predictors of stent thrombosis:

Renal failure (OR=11.5),Bifurcation (7.2),Prior Brachy Rx (4.2),Diabetes(3.4),And Low LVEF(1.1)

Late Incomplete AppositionDrug-eluting stent

Dante Pazzanese Experience - 5% at 6 mths (20% had ST)

Impaired Re-endothelializationPathology findings:

Sirolimus-Eluting stents from different coronary arteries in the same patient (delayed healing)

BMS24 months after

deployment

Cypher16 months after

deployment

Delayed Arterial healing in DES

Joner, JACC 2006

Lack of Re-Endothelialization at sites of Thrombosis in DES

Percentage of Endothelialization in Drug-eluting Stents (DES) VERSUS Bare-metal Stents (BMS)

as a function of Time

J Am Coll Cardiol 2006

Granulomatous reaction seen in 12.5 and 35% of CYPHER stents implanted for 28 & 90 days in Pig

Coronary Arteries

Case presented in EURO PCR-05

• A 38 year old female died suddenly, 6 months following Taxus stent placement for AMI

No healing or inflammation observed over the 6 months stent implantation time

DES failed to cross a heavily calcified lesion!!

Undamaged polymerUndamaged polymer

Severe polymer damageSevere polymer damage

Columbia University Medical CentreCardiovascular Research Foundation

Mechanisms leading to incomplete stent apposition

Cook, S. et al. Circulation 2007;115:2426-2434

The protocol sequence of IVUS imaging in very late ST patients is depicted in A, as follows: (1) After administration of nitroglycerin (0.2 mg), an

angiogram with the use of a 6F guiding catheter was performed to define the site of thrombotic stent occlusion

Cook, S. et al. Circulation 2007;115:2426-2434

Clinical outcomes and Stent Thrombosis following off-label use of drug eluting stents

Antiplatelets 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)

Premature Discontinuation

Study Yes No RR (95% CI) PAR

Iakovou et al.,2005 (7)

5/17 (29%) 24/2,212 (1.0%)

27 (12, 63) 17%

Kuchulakanti et al.,2006 (8)

14/310 (4.5%) 24/2,658 (0.9%)

5 (3,10) 29%

PAR= Pr * [(RR-1)/Pr * (RR-1)+1]CI= confidence interval; DES= drug eluting stent; PAR= population attributable risk; Pr=prevalence of clopidogrel discontinuation; RR= relative risk

Clopidogrel and DES

Late clinical events after clopidogrel discontinuation may limitthe benefit of drug-eluting stents.An observational study of DES versus BMS –BASKET-Late study

Timing of late thrombotic events after clopidogrel discontinuation

Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Pfisterer, M. et al. J Am Coll Cardiol 2006;48:2584-2591

SES Thrombosis in Diabetic And Non Diabetic Patients

JACC 2007, 50, 501

EVASTENT REGISTRY

0 100 200 300 400 500 600

0.85

0.90

0.95

1.00

Follow-up (days)

MAC

E fr

ee S

urvi

val

SVD db -

MVD db -

SVD db +

MVD db +Log Rank P <= 0.001

SVD db – 504 498 483 251 121 72

MVD db – 357 347 337 186 87 53

SVD db + 472 459 444 230 114 69

MVD + 334 321 312 164 91 97

JACC 2007, 50, 501

0.80

0.85

0.90

0.95

1.00

0 200 400 600

Db - 870 861 835 448 216 129 pts

Db + 818 799 774 401 212 144 pts

Logrank p = 0.0001

Follow-up (days)

Su

rviv

al

Non-diabeticDiabetic

0.80

0.85

0.90

0.95

1.00

0 200 400 600

Db - 859 847 823 437 210 125 pts

Db + 800 776 755 394 202 135 pts

Log rank p = 0.003

Follow-up (days)

Ste

nt

Th

rom

bosi

s F

ree S

urv

ival

Non-diabeticDiabetic

EVASTENT REGISTRY – SES Diabetic Vs Non Diabetic Patients

Follow-up (days)

0.80

0.85

0.90

0.95

1.00

0 200 400 600

Db - 858 835 805 426 203 123 pts

Db + 797 753 722 368 195 128 pts

Logrank p = 0.0001

TV

F F

ree S

urv

ival

Non-diabeticDiabetic

0 200 400 600Follow-up (days)

0.80

0.85

0.90

0.95

1.00

Db - 867 848 821 436 210 126 pts

Db + 814 775 747 388 200 134 pts

Log rank p = 0.032

Non-diabeticDiabetic

TL

R F

ree S

urv

ival

JACC 2007, 50, 501

AMI Stent THROMB. vs DENOVO (table 1)Baseline clinical characteristics

STEMI(n=98)

STEMI with ST(n= 86)

P Value

Age (yrs) 62.9 _+ 10.3 66.0 _+11.9 0.06

Male 81 (82.7%) 68 (79.1%) 0.5

Cardiac risk factors

Hypertension 45 (45.9%) 44 (51.8%) 0.4

Diabetes Mellitus 14 (14.3%) 21 (25.3%) 0.06

Hypercholesterolemia 34 (34.7%) 37 (43.4%) 0.2

Current smoker 47 (48.0%) 23 (26.5%) 0.003

Family history of CAD 35 (35.7%) 23 (26.5%) 0.2

Creatine >= 1.5mg/dl 4 (4.1%) 13 (15.7%) 0.008

COPD 3 (3.1%) 8 (9.5%) 0.07

Prior MI 11 (11.2%) 59 (68.2%) < 0.0001

Prior stroke 0 (0%) 6 (7.1%) 0.007

AMI Stent THROMB. vs DENOVO (table 2)ST characteristics (n=92)

Definite ST (ARC definition) 92 (100%)

Thrombosis timing (ARC definition)

Early (< 30 days) 59 (64.1%)

Late (30-360 days) 14 (15.2%)

Very Late (> 360 days) 19 (20.7%)

Clinical presentation at the Index procedure 43 (46.5%)

MI (acute or sub acute) 38 (41.9%)

UA/ NSTEMI stable angina or silent ischemia 11 (11.6%)

Double antiplatelet therapy at the moment of stent thrombosis 62 (67.4%)

Early discontinuation of double antiplatelet therapy 6 (6.9%)

Stent

BMS 22 (23.9%)

DES 70 (76.1%)

Stent Length 25.2_+ 12.7

Stent diameter 2.8_+ 0,3

ARC= Academic Reasearch Consortium; BMS= abre-metal stent; DES=drug eluting stent; MI=myocardial infarction; ST=stent thrombosis; UA/NSTEMI= unstable angina/non- ST-segment elevation myocardial infarction

AMI Stent THROMB. vs DENOVO (table 3)Angiographic AnalysisSTEMI(n=98)

STEMI with ST(n= 92)

p Value

Pre-procedural TIMI flow <=1 77 (78.6%) 69 (80%) 0.8Post-procedural TIMI flow =3 95 (96.9%) 74 (80.4%) < 0.0001Pre-procedural TG >= 3 92 (93.9%) 92 (100%) 0.01Post-procedural myocardial blush <=1

1(1.0%) 12 (13.0%) 0.001

Post-procedural cTFC* 24.2 _+ 12.6 21.2 _+ 9.4 0.1Successful reperfusion 95 (96.9%) 74 (80.4%) <0.0001Distal Embolization 0(0%) 6 (6.5%) 0.01Residual dissection 1(1.0%) 15 (16.3%) <0.0001Post-procedural QCA analysisRVD (mm) 3.2 _+ 0.4 2.9 _+ 0.3 <0.0001Lesion length (mm) 2.9 _+ 2.6 7.0 _+ 4.7 < 0.0001MLD (mm) 2.9 _+ 0.4 2.0 _+ 0.7 < 0.0001Diameter stenosis (%) 8.1 _+ 6.6 31.8 _+ 24.9 < 0.0001

Successful Reperfusion

Chechi, T. et al. J Am Coll Cardiol 2008;51:2396-2402

All-Cause Mortality and Cumulative MACCE Rate

Chechi, T. et al. J Am Coll Cardiol 2008;51:2396-2402

Stent thrombosis in DM NDMRisk factors for stent thrombosis after implantation of Sirolimus-

eluting stents in Diabetic and Nondiabetic patients.The EVASTENT Matched-Cohort Registry

Independent predictors of stent thrombosis

Parameter QR (95% CI) p Value

Overall population

Previous stroke 3.2 (0.99-1.0) 0.052

Renal failure 3.6 (1.6-7.7) 0.001

Insulin-requiring diabetes 2.7 (1.4-5.2) 0.004

Calcified lesion 3.7 (1.8-7.7) 0.001

Lower EF (per U) 0.95 (0.93-0.97) <= 0.001

Length stented (per mm) 1.01(1.0-1.03) 0.045

Very Late DES Thrombosis On-Label Use>1 Year Post Implant Pooled RCTs

Aalen-Nelson Estimate Curves of Cumulative Hazard Function for Stent Thrombosis

Park, D.-W. et al. J Am Coll Cardiol Intv 2008;1:494-503

Kaplan-Meier Curves of Cumulative Incidence of Stent Thrombosis

Park, D.-W. et al. J Am Coll Cardiol Intv 2008;1:494-503

Rates of Stent Thrombosis in Meta-analysisReference Year Patients Stents FU ST RateMoreno 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%

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 with a reduction in MACE, including ST, and may be a therapeutic option for patients at high risk for ST.

Triple Versus Dual Antiplatelet Therapy

J. Am. Coll. Cardiol. 2005;46;1833-1837

Dual(n=1597)

Triple(n= 1415)

p Value

Stent thrombosis 9 (0.596) 1 (0.196) 0.024

Acute stent occlusion 3(0.296) 0 0.252

Sub acute stent thrombosis

6(0.396) 1(0.196) 0.223

Major cardiac events

Myocardial infarction 11(0.796) 3(0.296) 0.063

Target lesion revascularization

9(0.596) 1(0.196) 0.024

Repeat intervention 8(0.697) 1(0.196)

Emergency bypass 1(0.02) 0

Death 5(0.396) 3(0.296) 0.730

Primary end point 13(0.896) 4(0.396) 0.085

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