Selección lógica de
antiplaquetarios en SCA-ICP
SOLACI Simposium, México, 9-VIII-2012
Dr. José Luis Ferreiro
Hospital Universitario de Bellvitge: Área de Enfermedades del Corazón
Unidad de Cardiología Intervencionista – Laboratorio de Investigación Cardiovascular
CONFLICTS OF INTEREST
Honoraria for lectures:
 Eli Lilly Co; Daiichi Sankyo, Inc.; AstraZeneca
Research grants:
 Spanish Society of Cardiology
AVAILABLE ANTIPLATELET DRUGS
P2Y12 INHIBITORS
Ticlopidine
Clopidogrel
Prasugrel
Ticagrelor
TxA2 INHIBITORS
COX-1 Inhibitors
Aspirin
G
Intracellular signaling
PI3K
AA
COX-1
GP VI GP Ib/IX/V
GP IIB/IIIA INHIBITORS
Abciximab
Tirofiban
Eptifibatide
fibrinogen
GP IIb/IIIa
Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:433-45.
AGENTS ON DEVELOPMENT
PAR-1 INHIBITORS
P2Y12 INHIBITORS
TxA2 INHIBITORS
Vorapaxar
Atopaxar
Cangrelor
Elinogrel
TP inhibitors
Picotamide
Ridogrel
Ramatroban
Terutroban
EV-077
G
Intracellular signaling
PI3K
AA
COX-1
GP VI GP Ib/IX/V
fibrinogen
GP IIb/IIIa
PIP3K inhibitors
TGX-221
5HT2A antagonists
APD791
P2Y1 inhibitors
GP Ib antagonists
MRS2179
6B4-Fab
MRS2500
EP antagonists
GP VI antagonists
DG-041
Kistomin
Revacept
Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:433-45.
Does one size fit all??
INDEX
Clopidogrel variability in response
Novel P2Y12 inhibitors
Prasugrel
Ticagrelor
Subgroup analyses
Balancing efficacy and safety
CLOPIDOGREL:
VARIABILITY IN RESPONSE
CLOPIDOGREL: EFFICACY
Primary Endpoint—MI / stroke/ CV Death
0.14
0.12
Cumulative Hazard Rate
p=0.00009
N=12,562
20% RRR
Placebo
+ ASA*
0.10
0.08
Clopidogrel
+ ASA*
0.06
Suboptimal response?
0.04
0.02
Primary outcome: 9.3% in clopidogrel + ASA group
and 11.4% in placebo + ASA group.
0.00
0
3
6
9
12
Months of Follow-Up
*Other standard therapies were used as appropriate.
Yusuf S et al. N Engl J Med 2001;345:494-502.
CLOPIDOGREL: VARIABILITY IN RESPONSE
20
Patients (n)
15
10
↑ Bleeding risk
↑ Ischemic risk
5
0
2.5
12.5
22.5
32.5
42.5
52.5
62.5
72.5
82.5
92.5
7.5
17.5
27.5
37.5
47.5
57.5
67.5
77.5
87.5
97.5
% Platelet aggregation (LTA-ADP 20mM)
Angiolillo DJ et al. Am J Cardiol 2006;97:38-43.
CURRENT/OASIS 7: STUDY DESIGN
Patients with UA/NSTEMI or STEMI planned for early invasive strategy
i.e. intent for PCI as early as possible within 72 hours
n=25,087
Randomize
Double Blind
Clopidogrel Standard Dose Group
300 mg Day 1; 75 mg Days 2-30
Clopidogrel High Dose Group
600 mg Day 1; 150 mg Days 2-7; 75 mg Days 8-30
Randomize
ASA low dose
At least 300 mg Day 1;
75-100 mg Days 2-30
Randomize
ASA high dose
At least 300 mg Day 1;
300-325 mg Days 2-30
ASA low dose
At least 300 mg Day 1;
75-100 mg Days 2-30
Primary Efficacy Outcome
Composite of CV Death, MI, or stroke up to day
30
Primary Safety Outcome
Major Bleeding up to day 30
Mehta SR et al. NEJM 2010;363:930-42.
Open
Label
ASA high dose
At least 300 mg Day 1;
300-325 mg Days 2-30
CURRENT OASIS-7 TRIAL
COMPARISON OF CLOPIDOGREL DOSING: PRIMARY OUTCOME AND COMPONENTS
Measure
CV death, MI, and stroke,
overall cohort (n=25,087)
● PCI cohort (n=17,232)
● No PCI cohort (n=7,855)
Standard
Dosing
Double
Dosing
4.4
4.2
4.5
3.9
4.2
4.9
MI, overall cohort
2.2
1.9
● PCI cohort
2.6
2.0
● No PCI cohort
1.4
Double
Better
Standard
Better
P=0.016
P=0.025
1.7
0.5
Mehta SR et al. NEJM 2010;363:930-42.
1
Odds Ratio
1.5
2
NOVEL P2Y12
INHIBITORS
P2Y12 INHIBITORS
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Elinogrel
Thienopyridine
Thienopyridine
CPTP
ATP analog
Quinazolinedione
oral
oral
oral
IV
IV and oral
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 minutes
50 min (IV)
12 h (oral)
yes
no
yes
no
no
Group
Administration
Receptor
blockade
CYP drug
interactions
Modified from Angiolillo DJ and Ferreiro JL. Rev Esp Cardiol 2010;63:60-76
NOVEL ORAL P2Y12 INHIBITORS
More potent and less variability!!
Angiolillo DJ et al. JACC Interv 2011
TRITON TIMI-38: STUDY DESIGN
Wiviott SD et al. NEJM 2007;357:2001-15.
PLATO: STUDY DESIGN
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12-month exposure
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;
CV = cardiovascular; TIA = transient ischaemic attack
Wallentin L et al. NEJM 2009;361:1045-57.
TRITON VERSUS PLATO
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
PRASUGREL VERSUS TICAGRELOR
TRITON TIMI 38
(prasugrel vs clopidogrel)
Non-CABG TIMI major bleeding
TRITON
PLATO
Prasugrel vs Clopidogrel
Ticagrelor vs Clopidogrel
2.4% vs 1.8%
2.8% vs 2.2%
ARD 0.6%
HR 1.32
P=0.03
NNH=167
ARD 0.6%
HR 1.25
P=0.03
NNH=167
PLATO
(ticagrelor vs clopidogrel)
GUIDELINES
2011 ACCF/AHA
UA/NSTEMI
2011 ACCF/AHA/SCAI
PCI
2011 ESC NSTEACS
2010
ESC/EACTS/EAPCI
Myocardial
Revascularization
Clopidogrel
Prasugrel
Class I; LOE A
Class I; LOE B
Class I; LOE B*
Class I; LOE B*
Ticagrelor
Not FDA approved or marketed at
the time of writing of Guidelines
Class I; LOE B*
OK, but… what do we do?
Class I; LOE A
Elective PCI: Class I; LOE A
NSTE-ACS: Class I; LOE B
STEMI: Class I; LOE C
Class I; LOE B
Class I; LOE B
NSTE-ACS: Class IIa; LOE B
NSTE-ACS: Class I; LOE B
STEMI: Class I; LOE B
STEMI: Class I; LOE B
CLOPIDOGREL: STEMI
24,3% patients with
poor response to ASA
89,2% patients with poor
response to clopidogrel
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.
PRASUGREL: STEMI
Pretreatment
allowed
Montalescot G et al. Lancet 2009;373:723-731.
TICAGRELOR: STEMI
K-M estimate of time to first primary efficacy
event (composite of CV death, MI or stroke)
HR, 0.87; 95% CI, 0.75 to 1.01; P=0.07)
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
Steg PG et al. Circulation 2010;122:2131-2141
PRASUGREL: DM PATIENTS
18
(n=3146)
16
17.0
CV Death/MI/Stroke
14
Endpoint (%)
Clopidogrel
12.2
12
Prasugrel
10
HR 0.70
P<0.001
8
NNT=21
6
TIMI Major
Non-CABG Bleeds
4
Clopidogrel
2
Prasugrel
2.6
2.5
0
0
30 60 90
180
270
360
Days
Wiviott SD et al. Circulation 2008;118:1626–36.
450
NEW STRATEGIES IN ACS: DM PATIENTS
Study
% of Events
Standard
Hazard Ratio (95% confidence interval)
New Drug/Approach
TRITON-TIMI 38
17.0
12.2
0.70 (0.58 – 0.85)
PLATO
16.2
14.1
0.88 (0.76 – 1.03)
5.6
4.9
0.87 (0.66 – 1.15)
CURRENT OASIS 7
(PCI Cohort)
0
0.5
New Drug/Approach
Better
1
1.5
Standard Clopidogrel
Better
Ferreiro JL et al. Circulation 2011. 123:798-813.
NEW STRATEGIES IN ACS/PCI: STENT THROMBOSIS
Study
% of events
Standard
Hazard Ratio
[95% confidence interval]
New Drug / Approach
TRITON-TIMI 38
2.4
1.1
0.48 [0.36 - 0.64]
PLATO
3,0
2.2
0.73 [0.57 - 0,94]
CURRENT-OASIS 7 2.3
1.6
0.68 [0.55 - 0,85]
0
0.5
New Drug / Approach
Better
1
1.5
Standard Clopidogrel
Better
Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:433-45.
TICAGRELOR
Useful in non-invasive strategy
James SK et al. BMJ 2011.
PRASUGREL: MEDICAL TREATMENT
Treatment Decision for
Medical Management
determined < 24 hrs
Randomize < 24 h
Clopidogrel
300 mg LD
75 mg MD
Prasugrel
30 mg LD
10/5 mg MD*
N = 7,800 <
75 yrs,
N ~ 2,500 
75 yrs
Treatment Decision
determined > 24 hrs OR
chronic Clopidogrel Rx
Start/Continue Clopidogrel < 24 h
Randomize between
1-7 days
Clopidogrel
75 mg MD
Prasugrel
10/5 mg MD*
* 5 mg MD of prasugrel for age  75 yrs or weight < 60 kg
Median duration of treatment ~ 18 months
TICAGRELOR: CKD
CV death, MI or stroke (%)
CKD
Renal function analytic control
p for interaction = 0,13
1 month after initiating
therapy
Normal renal function
Days after randomization
James S et al. Circulation. 2010;122:1056–1067.
PRASUGREL: VULNERABLE SUBGROUPS
Risk (%)
Prior
Stroke / TIA
Age
Yes
+ 54
No
Pint = 0.006
-1
>=75
Pint = 0.18
< 75
Wgt
-16
+3
< 60 kg
>=60 kg
Pint = 0.36
-14
-13
OVERALL
0.5
-16
1
Prasugrel Better HR
2
Clopidogrel Better
Wiviott SD et al. NEJM 2007;357:2001-15.
AGE & DM
CV Death, Nonfatal MI,
or Nonfatal Stroke (%)
30
25
Prasugrel
HR=0.72
(95% CI, 0.6–0.9)
HR=0.64
(95% CI, 0.4–1.0)
HR=0.82
(95% CI, 0.7–0.9)
Clopidogrel
HR=1.1
(95% CI, 0.8–1.4)
P=0.034
21.8
20
P=NS
P=0.002
16.4
15
14.8
14.9
15.3
P=0.004
10
10.8
9.5
7.8
5
n=1327
n=1336
0
<75 years
n=249
n=234
≥75 years
With Diabetes
*Composite of CV death, nonfatal MI, or nonfatal stroke.
n=4585
n=4551
<75 years
n=652
n=674
≥75 years
Without Diabetes
BALANCING ISCHEMIC
AND BLEEDING RISK
BALANCING ISCHEMIA / BLEEDING
High risk of
ischemic events
“Sweet spot”
High risk of
bleeding events
Inhibition of platelet aggregation
Ischemic risk
Ferreiro JL et al. Thromb Haemost 2010;103:1128-35.
Bleeding risk
THERAPEUTIC WINDOW
Elective PCI
OR 0.40, 95% CI 0.22-0.75
Sibbing et al. JACC 2010;56:317-8
Incidence of events (%)
50
THERAPEUTIC WINDOW
Elective PCI
Ischemic end point (iep)
Bleeding end point (bep)
40
p<0.01
30
20
10
0
PRU 85
PRU 86-238
PRU 239
75 (25%) pts
1 (1.3%) iep
15 (20%) bep
185 (62%) pts
3 (1.6%) iep
3 (1.6%) bep
40 (13%) pts
17 (42.5%) iep
1 (2.5%) bep
Campo G et al. J Am Coll Cardiol. 2011;57:2474-83.
CONCLUSIONS
 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
Does one size fit all??
Individualized
therapy
Hospital Universitario de Bellvitge: Indicaciones de Antiagregación Oral en SCA
IAMCEST
IAM extenso*
ECG: Anterior (≥4 derivaciones) e Inferoposterior
KT: Segmento proximal (arteria extensa)
NO riesgo alto de sangrado
No ictus previo y >60Kg y ≤75 años
(Individualizar en DM >75 años)
PRASUGREL
IAM no extenso
Riesgo alto de sangrado
Valorar: edad >80 años; ictus previo; HTA severa;
antecedentes hemorrágicos; Hto<34%; ACO;
vasculopatía periférica; acceso femoral; neoplasia activa;
IRC severa; IQ reciente o ineludible
Ictus previo o ≤60Kg o >75 años
TICAGRELOR
*A valorar Inhibidores de la GP IIb/IIIa en pacientes con alto contenido trombótico
CLOPIDOGREL
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
(Pacientes en que se indica estrategia invasiva)
Riesgo bajo / intermedio
Riesgo alto de sangrado
NO riesgo alto de sangrado
Valorar: edad >80 años; ictus previo; HTA severa;
antecedentes hemorrágicos; Hto<34%; ACO; vasculopatía
periférica; acceso femoral; neoplasia activa; IRC severa;
IQ reciente o ineludible
DM
No DM
No ictus previo y >60Kg
(Individualizar en >75 años)
PRASUGREL
Ictus previo o ≤60Kg
TICAGRELOR
*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
**Valorar ticagrelor
en pacientes con IRC
CLOPIDOGREL**
Unidad de Cardiología
Intervencionista
Laboratorio de Investigación
Cardiovascular
 Jefe de Sección: Dr. J.A. Gómez-Hospital
 Director: Dr. José Luis Ferreiro
 Dr. José Luis Ferreiro
 Sra. Gabriela Sosa
 Dr. Gerard Roura
 Sra. Paula Campreciós
 Dr. Francesc Jara
 Sra. Laia Rosenfeld
 Dr. Luis Teruel
 Sra. Olga Cañavate
 Dr. Josep Gómez-Lara
 Sra. Sonia Gómez
 Dra. Silvia Homs
 Dr. Kristian Rivera
 Dr. Guillermo Sánchez-Elvira
 Dra. Ana Marcano
 Dr. Daniel Rivero
Heart Diseases Institute. Director: Dr. Ángel Cequier
Interesados en fellowship:
AMCInv@bellvitgehospital.cat
AMCDir@bellvigehospital.cat
GRACIAS POR SU
ATENCIÓN
Interesados en fellowship:
AMCInv@bellvitgehospital.cat
AMCDir@bellvigehospital.cat
BACKUP SLIDES
CLOPIDOGREL IN ACS/PCI
UA/NSTEMI
PCI
Acute STEMI
COMMIT
(CCS-2)
1 Year
+ Benefit
1 Year
+ Benefit
NEJM 2001
JAMA 2002
30 Days
+ Benefit
NEJM 2005
Lancet 2005
TRITON TIMI-38: EFFICACY AND SAFETY
15
138
events
Clopidogrel
12.1
Endpoint (%)
CV Death / MI / Stroke
9.9
10
HR 0.81
(0.73-0.90)
P=0.0004
NNT = 46
Prasugrel
5
TIMI Major
NonCABG Bleeds
Prasugrel
2.4 HR 1.32
1.8 (1.03-1.68)
Clopidogrel
P=0.03
0
0 30 60 90
180
35
events
270
360
DAYS
Wiviott SD et al. NEJM 2007;357:2001-15.
450
NNH = 167
Cumulative incidence (%)
PLATO: EFFICACY
13
12
11
10
9
8
7
6
5
4
3
2
1
0
9.8
Ticagrelor
HR 0.84 (95% CI 0.77–0.92), p=0.0003
0
No. at risk
Ticagrelor
11.7
Clopidogrel
60
120
180
240
300
360
Days after randomisation
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel 9,291
8,521
8,362
8,124
6,743
5,096
4,047
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
Wallentin L et al. NEJM 2009;361:1045-57.
PLATO: SAFETY
K-M estimated rate (% per year)
9
Ticagrelor
Clopidogrel
NS
7.9
8
7.4
7
NS
5.8
6
5.3
p=0.026
5
4
4.5
3.8
p=0.03
2.8
3
2.2
2
1
0
Non-CABG
PLATO major
bleeding
Non-CABG
TIMI major
bleeding
CABG
PLATO major
bleeding
Wallentin L et al. NEJM 2009;361:1045-57.
CABG
TIMI major
bleeding
PRASUGREL VERSUS TICAGRELOR
Efficacy
A reduction in:
CV Death/MI/Stroke
Stent thrombosis
MI
CV death
Early benefit
Prasugrel
19%
52%
24%
11%
Ticagrelor
16%
25%
16%
21%
18%
12%
(3 days)
Late benefit
(30 days)
20%
20%
(~14.5 mo)
(~9 mo)
“SWITCHING”:
FROM CLOPIDOGREL TO PRASUGREL
Maximum Platelet Aggregation (%)
Similar findings obtained with MPA to 5 µM ADP, VASP PRI, and Verify Now® PRU
100
Placebo LD/Clopidogrel 75 mg MD (n=33)
Placebo LD/Prasugrel 10 mg MD (n=36)
Prasugrel 60 mg LD/10 mg MD (n=31)
80
60
*
*
40
*†
*†
**
20
* p<0.0001 vs clopidogrel 75 mg MD
† p<0.0001 vs prasugrel 10 mg MD
Mean±SE
0
0 2
12
Time, hours
24
4
6
8 10 12 14
Time, days
Angiolillo DJ et al. J Am Coll Cardiol 2010; 56:1017-23.
TICAGRELOR: CABG
Major Fatal/Life-Threatening Bleeding by Days from Last Dose of
Treatment to CABG
% Patients with Bleeding
post-CABG
100%
Ticagrelor
80%
Clopidogrel
60%
40%
20%
0%
1
2
3
4
5
6
7
>8
Days
Bleeding differences favor ticagrelor >5 days post discontinuation
ISSUE OF PRETREATMENT
NSTEMI / Troponin +, n~4100+ (Event Driven)
Clopidogrel Naive or Longterm 75mg
Diagnosis
+
Transfer
to Cathlab
>2h to <24h
Plan Angio/PCI >2h and <24h
Randomize
Pras 30
Inactive
Angio
Angio
Cathlab
PCI
30d FU
Pras 30
PCI
Pras 60
PE: CV-D, MI, stroke, Urgent Revasc., GPI bailout @ 7d
SEs: All TIMI Major Bleeding @ 7d; NetClinBenefit @ 7d
Pras 10(5)
for 30d
PRASUGREL AFTER CLOPIDOGREL LOADING
Arm A
• Placebo < 24hr pre-PCI
• Prasugrel 60mg during PCI
• Prasugrel 10mg MD
ARM B
• Clopidogrel 600mg < 24hr
pre-PCI
• Prasugrel 60mg during PCI
• Prasugrel 10mg MD
Arm C
• Clopidogrel 600mg < 24hr
pre-PCI
• Prasugrel 30mg during PCI
• Prasugrel 10mg MD
PRASUGREL RELOAD
Patients on aspirin (81 mg/day) and
prasugrel (10 mg/day) ≥ 14 days post-PCI
Pharmacodynamic testing: Baseline
10 mg prasugrel
(N=22)
30 mg prasugrel
(N=21)
Pharmacodynamic testing: 1 hour
Pharmacodynamic testing: 4 hour
Angiolillo DJ et al. J Am Coll Cardiol 2012 [in press]
60 mg prasugrel
(N=21)
PRASUGREL RELOAD
50
10 mg
30 mg
60 mg
P2Y12 Reactivity Index (%)
45
40
p=0.577
35
p=0.002
p<0.001
30
25
*
20
15
†
**
10
††
5
0
Baseline
1 hour
4 hours
* 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
Values are represented as LSM±SEM; p values for trend analyses at each time point are provided
Angiolillo DJ et al. J Am Coll Cardiol 2012 [in press]
PRASUGREL: CABG
Wiviott SD et al. NEJM 2007;357:2001-15.