updated guideline of glycoprotein iib/iiiainhibitor for...

Updated Guideline of Glycoprotein IIb/IIIa Inhibitor

for Acute Coronary Syndrome

1

YoungYoung--Hak Kim, MD, PhDHak Kim, MD, PhD

Heart Institute, Heart Institute, AsanAsan Medical Center, Medical Center, University of Ulsan College of Medicine, Seoul, KoreaUniversity of Ulsan College of Medicine, Seoul, Korea

Disclosure InformationDisclosure Information

Honorarium from Handok Corp

Acute Coronary Syndrome

Clinical Classification of ACSClinical Classification of ACS

No ST Elevation

Unstable Angina

ST Elevation

STEMI

Hx

EKG

Cardiac Biomarker

Final Dx

Non-STEMI

3

Platelet ActivationPlatelet Activation

PlateletAspirin

Epinephrine

ADP

CollagenThrombin

Platelet Membrane

GP IIb/IIIa

Fibrinogen

AA

TxA2

GPIIb/IIIa inhibitors

Thienopyridines

ll ThrombinThrombin

ll SerotoninSerotonin

ll ADPADP

ll TXATXA22

ll OthersOthers

Target Sites of Antiplatelet TherapyTarget Sites of Antiplatelet Therapy

DirectDirectAntithrombinsAntithrombins

Disruption ofDisruption ofEndotheliumEndothelium

PlateletPlateletAdhesionAdhesion

PlateletPlateletActivationActivation

PlateletPlateletReleaseRelease

PlateletPlateletAggregationAggregation

Prostaglandins Prostaglandins

GPlb/vWFGPlb/vWFAntagonists,Antagonists,DipyridamoleDipyridamole

Aspirin,Aspirin,TxS InhibitorsTxS Inhibitors

GPllb/lllaGPllb/lllaAntagonistsAntagonists

Shear Stress,Shear Stress,Binding of Agonists:Binding of Agonists:

Schafer AI. Am J Med. 1996;101:202.

SerotoninSerotoninAntagonistsAntagonists

ClopidogrelClopidogrelTiclopidineTiclopidine

TXATXA22 ReceptorReceptorAntagonistsAntagonists

GP = GlycoproteinvWF = von Willebrand factor TxS = Thromboxane synthaseTXA2 = Thromboxane A2

Parenteral GP IIb/IIIa inhibitors

Antibody• abciximab

(ReoProâ, Centocor/Lilly)

Cyclic peptide• eptifibatide

(INTEGRILIN®, COR/Key)

Nonpeptide• tirofiban HCI

(Aggrastatâ, Merck)

GP IIb/IIIa Receptor AntagonistsGP IIb/IIIa Receptor AntagonistsAbciximab (ReoPro®)

Tirofiban (Aggrastat®)

Eptifibatide (Integrilin®)

Pharma

Renal Adj.

Dosage

No

0.25 mcg/kg bolus followed by 0.125 mcg/kg/min drip (max 10 mcg/min) for 12-24 hours

Synthetic non-peptide

Yes

0.4 mcg/kg/min for 30 minutes followed by 0.1 mcg/kg/min drip for 48-96 hours

Cyclic heptapeptide

Yes

180 mcg/kg bolus (x2) followed by 2.0 mcg/kg/min drip for 18-24 hours

Fab portion of chimeric monoclonal antibody

Half-life 30 minutes 1.8 hours 2.5 hours

Early Abciximab PCI TrialsEarly Abciximab PCI Trials

NEJM 1997; 336:1689-96

Death, MI, Urgent Revascularization Death, MI, Urgent Revascularization –– 30 Days30 Days

DaysDays00

44

88

1212 BolusBolus

Bolus + InfusionBolus + Infusion

PlaceboPlacebo 12.812.8

8.38.3

EPICEPIC

Absolute Absolute -- 4.5%4.5%Relative Relative –– 35%35%

p = 0.008p = 0.008

DaysDays

PlaceboPlacebo 11.711.7

5.25.2AbciximabAbciximab

EPILOGEPILOG


p < 0.001p < 0.001

10.810.8

6.96.9

Placebo + StentPlacebo + Stent

Abciximab + PTCAAbciximab + PTCA5.35.3Abciximab + StentAbciximab + Stent

00 3030DaysDays

EPISTENTEPISTENT


p < 0.001p < 0.001

NEJM 1994; 330:956NEJM 1994; 330:956--6161 Lancet 1998; 352:87Lancet 1998; 352:87--9292

00 303000 3030

For STEMIFor STEMI

Primary PCI30 Day Death, MI or Urgent TVR

11.210.5

14.6

6.9

10.5

5.8 5.06.0

4.5 4.5

0

5

10

15

20

% o

f Pat

ient

s

Placebo Abciximab

¯ 48%p = 0.03

¯ 52%p = 0.04

¯ 52%p = 0.01

¯ 30%p = 0.02

JACC 2000;35:915-21.

NEJM 2001;41:1895-03.

Circ 1998;98:734-41.

n = 401 n = 300 n = 2082n = 483ISAR-2 ADMIRAL CADILLAC*RAPPORT

¯ 57%p = 0.02

n = 400ACE**

NEJM 2002;346:957-66

Ellis S. Ellis S. ESC ESC N Engl J Med 2008;358:2205

*All-cause mortality; rehosp or ED visit for CHF; VF >48 hours after randomization; cardiogenic shock. N=2452.

FINESSE – 90-Day Endpoints FINESSE – 90-Day Endpoints P

erce

ntP

erce

nt

4.5

8.9

2.2

10.5

5.5

7.5

2.9

9.8

5.2

7.4

1.9

10.7

0

2

4

6

8

10

12

Composite* Death MI Comp CHF

Primary PCI (806) PCI+Abcix (818) PCI+Abcix+Reteplase (828)

FINESSE – 90-Day Bleeding FINESSE – 90-Day Bleeding P

erce

ntP

erce

nt

**

******

* p= 0.025. ** p < 0.01. *** p < 0.001

********** ****

2.64.3

10.1

4.16

14.5

4.8

9.7

6.9

0

2

4

6

8

10

12

14

16

Overall TIMI Major TIMI Minor

Primary PCI (806) PCI+Abcix (818) PCI+Abcix+Reteplase (828)

Ellis S. Ellis S. ESC ESC N Engl J Med 2008;358:2205

Di Mario C. Lancet 2008; 371: 559–68

CARESS Abciximab with ½ Dose Reteplase

CARESS Abciximab with ½ Dose Reteplase

Composite = 30-day Death, Re-MI, Refractory ischemia. N=600

Per

cent

Per

cent

P=0.032P=0.032P=0.001P=0.001

3.1

0.3 0.7

12.2

3.7

11.1

4.4

1.7

5

7.4

2

4.1

0

2

4

6

8

10

12

14

Composite Death Re-MI Ischemia Bleed Transfuse

Immediate PCI (N=298) Rescue PCI (N=300)

On-TIME 2: Study DesignOn-TIME 2: Study Design

Angiogram

HDB Tirofiban*Placebo

Transportation

PCI centerAngiogram

ProvisionalHDB Tirofiban

Tirofibancont’d

N=984Jun 2006–Nov 2007

PCI

*Bolus: 25 µg/kg and 0.15 µg/kg/min infusion.

STEMIdiagnosed in ambulance or

referral centerASA + 600 mg clopidogrel + UFH

van ‘t Hof AWJ, et al. Lancet 2008;16;372(9638):537-46

BRAVE-3Abciximab before Primary PCI

30-day Death, MI, Revas, and Stroke

BRAVE-3Abciximab before Primary PCI

30-day Death, MI, Revas, and Stroke

Mehilli et al. Circulation. 2009;119

On-TIME 2Pre-hospital High Dose Tirofiban

ST-Resolution Time

Lancet. 2008;372:537

(Complete) post-PCI

P=0.033 P=0.020 P=NS P=NS P=NS

Bleeding

Pre-treated with aspirin, heparin & 600 mg clopidogrel

Composite: death, recurrent MI, urgent revascularization

IIB/IIIa Meta-regression30-Day Mortality

IIB/IIIa Meta-regression30-Day Mortality

De Luca G. et al. Eur Heart J 2009;30:2705

GP IIb/IIIa Guideline for STEMI2009

GP IIb/IIIa Guideline for STEMI2009

Early invasive / PCI Medical Management

ACC / AHA ESC ACC / AHA ESC

Class IIaAbciximab

Class IIbTirofiban,eptifibatide

Class IWithout stenting

Class IIaWith stenting

Class IIbAbciximab with half-dose lyticfor patients age < 75 years

Class III

GPI = glycoprotein IIb/IIIa inhibitor

For UA / NSTEMIFor UA / NSTEMI

15.6%

10.1%11.3%

8.0%

14.5%

7.8%

10.8%

8.7%

0%

5%

10%

15%

20%

PURSUIT PRISM PLUS PARAGON B GUSTO-IV ACS

Placebo2b3a Inhibitor

Medical vs Interventional Therapy30-day Death or MI – No Early PCI

P=NSp=NS

p=NS

p=NS

16.7%

10.2%

18.5%

9.0%

11.6%

5.9%

11.6%

4.8%

0%

5%

10%

15%

20%

PURSUIT PRISM PLUS PARAGON B CAPTURE

Placebo2b3a Inhibitor

Medical vs Interventional Therapy30-day Death or MI – Early PCI

P<0.05

p=NS

p=0.01

p=0.03

0.3%

3.8% 4.0%

0.6%0.3%

3.7% 4.0%

0.9%

0%

5%

10%

Death MI Death/MI Urg Revac

PlaceboAbciximab

ISAR-REACTPCI for Low-risk SA Patients – 30 Days

p=NSp=NSp=NS p=NS

NEJM 2004;350:232-8

1.6%

10.5%11.5%

1.2%1.1%

8.1%8.6%

1.0%

0%

5%

10%

Death MI Death/MI Urg Revac

Placebo (1012)Abciximab (1010)

ISAR-REACT 2PCI for Higher-risk ACS Patients – 30 Days

p=0.06p=0.03

p=0.34 p=0.64

JAMA 2006;295:1531-38

ISAR-REACT 2Higher-risk Patients (ACS) – 30 Days

JAMA 2006;295:1531-38

ASA/heparin thienopyridine

tirofiban


• Angina at rest within 12 h of admission

• Unequivocal changes on ECG during angina

• cTnI elevation

Intent to PTCA/stent24 - 48 hours

+ Abciximab


+ HDB tirofiban

J Am Coll Cardiol. 2006;47(3):522-528.

EVEREST: Study DesignEVEREST: Study Design

“In-Lab” Abciximab

“In-Lab” HDB Tirofiban


“Upstream” Tirofiban


High-riskNSTEMI

ACS

HDB, high dose bolus

EVERESTTissue-Level Perfusion by TMPG

EVERESTTissue-Level Perfusion by TMPG

Pre-PCI Post-PCI

TMPG

0/1

(%)

UpstreamTirofiban

HDBTirofiban

Abciximab

P=.015

TMPG

0/1

(%)

UpstreamTirofiban

HDBTirofiban

Abciximab

P=.0009

n=93

Bolognese L, et al. J Am Coll Cardiol. 2006;47(3):522.

TMPG, TIMI perfusion grade

EVEREST Tissue-Level Perfusion by

Myocardial Contrast Echocardiography

EVEREST Tissue-Level Perfusion by

Myocardial Contrast Echocardiography

UpstreamTirofiban

HBDTirofiban

Normal tissue-level perfusion by MCE

UpstreamTirofiban

HBDTirofiban

Abciximab

P=.04

MCE score index

Abciximab

P=.012

Bolognese L, et al. J Am Coll Cardiol. 2006;47(3):522-528.

Patie

nts

Perf

used

(%)

MC

E Sc

ore

Inde

x

n=93

EVERESTPeak cTnI Levels Post-PCI

EVERESTPeak cTnI Levels Post-PCI

UpstreamTirofiban

HBDTirofiban

Abciximab

ng/m

L

Bolognese L, et al. J Am Coll Cardiol. 2006;47(3):522-528.

n=93P=.0002

P=.015

ACUITY TimingModerate-high risk ACS

undergoing invasive strategy (N=13,800)PCI in 57%

ACUITY TimingModerate-high risk ACS

undergoing invasive strategy (N=13,800)PCI in 57%

JAMA. 2007;297:591

ACUITY TimingIschemic Composite

ACUITY TimingIschemic Composite

Ischemic Death MI Unplanned revcomposite for ischemia

JAMA. 2007;297:591

ACUITY TimingMajor Bleeding

ACUITY TimingMajor Bleeding

JAMA. 2007;297:591

EARLY-ACS: Primary EndpointInvasive Strategy

Death, MI, Urgent revasc., Thrombotic events

EARLY-ACS: Primary EndpointInvasive Strategy

Death, MI, Urgent revasc., Thrombotic events

Giugliano et al. N Engl J Med 2009;360

Dea

th, M

I, R

IUR

or T

BO

(%)

0

5

10

15

Time Since Randomization (Hours)

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96

10.0%

9.3%

Delayed provisional eptifibatide

4684469

Early routineeptifibatide

4722439

P = 0.23(stratified for intended early

clopidogrel use)

N# Events


Early routine eptifibatide

Early-ACS: 30-day Death or MIEarly-ACS: 30-day Death or MID

eath

or M

I (%

)

0

5

10

15

Time Since Randomization (Days)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

12.4%

11.2%

P = 0.079(stratified for intended early

clopidogrel use)


4684578

2.1 (1.0, 5.8)

Early routineeptifibatide

4722528

2.7 (1.0, 4.9)

N# Events

Days to Event


Early routine eptifibatide

39% use of eptifibatide

Giugliano et al. N Engl J Med 2009;360

GP IIb/IIIa Guideline for UA / NSTEMI2009

GP IIb/IIIa Guideline for UA / NSTEMI2009

Early invasive / PCI Medical Management

ACC / AHA ESC ACC / AHA ESC

Class IEither GPI or clopidogrel in addition to aspirin should be initiated before angiography

Class IIaReasonable to initiate antiplatelet therapy with both GPI and clopidogrel

Class I (high risk)

Class IIf subsequent recurrent symptom/ischemia, heart failure, or serious arrhythmia occur, angiography should be performed with upstream use of either clopidogrel or GPI

Class IIaIf recurrent ischemic discomfort with clopidogrel, it is reasonable to add a GPI before angiography

Class IIbMay be reasonable to add GPI to oral antiplatelet and anticoagulant therapy

Class II (high risk)

GPI = glycoprotein IIb/IIIa inhibitor

ICE TrialIntracoronary Injection of Eptifibatide

ICE TrialIntracoronary Injection of Eptifibatide

Pre-PCI Post-PCICirculation. 2010;121:784

180-g/kg eptifibatide IC bolus

ConclusionConclusion• Extensive data support the use of IV GPIs in the setting of

moderate- or high-risk NSTE-ACS, particularly if an early invasive strategy is planned.

• Patients who present with STEMI who are undergoing primary PCI also appear to benefit; however, the benefit is less evident.

• In the setting of low-risk ACS, GPIs may not be useful.• In spite of extensive studies, open questions remain,

including the timing of initiation, their clinical utility in combination with and compared with newer antithrombotics, and optimal dosing in certain patient populations (i.e., the elderly, patients with renal insufficiency).

Reimbursement Policy in KoreaReimbursement Policy in Korea

Abciximab Tirofiban

o High risk PCI

o PCI for high risk AMI

o Acute closure due to thrombus

o No reflow after stenting

o Threatening of acute closure due

to no reflow, new thrombus,

intramural hazziness during PCI

o High risk ACS with elevated

troponin or change of EKG

updated guideline of glycoprotein iib/iiiainhibitor for...

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