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AntiPlatelet Therapy in ACS and PCI

Stephen D. Wiviott, MDAssociate Physician, Cardiovascular

Division, Brigham and Women's Hospital Investigator, TIMI Study Group

Harvard Medical School Boston, MA

Antiplatelet Therapy in ACS and Antiplatelet Therapy in ACS and PCI: Challenges and Future PCI: Challenges and Future

DirectionsDirectionsStephen D. WiviottStephen D. Wiviott

Cardiovascular DivisionCardiovascular DivisionBrigham and Women’s HospitalBrigham and Women’s Hospital

Harvard Medical SchoolHarvard Medical School TIMI Study Group TIMI Study Group

DisclosuresDisclosuresSpeakers Bureau: Pfizer; CME Honoraria: Speakers Bureau: Pfizer; CME Honoraria:

Eli Lilly, Merck, Pfizer, Sankyo; Eli Lilly, Merck, Pfizer, Sankyo; Accumetrics. Consultancies: Amgen, Accumetrics. Consultancies: Amgen,

Transform Pharmaceuticals, Forrest Labs, Transform Pharmaceuticals, Forrest Labs, Biogen-Idec, Sanofi-AventisBiogen-Idec, Sanofi-Aventis

TIMI Study GroupTIMI Study Group Receives Research Receives Research Funding From: Eli Lilly, Sankyo, Merck, Funding From: Eli Lilly, Sankyo, Merck, Schering Plough, Pfizer, Sanofi-Aventis, Schering Plough, Pfizer, Sanofi-Aventis, Astra Zeneca, CV Therapeutics, Corvas, Astra Zeneca, CV Therapeutics, Corvas,

AccumetricsAccumetrics

1 0

1 2

Dual Antiplatelet Rx for PCI Dual Antiplatelet Rx for PCI

8.6

2.7

11

6.2

1.6

5.7

0.5

5.8

0

2

4

6

8

10

12 OAC + ASATiclopidine + ASA

Circ 102: 624,2000

ISAR FANTASTIC STARS MATTIS CLASSICS

% M

AC

E

0.91.5 1.2

CURE

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Cum

ulat

ive

Haz

ard

Rat

e

Clopidogrel Clopidogrel + ASA*+ ASA*

33 66 99

Placebo Placebo + ASA*+ ASA*

Months of Follow-UpMonths of Follow-Up

11.4%11.4%

9.3%9.3%

20% RRR20% RRRPP < 0.001 < 0.001

N = 12,562N = 12,562

00 1212

* In combination with standard therapy

The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Primary End Point - MI/Stroke/CV Primary End Point - MI/Stroke/CV DeathDeath

NSTEACS: Clopidogrel (300/75) vs Placebo

Co

mb

ined

En

dp

oin

t C

om

bin

ed E

nd

po

int

Occ

urr

ence

(%

)O

ccu

rren

ce (

%)

Days From RandomizationDays From Randomization

No-PT - Placebo*No-PT - Placebo*

PT- Clopidogrel*PT- Clopidogrel*

00

55

1010

00 77 1414 2121 2828

PT = Pre-treatmentPT = Pre-treatment

*Plus ASA and other standard therapies*Plus ASA and other standard therapies

Death, MI, UTVR- PP PopulationDeath, MI, UTVR- PP Population

18.5% 18.5% RRRRRR

P=0.23P=0.23

99

88

11

44

33

22

77

66

8.3%8.3%

6.8%6.8%

Steinhubl S, Berger P, Tift Mann III J et al. Steinhubl S, Berger P, Tift Mann III J et al.

JAMAJAMA. 2002;Vol 288,No 19:2411-2420.. 2002;Vol 288,No 19:2411-2420.

Early Effects of Pre-treatment with Early Effects of Pre-treatment with Clopidogrel – 28 Day ResultsClopidogrel – 28 Day Results

- 6

- 5

- 4

- 3

- 2

0 5 10 15 20 25 30

Hours Prior to PCI of Study Drug Loading Dose

Lo

g O

dd

s o

f D

eath

, MI o

r U

TV

R a

t 28

Day

s

Placebo

Clopidogrel

P=0.020for treatment/timing

interaction

CREDO: Clopidogrel Loading Dose Timing and Risk of MACE

Steinhubl, et al

Limitations of Current thienopyridines

Slow onset: requires prolonged pretreatment for PCI efficacy

Bleeding (especially related to CABG)

Modest levels of platelet inhibition

Variability of response

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

2 Hours 24 Hours

5 Days 30 Days

Aggregation (%)

Resistance = 63% Resistance = 31%Resistance

Resistance = 31%

Resistance

Resistance = 15%

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

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 (

%)

Potential Mechanisms of Response Variability

Extrinsic Mechanisms•Non-compliance

•Under-dosing

•Drug-drug interactions

•Absorption and/or metabolism

•Patient Factors (DM, ACS, etc…)

Intrinsic Mechanisms•P2Y12 receptor affinity (ADP or Drug) or number

•Variable response to agonist:

•Release

•GP IIb/IIIa receptor activationWiviott and Antman Circ 2004

CYP 3A4 Activity* Correlates Inversely with Platelet Aggregation

Following Clopidogrel Loading

*Erythromycin breath test. Lau WC, et al. Circulation. 2004;109:166-171.

Pla

tele

t A

gg

reg

atio

n (

%)

14CO2 Exhaled/Hour (%)

r=–0.6P=0.003

100

90

80

70

60

50

40

30

20

10

00 .5 1 1.5 2 2.5 3 3.5 4

Clinical Importance of Response Variability ?

Failure of Therapy = Drug Resistance

Failure of Therapy Successful Therapy

Lesser Response

Greater Response

0

20

40

60

80

100

120

0

10

20

30

40

5 µM ADP induced plt agg Death/ACS/CVA by 6 m

Days1 2 3 4 5 6

Bas

elin

e (%

)

Quartiles of response

Q1

Q2

Q3

Q4

Clop resist 40

6.7

0 0P

erce

nt

P=0.007

Q1 Q2 Q3 Q4

Matetzky S, et al. Circulation. 2004;109:3171-3175.Wiviott SD, Antman EM. Circulation. 2004 109:3064-3067.

Clopidogrel Resistance andIncreased Risk of Ischemic Events

N = 60 Prim PCI for STEMI

*5 m ADP.Gurbel PA, et al. Circulation. 2005;111:1153-1159.

Platelet Reactivity* Correlateswith CK-MB Release: CLEAR Platelet Study

P<0.001

P<0.001 P=0.015

CK-MB(NL)

CK-MB(>1-3x ULN)

CK-MB(>3x ULN)

100

90

80

70

60

50

40

30

20

10

0

Mea

n P

late

let

Rea

ctiv

ity

The Clopidogrel REsistance andStent Thrombosis (CREST) Study

Platelet Reactivity in Patients with SAT(N=20) versus no SAT (N=50)

 

LTA – 5 M ADP (%) LTA – 20 M ADP (%)

Gurbel PA, et al. J Am Coll Cardiol. 2005 (in press).

49

26

0

10

20

30

40

50

60

70

SAT No SAT

65

46

0

10

20

30

40

50

60

70

SAT No SAT

P<0.001 For Each

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 Hours

Pat

ien

ts (

%) Resistance = 28% (300 mg)

Resistance = 8% (600 mg)

ISAR - CHOICE

Von Beckenrath et al Circ 2005

Platelet AggregationMetabolite

Concentrations

ARMYDA-2 Trial: Primary endpointARMYDA-2 Trial: Primary endpoint

4%

12%

0%

2%

4%

6%

8%

10%

12%

14%

600 mg 300 mg

4%

12%

0%

2%

4%

6%

8%

10%

12%

14%

600 mg 300 mg

Primary Composite of death, MI, and target vessel revascularization

p = 0.04

Circulation 2005Circulation 2005

255 patients with stable CAD or UA/NSTEMI

4-8 hours prior to PCI

13% received IIb/IIa inhibitors and 20% drug-

eluting stents

255 patients with stable CAD or UA/NSTEMI

4-8 hours prior to PCI

13% received IIb/IIa inhibitors and 20% drug-

eluting stents

Primary Endpoint: Composite of death, MI, or target vessel revascularization (TVR) at 30 days

Primary Endpoint: Composite of death, MI, or target vessel revascularization (TVR) at 30 days

Clopidogrel High-Dose GroupClopidogrel High-Dose GroupClopidogrel 600 mg loading dose day 1 followed by Clopidogrel 600 mg loading dose day 1 followed by 150 mg from days 2 to 7; 75 mg from days 8 to 30150 mg from days 2 to 7; 75 mg from days 8 to 30

Clopidogrel Standard-Dose GroupClopidogrel Standard-Dose GroupClopidogrel 300 mg (+ placebo) day 1 followedClopidogrel 300 mg (+ placebo) day 1 followed

by 75 mg (+ placebo) from days 2 to 7;by 75 mg (+ placebo) from days 2 to 7;75 mg from days 8 to 3075 mg from days 8 to 30

Patients with UA/NSTEMI planned for early invasivePatients with UA/NSTEMI planned for early invasiveStrategy; ie, intend for PCI as early as possible within 24 hrsStrategy; ie, intend for PCI as early as possible within 24 hrs

RANDOMIZERANDOMIZE

PCI: Percutaneous coronary interventionUA/NSTEMI: Unstable angina/non-ST-segment elevation myocardial infarction

CClopidogrel optimal loading doselopidogrel optimal loading dose U Usagesage toto R Reduceeduce RRecurrent ecurrent EEveveNTNTs/s/OOptimal ptimal AAntiplateletntiplatelet S Strategytrategy forfor

IInterventionnterventionSS

CURRENT/OASIS 7CURRENT/OASIS 7

RANDOMIZERANDOMIZERANDOMIZERANDOMIZE

ASA low-dose groupASA low-dose groupAt least 300 mg day 1;At least 300 mg day 1;

75–100 mg75–100 mgfrom days 2 to 30from days 2 to 30

ASA high-dose groupASA high-dose groupAt least 300 mg day1;At least 300 mg day1;

300–325 mg300–325 mgfrom days 2 to 30from days 2 to 30

ASA high-dose groupASA high-dose groupAt least 300 mg day 1;At least 300 mg day 1;

300–325 mg300–325 mgfrom days 2 to 30from days 2 to 30

ASA low-dose groupASA low-dose groupAt least 300 mg day 1;At least 300 mg day 1;

75–100 mg75–100 mgfrom days 2 to 30from days 2 to 30

Change the Agent?Change the Agent?Change the Agent?Change the Agent?

PrasugrelPrasugrel

Sankyo Ann Report 51:1,1999

Pro-drugPro-drugPro-drugPro-drug

OxidationOxidation(Cytochrome P450)(Cytochrome P450)

OxidationOxidation(Cytochrome P450)(Cytochrome P450)

HOOCHOOC

* HS* HS

NN

OO

FF

Active MetaboliteActive MetaboliteActive MetaboliteActive Metabolite

NN

SS

OO

FFOO

Sem Vasc Med 3:113, 2003

HydrolysisHydrolysis(Esterases)(Esterases)

HydrolysisHydrolysis(Esterases)(Esterases)

NN

SS

OO

CCHH33

CCOO

FFOONN

SS

OO

ClCl

OO CHCH33CHCH33CCCC

ClopidogrelClopidogrel

85% Inactive 85% Inactive MetabolitesMetabolites

EsterasesEsterases

85% Inactive 85% Inactive MetabolitesMetabolites

EsterasesEsterases

NN

SS

OO

ClCl

OO CHCH33CHCH33CCCC

OONN

SS

OO

ClCl

OO CHCH33CHCH33CCCC

Active MetaboliteActive MetaboliteActive MetaboliteActive Metabolite

HOOCHOOC

* HS* HS

NN

OO

ClCl

OCH3OCH3

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

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

Response to Response to PrasugrelPrasugrel

Response to Response to ClopidogrelClopidogrel

Clopidogrel ResponderClopidogrel Non-responder

*Responder = *Responder = 25% IPA at 4 and 24 25% IPA at 4 and 24 hh

Inte

rpat

ien

t Va

ria

bilit

y

Interp

atient

Va

riab

ility

Brandt, Payne, Wiviott et al AHJ 2007

Inhibition of Platelet Aggregation (Stable Atherosclerosis)

Inhibition of Platelet Aggregation (Stable Atherosclerosis)

Prasugrel (40 mg LD/5 mg MD)

Prasugrel (40 mg LD/7.5 mg MD)

Prasugrel (60 mg LD/10 mg MD)Prasugrel (60 mg LD/15 mg MD)

Clopidogrel(300 mg LD/75 mg MD)

Mea

n I

PA

(%

)

-10

0

10

20

30

40

50

60

70

Day/Hour Post Dosing

1/0 1/2 1/4 1/6 7/1 7/2 28/0 28/2 28/4 28/6

Loading dose (LD) Maintenance dose (MD)

Jernberg, T et al EHJ 2006

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. control

Prasugrel AMPrasugrel AM(IC(IC5050 = 51 = 51 μμM)M)

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

Clopidogrel AMClopidogrel AM(IC(IC5050 = 41 = 41 μμM)M)

(A) Rat(A) Rat (B) Human(B) Human

Concentration (Concentration (μμM)M) Concentration (Concentration (μμM)M)

7070

6060

5050

4040

3030

2020

1010

Pla

tele

t a

gg

reg

ati

on

P

late

let

ag

gre

ga

tio

n

(%)

(%)

001100 100100 100010001010

****

********

****

****

1100 1001001010

****

********

**

Pla

tele

t a

gg

reg

ati

on

P

late

let

ag

gre

ga

tio

n

(%)

(%)

8080

6060

4040

00

2020

10001000

Ogawa, et al ESC 2005.Ogawa, et al ESC 2005.

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)

STUDY DESIGNSTUDY DESIGNSTUDY DESIGNSTUDY DESIGN

Study Drug in lab; Stratify for GP IIb/IIIa

Maintenance Rx for 30 days

PRASUGREL

LD 40 mg

MD 7.5 mg

N=200

PRASUGREL

LD 60 mg

MD 10 mg

N=200

CLOPIDOGREL

LD 300 mg

MD 75 mg

N=250

1o endpoint: Significant (non-CABG) bleeding through 30 D

2o endpoints: CV MACE through 30 D, Major Bleeding, Component Clinical Endpoints

PRASUGREL

LD 60 mg

MD 15 mg

N=250

PCI with stenting (N=900)

Wiviott et al Circ 2005

110 0 EP: Significant Non-CABG Bleeding 30 DEP: Significant Non-CABG Bleeding 30 D110 0 EP: Significant Non-CABG Bleeding 30 DEP: Significant Non-CABG Bleeding 30 D

1.2%

2.0%1.5%

1.7% 1.6%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

Clop Pras 40/7.5 60/10 60/15

P= NS

3/254 11/650 3/199 4/200 4/251R/N

P = 0.77

Prasugrel LD/MDTreatment Group

Dose RangingClop. vs Prasugrel

Wiviott et al Circ 2005

MI at 30 DMI at 30 DMI at 30 DMI at 30 D

4.0%

5.7%

7.0%6.5%

7.9%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

Clop Pras 40/7.5 60/10 60/15

P= NS

20/254 37/650 14/199 13/200 10/251R/N

RR=0.72 [0.4,1.2]

P = 0.23

Prasugrel LD/MDTreatment Group

Wiviott et al Circ 2005

ImplicationsImplicationsIn patients undergoing PCI, prasugrel:

• Demonstrated a similar safety profile to standard dose clopidogrel

• Resulted in non-significant, but lower rates of ischemic events compared to patients treated with standard doses of clopidogrel

QUESTION: Would prasugrel, with higher and more consistent levels of platelet inhibition, be superior to clopidogrel in reducing ischemic events in a trial powered to detect a clinically significant difference?

STUDY DESIGNSTUDY DESIGNSTUDY DESIGNSTUDY DESIGN

Double-blindDouble-blind

ACS (STEMI or UA/NSTEMI) & Planned PCIACS (STEMI or UA/NSTEMI) & Planned PCI

ASAASA

PRASUGRELPRASUGREL60 mg LD/ 10 mg MD60 mg LD/ 10 mg MD

PRASUGRELPRASUGREL60 mg LD/ 10 mg MD60 mg LD/ 10 mg MD

CLOPIDOGRELCLOPIDOGREL300 mg LD/ 75 mg MD

CLOPIDOGRELCLOPIDOGREL300 mg LD/ 75 mg MD

11oo endpoint: endpoint: CV death, MI, StrokeCV death, MI, Stroke22oo endpoints: endpoints: CV death, MI, Stroke, Rehosp-Rec IschCV death, MI, Stroke, Rehosp-Rec Isch

CV death, MI, UTVRCV death, MI, UTVR

Median duration of therapy - 12 monthsMedian duration of therapy - 12 months

N= 13,000N= 13,000

Wiviott et al, AHJ 2006

Enrollment CompleteEnrollment Complete January 2007January 2007

ImplicationsImplications

•Establish the safety and efficacy of prasugrel compared to clopidogrel in patients with ACS undergoing PCI in this registry pathway trial

•Proof of Concept:

Does an agent that has higher inhibition of platelet aggregation and less “thienopyridine resistance” result in improved clinical outcomes in an adequately powered clinical trial?

Wiviott et al, AHJ 2006

TIMI 38 C R Hypotheses

1.Patients withdrawn from thienopyridine at study completion will have a higher rate of stent thrombosis than those continuing therapy in the registry follow up period

2.Patients treated with DES will have higher rates of stent thrombosis than those treated with BMS over the entire treatment period (trial plus registry)

In the follow up phase, beyond completion of TRITON – TIMI 38*:

*Analyses adjusted for baseline, procedural features, and propensity for clopidogrel use

TIMI 38 C R

DES

BMS

TRITON – TIMI 38

Clinical Trial

Prasugrel vs Clopidogrel

Open LabelThienopyridine

Continue

Discontinue

Continue

Discontinue

24 M Following LPV in TRITON – TIMI 38

30 - 54 Months

Registry + Trial Duration

Registry Duration

Summary of Analytical Groups and Trial/ Registry Timing

6-15 Months

Trial Duration

Prasugrel 10 mg MD vs. Clopidogrel 75 mg MD: Higher IPA During Maintenance Dosing

mean ± SEM 20 μM ADP

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

ati

on

(%

)

0

20

40

60

80

100

Loading Dose Maintenance Doses

Time Hours Days

0.25 0.5 1 2 4 6 24 3 4 5 6 7 8 90

Clop 300 mg

Clop 75 mg

††

!

!

† §

†p<0.001 vs. Clop 300!

p<0.05 vs. Clop 300§p<0.05 vs Clop 300/75

Clop 600 mg

Clop 75 mg

*

*

** * *

* * * * * * *

*p<0.001 vs. Clop 300 mg or 600 mg LD

Pras 60 mg

Pras 10 mg

Planned Elective PCIAggregometry*and Biomarkers√

ASA

CLOPIDOGREL Naive

ClopidogrelClopidogrel600 mg600 mg

Prasugrel Prasugrel 60 mg60 mg

0.5, hour post-LD Aggregometry* and Biomarkers√

Diagnostic Catheterization Anatomy Suitable for PCI

Post Cath† aggregometry

Planned GP IIb/IIIa Prohibited

N < 180

N = 100 PCI

6, 18-24 h, Aggregometry*, biomarkers

†Or 2 h whichever is sooner

Primary Endpoint: Mean IPA (6h) in all treated subjects

PHASE I

Protocol DesignPRINCIPLE – TIMI 44 (PCI Subjects Only) – Phase I

Protocol Design

√ Biomarkers (VASP, CD40L, P-selectin, LPA, Tn, CK-MB, CRP, MPO)

*Aggregometry: Primary (20 uM ADP), secondary (5 uM ADP), Accumetrics

PrasugrelPrasugrel10 mg x 14d10 mg x 14d

14 d clinical events, biomarkers

√, aggregometry*, CROSSOVER

PRINCIPLE – TIMI 44 (PCI Subjects Only) – Phase II

Clopidogrel Clopidogrel 150 mg 150 mg

x14dx14d

PrasugrelPrasugrel10 mg x 14 10 mg x 14

dd

Clopidogrel Clopidogrel 150 mg 150 mg

x14dx14d30 d clinical events,biomarkers

√, aggregometry*

Confidential

Primary Endpoint: Mean IPA (14d&30d) in all treated subjects

PHASE II PCI

Change the Agent?AZD6140 Characteristics

*cyclo-pentyl-triazolo-pyrimidine

•Class: CPTP* (non-thienopyridine)

•Reversible platelet P2Y12 receptor antagonist

•Orally active

•Rapid onset of action (2 h) with or without a loading dose

•Acts directly (no metabolic activation required)

•Plasma t½ ~12 h (BID Drug)

OH OH

N

N

NN

NH

SNO

F

F

OH

AZD6140AZD6140

Maximal and Final IPA on Day 1 Clopidogrel Naive Patients

AZD6140 90 mg AZD6140 180 mg AZD6140 270 mg CLOP 300 mg

0

25

50

75

100

IPA

(%

)M

ea

n ±

SE

M

0

25

50

75

100

0 2 4 8 12

Time, h0 2 4 8 12

Time, h

Maximal Extent Final Extent

P<0.0176 for all AZD6140 groups vsclopidogrel at 4 h

P<0.0002 for all AZD6140 groups vs clopidogrel at 4 h

UA/NSTEMI (mod-high risk)

STEMI (if primary PCI)All Receiving ASA

Clopidogrel Treated or Naïve

ClopidogrelIf pretreated, no additional load;if naïve, standard 300 mg load,

then 75 mg od maintenance(additional 300 mg allowed pre-PCI)

Primary Endpoint: CV Death/MI/StrokeSecondary EP: CV Death/MI/Stroke/Revascularization with PCI;

CV Death/MI/Stroke; Severe Recurrent Ischemia

12 month maximum exposure12 month maximum exposure(Min=6 mo, max=12 mo, mean=11 mo)(Min=6 mo, max=12 mo, mean=11 mo)

n=18,000 ptsn=18,000 pts

AZD6140180 mg load, then

90 mg bid maintenance(additional 90 mg pre-PCI)

ClinicalTrials.gov Identifier: NCT00391872

Change The Agent and the Route: Cangrelor?

Low volume of distribution, extensively protein bound

Short half-life (3-5 min), full recovery 20 min

Unlike thienopyridines, direct P2Y12 inhibition, independent of CYP 3A4 metabolism

? Competitive inhibition of clopidogrel

Fo

ld I

nc

rea

se i

n B

leed

ing

Tim

e

Stepped infusion period

Inh

ibit

ion

of

Ag

gre

gat

ion

(%

)

0

20

40

60

80

100

0

1

2

3

4

5

6

7

8

50 100 500 1000 2000

AggregationAggregation

Bleeding timeBleeding time

+ Aspirin/heparin/GTN+ Placebo

Cangrelor (ng.kg-1.min-1) Recovery period

7 15 20 45 60 min

Clopidogrel Response Variability: Change the Dose and the Route of Administration?

Nassim MA. J Am Coll Cardiol. 1999;33:225A.

CHAMPION PCI (Phase III)CHAMPION PCI (Phase III)

Double-blindDouble-blind

UA, MI, or ACS

CANGRELORCLOPIDOGREL

1o endpoint: All-cause mortality, MI, and IDR in the 48 hours after randomization 2o endpoints: All-cause mortality and MI at 48 hours

n=9,000n=9,000

Accessed September25, 2006, at http://www.clinicaltrials.gov/ct/show/NCT00305162?order=1.

Primary Objective: Superiority or noninferiority of cangrelor versus clopidogrel for PCI

Summary

1. ADP induced platelet activation plays a central role in ACS and PCI complications

2. Thienopyridines have become a key component of therapy

3. Current thienopyridines have important limitations including response variability

4. Agents in development offer improved pharmacological profiles, and results of ongoing trials will determine clinical efficacy

Question Question

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AnswerAnswer

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