selección lógica de antiplaquetarios en sca-icp dr. josé luis ferreiro hospital universitario de...

Selección lógica de antiplaquetarios en SCA-ICP

Dr. José Luis FerreiroHospital Universitario de Bellvitge: Área de Enfermedades del CorazónUnidad de Cardiología Intervencionista – Laboratorio de Investigación Cardiovascular

SOLACI Simposium, México, 9-VIII-2012

CONFLICTS OF INTERESTHonoraria for lectures:

Eli Lilly Co; Daiichi Sankyo, Inc.; AstraZeneca

Research grants:Spanish Society of Cardiology

G

COX-1

AA

TxA 2

G

ADP

G

Thrombin

TxA2 INHIBITORS

P2Y12 INHIBITORS

COX-1 Inhibitors Aspirin

TxA 2

TiclopidineClopidogrelPrasugrelTicagrelor

GP IIB/IIIA INHIBITORSAbciximabTirofibanEptifibatide

G

5HT2

A

fibrinogen

G

ADP

G

PGE

PI3K

Intracellular signaling

GP IIb/IIIa

GP VI GP Ib/IX/V

AVAILABLE ANTIPLATELET DRUGS

Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:433-45.

G

COX-1

AA

TxA 2

G

ADP

G

Thrombin

TxA2 INHIBITORS

P2Y12 INHIBITORS PAR-1 INHIBITORS

TP inhibitors Picotamide Ridogrel Ramatroban Terutroban EV-077

TxA 2

CangrelorElinogrel

VorapaxarAtopaxar

G

5HT2

A

fibrinogen

G

ADP

G

PGE

PI3K

Intracellular signaling

GP IIb/IIIa

GP VI GP Ib/IX/V

GP VI antagonists Kistomin Revacept

GP Ib antagonists 6B4-Fab

5HT2A antagonists APD791

EP antagonists DG-041

P2Y1 inhibitors MRS2179 MRS2500

PIP3K inhibitors TGX-221

AGENTS ON DEVELOPMENT


Does one size fit all??

INDEX

Clopidogrel variability in response

Novel P2Y12 inhibitorsPrasugrel TicagrelorSubgroup analyses

Balancing efficacy and safety

CLOPIDOGREL: VARIABILITY IN

RESPONSE

Primary Endpoint—MI / stroke/ CV Death

Months of Follow-Up*Other standard therapies were used as appropriate.

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Cu

mu

lati

ve

Ha

zard

Ra

te

Clopidogrel + ASA*

3 6 9

Placebo + ASA*

p=0.00009N=12,56220% RRR

0 12

Primary outcome: 9.3% in clopidogrel + ASA group and 11.4% in placebo + ASA group.

Suboptimal response?

Yusuf S et al. N Engl J Med 2001;345:494-502.

CLOPIDOGREL: EFFICACY

% Platelet aggregation (LTA-ADP 20mM)

97.5

92.5

87.5

82.5

77.5

72.5

67.5

62.5

57.5

52.5

47.5

42.5

37.5

32.5

27.5

22.5

17.5

12.5

7.5

2.5

20

15

10

5

0

Pat

ient

s (n

)

Angiolillo DJ et al. Am J Cardiol 2006;97:38-43.

↑ Ischemic risk

CLOPIDOGREL: VARIABILITY IN RESPONSE

↑ Bleeding risk

Patients with UA/NSTEMI or STEMI planned for early invasive strategy i.e. intent for PCI as early as possible within 72 hours

Randomize

Clopidogrel Standard Dose Group300 mg Day 1; 75 mg Days 2-30

Clopidogrel High Dose Group600 mg Day 1; 150 mg Days 2-7; 75 mg Days 8-30

Randomize Randomize

ASA low doseAt least 300 mg Day 1; 75-100 mg Days 2-30

ASA high doseAt least 300 mg Day 1; 300-325 mg Days 2-30

ASA low doseAt least 300 mg Day 1; 75-100 mg Days 2-30

ASA high doseAt least 300 mg Day 1; 300-325 mg Days 2-30

Primary Efficacy OutcomeComposite of CV Death, MI, or stroke up to day

30Primary Safety Outcome

Major Bleeding up to day 30

n=25,087

Double Blind

Open Label

CURRENT/OASIS 7: STUDY DESIGN

Mehta SR et al. NEJM 2010;363:930-42.

Measure Standard Dosing

Double Dosing

CV death, MI, and stroke, overall cohort (n=25,087) 4.4 4.2

● PCI cohort (n=17,232) 4.5 3.9

● No PCI cohort (n=7,855) 4.2 4.9

MI, overall cohort 2.2 1.9

● PCI cohort 2.6 2.0

● No PCI cohort 1.4 1.7

0.5 1 1.5 2

CURRENT OASIS-7 TRIALCOMPARISON OF CLOPIDOGREL DOSING: PRIMARY OUTCOME AND

COMPONENTS

Odds Ratio

P=0.016

P=0.025

Double Better

Standard Better

Mehta SR et al. NEJM 2010;363:930-42.

NOVEL P2Y12 INHIBITORS

Clopidogrel Prasugrel Ticagrelor Cangrelor Elinogrel

Group Thienopyridine Thienopyridine CPTP ATP analog Quinazolinedione

Administration oral oral oral IV IV and oral

Receptor blockade

irreversible irreversible reversible reversible reversible

Onset of action 2-8 h 30 min-4 h 30 min – 2 h seconds seconds

Offset of action 7-10 days 7-10 days 3-5 days 60-90 minutes50 min (IV)12 h (oral)

CYP drug interactions

yes no yes no no

P2Y12 INHIBITORS

Modified from Angiolillo DJ and Ferreiro JL. Rev Esp Cardiol 2010;63:60-76

Angiolillo DJ et al. JACC Interv 2011

NOVEL ORAL P2Y12 INHIBITORS

More potent and less variability!!

TRITON TIMI-38: STUDY DESIGN

Wiviott SD et al. NEJM 2007;357:2001-15.

Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding

6–12-month exposure

ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)

Ticagrelor180 mg loading dose, then

90 mg bid maintenance;(additional 90 mg pre-PCI)

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;

randomised within 24 hours of index event (N=18,624)

PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

PLATO: STUDY DESIGN

Wallentin L et al. NEJM 2009;361:1045-57.

Differences between studies

Population TRITON: ACS undergoing PCI PLATO: all ACS

Pretreatment (before PCI) TRITON: Not allowed (except STEMI) PLATO: Allowed

Loading dose of clopidogrel TRITON: 300mg PLATO: 300-600mg

Study length (median) TRITON: 14.5 months PLATO: 9 months

TRITON VERSUS PLATO

TRITON TIMI 38

(prasugrel vs clopidogrel)

PLATO(ticagrelor vs clopidogrel)

Prasugrel vs Clopidogrel

2.4% vs 1.8%

ARD 0.6%HR 1.32P=0.03

NNH=167

Ticagrelor vs Clopidogrel

2.8% vs 2.2%

ARD 0.6%HR 1.25P=0.03

NNH=167

Non-CABG TIMI major bleeding

TRITON PLATO

PRASUGREL VERSUS TICAGRELOR

Clopidogrel Prasugrel Ticagrelor

2011 ACCF/AHA

UA/NSTEMIClass I; LOE A Class I; LOE B

Not FDA approved or marketed

at the time of writing of

Guidelines

2011 ACCF/AHA/SCAI

PCIClass I; LOE B* Class I; LOE B* Class I; LOE B*

2011 ESC NSTEACS Class I; LOE A Class I; LOE B Class I; LOE B

2010

ESC/EACTS/EAPCI

Myocardial

Revascularization

Elective PCI: Class I; LOE A

NSTE-ACS: Class I; LOE B

STEMI: Class I; LOE C

NSTE-ACS: Class IIa; LOE B

STEMI: Class I; LOE B

NSTE-ACS: Class I; LOE B

STEMI: Class I; LOE B

GUIDELINES

OK, but… what do we do?

CLOPIDOGREL: STEMI

89,2% patients with poor response to clopidogrel

24,3% patients with poor response to ASA

Patients with suboptimal response (%)

ASA Clopidogrel

VerifyNow 24.3% 89.2%

LTA (AA/ADP) 38.9% 84.2%

MEA 95%

Ferreiro JL et al. Reunión de la Sección de Hemodinámica, Santander 2012.

Montalescot G et al. Lancet 2009;373:723-731.

PRASUGREL: STEMI

Pretreatment allowed

K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke)

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Steg PG et al. Circulation 2010;122:2131-2141

HR, 0.87; 95% CI, 0.75 to 1.01; P=0.07)

TICAGRELOR: STEMI

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

En

dp

oin

t (%

)

CV Death/MI/Stroke

TIMI Major Non-CABG Bleeds

NNT=21

(n=3146) 17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

Wiviott SD et al. Circulation 2008;118:1626–36.

PRASUGREL: DM PATIENTS

Ferreiro JL et al. Circulation 2011. 123:798-813.

NEW STRATEGIES IN ACS: DM PATIENTS

TRITON-TIMI 38 17.0 12.2 0.70 (0.58 – 0.85)

PLATO 16.2 14.1 0.88 (0.76 – 1.03)

CURRENT OASIS 7 5.6 4.9 0.87 (0.66 – 1.15)(PCI Cohort)

Study % of Events Hazard Ratio (95% confidence interval) Standard New Drug/Approach

New Drug/ApproachBetter

Standard ClopidogrelBetter

0 0.5 1 1.5

0 0.5 1 1.5

Hazard Ratio[95% confidence interval]

Study

0.48 [0.36 - 0.64]

0.73 [0.57 - 0,94]

0.68 [0.55 - 0,85]

TRITON-TIMI 38

PLATO

CURRENT-OASIS 7

% of eventsStandard New Drug / Approach

3,0 2.2

2.3 1.6

2.4 1.1

New Drug / ApproachBetter

Standard ClopidogrelBetter

NEW STRATEGIES IN ACS/PCI: STENT THROMBOSIS


TICAGRELOR

James SK et al. BMJ 2011.

Useful in non-invasive strategy

PRASUGREL: MEDICAL TREATMENT

Treatment Decision for Medical Management determined < 24 hrs

Treatment Decision determined > 24 hrs OR chronic Clopidogrel Rx

Clopidogrel300 mg LD75 mg MD

Prasugrel30 mg LD

10/5 mg MD*

N = 7,800 < 75 yrs,

N ~ 2,500 75 yrs

Start/Continue Clopidogrel < 24 h

Clopidogrel75 mg MD

Prasugrel10/5 mg MD*

* 5 mg MD of prasugrel for age 75 yrs or weight < 60 kg

Randomize < 24 h

Randomize between 1-7 days

Median duration of treatment ~ 18 months

James S et al. Circulation. 2010;122:1056–1067.

TICAGRELOR: CKDCKD

Normal renal functionC

V d

eath

, M

I o

r st

roke

(%

)

Days after randomization

p for interaction = 0,13

Renal function analytic control 1 month after initiating therapy

OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior Stroke / TIA

Age

Wgt

Risk (%)

+ 54

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36

PRASUGREL: VULNERABLE SUBGROUPS


AGE & DM

With Diabetes Without Diabetes

CV

Dea

th,

No

nfa

tal

MI,

o

r N

on

fata

l S

tro

ke (

%)

0

5

30

<75 years ≥75 years <75 years ≥75 years

P=0.034

P=0.002

P=0.004

10

15

20

25

14.8

n=1336

10.8

n=1327

21.8

n=234

14.9

n=249

9.5

n=4551

7.8

n=4585

15.3

n=674

16.4

n=652

*Composite of CV death, nonfatal MI, or nonfatal stroke.

P=NS

HR=0.64(95% CI, 0.4–1.0)

HR=1.1(95% CI, 0.8–1.4)

HR=0.72(95% CI, 0.6–0.9)

HR=0.82(95% CI, 0.7–0.9)

ClopidogrelPrasugrel

BALANCING ISCHEMIC AND BLEEDING RISK

BALANCING ISCHEMIA / BLEEDING

Inhibition of platelet aggregation

High risk ofischemic events

High risk ofbleeding events

Ris

k o

f an

y e

ve

nt

Ris

k o

f an

y e

ve

nt

“Sweet spot”

Ischemic risk Bleeding riskIschemic risk Bleeding risk

Ferreiro JL et al. Thromb Haemost 2010;103:1128-35.

THERAPEUTIC WINDOW

Sibbing et al. JACC 2010;56:317-8

OR 0.40, 95% CI 0.22-0.75

Elective PCI

PRU 85 PRU 86-238 PRU 2390

10

20

30

40

50Bleeding end point (bep)

Ischemic end point (iep)

75 (25% ) pts 1 (1.3% ) iep15 (20% ) bep

185 (62% ) pts 3 (1.6% ) iep 3 (1.6% ) bep

40 (13% ) pts17 (42.5% ) iep 1 (2.5% ) bep

p<0.01

Inci

dence

of events

(%

)

THERAPEUTIC WINDOW

Campo G et al. J Am Coll Cardiol. 2011;57:2474-83.

Elective PCI

Clopidogrel: Great variability in response

Novel P2Y12 inhibitors: Prasugrel and Ticagrelor Proof of concept: More potent platelet inhibition is needed in ACS

Risk of bleeding, but favorable efficacy and safety profile

Subgroup analyses has limitations, but may help to define strategy

Prasugrel: only ACS undergoing PCI Particular benefit in DM, STEMI, stent thrombosis

Contraindications: high risk of bleeding, prior stroke

Considerations: elderly, low-weight patients; CABG: 7 days

Ticagrelor: full spectrum of ACS Particular benefit: CKD; reduction in CV mortality

Contraindications: high risk of bleeding, intracranial hemorrhage

Considerations: ASA dose, comorbidities (COPD), compliance; CABG: 5 days

Several agents: Which one is the best? Individualized therapy Balance between ischemia and bleeding

Platelet function testing may play a role

CONCLUSIONS

Does one size fit all??

Individualized therapy

IAMCEST

IAM extenso*ECG: Anterior (≥4 derivaciones) e Inferoposterior

KT: Segmento proximal (arteria extensa) IAM no extenso

CLOPIDOGRELTICAGRELORPRASUGREL

NO riesgo alto de sangrado Riesgo alto de sangradoValorar: edad >80 años; ictus previo; HTA severa;

antecedentes hemorrágicos; Hto<34%; ACO; vasculopatía periférica; acceso femoral; neoplasia

activa; IRC severa; IQ reciente o ineludible

No ictus previo y >60Kg y ≤75 años(Individualizar en DM >75 años) Ictus previo o ≤60Kg o >75 años

*A valorar Inhibidores de la GP IIb/IIIa en pacientes con alto contenido trombótico

Hospital Universitario de Bellvitge: Indicaciones de Antiagregación Oral en SCA

SCASEST

Riesgo alto*alteraciones segmento ST; elevación troponina >10 veces el límite inferior;

angor refractario; insuficiencia cardiaca

Riesgo bajo / intermedio

CLOPIDOGREL**TICAGRELORPRASUGREL

NO riesgo alto de sangrado Riesgo alto de sangradoValorar: edad >80 años; ictus previo; HTA severa;

antecedentes hemorrágicos; Hto<34%; ACO; vasculopatía periférica; acceso femoral; neoplasia activa;

IRC severa; IQ reciente o ineludible

No ictus previo y >60Kg(Individualizar en >75 años) Ictus previo o ≤60Kg

*A valorar uso upstream de Inhibidores de la GP IIb/IIIa en pacientes con:a) angor refractario pese a tratamiento completo o b) cambios ECG extensos con insuficiencia cardiaca

DM No DM

**Valorar ticagrelor en pacientes con IRC

(Pacientes en que se indica estrategia invasiva)

Hospital Universitario de Bellvitge: Indicaciones de Antiagregación Oral en SCA

Unidad de Cardiología Intervencionista

Jefe de Sección: Dr. J.A. Gómez-Hospital Dr. José Luis Ferreiro Dr. Gerard Roura Dr. Francesc Jara Dr. Luis Teruel Dr. Josep Gómez-Lara Dra. Silvia Homs Dr. Guillermo Sánchez-Elvira Dr. Daniel Rivero

Laboratorio de Investigación Cardiovascular

Director: Dr. José Luis Ferreiro Sra. Gabriela Sosa Sra. Paula Campreciós Sra. Laia Rosenfeld Sra. Olga Cañavate Sra. Sonia Gómez Dr. Kristian Rivera Dra. Ana Marcano

Heart Diseases Institute. Director: Dr. Ángel Cequier

Interesados en fellowship:

[email protected] [email protected]

GRACIAS POR SU ATENCIÓN

Interesados en fellowship:

[email protected] [email protected]

BACKUP SLIDES

UA/NSTEMI

+ Benefit1 Year 1 Year

+ Benefit

PCI

COMMIT(CCS-2)

Acute STEMI

30 Days+ Benefit

NEJM 2001 JAMA 2002NEJM 2005

Lancet 2005

CLOPIDOGREL IN ACS/PCI

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

DAYS

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

TRITON TIMI-38: EFFICACY AND SAFETY


PLATO: EFFICACY

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,521

8,628

8,362

8,460

8,124

Days after randomisation

6,743

6,743

5,096

5,161

4,047

4,147

0 60 120 180 240 300 360

121110

9876543210

13

Cu

mu

lati

ve in

cid

ence

(%

)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval


K-M

est

imat

ed r

ate

(%

per

yea

r)

Non-CABGPLATO major

bleeding

Non-CABGTIMI major bleeding

CABGPLATO major

bleeding

CABG TIMI major bleeding

p=0.026

p=0.03

NS

NS

9

8

7

6

5

4

3

2

1

0

4.5

3.8

2.8

2.2

7.4

7.9

5.3

5.8

TicagrelorClopidogrel

PLATO: SAFETY


EfficacyA reduction in: Prasugrel Ticagrelor

CV Death/MI/Stroke 19% 16% Stent thrombosis 52% 25%

MI 24% 16%CV death 11% 21%

Early benefit 18% 12%(3 days) (30 days)

Late benefit 20% 20%(~14.5 mo) (~9 mo)

PRASUGREL VERSUS TICAGRELOR

Ma

xim

um

Pla

tele

t A

gg

reg

ati

on

(%

)

0

20

40

60

80

100

*†

p<0.0001 vs clopidogrel 75 mg MDp<0.0001 vs prasugrel 10 mg MD

Time, days

* †

Mean±SE

Time, hours

0 2 24 4 6 8 10 12 1412

* †* **

*

Placebo LD/Prasugrel 10 mg MD (n=36)Prasugrel 60 mg LD/10 mg MD (n=31)

Placebo LD/Clopidogrel 75 mg MD (n=33)

Similar findings obtained with MPA to 5 µM ADP, VASP PRI, and Verify Now® PRU

Angiolillo DJ et al. J Am Coll Cardiol 2010; 56:1017-23.

“SWITCHING”:FROM CLOPIDOGREL TO PRASUGREL

0%

20%

40%

60%

80%

100%

1 2 3 4 5 6 7 >8

Ticagrelor

Clopidogrel

Major Fatal/Life-Threatening Bleeding by Days from Last Dose of Treatment to CABG

% P

atie

nts

with

Ble

edi

ng

pos

t-C

AB

G

Days

Bleeding differences favor ticagrelor >5 days post discontinuation

TICAGRELOR: CABG

Plan Angio/PCI >2h and <24h

Randomize

Diagnosis+

Transferto Cathlab

>2h to <24h Pras 30

Cathlab

PCIPras 60 Pras 30

Pras 10(5) for 30d30d FU

PCI

PE: CV-D, MI, stroke, Urgent Revasc., GPI bailout @ 7dSEs: All TIMI Major Bleeding @ 7d; NetClinBenefit @ 7d

Inactive

Angio Angio

NSTEMI / Troponin +, n~4100+ (Event Driven)Clopidogrel Naive or Longterm 75mg

ISSUE OF PRETREATMENT

Arm A

ARM B

Clopidogrel 600mg < 24hr pre-PCIPrasugrel 60mg during PCIPrasugrel 10mg MD

Arm C

Clopidogrel 600mg < 24hr pre-PCIPrasugrel 30mg during PCIPrasugrel 10mg MD

Phase 2 randomized, double blind, double dummy, 3-arm, parallel, active comparator, controlled study

TRansferring from clopIdogrel loading Dose to Prasugrel Loading dose in ACS patiEnTs (TRIPLET)

PRASUGREL AFTER CLOPIDOGREL LOADING

Patients on aspirin (81 mg/day) and prasugrel (10 mg/day) ≥ 14 days post-PCI

10 mg prasugrel(N=22)



Pharmacodynamic testing: 1 hour

Pharmacodynamic testing: Baseline

Pharmacodynamic testing: 4 hour

PRASUGREL RELOAD

Angiolillo DJ et al. J Am Coll Cardiol 2012 [in press]

0

5

10

15

20

25

30

35

40

45

5010 mg 30 mg 60 mg

* p=0.058 versus prasugrel 10 mg** p<0.171 versus prasugrel 30 mg and p=0.002 versus prasugrel 10 mg† p<0.001 versus prasugrel 10 mg†† p<0.05 versus prasugrel 30mg and p<0.001 versus prasugrel 10mg

Baseline 1 hour 4 hours

p=0.577

p<0.001p=0.002

Values are represented as LSM±SEM; p values for trend analyses at each time point are provided

*

†**

††P2Y

12 R

eact

ivit

y In

dex

(%

)

Angiolillo DJ et al. J Am Coll Cardiol 2012 [in press]

PRASUGREL RELOAD

PRASUGREL: CABG


selección lógica de antiplaquetarios en sca-icp dr. josé luis ferreiro hospital universitario de...

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