Oral Antiplatelet Agents

George D. Dangas, MD, PhD, FSCAI, FACC Associate Professor of Medicine

Columbia University Medical Center The Cardiovascular Research Foundation

Inhibitors of Platelet Activation

Clopido=rel/ticlopidine/prasu=rel

ADP

Dipyridamole/Cilosta"ol ADP PD#

PGI!
Gs
GP IIb/IIIa Receptor
AC

Gi

P!9)!
ADP

ATP
<<

;;
Aspirin

cAMP

Ca<<

P!

Ca

C$

Ca<<
T A!

IP4

PIP! G:

TP/

Colla=en Thrombin T A!

%cha&er AI' Am ( Med' )**+,)-).)**/!-* 0 %chr1r 2' Vasc Med )**3,4.!5678)'

Aspirin
> The simplest drug available in cardiology

Old and oral, once a day

> One of the most efficacious > The cheapest available > Therefore:

The most cost-effective

Dose-dependence and Aspirin Efficacy

Aspirin Dose C Trials $RD EFG $dds Ratio

8--/)8-- m= )+-/4!8 m= 68/)8- m= @68 m= Any aspirin

45 )* )! 4 +8

)* !+ 4! )4 !4
-'8 )')'8 !'A%A Aetter A%A Borse

Antithrombotic Trialists? Collaboration' BMJ' !--!,4!5.6)73+'

andomi!ed Trials of Aspirin in PT"A

F MaLor Ischemic Complications )! )!'+
Meparin )-I--- units A%A / Dipyridamole < Meparin Ticlopidine < Meparin

3 +'* 5 66F P=0.0113 )'+ %chHart" et al JK46+ Bhite et al JK446

BhiteI Coronary Artery Disease )**),!.686

68F P<0.001 4'! !'5

%chHart"I N Engl J Med )*33,4)3.)6)5

"AP IE Efficacy of "lopidogrel vs# Aspirin in $I, Ischemic %tro&e, or 'ascular Death (n)*+,*,-.
#vent Rate per 9ear
)+
3'6FD $verall Relative RisN Reduction

Cumu lative #vent Rate EFG

)! 3 5 -

Aspirin 8'34F 8'4!F Clopido=rel PK'-58

4 + * )! )8 )3 !) !5 !6 4- 44 4+

Months o& FolloH Up

D ITT analysis CAPRI# %teerin= Committee' Lancet' )**+,453.)4!*7)44*'

"ombination Antiplatelet Therapy educes "oronary Events after %tenting

Mall E)**+G) JK!!+ I%AR E)**6G! JK8)6 %TAR% E)**3G4 JK)+84 MATTI% E)**3G5 JK48-'8 4'+ !'6 8'+ -'3 4'* )'+

P=0.1 P=0.01
+'!

A%A < Ticlopidine A%A only A%A < Bar&arin

P<0.001 P=0.0!
))'-

FAJTA%TIC E)**3G8

J K538 ) !

8'6

P=0.3!
3'4

4'-

8'-

3'-

)!

Cumulative #vent Rate EFG

Mall PI et al' Circ lation' )**+,*4.!)87!!!' %ch1mi= AI et al' N Engl J Med' )**+,448.)-357)-3*' 4 Oeon MI et al' N Engl J Med' )**3.44*.)++876)' 5 Urban PI et al' Circ lation' )**3 *3.!)!+7!)4!' 8 Aertrand MI et al' Circ lation. )**3,*3.)8*67)+-4' E#vents include deathI P7Have or non7P7Have MIG'

#PI%T#JT. Impact o& IQ < po Platelet RR

IQ placebo/abciRimab 0 po ticlopidine preRR/no7preRR
*-

44F P=0.033

)4'5
F MAC# EDeathI MII Ur=ent RevascG
*/

43F P=0.0"#

3'*
-

8'8
Placebo/ Jo PreRR JK454 Placebo/ PreRR JK5++ AbciRimab/ Jo PreRR JK4!3

8'!
AbciRimab/ PreRR JK5++

%teinhubl %RI Circ lation )**3,*3.I7864

Effect of Oral "lopidogrel on AA-induced Platelet %urface P-selectin

In A%A-treated patients, there is a residual AA0induced platelet activation: > (*. is caused by underdosing and1or noncompliance in 23 of patients > (2. in most patients, occurs via a "O4-* and "O4-2 independent path5ay, in direct proportion to the degree of baseline platelet activation is mediated in part by ADP0induced platelet activation
Frelin=er AO et al' Circulation !--+,))4.!333

" EDO: Per-Protocol and Intent-to-Treat Populations Pts 6ndergoing P"I-stent

Clopido=rel pretreatment Eloadin= dose 4-- m=G < clopido=rel lon=7term E) yearG nK!I))+ Jo pretreatment < clopido=rel short7term E!3 daysG

ITT nK)I-84

ITT nK)I-+4

PP nK*--

PP nK*)8

ITT K Intent7to7treat, PP K Per Protocol

%teinhubl %R et al' AMA !--!' JAMA !--!

CR#D$

7enefits of "lopidogrel in P"I Patients at 'arious Time Intervals

MII %troNeI or Death / ITT Population
)!

Combined #nd Point $ccurrence EFG

!+'*F RRRS P=0.0"

))'8S

PlaceboD Clopido=relD

3'8S

)*'6F RRRS P=0."1

+'*T 8'8T

46'5F RRRS P=0.0$

5'+T !'*T

Rand' to ) 9ear Rand' to Day !3 Day !* to ) year

D Plus A%A and other standard therapies. S %teinhubl %I Aer=er PI Ti&t Mann III ( et al' JAMA' !--!,Qol !33IJo )*.!5))7!5!-' T %teinhubl %' AMA %cienti&ic %essionsI Chica=o !--!'

Timing of 8oading Dose and 2,-Day Endpoint

#vents EFG
Time o& Ooad @+h +7)! h U )! h + to !5 hours Jo Pretreat Pretreat 6'* 6') 8'4 8'3 6'))'3'3 *'5 J **4 !4+!) 38)
-'5 -'+ -'3 )'-

Clopido=rel Pretreatment Aetter

Jo Pretreatment Aetter

RRR 43'+ P=0.0%1

)'!

Ma"ard ratio E*8F CIG

Peri-P"I platelet inhibition after clopidogrel loading: impact on $A"E

> JK3-! pts Hith PCI > Pre7treated Hith +--m= clopido=rel and aspirin > Platelet a==re=ation Has measured a&ter addition o&
ADP at a &inal concentration o& 8 mol/l by 57channel Aio/Data PAP5 a==re=ometer'

> Four =roups by :uartiles o& ADP7induced platelet

a==re=ation

Mochhol"er B et al' ( Am Coll Cardiol !--+,53.!)63

5ith 9uartiles of ADP-induced Platelet Aggregation

"umulative Incidence of $A"E

MAC#KdeathI MI and TOR

Mochhol"er B et al' ( Am Coll Cardiol !--+,53.!)63

%tratification: 8oading Time of "lopidogrel pre-P"I

3 Aggregation above $edian (:*;3.

,/ 3 Patients 5ith ADP-Induced Aggregation :*;3

P@-'--)
</

PK-'5)3 PK-'558

;/

2/

JK

!5!

!84

)45

)64

=2h

2-;h

;-<h

: <h

Mochhol"er B et al' ( Am Coll Cardiol !--+,53.!)63

"6 E %tudy Design

Clopido=rel 4-- m= loadin= dose

Patients Hith Acute Coronary %yndrome Eunstable an=ina or non/P7Have MIDG JK)!I8+!

Clopido=rel 68 m= :d < A%A 68 to 4!8 m= :dS E+I!8* patientsG

4 months double7blind treatment )! months

Placebo < A%A 68 to 4!8 m= :dS E+I4-4 patientsG

Da y)

Placebo loadin= dose

RKRandomi"ation' D Also NnoHn as non/%T7se=ment elevation MI EJ%T#MIG' S $ther standard therapies Here used as appropriate' The CUR# Trial Investi=ators' N Engl J Med. !--),458.5*578-!'

or )!7 Fin Mo al nth Qi sit

7enefit of "lopidogrel Therapy at CUR# 'arious Time Intervals

MII stroNeI CQ Death. -/4- days
)'--

MII stroNeI CQ Death. 4) d 7 ) y

)'--'*3

Proportion #vent7Free

-'*3

Clopido=rel < A%A

Proportion #vent7Free

Clopido=rel < A%A

-'*+

-'*5

-'*!

RRR !)F *8F CI -'+6/ -'*! P=0.003

) ! BeeNs 4 5

-'*! -'*-

-'*5

Placebo < A%A

-'*+

Placebo < A%A

RRR )3F *8F CI -'6-/ -'*8 P=0.00&

) 5 + 3 )Months )!

9usu& % et al &or the CUR# Trial Investi=ators' Circ lation' !--4,)-6.*++7*6!'

-'*-

PCI7CUR#

Overall 8ong-Term esults

Composite o& MI or Cardiovascular Death From Randomi"ation to #nd o& FolloH7Up

-')8

Cumulative Ma"ard Rate

Placebo < A%AD

)!'+F

-')Clopido=rel < A%AD -'-8

3'3F

$verall Relative RisN Reduction

4)F

-')--

P=0.00" JK!I+83

Days o& FolloH7Up

!--

4--

5--

D In addition to other standard therapies' Mehta %RI et alI &or the CUR# Investi=ators' Lancet. !--),483.8!67844'

CUR#
#vent

7leeding esults
Clopido=rel < A%AD nK+I!8* 4'6F !'!F Placebo < A%AD nK+I4-4 !'6F )'3F P value

MaLor bleedin=S Oi&e7threatenin= bleedin= $ther maLor bleedin= Minor bleedin=

-'--) -')4

)'+F 8')F

)'-F !'5F

-'--8 @-'--)

CUR#

$a>or 7leeding by A%A Dose

A%A Dose @)-- m= )--/!-- m= U!-- m=

Clopido=rel < A%AD !'+F 4'8F 5'*F

Placebo < A%AD !'-F !'4F 5'-F

Pharmacodynamics of "lopidogrel: 8oading Dose of ?// mg vs# @- mg 9D

F inhibition o& 8 VM ADP7 induced a==re=ation
)--F 68 m= PD &or 3 days JK)-D 4-- m= loadI &olloHed by 68 m= PD &or 3 days JK)-D 3-F

+-F

Aase7line

! hours

+ hours

Day !

Day 3

DAll patients Hith stable arterial disease Mel&t G' Arterioscler '(ro)* Vasc Biol !---,!-.!4)+7!)

"lopidogrel 8D: Is Aigher Dosage 7etterB

F o& !- VM ADP7induced a==re=ation )-Ticlopidine !R 8--m=I then !8- AID Clopido=rel 4-- m=I then 68 m= PD Clopido=rel +-- m=I then 68 m= AID

+-

!5

Time a&ter Administration EhoursG

!5

53

Muller I' +eart !--),38.*!74

?// vs# <// vs# +// mg "lopidogrel 8oading $aCimal ADP-induced Platelet Aggregation
ADP E8 Wmol/OG7induced A==re=ation EFG ADP E!- Wmol/OG7induced A==re=ation EFG

+-- better than 4--I but *-- similar to +--m= loadin=

Qon AecNerath J et al' Circulation !--8,))!.!*5+

<//mg 8oading Dose in Patients on "hronic "lopidogrel Therapy

First Use EJK!-G
)!-

Chronic Use EJK!-G

3MaRimal A==re=ation to 8M ADP 5P<0.001 P<0.001

Ae&ore

A&ter

Ae&ore

A&ter

2astrati A' Circ lation !--5,))-

ARMYDA-Reload Clinical !utco"es Evaluation of 600mg clopidogrel dose in pts who are already on chronic clopidogel therapy
30-day MACE IN Stable and ACS pts undegoing PCI
Deat)*MI*Repeat +e,ascula+i-ation ./0 &0 %' P10203( .ACS Placebo ,s ACS Reload0 %& $ # 0 ( %0 %( Days &0 &( 30 ACS Placebo ACS - Reload Stable Angina - Placebo Stable Angina - Reload

Di Sciascio et al, SCAI-ACCi2 2008

QA%P POAT#O#T M$JIT$RIJG

Mean ,-D QA%P a&ter &irst ODI F QA%P a&ter adLustmentI F Control +3 X)) QA%P7=uided +* X)43 X)5D p -'5 D@-'--)

7#ach additionnal bolus o& +-- m= o& clopido=rel decreased the number o& patients Hith loH response &rom 48 to 5*F' 7Despite !5-- m= o& clopido=rel )) E)5FG patients remained loH7 responders' Aonello et alI %CAI7ACCi! !--3

QA%P platelet monirin= study PRIMAR97#JD P$IJT . #FFICAC9

YMAC#, n EFG Cardiovascular death Acute and %ub7acute stent thrombosis Revasculari"ation $verall MAC# Control EnK35G ! E!G 5 E8GS ! E!G 3 E)-GD
S p K-'-8* D p K-'--6

QA%P7=uided EnK63G MAC#. CQ deathI MII revasculari"ation Oo= ranN p K-'--6

No significant difference in bleeding

Bonello et al, SCAI-ACCi2 2008

CLopidogrel as Adjunctive eperfusIon !herap" # $!IMI% &' Double7blindI randomi"edI placebo7controlled trial in 45*) patientsI a=e )3768 yrs Hith %T#MI @ )! hours FibrinolyticI A%AI Meparin
randomi"e

"8A ITD %tudy Design

%tudy Dru=

Clopido=rel 4-- m= < 68 m= :d

Placebo

Coronary An=io=ram
E!73 daysG
$pen7label clopido=rel per MD in both =roups Primary endpoint.
$ccluded artery ETIMI FloH Grade -/)G or D/MI by time o& an=io

4-7day clinical &olloH7up

Occluded Artery (or D1$I thru Angio1AD.

2-

Primary Endpoint:
2*#@

Occluded Artery or Death1$I (3.

4+F
2/

$dds Ratio -'+5

E*8F CI -'847-'6+G P=0.0000003.

$dds Reduction

*-#/
*-

*/

nK)68!

nK)64*
-'5 -'+ -'3 )'- )'! )'+

Clopido=rel better
"lopidogrel Placebo

Placebo better

"' Death, $I,

)8 Percenta=e Hith endpoint EFG 8 )-

I 6rg evasc
!-F Clopido=rel

Placebo

$dds Ratio -'3E*8F CI -'+87-'*6G P=0.0".

)-

)8 Days !-

!8

4-

7leeding
$utcome
Throu=h an=io=raphy

Clopido=rel Placebo
EFG EFG

P value

> TIMI maLor EM=b U8 =/dO or ICMG > TIMI minor EM=b 478 =/dOG > Intracranial hemorrha=e
Throu=h 4- days

)'4 )'-'8 )'* 6'8 *') )'+

)') -'8 -'6 )'6 6'! 6'* -'*

J% J% J% J% J% J% J%

> TIMI maLor

In those under=oin= CAAG CAAG H/in 8 d o& study med

> TIMI minor

$(oint )tili*ation of Medications to +loc, Platelets -pti.all/%

#lective or Ur=ent PCI Hith intent to stent
A%A 4!8 m= Parallel Randomi"ation Ma/or e0cl sions1 Prim PCI &or %T#MII O Main U 8-FI Tar=et in %QG or Art ConduitI #F @ 4-F or J9MA CMF II Aleedin= RisNsI $ral A/CI thienopyridine @ 8 dI RR Hith PPI

E6$7O-TI$I 2< %tudy Design

*-- patients
%tudy Dru= in Oab Prior to PCI, %trati&y Aased on IQ GP IIb/IIIa Use Double7blind Prasu=rel Lo2 dose E5-/6'8G Prasu=rel 3nter). dose E+-/)-G Prasu=rel +ig( dose E+-/)8G Clopido=rel Ooad 4-- m= Maint' 68 m=

Maintenance RR &or 4- days

)o endpoint. %i=ni&icant Aleedin= Enon CAAGG bleedin= throu=h 4- days !o endpoints. MaLor bleedin= Enon CAAGG throu=h 4- days CQ MAC# throu=h 4- days %i=ni&icant bleedin= < CQ MAC# throu=h 4- days

?/-Day *F Endpoint (Gon-"A7H (UMA$7TIMI !+ 7leed. and $A"E

Jon7CAAG Aleed
)-F *'5 6'! +F 6'8 6'8

MAC#

P=N- 4or all

+'3

!F

)'!

)'6

)'8

)'+

Clop
#%C !--5

Prasu=rel

O$B

M#DIUM
Prasu=rel Dosa=e

MIGM

T ITOG-TI$I ?,
> Prasugrel vs# clopidogrel (double-blind. > A"% (%TE$I or 6A1G%TE$I. I
planned P"I

> n)*?,/// > $edian duration of therapy *2 months > Primary Endpoint: "' death, $I, stro&e

PRIJCIPO#7TIMI 55. Comparison o& Prasu=rel Hith Mi=her Dose Clopido=rel

IPA EF, !- M ADPG
JK!-) P@-'---) &or each
Prasu=rel +- m=

IPA EF, !- M ADPG

P@-'---)

Clopido=rel +-- m=

Clopido=rel )8- m=

Prasu=rel )- m=

Mours
Biviott et al Circ !--6

)5 Days

TRIT$J7TIMI 43 Main Trial Primary Results

15

Clopido=rel CQ Death / MI / %troNe #ndpoint EFG

10 )!') *'*

MR -'3) E-'647-'*-G PK-'---5

Prasu=rel

TIMI MaLor JonCAAG Aleeds

!'5 MR )'4! )'3 E)'-47)'+3G Clopido=rel PK-'-4 270 360 450

Prasu=rel

0 30 60 90

180

Days

Biviott %DI AraunHald #I McCabe CM et al J#(M!--6

TRIT$J7TIMI 43
8

Timin= o& Aene&it EOandmarN AnalysisG

Clopido=rel +'* 8'+

Primary #ndpoint EFG

Clopido=rel
6

8'+ 5'6 Prasu=rel Prasu=rel

MR -'3! PK-'-)
1

MR -'3PK-'--4

30 60 90

180

270

360

450

Loading Dose

Days

Maintenance Dose

TI$I-?, %TEGT AGA8D%I% Definite1Probable %T: DE% Only (G)-@;?.

#ARO9 %T
MR -'!* Z-')87-'8+[ PK-'---)
2 .5 2 .5

OAT# %T
MR -'5+ Z-'!!7-'*6[ PK-'-5

F o& %ubLects

CO$PID$GR#O PRA%UGR#O

)'55F
1 .5 1 .5

6)F -'5!F

-'*)F

85F
0 .5 0 .5

-'5!F
0 30 90 150 210 270 330 390 450

0 0 5 10 15 20 25 30

DA9%
Wiviott et al, SCAI-ACCi2 2008

TI$I-?, %TEGT AGA8D%I% Definite1Probable %T 7$% Only (G)<;<*.

#ARO9 %T
MR -'58 Z-'!37-'64[ PK-'---*
2 .5 2 .5

OAT# %T
MR -'+3 Z-'487)'4)[ PK-'!5

F o& %ubLects

)'++F 88F

CO$PID$GR#O PRA%UGR#O

1 .5

1 .5

-'63F

4!F
0 .5

-'68F
0 5 10 15 20 25 30

0 .5

-'84F
0 0 30 90 150 210 270 330 390 450

DA9%
Wiviott et al, SCAI-ACCi2 2008

7leeding Events Safet/ Cohort

(G)*?,;-@.
;
Clopido=rel Prasu=rel F #vents
ICM in Pts H Prior %troNe/TIA EJK8)3G Clop - E-G F Pras + E!'4GF EPK-'-!G

2#; 2 *#, *#; /#+ /#+ *#* /#* /

TI$I $a>or 7leeds
ARD -'+F MR )'4! PK-'-4 JJMK)+6

/#;

/#?
I"A

/#?

8ife Threatening
ARD -'8F MR )'8! PK-'-)

Gonfatal
ARD -'!F PK-'!4

Jatal
ARD -'4F PK-'--!

ARD -F PK-'65

Diabetic %ubgroup
18 16

JK4)5+
)6'-

Clopido=rel CQ Death / MI / %troNe

#ndpoint EFG

14 12 10 8 6 4 2 0 0

)!'!

Prasu=rel

MR -'6P@-'--) JJT K 5+

TIMI MaLor JonCAAG Aleeds

Clopido=rel Prasu=rel

!'+ !'8 450

30 60 90

180

Days

270

360

Allergy Issues
> A%A and clopidogrel allergy is very
important in DE% implantation decisions > A%A desensiti!ation is possible

GOT for anaphylaCis

> "lopidogrel desensiti!ation reported > ""6 setting for desensiti!ation attempts > Ticlopidine, cilosta!ol, prasugrel other
alternative options

Clopido=rel Desensiti"ation A&ter Dru=7#lutin= %tent Placement

Reactions Durin= Desensiti"ation
*// ,/ </ ;/ 2/ / Pruritus alone *? / ash alone ; Pruritic rash Gone

F
,?

4/!5

-/!5

)/!5

!-/!5

Qon TiehlI 2F et al' ( Am Coll Cardiol'!--6,8-.!-4*754

Prevalence of A%A- esistance in "'D

Pros5ecti6e -t dy o4 3". 5ts 2it( CVD 7ecei6ing A-A Alone 83"% )g9d : !d;

> A%A resistance defined as mean aggregation

@/3 5ith */K$ ADP and mean aggregation 2/3 5ith /#- mg1ml arachadonic acid > -#23 pts: A%A resistantL 2?#,3 pts: A%A semi responders > A%A resistant and A%A semi responders are more li&ely to be 5omen (?;#;3 vs *@#?3, p)/#//*. and less li&ely to be smo&ers (/3 vs ,#?3, p)/#/2;. than A%A-sensitive patients
Gum PA et al A) J Cardio !--), 33.!4-

P8A2 and A"E MDN Polymorphisms

3ncreased 7is< o4 7ec rrent E6ent Post AM3
> "A E Trial, ;*+- pts 5ith $I randomi!ed to > > > >
pravastatin or placebo, f1u - years P8A2 and A"E genotypes determined in @<@ pts (?,5ith recurrent primary events vs ?,2 matched controls. Placebo, P8 genotype confired of *#?, ("I *#/; *#,?, p)/#/2,. for primary end point Pravastatin reduced eCcess of death and recurrent $I in the P8 population by ?*3 (p)/#/<. The P8 genotype 5as associated 5ith eCcess recurrent events post $I 5ho did not receive pravastatin, and A"E D allele added to this ris&

Aray PF et al' A) J Cardiol !--), 33.456

PlA2 Polymorphism and Aspirin

F A==re=ation
3P=0.0" P=0.01 5-

esistance

PlA)/A!

+-

PlA)/A)
!-

-') ) ))--

Aspirin Vmol/O
CooNeI Lancet *3, Qol 48)

In&luence o& $mepra"ole on the Antiplatelet Action o& Clopido=rel Associated Bith Aspirin Mean PRI on Days ) and 6
A&ter initial incubation Hith PG#) Hith or Hithout )- mol/l ADPI platelets Here &iRed' The second sta=e consists o& couplin= phosphorylated QA%P Hith a monoclonal &luorescein isothiocyanate/labeled antibody speci&ic to the phosphorylated &orm o& QA%P' Platelet mean &luorescence intensity EMFIG Has then determined usin= a &loH cytometer countin= )-I--- platelets' Platelet reactivity Has eRpressed as a PRI calculated as. PRI==EMFI ZPG#)[ / MFIZ PG#)ADP[G / MFIE PG#)GR)--' Patients are =ood responders to clopido=rel i& PRI is 8-F and poor responders i& PRI is 8-F'

GilardI M et al' ( Am Coll Cardiol'!--3,8).!8+7+-

P"I study on dual antiplatelet resistance in P"I (n)*-/.

> ECclusion

A$I 5ithin * 5ee& "ontraindication to aspirin, clopidogrel, bivalirudin Aematologic disease Aeparin or HP IIb1IIIa use during P"I Aspirin ,* to ?2- mg for O * 5ee& Go thienopyridine or HP IIb1IIIa before * 5ee& 7ivalirudin use for P"I Immediately after P"I ?//mg clopidogrel and ?2-mg aspirin Daily @-mg clopidogrel and ?2-mg aspirin 7aseline and 2/ to 2; h after P"I
Oev #I et al' ( Am Coll Cardiol !--+,56.!6

> $edication before and during P"I

> $edications after P"I

> 7lood sample

Definitions of

esistance

> Aspirin resistance (more than 2.

/#-mg1ml AA-induced platelet aggregation O 2/3 - Pmol1l ADP-induced platelet aggregation O @/3 PJA(rapid platelet function assay.-A%A A 6(aspirin reaction unit. O --/

> "lopidogrel resistance

Absolute difference bet5een baseline and posttreatment aggregation Q */3 in response to both and 2/ Pmol1l ADP

> Aigh post-clopidogrel platelet aggregation

: @-th percentile aggregation in response to - and 2/ Pmol1l ADP

Oev #I et al' ( Am Coll Cardiol !--+,56.!6

Distribution o& Aspirin Response

-'8 m=/dl AA a==re=ation EFG
;/

?/ Patients, 3

2/

*/

-74

576

37))

)!7)8

)+7)*

!-7!4

\ !5

Oev #I et al' ( Am Coll Cardiol !--+,56.!6

Distribution o& Clopido=rel Response

Chan=e in 8 Wmol ADP a==re=ation EFG
;/

?/ Patients, 3

2/

*/

7)-7-

)7)-

))7!-

!)74-

4)75-

5)78-

\ 8)

Oev #I et al' ( Am Coll Cardiol !--+,56.!6

Incidence of "R-$7 Elevation Above Gormal

esistant
-/ ;/
?,#+

%ensitive
;;#;

PatientsI F

P=0.0$

?2#;

P=0.0% P=0.0.
*@#?

?/ 2/ */ /
*,#?

*-#,

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esponse

"lopid

esponse

Dual

esponse

Oev #I et al' ( Am Coll Cardiol !--+,56.!6

Impact o& Platelet Reactivity A&ter Clopido=rel Administration on Dru=7#lutin= %tent Thrombosis %iR7month clinical outcomes
Gonresponders (G)*/-. esponders (G)<++.

F
*/ , < ; 2 /

P@'--)
,#<

PK-'+)

P@'--)
,#<

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;#, *#+ 2#? *#? /#< Defenite or Probable %T 8ate %T

*#;

"ardiac death

Defenite %T

Patients Hith platelet a==re=ation by )-7mol ADP *-th percentile o& controls Here de&ined as nonresponders' AuonamiciI P et al' ( Am Coll Cardiol'!--6,5*.!4)!76

Antiplatelet Resistance
C-0CL)SI-0S
> A%A7R may simply mean pro7thrombosis in > > > >
the platelet lan=ua=e Incidence varies by de&inition Aspirin7resistant patients may have reduced response to clopido=rel' Clopido=rel resistance eRists and may also be dose7dependent Dual antiplatelet dru= resistance has been documented Ebut MAC# is not )--FG
Oev #I et al' ( Am Coll Cardiol !--+,56.!6

A]D+)5-. Inhibition o& Platelet a==re=ation Compared Bith Clopido=rel in J%T#MI AC% Patients EDI%P#R%#7 !G
Inhibition o& platelet a==re=ation a&ter initial doses

DP@-'-8

Mean F inhibition o& platelet a==re=ation derived &rom maRimum a==re=ation response a&ter addition o& ADP !- mol/l Eoptical a==re=ometryG' %toreyI RF et al' ( Am Coll Cardiol'!--6,8-.)38!7+

Initial #&&icacy o& A]D+)5- Compared Bith Clopido=rel in J%T#MI AC% Patients EDI%P#R%#7!G
Aleedin= events throu=h )! HeeNs
"lopidogrel @- mg (G)?2@. ASD<*;/ +/ mg (G)??;.
PK-'4! PK-'*+ PK-'+) PK-'88

ASD<*;/ *,/ mg (G)?2?.

PK-'-) PK-')3

**2 + < ? /

PK-'6! PK-'+!

+#+

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Total
D Oi&e threatenin=

$a>or

$a>or-8T

$inor

CannonI P et al' ( Am Coll Cardiol'!--6,8-.)35578)

Initial #&&icacy o& A]D+)5- Compared Bith Clopido=rel in J%T#MI AC% Patients EDI%P#R%#7!G
Clinical events throu=h )! HeeNs
"lopidogrel @- mg (G)?2@. ASD<*;/ +/ mg (G)??;. ASD<*;/ *,/ mg (G)?2+.

, < ;

F
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All PKJ'%'

2 /

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CannonI P et al' ( Am Coll Cardiol'!--6,8-.)35578)

Antiplatelet Therapy %ummary

> $a>or recent advances in clinical research have > > > >
established the value of early T sustained therapy 5ith combination oral antiplatelet agents for "AD In several instances this has challenged the incremental value offered by I' HPIIb1IIIa inhibitors $ore compleC combination regimens are under investigations that address the different clinical situations (elective P"I, acute $I, A"%. Ue understand the Vuestion of drug resistance is not limited to aspirin and affects a small, but finite, fraction of treated patients "ilosta!ol and other ne5er agents are mostly reserved for allergic patients to aspirin and thienopyridines

?ple combination therapy investigational

Uhich of the follo5ing statements is falseB

*# Aspirin inhibits the cyclooCygenase-* path5ay# 2# "lopidogrel inhibits ADP-induced platelet activation# ?# "lopidogrel is an active substance and undergoes first-pass elimination in the liver# ;# Aspirin inhibits the synthesis of thromboCane# -# The distribution of ticlopidine and clopidogrel is +,3 in plasma proteins

Uhich of the follo5ing statements is falseB

*# Aspirin inhibits the cyclooCygenase-* path5ay# 2# "lopidogrel inhibits ADP-induced platelet activation# ?# Clopidogrel is an active su1stance and undergoes first2pass eli.ination in the liver. ;# Aspirin inhibits the synthesis of thromboCane# -# The distribution of ticlopidine and clopidogrel is +,3 in plasma proteins

Uhich of the follo5ing statements is false regarding the thienopyridine class of drugsB
*# This class includes ticlopidine and clopidogrel# 2# 7oth ticlopidine and clopidogrel 5or& by reversibly inhibiting the binding of ADP to its receptor found on the platelet surface# ?# 7oth agents prolong the bleeding time, but neither drug affects the partial thromboplastin time (PTT. or activated clotting time (A"T.# ;# 7oth agents prevent ADP-mediated upregulation of the platelet glycoprotein IIb1IIIa receptor, and reduce thrombosis from shear stress# -# 7oth agents are metaboli!ed by the liver to active metabolites and ta&e several days to achieve maCimal platelet inhibition

Uhich of the follo5ing statements is false regarding the thienopyridine class of drugsB
*# This class includes ticlopidine and clopidogrel# 2# +oth ticlopidine and clopidogrel 3or, 1/ reversi1l/ inhi1iting the 1inding of ADP to its receptor found on the platelet surface. ?# 7oth agents prolong the bleeding time, but neither drug affects the partial thromboplastin time (PTT. or activated clotting time (A"T.# ;# 7oth agents prevent ADP-mediated upregulation of the platelet glycoprotein IIb1IIIa receptor, and reduce thrombosis from shear stress# -# 7oth agents are metaboli!ed by the liver to active metabolites and ta&e several days to achieve maCimal platelet inhibition

The combination of ticlopidine and aspirin reduced the incidence of stent thrombosis to =*3

*# "orrect 2# Urong ?# Irrespective of the final angiographic result ;# Irrespective of the indication for stenting -# In elective stent implantation 5ith optimal angiographic results

The combination of ticlopidine and aspirin reduced the incidence of stent thrombosis to =*3

*# "orrect 2# Urong ?# Irrespective of the final angiographic result ;# Irrespective of the indication for stenting -. In elective stent i.plantation 3ith opti.al angiographic results