Amber MalikDirector Cath Lab Services

Shaikh Zayed Hospital, Lahore

Platelet aggregation contributes to atherothrombosis which in turn is associated with Acute Coronary Syndromes

ACS often precipitates cardiovascular death

No ST elevation ST elevation

Acute coronary syndrome

Antiplatelet Rx

Antithrombin Rx

Complete obstruction

Partial flow

UA/NSTEMI STEMI

X TF/ VIIa

VaCa++

FGN

FGN

IXa

XI

VIIIa

FGN

FibrinXa

Plt

Prothrom Thrombin

Collagen fibrils

Inactive platelet

GP Ia/IIa

GP VI

Platelet activation: Release of contents,

surface receptor expression

ADP

Collagen

Thrombin

Epinephrine

Tx A2

Serotonin

Ca++

PGG2-PGH2

AA release

Tx A2

COX

Tx Syn

Tx A2

RBCs

Endothelial cells

ADP

Collagen

Thrombin

Epinephrine

Tx A2

Serotonin

GP IIb/IIIareceptoractivation

IIb/IIIa

Shear forces

FGN

IIb/IIIa inhibitor

Risk during and after ACS can be reduced by optimal anticoagulation and antiplatelet treatment in conservatively treated as well as revascularised patients

In PCI with stents effective AP inhibition is highly mandatory as the processes themselves are thrombogenic and add to the risk

Prothrombin Thrombin

Xa

X

Va,Ca2+

Platelet

UFH

LMWHUFH

DTIs

GP IIb/IIIa

inhibitor

ASAClopidogrel

LMWH, pentasaccharide

DAPT ( aspirin and clopidogrel) for NSTEMI for 1 year (CURE trial )

DAPT for STEMI for at least 30 days (CLARITY- TIMI 28 trial )

DAPT mandatory post PCI with stents• BMS at least 1 month• DES at least 1 year

Even though CURE shows a RRR of 20% of composite end point which occurred in 9.3% vs 11.4 % on placebo .

The 9.35 % event rate is still quite high inspite of DAPT, which rose to 16.3% when recurrent ischemia was included.

Hence the desire to improve outcome even further

Cox inhibitors :Aspirin

ADP receptor antagonist :TiclopidineClopidogrelPrasugrelCangrelorTicagrelor(AZD6140)

Phosphodiesterase inhibitors :CilostazolDipyridamole

Thrombin inhibitor :Bivalirudin

Glycoprotein IIb/IIIA inhibitors :AbciximabEptifibatideTirofiban

Ticlopidine

(1st generation)

N

SCl

N

SCl

COOCH3

N

F

O

SO

OC H3

Clopidogrel

(2nd generation)

Prasugrel (CS-747) (LY640315)

(3rd generation)

Slow onset: requires prolonged pretreatment for PCI efficacy

Optimal interval from delivery to max drug effect is >15 hrs

Bleeding (especially related to CABG)

Modest levels of platelet inhibition

Variability of response is upto 30% depending on the measure of platelet aggregation used

ESC guidelines recommend 300mg loading dose > 6 hrs pre PCI

Reality is very different

Common practise CAG is often followed by ad hoc PCI with very little time for optimal dosing etc and exposing patients to an increased risk of bleeding

PRAGUE 8 concluded that non selective treatment of pts with high dose clopidogrel should not be routinely undertaken

Failure of Therapy = Drug Resistance

Failure of Therapy Successful Therapy

Lesser Response

Greater Response

PrasugrePrasugrell

Sankyo Ann Report 51:1,1999

Pro-drugPro-drugPro-drugPro-drug

OxidationOxidation(Cytochrome (Cytochrome

P450)P450)

OxidationOxidation(Cytochrome (Cytochrome

P450)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

ClopidogreClopidogrell

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

-20.0-20.0

0.00.0

20.020.0

40.040.0

60.060.0

80.080.0

100.0100.0

Inhib

itio

n o

f Pla

tele

t A

ggre

gati

on (

%)

Inhib

itio

n o

f Pla

tele

t A

ggre

gati

on (

%)

Response Response to 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

rpati

en

t V

ari

ab

ility

Inte

rpatie

nt

Varia

bility

Brandt, Payne, Wiviott et al AHJ 2007

PRASUGREL

Faster and more potent IPA :• Less dependent on CYP450 for metabolism• More extensively metabolised to its active

metabolite• Reaches higher concentrations with a 60mg LD and

10mg MD vs 300mgLD and 75mg MD as well as high dose 600mg LD and 150 mg MD clopidogrel

Less variabilty of response

Benefits demonstrated in both healthy volunteers and CAD pts.

TRITON-TIMI 38TRITON-TIMI 38AHA 2007AHA 2007

Orlando, FloridaOrlando, Florida

Disclosure StatementDisclosure Statement: : The TRITON-TIMI 38 trial was supported by a research grant to the Brigham The TRITON-TIMI 38 trial was supported by a research grant to the Brigham

and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.

NEJM 357: 2001-2015, 2007 www.NEJM.org

Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:

Ticlopidine Ticlopidine ClopidogrelClopidogrel Clinical need to improve on benefits observed with Clinical need to improve on benefits observed with clopidogrelclopidogrel PrasugrelPrasugrel

Novel thienopyridineNovel thienopyridine

Efficient generation of active metaboliteEfficient generation of active metabolite

High levels of IPA achieved rapidlyHigh levels of IPA achieved rapidly

High IPA in High IPA in clopidogrelclopidogrel “hyporesponders”“hyporesponders”

Encouraging Phase 2 dataEncouraging Phase 2 data

1.To test the hypothesis that higher and less variable IPA prevents clinical ischemic events.

2.To evaluate the safety of a regimen that produces higher IPA.

These goals were achieved by evaluating the efficacy and safety of prasugrel compared to clopidogrel in mod/high risk patients with ACS undergoing PCI on a background of ASA.

Trial Leadership: TIMI Study GroupTrial Leadership: TIMI Study GroupEugene Braunwald,Chairman, Elliott M. Antman,PI, Eugene Braunwald,Chairman, Elliott M. Antman,PI, Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe, Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe, Sabina A. Murphy, Susan McHale Sabina A. Murphy, Susan McHale

Sponsors: Daiichi Sankyo and Eli Lilly Sponsors: Daiichi Sankyo and Eli Lilly J. Anthony Ware, Jeffrey Riesmeyer, William Macias, J. Anthony Ware, Jeffrey Riesmeyer, William Macias, James Croaning, Govinda Weerakkody, Francis Plat, James Croaning, Govinda Weerakkody, Francis Plat, Tomas Bocanegra Tomas Bocanegra

Data Center and Site Management: Quintiles IncData Center and Site Management: Quintiles Inc

Data Safety Monitoring BoardData Safety Monitoring Board David Williams (Chair) , Christophe Bode, Spencer King, David Williams (Chair) , Christophe Bode, Spencer King, Ulrich Sigwart, David DeMets Ulrich Sigwart, David DeMets

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

•Inclusion Criteria Planned PCI for :

Mod-High Risk UA/NSTEMI (TRS > 3)STEMI: < 14 days (ischemia or Rx

strategy)STEMI: Primary PCI

•Major Exclusion Criteria:– Severe comorbidity– Increased bleeding risk– Prior hemorrhagic stroke or any stroke < 3

mos– Any thienopyridine within 5 days– No exclusion for advanced age or renal

function

KnownAnatomy

30 Countries30 Countries 707 Sites707 Sites LTFU = 14 (0.1%) LTFU = 14 (0.1%)

Argentina (195)Argentina (195) Finland (116)Finland (116) New Zealand (49)New Zealand (49)

Australia (217)Australia (217) France (146)France (146) Poland (1938)Poland (1938)

Austria (182)Austria (182) Germany (999)Germany (999) Portugal (67)Portugal (67)

Belgium (287)Belgium (287) Hungary (695)Hungary (695) Slovakia (140)Slovakia (140)

Brazil (225)Brazil (225) Iceland (10)Iceland (10) South Africa (404)South Africa (404)

Canada (251)Canada (251) Israel (1219)Israel (1219) Spain (178)Spain (178)

Chile (114)Chile (114) Italy 782)Italy 782) Sweden (154)Sweden (154)

Czech Rep (340)Czech Rep (340) Latvia (21)Latvia (21) Switzerland (136)Switzerland (136)

Denmark (33)Denmark (33) Lithuania (54) Lithuania (54) United Kingdom (73)United Kingdom (73)

Estonia 134)Estonia 134) Netherlands (390)Netherlands (390) United States (4059)United States (4059)

Clopidogrel (N=6795)

%

Prasugrel (N=6813)

%

UA/NSTEMI 74 74

STEMI 26 26

Age, median (IQR)

> 75 y

61 (53,69) y

13

61 (53, 70) y

13

Wgt, median (IQR) < 60 kg

83 kg (72, 92)5.3

84 kg (73, 93)4.6

Female 27 25*

Diabetes 23 23

Prior MI 18 18

CrCl (ml/min)>60<60

8812

8911

*P<0.05

Clopidogrel (N=6795)

%

Prasugrel (N=6813)

%

PCI / CABG 99 / 1 99 / 1

Any Stent 95 94

BMS 47 48

DES 47 47

Multivessel PCI 14 14

UFH / LMWH / Bival 65 / 8 / 3 66 / 9 / 3

GP IIb/IIIa 55 54

LD of Study Rx Pre PCI

During PCI Post PCI

25741

26731

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

Pri

mary

En

dp

oin

t (%

)

12.1(781)9.9 (643)

Primary EndpointPrimary EndpointCV Death,MI,StrokeCV Death,MI,Stroke

NNT= 46

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

This was primarily driven by a reduction in the rate of non-fatal MI 7.3 vs 9.5%; p<0.0001 at 6- 15 months

There was no significant difference between the incidence of rates of CV death or nonfatal stroke

Prasugrel compared to clopidogrel reduces the incidence of recurrent MI

Also reduces the severity of recurrent MI

• Overall MI RRR – 24%• MI followed by death RRR - 42%

The rapid onset time of prasugrel upto 30 mins means that the physician can afford to take the time to determine coronary anatomy ( rule out urgent CABG), yet still have time to achieve high levels of IPA for ?proceed PCI

• LD and day 3 RRR 19 %• MD and day 450 RRR 31%

0

2

4

6

8

0 1 2 3

1

0

3060 90 180 270 360 450

HR 0.82P=0.01

HR 0.80P=0.003

5.6

4.7

6.9

5.6

Days

Pri

mary

En

dp

oin

t (%

)

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel

Loading Dose Maintenance Dose

Timing of BenefitTiming of Benefit(Landmark Analysis)(Landmark Analysis)

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

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

Balance of Balance of Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

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

% E

ven

ts%

Even

ts

ARD 0.6%ARD 0.6%HR 1.32HR 1.32P=0.03P=0.03NNH=167 NNH=167

ClopidogrelClopidogrel PrasugrelPrasugrel

ARD 0.5%ARD 0.5%HR 1.52HR 1.52P=0.01P=0.01

ARD 0.2%ARD 0.2%P=0.23P=0.23

ARD 0%ARD 0%P=0.74P=0.74

ARD 0.3%ARD 0.3%P=0.002P=0.002

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

Clop 0 (0) %Clop 0 (0) % Pras 6 (2.3)%Pras 6 (2.3)% (P=0.02) (P=0.02)

0

5

10

15

0 30 60 90 180 270 360 450Days

En

dp

oin

t (%

)

HR 0.87P=0.004

13.9

12.2

Prasugrel

ClopidogrelITT= 13,608ITT= 13,608

-23

6

-25

-20

-15

-10

-5

0

5

10

Events per 1000 ptsEvents per 1000 pts

MIMI Major BleedMajor Bleed(non CABG)(non CABG)

++All CauseAll CauseMortalityMortality

Clop 3.2%Clop 3.2%Pras 3.0 %Pras 3.0 %P=0.64P=0.64

B

OVERALL

No GPIGPI

DESBMS

DMNo DM

>7565-74<65

FemaleMale

STEMIUA/NSTEMI

0.5 1 2Prasugrel Better Clopidogrel BetterHR

Age

Reduction in risk (%) 18

2112

25146

1430

2018

2116

19

21

Pinter = NS

CV Death, MI, CV Death, MI, StrokeStrokeMajor SubgroupsMajor Subgroups

CrCl > 60CrCl < 60 14

20

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

Significant Net Clinical Benefit with Prasugrel80%

MD MD 10 mg10 mg

Reduced MD

Guided by PK

Age > 75 or

Wt < 60 kg

16%

Avoid

Pra

sugre

l

Prio

r

CV

A/T

IA 4%4%

Safety

Significant increase in serious bleeding(32% increase)

Avoid in pts with prior CVA/TIA

Efficacy

1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%

MI 24%

2. An early and sustained benefit

3. Across ACS spectrum

Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD

Net clinical benefit significantly favored PrasugrelNet clinical benefit significantly favored Prasugrel

Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balancebenefit : risk balance

Prasugrel compared with clopidogrel significantly reduced the incidence of ischemic events , both in the acute and long term

The increased efficacy of prasugrel was associated with an increased risk of bleeding.

The balance of efficacy and safety revealed an early and sustained net clinical benefit over the entire spectrum of ACS investigated

Avoid in pts with prior stroke / TIA

Very old and low body weight may require reduced dose

Patients with DM and AMI derived the greatest net clincal benefit from prasugrel as compared to clopidogrel

STEMI 3534 pts Primary PCI 2438(69%) Secondary PCI 1094(31%)

Baseline characteristics well matched More frequent use of Gp 11b111a

inhibitorswith clopidogrel due to bail out

Benefit of prasugrel across the overall spectrum of ACSs but particularly pronounced in STEMI pts.

Primary end point significant reduction

• 6.5 vs 9.5%; p=0.002

Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.

Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction

Loading dose Maintenance dose

MI (%)

6

4

2

00 1 2 3 60 180 270 360 450

Prasugrel

HR 0.69(0.58-0.83)P < 0.0001

HR 0.81(0. 70-0.95)P = 0.008

Prasugrel

Clopidogrel

Clopidogrel

5.24

4.27

4.79

3.40

Time (days)

Secondary end point of CV death, MI and UTVR at 30 days was reduced

6.7%vs 8.8% p=0.02

Benefit persisted through 15 months

Multivariate analyses were performed to identify predictors of CV death, MI and UTVR

Common indicators of high risk remained the same :• Gp11b111a use , BMS, multivessel PCI, prior

MI >75yrs age. Only factor that reduced HR was

treatment with prasugrel

Efficacy profile Reduced rate of :

• single end points of all cause death , MI and stent thromboses

• Dual end points of CV death and MI• Non significant trend towards a reduced

rate of UTVR Efficacy profile was maintained

throughout 15 months

Safety profile :

• After 15 months rate of TIMI major non- CABG bleed in prasugrel and clopidogrel was similar

• 30 day incidence was higher with clopidogrel due to increased Gp2b3a use.

Net clinical benefit analysis CV death , MI, non fatal stroke, or

TIMI major non CABG bleed after 15 months of treatment with prasugrel vs

clopidogrel significant benefit

12.2 vs 14.6% p=0.02

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 = 21

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

The primary end point was again driven by a reduction in the rate of MI in pts treated with Prasugrel

• 8.2 vs 13.2% p<0.001

A total of 21 pts with DM would need to be treated with prasugrel to avoid one case of the primary end point if the pt was treated with clopidogrel

In the overall study population the efficacy of prasugrel is at the expense of an increased risk of bleeding.

In this analysis in the DM subset prasugrel did not significantly increase the risk of non CABG bleed

Multiple sub group analysis showed that the reductions in the rate of stent thrombosis were in favour of prasugrel as compared with clopidogrel in every instance

Randomized 13,608

Stent Placed 12,844 (94%)

STENT ANALYSIS

BMS Only 6461 (47%)

DES Only 5743 (42%)

Both BMS/DES 640 (5%)

PES Only 2766 (20%)

SES Only 2454 (18%)

Other/Mixed523 (4%)

Any Stent (N=12844)

94 %

UA/NSTEMI 75

STEMI 25

Age, median (IQR)

> 75 y

60 (53,69) y

13

Female 26

Diabetes 23

Smoker 38

North America 32

Prior MI 17

CrCl (ml/min)>60<60

8911

STENT ANALYSIS

Blinded CEC review of using source documents incl imaging reports:

Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of the stent AND a clinical syndrome <48 h.

Probable: unexplained death < 30 days or MI in stented territory w/o angiographic confirmation ST AND w/o alternative cause

Possible: unexplained death > 30 days following stenting

Early: 0 – 30 days after randomizationLate > 30 days after randomization (landmark analysis)

Based on ARC Definitions Mauri L et al NEJM 2007

25.9

2.6

0

5

10

15

20

25

30

Stent Thrombosis No Stent Thrombosis

Clopidogrel

Mortality During Follow up (%) Post-Stent Thrombosis

STENT ANALYSIS

N=210 N=12634

HR 13.1 (9.8 – 17.5) P<0.0001

% o

f Subje

cts

25.9

2.6

Stent thrombosisNo SAT

CLOPIDOGREL

0

0.5

1

1.5

2

2.5

0 50 100 150 200 250 300 350 400 450

% o

f Subje

cts

HR 0.48 [0.36-0.64] P<0.0001

1 year: 1.06 vs 2.15%HR 0.48 [0.36-0.65],

P<0.0001

2.35%

1.13%

52%

DAYS

CLOPIDOGREL

PRASUGREL

0

0.5

1

1.5

2

2.5

0 5 10 15 20 25 300

0.5

1

1.5

2

2.5

30 90 150 210 270 330 390 450

% o

f Subje

cts

HR 0.41 [0.29-0.59]P<0.0001

HR 0.60 [0.37-0.97]P=0.03

DAYS

EARLY ST LATE ST

STENT ANALYSIS

1.56%

0.64%

59% 0.82%

0.49%

40%

CLOPIDOGREL

PRASUGREL

STENT ANALYSIS

DEF/PROBHR 0.48 (0.36-

0.64) P<0.0001

DEFINITEHR 0.42 (0.31-

0.59) P<0.0001

DEF/PROB/POSSHR 0.56 (0.43-

0.73) P<0.0001

CLOPIDOGREL

PRASUGREL

% o

f Subje

cts

BB

BB

BB

B

B

B

B

BB

B

B

BB

B

B

MenWomen

Age < 75Age >=75

No DMDM

GPINo GPI

Prior MINo Prior MI

CrCl< 60CrCl >=60

Bifurcation StentNo Bifurcation Stent

Stent <= 20 mmStent > 20 mm

UA/NSTEMISTEMI

0.1 1 2PRASUGREL

BETTERCLOPIDOGREL

BETTER

PRAS

CLOP

RISK (%)

1.6 2.8 42%1.0 2.2 57%

1.4 2.9 53%0.9 1.9 52%

1.1 2.2 50% 1.4 4.6 69%

1.1 2.1 51%1.1 3.9 70%

1.2 2.1 45%0.8 3.4 75%0.9 2.0 54%1.3 2.6 51%2.0 3.6 48% 0.9 2.0 55% 1.8 3.4 44%1.0 2.2 54%0.9 2.3 61% 1.2 2.4 50%

0

0.5

1

1.5

2

2.5

0 50 100 150 200 250 300 350 400 450

% o

f Subje

cts

HR 0.36 [0.22-0.58]P<0.0001

1 year: 0.74% vs 2.05% HR 0.35 [0.21-0.58],

P<0.0001

2.31%

0.84%

64%

STENT ANALYSIS

DAYS

CLOPIDOGREL

PRASUGREL

% o

f Subje

cts

HR 0.29 [0.15-0.56]P=0.0001

HR 0.46 [0.22-0.97]P=0.04

DAYS

0

0.5

1

1.5

2

2.5

0 5 10 15 20 25 300

0.5

1

1.5

2

2.5

30 90 150 210 270 330 390 450

STENT ANALYSIS

EARLY ST LATE ST

1.44%

0.42%

71%

0.91%

0.42%

54%

CLOPIDOGREL

PRASUGREL

2.41%

1.27%

0

0.5

1

1.5

2

2.5

0 50 100 150 200 250 300 350 400 450

% o

f Subje

cts

HR 0.52 [0.35-0.77] P=0.0009

1 year: 1.22 vs 2.27%HR 0.53 [0.36-0.79],

P=0.0014

48%

STENT ANALYSIS

DAYS

CLOPIDOGREL

PRASUGREL

% o

f Subje

cts

HR 0.45 [0.28-0.73] P=0.0009

HR 0.68 [0.35-1.31]P=0.24

DAYS

0

0.5

1

1.5

2

2.5

30 90 150 210 270 330 390 4500

0.5

1

1.5

2

2.5

0 5 10 15 20 25 30

STENT ANALYSIS

EARLY ST LATE ST

1.66%

0.75%

55%

0.78%

0.53%

32%

CLOPIDOGREL

PRASUGREL

Intensive antiplatelet therapy with PRASUGREL in stented patients compared to CLOPIDOGREL:

•Substantial reduction in ST:

•Regardless of stent type or ST definition

•Early and Late

•A broad range of clinical/procedural

characteristics

•Fewer ischemic events, more major bleeding

STENT ANALYSIS

STENT ANALYSIS

Stent Thrombosis

CVD/MI/CVA w/o ST

Even

ts p

er

100

0 p

ati

ents

tre

ate

d

+5

-15

-12

TIMI MajorNon CABG bleed

•Stent Thrombosis is a rare, but devastating complication of PCI associated with a high mortality. Efforts to reduce ST have focused on compliance w/ and duration of ASA/clopidogrel

•Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a broad array of clinical procedural characteristics

STENT ANALYSIS

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In addition to reducing ST prasugrel also reduced the primary end point , in the stented population, the BMS pop, and the DES pop.

STENT ANALYSIS

Net Clinical BenefitSTENT ANALYSIS

HR 0.88(0.77-1.01)

p=0.07

HR 0.86 (0.77-0.95)

p=0.002

HR 0.84(0.72-0.98)

p=0.025

N=12844 N=6461 N=5743

% o

f Subje

cts

Any BMS DES

13.712

13.612.3

13.4

11.4

HR 0.84P=0.025

CVD/MI/CVA MAJOR BLEEDING

STENT ANALYSIS

HR 0.80(0.69-0.93)

p=0.003

HR 0.81 (0.72-0.90)

p=0.0001

HR 0.82 (0.69-0.97)

p=0.02

HR 1.37 (0.95-1.99)

p=0.09

HR 1.27 (0.99-1.63)

p=0.06

HR 1.19 (0.83-1.72)

p=0.34

N=12844 N=6461 N=5743

CLOPIDOGREL

PRASUGREL

Prasugrel as compared to clopidogrel significantly reduced :• Incidence of combined end point of CV

death, MI and nonfatal stroke• NNT 46; p<0.0001

This benefit came at the cost of an increase in major non-CABG bleeds • NNH 167; p=0.03

Prasugrel is more effective than clopidogrel for the prevention of ischemic events including stent thrombosis, in ACS pts undergoing PCI esp high risk e.g STEMI, diabetic and stent pop.

The reduction is primarily MI prevention driven

Safety profile is comparable to that of clopidogrel in this high risk subset

0

1 08

Placebo APTC CURE TRITON-TIMI 38Single Antiplatelet Rx

Dual Antiplatelet Rx

Higher IPA

ASA ASA + Clopidogrel ASA +

Prasugrel

- 22%

- 20%

- 19%

+ 60% + 38% + 32%

Reduction inIschemicEvents

Increase in Major Bleeds

ACS can lead to CV death Post PCI – SAT , death, MI or UTVR Clopidogrel is not enough PRASUGREL

• Pharmacokinetics• Pharmacodynamics• Good clinical impact as it reduces MI Prasugrel better Bleeding risk ????

THANKYOU