prasugrel background and principle – timi 44 stephen d. wiviott, md cardiovascular division...

Prasugrel Background and Prasugrel Background and

PRINCIPLE – TIMI 44PRINCIPLE – TIMI 44

Stephen D. Wiviott, MDStephen D. Wiviott, MDCardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s HospitalAssistant Professor of MedicineAssistant Professor of Medicine

Harvard Medical SchoolHarvard Medical School Investigator, TIMI Study Group Investigator, TIMI Study Group

Adhesion1

Platelets

Lipidcore

CollagenGP la/lla bind

von WillebrandFactor/GP lb bind

Activation2

Thrombin

ADP

5 HT

TXA2 Aggregation3

Fibrinogen

ActivatedGP llb/llla

Handin RI. Harrison’s Principles of Internal Medicine. Vol 1. 14th ed. NY, NY: McGraw-Hill; 1998:339.

Schafer AI. Am J Med. 1996;101:199-209.

Platelet CascadePlatelet Cascadein Thrombus Formationin Thrombus Formation

Inhibition of Platelet Purinergic ReceptorsInhibition of Platelet Purinergic Receptors

Storey F, et al. Storey F, et al. Platelets.Platelets. 2001;12:197. 2001;12:197.

ReceptorReceptorsubtypesubtype

MolecularMolecularstructurestructure

SecondarySecondarymessengermessengersystemsystem

FunctionalFunctionalresponseresponse

P2YP2Y12 12 InhibitorInhibitor

P2XP2X11 P2Y P2Y11 P2YP2Y12 12

G proteinG protein G proteinG protein

Intrinsic ion Intrinsic ion GPCRGPCR GPCR GPCRchannelchannel GGqq GGii

↓↓ ↓↓ ↓↓ ↑↑[Na[Na++/Ca/Ca2+2+]]ii ↑PLC/IP↑PLC/IP3 3 ↓AC↓AC

↑ ↑[Ca[Ca2+2+]]ii ↓[cAMP]↓[cAMP]

↓↓ ↓↓ ↓↓Shape change Shape change Shape change Shape change SustainedSustained aggregation aggregation transient aggregation transient aggregation aggregationaggregation

secretionsecretion

Clopidogrel Across Spectrum of CAD Clopidogrel Across Spectrum of CAD

COMMITCOMMIT††

(CCS-2)(CCS-2)

CAPRIECAPRIE§§

Lancet 1996Lancet 1996

MI/SMI/Stroke/PADtroke/PAD High-RiskHigh-RiskVascular DiseaseVascular Disease

STEMISTEMI

Acute STEMIAcute STEMI Long-term 2Long-term 2oo (1º) prevention (1º) preventionUA/NSTEMIUA/NSTEMI

PCIPCIUA/NSTEMI UA/NSTEMI

+ Benefit+ Benefit + Benefit+ Benefit

1 Year1 Year 1 Year1 Year

+ Benefit+ Benefit

1-3 Years1-3 Years30 Days30 Days

+ Benefit+ Benefit

CLARITYCLARITY** CURECURE†† CREDOCREDO†† CHARISMACHARISMA††

*Clopidogrel vs. placebo. †Clopidogrel + ASA. §Clopidogrel vs. ASA.

CLARITY20%CV death/MI/re-ischCOMMIT 9%death/MI/stroke

18.4%CV death/MI/

stroke

26.9% death/MI/

stroke

8.7% risk reduction death/MI/

stroke

7%CV death/MI/

stroke

PCIPCI

Up to 3.5 yearsUp to 3.5 yearsBenefit in symptomatic Benefit in symptomatic

patients onlypatients only

The First Clopidogrel Resistance Study (300 mg):The First Clopidogrel Resistance Study (300 mg): A “Fingerprint” of Clopidogrel Response A “Fingerprint” of Clopidogrel Response

VariabilityVariability

Gurbel PA et al. Circulation. 2003;107:2908-2913.

2 Hours

5 Days

Aggregation (%)

Resistance = 63% Resistance = 31%Resistance

Resistance = 31%

Resistance

Resistance = 15%

Aggregation (%) Aggregation (%)

Resistance

Pat

ien

ts (

%)

12

24

≤ -30(-30,-20]

(-20,-10](-10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

>60

Pat

ien

ts (

%)

11

22

≤ -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60

14

28

≤ -30

(-30,-20]

(-20,-10]

(-10,0]

(0,10]

(10,20]

(20,30]

(30,40]

(40,50]

(50,60]

>60

10

20

≤ -30(-30,-20]

(-20,-10](-10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

>60

Aggregation (%)

Resistance

Pat

ien

ts (

%)

Pat

ien

ts (

%)

24 Hours

30 Days

GP IIb/IIIa receptor expression

P2Y12 receptor(irreversible inhibition)

Active metabolite

Hepatic metabolismCytochrome P450 pathway

Intestinal absorption Variable absorption

Drug-drug interactions

Genetic polymorphisms CYP enzymes

Drug-drug interactions

Genetic polymorphisms P2Y12 receptor

Alternate pathways of platelet activation

↑ release of circulating ADP

Higher baseline platelet reactivity Genetic polymorphisms

Poor compliance

Inadequate administration

Potential Sites for Response VariabilityPotential Sites for Response Variability

O’Donoghue M and Wiviott SD Circulation 2007

Clopidogrel Response Variability: Clopidogrel Response Variability: Increase the Dose (300 mg vs. 600 mg)Increase the Dose (300 mg vs. 600 mg)

Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.

03

6

9

12

15

18

21

24

27

30

33

≤-30(-30,-20]

(-20,-10](-10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

(60,70]> 70

300 mg Clopidogrel

600 mg Clopidogrel

Aggregation (5 µM ADP-induced Aggregation) at 24 Hr

Pat

ien

ts (

%) Resistance = 28% (300 mg)

Resistance = 8% (600 mg)

Clopidogrel Response Variability: Clopidogrel Response Variability: Change the Agent?Change the Agent?

PrasugrelPrasugrel

Pro-drugPro-drug

OxidationOxidation(Cytochrome (Cytochrome

P450)P450)

HOOCHOOC

* HS* HS

NN

OO

FF

Active MetaboliteActive Metabolite

NN

SS

OO

FF

OO

HydrolysisHydrolysis(Esterases)(Esterases)

NN

SS

OO

CC HH33

CCOO

FF

OONN

SS

OO

ClCl

OO CHCH33CC

ClopidogrelClopidogrel

85% Inactive 85% Inactive MetabolitesMetabolitesEsterasesEsterases

NN

SS

OO

ClCl

OO CHCH33CC

OONN

SS

OO

ClCl

OO CHCH33CC

Active MetaboliteActive Metabolite

HOOCHOOC

* HS* HS

NN

OO

ClCl

OCHOCH33

Herbert JM, Savi P. Sem Vasc Med. 2003;3:113-122.

Inhibition of Platelet AggregationInhibition of Platelet Aggregation(IPA) at 24 Hours (Healthy Volunteers)(IPA) at 24 Hours (Healthy Volunteers)

-20.0-20.0

0.00.0

20.020.0

40.040.0

60.060.0

80.080.0

100.0100.0

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

atio

n (

%)

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

atio

n (

%)

Response to PrasugrelResponse to PrasugrelResponse to ClopidogrelResponse to Clopidogrel

Clopidogrel Responder

Clopidogrel Non-responder

*Responder = 25% IPA at 4 and 24 h

Inte

rpat

ien

t V

aria

bil

ity

Inte

rpat

ien

t V

aria

bil

ity

Brandt JT et al. Am Heart J. 2007;153:66.e9-e16.

In Vitro Antiplatelet Effects of Active In Vitro Antiplatelet Effects of Active Metabolites in PRPMetabolites in PRP

* * PP < 0.05 ** < 0.05 ** PP < 0.01 vs. control < 0.01 vs. controlOgawa, et al ESC 2005.Ogawa, et al ESC 2005.

Prasugrel AMPrasugrel AM(IC(IC5050 = 26 = 26 μμM)M)

Concentration (Concentration (μμM)M)

1100 1001001010

****

********

**

Pla

tele

t a

gg

reg

ati

on

P

late

let

ag

gre

ga

tio

n

(%)

(%)

8080

6060

4040

00

2020

10001000

Clopidogrel AMClopidogrel AM(IC(IC5050 = 21 = 21 μμM)M)

****

****

********

Prasugrel 60 mg

0.1

1

10

100

1000

0 18126 24Time in Hr

Pla

sma

Co

nce

ntr

atio

n

(ng

/ml)

Clopidogrel 300 mg

ISTH 2005 Payne et al, P0952

Insights into Potency : Active Metabolite Insights into Potency : Active Metabolite Levels in Humans (Crossover Study)Levels in Humans (Crossover Study)

Copyright ©2007 American Heart Association

Wiviott SD et al, Circulation 2007Copyright ©2007 American Heart Association

Wiviott SD et al, Circulation 2007

PRPRasugrel asugrel ININ Comparison to Comparison to CClopidogrel for lopidogrel for IInhibition of nhibition of PLPLatelet atelet

Activation and AggrActivation and AggrEEgation gation (PRINCIPLE) – TIMI 44(PRINCIPLE) – TIMI 44




Study DesignStudy DesignLoading Phase

N=201

Maintenance Phase

N=100

No PCI

6h* Labs, 15d Events

Coronary AngiographyPost-Angiography Labs

Planned Elective PCIBaseline Laboratory Measures

Prasugrel60 mg

Clopidogrel600 mg

0.5 h Post-Loading Dose Labs

PCI

6h* Labs, 18-24h Labs

Clopidogrel150 mg x 14d

Prasugrel10 mg x 14d

Prasugrel10 mg x 14d

Clopidogrel150 mg x 14d 15d Clinical Events,

Labs,† CROSSOVER

29d Clinical Events, Labs†

Clopidogrel naïve

No planned GP IIb/IIIa use

1º EPs: *Loading = 6h IPA (20 µM ADP); †Maintenance = 15d or 29d IPA (20 µM ADP)



PRINCIPLE – TIMI 44

14

Trial Organization Trial Organization Trial Organization Trial Organization

US Lead and PI: S Wiviott ROW Lead: FJ Neumann

US Sites (4)D. Angiolillo

E. BatesM. FurmanD. Purdy

France Lead: G. Montalescot

Israel Lead: H. Hod

German Lead: FJ Neumann

France Sites (3)J-L Bonnet

B CharbonnierE Van Belle

German Sites (5)M Gawaz

A SchomigR Voss

B WitzenblicherFJ Neumann

Israel Sites (3)L Gruberg

H DanenbergS Matetsky

Study Chairman: Eugene Braunwald Director: Carolyn McCabe




PRIMARY EP Acute Phase: IPA 20 uM ADP

Prasugrel 60 mg

P<0.0001 for each

IPA

(%

; 20

M

AD

P)



Hours




Maximal Platelet Aggregation (MPA)

Prasugrel 60 mg

P<0.0001 for each

MP

A

(%;

20

M A

DP

)

Hours




Prasugrel 10 mg Prasugrel 10 mg

Difference Between Treatments: 14.9 [95% CI 10.6 – 19.3], P<0.0001

IPA

(%

; 20

M

AD

P)

Days

PRIMARY EP Chronic Phase: IPA 20 uM ADP




Maximal Platelet Aggregation (MPA)

Prasugrel 10 mg Prasugrel 10 mg

Difference Between Treatments: 11.3 [95% CI 8.1 – 14.5], P<0.0001

Clopidogrel 150 mg Clopidogrel 150 mg

MP

A (

%;

20

M A

DP

)

Days




Thienopyridine Hyporesponsiveness:

IPA 20 uM ADP < 20%

87.7

55.1

27.330.4

15.210

42.9

2.7 0 0 2.5 2.20

20

40

60

80

100

0.5 2 6 24 Day 15 Day 29

P =0.06

P =0.18

P =0.0002P =0.0005

P <0.0001

P =0.0008

ClopidogrelPrasugrel

Hours

Per

cen

t o

f S

ub

ject

s



ImplicationsImplications

PRINCIPLE – TIMI 44 extends the pharmacologic superiority of the TRITON – TIMI 38 dose of prasugrel (60 mg/10 mg) to higher doses of

clopidogrel (600 mg/150mg) in PCI.

TRITON – TIMI 381 tested hypothesis that an agent with higher and more consistent IPA than standard approved clopidogrel (300 mg/ 75 mg) will improve

clinical outcomes

1 Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

prasugrel background and principle – timi 44 stephen d. wiviott, md cardiovascular division...

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