selección lógica de antiplaquetarios en sca-icp dr. josé luis ferreiro hospital universitario de...
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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
Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:433-45.
INDEX
Clopidogrel variability in response
Novel P2Y12 inhibitorsPrasugrel TicagrelorSubgroup analyses
Balancing efficacy and safety
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.
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!!
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.
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
Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:433-45.
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
Wiviott SD et al. NEJM 2007;357:2001-15.
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 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.
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
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:
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
Wiviott SD et al. NEJM 2007;357:2001-15.
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
Wallentin L et al. NEJM 2009;361:1045-57.
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
Wallentin L et al. NEJM 2009;361:1045-57.
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)
30 mg prasugrel(N=21)
60 mg prasugrel(N=21)
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