1. TREATMENT OF LATE AND VERY LATE
STENT THROMBOSIS
DEV PAHLAJANI MD,FACC,FSCAI
CHIEF OF INTERVENTIONAL CARDIOLOGY,
BREACH CANDY HOSPITAL,MUMBAI

2. 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.

3. BMS VS DES –ADVERSE EVENTS
Incidences of serious adverse events (Death or MI)
N=878
N=870
N=1675 N=1685

4. Study Design: BASKET LATE trial
743 patients randomized in the BASKET trial and without an event during the 6 month Clopidogrel phase
Drug eluting stents(DES)
Bare metal
(pooled paclitaxel and
VISION stents (BMS)
sirolimus DES groups)
N=244
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

5. 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”

6. BASKET-LATE
n = 743, 6 – 18 months
Pfisterer M. JACC 2006

7. 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 ischemia
6. 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 days
2. Any MI (related to documented acute ischemia and without another obvious cause) in
the territory of the stent
POSSIBLE: Any unexplained death >30 days

8. ARC Definitions of Stent Thrombosis - Gaps
Best Balance
Includes MI with or
without angio, but
Too Narrow not 1.5%/year Too Broad
natural history
Misses people who deaths Includes natural
have an MI but don’t history events (equal
have an angiogram in both arms) that
dilute out true ST
signal*
* Worse if you include post TLR events
• Restenotic stent can’t really develop ST
• Brachytherapy or new DES certainly can
Dr. Don Baim, TCT 2006.
• More such events occur in the BMS arm

9. Thrombosis Can Occur Any Time
Post-Stent Implantation
Very
Late ST
Late ST
SAT
Acute ST

10. Time Frame Classification
365 days
90 days
30 days
0 days

11. Occurrence of Stent Thrombosis
EVASTENT REGISTRY
ST+ (n=) 23 26 36 41
ST- (n=) 1692 1679 1669 1664
Cumulative probability of stent
2.5
2.0
1.5
thrombosis (%)
1.0
0.5
0.0
0 30 90 180 365
Follow-up (days)
JACC 2007, 50, 501

12. Stent Thrombosis
Bern-Rotterdam
3.5
3.2
3
Percent Stent Thrombosis
Bern Cypher 2.7
Bern Taxus
2.5 2.5
Bern BMS
1.9
2
1.5 1.6
1
0.5
0
0 10 30 365 730 1095
Days
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.

13. LATE STENT THROMBOSIS
 STEMI
 ACUTE CORONARY SYNDROME
 LEFT VENTRICULAR FAILURE
 CARDIOGENIC SHOCK

14. 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

15. Clinical importance of stent thrombosis
Author/Year BMS/DES ST def Death or MI Death
Cutlip 2001 BMS Angio or 70% 21%
clinical
Heller 2001 BMS Angio + AMI 100% 17 %
Iakovou 2005 DES Angio or 45 %
clinical
Ong 2005 DES Angio & 100 % 25 %
clinical
Kuchulakanti DES Angio 31 %
2006

16. ‘Real-world’ outcomes through 1 year
CYPHER (n=2067) TAXUS (n=7393)
e-CYPHER ARRIVE 1& 2
Stent P value Stent P value
Thrombosis Thrombosis
2.87 vs. 2.03 0.10
Diabetes vs. No Diabetes 1.12 vs. 0.75 0.44
3.06 vs. 1.95 0.03
2.5 mm vs. >2.5 mm 1.02 vs. 0.73 0.47
4.49 vs. 1.96 <0.0001
>28 mm vs. 28 mm 1.90 vs. 0.76 0.22
4.20 vs. 1.43 <0.0001
Multiple vs. Single stents 1.35 vs. 0.73 0.22
3.53 vs. 2.05 0.01
Multiple vs. Single Vessel 1.16 vs. 0.59 0.04
3.49 vs. 2.12 0.07
Acute MI vs. Non-AMI 0.67 vs. 0.88 1.00

17. Incidence of Late stent Thrombosis >30 days
meta-analysis of 14 randomized clinical trials 6675 pts
Am J of Medicine 2006;119, 1056-1061

18. Bern-Rotterdam Analysis: Summary
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.

19. Late Stent Thrombosis—
Factors to Consider

20. Incidence of Late Stent Thrombosis DES
McFadden E et al. Lancet 2004;364:1519

21. Incidence of Thrombosis in 40 autopsy cases of
DES

22. 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

23. Independent Predictors of Late ST
Iakovou I et al JAMA. 2005;293:2126-2130

24. 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
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)
Iakovou I et al JAMA. 2005;293:2126-2130

25. Late Incomplete Apposition
Drug-eluting stent
Dante Pazzanese Experience - 5% at 6 mths (20% had ST)

26. Impaired Re-endothelialization
Pathology findings:
Sirolimus-Eluting stents from different coronary arteries in the same patient
(delayed healing)
Cypher
16 months after
deployment
BMS
24 months after
deployment

27. Delayed Arterial healing in DES
Joner, JACC 2006

28. Lack of Re-Endothelialization at sites of
Thrombosis in DES

29. Percentage of Endothelialization in Drug-eluting
Stents (DES) VERSUS Bare-metal Stents (BMS)
as a function of Time
J Am Coll Cardiol 2006

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

31. 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

32. DES failed to cross a heavily calcified lesion!!
Undamaged Severe polymer
polymer damage
Columbia University Medical Centre
Cardiovascular Research Foundation

33. Mechanisms leading to incomplete stent
apposition
Cook, S. et al. Circulation 2007;115:2426-2434

34. 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

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

36. 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 5/17 (29%) 24/2,212 27 (12, 63) 17%
al.,2005 (7) (1.0%)
Kuchulakanti et 14/310 (4.5%) 24/2,658 5 (3,10) 29%
al.,2006 (8) (0.9%)
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

37. Clopidogrel and DES
Late clinical events after clopidogrel discontinuation may limit
the benefit of drug-eluting stents.
An observational study of DES versus BMS –BASKET-Late study

38. Timing of late thrombotic events after
clopidogrel discontinuation
Pfisterer, M. et al. J Am Coll Cardiol 2006;48:2584-2591
Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

39. JACC 2007, 50, 501
SES Thrombosis in Diabetic And Non Diabetic
EVASTENT REGISTRY Patients
1.00
SVD db -
MVD db -
MACE free Survival
0.95
SVD db +
MVD db +
Log Rank P <= 0.001
0.90
0.85
0 100 200 300 400 500 600
Follow-up (days)
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

40. EVASTENT REGISTRY –
SES Diabetic Vs Non Diabetic Patients
1.00
0.95 1.00
Stent Thrombosis Free Survival
Survival
0.90 Non-diabetic 0.95
Diabetic
0.90 Non-diabetic
0.85 Diabetic
Logrank p = 0.0001
0.80 0.85
Log rank p = 0.003
0 200 400 600 0.80
Follow-up (days)
0 200 400 600
Follow-up (days)
Db - 870 861 835 448 216 129 pts
Db + 818 799 774 401 212 144 pts
Db - 859 847 823 437 210 125 pts
Db + 800 776 755 394 202 135 pts
JACC 2007, 50, 501

41. 1.00
TLR Free Survival
0.95
0.90 Non-diabetic
Diabetic
1.00
0.85 Log rank p = 0.032
0.95
TVF Free Survival
0.80
0.90 Non-diabetic
Diabetic
0 200 400 600
Follow-up (days) 0.85 Logrank p = 0.0001
Db - 867 848 821 436 210 126 pts 0.80
Db + 814 775 747 388 200 134 pts
0 200 400 600
Follow-up (days)
Db - 858 835 805 426 203 123 pts
Db + 797 753 722 368 195 128 pts
JACC 2007, 50, 501

42. AMI Stent THROMB. vs DENOVO (table 1)
Baseline clinical characteristics
STEMI STEMI with ST P Value
(n=98) (n= 86)
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

43. 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

44. AMI Stent THROMB. vs DENOVO (table 3)
Angiographic Analysis
STEMI STEMI with ST p Value
(n=98) (n= 92)
Pre-procedural TIMI flow <=1 77 (78.6%) 69 (80%) 0.8
Post-procedural TIMI flow =3 95 (96.9%) 74 (80.4%) < 0.0001
Pre-procedural TG >= 3 92 (93.9%) 92 (100%) 0.01
Post-procedural myocardial 1(1.0%) 12 (13.0%) 0.001
blush <=1
Post-procedural cTFC* 24.2 _+ 12.6 21.2 _+ 9.4 0.1
Successful reperfusion 95 (96.9%) 74 (80.4%) <0.0001
Distal Embolization 0(0%) 6 (6.5%) 0.01
Residual dissection 1(1.0%) 15 (16.3%) <0.0001
Post-procedural QCA analysis
RVD (mm) 3.2 _+ 0.4 2.9 _+ 0.3 <0.0001
Lesion length (mm) 2.9 _+ 2.6 7.0 _+ 4.7 < 0.0001
MLD (mm) 2.9 _+ 0.4 2.0 _+ 0.7 < 0.0001
Diameter stenosis (%) 8.1 _+ 6.6 31.8 _+ 24.9 < 0.0001

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

46. All-Cause Mortality and Cumulative MACCE
Rate
Chechi, T. et al. J Am Coll Cardiol 2008;51:2396-2402

47. Stent thrombosis in DM NDM
Risk 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

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

49. 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

50. Kaplan-Meier Curves of Cumulative Incidence
of Stent Thrombosis
Park, D.-W. et al. J Am Coll Cardiol Intv 2008;1:494-503

51. Rates of Stent Thrombosis in Meta-analysis
Reference Year Patients Stents FU ST Rate
Moreno 2005 5,030 BMS 48% 6–12 mn SAT: 0.35% (BMS = DES)
SES 17% LST: 0.23% (BMS = DES)
PES 34%
Bavry 2005 3,817 BMS 48% 6–12 mn SAT + LST: 0.76% (PES = BMS)
PES 52%
Morice 2006 1,386 SES 51% 12 mn SAT: SES 0.4%, PES 1.0%
(REALITY) PES 49% LST: SES 0%, PES 0.3%
Kastrati 2005 3,669 SES 50% 6–13 mn SAT + LST: 1.0% (PES = SES)
PES 50%
Spalding 2007 1,748 BMS 50% 48 mn SAT: SES 0.5%, BMS 0.5%
SES 50% LST: SES 0.3%, BMS 1.3%
VLST: SES 2.8%, PES 1.7
Mauri 2007 4,545 SES 19% 48 mn SAT: SES 0.5%, BMS 0.3%
PES 31% LST: SES 0.1%, BMS 1.0%
BMS 50% 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%

52. 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.

53. Triple Versus Dual Antiplatelet Therapy
Dual Triple p Value
(n=1597) (n= 1415)
Stent thrombosis 9 (0.596) 1 (0.196) 0.024
Acute stent occlusion 3(0.296) 0 0.252
Sub acute stent 6(0.396) 1(0.196) 0.223
thrombosis
Major cardiac events
Myocardial infarction 11(0.796) 3(0.296) 0.063
Target lesion 9(0.596) 1(0.196) 0.024
revascularization
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
J. Am. Coll. Cardiol. 2005;46;1833-1837

54. THANK YOU!