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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$$ee. Lancet 1996; 348: 1329–39.
Months o ollo@?u-
8.7 )er#ll
rel#$i eri
re"uc$io,
0
4
8
12
16
0 3 6 9 12 15 18 21 24 27 30 33 36
C u m u
l a t i " e e " e n
t r a t e 0 (
!S!
p 0.043 , 19 185
Clopi"o/rel
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CAP.I ; 9ene it o Clo-idogrel o"er ASA in the .eduction oMyocardial In arction 1
1& e,$ . Circulation 1997; 96( uppl 8 : * 467.
Months o ollo@?u-
0
1
2
3
4
5
0 3 6 9 12 15 18 21 24 27 30 33 36
C u m u
l a t i " e e " e n
t r a
t e 0 (
p 0.008 , 19 185
!S! 3.6
Clopi"o/rel 2.9
Clopi"o/rel
!S! 19.2 )-el#$i e
rire"uc$io,
)*++ #,#ly i
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$3
As-irin12$
Clo-idogrel12$
$6(
3
1
13
$
$%1+
" e n
t s P r e " e n
t e d / B e a r / 1 2
P a
t i e n
t s
)( * i che&ic $ro e #," # cul#r "e#$h)) # e" o, $he C!P-* $ri#l #," !,$ipl#$ele$+ri#li $ Coll#bor#$io, &e$# #,#ly i # piri,c#, be e pec$e" $o pre e,$ 19 i che&ice e,$ ) %or e ery 1 000 p#$ie,$ $re#$e" perye#r 1 2. *, co,$r# $ clopi"o/rel c#, be
e pec$e" $o pre e,$ 24 i che&ic e e,$ ) %ore ery 1000 p#$ie,$ $re#$e" # 26"i%%ere,ce.
1C!P-* S$eeri,/ Co&&i$$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
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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
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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
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Distory o MI )$&% )$&
CA9< surgery/PTCA 1'&' 1*&1Stroke %&% )&'
Deart ailure '&% '&*
Dy-ertension 3+&+ 3'&*
#iabetes $$&% $$&*
Current or ormer smoker 6 &6 6 &+
Clo-idogrel n = 62$3+
0(
Placebon = 62) )
0(
Patient Distory
+he CD- +ri#l *, e $i/#$or . N Engl J Med. 2001;345:494 502.
CU. Study
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As-irin ++&+ ++&+
De-arin 0U8D2 >MLD +$&% +$&%
9eta blockers *%&1 *)&3
Calcium?channel blockers %+&* %*&'
AC inhibitors 61&+ 61&3
>i-id?lo@ering agents 6%&3 6%&%
Clo-idogr el
0(Placebo
0(
'#$# o, %ile S#,o%i Sy,$hel#bo *,c.
Medications A ter .andomiEation
CU. Study
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Primary outcome +&)( 11&%( $ (& +
0MI2 stroke2 CV deathCo?-rimary outcome 4 16&3( 1*&*( 1%(
& 3All indi"idual outcome e"ents;
MI 3&$( 6&6( $)(Stroke 1&$( 1&%( 1%(
CV death 3&1( 3&3( '(.e ractory ischemia *&'( +&)( '(
.elati"e .isk.eduction P "alue
7utcomeClo-idogrel
ASA,n = 62$3+
Placebo ASA,
n = 62) )
CU. StudyMain icacy .esults;Combined Co?-rimary nd Points
) $her $#,"#r" $her#pie >ere u e" # #ppropri#$e.? * $ro e CE "e#$h or re%r#c$ory i che&i#.F
+he i,"i i"u#l co&po,e,$ repre e,$ $he $o$#l ,u&ber o% ubGec$ e perie,ci,/ #, e e,$ "uri,/$he cour e o% $he $u"y.
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Primary nd PointNMI/Stroke/CV #eath
Clo-idogrel ASA,
) 6 +
Placebo ASA,
Months o 8ollo@?U-
P = & +4
= 1$236$
1$
) $her $#,"#r" $her#pie >ere u e" # #ppropri#$e.?PL!E*H Pre cribi,/ *,%or$io,.
!"#p$e" >i$h per&i io, (2002 %ro& $he # #chu e$$ 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-&
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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
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#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
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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
) $her $#,"#r" $her#pie >ere u e" # #ppropri#$e.PL!E*H Pre cribi,/ *,%or$io,.
CU St d
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Placebo ASA,
Clo-idogrel ASA,
Ma:or 9leeding by ASA #ose
O1 mg $&6( $& (
1 F$ mg )&3( $&)(
K$ mg %&+( %& (
ASA #ose
CU. Study
) $her $#,"#r" $her#pie >ere u e" # #ppropri#$e.PL!E*H Pre cribi,/ *,%or$io,.
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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(
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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
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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
*
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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
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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.
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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
$
$3
P r i m a r y e n
d - o
i n t , 0 (
)6( reduction,- O & 1
1. S#b#$i,e e$ #l. New Eng J Med 2005; 352: 1179–1189.
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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,$er #l
1. S#b#$i,e e$ #l. New Eng J Med 2005; 352: 1179–1189.
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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
1. S#b#$i,e e$ #l. New Eng J Med 2005; 352: 1179–1189.
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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
1. S#b#$i,e e$ #l. New Eng J Med 2005; 352: 1179–1189.
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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.
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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
1. S#b#$i,e e$ #l. New Eng J Med 2005; 352: 1179–1189.
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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
1. S#b#$i,e e$ #l. New Eng J Med 2005; 352: 1179–1189.
S=not statistically signi icant
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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
1. S#b#$i,e e$ #l. New Eng J Med 2005; 352: 1179–1189.
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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
.
1. CCS 2 Coll#bor#$i e roup. J Cardiovasc Ris 2000; 7: 435 − 441.
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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
1. CCS 2 Coll#bor#$i e roup. J Cardiovasc Ris 2000; 7: 435 − 441.
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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
1. CCS 2 Coll#bor#$i e roup. J Cardiovasc Ris 2000; 7: 435 − 441.
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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 $$&%( $$&$(Calcium antagonists 11&*( 11&*(
Concomitant Medications #uring IndeDos-italiEation 1
1. Che, e$ #l. r#l pre e,$#$io, !CC 2005. ! #il#ble #$: D-L: h$$p:KK>>>.co&&i$ cc 2.or/. !cce e" !pril 2005.
http://www.commit-ccs2.org/http://www.commit-ccs2.org/
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Clo-idogrel .educed the Com-osite o #eath2MI or Stroke by +( 1
' 1% $1 $*
1$)%36'*+
1
#ays 0u- to $* days
Clo-idogrel0+&)(
Placebo
01 &1(
" e n t s
0 (
...=+(-= & $
...=relati"e risk reduction
1. Che, e$ #l. r#l pre e,$#$io, !CC 2005. ! #il#ble #$: D-L: h$$p:KK>>>.co&&i$ cc 2.or/. !cce e" !pril 2005.
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Clo-idogrel .educed Mortality by '( 1
' 1% $1 $*
1
$
)
%
3
6
'
*
+
#ays 0u- to $* days
Clo-idogrel0'&3(
Placebo
0*&1( ...='(-= & )
M o r t a
l i t y
0 (
1. Che, e$ #l. r#l pre e,$#$io, !CC 2005. ! #il#ble #$: D-L: h$$p:KK>>>.co&&i$ cc 2.or/. !cce e" !pril 2005.
http://www.commit-ccs2.org/http://www.commit-ccs2.org/
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Clo-idogrel #ecreased .e?In arction 1
7dds ratio +3( CIClo-idogrel better Placebo better
7utcome Clo-idogrel Placeboa ter re?MI 0n=$$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&
1. Che, e$ #l. r#l pre e,$#$io, !CC 2005. ! #il#ble #$: D-L: h$$p:KK>>>.co&&i$ cc 2.or/. !cce e" !pril 2005.
http://www.commit-ccs2.org/http://www.commit-ccs2.org/
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ects o Clo-idogrel on Stroke 1
7dds ratio +3( CIClo-idogrel better Placebo better
Clo-idogrel PlaceboTy-e 0n=$$2+3* 0n=$$2*+1
Ischemic 16$ 0 &'( 1+$ 0 &*(
Demorrhagic 33 0 &$( 33 0 &$(
A>> $16 0 &+( $%+ 01&1( 1%(reduction
-= S
&% &6 &* 1& 1&$ 1&% 1&
1. Che, e$ #l. r#l pre e,$#$io, !CC 2005. ! #il#ble #$: D-L: h$$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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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$% 0 &3%(
1. Che, e$ #l. r#l pre e,$#$io, !CC 2005. ! #il#ble #$: D-L: h$$p:KK>>>.co&&i$ cc 2.or/. !cce e" !pril 2005.
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ects o Clo-idogrel on #eath2 .e?MI orStroke by #ays to "ent 1
7dds ratio +3( CIClo-idogrel better Placebo better
Clo-idogrel Placebo"ents by day 0n=$$2+3* 0n=$$2*+1
%6) 0$& 3$) 0$&)
1 %*6 0$&1 3$' 0$&)$ ) %%+ 0$& %31 0$&
% ' %)$ 01&+ %6) 0$&
* $* $+3 01&) )%' 01&3
A>> $1$3 0+&)( $)11 01 &1(
&% &6 &* 1& 1&$ 1&% 1&
+(
increase-= & $
1. Che, e$ #l. r#l pre e,$#$io, !CC 2005. ! #il#ble #$: D-L: h$$p:KK>>>.co&&i$ cc 2.or/. !cce e" !pril 2005.
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Consistent ects o Clo-idogrel on #eath2.e?MI or Stroke by Age and
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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. Che, e$ #l. r#l pre e,$#$io, !CC 2005. ! #il#ble #$: D-L: h$$p:KK>>>.co&&i$ cc 2.or/. !cce e" !pril 2005.
1
http://www.commit-ccs2.org/http://www.commit-ccs2.org/
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Clo-idogrel 0'3 mg once daily on a background o standardthera-y including ASA @as bene icial at % @eeks or a @iderange o acute ST MI -atients
− Clo-idogrel reduced mortality, by '( 0-= & )− Clo-idogrel reduced the risk o death2 non? atal MI or
non? atal stroke by +( 0-= & $
o signi icant increase in the risk o ma:or 0 atal ortrans used bleeding occurred @ith clo-idogrel
,#eath during initial hos-italiEation
Conclusions 1
1. Che, e$ #l. r#l pre e,$#$io, !CC 2005. ! #il#ble #$: D-L: h$$p:KK>>>.co&&i$ cc 2.or/. !cce e" !pril 2005.
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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
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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
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) *, #""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
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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
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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
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-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 $; #osis de Mantenimiento mXs altas -roducen Inhibici n
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PO & 1
Clo-idogrel
0A
PlaHuetaria mXs intensa en -acientes sometidos a PCI 1
*P!: *,hibi$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
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"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
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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
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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
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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
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.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
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.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 #$$e,"#,$ #ce$yl #licylic #ci"
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1. eh$# S- et al. !" Heart J 2008;156:1080–1088e1'?days double?dose P>AVI \ regimen
• P#$ie,$ >i$h unstable angina or non?ST?segment ele"ation myocardial in arction;* ch#e&ic y&p$o& u pec$e" $o repre e,$ # ,o, S+ e/&e,$ ele #$io, #cu$e coro,#ry
y,"ro&e "e%i,e" # : – Cli,ic#l hi $ory co, i $e,$ >i$h ,e> o, e$ or # >or e,i,/ p#$$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 $her#py
Poblaci n del studio
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7b:eti"os de icacia
bGe$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
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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:
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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$>ee, !S! "o e /roup
* lee" : 30 (0.24 47 (0.38 P 0.051
Clo-idogrel #ose Com-arison
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Clo-idogrel #ose Com-arison
2 Si/,i%ic#,$ *,$er#c$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
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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
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#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
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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
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#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 &%$? &'+P= & 1
Trombosis del Stent Con irmada
Clo-idogrel; #ouble " Standard #osePCI Cohort Subgrou-s
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&3 1&3
er#ll
@S+ *KD!S+ *
#leMele
!/e A 65 yr
!/e Z 65 yr@o, 'i#be$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
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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 %
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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 $% $' )
Clo-i standard2 A 9a:
Clo-i standard2 A Alta
Clo-i #oble2 A 9a:a
Clo-i #oble2 A Alta
Standar d Clo-
#oubleClo- D. P
PInt n
Digh ASA 1.2 0.6 0.49 0.003
>o@ ASA 1.2 0.8 0.6 0.058 0.35
Conclusionesd
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#osis de Clo-idogrel
1. 'o i "oble "el clopi"o/rel i/,i%ic#$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$# (!S! 300 325 &/ y "o i
b#G# "e !!S (75 100 &/ .
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Im-licaciones Clinicas
1. Por c#"# 1 000 p#cie,$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.
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7 #
$ e r i #
l " e e ,
$ r e , # &
i e ,
$ o
S L
P ! - ! D S
* @ + - @
89
P>AT7
Challenging the
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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 #
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7 #
$ e r i #
l " e e ,
$ r e , # &
i e ,
$ o
S L
P ! - ! D S
* @ + - @
91
PL!+ : %%ic#cy
PL! S#% $
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7 #
$ e r i #
l " e e ,
$ r e , # &
i e ,
$ o
S L
P ! - ! D S
* @ + - @
92
PL!+ : S#%e$y
Challenging the
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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 $*
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T.IT7 ?TIMI $*Prasugrel ,, ient +
Study #esign
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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
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• 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
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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
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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$&10'*1
+&+06%)
CV #eath2MI2Stroke
T= %6
ITT= 1)26 * >T8U = 1% 0 &1(
9alance oicacy and Sa ety
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0
5
10
15
0 30 60 90 180 270 360 450
D. &*10 &')? &+P= & %
Prasugrel
Clo-idogrel
#ays
n
d - o i n
t 0 (
1$&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
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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
$6')1
9leeding "entsSafety Cohort
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0 =1)2%3'
( " e n
t s
A.# &6(D. 1&)$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
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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- )&$(
Pras )& (P= &6%
Com-arison o #e initions Across Trials;CU T2 T IT7 2 d P AT7
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1. Mehta SR et al. Am Heart J. 2008;156:1080-1088; 2. Wiviott SD et al.N Engl J Med. 2007;357:2001-2015;3. James et al. Am Heart J . 2009;157:599-605.
CU.. T1
T.IT7$
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
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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
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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&
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