rob storey reader and honorary consultant in cardiology,

Rob Storey

Reader and Honorary Consultant in Cardiology, University of Sheffield

The changing world of adjunctive pharmacology

2

Disclosures

Company Name Relationship• AstraZeneca Research grants, speaker

fees, consultant, travel

• Eli Lilly / Daiichi Sankyo Research grant, speaker fees, consultant, travel

• Schering-Plough Research grant, consultant

• Teva Consultant

• Novartis Consultant

• The Medicines Company Consultant

• Dynabyte Research consumables

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

Targets 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


P2YP2Y1212 as a therapeutic target as a therapeutic target

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

IIb3

IIb3

FibrinogenIIb3

Aggregation


granule


TP

Coagulation

GPVI

Collagen

ATPATP

P2X1

TICLOPIDINECLOPIDOGRELPRASUGREL

ACTIVE METABOLITE


ThrombinThrombin

5

Activation/inactivation of clopidogrel

CYP = cytochrome P450.Farid NA, et al. Clin Pharmacol Ther. 2007;81:735-741.

S

N

O

Cl SO

N

O

Cl

N

SH

COOHO

Cl

S

N

OHO

Cl

Clopidogrel

CYPs

Esterases

CYPs

2-Oxo-clopidogrel R-130964

SR26334 (Inactive)

OCH3 OCH3OCH3

Platelet aggregation before and 4 hours after clopidogrel 600 mg in patients undergoing PCIWhole blood single platelet counting in response to ADP 10 uM

Baseline Post clopidogrel0

20

40

60

80

100

% a

gg

reg

ati

on

Patient with subacute stentthrombosis

Smith SMG et al. Platelets 2006; 17: 250-258

VerifyNow P2Y12 assay

7

Multiplate MEA

8

Clinical outcomes according to platelet aggregometry results with MEA

Sibbing, D. et al. JACC 2009; 53: 849-56

Sibbing, D. et al. Eur Heart J 2009 30:916-922

Clopidogrel, CYP 2C19 and stent thrombosisClopidogrel, CYP 2C19 and stent thrombosis

11

Prasugrel

Comparison of prasugrel with higher dose clopidogrel

P<0.0001 for each

IPA (%; 20 M ADP)

Hours 14 Days

IPA (%; 20 M ADP)

P<0.0001

Prasugrel 10 mg

Clopidogrel 150 mg

Wiviott et al Circ 2007

N=201

Prasugrel 60 mg

Clopidogrel 600 mg

TRITON Study Design

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch, CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

TRITON-TIMI study TRITON-TIMI study Balance of Efficacy and SafetyBalance of Efficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

TRITON-TIMI study TRITON-TIMI study 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

TRITON Diabetic Subgroup

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

En

dp

oin

t (%

)

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

TRITON STEMI cohortPrimary EP (CV death, MI and stroke at 15 months)

Montalescot et al. ESC 2008

Time (Days)

5

10

15

00 50 100 150 200 250 300 350 400 450

Pro

po

rtio

n o

f p

atie

nts

(%

)

9.5

6.5

12.4

10.0

HR=0.79 (0.65–0.97) NNT=42

p=0.02RRR=21%

p=0.002RRR=32%

Clopidogrel

Prasugrel

Age-adjusted HR=0.81 (0.66-0.99)

TRITON Net Clinical BenefitBleeding Risk Subgroups

OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior Stroke / TIA

Age

Wgt

Risk (%)

+ 37

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Post-hoc analysisPost-hoc analysis

Ticagrelor Ticagrelor The first oral reversible P2YThe first oral reversible P2Y1212 antagonist antagonist

Time (hours) Onset Maintenance Offset

100

90

80

70

60

50

40

30

20

10

0

IPA

%Ticagrelor 180mg LD / 90 mg bd (n=54)Clopidogrel 600mg LD / 75 mg od (n=50)

0 .5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240

*

*

* * *

*

*

*

*

‡

†

†

ONSET/OFFSET Study IPA with ADP 5uM (final extent)

Gurbel PA et al. Circulation 2009

PLATO PLATELET – VerifyNow P2Y12 assay comparing maintenance therapy with

clopidogrel (C) vs ticagrelor (T)

C T C T0

100

200

300

400

500

Trough Peak

**** ****

235PRU

PL

AT

EL

ET

RE

AC

TIO

N U

NIT

S (

PR

U)

Storey RF et al. Presented at American Heart Association annual scientific sessions Nov 2009

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,560

8,678

8,405

8,520

8,177

Days after randomisation

6,703

6,796

5,136

5,210

4,109

4,191

0 60 120 180 240 300 360

6

5

4

3

2

1

0

7

Cum

ula

tive

inci

denc

e (%

)

Clopidogrel

Ticagrelor

5.8

6.9

8,279

HR 0.84 (95% CI 0.75–0.95), p=0.005

0 60 120 180 240 300 360

6

4

3

2

1

0

Clopidogrel

Ticagrelor

4.0

5.1

HR 0.79 (95% CI 0.69–0.91), p=0.001

7

5

9,291

9,333

8,865

8,294

8,780

8,822

8,589

Days after randomisation

7079

7119

5,441

5,482

4,364

4,4198,626

Myocardial infarction Cardiovascular death

Cum

ula

tive

inci

denc

e (%

)

Secondary efficacy endpoints over time

Total major bleeding

NS

NS

NS

NS

NS

0K-M

est

imat

ed r

ate

(% p

er y

ear)

PLATO major bleeding

1

2

3

4

5

6

7

8

9

10

12

11

13

TIMI major bleeding

Red cell transfusion*

PLATO life-threatening/fatal bleeding

Fatal bleeding

Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; *Proportion of patients (%); NS = not significant

11.611.2

7.9 7.7

8.9 8.9

5.8 5.8

0.3 0.3

TicagrelorClopidogrel

Non-CABG and CABG-related major bleeding

p=0.026

p=0.025

NS

NS

9K

-M e

stim

ated

rat

e (

% p

er y

ear)

Non-CABGPLATO majorbleeding

8

7

6

5

4

3

2

1

0Non-CABGTIMI major bleeding

CABGPLATO major bleeding

CABG TIMI major bleeding

4.5

3.8

2.8

2.2

7.4

7.9

5.3

5.8

TicagrelorClopidogrel

PLATO - Dyspnoea

All patientsTicagrelor(n=9,235)

Clopidogrel(n=9,186) p value*

Dyspnoea, %

Any

With discontinuation of study treatment

13.8

0.9

7.8

0.1<0.001

<0.001

*p values were calculated using Fischer’s exact test

PLATO Conclusions• Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelor in

comparison with clopidogrel in a broad population with ST- and non-ST-elevation

ACS provides

– Reduction in myocardial infarction and stent thrombosis

– Reduction in cardiovascular and total mortality

– No change in the overall risk of major bleeding

• Ticagrelor is a more effective alternative than clopidogrel for the continuous prevention of

ischaemic events, stent thrombosis and death in the acute and long-term treatment of

patients with ACS• Clinicians will need to learn how to identify and manage dyspnoea associated with ticagrelor

Cangrelor Cangrelor Intravenous reversible P2YIntravenous reversible P2Y1212 antagonist antagonist

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

BRIDGE study design (provisional) ACS treated with clopidogrel, scheduled for CABG

Stop clopidogrel x days prior to CABG

Cangrelor infusionPlacebo infusion

1o end point: Bleeding2o end points: Inhibition of platelet function, ischaemic events

Primary objective: To assess safety of cangrelor compared to placebo prior to CABG surgery

Stop x hours prior to CABG surgery

PD measurements

Elinogrel Elinogrel Intravenous and oral reversible Intravenous and oral reversible

P2YP2Y1212 antagonist antagonist

Elinogrel

• Reversible P2Y12 inhibitor in phase 2/3 development

• IV and oral formulations

• Half-life ~12 hours

• Competitive mechanism of action – competes with ADP for binding to receptor, greater IPA for low vs high concentrations of ADP

32

Targeting PAR-1


Targets for Platelet Inhibition

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

IIb3

IIb3

FibrinogenIIb3

Aggregation


granule


TP

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN


ACTIVE METABOLITE



xx

SCH 530348SCH 530348E5555

x

TERUTROBAN

x

HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABANAPIXABANDABIGATRAN Thrombin

x

No significant compromise to haemostasis with SCH 530348

Surgical blood loss (ml/hr)

Vehicle T-1 T-2 T-30

1

2

3

* *

Treament

Blo

od

Lo

ss (m

ls)

Bleeding time

Vehicle T-1 T-2 T-30

10

20

30 * *

TreatmentT

emp

late

ble

edin

gti

me

(min

)T-1 = SCH 530348 1 mg/kgT-2 = Aspirin (10 mg/kg) plus Clopidogrel (2 mg/kg)T-3 = SCH 530348, Aspirin plus Clopidogrel

Cynomolgus monkey model.

Chintala M et al. Arterioscl Thromb Vasc Biol. 2008; 28: e138–e139

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)


ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

IIb3

IIb3

FibrinogenIIb3

Aggregation


granule


TP

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN


ACTIVE METABOLITE



xx

SCH 530348E5555

x

TERUTROBAN

x

HEPARINSFONDAPARINUXBIVALIRUDINRIVAROXABANAPIXABANDABIGATRAN Thrombinx

?

QuestionsQuestions

rob storey reader and honorary consultant in cardiology,

Documents