Nuevos antiagregantes Nuevos antiagregantes plaquetariosplaquetarios

XII Curso de Formación Continuada XII Curso de Formación Continuada

26-28 marzo 2014 Hotel El Montanyà. Seva, Barcelona 26-28 marzo 2014 Hotel El Montanyà. Seva, Barcelona

¿Sigue siendo importante el pretratamiento con los nuevos

antiagregantes plaquetarios?

Concepto de pretratamiento en SCA

SCACEST SCASEST

ICP1ªICP1ª ICPICPTto.Tto.

médicomédicoCirugíaCirugía

AASAAS

P2Y12 antg.P2Y12 antg. ?

Clopidogrel pretreatment and early risk

PCI-CURE CREDO

30-day death, MI & urg. TVR (%)

p=0.01 p=0.05

300 mg + 75 mg for median of 10 days

300 mg<6 hrs 6–24 hrs

No pretreatmentPretreatment

Clopidogrel: ¿Cúal es la dosis óptima?Clopidogrel: ¿Cúal es la dosis óptima?

0

20

40

60

80

100p<0.0001

p=0.009p=0.005

p=0.001 (MANOVA)

Basal 4h 24h 48h PostACTP

Activación GPIIb/IIIa (ADP2M)

% C

el. p

ositiv

as

Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al. Eur Heart J 2004;25(21):1903-10

300 mg ( n=20)

600 mg ( n=20)

PCI 600 mgPreloadN= 204

Primaryend point:

cardiac death, MI, TVR

536 Patients with

•Stable angina

or

•NSTE-ACS

undergoingcoronary

angiography

30 days

Clopidogrel600 mg given

4-8 hrs before angio

N= 267

Clopidogrel600 mg at the time of PCI N= 269

PCI 600 mg in-lab

N= 205

Medical RxN= 72

CABGN= 55

N= 409

• CKa-MB

• Troponin-I

• PRU

1st blood sample

Baseline

2nd, 3rd, 4th and 5th blood samples

At the time of PCI

2 hrs after PCI

8 and 24 hrsafter PCI

• PRU • CK-MB

• Troponin-I

• PRU

• PRU

ARMYDA-5 PRELOAD: Study design

R

an

do

miz

atio

n

Angiography

Di Sciascio G et al. J Am Coll Cardiol 2010;56:550-557

0

4

8

12

16

20

In-lab load Preload

p=0.72

5 10 15 20 25 30

Days after PCI

Cum

ulat

ive

inci

denc

e of

MA

CE

(%

)

ARMYDA-5 PRELOAD: Primary endpoint

Adverse events at 30 days(Clopidogrel in-lab load vs preload)

Di Sciascio G et al. J Am Coll Cardiol 2010;56:550-557

0

4

8

12

16

20

Majorbleeding

In-lab loadPreload

% o

f pat

ient

s%

of p

atie

nts

0

7.8

5.4

p=0.42

Minorbleeding

0

ARMYDA-5 PRELOAD: Safety secondary end point

Di Sciascio G et al. J Am Coll Cardiol 2010;56:550-557

1. Wiviott SD et al. Am Heart J. 2006;152:627-635.2. Payne CD et al. Am J Cardiol. 2006;98:S8.

New P2Y12 AntagonistsEarly onset and high inhibition

mean ± SEM 20 μM ADP

Time after loading dose (hrs)

Inh

ibit

ion

of

pla

tele

t a

gg

reg

atio

n (

%)

0

20

40

60

80

100

Clop 300 mg LD

0.25 0.5 1 2 4 6 24

Loading dose

†p<0.001 vs. Clop 300 mg

† †

!†

!p<0.05 vs. Clop 300 mg!

Clop 600 mg LD

*

*

** * *

p<0.001 vs. Clop 300 mgor 600 mg LD*Pras 60 mg LD

0

LD, Loading dose

• Pre-treatment with aspirin and a P2Y12 antagonist is a class I recommendation and is common practice for the treatment of NSTE-ACS

• In CURE, patients were managed conservatively

• In TRITON, patients were not pretreated before cath

• In PLATO, patients were pretreated before cath

• No trial had ever randomized patients presenting with NSTE-ACS, invasively managed, to pre-treatment with clopidogrel, prasugrel or ticagrelor vs. no pre-treatment …… ACCOAST

ACCOAST design

Prasugrel 30 mg

Prasugrel 60 mg Prasugrel 30 mg

Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days

PCI

1° Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa inh. Bailout, at 7 days

Placebo

CoronaryAngiography

n~4100 (event driven)

CoronaryAngiography

PCI

CABG or

MedicalManagement

(no prasugrel)

CABG or

MedicalManagement

(no more prasugrel)

Montalescot G et al. Am Heart J 2011;161:650-656

Randomize 1:1Double-blind

NSTEMI + Troponin ≥ 1.5 times ULN local lab valueClopidogrel naive or on long term clopidogrel 75 mg

Pharmacodynamic Sub-Study

Data presented as median ± SEM. * p<0.05 relative to the No pre-treatment group. LD = loading dose.Pretreatment=Prasugrel 30 mg/Prasugrel 30 mg; No Pre-treatment=Placebo/Prasugrel 60 mg

Hours (post LD2)

P2Y

12

Rea

ctio

n U

nit

s

0

50

100

150

200

250

300

350Pre-treatment (30/30)No Pre-treatment (0/60)

Pre LD1(baseline)

Pre LD2 0.5 2 3 41 24

Approximatetime of PCI

*

*

30 mgLD1

PlaceboLD1

60 mgLD2

30 mgLD2

*P<0.05

Days From First Dose

0 5 10 15 20 25 30

En

dp

oin

t (%

)

0

5

10

15

1996

20371788

1821

1775

1809

1769

1802

1762

17971752

1791

CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout

1621

1616

No. at Risk, Primary

Efficacy End Point:

No pre-treatment

Pre-treatment

Pre-treatment10.810.0

Pre-treatment

Hazard Ratio, 0.997 (95% 0.83, 1.20)P=0.98P=0.81

(95% 0.84, 1.25) Hazard Ratio, 1.02

No Pre-treatment10.8

9.8No Pre-treatment

1° Efficacy End Point @ 7 + 30 days (All Patients)

All TIMI (CABG or non-CABG) Major Bleeding

(All Treated patients)

Days From First Dose0 5 10 15 20 25 30

En

dp

oin

t (%

)

0

1

2

3

4

5

All TIMI Major Bleeding

Pre-treatment2.9

Pre-treatment2.6

No Pre-treatment1.5

No Pre-treatment1.4

19962037

19471972

13281339

12971310

12881299

12841297

12631280

No. at Risk, All TIMI Major Bleeding:No pre-treatmentPre-treatment

Hazard Ratio, 1.97 (95% 1.26, 3.08)P=0.002

Hazard Ratio, 1.90(95% 1.19, 3.02) P=0.006

*Hazard ratio not evaluated for <10 events.†Interaction p-value is from a Cox proportional hazards model with treatment, subgroup, and the treatment-by-subgroup interaction as fixed effects; ‡CRUSADE score is a post-hoc analysis; PCI includes 11 patients with PCI + CABG.

Overall (pre-treatment vs. no pre-treatment)

PCICABG

SexMaleFemale

Age<75 years>75 years

RegionEastern Europe/IsraelWestern Europe/Canada

DiabetesYesNo

52 (2.55)

Hazard Ratio(95% CI)

1.90 (1.19, 3.02)

TotalPatients

4033

2781

Medical Management*

GRACE score<140>140

Weight<60 kg*>60 kg

22 (1.57) 1.98 (0.96, 4.09)238 25 (20.66) 1.59 (0.85, 2.98)

1014 5 (0.97)

Pre-tx(%)

1990 28 (2.75) 1.50 (0.83, 2.71)2008 24 (2.40) 2.70 (1.25, 5.80)

1998 27 (2.72) 2.28 (1.16, 4.51)2003 24 (2.35) 1.54 (0.81, 2.93)

3079 34 (2.22) 1.92 (1.09, 3.41)852 16 (3.54) 1.76 (0.75, 4.12)

2923 31 (2.09) 1.43 (0.82, 2.49)1110 21 (3.80) 3.61 (1.46, 8.95)

3318 36 (2.16) 1.64 (0.96, 2.78)715 16 (4.29) 2.95 (1.08, 8.05)

205 5 (4.85)3824 47 (2.43) 1.78 (1.10, 2.87)

1692

2341

820 6 (1.45) 0.98 (0.32, 3.05)3213 46 (2.83) 2.16 (1.29, 3.62)

InteractionP-value†

0.74

0.23

0.41

0.31

0.09

0.35

0.22

0.87

27 (1.35)

No Pre-tx(%)

11 (0.80)16 (13.68)

0 (0.00)

18 (1.86)9 (0.89)

12 (1.20)15 (1.53)

18 (1.16)8 (2.00)

21 (1.46)6 (1.08)

22 (1.33)5 (1.46)

1 (0.98)26 (1.37)

6 (1.47)21 (1.32)

AccessFemoralRadial

2276 29 (2.54) 1.62 (0.90, 2.91)1711 22 (2.53) 2.67 (1.19, 6.00)

0.6618 (1.58)8 (0.95)

14 (1.62) 2.69 (0.97, 7.47)5 (0.60)

38 (3.24) 1.74 (1.03, 2.94)22 (1.89)

0.46

Pre-treatment better No pre-treatment better

Time from Sx to LD <median>median

Time from first LD to angio/PCI <median>median

NE

NE

CRUSADE score‡<median>median

2051 23 (2.23) 2.29 (1.09, 4.81)1789 27 (2.97) 1.75 (0.93, 3.28)

0.5910 (0.98)15 (1.71)

0.2 0.5 1 2 5 10 15

All TIMI Major Bleeding for Prespecified Subgroups Through 7 days (All Treated Patients)

¿Existe evidencia del beneficio del pretatamiento con clopidogrel?

¿Necesitan todos los pacientes pretratamiento?

Con los nuevos antiagregantes, ¿es importante el pretratamiento?

¿Es igual con prasugrel que con tricagrelor?

¿Influye la precocidad en realizar la coronariografía?

¿ Dónde iniciar el tratamiento de los nuevos antiagregantes?, ¿ambulancia?, ¿urgencias?, ¿lab. hemodinámica?

Pretratamiento en SCASCEST: preguntas