Transcript Document

Antiagregantes Plaquetarios en
Pacientes con SCA
Dr Ramón Corbalán
Departamento Enfermedades Cardiovaculares
Pontificia Universidad Cátolica de Chile
Terapia Antiplaquetaria Dual
• La inhibición de las plaquetas es una estrategia clave en el tratmiento de pacientes
con sindromes coronarios agudos1,2, sometidos a PCI3
• Las metas de este tratamiento son la inhibición rápida, consistente y efectiva de la
activación y agregación plaquetaria3-5
• La terapia antiplaquetaria dual con AAS y una tienopiridina constituyen el goal
standard de tratamiento en pacientes con SCA desde que se inicia y progresa en la
terapia intervencional
• Las preguntas pendientes: ¿Duración del tratamiento? ¿ Efectos en pacientes
tratados solo médicamente? ¿Riesgo de hemorragias? ¿Alternativas diferentes?
ASA=Acetylsalicylic Acid; ACS=Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention
1Anderson
JL et al. Circulation 2007;116:e148-304
2Antman EM et al. Circulation 2008;117:296-329
3King SB et al. Circulation 2008;117:261-295
4Hochholzer
5Wiviott
W et al. Circulation 2005;111:2560-2564
SD et al. Rev Cardiovasc Med 2006;7:214-225
Los Estudios que avalan
Terapia Antiplaquetarias Dual:

CURE

CREDO

CREDO-PCI

CLARITY

COMIT
Limitaciones de Clopidogrel

Latencia de su efecto

Variantes genéticas

Resistencia a la droga

¿Alternativas?
Inhibidores Receptor P2Y12
Riesgo de eventos CV en portadores de gen CYP2C19*2 LOF tratados con clopidogrel
Meta-análisis de 10 estudios (11,959 pacientes)
Eventos
MACE
Portador de gen
No portador (%)
LOF (%)
9,7
OR (95% IC)
p
7,8
1,29
(1,12-1,49)
<0,001
<0,001
0,019
Trombosis
Intrastent
2,9
0,9
3,45
(2,14-5,57)
Muerte
1,8
1,0
1,79
(1,10-2,91)
Hulot JS et al. JACC 2010; 56:134-143.
Clopidogrel Response Variability and
Increased Risk of Ischemic Events Primary PCI for STEMI (N = 60)
5 µM ADP-induced Platelet Aggregation
Clop resist
100
Q1
80
Q2
60
Q3
40
40
P = 0.007
Percent
Baseline (%)
120
Death/ACS/CVA by 6 mo
30
20
40
Q4
20
0
10
6.7
Quartiles of response
1
2
3
4
Days
5
6
0
Q1
Q2
0
0
Q3
Q4
Matetzky S et al. Circulation. 2004;109:3171-3175. Wiviott SD, Antman EM. Circulation. 2004;109:3064-3067.
Patients (%)
Variabilidad de Respuesta a Clopidogrel:
Aumento de la Dosis (300 mg vs. 600 mg)
33
30
27
24
21
18
15
12
9
6
3
0
300 mg Clopidogrel
600 mg Clopidogrel
Resistance = 28% (300 mg)
Resistance = 8% (600 mg)
≤-30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
(60,70]
> 70
D Aggregation (5 µM ADP-induced Aggregation) at 24 Hr
Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.
CURRENT-OASIS 7: Eventos Primarios y Dosis
de Clopidogrel /AAS a 30 Días
Mehta SR, et al, ESC; September 2009; Barcelona, Spain.
CURRENT-OASIS 7: Muerte CV, IM, AVE a 30 Días
Mehta SR, et al, ESC; September 2009; Barcelona, Spain.
CURRENT-OASIS 7: Conclusiones Autores
Test a doble dosis de clopidogrel redujo significativamente la
trombosis de stents y eventos CV mayores
En pacientes no sometidos a PCI la doble dosis de clopidogrel
no tuvo diferencia con la dosis estándar
Un exceso modesto de hemorragias mayores por criterios
CURRENT, pero no hubo diferencias en HIC, hemorragias
fatales o post CRVM
Novedades en Antiplaquetarios...

“Armamentario Terapeútico” más allá del Clopidogrel:
¿qué tenemos?

Bloqueo plaquetario Triple: ¿realidad o ficción?

Cuales son los antiplaquetarios con mejores perspectivas
futuras?
Platelet P2 Receptors/Inhibitors
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor
ADP
Receptor subtype
X
P2Y12
P2Y1
P2X1
Molecular structure
Secondary
Messenger system
Functional response
Intrinsic ion
channel
[Na+/Ca2+]i
Shape Change
Aggregation
G protein
G protein
GPCR
Gq
GPCR
Gj
PLC/IP3
[Ca2+]j
AC
[cAMP]
Shape change
Transient
aggregation
Adapted From Bhatt and Topol, Nature Reviews Drug Disc 2:15-28, 2003
Sustained
aggregation
Secretion
Inhibidores Receptor P2Y12
•
•
Indirectos (Tienopiridinas)
-
Ticlopidina
-
Cangrelor
Necesidad de nuevos agentes antiplaquetarios:
Clopidogrel
1. Prodroga
2. Variabilidad Interindividual
Prasugrel
3. Bloqueador Irreversible
4. Resistencia
Directos (No Tienopiridinas)
5. Interacción medicamentos
Ticagrelor
Elinogrel
Comparing Response of Clopidogrel (300 mg) and Prasugrel (60
mg) by IPA at 24 Hours
100.0
Inhibition of Platelet Aggregation (%)
(20 µM ADP)
80.0
60.0
40.0
20.0
Background
Variability
0.0
-20.0
Response to Clopidogrel
Response to
Prasugrel
Brandt J et al. Am Heart J. 2007;153:66.e9-66.e16
TRITON TIMI-38 Study Design
ACS (STEMI or UA/NSTEMI) and Planned PCI
ASA
N=13,600
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy: 12 months
First-degree end point:
CV death, MI, stroke
Second-degree end points: CV death, MI, stroke, rehospitalization,
recurrent ischemia, UTVR
UTVR = urgent target vessel revascularization; TRITON TIMI = TRial to assess Improvement in Therapeutic Outcomes by optimizing
platelet inhibitioN with prasugrel Thrombolysis In Myocardial Infarction
FDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading dose
Prasugrel is not yet approved for use
Wiviott SD, et al. Am Heart J. 2006;152:627-635.
TRITON TIMI-38: Balance of Efficacy
and Safety
15
End Point (%)
CV Death/MI/Stroke
Clopidogrel
138
events
12.1
9.9
10
Prasugrel
TIMI Major
Non-CABG Bleeds
5
Prasugrel
2.4
1.8
Clopidogrel
0
0 30 60 90
180
270
360
450
HR 0.81
(0.73-0.90)
P = .0004
NNT = 46
35
events
HR 1.32
(1.03-1.68)
P = .03
NNH = 167
Days
HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm
Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
TRITON TIMI-38 Net Clinical Benefit:
Bleeding Risk Subgroups
Risk (%)
Prior
Stroke / TIA
Age
Weight
Yes
+ 37
No
-16
≥75
-1
<75
-16
<60 kg
+3
≥60 kg
-14
Pint = 0.18
Pint = 0.36
-13
Overall
0.5
Pint = 0.006
Prasugrel Better
1
HR
Clopidogrel Better
2
Post-hoc analysis
Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
Subgrupos de Riesgo de Hemorragias
Consideraciones terapeuticas
16%
4%
MD
10 mg
Significant
Net Clinical Benefit with
Prasugrel
80%
Terapia Antiplaquetaria en SCA
ASA
ASA + Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
+ 60%
Placebo
APTC
Single
Antiplatelet Rx
+ 38%
+ 32%
CURE
TRITON-TIMI 38
Dual
Antiplatelet Rx
Higher
IPA
Increase
in
Major
Bleeds
Ticagrelor (AZD 6140): an oral reversible
P2Y12 antagonist
HO
N
N
N
H
N
HO
O
N
F
N
S
Ticagrelor is a cyclo-pentyl-triazolopyrimidine (CPTP)
F
OH
• Direct acting
– Not a pro-drug; does not require metabolic activation
– Rapid onset of inhibitory effect on the P2Y12 receptor
– Greater inhibition of platelet aggregation than clopidogrel
• Reversibly bound
– Degree of inhibition reflects plasma concentration
– Faster offset of effect than clopidogrel
– Functional recovery of circulating platelets within ~48 hours
PLATO study design
NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624)
Clopidogrel-treated or -naive; randomized <24 hours of index event
After randomization, 1,261 patients underwent CABG and were on
study drug treatment for ≤7 days prior to surgery
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 months treatment
Primary endpoint: CV death + MI + Stroke
Primary safety endpoint: Total major bleeding
Recommendations for patients undergoing CABG:
Study drugs withheld prior to surgery – 5 days for clopidogrel and 24–72 hours for
ticagrelor. Study drug be restarted as soon as possible after surgery and prior to
discharge
PCI = percutaneous coronary intervention
CV = cardiovascular
PLATO main endpoints*
Primary safety endpoint
Primary efficacy endpoint
13
15
12
11.7
Clopidogrel
11
Ticagrelor
9.8
9
K-M estimated rate (%)
K-M estimated rate (%)
10
Ticagrelor
8
7
6
5
4
10
11.58
11.20
Clopidogrel
5
3
2
HR 0.84 (95% CI 0.77–0.92), p=0.0003
1
HR 1.04 (95% CI 0.95–1.13), p=0.434
0
0
0
No. at risk
2
4
6
8
10
12
0
2
Months from randomization
4
6
8
10
12
Months from randomization
Ticagrelor
9,333 8,628
8,460
8,219
6,743 5,161 4,147
9,235
7,246
6,826
6,545
5,129
3,783
3,433
Clopidogrel
9,291 8,521 8,362
8,124
6,743 5,096
4,047
9,186
7,305
6,930
6,670
5,209
3,841
3,479
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
* Wallentin, L et al., New Eng J Med. 2009;361:1045–1057
PLATO
Ticagrelor: Impacto en Mortalidad Cardiovascular
7
Disminución de mortalidad cardiovascular
6
Clopidogrel
Cumulative incidence (%)
5
5.1
4.0
4
Ticagrelor
3
2
1
HR 0.79 (95% CI 0.69–0.91), p=0.001
0
0
60
120
180
240
300
360
Days after randomisation
9,333
8,294
8,822
8,626
7119
5,482
4,419
9,291
8,865
8,780
8,589
7079
5,441
4,364
Cannon et al. Lancet 2010;375:283-293.
PLATO: Dosis de AAS y eficacia:
Conclusiones
►
Los pacientes con bajo peso o signos de insuficiencia renal
tienen mayor riesgo de sangrado con terapia dual.
►
En esos casos las dosis de AAS deben ser bajas y las
tienopiridinas y bloqueadores ADP deben reducirse a la
mitad de la dosis
►
La terapia dual está contraindicada en pacientes con
antecedentes de AVE previo por mayor riesgo de HIC
►
Los nuevos antiagregantes son más potentes, pero a
expensas de un mayor riesgo de sangrado
Platelet Receptors
Platelet
Thrombin
PAR-1
PAR-4
ADP
Epinephrine
Serotonin
Collagen
Fibrinogen
GP
IIb/IIIa
P2Y1
P2Y12
TBX A2
Platelet
TBXA2-R
GP
IIb/IIIa
EPI-R
5HT2A
GP VI
GP Ia
Anionic
phospholipid
surfaces
Antagonista de los receptores de Trombina (TRA) y
Triple Inhibición Plaquetaria

SCA se caracterizan por formación aumentada de trombina que persiste
incluso luego del evento agudo

Trombina es el principal activador de la plaqueta

Actúa a través de receptor PAR-1

El bloqueo de los receptores PAR-1 tendría ventajas potenciales en el corto
y largo plazo

Estudios iniciales en pacientes sometidos a PCI electiva han mostrado
resultados alentadores: TRA-PCI

Estudios Terminados:
TRACER y TRA 2P
Morrow et al. ACC 2012, Chicago, March 24, 2012
TRACER
SCH 530348 (Vorapaxar) en SCA
Thrombin Receptor Antagonist for Clinical Event Reduction in Acute
Coronary Syndrome
SCA SIN SDST
N = 10,000
SCH 530348
40 mg carga, 2.5 mg/día
n=5000
Placebo
(y terapia usual)
n=5000
STOP !!!!
• Muerte cardiovascular a 1 año, IAM, Stroke, Isquemia recurrente con Rehosp,
Revascularización Coronaria Urgente •
Morrow et al. ACC 2012, Chicago, March 24, 2012
Morrow et al. ACC 2012, Chicago, March 24, 2012
Morrow et al. ACC 2012, Chicago, March 24, 2012
Morrow et al. ACC 2012, Chicago, March 24, 2012
Morrow et al. ACC 2012, Chicago, March 24, 2012
Conclusiones
►
Actualmente importante “armamentario” de antiagregantes
plaquetarios para el manejo de los SCA y uso rutinario en
PCI.
►
Bloqueo plaquetario triple: atractiva posibilidad pero riesgo
de más hemorragias
►
Mejores perspectivas para TAD:
●
●
●
Prasugrel
Ticagrelor
Vorapaxar (??)
Conclusiones
►
Los nuevos antiagregantes (Prasugrel, Ticagrelor) son más
potentes que Clopidogrel, pero se asocian a mayor riesgo de
sangrado.
►
La inhibición antiplaquetaria triple (AAS+Clop+Vorapaxar) no
está indicada en SCA y sería efectiva en prevención
secundaria solo en pacientes con IAM previo.
►
La prevención secundaria con TAD o TAT tendría efectos
benéficos en pacientes con IAM previo: CHARISMA, TRA 2P
¿PEGASUS?
Trial Schema
N ~ 21,000
Stable pts with history of MI 1-3 yrs prior
+ 1 additional atherothrombosis risk factor*
RANDOMIZE
DOUBLE BLIND
Ticagrelor
90 mg bid
* Age >65 yrs, diabetes, 2nd prior MI, multivessel CAD,
or chronic non-end stage renal dysfunction
Planned treatment with ASA 75 – 150 mg &
Standard background care
Ticagrelor
60 mg bid
Placebo
Follow-up Visits
Q4 mos for 1st yr, then Q6 mos
Min 12 mos and median 26 mos follow-up
Event-driven trial
Primary Efficacy Endpoint: CV Death, MI, or Stroke
Primary Safety Endpoint: TIMI Major Bleeding
TRILOGY ACS: TaRgeted platelet Inhibition
to cLarify the Optimal strateGy to medicallY
manage Acute Coronary Syndromes
Protocol Synopsis
Presented by
Helene Petitjean, MD
Daiichi-Sankyo
An Unmet Medical Need:
Medically-Managed UA/NSTEMI Patients
• Substantial sub-group of ACS population
despite trend towards invasive/interventional
treatment
• Different from PCI population: older, high
incidence of renal insufficiency, more comorbidities
• Less commonly studied in randomized
clinical trials
Study Design
9326 patients in 8 regions, 52 countries
(Primary: 7243 patients < 75 years old)
Medically Managed UA/NSTEMI Patients
Median Time
to Enrollment
= 4.5 Days
Randomization Stratified by:
Age, Country, Prior Clopidogrel Treatment
(Primary analysis cohort — Age < 75 years)
Medical Management Decision ≤ 72 hrs
(No prior clopidogrel given) — 4% of total
Clopidogrel1
300 mg LD
+
75 mg MD
Prasugrel1
30 mg LD
+
5 or 10 mg MD
Medical Management Decision ≤ 10 days
(Clopidogrel started ≤ 72 hrs in-hospital OR
on chronic clopidogrel) — 96% of total
Clopidogrel1
Prasugrel1
75 mg MD
5 or 10 mg MD
Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months
Primary Efficacy Endpoint: CV Death, MI, Stroke
1. All patients were on aspirin, and low-dose aspirin (< 100 mg) was strongly recommended. For patients < 60 kg or ≥ 75 years, 5
mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1.
Roe Mt et al NEJM 2012
Primary Efficacy Endpoint and
TIMI Major Bleeding Through 30 Months
Endpoint (%)
(Age < 75 years; 7243)
HR (95% CI):
0.91 (0.79, 1.05)
P = 0.21
HR (95% CI):
1.31 (0.81, 2.11)
P = 0.27
Roe MT et al NEJM 2012
Incidence of Outcomes
by Angiography Status
(Age < 75 years)
P < 0.001
P < 0.001
P = 0.09
Primary Efficacy Endpoint to 30 Months
(Age < 75 years)
Angio
No Angio
N=3085
N=4158
10.7% vs 14.9%
P = 0.031
16.3% vs 16.7%
P = 0.954
HR (95% CI):
0.77 (0.61, 0.98)
HR (95% CI):
1.01 (0.84, 1.20)
P interaction = 0.08
Myocardial Infarction
Angio
No Angio
7.2% vs 10.3%
P = 0.042
9.2% vs 10.6%
P = 0.989
HR (95% CI):
0.74 (0.55, 1.00)
HR (95% CI):
1.00 (0.79, 1.26)
P interaction = 0.12
Stroke
Angio
No Angio
0.6% vs 2.4%
P = 0.004
2.2% vs 2.0%
P = 0.933
HR (95% CI):
0.30 (0.13,0.71)
HR (95% CI):
1.03 (0.58,1.83)
P interaction = 0.02
Conclusions
 Overall, in the TRILOGY ACS Trial prasugrel did not reduce
cardiovascular events among patients managed medically
for ACS.
 When treated with prasugrel compared to clopidogrel,
patients triaged to medical therapy following angiography
tended to have:
• Lower rates of the combined endpoint of CVD/MI/CVA
• Lower rates of MI, CVA alone, and recurrent ischemic events
• A trend to higher rates of TIMI major bleeding.
 Though hypothesis generating, these results are consistent
with previous trials and suggest that when angiography is
performed and coronary disease is confirmed, the benefits
and risks of intensive antiplatelet therapy exist whether
medical therapy or PCI is elected.