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