George D. Dangas, MD, FACC, FESC
Professor of Cardiology & Vascular Surgery Icahn School of Medicine at Mount Sinai
New York, NY Καθηγητής Καρδιολογίας ΕΚΠΑ
Stent Thrombosis How to Predict & Prevent It!
History of Stent Thrombosis
1. Schatz RA et al. Circulation.1991;83:148; 2. Fischman DL et al. N Engl J Med. 1994;331496; 3 Colombo A et al. Circulation.1995;91:1676; 4. Schömig A et al.Circulation.1994,90:2716; 5. Leon M et al. N Engl J Med. 1998;339:1665; Joner M et al. J Am Coll Cardiol. 2006;48:193
0
4
8
12
16
1 2 3 4 5PS1 1991
STRESS2 1993
Colombo3 1995
STARS5 1997
Sten
t thr
ombo
sis
(%)
16%
3.5%1.4%
0.6%0.8%
ISAR4 1996
CoumadinHigh-pressure balloons
and DAPT
Very Late
> 1 year
Late
Subacute 24 hours to 30 days
24 Hours
Timing of ST After Stent Implantation
Acute ST
>30 days (but within 1 year)
Cutlip DE et al. Circulation. 2007;115:2344-51
“Early”
Procedure
Predictors of Stent Thrombosis The good (Patient), the bad (Procedure) and the ugly (Device)
Stent Thrombosis
Patient
Device• Type of stent • Polymer integrity and
reactions • Drug effects • Covered Stents • Incomplete Vascular Healing
and / or Inadequate Neointimal Coverage
• Hypersensitivity to drug coating or polymer
• Neoatherosclerosis
• Residual Edge Dissection Dissection
• Lesion / Stent Length • Vessel / Stent Diameter • Complex Lesions • Incomplete Stent Apposition
• ACS / STEMI • Diabetes Mellitus • Chronic Kidney Disease • LV Dysfunction • Saphenous Vein Graft
• Platelet Reactivity • Premature cessation of
DAPT • APT Non-Responsiveness • Malignancy
Stent Thrombosis With Drug-Eluting Stents and Bioresorbable Scaffolds Evidence From a Network Meta-Analysis of 147 Trials
A total of 147 trials including 126,526 patients
Kang S et al., J Am Coll Cardiol Intv. 2016;9(12):1203-1212
0
1,8
ML VISION (81 µm) TS Vision (162 µm) Xience V (96,6 µm)
0,8
1,5
1,0
Impact of strut thickness
Kolandaivelu K et al., Circulation 2011; 123:1400-1409
Relative ex vivo thrombogenicityLD
H A
dsor
banc
e fo
r Ste
nt F
orm
ulat
ion
/ LD
H A
bsor
banc
e fo
r ML
Visi
on (8
1µm
)
Hematotoxilin and eosin staining, 3 days
after implantation
Computational models depicting flow
alterations
Pathobiology of ST with DES
INCOMPLETE STENT APPOSITION
Attizzani GF et al., J Am Coll Cardiol. 2014 Apr 15;63(14):1355-67
Positive Vessel Remodeling
Thrombus Dissolution
Stent – Vessel Size Mismatch
Cook S et al., Circulation. 2007;115:2426-2434
Stent Underexpansion Poses a ST Risk
Adjusted risk of definite or probable stent thrombosis across complex PCI
components
Giustino G et al; J Am Coll Cardiol. 2016 Aug 25. pii: S0735-1097(16)34935-X
429 Healthy Amish after Clopidogrel 75
mg X 7dP=1.5 X 10-13
Shuldiner AR et al., JAMA 2009;302(8):849-858
CPY2C19*2 explained 12% of variance in Clopidogrel Response
CYP2C19 and Clopidogrel Responsiveness
Combined clinical and genetic model for ST risk prediction
Cayla G. et al., JAMA. 2011;306:1765-1774.
Genetic Model – AUC: 0.68; 95% CI, 0.62-0.74; P < 0.001
Clinical Model – AUC: 0.73; 95% CI, 0.67-0.78; P < 0.001
Combined Model – AUC: 0.78; 95% CI: 0.73-0.83; P < 0.001
* Log-rank P values adjusted for multiple comparisons
N=3041
Q1 taken as referent
Meta-Analysis of OTR and Ischemic Events Post-PCI Increasing Risk With Greater Residual Reactivity
Brar S et al, J Am Coll Cardiol. 2011 Nov 1;58(19):1945-54
ADAPT-DES: Unadjusted and
Adjusted ST Rates According to PRU
Stone G et al - Lancet 2013; 382: 614–23
ADAPT-DES IVUS SUBSTUDY: IVUS Planar Analysis
A. Maehara – TCT 2014
Use of IVUS Reduces Stent Thrombosis and Myocardial Infarction Results from the Prospective, Multicenter
ADAPT-DES Study
A. Maehara – TCT 2014
STENT THROMBOSIS -Pharmacotherapy-
2277923
2253 2143 2088 2027 1684898 847 835 801 673
Number at riskP-R HeparinNo P-R Heparin
p =
Clopidogrel Double vs Standard Dose
Mehta S. et al. Lancet. 2010 Oct 9;376(9748):1233-43
Clopidogrel standard dose Clopidogrel double dose
Adjusted HR 0.54 (0.39-0.74) P=0.0001
Clopidogrel standard-dose Clopidogrel double-dose
Number at risk
8703 8560
8561 8444
8482 8390
8455 8366
8438 8356
8428 8347
0 3 6 9 12 15 18 21 24 27 300%
0.6%
0.8%
1.0%
1.2%
1.4%
0.4%
0.2%Ste
nt th
rom
bosi
s (%
)
Days
Definite Stent Thrombosis (angio confirmed)
TRITON-TIMI-38
Wiviott S.D. et al. Lancet. 2008;371:1353-63
DAYS
HR 0.41 [0.29-0.59] P
PLATO Stent Thrombosis
12 M
onth
Ev
entR
ate
(%)
0
1,3
2,5
3,8
5
Definite Definite, probable or possible
2,82,1
1,3
3,62,8
1,9
Clopidogrel (n=5,649) Ticagrelor (n=5,640)
HR(95%CI) = 0.67 (0.50–0.91)
P=0.009
HR(95%CI) = 0.77 (0.62–0.95)
P=0.01
HR(95%CI) = 0.75 (0.59–0.95)
P=0.02
Wallentin L. et al. NEJM 2009;361:1045-57
CHAMPION-PHOENIX Stent Thrombosis reduction with Cangrelor
Bhatt DL et al ., N Engl J Med. 2013 Apr 4;368(14):1303-13
IPST in CHAMPION PHOENIX
Généreux P et al. JACC Vol. 63, No. 7, 2014
10,939 pts assessed by a blinded core lab Impact on 30-day mortality
Dangas GD et al; JACC 2012;59(20):1752-9
Mortality Following Stent Thrombosis Occurring In-Hospital versus
Out-Of-Hospital: Results from HORIZONS-AMI Mortality according to ARC timing definitions of ST
• Patient-level pooled analysis from HORIZONS-AMI and EUROMAX
• 30-day outcomes in 4935 patients undergoing pPCI with stent implantation at 188 international sites, randomized to either bivalirudin or UFH±GPI.
• Among patients with early ST, the propensity-adjusted risk of subsequent mortality within 30 days was determined for patients treated with bivalirudin versus heparin±GPI in a Cox multivariable model, with ST treated as a time-dependent variable; all differing baseline covariates were included in the propensity model.
Dangas GD et al. Circulation Cardiovasc Interv. 2016;9:e003272. DOI: 10.1161/CIRCINTERVENTIONS.115.003272
Early Stent Thrombosis and Mortality After Primary Percutaneous Coronary Intervention in
ST-Segment–Elevation Myocardial Infarction
A Patient-Level Analysis of 2 Randomized Trials
0,0
0,8
1,5
0 2 4 4 6 8 10 12 14 16 18 20 22 24
Bivalirudin 2479 2448 2436 2434 2433 2431 2431 2430 2430 2429 2429 2429 2428
Heparin ± GPI 2456 2448 2447 2447 2445 2445 2443 2442 2442 2442 2442 2442 2442
Sten
t Thr
ombo
sis
(%)
Time in Hours
BivalirudinHeparin ± GPI
1.1%
0.04%
0.4%
0.2%
Log Rank P-Value:
Kaplan–Meier estimates of 30-day mortality in patients with stent thrombosis (ST) according to the timing of the ST
event and regimen
Dangas GD et al. Circulation Cardiovasc Interv. 2016;9:e003272. 10.1161/CIRCINTERVENTIONS.115.003272
Stent Thrombosis in 2016 and the
BVS ERA
DAPT Cessation And 2-Year Definite / Probable Stent
Thrombosis
Mehran R et al; Lancet. 2013 Nov 23;382(9906):1714-22
Numbers of patients at low, intermediate, and high bleeding risk, respectively, with similar proportions observed for the different thrombotic risk categories.
Coronary Thrombosis and Major Bleeding After PCI With Drug-Eluting Stents
Baber U et al., J Am Coll Cardiol. 2016 May 17;67(19):2224-34
Predicting Risks for Coronary Thrombosis and Major Bleeding After PCI with DES: Risk Scores from PARIS Registry
Integer Risk Score for Major Bleeding
Parameter Score
Age, years< 50 50-59 60-69 70-79 >80
0 +1 +2 +3 +4
BMI, kg/m2 35
+2 0 +2
Current Smoking
Yes No
+2 0
AnemiaPresent Absent
+3 0
CKD*Present Absent
+2 0
3ple Therapy on discharge
Yes No+2 0
Integer Risk Score for Coronary Thrombosis
Parameter Score
Diabetes MellitusNone Non-Insulin Insulin
0 +1 +3
Acute Coronary Syndrome
No Yes, Tn (-) Yes, Tn (+)0 +1 +2
Current SmokingYes No
+1 0
CKD* CrCl < 60 mL/min/1.73 m2
Present Absent
+2 0
Prior PCI Yes No+2 0
Prior CABGYes No
+2 0
Baber U et al., J Am Coll Cardiol. 2016 May 17;67(19):2224-34
PCI complexity & Stent thrombosis
Complex PCI is strongly associated with increased risk of definite or probable ST with a magnitude that was comparable to that of a history of prior MI or high-risk ACS presentation.
Giustino G et al., J Am Coll Cardiol. 2016 Aug 25. pii: S0735-1097(16)34935-X
ST risk score (UA/nonSTEMI & STEMI) Based on ACUITY & HORIZONS datasets
Variable Calculation Integer Assignment for Stent Thrombosis Risk Score
Type of Acute Coronary
Syndrome
NSTE-ACS w/o
ST changes +1
NSTE-ACS with ST
deviation +2 STEMI+4
Current Smoking Yes: +1 No: +0
Insulin treated diabetes Yes: +2 No: +0
History of PCI Yes: +1 No: +0
Baseline Platelet Count 400K/ul: +2
Absence of pre-PCI Heparin Yes: +1 No: 0Aneurysm or Ulceration Yes: +2 No: 0
Baseline TIMI flow grade 0/1 Yes: +1 No: 0
Final TIMI flow grade < 3 Yes: +1 No: 0
Number of Vessels Treated 1 vessel: +0 2 vessels: +1 3 vessels: +2
Dangas GD et al; JACC Cardiovasc Interv. 2012 Nov;5(11):1097-105
Derivation cohort
Validation cohort
Dangas GD et al., JACC Cardiovasc Interv. 2012 Nov;5(11):1097-105
Risk of ST with 1st- and 2nd-Generation Drug-Eluting Stents According to Duration of Dual Antiplatelet Therapy
Giustino G et al., J Am Coll Cardiol. 2015 Apr 7;65(13):1298-310
Timing of strut reabsorption
Indolfi C et al., Nat Rev Cardiol. 2016 Sep 29. doi: 10.1038/nrcardio.2016.151
Timing of vascular scaffold reabsorption
Gregg SW TCT presentation 2016
Puricel S. et al ., J Am Coll Cardiol. 2016 Mar 1;67(8):921-31
The implantation protocol used was an independent predictor of ScT
*For a 2.5-3.0 mm and 3.5 mm scaffold respectively
BVS specific protocol
Do not accept MLD
Timing and Mechanism of DES Thrombosis
Nakazawa et al. J Cardiol 2011;58:84-91 Claessen BE…Dangas GD; JACC Cardiovasc Interv 2014;7:1081-92
Early (12 Mo)
Procedural Delayed healing Abnormal vascular response
Underexpansion Uncovered struts Hypersensitivity
Edge dissection Fibrin deposition Extensive fibrin deposition Residual plaque Late malapposition?
Neoatherosclerosis
How to Minimize Stent Thrombosis• Better Patient selection
Screening for adherence and bleeding risk / ability to tolerate DAPT No upcoming surgical procedures (6 wk for BMS, 6–12 m for DES)
• Better Stent selection and deployment Consider use of stents with proven lower stent thrombosis rates Appropriate vessel sizing, high-pressure deployment/post-dilation Ensuring absence of edge dissections and adequate inflow/outflow Avoiding the use of 2 stents in bifurcation lesions (if possible)
• Better Peri- and post-procedure care Use of more potent oral antiplatelet regimens in appropriately indicated clinical scenarios (e.g. ACS with acceptable bleeding risk) Patient education and clinical follow-up are critical Continuation of DAPT without interruption whenever possible
Kirtane AJ. et al Circulation. 2011 Sep 13;124(11):1283-7
2nd Generation
DES (ZES, EES)
With or without potent
antiplatelet agents
(prasugrel, ticagrelor)
Short term DAPT
Prevention of Stent Thrombosis and DAPT
Favors the stronger antiplatelet agents/regimens Is Closely related to type of stent & adherence
Vulnerable Stent vs Patient ??
What are we treating?
20-25% risk of “falling” again in the
next 5 yearsc/o Dominic Angiolillo
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