antiplatelettherapy-wherearewegoing-

7/31/2019 AntiplateletTherapy-WhereAreWeGoing-

1/20

Antiplatelet Therapy: WhereAre We Going?

Shamir R Mehta MD MScAssociate Professor of Medicine

McMaster UniversityDirector, Interventional Cardiology

Hamilton Health SciencesHamilton, ON


2/20

Medical Rx Group

Placebo

Clopidogrel

RR: 0.80 (0.69-0.92)

0.20

4

0.15

0.10

0.05

0.0

100 200 300

Clopidogrel

0.20

4

0.15

0.10

0.05

0.0

100 200 300

PCI Group

Placebo

RR: 0.72 (0.57-0.90)

0.20

4

0.15

0.10

0.05

0.0

100 200 300

CABG Group

Placebo

Clopidogrel

RR: 0.89 (0.71-1.11)

CURE: Benefit of Clopidogrel Irrespectiveof Revascularization Status

CV

D/MI/stroke

C

VD/MI/stroke

CVD/MI/stroke

Fox KA, et al. Circulation. 2004;110:1202-1208.

Reproduced with permission.


3/20

Days of follow-up

CV death, MI, UR

0 5 10 15 20 25 30

0.0

0.02

0.04

0.06

0.08

Cum

ulativehazardrate 44%Relative

RiskReduction

P= 0.017(0.35-0.90)

Clopidogrel

pretreated

Placebopretreated

Benefit of Clopidogrel Pretreatment:PCI CURE and PCI CLARITY

0

2

4

6

0 10 20 30Days post PCI

Percen

tagewithoutcome

(%)

No pretreatment

Clopidogrelpretreatment

P= 0.008(95% CI 0.35-0.85)

PCI

46%RelativeRiskReduction

CV death, MI


1. Mehta SR, et al. Lancet.2001;358:527-533.

2. Sabatine MS, et al.JAMA. 2005;294:1224-1232.


4/20

Initial Invasive Strategy:Antiplatelet Therapy

For UA/NSTEMI patients in whom an initialinvasive strategy is selected, antiplatelettherapy in addition to ASA should beinitiated before diagnostic angiography

(upstream) with either clopidogrel (loadingdose followed by daily maintenance dose)*or an IV GP IIb/IIIa inhibitor.

III IIaIIaIIaIIbIIbIIbIIIIIIIIIIII IIaIIaIIaIIbIIbIIbIIIIIIIIIIII IIaIIaIIaIIbIIbIIbIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIII

*Some uncertainty exists about optimum dosing of clopidogrel. Randomized trials establishing itsefficacy and providing data on bleeding risks used a loading dose of 300 mg orally followed by a

daily oral maintenance dose of 75 mg. Higher oral loading doses such as 600 or 900 mg ofclopidogrel more rapidly inhibit platelet aggregation and achieve a higher absolute level ofinhibition of platelet aggregation, but the additive clinical efficacy and the safety of higher oralloading doses have not been rigorously established; Factors favoring administration of bothclopidogrel and a GP IIb/IIIa inhibitor include: delay to angiography, high-risk features, and earlyischemic discomfort.

Anderson JL, et al.J Am Coll Cardiol. 2007;50:e1-157.


5/20

TRITON TIMI-38: Study Design

Planned PCI &ACS (STEMI or UA/NSTEMI)

No pretreatmentASA

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 IschCV death, MI, UTVRStent thrombosis (ARC definite/prob)

Safety endpoints: TIMI major bleeds, life-threatening bleeds

Key substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N = 13,600

Coronary anatomy defined


6/20

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73 - 0.90)P= 0.0004

Prasugrel

Clopidogrel

HR 0.80P= 0.0003

HR 0.77P= 0.0001

Days

Primaryendpoint(%)

12.1(781)

9.9(643)

TRITON TIMI-38: Primary Endpoint CVDeath, MI, Stroke

NNT = 46

ITT = 13,608 LTFU = 14 (0.1%)


Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.


7/20

TRITON TIMI-38: Stent Thrombosis(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P< 0.0001

Prasugrel

Clopidogrel

2.4(142)

NNT= 77

1.1(68)

Days

Endpo

int(%)

Any stent at index PCI

N = 12,844


Wiviott SD, et al. Lancet. 2008;371:1353-1363.


8/20

1.8

0.9 0.9

0.1

0.3

2.4

1.41.1

0.4 0.3

0

2

4

TIMI Major

Bleeds

Life

Threatening

Nonfatal Fatal ICH

TRITON TIMI-38: Bleeding Events Safety Cohort

%Even

ts

ARD 0.6%HR 1.32

P= 0.03NNH = 167

ClopidogrelPrasugrel

ARD 0.5%HR 1.52

P= 0.01

ARD 0.2%P= 0.23

ARD 0%P= 0.74

ARD 0.3%P= 0.002

ICH in pts wprior stroke/TIA(N = 518)

Clop 0 (0) %Pras 6 (2.3)%

(P= 0.02)


(N = 13,457)

ARD = absolute risk difference

NNH = number needed to harm


9/20

TRITON TIMI-38: Net Clinical BenefitBleeding Risk Subgroups Post-hoc Analysis

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 analysis



10/20

ALBION Study: Primary Endpoint: Faster Onset of

Action and Higher Level of Platelet Inhibition

0

5

10

15

20

25

30

35

40

45

1 2 3 4 5 6 24

Montalescot G, et al.J Am Coll Cardiol. 2006;48:931-938.Reproduced with permission.

Shortened time to reach the highestlevel of inhibition of the 300 mg LD

300 mg LD

600 mg LD

900 mg LD

P< 0.05 vs 300 mg LD

%Inhibition

Time (h)

Maximum inhibition of platelet aggregation(5 mol/L ADP)


11/20

20,000 ACS or STEMI patientsAngiography with intended PCI < 24 hrs

No restriction on use of GP IIb/IIIa inhibitors

High-doseclopidogrel 600 mgthen 150 mg OD x

7d then 75 mg OD

Standard-doseclopidogrel 300 mgfollowed by 75 mg

daily

CURRENT-OASIS 7 Trial

Randomized

Outcomes (30 Days)

Death / MI /stroke

Secondary outcome

30-day bleedingcomplications

High-doseASA

( 300 mg)

Low-doseASA

( 100 mg)

High-doseASA

( 300 mg)

Low-doseASA

( 100 mg)

A randomized, double-blind, 2X2 factorial trial of clopidogrel high vsstandard loading dose and high- vs low-dose ASA in ACS or STEMI

managed with an early invasive strategy

http://www.clinicaltrials.gov/ct/show/NCT00335452


12/20

Standard Therapyclopidogrel 75 mg +placebo/day

Standard Therapyclopidogrel 75 mg +placebo/day

Tailored Therapyclopidogrel 150 mg/day

Successful PCI with DES without major complication or GP IIb/IIIa use

Post-PCI VerifyNow P2Y12 Assay (PRU) 12-24 hours post-PCI

PRU 230?

Non-responder

Clinical follow-up and VerifyNow assessment at 30 days, 6 months

Primary endpt: 6 month CV Death, Non-Fatal MI, ARC Def/Prob Stent Thrombosis

Yes No

N ~ 6600

N = 1100 N = 583

Responder

A B C

Random selection

N = 1100

G R A V T A S

Coordinating Center: Scripps Advanced Clinical TrialsStudy PI: Matthew J Price MD

http://www.clinicaltrials.gov/ct/show/NCT00645918


13/20

AZD6140 (Ticagrelor)

A non-thienopyridine, in the chemical class CPTP

(CycloPentylTriazoloPyrimidine)

First oral reversible ADP P2Y12 receptor antagonist

Direct acting via the P2Y12 receptor - metabolism notrequired for activity

More potent platelet inhibitor than clopidogrel

HO

HN

HO OH

O S

F

F

N

NN

NN


14/20

UA/NSTEMI (mod-high risk)

STEMI (if primary PCI)All receiving ASA

Clopidogrel treated or nave

ClopidogrelIf pretreated, no additional load;if nave, standard 300 mg load,then 75 mg o.d. maintenance;

(additional 300 mg allowed pre-PCI)

Primary endpoint: CVdeath/MI/strokeSecondary EP: CVdeath/MI/stroke/revascularization with PCI;

CVdeath/MI/stroke, severe recurrent ischemia

12 month maximum exposure

(min = 6 mo, max = 12 mo, mean = 11 mo)

N = 18,000 pts

AZD6140180 mg load, then90 mg bid maintenance;

(additional 90 mg pre-PCI)

http://www.clinicaltrials.gov/ct/show/NCT00391872.


15/20

%

Inhibitionofaggregation

F

oldincreaseinb

leedingtime

0

20

40

60

80

100

0

1

2

3

4

5

6

7

8

50 100 500 1000 2000

Aggregation

Bleeding time

+ aspirin/heparin/GTN

+ placebo

AR-C69931 (ng.kg-1.min-1) Stepped infusion period Recovery period

7 15 20 45 60 min

Cangrelor: Key Phase II Result

Rapid reversal of dose-dependent effect


16/20

CHAMPION

Double-blind

UA, MI, or ACS and require PCI

CANGRELOR30 g/kg IV bolus + 4g/kg/min IV infusion

CLOPIDOGREL600 mg

1o endpoint: All-cause mortality, MI, and ischemia-drivenrevascularization in the 48 hours after randomization2o endpoints: All-cause mortality and MI at 48 hours and safetyFollow-up: 6-mo and 1-year mortality

CHAMPION Platform = http://www.clinicaltrials.gov/ct/show/NCT00385138and CHAMPION PCI =NCT00305162.

Primary objective: Superiority or noninferiority of cangrelorvs clopidogrel for PCI

Platformn = 4400Clopidogrel after PCI

PCIn = 9000Clopidogrel before


17/20

Protease-Activated-Receptor(PAR-1) Inhibition

Brass L. Chest. 2003;124:18S-25.Reproduced with permission.

SCH 530348E 5555


18/20

TRA-PCI: TRA (SCH 530348)MI & Bleeding

Moliterno DJ. ACC; 2007.


19/20

TRA (SCH 530348) Program

(29,500 pts)

1o EP: Composite of CVdeath, MI, stroke, and

urgent revascularization

TRA (SCH 530348) ProgramEvaluation of efficacy and safety in acute and chronic atherothrombosis

CER

NSTEACS10,000 pts

2 Prevention19,500 pts

SCH 53034840 mg LD2.5 mg daily

Placebo SCH 5303482.5 mg daily Placebo

F/up: 30 days, 4, 8, 12 months, and 6 months thereafter

F/up 1 yr minimum

1o EP: Composite of CV death,MI, stroke, urgent

revascularization andrecurrent ischemia w/ rehosp

TRA-CER = http://www.clinicaltrials.gov/ct/show/NCT00527943 andTRA-2P = NCT00526474


20/20

Summary: New Trials of Antiplatelet Agents

Agent Class Route Key Trial(s) Status

ClopidogrelADP P2Y12 Receptor

AntagonistOral

CURRENT/OASIS-7

Completionexpected in

2009

PrasugrelADP P2Y12 Receptor

AntagonistOral

TRITON/TIMI-38

Published

Under FDA

Review

AZD6140ADP P2Y12 Receptor

AntagonistOral PLATO

Completionexpected in

2009

Cangrelor

ADP P2Y12 Receptor

Antagonist IV

CHAMPION,

PLATFORMand PCI

Completion

expected in2009

SCH 530348PAR-1 Receptor

AntagonistOral

TRACER,TRA-2P

Completionexpected2010/2011

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