Rob Storey Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield, Sheffield UK Adjunctive Therapy New Agents – Will They Have.

Rob Storey

Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield,

Sheffield UK

Adjunctive TherapyNew Agents – Will They Have A

Role?

My Conflicts of Interest Are:My Conflicts of Interest Are:

Company Name Relationship

AstraZeneca Research grant, honoraria, consultant

Eli Lilly / Daiichi Sankyo Research grant, honoraria

The Medicines Company Honoraria, consultant

Schering-Plough Research grant

GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.

Targets for Platelet InhibitionTargets for Platelet Inhibition

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

IIb3

IIb3

FibrinogenIIb3

Aggregation

AmplificationAmplificationAlpha

granule

Coagulation factorsInflammatory mediators

TP

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN

x TICLOPIDINECLOPIDOGRELPRASUGREL

ACTIVE METABOLITE

x TICAGRELOR CANGRELOR

GP IIb/IIIa ANTAGONISTS

xx

SCH 530348E5555

x

HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABANAPIXABANDABIGATRAN Thrombin

x

Irreversible P2YIrreversible P2Y1212 Receptor Inhibition: Receptor Inhibition:

Thienopyridine active metaboliteThienopyridine active metabolite

Savi P, et al. Proc Natl Acad Sci USA. 2006;103:11069-11074.

5

*P<0.0001 vs clopidogrel. Data are mean ± SD.PRI = platelet reactivity index; PRINCIPLE-TIMI 44 = Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation - Thrombolysis in Myocardial Infarction 44; VASP = vasodilator-stimulated phosphoprotein.Wiviott SD, et al. Circulation. 2007;116:2923-2932.

PRINCIPLE-TIMI 44: Effects of Clopidogrel and PRINCIPLE-TIMI 44: Effects of Clopidogrel and Prasugrel Loading on VASP PhosphorylationPrasugrel Loading on VASP Phosphorylation

Time, h

VA

SP

PR

I, %

21.5*

7.4* 10.3*

75.068.4 64.3

0

20

40

60

80

100

0 4 8 12 16 20 24

Prasugrel 60 mg Clopidogrel 600 mg

Stent Thrombosis(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P <0.0001

Prasugrel

Clopidogrel2.4

(142)

NNT= 77

1.1 (68)

Days

En

dp

oin

t (%

)

Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844

Wiviott SD et al. N Engl J Med. 2007 Nov 15;357(20):2001-15

7

TRITON-TIMI 38: Bleeding Events

ARD = absolute risk difference; HR = hazard ratio; ICH = intracranial haemorrhage; NNH = number needed to harm; TIA = transient ischemic attack; TIMI = Thrombolysis in Myocardial Infarction.Adapted from Wiviott SD, et al. Presented at: American Heart Association Scientific Sessions 2007; 4-7 November, 2007; Orlando, FL.Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.

ARD 0%P=0.74

Eve

nts

, %

ARD 0.6%HR 1.32P=0.03

NNH=167

ARD 0.5%HR 1.52P=0.01

ARD 0.2%P=0.23

ARD 0.3%P=0.002

1.8

0.9 0.9

0.10.3

2.4

1.41.1

0.4 0.3

0

2

4

TIMI MajorBleeds

LifeThreatening

Nonfatal Fatal ICH

Pts w/ Prior Stroke / TIA (N=518)

Eve

nts

, % P=0.02

ICH

ClopidogrelPrasugrel

Safety Cohort (N=13,457)Safety Cohort (N=13,457)

Ticagrelor (AZD6140)Ticagrelor (AZD6140)The first oral reversible P2YThe first oral reversible P2Y1212 antagonist antagonist

Reversible P2YReversible P2Y1212 Receptor Receptor

Inhibition: CPTPsInhibition: CPTPs

CPTP = cyclo-pentyl-triazolo-pyrimidine.

Effect of ticagrelor on thrombus formation

Data are means ± standard deviation (SD). n=4 animals per group.Patil SBG, et al. Presented at: International Society on Thrombosis and Haemostasis XXIst Congress; 6-12 July, 2007; Geneva, Switzerland.

Laser-Injury Model: Mean Thrombus Area in P2Y12 +/+, +/–, and –/– Mice

+/+

Are

a,

µm

2

0

500

1000

1500

2000

2500

3000

0 20 40 60 80 100

Time, s

+/+Ticagrelor treated

0

500

1000

1500

2000

2500

3000

0 20 40 60 80 100

Are

a,

µm

2

+/–

0

500

1000

1500

2000

2500

3000

0 20 40 60 80 100

Are

a,

µm

2

–/–

0

500

1000

1500

2000

2500

3000

0 20 40 60 80 100

Time, s

Are

a,

µm

2

Clopidogrel 75 mg od

AZD6140 50 mg bd

AZD6140 100 mg bd

AZD6140 200 mg bd

AZD6140 400 mg od

0

250

500

750

1000

1250

1500

AU

C (

IPA

0-1

2 h

, Fin

al)

DISPERSE: AUC for IPA at Day 28 (Final Extent)

AUC = area under the curve; DISPERSE = Dose confirmatIon Study assessing anti-Platelet Effects of AZD6140 vs clopidogRel in NSTEMI; NSTEMI = non-ST-segment elevation myocardial infarction.Storey RF, et al. Presented at: American Heart Association 2006 Scientific Sessions; November 12-15, 2006; Chicago, Ill, USA.

DISPERSE2 Substudy: Clopidogrel 300 mg ld vs Ticagrelor (AZD6140) 90-270 mg ld* in NSTE-ACS

*~50% of ticagrelor patients in each arm received a 270-mg loading dose.NSTE = non-ST-segment elevation.Storey RF, et al. J Am Coll Cardiol. 2006;47(suppl A):204A. Abstract 821-3.

Inhibition of Platelet Aggregation Induced by ADP 20 μM (Final Extent, Day 1)

Ticagrelor 90 mg

Ticagrelor 180 mg

Ticagrelor 270 mg

Clopidogrel 300 mg

0 2 4 6 8 10 120

25

50

75

100

Time Postdose, h

IPA

, %

(M

ea

n ±

SE

M)

Ticagrelor and dyspnoea: DISPERSE2

Cannon CP, et al. Presented at: American Heart Association 2005 Scientific Sessions; November 13-16, 2005; Dallas, TX, USA.

Pat

ien

ts w

ith

Dys

pn

oea

, %

0

5

10

15

20

25

Clopidogrel75 mg od(n=327)

AZD614090 mg bd(n=334)

AZD6140180 mg bd

(n=323)

6.4

10.5

15.8

Recruitment October 2006 to July 2008; estimated final data collection March 2009 and study completion June 2009

PLATO Study Design

Primary end point: CVD/MI/stroke

Secondary end point: CVD/MI/stroke/revascularisation with PCI;CVD/MI/stroke, severe recurrent ischaemia

12-month maximum exposure(Min = 6 mo, Max = 12 mo, Mean = 11 mo)

(N=18,500)

ASA + Clopidogrel300 mg ld/75 mg od

600 mg ld allowed in PCI

ASA + Ticagrelor180 mg ld/90 mg bd

Moderate- to High-Risk ACS patients (UA/NSTEMI/STEMI, PCI,

Medically-Managed, or CABG)

STEMI = ST-segment elevation myocardial infarction; UA = unstable angina.

Cangrelor Cangrelor The first intravenous reversible P2YThe first intravenous reversible P2Y1212 antagonist antagonist

Cangrelor: Stabilised Analogue of ATP

IV = intravenous.van Giezen JJJ, Humphries RG. Semin Thromb Hemost. 2005;31:195-204.

PO

PP

O–

OOO

O– O–

–O

Cl

Cl O

HO OH

O N

N N

HN

N

SMe

SCF3

4Na+

4Na+

O

HO OH

OP

OP

OP

O–

OOO

O– O–

–ON

N N

NH2

N

ATP Cangrelor (IV)

HOO

OH OH

N

N

N S F

FF

N

HNS

_

O_

P

O_

O Cl

ClP

O

O

OP

O

_O

OO

OH OH

N

N

N S F

FF

N

HNS

4Na+

Inactivation by Dephosphorylation

Effect of Cangrelor on ADP-Induced Platelet Aggregation in Patients with NSTE-ACS

Whole Blood Impedance Aggregometry

Storey RF, et al. Thromb Haemost. 2001;85:401-407.

Time after onset of infusion, h Time after terminationof infusion

0.05 g/kg/min

0.2 g/kg/min

0.5 g/kg/min

2.0g/kg/min

Infusion dose

0

20

40

60

80

100

0.5 1.5 2.5 3.5 5 24 20 mPost

1 h

IPA

, % (

Mea

n ±

SE

M)

Post

0

Clinical interaction of cangrelor Clinical interaction of cangrelor with clopidogrelwith clopidogrel

Cangrelor = 30 μg/kg IV bolus + 4 μg/kg/min infusion; clopidogrel = 600 mg loading dose.Data are means ± standard error.Steinhubl SR, et al. Thromb Res. 2008;121:527-534.

1 h cangrelor, then clopidogrelClopidogrel Clopidogrel (T=0) + 2 h cangrelor

Time, h

14

16

Imp

edan

ce, o

hm

s

10

12

6

8

2

4

01.0 2.0 3.0 4.0 5.0 6.0 7.0

Whole-Blood Impedance Aggregometry

• N = 9000• SA/NSTEMI/STEMI• April 2008: 5800

enrolled

PCI

PLATFORM

Cangrelor infusion

Placebo infusion

Clopidogrel Placebo

PCI

Placebo

• N = 6400• SA/NSTEMI• April 2008: 2300

enrolled Cangrelor infusion

Placebo infusion

Placebo

PCI

Placebo

Randomization Treatment

R

R

CHAMPION Studies Program

Clopidogrel

Clopidogrel

Clopidogrel

Primary endpoint 48 hours Composite incidence of death, MI and IDR

Secondary endpoints

48 hours

30 days

1-year

•Death/MI•Components of composite•Stroke (distinguished by type)

•Incidence of (threatened) abrupt closure•Need for urgent CABG•Unsuccessful procedure during the index PCI•Death at 6 months

Safety assessment

• Hemorrhage (e.g. ACUITY, GUSTO, TIMI criteria)• Transfusions• SAE/AE through 48 hrs post-randomization.

CHAMPION Program EndpointsCHAMPION Program Endpoints

Platelet

2 1 Integrin

Collagen

vWF

GPIIb/IIIa

P-Selectin

PSGL-1

Mac-1

• Chemotactic Molecules: MCP-1

• Proteolytic Enzymes: MMPs, PA’s

• Pro-thrombotic molecules : Tissue Factor

• Cytokines: Il-1, Il-8, TNF-

• Adhesion Molecules: Mac-1, PSGL-1

Monocyte

• Inflammatory mediators: Il-1, TGF- , PDGF, FGF-2, RANTES, CD40L.

• Platelet Activation/aggregation: ADP, ATP, Thrombin.

• Adhesion Molecules: P-Selectin, GPIIb/IIIa,, Fibrinogen, Fibronectin, vWF.

• Coagulation Factors: PAI-1, Plasminogen, protein S, Factor V, Factor XI.

GP1b

Platelets and inflammation

Role of P2Y12 in Neointima FormationP2Y12+/+ P2Y12 –/–

30 Min Post-injuryAlcian Blue / Elastic van Gieson stain

21 Days Post-injuryAlcian Blue / Elastic van Gieson stain

21 Days Post-injury-smooth-muscle actin antibody

Representative sections. Scale bar = 500 μm.

Evans DJW, et al. Circulation 2009

Neointima at 21 Days Post-injury

P2Y12 +/+ P2Y12 –/–0

1

2

3

*Inti

ma

: M

edia

Ra

tio

Data are mean ± standard error of the mean (SEM); n=4. *P<0.05 vs wild type (Mann-Whitney).Evans DJW, et al. Circulation 2009

GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.

Targets for Platelet InhibitionTargets for Platelet Inhibition

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

IIb3

IIb3

FibrinogenIIb3

Aggregation

AmplificationAmplificationAlpha

granule

Coagulation factorsInflammatory mediators

TP

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN

x TICLOPIDINECLOPIDOGRELPRASUGREL

ACTIVE METABOLITE

x TICAGRELOR CANGRELOR

GP IIb/IIIa ANTAGONISTS

xx

SCH 530348SCH 530348E5555

x

TERUTROBAN

x

HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABANAPIXABANDABIGATRAN Thrombin

x

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

TIMI major/minor T IMI major T IMI minor

% p

ati

en

ts

Placebo (n=151)

All doses (n=422)

All 10 mg (n=129)

All 20 mg (n=120)

All 40 mg (n=173)

TRA.PCI study PCIcohort: Bleeding results

Moliterno D, et al. American College of Cardiology 2007 Scientific Sessions. March 24, 2007

Moliterno D, et al. American College of Cardiology 2007 Scientific Sessions. March 24, 2007

TRA.PCI study PCI cohort: Cardiac events

0

1

2

3

4

5

6

7

8

9

10

Death/MACE/stroke (%)

Death/MI (%) MI (%)

% p

ati

en

ts

Placebo (n=151)

All doses (n=422)

10 mg (n=129)

20 mg (n=120)

40 mg (n=173)

MACE= MI/ischemia requiring hospitalization/coronary revascularization

Study started December 2007

Estimated study completion July 2011

TRACER Study Design

Primary end point: CV death/MI/stroke/recurrent ischaemia

with rehospitalisation/urgent coronary revascularisation

12-month minimum exposure

(N=10,000)

Standard therapy + placebo

Standard therapy + SCH 530548

40 mg LD then 2.5 mg od

Moderate- to High-Risk ACS patients (UA/NSTEMI, PCI,

Medically-Managed, or CABG)

x

GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.

Targets for Platelet InhibitionTargets for Platelet Inhibition

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

IIb3

IIb3

FibrinogenIIb3

Aggregation

AmplificationAmplificationAlpha

granule

Coagulation factorsInflammatory mediators

TP

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN

x TICLOPIDINECLOPIDOGRELPRASUGREL

ACTIVE METABOLITE

x TICAGRELOR CANGRELOR

GP IIb/IIIa ANTAGONISTS

xx

SCH 530348E5555

x

TERUTROBAN

x

HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABAN

APIXABANAPIXABANDABIGATRAN Thrombin

GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

IIb3

IIb3

FibrinogenIIb3

Aggregation

AmplificationAmplificationAlpha

granule

Coagulation factorsInflammatory mediators

TP

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN

x TICLOPIDINECLOPIDOGRELPRASUGREL

ACTIVE METABOLITE

x TICAGRELOR CANGRELOR

GP IIb/IIIa ANTAGONISTS

xx

SCH 530348E5555

x

TERUTROBAN

x

HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABANAPIXABANDABIGATRAN Thrombinx

?

DiscussionDiscussion