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8/17/2019 Presentacion Plavix ES Para Ponentes

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UnstableanginaMI

Ischemicstroke/TIA

Critical legischemiaIntermittentclaudication

CV death

ACS

Atherosclerosis

Stable angina/intermittent claudication

Thrombosis

1. Libby P. Circulation 2001; 104: 365–372.

Pathologic Progression to Atherothrombosis 1

MI=myocardial in arction! ACS=acute coronary syndromes!TIA=transient ischemic attack! CV=cardio"ascular


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Cardio"ascular disease

Cerebro"asculardisease

PA#

$%&'(

)&*( 11&*(

$+&+(

)&)(

'&%(

1+&$(

,#ata rom the Clo-idogrel "ersus As-irin in Patients at.isk o Ischemic "ents 0CAP.I study 0n=1+21*34

Total does not add u- because o rounding

A total o 5$6( o -atientshad mani estations oatherothrombosis in

more than one arterial bed

$6&$( 4

1. Coccheri S. Eur Heart J 1998; 19(Suppl : 227.

Atherothrombosis is 7 ten 8ound in More Than7ne Arterial 9ed ,1


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Ma:or Clinical Mani estationso Atherothrombosis

!"#p$e" %ro&: 'roue$ L. Cerebrovasc Dis 2002; 13( uppl 1 : 1–6.

Transientischemic attack

Angina;• Stable• Unstable

Ischemicstroke

Myocardialin arction

Peri-heral arterialdisease;• Intermittent claudication• .est Pain•


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CAP.I ; >ong?Term 9ene it o Clo-idogrel Com-ared @ithASA 1

Cumulati"e "ent .ate0Myocardial In arction2 Ischemic Stroke or Vascular #eath

)*++ #,#ly i

1& C!P-* S$eeri,/ Co&&i$$ee. Lancet 1996; 348: 1329–39.

Months o ollo@?u-

8.7 )er#ll

rel#$i eri

re"uc$io,

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30 33 36

C u m u

l a t i " e e " e n

t r a t e 0 (

!S!

p 0.043 , 19 185

Clopi"o/rel


5/106

CAP.I ; 9ene it o Clo-idogrel o"er ASA in the .eduction oMyocardial In arction 1

1& e,$ . Circulation 1997; 96( uppl 8 : * 467.

Months o ollo@?u-

0

1

2

3

4

5

0 3 6 9 12 15 18 21 24 27 30 33 36

C u m u

l a t i " e e " e n

t r a

t e 0 (

p 0.008 , 19 185

!S! 3.6

Clopi"o/rel 2.9

Clopi"o/rel

!S! 19.2 )-el#$i e

rire"uc$io,

)*++ #,#ly i


6/106

$3

As-irin12$

Clo-idogrel12$

$6(

3

1

13

$

$%1+

" e n

t s P r e " e n

t e d / B e a r / 1 2

P a

t i e n

t s

)( * i che&ic $ro e #," # cul#r "e#$h)) # e" o, $he C!P-* $ri#l #," !,$ipl#$ele$+ri#li $ Coll#bor#$io, &e$# #,#ly i # piri,c#, be e pec$e" $o pre e,$ 19 i che&ice e,$ ) %or e ery 1 000 p#$ie,$ $re#$e" perye#r 1 2. *, co,$r# $ clopi"o/rel c#, be

e pec$e" $o pre e,$ 24 i che&ic e e,$ ) %ore ery 1000 p#$ie,$ $re#$e" # 26"i%%ere,ce.

1C!P-* S$eeri,/ Co&&i$$ee. L#,ce$1996;348:1329 1339. 2 !,$ipl#$ele$ +ri#li $Coll#bor#$io,. < 1994; 308:81 106.

Clo-idogrel -re"ents$6( more ischemice"ents, than as-irin

annually,,

Clo-idogrel; Clinical "idence o icacy

12


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1& C!P-* S$eeri,/ Co&&i$$ee. Lancet 1996; 348: 1329–39. $& =#r er L! et al .Drug Safety 1999; 21: 325–35.

)P#$ie,$ >i$h !S! i,$oler#,ce >ere e clu"e"?Cli,ic#lly e ere or re ul$i,/ i, e#rly "ru/ "i co,$i,u#$io,

CAP.I ; 8a"orable Sa ety or Clo-idogrel Com-aredASA ,

Ad"erse e -eriences 4

'i#rrhe# ( e ere 1

# $ri$i 2

# $ro i,$e $i,#l ulcer 2

# $ro i,$e $i,#l he&orrh#/e( e ere 1

*,$r#cr#,i#l he&orrh#/e 1

-# h ( e ere 1

@eu$rope,i# 2

ASA0n = +23*6

Clo-idogrel0n = +23++

p "alue

@SA 0.001

0.001

A 0.05

@S

A 0.05@S

0.111.32

1.15

0.71

0.49

0.10

0.17

0.230.75

0.68

0.49

0.35

0.26

0.10


8/106

CAP.I Study; Demorrhagic "ents

B =o pi$#li #$io, "ue $o * blee"i,/ e e,$ : 71 (0.74 i, clopi"o/rel /roup. 104 (1.08 i, # piri, /roup

B ore /# $roi,$e $i,#l he&orrh#/e i, # piri, /roup ( p A0.002B +re," $o &ore cerebr#l he&orrh#/e %#$#l or ,o, %#$#l #," &ore he&orrh#/ic

"e#$h i, # piri, /roup: 37 er u 51 (0.39 . 0.53

)

3

1

13

$

$3

Clo-idogrelAs-irin

Dos-italiEation or


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Study 7b:ecti"es• Primary

– "aluate the early and long?term e icacy o clo-idogrel "s-lacebo2 both gi"en in addition to as-irin 0ASA and otherstandard thera-y2 in reducing ischemic com-lications in-atients @ith ACS @ithout ST?segment ele"ation 0unstableangina or nonFG?@a"e MI,

• Secondary – "aluate the sa ety o clo-idogrel in addition to ASA thera-y

in -atients @ith ACS

)!l o ,o>, # ,o,–S+ e/&e,$ ele #$io, * (@S+ * .+he CD- +ri#l *, e $i/#$or . N Engl J Med. 2001;345:494 502.

CU. Study


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Clo-idogrel '3 mgHd ASA '3 to )$3

mg Hd 4 062$3+ -atients

Placebo ASA'3 to )$3 mg Hd 4062) ) -atients

# a y 1

6 ? M o

n t h V i s i

t

+ ? M o

n t h V i s i

t

1 $ ? M o

n t h

o r 8 i n

a l V i s i t

) ? M o n t h V

i s i t

# i s c h a

r g e V i s i

t

1 ? M o

n t h V i s i

t

Patients @ithAcute Coronary

Syndrome

0unstable anginaor

nonFG?@a"e MI,=1$236$

.

Placeboloadingdose

- -#,"o&i #$io,.)!l o ,o>, # ,o,–S+ e/&e,$ ele #$io,

* (@S+ * .?*, #""i$io, $o o$her $#,"#r" $her#py.+he CD- +ri#l *, e $i/#$or . N Engl J Med. 2001;345:494 502.

Study #esign

) months double?blind treatment 1$ months

Clo-idogrel )mgloading dose

CU. Study


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Jey Inclusion Criteria• Sus-ected UA or nonFG?@a"e MI,

0no ST K1& mm• Presentation $% hours a ter onset o

sym-toms• C< changes com-atible @ith ischemia or

ele"ated cardiac enEymes or tro-onin I or T ≥ $ U>

)!l o ,o>, # ,o,–S+ e/&e,$ ele #$io, * (@S+ * .

+he CD- +ri#l *, e $i/#$or . N Engl J Med. 2001;345:494502.

CU. Study


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1. CD- S$u"y *, e $i/#$or . Eur Heart J. 2000;21:2033 2041.

2. +he CD- +ri#l *, e $i/#$or . N Engl J Med. 2001;345:494502.

Jey clusion Criteria• Se"ere heart ailure 0Class IV 1

• Current use o oral anticoagulants or long?termtreatment $

• IV


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icacy AnalysesPrimary nd Point

8irst occurrence o any com-onent o the clustero

• yoc#r"i#l i,%#rc$io,• S$ro e (i che&ic he&orrh#/ic or o% u,cer$#i,

$ype• C#r"io # cul#r "e#$h

Co?Primary nd Point8irst occurrence o any com-onent o the clustero

• yoc#r"i#l i,%#rc$io,• S$ro e (i che&ic he&orrh#/ic or o% u,cer$#i,

$ype+he CD- +ri#l *, e $i/#$or . N Engl J Med. 2001;345:494 502.

CU. Study


14/106

9aseline CharacteristicsClo-idogr

el n =62$3+

Placebon = 62) )

Age 0mean 6%&$ 6%&$Mean time rom -ain onset torandomiEation 0hrs

1%&$ 1%&1

Mean heart rate 0beats/min ')&$ ')&Mean systolic 9P 0mm Dg 1)%&% 1)%&18emale 0( )*&' )*&)

#iagnosis at entryUnstable angina 0( '%&+ '%&+

onFG?@a"e MI, 0( $3&1 $3&1C< abnormalities 0( +)&' +)&+

)!l o ,o>, # ,o,–S+ e/&e,$ ele #$io, * (@S+ * .

+he CD- +ri#l *, e $i/#$or . N Engl J Med. 2001;345:494 502.

CU. Study


15/106

Distory o MI )$&% )$&

CA9< surgery/PTCA 1'&' 1*&1Stroke %&% )&'

Deart ailure '&% '&*

Dy-ertension 3+&+ 3'&*

#iabetes $$&% $$&*

Current or ormer smoker 6 &6 6 &+

Clo-idogrel n = 62$3+

0(

Placebon = 62) )

0(

Patient Distory

+he CD- +ri#l *, e $i/#$or . N Engl J Med. 2001;345:494 502.

CU. Study


16/106

As-irin ++&+ ++&+

De-arin 0U8D2 >MLD +$&% +$&%

9eta blockers *%&1 *)&3

Calcium?channel blockers %+&* %*&'

AC inhibitors 61&+ 61&3

>i-id?lo@ering agents 6%&3 6%&%

Clo-idogr el

0(Placebo

0(

'#$# o, %ile S#,o%i Sy,$hel#bo *,c.

Medications A ter .andomiEation

CU. Study


17/106

Primary outcome +&)( 11&%( $ (& +

0MI2 stroke2 CV deathCo?-rimary outcome 4 16&3( 1*&*( 1%(

& 3All indi"idual outcome e"ents;

MI 3&$( 6&6( $)(Stroke 1&$( 1&%( 1%(

CV death 3&1( 3&3( '(.e ractory ischemia *&'( +&)( '(

.elati"e .isk.eduction P "alue

7utcomeClo-idogrel

ASA,n = 62$3+

Placebo ASA,

n = 62) )

CU. StudyMain icacy .esults;Combined Co?-rimary nd Points

) $her $#,"#r" $her#pie >ere u e" # #ppropri#$e.? * $ro e CE "e#$h or re%r#c$ory i che&i#.F

+he i,"i i"u#l co&po,e,$ repre e,$ $he $o$#l ,u&ber o% ubGec$ e perie,ci,/ #, e e,$ "uri,/$he cour e o% $he $u"y.


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Primary nd PointNMI/Stroke/CV #eath

Clo-idogrel ASA,

) 6 +

Placebo ASA,

Months o 8ollo@?U-

P = & +4

= 1$236$

1$

) $her $#,"#r" $her#pie >ere u e" # #ppropri#$e.?PL!E*H Pre cribi,/ *,%or$io,.

!"#p$e" >i$h per&i io, (2002 %ro& $he # #chu e$$ e"ic#l Socie$y.+he CD- +ri#l *, e $i/#$or . N Engl J Med. 2001;345:494 502.

$ (.elati"e .isk

.eduction

CU. Study

The -rimaryoutcome occurredin +&)( o -atientsin the clo-idogrel ASA grou- and

11&%( in the -lacebo ASA grou-&


19/106

CU. ; Clo-idogrel .educed Clinical "ents by $ ( at ) #ays 1

) "" r#$io i, CE "e#$h * or recurre,$ i che&i# le#"i,/ $o ur/e,$ re # cul#ri #$io,

Time 0days

P a

t i e n

t s @

i t h e n

d - o

i n t 0 (

3

1

13

3 1 13 $ $3 )

$ (,-= & )

Clo-idogrel011&6(

Placebo01%&1(

1. S#b#$i,e e$ #l. New Eng J Med 2005; 352: 1179–1189.

d


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Primary outcome +&)( 11&%( $ (& +

0MI2 stroke2 CV deathCo?-rimary outcome 4 16&3( 1*&*( 1%(& 3

All indi"idual outcome e"ents;MI 3&$( 6&6( $)(

Stroke 1&$( 1&%( 1%(

CV death 3&1( 3&3( '(.e ractory ischemia *&'( +&)( '(

.elati"e.isk

.eduction P "alue7utcomeClo-idogrel

ASA,n = 62$3+

Placebo ASA,

n = 62) )

PL!E*H Pre cribi,/ *,%or$io,.

Main icacy .esults;Combined Co?-rimary nd Points

) $her $#,"#r" $her#pie >ere u e" # #ppropri#$e.? * $ro e CE "e#$h or re%r#c$ory i che&i#.F+he i,"i i"u#l co&po,e,$ repre e,$ $he $o$#l ,u&ber o%

ubGec$ e perie,ci,/ #, e e,$ "uri,/ $he cour e o% $he $u"y.

CU. Study

CU S d


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Main icacy .esults;7ther In?hos-ital 7utcomes

7utcome

Clo-idogrel ASA,

n = 62$3+

Placebo ASA,

n = 62) )

.elati"e.isk

.eduction P "alue

.e ractory ischemiaIn hos-ital 1&%( $& ( )$( & '

.e ractory ischemiaA ter discharge '&6( '&6( 1( S

7ther se"ere ischemia $&*( )&*( $6( & )

7ther recurrentangina $ &+( $$&+( +(

& 1

.e"asculariEation-rocedure $ &*( $$&'( *( & )

Deart ailure )&'( %&%( 1*( & )

+he CD- +ri#l *, e $i/#$or .N Engl J Med. 2001;345:494 502. @S ,o$ i/,i%ic#,$.) $her $#,"#r" $her#pie >ere u e" #

CU. Study

CU S d


22/106

#e inition o 9leeding• lee"i,/ ># "e%i,e" # IGorJ or I&i,orJ• #Gor blee"i,/ ># "e%i,e" # %ollo> :

– Li%e $hre#$e,i,/: %#$#l 5 /K"L he&o/lobi, "ropre uiri,/ ur/ic#l i,$er e,$io, he&orrh#/ic $ro ere uiri,/ i,o$rope or re uiri,/ $r#, %u io, (4 or&ore u,i$ o% bloo"

– $her Gor blee"i,/: ub $#,$i#lly "i #bli,/i,$r#ocul#r blee"i,/ le#"i,/ $o i io, lo or

re uiri,/ 2–3 u,i$ o% bloo"• i,or blee"i,/ ># "e%i,e" # :

– !,y o$her blee"i,/ $h#$ le" $o i,$errup$io, o% $u"y&e"ic#$io,

CU. Study

PL!E*H Pre cribi,/ *,%or$io,.

CU S d


23/106

9leeding .esults

"ent

Clo-idogrel

ASA,n = 62$3+

Placebo ASA,

n = 62) ) P "alue

Ma:or bleeding4

)&'( $&'( & 1>i e?threatening

bleeding $&$( 1&*( &1)

7ther ma:or bleeding 1&6( 1& ( & 3

Minor bleeding 3&1( $&%( O & 1

CU. Study

) $her $#,"#r" $her#pie >ere u e" # #ppropri#$e.?

Li%e $hre#$e,i,/ #," o$her Gor blee"i,/.PL!E*H Pre cribi,/ *,%or$io,.

CU St d


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>i e?threatening 9leeding

>i e?threatening $&$1&*

8atal &$ &$

3 g/d> dro- hemoglobin &+ &+

Dy-otension?inotro-ic thera-y &3 &3

Surgery reHuired &' &'

Demorrhagic strokes &1 &1

.eHuiring trans usion 0≥ % units o blood 1&$ 1&

Clo-idogrel ASA,

n = 62$3+ 0(

Placebo ASA,

n = 62) ) 0(

) $her $#,"#r" $her#pie >ere u e" # #ppropri#$e.PL!E*H Pre cribi,/ *,%or$io,.

CU. Study

CU St d


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7ther Ma:or 9leeding

7ther ma:or bleeding 1&61&

Signi icantly disabling &% &)

Intraocular bleeding @ith

signi icant loss o "ision & 3 & ).eHuiring $ to ) units o blood 1&) &+

Clo-idogrel ASA,

n = 62$3+ 0(

Placebo ASA,

n = 62) ) 0(

CU. Study


CU St d


26/106

Placebo ASA,

Clo-idogrel ASA,

Ma:or 9leeding by ASA #ose

O1 mg $&6( $& (

1 F$ mg )&3( $&)(

K$ mg %&+( %& (

ASA #ose

CU. Study



27/106

PCI CURE – From PCI to 30 daysComposite of CV death, MI, or urgent revas u!ari"ation

0 # $0 $# %0 %# 30

0,0

0,0%

0,0&

0,0'

0,0( P!a e)oC!opidogre!

30% RRRp=0.03n=2658

Days of follow-up

C u m u

l a t i v e

h a

z a ! a

t e s

"he C#R$ nvesti&ato s. Lancet 'u&ust 200(


28/106

PCI CU. – >ong term icacy o Clo-idogrelCom-osite o CV death or MI rom randomiEation to end o ollo@?u- *

0.(5

0.(0

0.05

0.0(00 )0 (00 200 300 )00

C u m u

l a t i v e

h a

z a ! a

t e s

3(% RRRp=0.002

n=2658

Days of follow-upa *

+la,e*o Clopi!o& el

a = me!ian time f om an!omization to +C (0 !ays/* = 30 !ays afte me!ian time of +C

up to (2 months on top of stan!a ! the apy in,lu!in& '1'

(2.6%

8.8%

"he C#R$ nvesti&ato s. Lancet 'u&ust 200(


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PCI?C>A.ITB; .eduction in CV "ents romPCI to ) #ays

,.eduction in the odds o CV death2 MI or stroke a ter PCI through ) days& "" r#$io #"Gu $e" %or prope, i$y core %or li elihoo" o% PC* $ype o% ly$ic i,i$i#l

$ype o% hep#ri, #," i,%#rc$ loc#$io,.

#ays Post PCI

P e r c e n

t a g e @ i

t h 7 u

t c o m e

0 (

$

3 1 13 $ $3 )

%6(,-= & *

Clo-idogrel Pretreatment0)&6(

o Pretreatment06&$(

%

6

*

S#b#$i,e e$ #l. 2005


30/106

PCI?C>A.ITB; .eduction in CV "ents rom.andomiEation to PCI

, .eduction in the odds o a recurrent MI or stroke -rior to PCI& "" r#$io #"Gu $e" %or prope, i$y core %orli elihoo" o% PC* $ype o% ly$ic i,i$i#l $ype o% hep#ri, #," i,%#rc$ loc#$io,.

S#b#$i,e e$ #l. 2005.

#ays -re PCI

P e r c e n

t a g e @ i t

h o u

t c o m e

0 (

) % 6

Clo-idogrel Pretreatment0%& (

1 3

o Pretreatment06&$(

)*(,-= & $*

$

$

%

6

*


31/106

PCI?C>A.ITB; 7"erall .esults

,MI2 Stroke2 or CV #eath,,MI or Stroke

P a

t i e n

t s @

i t h

e n

d - o

i n t 0 (

3

1

13

'&3

1$& Clo-idogrel Pretreatment 0n=+))

o Pretreatment 0n=+)

%1(-= & 1

7"erall"ents,

Pre?PCI"ents,,

%&6&$

)*(-= & )

)&6

6&$

%6(-= & *

Post?PCI"ents,

7"erall e"ents includes e"ents rom randomiEation through ) days& Percent reduction based on odds ratio or e"entrates& 7dds ratios ad:usted or -ro-ensity score or likelihood o PCI2 ty-e o lytic2 initial ty-e o he-arin2 and in arctlocation&

S#b#$i,e e$ #l. 2005


32/106

Inde-endientemente del ti-o de SCA2 el sangrado mayor es unactor de riesgo de muerte durante la hos-italiEacion 1

• l #,/r#"o yor e u, %#c$or "e rie /o "e &uer$e e, p#cie,$e co, SC!

• - !Gu $#"o p#r# l# cohor$e $o$#l 1.64 95 C* 1.18–2.28

'#$o "el -e/i $ro -!C1. o cucci e$ #l. Eur Heart J 2003;24:1815–1823.


33/106

Clo-idogrel Im-ro"ed Coronary Per usion 1

) # e" o, o"" o% #, occlu"e" i,%#rc$ rel#$e" #r$ery (+M 0K1"e#$h or * by #,/io/r#phy %or clopi"o/rel er u pl#cebo(o"" r#$io: 0.64 N0.53 − 0.76O; p A0.001

Placebo0n=12')+Clo-idogrel0n=12'3$

$1&'

13&

3

1

13

$

$3

P r i m a r y e n

d - o

i n t , 0 (

)6( reduction,- O & 1



34/106

Clo-idogrel .educed Primary nd-oint by )6( 1

Clo-idogrel Placebo 7dds ratio0n=12'3$ 0n=12')+ 0+3( CI - "alue

Primary com-osite end-oint 0(T8< /12 MI or death 13& $1&' &6% 0 &3) &'6 O & 1

Indi"idual com-onents o -rimary end-oint 0(T8< /1 11&' 1*&% &3+ 0 &%* &'$ O & 1.ecurrent MI $&3 )&6 &' 0 &%' 1& % & *#eath $&6 $&$ 1&1' 0 &'3 1&*$ &%+

C* co,%i"e,ce i,$er #l



35/106

umber o 7dds Patients @ith e"ent0(

Characteristic -atients reduction Clo-idogrel Placebo

7V .A>> )%+1 )6 13& $1&'Age

O63 years $%66 %$ 1)&$ $1&≥ 63 years 1 13 $$ 1+& $)&1

MLD 1%$+ )1 11&% 13&'U8D 1%)1 %$ 1'&* $'&1

one 6$1 $6 1'&1 $1&+

1&&% &6 &* 1&$ 1&6Clo-idogrel better Placebo better

Consistent .esults or Primary nd-ointAcross Subgrou-s 1



36/106

Clo-idogrel Im-ro"ed Angiogra-hic 7utcomes 1

Clo-idogrel Placebo 7dds ratio0n=12'3$ 0n=12')+ 0+3( CI - "alue

Angiogra-hic outcomes 0(

T8< ) 6'&* 6 &*1&)6 01&1* 1&3' O & 1TMP< ) 33&*31&$1&$1 01& 3 1&% & *Thrombus %)& 3 &* &') 0 &6% &*% O & 1



37/106

Clo-idogrel .educed Clinical "ents by $ (at ) #ays 1

) "" r#$io i, CE "e#$h * or recurre,$ i che&i#

le#"i,/ $o ur/e,$ re # cul#ri #$io,

Time 0days

P a

t i e n

t s @

i t h

e n

d - o

i n t 0 (

3

1

13

3 1 13 $ $3 )

$ (,-= & )

Clo-idogrel011&6(

Placebo01%&1(



38/106

Consistent .esults Across ) ?day nd-oints 1

7ddsreduction Clo-idogrel Placebo

CV death ) %&% %&3.ecurrent MI )1 %&1 3&+

.ecurrent ischemialeading to urgent $% )&3 %&3re"asculariEation

Stroke%6

&+ 1&'CV death or MI 1' *&% +&+

CV death2 MI or stroke 1* +&1 1 &+

CV death2 MI or recurrentischemia leading to urgent $ 11&6 1%&1re"asculariEationCV death2 MI2 stroke or recurrent ischemia leading

$1 1$&) 13&

to urgent re"asculariEation

Patients @ith e"ent 0(nd-oint 7dds ratio0+3( CI

1&&% &6 &* 1&$Clo-idogrel better Placebo better

1&6



39/106

Sa ety 1

Clo-idogrel Placebo0n=1')) 0n=1'1+ - "alue

Primary bleeding end-oint2 n 0(TIMI ma:or $) 01&) 1+ 01&1 S

Secondary bleeding end-oints2 n 0(

TIMI minor 1' 01& + 0 &3 STIMI ma:or or minor % 0$&) $* 01&6 SICD * 0 &3 1$ 0 &' S

9leeding through ) days2 n 0(TIMI ma:or )) 01&+ ) 01&' STIMI minor $' 01&6 16 0 &+ STIMI ma:or or minor 3+ 0)&% %6 0$&' S


S=not statistically signi icant


40/106

Summary 1

In -atients aged '3 years @ith ST MI2 recei"ing ASA andstandard ibrinolytic thera-y2 a loading dose o ) mg oclo-idogrel ollo@ed by clo-idogrel '3 mg once daily resulted in;

− A )6( reduction 0- O & 1 in the odds o an occluded in arct?related artery2 or death or MI by time o -re?discharge

angiogra-hy or hos-ital discharge 0ma imum * days

− Consistent results across all ma:or subgrou-s

−

At ) days2 a $ ( reduction 0-= & ) in CV death2 MI orrecurrent ischemia leading to urgent re"asculariEation

− o signi icant e cess in TIMI ma:or bleeding or ICD



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1. CCS 2 Coll#bor#$i e roup. J Cardiovasc Ris 2000; 7: 435 − 441.

C7MMIT/CCS?$; Cl7 -idogreland Meto-rolol in MyocardialIn arction Trial

Pur-ose;To determine @hether adding clo-idogrelcan -roduce a urther reduction in mortalityand the risk o "ascular e"ents inhos-italiEed -atients admitted @ith acuteST MI 1


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#ouble?blind treatment until hos-italdischarge or or a ma imum o % @eeks

0n=5$)2

n=5%62

Patients @ithacute ST MI

$% hours

)!ll p#$ie,$ recei e" # b#c /rou," o% !S! 162 &/K"#y"uri,/ $he $u"y

0$ $ actorial @ith meto-rolol

Study #esign 1

Clo-idogrel '3 mg once daily,

Placebo,

0n=5$)2

.



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Inclusion/ clusion Criteria 1

Inclusion criteria;Sus-ected acute MI 0@ith de inite C< changes; ST ele"ationor le t bundle block branch Q>999RLithin $% hours o the onset o sym-toms

o clear indication/contraindication to trial treatmentsclusion criteria;

Digh risk o ad"erse drug reactions;− Allergy to ASA or any trial drug− Acti"e bleeding or hematologic disorder− Persistent hy-otension or bradycardia− Digh?degree atrio"entricular 0AV block2 -acemaker2

cardiogenic shockSmall likelihood o -otential bene its;

− >o@ risk o MI death 0non?ty-ical MI2 -rimary PCI



44/106

Study nd-oints 1

Co?-rimary end-oints;#eath#eath2 non? atal MI or non? atal stroke

Sa ety end-oints;

Ma:or non?cerebral bleeding 0 atal or trans usedDemorrhagic stroke



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Clo-idogrel PlaceboCharacteristic 0n=$$2+6 0n=$$2*+18emale 0( $'&' $'&+Age K' 0( $6& $6&Time delay O6 hours 0( ))&* ))&'

Jilli- class II/III 0( $%&1 $%&ST MI/>999 0( +)&1+)&18ibrinolytic;

All -atients 0( %+&'%+&* ST MI O1$ hours 0( 6'&* 6'&'

Patient 9aseline Characteristics 1

1. Che, e$ #l. r#l pre e,$#$io, !CC 2005. ! #il#ble #$: D-L: h$$p:KK>>>.co&&i$ cc 2.or/. !cce e" !pril 2005.

http://www.commit-ccs2.org/http://www.commit-ccs2.org/


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Clo-idogrel PlaceboThera-y 0n=$$2+6 0n=$$2*+1 Anticoagulants '%&1( '3& (AC inhibitors 6*&$( 6*&)(

itrates 0oral or i" +%&1( +%&)(#iuretics $)&)( $)&)(Anti?arrhythmics $$&%( $$&$(Calcium antagonists 11&*( 11&*(

Concomitant Medications #uring IndeDos-italiEation 1




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Clo-idogrel .educed the Com-osite o #eath2MI or Stroke by +( 1

' 1% $1 $*

1$)%36'*+

1

#ays 0u- to $* days

Clo-idogrel0+&)(

Placebo

01 &1(

" e n t s

0 (

...=+(-= & $

...=relati"e risk reduction




48/106

Clo-idogrel .educed Mortality by '( 1

' 1% $1 $*

1

$

)

%

3

6

'

*

+

#ays 0u- to $* days

Clo-idogrel0'&3(

Placebo

0*&1( ...='(-= & )

M o r t a

l i t y

0 (




49/106

Clo-idogrel #ecreased .e?In arction 1

7dds ratio +3( CIClo-idogrel better Placebo better

7utcome Clo-idogrel Placeboa ter re?MI 0n=$$2+3* 0n=$$2*+1

8atal MI $ + 0 &+( $$) 01& (

on? atal MI $') 01&$( )) 01&%(

A>> %*$ 0$&1( 33) 0$&%( 1)(reduction

-= & $

&% &6 &* 1& 1&$ 1&% 1&




50/106

ects o Clo-idogrel on Stroke 1


Clo-idogrel PlaceboTy-e 0n=$$2+3* 0n=$$2*+1

Ischemic 16$ 0 &'( 1+$ 0 &*(

Demorrhagic 33 0 &$( 33 0 &$(

A>> $16 0 &+( $%+ 01&1( 1%(reduction

-= S

&% &6 &* 1& 1&$ 1&% 1&




51/106

C7MMIT; 8atal and on?8atal Ma:or 9leeds 1

Clo-idogrel PlaceboTy-e 0n=$$2+3* 0n=$$2*+1

Cerebral8atal )+ %

on? atal 16 13on?cerebral

8atal )6 )'on? atal %6 )6

Any ma:or bleed 1)% 0 &3*( 1$% 0 &3%(




52/106

ects o Clo-idogrel on #eath2 .e?MI orStroke by #ays to "ent 1


Clo-idogrel Placebo"ents by day 0n=$$2+3* 0n=$$2*+1

%6) 0$& 3$) 0$&)

1 %*6 0$&1 3$' 0$&)$ ) %%+ 0$& %31 0$&

% ' %)$ 01&+ %6) 0$&

* $* $+3 01&) )%' 01&3

A>> $1$3 0+&)( $)11 01 &1(

&% &6 &* 1& 1&$ 1&% 1&

+(

increase-= & $




53/106

Consistent ects o Clo-idogrel on #eath2.e?MI or Stroke by Age and


54/106

ects o Clo-idogrel on #eath2 .e?MI orStroke by Time #elay and 8ibrinolytic Use 1

7dds ratio +3( CI

Clo-idogrel better Placebo better 9aseline Clo-idogrel Placebo

eatures 0n=$$2+3* 0n=$$2*+1

Time delay 0hours

6 ''6 0+&)( + % 01 &+( ' 1$ 6'$ 0+&'( ')3 01 &'(

1) $% 666 0*&*( 666 0*&'(8ibrinolytic used Bes 1 3 0*&*( 11$) 0+&+( o 11$ 0+&'( 11** 01 &)(

A>> $1$3 0+&)( $)11 01 &1( +(

reduction-= & $

&% &6 &* 1& 1&$ 1&% 1&


1



55/106

Clo-idogrel 0'3 mg once daily on a background o standardthera-y including ASA @as bene icial at % @eeks or a @iderange o acute ST MI -atients

− Clo-idogrel reduced mortality, by '( 0-= & )− Clo-idogrel reduced the risk o death2 non? atal MI or

non? atal stroke by +( 0-= & $

o signi icant increase in the risk o ma:or 0 atal ortrans used bleeding occurred @ith clo-idogrel

,#eath during initial hos-italiEation

Conclusions 1




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Incidence o ACS in the US

ACS126')2 1

Unstable angina

'$*21,

MI

+')21,

ST MI33F' ( o ACS -atients $

ST MI) F%3( o ACS -atients $

1. !&eric#, =e#r$ ! oci#$io,. =e#r$ #," S$ro e $#$i $ic#l up"#$e. '#ll# +e # : !&eric#, =e#r$ ! oci#$io, 2005. 2. @- * 4. J !" Coll Cardiol 2003; 41: 365!–366!.

,$*2 hos-italiEations recei"ed both diagnoses or UA and MI

umber o -atients @ith ACS discharged rom US hos-itals in $ $0including secondary discharges

Sco-e o the CU. trialSco-e o the C>A.ITB/C7MMIT trials

l h l 1


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"olution o Pharmacologic .e-er usion 1

$ 3! )&3 days

TPASJ

TIMI 1 1

ASA clo-idogrel

ASA

AP.IC7T $

Placebo ASA

1+*3! + minutes 1++)! ) months

11&'

)$

1*&%

$3)

3'

1

$

)

%

3

6

7 c c l u

d e

d i n a r c

t ? r e l a

t e d a r t e r y

0 (

%'(- O & 1

$$(-= &$6

)6(- O & 1

AP.IC7T=Antithrombotics in the Pre"entiono .eocclusion In C7ronary Thrombolysis

1. +* * S$u"y roup. New Engl J Med 1985; 312: 932–936. 2. eiGer ! e$ #l. Circulation 1993 87: 1524–1530. 3. S#b#$i,e e$ #l. New Eng J Med 2005; 352: 1179–1189.

)

C l l C A ITB d


58/106

Com-lementary .esults o C>A.ITB andC7MMIT or Patients @ith ST MI

Signi icant im-ro"ement in coronary -er usion andclinical outcomes "ersus standard care 0C>A.ITB

Signi icant reduction in mortality or -atients recei"ingclo-idogrel "ersus standard care alone 0C7MMIT

o signi icant increase in ma:or bleeding or ICD 0C7MMITand C>A.ITB

CU. ; sta adici n de clo-idogrel a AAS comenE a reducir


59/106

) *, #""i$io, $o o$her $#,"#r" $her#pie1. Qu u% S et al. Circulation 2003;107:966–972. -epro"uce" >i$h per&i io,.

; gla isHuemia dentro de las -rimeras $% Doras 1

Cardio"ascular death2 myocardial in arction2 stroke2 se"ere ischemia

C u m u

l a t i " e

D a E a r d

. a

t e s

Clo-idogrel ASA,

Placebo ASA,

34-el#$i e

-i-e"uc$io,

Dours A ter .andomiEation

2.1 . 1.4 ;-- 0.66 (0.51–0.86P 0.003

0.025

0.020

0.015

0.010

0.005

0.0

0 2 4 6 8 10 12 14 16 18 20 22 24

l uso del Clo-idogrel AAS -re"io a la PCI redu:o los e"entos


60/106

gcardio"asculares en -acientes sometidos a este -rocedimiento 1

Com-osite o myocardial in arction2 urgent re"asculariEation2or cardio"ascular death at ) days

C u m u

l a t i " e

D a E a r d

. a

t e

Clo-idogrel ASA

Pretreated,

Placebo ASA

Pretreated,

6.4 . 4.5 ;-- 0.70 (0.50–0.97P 0.03

#ays o 8ollo@?u-PC*: Percu$#,eou coro,#ry i,$er e,$io,) *, #""i$io, $o o$her $#,"#r" $her#pie1. eh$# S- et al. Lancet 2001;358:527–533. -epro"uce" >i$h per&i io,.

C. #7; l tratamiento de los -acientes sometidos a PCI con Clo-idogrel


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AAS redu:o los e"entos CV durante el a o de tratamiento 1

Com-osite o death2 myocardial in arction2 and stroke at one year

PC*: Percu$#,eou coro,#ry i,$er e,$io,) *, #""i$io, $o o$her $#,"#r" $her#pie 1. S$ei,hubl S- et al. J!M! 2002;288:2411–2420. -epro"uce" >i$h per&i io,.

C o m

b i n e

d n

d - o

i n t 7 c c u r r e n c e

0 (

Months 8rom .andomiEation

27-el#$i e

-i

-e"uc$io,P 0.02

Clo-idogrel ASA,

Placebo ASA,

*&3(

11&3(

15

10

5

00 3 6 9 12

Tiem-o des-ues de la administraci n de 6 mg de


62/106

Clo-idogrel y su res-ecti"a Inhibicion PlaHuetaria 1

!'P: !"e,o i,e "ipho ph#$e1. =ochhol er R et al. Circulation 2005;111:2560–2564.

( A

g g r e g a

t i o n

Ma imal o-tical aggregation 03 WM A#P


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A.MB#A?$; #osis de Carga Mayores de Clo-idogrel


64/106

-ueden -re"enir mXs e"entos CV 1

+E-: +#r/e$ e el re # cul#ri #$io,1. P#$$i et al. Circulation 2005;111:2099–2106. -epro"uce" >i$h per&i io,.

Se (22–24 %ele u e o% P **bK***# i,hibi$or (13 #,"

"ru/ elu$i,/ $e,$ (19–21>ere i&il#r =i/h "o e /roup $e,"e" $o beyou,/er (63 . 65 #," &ore%re ue,$ly h#" &ul$i e el"i e# e

+he priry co&po i$ee,"poi,$ o% "e#$h &yoc#r"i#li,%#rc$io, +E- ># i/,i%ic#,$ly

lo>er i, $he hi/h "o eclopi"o/rel /roup #$ 30 "#y ;P 0.041+here ># o,e +E- i, $hehi/h "o e /roup #," ,o "e#$hi, ei$her #r&'o i $#,"#r"

, 129'o i #yore

, 126

12.0

4.0

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

# e a

t h 2

M y o c a r d

i a l I n a r c

t i o n o r

T V .

ISA.?CD7IC $; #osis de Mantenimiento mXs altas -roducen Inhibici n


65/106

PO & 1

Clo-idogrel

0A

PlaHuetaria mXs intensa en -acientes sometidos a PCI 1

*P!: *,hibi$io, o% pl#$ele$ #//re/#$io,PC*: Percu$#,eou coro,#ry i,$er e,$io,

!'P: !"e,o i,e "ipho ph#$e 1. o, ec er#$h @ et al. Eur Heart J 2007;28:1814–1819. -epro"uce" >i$h per&i io,.

3 Ymol/> A#P $ Ymol/> A#P

PO & 1

Clo-idogrel

09

>a Tera-ia Anti-laHuetaria .educe


66/106

"entos Vasculares en Pacientes de Alto .iesgo 1

CategorZa ( 7dds reduction

=i $ori# "e * 25 (4

* !/u"o 30 (4

=i $ori# "e CE o *C+ 22 (4

CE !/u"o 11 (3

$ro rie /o 26 (3

Todos los estudios 22 (21.00.50.0 1.5 2.0

Co,$rol eGor !,$ipl# ue$#ri# eGor

*: yoc#r"i#l i,%#rc$io,+*!: +r#, ie,$ i che&ic #$$#c1. !"#p$e" %ro&: !,$i$hro&bo$ic +ri#li $ Coll#bor#$io,. #MJ 2002;324:71–86. -epro"uce" >i$h per&i io,.

Com-araciones Indirectas de los studios no muestran


67/106

di erencias en e icacia entre las distintas dosis de AAS 1

o 0( de "entosVasculares 7dds ratio 0Cl

Categoriadel studio

o& otrials

@ith data

Allocatedanti-latelet

Ad:ustedcontrol

7bser"ed?e -ected Variance Anti-latelet ; Control

( 7ddsreduction

0S

AAS Sola

0mg diarios ;

500–1500 341 621K11 215

(14.51 930K11 236

(17.2147.1 707.8 19 (3

160–325 191 526K13 240

(11.51 963K13 273

(14.8219.9 742.6 26 (3

75–150 12 366K3 370(10.9517K3 406

(15.2 72.0 183.8 32 (6

A75 3 316K1 827(17.3354K1 828

(19.4 18.9 136.5 13 (8

CualHuier#osis de

ASA63

)2*$+/$+263$01$&+

%2'6%/$+2'%)016&

?%3$&) 12'1'& $) 0$

!S!: !ce$yl #licylic #ci"1. !"#p$e" %ro&: !,$i$hro&bo$ic +ri#li $ Coll#bor#$io,. #MJ 2002;324:71–86. -epro"uce" >i$h per&i io,.

CU. ; A mayores dosis de AAS2


68/106

mayor incremento en la tasa de Sangrados 1

!S!: !ce$yl #licylic #ci"1. Pe$er -< et al. Circulation 2003;108:1682–1687. -epro"uce" >i$h per&i io,.

T a s a

d e

S a n g r a

d o s

0 (

101–199&/(, 3 109

200&/(, 4 110

T100&/(, 5 320

ASA #osage

!S!P 0.0001

!S! U clopi"o/relP 0.0009


69/106

CURRENT OASIS 7: A 2X2 FactorialRandomized Trial of OptimalClopidogrel and A pirin !o ing in"atient #it$ ACS Undergoing anEarl% In&a i&e Strateg% #it$

Intent For "CI

!S*S 7

Shamir .& Mehta on behal o the CU.. T In"estigators

acional


70/106

.acional

Clo-idogrel• Clopi"o/rel 300 &/ e/ui"o "e 75 &/ "i#rio re"uce l# $# #"e e e,$o CE #yore # lo l#r/o "e $o"o el e pec$ro "eSC! y PC*

• '#$# recie,$e u/iere ue el "obl#r l# "o i "e c#r/# y "e,$e,i&ie,$o "e clopi"o/rel pu"ie e re ul$#r e, u,# #yor y V -#pi"# i,hibiciW, #,$ipl# ue$#ri#

As-irina•

L# "o i "e # piri,# #ri#, e,$re urop# y @!• @o e i $e, e $u"io #le#$ori #"o y co,$rol#"o # /r#, e c#l#ue co&p#re, l# "o i #l$# (300 325 &/ er u l# "o i

b#G# (75 100 "e # piri,# e, p#cie,$e co, SC! o&e$i"o #PC*

>os 9ene icios de la Tera-ia Anti-laHuetaria en


71/106

.educci n del .iesgo.elati"o

PCI Sin PCI

CD- : Clopi"o/rel 300K75 &/ Pl#cebo(CE'K * 30

1 19 2

S+ *: Clopi"o/rel 300K75 &/ Pl#cebo(CE'K *

46 3 9 4

+-*+ @: Pr# u/rel clopi"o/rel 300K75&/(CE'K *KS$ro e 195

@o #lu#"o

SCA son mayores en los -acientes Hueadicionalmente se someten a PCI

1. eh$# S- e$ #l. L#,ce$ 2001; 358(9281 :527 33.2. Mo X!! e$ #l. Circul#$io, 2004;110:1202 83. S#b#$i,e S e$ #l.

5. Ri io$$ S e$ #l. @ ,/l < e" 2007; 357: 2001–15.

#ise o del studio 1


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AT7.I[A. A> AT7.I[A.

ASA lo@ dose grou- !$ le# $ 300 &/ '#y 1;

75–100 &/%ro& '2 $o '30

ASA high dose grou- !$ le# $ 300 &/ '#y 1;

300–325 &/%ro& '2 $o '30

ASA high dose grou- !$ le# $ 300 &/ '#y 1;

300–325 &/%ro& '2 $o '30

ASA lo@ dose grou- !$ le# $ 300 &/ '#y 1;

75–100 &/%ro& '2 $o '30

-eclu$#&ie,$o u,"i#l – p#cie,$e co, D!K@S+ * o S+ * pl#,e#"o p#r# u,#

e $r#$e/i# i, # i # $e&pr#,# peG&. D,# PC* $#, pro,$o co&o e#po ible "e,$ro "e l# pri&er# 72 h

A> AT7.I[ACI7

PC*: Percu$#,eou coro,#ry i,$er e,$io,D!K@S+ *: D, $#ble #,/i,#K,o, S+ e/&e,$ ele #$io, &yoc#r"i#l i,%#rc$io,S+ *: S+ e/&e,$ ele #$io, &yoc#r"i#l i,%#rc$io,

1. eh$# S- et al. !" Heart J 2008;156:1080–1088e1

7-en >abel

'?days double?dose P>AVI \ regimen

#ise o del studio

#ise o del studio 0#osis de Clo-idogrel 1


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) !ll p#$ie,$ recei e #$$e,"#,$ #ce$yl #licylic #ci"


74/106

1. eh$# S- et al. !" Heart J 2008;156:1080–1088e1'?days double?dose P>AVI \ regimen

• P#$ie,$ >i$h unstable angina or non?ST?segment ele"ation myocardial in arction;* ch#e&ic y&p$o& u pec$e" $o repre e,$ # ,o, S+ e/&e,$ ele #$io, #cu$e coro,#ry

y,"ro&e "e%i,e" # : – Cli,ic#l hi $ory co, i $e,$ >i$h ,e> o, e$ or # >or e,i,/ p#$$er, o% i ch#e&ic che $ p#i, occurri,/ #$

re $ or >i$h &i,il e er$io, #," #$ le# $ o,e o% $he %ollo>i,/:• lectrocardiogram ( C ch#,/e co&p#$ible >i$h ,e> i ch#e&i# (S+ "epre io,

1&& or $r#, ie,$ S+ ele #$io, or S+ ele #$io, T 1&& or + ># e i, er io, Z 3&& i, #$le# $ $>o co,$i/uou le#"

-• le #$e" c#r"i#c e, y&e or bior er

-• P#$ie,$ >i$h ST?segment ele"ation myocardial in arction;

Si/, or y&p$o& o% #cu$e &yoc#r"i#l i,%#rc$io, l# $i,/ 20 &i,'e%i,i$e C ch#,/e co&p#$ible >i$h per i $e,$ S+ ele #$io, ( 2 && i, $>o co,$i/uou precor"i#l le#" or Z1 && i, #$ le# $ $>o li&b le#" or ,e> le%$ bu,"le br#,ch bloc or [ ># e i, $>o co,$i/uou le#"

Mor #ll p#$ie,$ :• .andomiEed @ithin 24 hour o% o, e$ o the most recent e-isode o chest -ain or sym-toms consistent @ith

ischaemia/in arction• Planned to be managed @ith early in"asi"e strategy2 i&e& @ith intent to -er orm -ercutaneous coronary

inter"ention 0PCI as early as -ossible @ithin '$ hours o randomiEation;

*, S+ * p#$ie,$ $hi i,clu"e" p#$ie,$ ,#/e" >i$h priry PC* or i,i$i#l &e"ic#l $her#py

Poblaci n del studio


75/106

7b:eti"os de icacia

bGe$i o Pririo "e %ic#ci#:Pri&er# ocurre,ci# "el $riple co&pue $o "e uer$e CE *,%#r$o #l

ioc#r"io (* o S$ro e #l "i# 30

bGe$ico Secu,"#rio "e %ic#ci#:Pri&er# ocurre,ci# "e uer$e CE * S$ro e o * ue&i# -e%r#c$#ri#'e e,l#ce "e e%ic#ci# i,"i i"u#li #"o #l "i# 30: uer$e CE uer$e+o$#l * * periproce"i&ie,$o $ro e (i ue&ico he&orr#/ico o "ei,cier$o $ipo i ue&i# recurre,$e re # cul#ri #cio, ur/e,e y$ro&bo i "el $e,$

Solo p#r# l# pobl#ciW, co, S+ * !r$eri# clui"# (MluGo +* * 0 o 1 . !r$eri# Per&e#ble (MluGo +* * 2 o3 eri%ic#"o por #,/io/r#%i# "e i,icio o #l e/re o ho pi$#l#riocu#l uier# ue ocurrier# pri&ero

1. eh$# S- et al. !" Heart J 2008;156:1080–1088e1'?days double?dose P>AVI \ regimen

Study #esign2 8lo@ and Com-liance


76/106

Study #esign2 8lo@ and Com-liance$32 *' ACS Patients 0UA/ ST MI ' &*(2 ST MI $+&$(

Pl#,,e" #rly (A24 h *, # i e #,#/e&e,$ >i$h intended PCI

* che&ic C \ (80.8 or ]c#r"i#c bior er (42

PCI1'2$)$0' (

Angio$%2'6+0++( o PCI '2*33

0) (

o Sig& CA# )2616 CA9< 12* + CA# $2%)

.andomiEed to recei"e 0$ $ actorial ;

C>7PI#7; #ouble?dose (600 &/ $he,150 &/K" 7" $he, 75 &/K" "s Standard dose (300 &/$he, 75 &/K"

ASA; Digh #ose (300 325 &/K" "s >o@ dose (75 100 &/K"

Clo- in 1st 'd 0median 'd ' d $ d'd

Com-lete8ollo@u-

++&*(

Co&pli#,ce:


77/106

Com-aracion entre las dosis de As-irina

ASA'3?1 mg

ASA) ?)$3

mg

D. +3( CI P

uer$e CE K* KS$ro e

PC* (2@ 17 232 4.2 4.1 0.98 0.84 1.13 0.76@o PC* (2@ 7855 4.7 4.4 0.92 0.75 1.14 0.44

er#ll (2@ 25 087 4.4 4.2 0.96 0.85 1.08 0.47

+ro&bo i "el S$e,$ 2.1 1.9 0.91 0.73 1.12 0.37

S#,/r#"o #yor +* * 1.03 0.97 0.94 0.73 1.21 0.71S#,/r#"o #yorCD-- @+

2.3 2.3 0.99 0.84 1.17 0.90

S#,/r#"o Se eroCD-- @+

1.7 1.7 1.00 0.83 1.21 1.00@o o$her i/,i%ic#,$ "i%%ere,ce be$>ee, !S! "o e /roup

* lee" : 30 (0.24 47 (0.38 P 0.051

Clo-idogrel #ose Com-arison


78/106

Clo-idogrel #ose Com-arison

2 Si/,i%ic#,$ *,$er#c$io, :

1. PC* @o PC* (P 0.016

2. !S! "o e (P 0.043

Clo-idogrel; #osis Altas "s& #osis standard7b:eti"o Primario y sus com-onentes


79/106

7b:eti o Primario y sus com-onentes Standard #ouble D. +3( CI P Intn P

Muerte CV/IM/Stroke

Co, PC* (2@ 17 232 4.5 3.9 0.85 0.74 0.99 0.036 0.016Si, PC* (2@ 7855 4.2 4.9 1.17 0.95 1.44 0.14

+o"o (2@ 25 087 4.4 4.2 0.95 0.84 1.07 0.370

IM

Co, PC* (2@ 17 232 2.6 2.0 0.78 0.64 0.95 0.012 0.025Si, PC* (2@ 7855 1.4 1.7 1.25 0.87 1.79 0.23

+o$#l (2@ 25 087 2.2 1.9 0.86 0.73 1.03 0.097

Muerte CV

Co, PC* (2@ 17 232 1.9 1.9 0.96 0.77 1.19 0.681.0Si, PC* (2@ 7855 2.8 2.7 0.96 0.74 1.26 0.77

+o$#l (2@ 25 087 2.2 2.1 0.96 0.81 1.14 0.628

Stroke

Co, PC* (2@ 17 232 0.4 0.4 0.88 0.55 1.41 0.590.50Si, PC* (2@ 7855 0.8 0.9 1.11 0.68 1.82 0.67

Clo-idogrel; #osis Altas "s #osis standard7b:eti"o Primario; Poblacion PCI


80/106

#ays

C u m u

l a t i " e

D a E a r d

0 . 0

0 . 0 1

0 . 0

2

0 . 0 3

0 . 0

4

0 3 6 9 12 15 18 21 24 27 30

;

Clo-idogrel Standard

Clo-idogrel #ouble

D. &*3+3( CI &'%? &++

P= & )6

13( ...

Muerte CV2 MI o Stroke

Clo-idogrel; #osis Altas "s& #osis standard


81/106

Sangrados; Toda la Poblaci n

Clo-idogrel

Standar d

=1$3'+

#ouble=1$3

*

DaEard.atio

+3( CI P

+* * #yor 1 0.95 1.04 1.09 0.85 1.40 0.50CD-- @+ #yor 2 2.0 2.5 1.25 1.05 1.47 0.01CD-- @+ Se ero 3 1.5 1.9 1.23 1.02 1.49 0.03M#$#l 0.11 0.13 1.15 0.56 2.35 0.71

*,$r#cr#,e#l 0.05 0.03 0.67 0.19 2.37 0.53+r#,%u io, - 2D 1.76 2.21 1.26 1.06 1.51 0.01C! #yor 0.9 1.0 1.10 0.85 1.42 0.48

1*C= =b "rop 5 /K"L (e#ch u,i$ o% - C $r#, %u io, cou,$ # 1 /K"L "rop or %#$#l2Se ere blee" U "i #bli,/ or i,$r#ocul#r or re uiri,/ $r#, %u io, o% 2 3 u,i$3

M#$#l or ^=b 5 /K"L i/ hypo$e, io, U i,o$rope K ur/ery *C= or $ , o% 4 u,i$

Clo-idogrel; #osis Altas "s& #osis standardTrombosis del Stent Con irmada


82/106

#ays

C u m u

l a t i " e

D a E a r d

&

&

%

& *

&

1 $

) 6 + 1$ 13 1* $1 $% $' )

Clo-idogrel Standard #ose

Clo-idogrel #ouble #ose

%$(...

D. &3*

+3( CI &%$? &'+P= & 1

Trombosis del Stent Con irmada

Clo-idogrel; #ouble " Standard #osePCI Cohort Subgrou-s


83/106

&3 1&3

er#ll

@S+ *KD!S+ *

#leMele

!/e A 65 yr

!/e Z 65 yr@o, 'i#be$icPre 'i#be$ic

@o *,ho p P**bK***#P**b i, ho p

@o Pro$ Pu&p *,hibPro$ Pu&p *,hib

@o, &o er Curre,$ S&o er

!S! Lo> !S! =i/h

17232

10886 6346

13009 4223

10975

625713400 3831

12288 4936

7675 5557

10845 6380

8620 8612

4.5

4.25.0

4.15.8

3.0

7.14.25.6

3.96.0

3.85.7

4.93.8

4.24.8

3.9

3.64.2

3.64.6

2.7

6.03.64.9

3.54.7

3.24.2

4.62.6

4.33.5

0.805

0.419

0.702

0.836

0.465

0.408

0.045

0.024

&3 1&3

3.7

3.64.0

3.54.6

2.9

5.23.64.1

3.15.2

3.14.8

3.93.4

3.63.8

3.0

3.12.8

3.03.0

2.2

4.42.83.6

2.54.1

2.33.3

3.52.1

3.22.7

0.248

0.148

0.418

0.567

0.894

0.613

0.050

0.191

CV #eath2 MI or Stroke MI or StentThrombosis

PCI Cohort Subgrou s

Std ( #ouble ( Std ( #ouble (Int n P Int n P

#ouble#ose9etter

#ouble#ose9etter

Std #ose9etter

Std #ose9etter

$

Clo-idogrel; #osis Altas "s& #osisstandard seg`n #osis de as-irina


84/106

Clo-idogrel D. +3( CI P P int_n

standard #oble

Muerte CV/IM/Stroke 0Todos

!!S !l$# 4.6 3.8 0.83 0.70 0.99 0.0360.043 !!S #G# 4.2 4.5 1.07 0.91 1.27 0.42

IM/Trombosis del Stent 0PCI -ts

!!S !l$# 3.8 2.7 0.71 0.56 0.90 0.005 0.19

!!S #G# 3.6 3.2 0.89 0.71 1.12 0.32

Sangrado Mayor0Total

!!S !l$# 2.2 2.4 1.08 0.86 1.37 0.510.099

!!S #G# 1.9 2.7 1.43 1.13 1.81 0.003

gusada

Trombosis del Stent en los %


85/106

0AngiogrX icamente Probado

#ays

C u m u

l a t i " e

D a E a r d

&

&

%

& *

&

1 $

) 6 + 1$ 13 1* $1 $% $' )

Clo-i standard2 A 9a:

Clo-i standard2 A Alta

Clo-i #oble2 A 9a:a

Clo-i #oble2 A Alta

Standar d Clo-

#oubleClo- D. P

PInt n

Digh ASA 1.2 0.6 0.49 0.003

>o@ ASA 1.2 0.8 0.6 0.058 0.35

Conclusionesd


86/106

#osis de Clo-idogrel

1. 'o i "oble "el clopi"o/rel i/,i%ic#$i #&e,$e re"uce, el rie /o "e $ro&bo i "el$e,$ y "e lo e e,$o CE yore ( uer$e CE * o S$ro e e, p#cie,$e o&e$i"o

# PC*.

2. , p#cie,$e ,o o&e$i"o # PC* el "obl#r l# "o i "e clopi"o/rel ,o %uei/,i%ic#$i #&e,$e "i%ere,$e # u #r l# "o i e $V,"#r.

3. =ubo u, &o"e $o i,cre&e,$o e, lo #,/r#"o $ipo CD-- @+ pero i, "i%ere,ci#e, lo #,/r#"o yore $ipo +* * #,/r#"o %#$#le #,/r#"o i,$r#cr#,e#le orel#cio,#"o # ciru/Y# "e by p# (C! rel#$e" blee" .

Conclusiones#osis de AAS


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#osis de AAS

Si, "i%ere,ci# i/,i%ic#$i # e, l# $# # "e e%ic#ci# o "e#,/r#"o e,$re "o i #l$# (!S! 300 325 &/ y "o i

b#G# "e !!S (75 100 &/ .


88/106

Im-licaciones Clinicas

1. Por c#"# 1 000 p#cie,$e co, SC! o&e$i"o # PC* el u #r "o i"oble "e clopi"o/rel por 7 "i# e, e "e l# "o i e $#,"#r"pre e,"rV 6 * #"icio,#le y 7 $ro&bo i "el $e,$ co, u, e ce o"e 3 #,/r#"o yore pero i, i,cre&e,$#r lo #,/r#"o%#$#le +* * #yor o rel#cio,#"o # Ciru/Y# "e y P# .

2. Lo p#cie,$e ,o o&e$i"o # PC* (,eG#"o &_"ic#&e,$e"eberV, co,$i,u#r co, l# "o i e $#,"#re "e clopi"o/rel.


89/106

7 #

$ e r i #

l " e e ,

$ r e , # &

i e ,

$ o

S L

P ! - ! D S

* @ + - @

89

P>AT7

Challenging the


90/106

7 #

$ e r i #

l " e e ,

$ r e , # &

i e ,

$ o

S L

P ! - ! D S

* @ + - @

90

50% of patients in the "i,a& elo a m e,eive! a Clopi!o& el loa!in& !ose

icacy Perce-tion

PL! %%i #


91/106

7 #

$ e r i #

l " e e ,

$ r e , # &

i e ,

$ o

S L

P ! - ! D S

* @ + - @

91

PL!+ : %%ic#cy

PL! S#% $


92/106

7 #

$ e r i #

l " e e ,

$ r e , # &

i e ,

$ o

S L

P ! - ! D S

* @ + - @

92

PL!+ : S#%e$y

Challenging the


93/106

7 # $ e r i #

l " e e ,

$ r e , # &

i e ,

$ o

S L

P ! - ! D S

* @ + - @

93

Sa ety Perce-tion

T IT7 ?TIMI $*


94/106

T.IT7 ?TIMI $*Prasugrel ,, ient +

Study #esign


95/106

7 # $ e r i #

l " e e ,

$ r e , # &

i e ,

$ o

S L

P ! - ! D S

* @ + - @

95

#ouble?blind

ACS 0ST MI or UA/ ST MI Planned PCI

ASA

P.ASU

6 mg >#/ 1 mg M#

C>7PI#7

) mg >#/ '3 mg M#

1o end-oint; CV death2 non? atal MI2 Stroke$o end-oints; Q) ?+ daysR CV death2 non? atal MI2 UTV.

Q ollo@?u-R Stent Thrombosis 0CV death2 non? atal MI2 stroke orStroke2 .ehos-italiEation?Cardiac ischemic e"ent

Sa ety end-oints; TIMI ma:or bleeding not related to CA9


96/106

• Inclusion Criteria Planned PCI or ;

Mod?Digh .isk UA/ ST MI 0T.S K )ST MI; O 1% days 0ischemia or . strategyST MI; Primary PCI

• Ma:or clusion Criteria ; – Se"ere comorbidity – Increased bleeding risk – Prior hemorrhagic stroke or any stroke O ) mos – Any thieno-yridine @ithin 3 days –

o e clusion or ad"anced age or renal unction

Known Anatomy

9aseline Characteristics


97/106

Clo-idogrel

0 =6'+3(

Prasugrel

0 =6*1)(

UA/ ST MI '% '%

ST MI $6 $6

Age2 median 0IG.K '3 y

61 03)26+ y1)

61 03)2 ' y1)

Lgt2 median 0IG.O 6 kg

*) kg 0'$2 +$3&)

*% kg 0')2 +)%&6

8emale $' $3,

#iabetes $) $)Prior MI 1* 1*

CrCl 0ml/minK6O6

**1$

*+11

*P


98/106

0

5

10

15

0 3060 90 180 270 360 450

D. &*10 &')? &+P= & %

Prasugrel

Clo-idogrel

D. &*P= & )

D. &''P= & 1

#ays

P r i m a r y

n d - o

i n t 0 (

1$&10'*1

+&+06%)

CV #eath2MI2Stroke

T= %6

ITT= 1)26 * >T8U = 1% 0 &1(

9alance oicacy and Sa ety


99/106

0

5

10

15

0 30 60 90 180 270 360 450

D. &*10 &')? &+P= & %

Prasugrel

Clo-idogrel

#ays

n

d - o i n

t 0 (

1$&1

+&+

D. 1&)$01& )?1&6*

P= & )

Prasugrel

Clo-idogrel1&*$&%

1)*

e"ents

)3

e"ents

icacy and Sa ety

CV #eath / MI / Stroke

TIMI Ma:oronCA9< 9leeds

T = %6

D = 16'

Inde Procedure


100/106

Clo-idogrel

0 =6'+3(

Prasugrel

0 =6*1)(

PCI / CA9< ++ / 1 ++ / 1

Any Stent +3 +%

9MS %' %*# S %' %'

Multi"essel PCI 1% 1%

U8D / >MLD / 9i"al 63 / * / ) 66 / + / )

# o Study . Pre PCI

#uring PCI Post PCI

$3'%1

$6')1

9leeding "entsSafety Cohort


101/106

0 =1)2%3'

( " e n

t s

A.# &6(D. 1&)$P= & )

D=16'

Clo-idogrelPrasugrel

A.# &3(D. 1&3$P= & 1

A.# &$(P= &$)

A.# (P= &'%

A.# &)(P= & $

ICD in Pts @Prior Stroke/TIA

0 =31*

Clo- 0 ( Pras 6 0$&) ( 0P= & $

et Clinical 9ene it#eath2 MI2 Stroke2


102/106

Ma:or 9leed 0non CA9<

0

5

10

15

0 30 60 90 180 270 360 450

#ays

n

d - o

i n t 0 (

D. &*'P= & %

1)&+

1$&$

Prasugrel

Clo-idogrelITT= 1)26 *

"ents -er 1 -ts

MI Ma:or 9leed0non CA9<

All CauseMortalityClo- )&$(

Pras )& (P= &6%

Com-arison o #e initions Across Trials;CU T2 T IT7 2 d P AT7


103/106

1. Mehta SR et al. Am Heart J. 2008;156:1080-1088; 2. Wiviott SD et al.N Engl J Med. 2007;357:2001-2015;3. James et al. Am Heart J . 2009;157:599-605.

CU.. T1

T.IT7$

P>AT7)

StudyPo-ulation

D!K@S+ *KS+ * p#$ie,$ e,rolle">i$hi, $he 24 hour o% y&p$o& o, e$#," pl#,,e" e#rly i, # i e $r#$e/y>i$hi, 72 hour o% r#,"o&i #$io,

D!K@S+ *KS+ * p#$ie,$ >i$h coro,#ry#,#$o&y ,o>, $o be ui$#ble %or PC* orS+ * p#$ie,$ pl#,,e" %orpriry #,/iopl# $y

D!K@S+ *KS+ * !CS p#$ie,$>i$h o, e$ "uri,/ $he pre iou 24hour pl#,,e" $o be ,#/e"ei$her e#rly i, # i ely orco, er #$i ely

Com-arison $ $ actorial;• Clo-i; 600K150K75 &/ ('#y 1 2 7

8 30 300K75 &/• ASA; 300–325 &/K"#y 75–100

&/K"#y (#ll p#$ie,$ recei e" #, !S! L' 300 &/

• >oading #ose; Pr# 60 &/ or c lop 300&/ L' #,y$i&e be$>ee, r#,"o& #," 1hour #%$er le# i,/ c#$h l#b. Coro,#ry#,#$o&y h#" $o be ,o>, be%orer#,"o&i #$io,

• Maintenance; Pr# 10 &/K"#y orclop 75 &/K"#y

• !S! 75 162 &/ "#ily ># reco&&e,"e".

• >oading #ose; +ic#/relor 180&/ or clop 300 &/ L'(#""i$io,#l 300 &/ clop L'#llo>e" #$ PC*

• Maintenance; +ic#/relor 90 &/orclop 75 &/K"#y

• ASA dose; !S! 75–100 &/K"#y• !S! L' (325 &/ pre%erre" %or

p#$ie,$ ,o$ #lre#"y o, !S!

Timing o P$B 1$ .ece-torAntagonist>oading #ose

! e#rly # po ible #%$err#,"o&i #$io, #," be ore coro,#ry#,/io/r#phy

A ter "i#/,o $ic #,/io/r#phy (e cep$ %orp#$ie,$ >i$h priry PC* %or S+ * >ho>ere #llo>e" $o recei e $he $u"y "ru/be%ore coro,#ry #,/io/r#phy•

`25 o% p#$ie,$ recei e" $he $u"y "ru/be%ore 1 $ coro,#ry /ui"e>ire ># pl#ce"• `74 o% p#$ie,$ "uri,/ PC* or >i$hi,

1 hour #%$er PC*• `1 o% p#$ie,$ &ore $h#, 1 hour #%$er

PC*

! oo, # po ible (T 24 h #%$eri,"e e e,$

CU.. T2 T.IT7 2 and P>AT7

Com-arison o #e initions Across Trials;CU T2 T IT7 2 and P>AT7 0cont


104/106

CU.. T1

T.IT7$

P>AT7)

Sam-leSiEe

$3 ** 1)26 * K1*2

Primaryicacy

nd-oint0s

CE "e#$h * or $ro e #$ 30"#y

CE "e#$h * or $ro e $hrou/h e,"o% $re#$&e,$

CE "e#$h * or $ro e $hrou/h e,"o% $re#$&e,$

JeySecondary

icacynd-oints

• CE"e#$hK *K $ro eKre%r#c$oryi che&i# #$ "#y 30;

• *,%#rc$ rel#$e" #r$ery p#$e,cy#$ $he $#r$ o% #,/io/r#phy orho pi$#l "i ch#r/e i, S+ *p#$ie,$

• CE "e#$h * or $ro e #$ 30"#y #," 90 "#y

• S$e,$ $hro&bo i (!-C"e%i,i$eKprob#ble )

• +he priry e,"poi,$ #pplie" $oub/roup >i$h i,$e,$ %or i, # i e

,#/e&e,$ #$ r#,"o&i #$io,• +he occurre,ce o% $e,$

$hro&bo i by !-C cri$eri# –"e%i,i$eKprob#bleKpo ible

Sa etynd-oints

• CD-- @+ "e%i,e" e ere oro$her Gor blee"i,/ #$ 30"#y

• +* * Gor #," &i,or

blee"i,/ #$ 30 "#y

• @o, C! rel#$e" +* * Gorblee"i,/

• @o, C! rel#$e" +* * li%e$hre#$e,i,/ blee"i,/ #," +* *

Gor or &i,or blee"i,/

• PL!+ "e%i,e" Gor blee"i,/$self%defined as broader definitiont&an '(M( or C)RE*

• PL!+ "e%i,e" &i,or blee"i,/

#uration 30 "#y 6–15 &o,$h 6–12 &o,$h

1. Mehta SR et al. Am Heart J. 2008;156:1080-1088; 2. Wiviott SD et al.N Engl J Med. 2007;357:2001-2015;3. James et al. Am Heart J . 2009;157:599-605. 4. Ma !i et al. " #$%l J Me& 2007;356:1020-9.

CU.. T2 T.IT7 2 and P>AT7 0cont

, A.C de inition o stent thrombosis; %

#e inite; -e uire" $he pre e,ce o% #, #cu$e coro,#ry y,"ro&e >i$h #,/io/r#phic or #u$op y e i"e,ce o% $hro&bu or occlu io,.Probable; D,e pl#i,e" "e#$h >i$hi, 30 "#y #%$er $he proce"ure or #cu$e &yoc#r"i#l i,%#rc$io, i, ol i,/ $he $#r/e$ e el $erri$ory>i$hou$ #,/io/r#phic co,%ir$io,.Possible; !ll u,e pl#i,e" "e#$h occurri,/ #$ le# $ 30 "#y #%$er $he proce"ure.

Com-arison o Ma:or9leeding #e initions


105/106

9leeding #e initions

CU.. T?7ASIS ' ma:orbleeding 1 CU. ma:or bleeding $ P>AT7 ma:or bleeding ) TIMI ma:or bleeding 1

Se"ere;• M#$#l blee" or "rop i,he&o/lobi, o% 5 /K"l or

i/,i%ic#,$ hypo$e, io, >i$h$he ,ee" %or i,o$rope orre uiri,/ ur/ery (o$her $h#,

# cul#r i$e rep#ir• Sy&p$o$ic i,$r#cr#,i#lhe&orrh#/e• @ee"i,/ $r#, %u io, o% 4u,i$ o% re" bloo" cell ore ui #le,$ >hole bloo"7ther ma:or bleeding;• Si/,i%ic#,$ly "i #bli,/*,$r#ocul#r blee"i,/ le#"i,/$o i/,i%ic#,$ lo o% i io, orblee"i,/ re uiri,/$r#, %u io, o% 2 or 3 u,i$ o%re" bloo" cell or e ui #le,$>hole bloo"

>i e?threatening;• M#$#l blee" or "rop i,he&o/lobi, 5 /K"l or

i/,i%ic#,$ hypo$e, io, >i$h,ee" %or i,o$rope orre uiri,/ ur/ery (o$her $h#,

# cul#r i$e rep#ir• Sy&p$o$ic i,$r#cr#,i#lhe&orrh#/e• @ee"i,/ $r#, %u io, o% 4u,i$ o% re" bloo" cell ore ui #le,$ >hole bloo"

on?li e?threatening;Si/,i%ic#,$ly "i #bli,/ ori,$r#ocul#r >i$h i io, lo

or ,ee"i,/ $r#, %u io, o% 2 u,i$ o% bloo"

>i e?threatening;• M#$#l or i,$r#cr#,i#l ori,$r#peric#r"i#l >i$h c#r"i#c$#&po,#"e or hypo ole&ic

hoc or e ere hypo$e, io,re uiri,/ pre or or ur/ery• ! oci#$e" "ecre# e i,h#e&o/lobi, Z50 /KL• @ee"i,/ $r#, %u io, o% 4u,i$ o% re" bloo" cell ore ui #le,$ >hole bloo"7ther;Si/,i%ic#,$ly "i #bli,/ (e/i,$r#ocul#r >i$h per,e,$

i io, lo or # oci#$e"

"ecre# e i, h#e&o/lobi, 30 50 /KL or ,ee"i,/

$r#, %u io, o% 2 3 u,i$ o%bloo".

• M#$#l blee"• *,$r#cr#,i#l he&orrh#/e• C#r"i#c $#&po,#"e'rop i, he&o/lobi, Z 5 /K"l%ro& b# eli,e

1. eh$# S- e$ #l. !" Heart J. 2008;156:1080 1088.

2. CD- +ri#l *, e $i/#$or . N Engl J Med. 2001;345:494 502.3.


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Ticagrelor&I IIa IIb III

B

Prasugrel&I IIa IIb III

I IIa IIb III

B

Clo-idogrel&

presentacion plavix es para ponentes

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