tct 2009 stent thrombosis following primary pci in stemi: predictors, clinical impact and preventive...

TCT 2009

Stent Thrombosis Following Primary PCI in STEMI:

Predictors, Clinical Impact and Preventive Strategies from the

Horizons AMI Trial

George D. Dangas, MD

Columbia University Medical Center

TCT 2009

Disclosures

Speaker honoraria Sanofi-Aventis, Astra Zeneca and BMS

– Not sponsors of this study

Speaker honoraria and consulting fees– Medicines Co – modest– Boston Scientific – modest

– Both provided research grant support for the Horizons Trial

– Eli Lilly– Astra Zeneca

TCT 2009

BackgroundBackground

Stent thrombosis (ST) is a serious adverse event Stent thrombosis (ST) is a serious adverse event which occurs more frequently in pts with STEMIwhich occurs more frequently in pts with STEMI

Since the pathophysiologic mechanisms of ST Since the pathophysiologic mechanisms of ST may vary, it is conventionally categorized may vary, it is conventionally categorized according to its timing after stenting: according to its timing after stenting:

– 0-24 hours (acute ST) 0-24 hours (acute ST)

– 1-30 days (subacute ST) 1-30 days (subacute ST)

– 1-12 months (late ST)1-12 months (late ST)

– Beyond 1 year (very late ST)Beyond 1 year (very late ST)

TCT 2009

HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in tents in AMIAMI

3602 pts with STEMI with symptom onset ≤12 hours3602 pts with STEMI with symptom onset ≤12 hours

Emergent angiography, followed by triage to…Emergent angiography, followed by triage to…

Primary PCIPrimary PCICABGCABG –– Medical RxMedical Rx––

UFH + GP IIb/IIIa inhibitorUFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)(abciximab or eptifibatide)

Bivalirudin monotherapyBivalirudin monotherapy(± provisional GP IIb/IIIa)(± provisional GP IIb/IIIa)

Aspirin, thienopyridineAspirin, thienopyridine R R 1:11:1

3006 pts eligible for stent randomization3006 pts eligible for stent randomization R R 3:13:1

Bare metal EXPRESS stentBare metal EXPRESS stentPaclitaxel-eluting TAXUS stentPaclitaxel-eluting TAXUS stent

Clinical FU at 30 days, 6 months, 1 year, and thenClinical FU at 30 days, 6 months, 1 year, and thenyearly through 5 years; angio FU at 13 monthsyearly through 5 years; angio FU at 13 months

Clinical FU at 30 days, 6 months, 1 year, and thenClinical FU at 30 days, 6 months, 1 year, and thenyearly through 5 years; angio FU at 13 monthsyearly through 5 years; angio FU at 13 months

TCT 2009

Diff = Diff = 0.0% [-1.6, 1.5] RR = 0.99RR = 0.99 [0.76, 1.30]

PPsupsup = 0.95 = 0.95

Primary Endpoints at 30 Days

Diff = Diff = -3.3% [-5.0, -1.6] RR = RR = 0.60 [0.46, 0.77]

PPNINI ≤ 0.0001 ≤ 0.0001

PPsupsup ≤ 0.0001 ≤ 0.0001

Diff = Diff = -2.9% [-4.9, -0.8]RR = RR = 0.76 [0.63, 0.92]

PPNINI ≤ 0.0001 ≤ 0.0001

PPsupsup = 0.005 = 0.005

1 endpoint 1 endpoint

Stone GW et al. Stone GW et al. NEJMNEJM 2008;358:2218-30 2008;358:2218-30

Major 2 endpoint

TCT 2009

1-Year Mortality (All-Cause)

Number at riskBivalirudin aloneHeparin+GPIIb/IIIa

1800 1705 1684 1669 15201802 1679 1664 1647 1487

Mo

rtal

ity

(%)

0

1

2

3

4

5

Time in Months

0 1 2 3 4 5 6 7 8 9 10 11 12

Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802) 4.8%

3.4%

Diff [95%CI] =

-1.4% [-2.7,-0.1]

HR [95%CI] =

0.70 [0.51, 0.98]

P=0.036P=0.036

3.1%

2.1%

Δ = 1.0%

P=0.049

Δ = 1.4%

TCT 2009

Stent Thrombosis Analysis

In the current analysis we included all HORIZONS-AMI pts who received a stent,

either DES (any type) or only BMS (n=3203)

Stent thrombosis (n=107 [3.3%] within 1-year) was defined as Definite or Probable by the

ARC criteria, as adjudicated by an independent CEC blinded to stent and

pharmacology use

TCT 2009

Objectives Stent thrombosis and timing according to:

– Stent type (any DES vs. onlyBMS, 94% rand)

– Antithrombin type (UFH+GPI vs. Bival, 100% rand)

– GPI selection (abciximab vs. eptifibatide, stratified)

– Clopidogrel loading dose (300 vs. 600 mg, stratified)

– Pre randomization UFH (yes vs. no, stratified)

Univariate and multivariable predictors of stent thrombosis (ARC Def/Prob) from 36 variables

– Acute, subacute, late, and 1-year

TCT 2009

Statistical MethodsStatistical Methods Kaplan-Meier methods were used to plot landmark time-to-event Kaplan-Meier methods were used to plot landmark time-to-event

curves, compared using the logrank testcurves, compared using the logrank test

Cox proportional hazards used to derive the independent Cox proportional hazards used to derive the independent predictors of ST via stepwise regression (predictors of ST via stepwise regression (αα=0.05)=0.05)

Potential covariates (36) for inclusion in the models:Potential covariates (36) for inclusion in the models:

– CLINICAL (20): CLINICAL (20): Bivalirudin (randomized v. UFH+IIb/IIIa), Bivalirudin (randomized v. UFH+IIb/IIIa), Any DES (v. BMS Any DES (v. BMS only), Age, Sex (Male), US clinical center, Clopidogrel Loading Dose, Pre-only), Age, Sex (Male), US clinical center, Clopidogrel Loading Dose, Pre-Randomization Heparin, Current Smoking, History of IDDM, History of MI, Randomization Heparin, Current Smoking, History of IDDM, History of MI, History of CHF, Killip Class 2-4, History of PVD, Anemia, Baseline Platelet History of CHF, Killip Class 2-4, History of PVD, Anemia, Baseline Platelet Count, Renal Insufficiency (Baseline CrCl<60), Anterior MI, Direct Stenting Count, Renal Insufficiency (Baseline CrCl<60), Anterior MI, Direct Stenting Attempted, Post Dilation balloon used, Max Balloon Pressure Attempted, Post Dilation balloon used, Max Balloon Pressure

– ANGIOGRAPHIC (16): ANGIOGRAPHIC (16): Baseline RVD, Total Lesion Length, Stent to Lesion Baseline RVD, Total Lesion Length, Stent to Lesion Length Ratio, Number of stents, Worst angiographic view - Thrombus, Worst Length Ratio, Number of stents, Worst angiographic view - Thrombus, Worst angiographic view - Ulceration, Aneurysm, Baseline TIMI flow 0/1, Bifurcation angiographic view - Ulceration, Aneurysm, Baseline TIMI flow 0/1, Bifurcation lesion, Moderate/Severe Calcification, Multiple Vessels Treated, Sustained lesion, Moderate/Severe Calcification, Multiple Vessels Treated, Sustained ventricular tachycardia or fibrillation on admission, Final TIMI flow 0/1, Final ventricular tachycardia or fibrillation on admission, Final TIMI flow 0/1, Final Lesion MLD , Final Lesion DS>50%, Final Angiography with No ReflowLesion MLD , Final Lesion DS>50%, Final Angiography with No Reflow

TCT 2009

Two-Year Stent ThrombosisTwo-Year Stent Thrombosis(ARC Definite or Probable)(ARC Definite or Probable)

p= 0.99p= 0.99

HR [95%CI]=HR [95%CI]=1.00 [0.66, 1.51]1.00 [0.66, 1.51]

4.1%4.1% 4.1%4.1%

Ste

nt

Th

rom

bo

sis

(%)

Ste

nt

Th

rom

bo

sis

(%)

00

11

22

33

44

55

66 TAXUS DES (n=2257)TAXUS DES (n=2257)

EXPRESS BMS (n=749)EXPRESS BMS (n=749)

00 33 66 99 1212 1515 1818 2121 2424

22382238 21082108 20612061 19981998 16611661

744744 696696 681681 661661 547547

Number at riskNumber at riskTAXUS DESTAXUS DES

EXPRESS BMSEXPRESS BMS

MonthsMonths

TCT 2009

Two Year Composite Safety Endpoints*Two Year Composite Safety Endpoints*TAXUSTAXUS

(N=2257)(N=2257)EXPRESSEXPRESS(N=749)(N=749) HR [95%CI]HR [95%CI] P P

ValueValue

Stent thrombosisStent thrombosis 4.1%4.1% 4.1%4.1% 1.00 [0.66,1.51]1.00 [0.66,1.51] 0.990.99

- ARC definite- ARC definite 3.7%3.7% 3.6%3.6% 1.01 [0.65,1.57]1.01 [0.65,1.57] 0.960.96

- ARC probable- ARC probable 0.6%0.6% 0.5%0.5% 0.91 [0.29,2.87]0.91 [0.29,2.87] 0.880.88

*Kaplan-Meier estimates*Kaplan-Meier estimates

Adverse Events Between 1 and 2 Years*Adverse Events Between 1 and 2 Years*TAXUSTAXUS

(N=2257)(N=2257)EXPRESSEXPRESS(N=749)(N=749) HR [95%CI]HR [95%CI] P P

ValueValue

Stent thrombosisStent thrombosis 1.1%1.1% 0.7%0.7% 1.51 [0.58,3.98]1.51 [0.58,3.98] 0.400.40

- ARC definite- ARC definite 1.1%1.1% 0.6%0.6% 1.81 [0.62,5.25]1.81 [0.62,5.25] 0.270.27

- ARC probable- ARC probable 0.05%0.05% 0.14%0.14% 0.33 [0.02,5.24]0.33 [0.02,5.24] 0.410.41

TCT 2009

2-Year Stent Thrombosis2-Year Stent Thrombosis(ARC Definite/Probable)(ARC Definite/Probable)

16111611 15091509 14751475 14441444 12061206

15911591 14821482 14491449 13861386 11531153

p= 0.73p= 0.73

HR [95%CI]=HR [95%CI]=0.94 [0.67, 1.32]0.94 [0.67, 1.32]

4.3%4.3% 4.6%4.6%

Ste

nt

Th

rom

bo

sis

(%

)S

ten

t T

hro

mb

os

is (

%)

00

11

22

33

44

55

66

00 33 66 99 1212 1515 1818 2121 2424

Number at riskNumber at riskBivalirudin aloneBivalirudin alone

Heparin+GPIIb/IIIaHeparin+GPIIb/IIIa

Bivalirudin alone (n=1800)Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802)Heparin + GPIIb/IIIa (n=1802)

MonthsMonths

TCT 2009

2.2% 2.2%

3.0% 3.0%

1.5%1.5%

0.3%0.3%

HR [95%CI] =HR [95%CI] = 1.73 [0.47-1.13]1.73 [0.47-1.13]

P = 0.06P = 0.06

HR [95%CI] =HR [95%CI] =5.93 [2.06-17.04]5.93 [2.06-17.04]

P = 0.0002P = 0.0002

1611161115911591

16001600 15621562 15251525 15061506 14851485 1355135515871587 15211521 14951495 14761476 14571457 13151315

Number at riskNumber at riskBivalirudinBivalirudinUFH+GPIIb/IIIaUFH+GPIIb/IIIa

Def

/Pro

b S

ten

t T

hro

mb

osi

s (%

)D

ef/P

rob

Ste

nt

Th

rom

bo

sis

(%)

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5

Time in DaysTime in Days

00 11 3030 9090 180180 270270 365365

Stent Thrombosis 1-Day Landmark Stent Thrombosis 1-Day Landmark Analysis:Analysis: Impact of Antithrombin Impact of Antithrombin

Bivalirudin monotherapyBivalirudin monotherapy

Heparin + GPIIb/IIIa inhibitorHeparin + GPIIb/IIIa inhibitor

TCT 2009

Acute Stent Thrombosis:Acute Stent Thrombosis: Impact of Impact of Pre-Randomization HeparinPre-Randomization Heparin

10661066 10521052 10511051 10501050 10491049

545545 531531 529529 528528 528528

Number at riskNumber at risk

P-R HeparinP-R Heparin

No P-R HeparinNo P-R Heparin

Def

/Pro

b S

ten

t T

hro

mb

osi

s (%

)D

ef/P

rob

Ste

nt

Th

rom

bo

sis

(%)

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5

Time in HoursTime in Hours00 66 1212 1818 2424

Pre-Randomization HeparinPre-Randomization HeparinNo Pre-Randomization HeparinNo Pre-Randomization Heparin

UFH+GPI UFH+GPI

UFH+GPIUFH+GPI

12111211 12081208 12071207 12071207 12071207

378378 377377 375375 374374 374374P-R HeparinP-R Heparin

No P-R HeparinNo P-R Heparin

BivalirudinBivalirudin

BivalirudinBivalirudin

0.1%0.1%

0.8%0.8%HR [95%CI] = 9.64 [1.00,92.70]HR [95%CI] = 9.64 [1.00,92.70]

P = 0.02P = 0.02

0.9%0.9%

2.6%2.6%

HR [95%CI] = HR [95%CI] = 3.07 [1.33,7.09]3.07 [1.33,7.09]

P = 0.006P = 0.006

PPintint antithrombin x pre-rand hep = 0.39 antithrombin x pre-rand hep = 0.39

TCT 2009

Independent Predictors of Acute ST Independent Predictors of Acute ST (Cox Model)(Cox Model)

Variable HR [95% CI] P-value

Pre-PCI TIMI flow 0/1 6.10 [1.43, 26.04] 0.01

Lesion ulceration 4.80 [1.41, 16.37] 0.01

Bivalirudin (v. UFH+GPI) 4.65 [1.59, 13.54] 0.005

Number of stents 1.50 [1.06, 2.12] 0.02

Pre-rand heparin 0.27 [0.12, 0.60] 0.002

TCT 2009

2.8% 2.8%

3.6% 3.6%

HR [95%CI] =HR [95%CI] =0.78 [0.44-1.37]0.78 [0.44-1.37]

P = 0.38P = 0.38

727727 693693 685685 678678 668668 592592829829 793793 778778 768768 759759 698698

Number at riskNumber at riskEptifibatideEptifibatideAbciximabAbciximab

Def

/Pro

b S

ten

t T

hro

mb

osi

s (%

)D

ef/P

rob

Ste

nt

Th

rom

bo

sis

(%)

00

11

22

33

44

Time in daysTime in days

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365

EptifibatideEptifibatide

AbciximabAbciximab

1-Year Stent Thrombosis: 1-Year Stent Thrombosis: Impact of Impact of GPI in the UFH Group GPI in the UFH Group

TCT 2009

3.0% 3.0%

3.8% 3.8%

HR [95%CI] = HR [95%CI] = 1.30 [0.86-1.95]1.30 [0.86-1.95]

P = 0.10P = 0.10

1-Year Stent Thrombosis1-Year Stent Thrombosis: Impact of : Impact of Clopidogrel Loading Dose (all pts)Clopidogrel Loading Dose (all pts)

19831983 19061906 18811881 18581858 18321832 1653165310341034 983983 974974 965965 952952 871871

Number at riskNumber at risk600 mg600 mg300 mg300 mg

600mg Clopidogrel600mg Clopidogrel


Def

/Pro

b S

ten

t T

hro

mb

osi

s (%

)D

ef/P

rob

Ste

nt

Th

rom

bo

sis

(%)

00

11

22

33

44

55

Time in daysTime in days

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365

TCT 2009

0.8%0.8%

2.2% 2.2%

3.2% 3.2%

0.8%0.8%

HR [95%CI] = HR [95%CI] = 0.96 [0.41-2.23]0.96 [0.41-2.23]

P = 0.92P = 0.92

HR [95%CI] = HR [95%CI] = 1.47 [0.93,2.33]1.47 [0.93,2.33]

P = 0.18P = 0.18

19831983

1034103419781978 19201920 18811881 18581858 18321832 16531653

10271027 990990 974974 965965 952952 871871

Number at riskNumber at risk

600 mg600 mg

300 mg300 mg

Def

/Pro

b S

ten

t T

hro

mb

osi

s (%

)D

ef/P

rob

Ste

nt

Th

rom

bo

sis

(%)

00

11

22

33

44

55

Time in DaysTime in Days

00 11 3030 9090 180180 270270 365365

Stent Thrombosis 1-Day Landmark Stent Thrombosis 1-Day Landmark Analysis:Analysis: Impact of Clopidogrel Loading Impact of Clopidogrel Loading



TCT 2009

Independent Predictors of Subacute ST Independent Predictors of Subacute ST (Cox Model)(Cox Model)


Insulin-treated diabetes 4.43 [2.03, 9.65] 0.0002

History of CHF 4.16 [1.61, 10.76] 0.003

Pre-PCI TIMI flow 0/1 2.21 [1.05, 4.63] 0.04

Final TIMI flow 0/1 3.72 [1.10, 12.55] 0.03

Stent to lesion length ratio 1.44 [1.20, 1.71] <0.0001

Clopidogrel loading dose 600 mg (vs. 300 mg)

0.49 [0.27, 0.89] 0.01

TCT 2009

Independent Predictors of Late ST Independent Predictors of Late ST (Cox Model)(Cox Model)


Current smoking 4.05 [1.73, 9.48] 0.001


History of prior MI 3.15 [1.39, 7.13] 0.006

Post stent dilation balloon used

2.75 [1.31, 5.80] 0.008

TCT 2009

Independent Predictors of 1-Year ST Independent Predictors of 1-Year ST (Cox Model)(Cox Model)



Lesion ulceration 2.28 [0.99, 5.27] 0.05

Pre-PCI TIMI flow 0/1 2.22 [1.37, 3.61] 0.001

Current smoking 1.81 [1.20, 2.72] 0.005

Number of stents 1.31 [1.07, 1.60] 0.04

Clopidogrel loading dose 600mg 0.65 [0.44, 0.97] 0.04

TCT 2009

Overall ConclusionsOverall Conclusions Following stent implantation in STEMI, ST occurs Following stent implantation in STEMI, ST occurs

frequently within the first 24 hours (0.9%), between frequently within the first 24 hours (0.9%), between 1 and 30 days (1.6%), and between 1 month and 1 1 and 30 days (1.6%), and between 1 month and 1 year (1.0%) year (1.0%) – 3.3% in total by 1 year– 3.3% in total by 1 year

– 4.1% by 2 years4.1% by 2 years

Acute, subacute and late ST appear to be related Acute, subacute and late ST appear to be related to different factors to different factors

– Pharmacological therapy, vessel flow, lesion Pharmacological therapy, vessel flow, lesion characteristics and number and length of stents are characteristics and number and length of stents are the most important predictors of acute and subacute the most important predictors of acute and subacute ST eventsST events

– Patient related factors including cigarette smoking Patient related factors including cigarette smoking and prior MI are most important for late ST eventsand prior MI are most important for late ST events

TCT 2009

ImplicationsImplications The type of stent implanted (DES vs. BMS) The type of stent implanted (DES vs. BMS)

was not related to ST during any time was not related to ST during any time interval interval up to 2-yearsup to 2-years

ST within 1-year occurred with similar ST within 1-year occurred with similar frequency in patients treated with UFH+GPI frequency in patients treated with UFH+GPI and bivalirudin aloneand bivalirudin alone

–However, acute ST was more common However, acute ST was more common with bivalirudin, especially within the 1with bivalirudin, especially within the 1stst 5 5 hours, whereas ST tended to be less hours, whereas ST tended to be less common with bivalirudin than with common with bivalirudin than with UFH+GPI beyond 24 hoursUFH+GPI beyond 24 hours

TCT 2009

In the primary results of the HORIZONS-AMI trial, bivalirudin In the primary results of the HORIZONS-AMI trial, bivalirudin monotherapy resulted in less major bleeding, comparable rates of monotherapy resulted in less major bleeding, comparable rates of ischemia and improved survival compared to UFH+GPI ischemia and improved survival compared to UFH+GPI

Taking under account the present analysis we may be able to Taking under account the present analysis we may be able to optimize adjunct pharmacology with bivalirudin during primary PCI optimize adjunct pharmacology with bivalirudin during primary PCI may further improve outcomes:may further improve outcomes:

– Pre-randomization UFH attenuated the risk of acute STPre-randomization UFH attenuated the risk of acute ST

– This is especially meaningful if bivalirudin is not stored at This is especially meaningful if bivalirudin is not stored at point of first medical contact (ED, ambulance etc)point of first medical contact (ED, ambulance etc)

– A 600 mg clopidogrel LD attenuated the risk of subacute STA 600 mg clopidogrel LD attenuated the risk of subacute ST

– Should be the dosage of choice in STEMIShould be the dosage of choice in STEMI

– Other means of intense antiplatelet therapy should be Other means of intense antiplatelet therapy should be important as well including prasugrel, ticagrelor and extended important as well including prasugrel, ticagrelor and extended double dose regimen of clopidogreldouble dose regimen of clopidogrel

Whether a prolonged bivalirudin infusion (4-6 hrs) post-PCI warrants Whether a prolonged bivalirudin infusion (4-6 hrs) post-PCI warrants further study as wellfurther study as well

Practical PointsPractical Points

tct 2009 stent thrombosis following primary pci in stemi: predictors, clinical impact and preventive...

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