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I P t t O l P2Y I hibitIs Potent Oral P2Y12 InhibitorEnough to Prevent Thrombotic EventsEnough to Prevent Thrombotic Events

in High-risk PCI Patients?

YoungYoung--HoonHoon JeongJeong M D Ph DM D Ph DYoungYoung HoonHoon JeongJeong, M.D., Ph.D., M.D., Ph.D.Department of Internal Medicine, Gyeongsang National University Hospital

and Gyeongsang National University School of Medicine, Jinju, Korea.and Gyeongsang National University School of Medicine, Jinju, Korea.

Disclosures

Research Grants/Support Otsuka

Honoraria/ConsultingOtsuka

Accumetrics Boehringer Ingelheim

Sanofi-AventisDaiichi Sankyo IncBoehringer-Ingelheim

Haemonetics Daiichi Sankyo Inc Astrazeneca

Dong-A Pharmaceutical Han-Mi Pharmaceutical

Nanosphere HaemoneticsHan-Dok Pharmaceutical

3-Year Mortality According to Periprocedural MI23,604 pts from 8 Korean RCTs and 3 registries (ASP+CLPD)

(CK-MB > x3)

HR, 1.47; P < 0.001

**** HR 1 20; p = 0 01HR 1 20; p = 0 01: Adjusted for study age sex DM history of MI PVD: Adjusted for study age sex DM history of MI PVD

Park DW et al. Eur Heart J 2013;Feb 12.

HR, 1.20; p 0.01HR, 1.20; p 0.01: Adjusted for study, age, sex, DM, history of MI, PVD, : Adjusted for study, age, sex, DM, history of MI, PVD, CKD, ACS, EF, MVD, LM disease, bifurcation disease, stent type, and # stents. CKD, ACS, EF, MVD, LM disease, bifurcation disease, stent type, and # stents.

Post-PCI Thrombosis is a Platelet-centric Event:Ischemic Outcomes Reduced Best by Most Potent and Reliable Agents

FibrinogenPCI-inducedPl R t Th biTh biTissuePlaque Rupture ThrombinThrombinTissue

Factor

Collagen XI iti l

CollagenvWF Amplification

PAR-1

X

Fibrin

Initial Activation Amplification

PAR 1

ADPP2Y12

TP

+Granule Secretion Platelet Platelet

AggregationAggregationGPIIb/IIIaActivation

X XTxA2

TP

Platelet-FibrinClot Formation

Activation

COX-1XClot Formation

Amplification

Adapted from Gurbel PA et al. J Am Coll Cardiol. 2007;50:1822-34

- Variable, moderate, slow- Inhibition of P2Y12 receptor only

XX

XXUniform potent reversible- Uniform, potent, reversible

- Immediate inhibition of all agonist-induced aggregation including thrombin

Available Strategies of P2YAvailable Strategies of P2Y1212 InhibitionInhibition

Therapeutic profile not affected by CYP, ABCB1genetic variationg

Schömig A. N Engl J Med 2009;361:1108-1111.

Prasugrel vs. Clopidogrel in Stable CAD PatientsPrasugrel 60 mg LD vs. Clopidogrel 600 mg LD (> 12hr before PCI)

52.9%

HPR1.9%

(PRU>208)

PMI (Troponin I): 23% vs. 44% P = 0.035

Hamilos et al. ESC 2012.

( opo ) 3% s % 0 035

GPIIb/IIIa InhibitorsElective PCI in Era of Routine Stents and Thienopyridines: Meta-Analysis

22 studies, n=10,113 patients, routine use of thienopyridines; 30-day outcomes

30-day MIAb i i bAbciximab

Small MoleculeOverall

p<0.0001

30-day MortalityAbciximab

Small MoleculeOverall p=0 27

30-day Major Bleeding

Overall p=0.27

30 day Major BleedingAbciximab

Small MoleculeOverall p=0.22

Winchester DE et al. J Am Coll Cardiol. 2011;57:1190-9

Minor Bleeding (GPI vs. control) = 3.0 vs. 1.7%, RR=1.70, p<0.001

Personalized GPIIb/IIIa Inhibitor Therapy: 3T/2R S d3T/2R Study

HPR patientsn = 147 CLPD NR (< 40% inhibition)

n = 23 ASA NR (ARU > 550)~ 70%: stable CAD

n = 23 ASA NR (ARU > 550)

n = 93 ASA and CLOP NR

Valgimigli M et al. Circulation 2009;119:3215-22.

BivalirudinBivalent Synthetic Direct Thrombin InhibitorBivalent Synthetic Direct Thrombin Inhibitor

Specifically inhibits

Fluid phase thrombinBivalirudin

– Fluid phase thrombin

– Clot-bound thrombin

– Thrombin-mediated platelet aggregation (blocks activation gg g (of PAR-1 and PAR-4 receptors): weak potencyp ) p y

Reversible

T 2 i T0.5 25 minutes

TopolTopol EJ: Textbook of Interventional CardiologyEJ: Textbook of Interventional Cardiology

Pharmacodynamics of P2Y12 Inhibitor vs. GPI vs. Bivalirudin

CLEAR PLATELETS-2 Gurbel et al. J Am Coll Cardiol. 2009;53:648-57

100100

Gurbel PA et al. Circulation. 2005;111:1153-9CLEAR PLATELETS-1

)

600 mg C+B600 mg C+B75 mg C+B75 mg C+B

PP--In

duce

dIn

duce

dio

n (%

)io

n (%

)

6060

8080

AD

P, M

ax)

600 C+B +GPI600 C+B +GPI75 mg C+B+GPI75 mg C+B+GPI

5 5 M

TR

AP

M T

RA

PA

ggre

gati

Agg

rega

ti

2020

4040**

** **

A (%

; 20 M

2525

00 BaselineBaseline 2 2 66--88 1818Hours

IPA

100

PRICIPLE TIMI-44 Wiviott SD et al,Circulation. 2007;116:2923-32.

Gurbel PA et al,Circulation. 2009;120:2577-85 ONSET/OFFSET

100

60

80

100Prasugrel 60 mg

p<0.0001 for each time pointAD

P, M

ax)

60

80

100Ticagrelor 180mg

p<0.0001 for each time pointA

DP,

Fin

al)

0

20

40Clopidogrel 600 mg

A(%

; 20 M

20

40 Clopidogrel 600 mg(%

; 20 M

A

00 4 8 12 16 20 24

Hours

IPA

00 4 8 12 16 20 24

Hours

IPA

.5

Impact of Bivalirudin vs. Abciximab in NSTEMI Patients with HPRin NSTEMI Patients with HPR

ISAR-REACT 4 Platelet Substudy

HPR: Multiplate ≥ 468 AU x min

* Bivalirudin: no protective effect on post-PCI events in AMI

Sibbing et al. J Am Coll Cadiol 2012;60:369-77.

Impact of Bivalirudin vs. Abciximab+Heparin in STEMI Patients (HORIZONS-AMI)in STEMI Patients (HORIZONS AMI)

2/3 received Pre – randomization heparin.

Aspirin, thienopyridineR

3,602 pts with STEMI with symptom onset ≤12 hours

R 1:1

UFH + GP IIb/IIIa inhibitor Bivalirudin monotherapy(abciximab or eptifibatide) (± provisional GP IIb/IIIa)

Emergent angiography, followed by triage to primary PCI, CABG or medical therapyEmergent angiography, followed by triage to primary PCI, CABG or medical therapy3006 pts eligible for stent randomization3006 pts eligible for stent randomization

R 1:3

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

Clinical FU at 30 days 6 monthsClinical FU at 30 days 6 monthsClinical FU at 30 days, 6 months,1 year, and then yearly through 5 years

Clinical FU at 30 days, 6 months,1 year, and then yearly through 5 years

Stone GW. New Engl J Med. 2008;358:2218-30.

HORIZON AMI: Primary Outcome MeasuresHeparin +GPI Bivalirudin Monotherapy

%)

Net Adverse Clinical Events

% (%)

MACE5.5%

Heparin +GPI a ud o ot e apyEv

ents

(% 12.2%

9.3%

Even

ts (

5.5%

30-D

ay E

HR=0.75;p=0.006

30-D

ay E

HR=1.00;p=0.98

3

Non-CABG Major Bleeding

8.4%s (%

) Mortality

3 1%s (%

)

y Ev

ents 3.1%

y Ev

ents

5.0%

HR=0.59;p<0.000130-D

ay 2.1%

HR=0.66;p=0.04830-D

ay

Time in Days Time in Days

Definite /Probable Stent Thrombosis in HORIZONSDefinite /Probable Stent Thrombosis in HORIZONS--AMIAMI

Bivalirudin monotherapyBivalirudin monotherapy Heparin + Heparin + GPIIbGPIIb//IIIaIIIa inhibitorinhibitor

33

1 Day 44 3.6% 3.6% 1 Year

HR =5.93, p = 0.0002HR =5.93, p = 0.000222

33

1 5%1 5% 22

33 3.2%3.2%

110.3% 0.3%

1.5%1.5%HR =1.13, p = 0.53HR =1.13, p = 0.53

11

22

00

Time in HoursTime in Hours00 66 1212 1818 2424

00

Time in daysTime in days00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365

Time in daysTime in days

* Bivalirudin: less MACE driven by less bleedingy gmore early stent thrombosis/PMI

* How to maximize the benefit of GPI treatment? How to maximize the benefit of GPI treatment? - radial approach

bolus or short time infusion- bolus or short-time infusion

ACUITY Trial: Bivalirudin reduces Major bleeding only in femoral access

Hamon M, et al. EuroIntervention. 2009;5:115-20.

Bolus-only or Short Infusion vs. Prolonged Infusion

Study BRIEF PCI EASY Kini et alStudy Type RCT, n=624 RCT, n=1005 Retrospective, n=2629

GPI Type Eptifibatide Abciximab Eptifibatide (72%)Abciximab (28)

Study Population ACS or Stable CAD 32% Troponin+

ACS or Stable CAD 20% Troponin+

ACS or Stable CAD14% Troponin+

B2/C Coronary L i (%)

63% 47% 80%Lesion (%)Duration of Infusion <2h vs. 18h bolus only vs. 12h bolus only vs. 12-18h

Adequate Clopidogrel 70% 92% 54%Adequate Clopidogrel Load Before PCI (%)

70% 92% 54%

Bolus only or Short Infusion vs. Prolonged Infusion

Death/MI/Urgent TVR at 30 days

4.8% vs. 4.5%, p=1.0 1.4% vs. 1.8%, p=ns 3.2% vs. 3%, p=0.7330 daysMajor Bleeding 1.0% vs. 4.2%, p=0.02 0.8% vs. 0.2% p=ns 0.8% vs. 1.6%; p=0.09

Minor Bleeding 17 6% vs 21 2% p=0 31 N/A 1 1% vs 2 2%; p=0 03

Hanna EB et al. J Am Coll Cardiol Intv. 2010;1209-19 Fung AY et al. J Am Coll Cardiol. 2009;53:837-45 (BRIEF-PCI)Bertard OF et al. Circulation 2006;114:2636-43 (EASY) Kini AS et al. Am Heart J. 2008;156:513-6

Minor Bleeding 17.6% vs. 21.2%, p=0.31 N/A 1.1% vs. 2.2%; p=0.03

Characteristics of Glycoprotein IIb/IIIa Inhibitors

Kristensen et al. Thromb Haemost 2012;107:215-24.

(High-dose bolus, HDB)

Reversibility of Reversibility of Glycoprotein IIb/IIIa Inhibitors

Small Molecules vs. Abciximab

100

atio

n (%

)at

ion

(%)

80

60

EptifibatideEptifibatide (~4hrs)(~4hrs)

et A

ggre

gaet

Agg

rega

60

40

20AbciximabAbciximab (~36 hrs)(~36 hrs)TirofibanTirofiban (~4 hrs)(~4 hrs)

Plat

ele

Plat

ele 20

0

00 66 1212 1818 2424 3030 3636

HoursHours

drug discontinuationdrug discontinuationAdapted from Tantry US and Gurbel PA. Future Cardiol. 2006;2:343-66.

Abciximab vs. HDB Tirofiban in Primary PCIAbciximab vs. HDB Tirofiban in Primary PCIAbciximab vs. HDB Tirofiban in Primary PCIAbciximab vs. HDB Tirofiban in Primary PCIValgimigli et al, JAMA 2008

STEMI all-comer PatientsSTEMI all-comer PatientsAspirin + Clopidogrel + UFHAspirin + Clopidogrel + UFHAspirin + Clopidogrel + UFH

Before Arterial Sheath InsertionAspirin + Clopidogrel + UFH

Before Arterial Sheath Insertion

1:11:1

Tirofiban*Tirofiban* AbciximabAbciximab1:11:11:11:1

SESSESSESSES BMSBMSBMSBMS SESSESSESSES BMSBMSBMSBMS1:11:11:11:1

Clinical FU only Clinical FU only @@ 1, 4, 8 ms, 1, 4, 8 ms, 1 d th l t 51 d th l t 5

Coronary Angiography±PCIStenting was the default strategy in pts1yr and then yearly up to 51yr and then yearly up to 5Stenting was the default strategy in pts

with a RVD≥ 2.5 mm at visual estimation*: given as a bolus of 25 g/kg, followed by an 18-24 hour infusion at 0.15 g/kg/min

30-Day Outcomes30-Day OutcomesyEfficacy Endpoints

(CEC dj di t d)

yEfficacy Endpoints

(CEC dj di t d)(CEC adjudicated)(CEC adjudicated)

P=0.85P=0.85Abciximab Tirofiban

4

Stent Thrombosis (ARC)

Stent Thrombosis (ARC)

P=0.85P=0.85P=0.98P=0.984%

P=0.59P=0.59 P=0.22P=0.222 5%2. 5

P=0.56P=0.56

2.5%

11%

MACEMACE Death/MIDeath/MI uTVRuTVR DefiniteDefinite Def/ProbDef/Prob-0. 5

MACEMACE Death/MIDeath/MI uTVRuTVR DefiniteDefinite Def/ProbDef/Prob

30-Day Outcomes30-Day OutcomesySafety Endpoints

(DSMB dj di t d)

ySafety Endpoints

(DSMB dj di t d)(DSMB adjudicated)(DSMB adjudicated)8

Abciximab Tirofiban8%

6

P=0.40P=0.406%

4

P 0 82P 0 82

P=0.004P=0.0044%

2

P=0.44P=0.44 P=0.82P=0.82P=0.03P=0.03

2%2%

0%0

MajorMajor MinorMinor RBC Tranfusion

RBC Tranfusion

SevereSevere AnyAnyThrombocytopeniaThrombocytopeniaTIMI-BleedingTIMI-Bleeding

0%

-2

y py pgg

Small Molecule vs. Abciximab AdministrationPrimary PCI: Meta-AnalysisPrimary PCI: Meta Analysis

6 RTs, n=1086 abciximab vs. 1115 small molecules (only high-dose bolus and infusion)

30 day Mortality30-day Mortality

30-day Secondary OutcomesOR (95% CI)

Reinfarction 0.94 (0.44, 2.04) Post-procedural TIMI flow Grade 3 1 05 (0 80 1 39)Post-procedural TIMI flow Grade 3 1.05 (0.80, 1.39)ST-segment resolution 0.96 (0.78, 1.17)

De Luca et al. J Am Coll Cardiol. 2009;53:1668-73

Pharmacodynamics of 600mg Clopidogrel LD in STEMI Pts Undergoing PPCIin STEMI Pts Undergoing PPCI

VASPVASP--P assay between 6 ~ 12 h after 600mg clopidogrel LDP assay between 6 ~ 12 h after 600mg clopidogrel LD

STEMI Pts = “Non-responder to P2Y12 Inhibitor”Predictors Predictors

of HPRof HPR OROR 95% CI95% CI PP

STEMI Pts Non responder to P2Y12 Inhibitor

Age Age (per 10 (per 10 yryr)) 1.011.01 1.001.00 –– 1.021.02 0.080.081. Splanchnic and liver hypoperfusion

HPR ≥50%

BMI (kg/m2)BMI (kg/m2) 1.111.11 1.07 1.07 –– 1.151.15 < 0.001< 0.001by hemodynamic instability: ↓ drug absorption and metabolism

DiabetesDiabetes 1.291.29 0.92 0.92 –– 1.801.80 0.140.14

OmeprazoleOmeprazole 1.631.63 1.09 1.09 –– 2.662.66 0.020.02

↓ d ug abso pt o a d etabo s

2 Catecholamine release and use:pp

STEMI (vs. STEMI (vs. UA/NSTEMI)UA/NSTEMI) 2.142.14 1.30 1.30 –– 3.503.50 0.0030.003

2. Catecholamine release and use: ↑ platelet baseline reactivity and turn-over

FibrinogenFibrinogen 1.241.24 1.07 1.07 –– 1.441.44 < 0.004< 0.004

SAP UA/NSTEMI STEMI

Bonello L, et al. Thromb Haemost. 2012 Apr 26;108(1).

N=344 N=339 N=150SAP UA/NSTEMI STEMI

(n=344) (n=339) (n=150)

Ticagrelor vs. Prasugrel in STEMI Patients (180 mg LD/90 mg bid MD vs. 60 mg LD/10 mg QD MD)(180 mg LD/90 mg bid MD vs. 60 mg LD/10 mg QD MD)

PPCIPPCI

HPR pointpoint

Alexopoulos D, et al. Circ CV Interv 2012;5:797-804.

Pharmacodynamic Effect of Prasugrel Alone vs. Prasugrel + HDB Tirofiban Infusion in STEMI PtsPrasugrel HDB Tirofiban Infusion in STEMI Pts

FABOLUS PRO Study (n = 100): Prasugrel 60mg LD FABOLUS PRO Study (n = 100): Prasugrel 60mg LD ±± TirofibanTirofiban 25 µg/kg bolus 25 µg/kg bolus ±± TirofibanTirofiban 0.15 µg/kg/min 2 hr infusion 0.15 µg/kg/min 2 hr infusion

Prasugrel LD + GPI bolus Prasugrel LD + GPI bolus obviates the need of continuous obviates the need of continuous

Valgimigli M, et al. JACC Cardiovasc Interv. 2012;5:268-77.

gginfusion and almost completely abolishes platelet activation.infusion and almost completely abolishes platelet activation.

Eptifibatide IC vs. IV in STEMI (ICE Trial)IC versus IV bolus (2 x Bolus within 10 min. 180 μg/kg Eptifibatide),

Followed by 2 μg/kg/min continuous infusion i.v. for 18 h

IPA periphery (20 μmol/L ADP) GPIIb/IIIa receptor-blockade

100

110P=0.67

100

110

P=0.013 P=0.995 P<0.001 P=0.001

A

70

80

90

ocka

de

70

80

90P 0.013 P 0.995 P 0.001 P 0.001

%IP

A

40

60

50 IC Eptifibatide n=21 R

ecep

tor-

Blo

40

60

50

10

20

30 IV Eptifibatide n=19 % R

10

20

30

Baseline 15 min post Bolus

30 min post Bolus

60 min post Bolus

0 0

Peripheral blood Coronary sinus blood

Bolus 1 Bolus 2 Bolus 1 Bolus 2

Deibele et al. Circulation 2010;121:784-791

IC Bolus-only vs. IV Bolus+Infusion Tirofiban in STEMI PatientsTirofiban in STEMI Patients

Tirofiban 25 μg/kg IC bolus only versus IV bolus+ 0 15μg/kg/min infusion IV for 18 hTirofiban 25 μg/kg IC bolus only versus IV bolus+ 0.15μg/kg/min infusion IV for 18 h

IMR cTFC

IC Tirofiban n=25 50IV Tirofiban n=24

40

P=0.08 P=0.13

30

20

10

Kirma et al. Cath Cardio Interv 2012;79:59–67.

0

IC vs. IV Abciximab Infusion in STEMI7 studies, n=3,311 patients, median follow-up of 3 months

All-cause Death

Recurrent MI

Kubica et al. Cardiol J 2012;19:230-42.

INFUSEINFUSE--AMI TrialAMI Trial452 pts with anterior STEMI452 pts with anterior STEMI

A ti i t dA ti i t d SS t PCI <5 h TIMI 0t PCI <5 h TIMI 0 2 fl i id LAD2 fl i id LADAnticipated Anticipated SxSx to PCI <5 hrs, TIMI 0to PCI <5 hrs, TIMI 0--2 flow in prox or mid LAD2 flow in prox or mid LADPrimary PCI with bivalirudin anticoagulationPrimary PCI with bivalirudin anticoagulation

Stratified by symptoms to angio <3 vs ≥3Stratified by symptoms to angio <3 vs ≥3PrePre--loaded with aspirin andloaded with aspirin and

R R 1:11:1

Stratified by symptoms to angio <3 vs ≥3 Stratified by symptoms to angio <3 vs ≥3 hrs, and prox vs mid LAD occlusionhrs, and prox vs mid LAD occlusion

PrePre--loaded with aspirin andloaded with aspirin andclopidogrel 600 mg or prasugrel 60 mgclopidogrel 600 mg or prasugrel 60 mg

Manual aspirationManual aspiration No aspirationNo aspiration

R R 1:11:1

R R 1:11:1

IC AbcxIC Abcx No AbcxNo Abcx IC AbcxIC Abcx No AbcxNo Abcx

Primary endpoint: Infarct size at 30 days (Primary endpoint: Infarct size at 30 days (cMRIcMRI))22ºº d i t TIMI fl bl h STd i t TIMI fl bl h ST l ti MACE (l ti MACE (30d30d 1 )1 )22ºº endpoints: TIMI flow, blush, STendpoints: TIMI flow, blush, ST--resolution, MACE (resolution, MACE (30d30d, 1 yr), 1 yr)

Stone et al. JAMA 2012;307:1817-26.

Infarct size at 30 days by CMRMedian [IQR]Median [IQR]

1 1%1 1%

Median [IQR]Median [IQR]17.9%17.9%

15.1%15.1%[6.8, 22.7][6.8, 22.7]

[10.3, 25.4][10.3, 25.4]

%LV

%LV P=0.03 Localized infusion of

IC abciximab bolus only

rct s

ize,

%rc

t siz

e, % IC abciximab bolus only

through the drug delivery balloon (ClearWay rx)

d d i f t i

Infa

rIn

far reduced infarct size:

↓15.6% versus ↓no abciximab arms

IC abciximabIC abciximabN=188N=188

No abciximabNo abciximabN=184N=184 Stone et al. JAMA 2012;307:1817-26.

Conclusions* C i di ti f GPI d i PCI* Common indications for GPI use during PCI

Clinical setting IndicationsClinical setting IndicationsNon-acute patients No pretreatment with or Poor response to P2Y12 inhibitor

Bail-out situations (thrombus formation vessel closure etc )Bail-out situations (thrombus formation, vessel closure, etc.)NSTE-ACS No pretreatment with or Poor response to P2Y12 inhibitor

High-risk patients (complex lesions large thrombiHigh risk patients (complex lesions, large thrombi,elevated troponin levels).Bail-out situations (thrombus formation, vessel closure, etc.)

STEMI High-risk patients (early phase after antiplatelet therapy LD, complex lesions, large thrombi, haemodynamicallycompromised patients)compromised patients).

In the era of potent P2YIn the era of potent P2Y1212 receptor inhibitor,receptor inhibitor,In the era of potent P2YIn the era of potent P2Y1212 receptor inhibitor, receptor inhibitor, GPI bolus (through IC delivery system) +/GPI bolus (through IC delivery system) +/--

shortshort--term IV infusion in highterm IV infusion in high--risk patients:risk patients:shortshort term IV infusion in highterm IV infusion in high risk patients: risk patients: ↓post↓post--PCI ischemic events w/o PCI ischemic events w/o ↑↑serious bleedingserious bleeding

Interaction of Haemostatic Components for PCI related Thrombosisfor PCI-related Thrombosis

Most thrombogenic en ironment100%

Most thrombogenic environment: “Intensified control” will save lives!

St t A t I t ti

Act

ivity

Stent-Artery Interaction

Platelet Activation

A

Inflammation

Procoagulant Activity

Inflammation…

Early Late Very Late

B l d C t l S f t & Bi l i C t lBalanced Control Safety & Biologic Control