Antiagregantes Plaquetarios en Pacientes con SCA
description
Transcript of Antiagregantes Plaquetarios en Pacientes con SCA
Antiagregantes Plaquetarios en Pacientes con SCA
Dr Ramón CorbalánDepartamento 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?
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
ASA=Acetylsalicylic Acid; ACS=Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention4Hochholzer W et al. Circulation 2005;111:2560-2564 5Wiviott 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 P2Y12Riesgo de eventos CV en portadores de gen CYP2C19*2 LOF tratados con clopidogrel
Eventos Portador de gen LOF (%)
No portador (%)
OR (95% IC) p
MACE 9,7 7,81,29
(1,12-1,49)
<0,001
Trombosis Intrastent
2,9 0,93,45
(2,14-5,57)
<0,001
Muerte 1,8 1,01,79
(1,10-2,91)
0,019
Meta-análisis de 10 estudios (11,959 pacientes)
Hulot JS et al. JACC 2010; 56:134-143.
0
20
40
60
80
100
120
0
10
20
30
40
5 µM ADP-induced Platelet Aggregation Death/ACS/CVA by 6 mo
Days1 2 3 4 5 6
Bas
elin
e (%
)
Quartiles of response
Q1
Q2
Q3
Q4
Clop resist 40
6.7
0 0
Perc
ent
P = 0.007
Q1 Q2 Q3 Q4
Matetzky S et al. Circulation. 2004;109:3171-3175. Wiviott SD, Antman EM. Circulation. 2004;109:3064-3067.
Clopidogrel Response Variability andIncreased Risk of Ischemic Events Primary PCI for STEMI (N = 60)
Variabilidad de Respuesta a Clopidogrel: Aumento de la Dosis (300 mg vs. 600 mg)
Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.
03
6
9
12
15
18
21
24
27
30
33
≤-30(-30,-20]
(-20,-10](-10,0]
(0,10](10,20]
(20,30](30,40]
(40,50](50,60]
(60,70]> 70
300 mg Clopidogrel
600 mg Clopidogrel
D D Aggregation (5 µM ADP-induced Aggregation) at 24 Hr
Patie
nts
(%)
Resistance = 28% (300 mg)Resistance = 8% (600 mg)
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
G protein
Molecular structure Intrinsic ionchannel
G protein
Receptor subtype
P2X1
P2Y1 P2Y12
GPCRGj
GPCRGq
PLC/IP3
[Ca2+]j
AC[cAMP]
Shape changeTransient
aggregation
Sustainedaggregation
Secretion
SecondaryMessenger system
Functional response
[Na+/Ca2+]i
Shape ChangeAggregation
ADP
TiclopidineClopidogrelPrasugrelCangrelorTicagrelor
X
Adapted From Bhatt and Topol, Nature Reviews Drug Disc 2:15-28, 2003
Inhibidores Receptor P2Y12
• Indirectos (Tienopiridinas)
- Ticlopidina
- Clopidogrel
- Prasugrel
• Directos (No Tienopiridinas)
- Cangrelor
- Ticagrelor
- Elinogrel
Necesidad de nuevos agentes antiplaquetarios:1. Prodroga2. Variabilidad Interindividual3. Bloqueador Irreversible4. Resistencia5. Interacción medicamentos
Necesidad de nuevos agentes antiplaquetarios:1. Prodroga2. Variabilidad Interindividual3. Bloqueador Irreversible4. Resistencia5. Interacción medicamentos
-20.0-20.0
0.00.0
20.020.0
40.040.0
60.060.0
80.080.0
100.0100.0
Inhi
bitio
n of
Pla
tele
t Agg
rega
tion
(%)
Response to Prasugrel
Response to Clopidogrel
Comparing Response of Clopidogrel (300 mg) and Prasugrel (60 mg) by IPA at 24 Hours
Brandt J et al. Am Heart J. 2007;153:66.e9-66.e16
(20 µM ADP)
Background Variability
TRITON TIMI-38 Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) and Planned PCI
ASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
First-degree end point: CV death, MI, strokeSecond-degree end points: CV death, MI, stroke, rehospitalization,
recurrent ischemia, UTVR
Median duration of therapy: 12 months
N=13,600
Wiviott SD, et al. Am Heart J. 2006;152:627-635.
UTVR = urgent target vessel revascularization; TRITON TIMI = TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel Thrombolysis In Myocardial InfarctionFDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading dosePrasugrel is not yet approved for use
Days
35 events
TRITON TIMI-38: Balance of Efficacy and Safety
HR 0.81(0.73-0.90)P = .0004
HR 1.32(1.03-1.68)
P = .03
138 events
NNT = 46
NNH = 167
Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
End
Poin
t (%
)
12.1
9.9
1.8
2.4
0
5
10
15
0 30 60 90 180 270 360 450
CV Death/MI/Stroke
TIMI Major Non-CABG Bleeds
Clopidogrel
Prasugrel
Prasugrel
Clopidogrel
HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm
TRITON TIMI-38 Net Clinical Benefit: Bleeding Risk Subgroups
Overall
≥60 kg
<60 kg
<75
No
Yes
0.5 1 2
Prior Stroke / TIA
Age
Weight
Risk (%)
+ 37
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Post-hoc analysisWiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
≥75
Subgrupos de Riesgo de Hemorragias Consideraciones terapeuticas
Significant Net Clinical Benefit with
Prasugrel80%
MD MD 10 mg10 mg
Reduced MD
Guided by PK
Age > 75 or
Wt < 60 kg16%
Avoid
Prasugrel
Prior
CVA/TIA4%4%
Terapia Antiplaquetaria en SCA
Placebo APTC CURE TRITON-TIMI 38Single
Antiplatelet RxDual
Antiplatelet RxHigher
IPA
ASAASA + Clopidogrel
ASA + Prasugrel
- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction in
IschemicEvents
Increase in
Major Bleeds
Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist
Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)
• 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
OH
OH
O
OH
N
S
NH
NN
NN
F
F
PLATO study design
6–12 months treatment
PCI = percutaneous coronary interventionCV = cardiovascular
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
Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding
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)
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
PLATO main endpoints*
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,521
8,628
8,362
8,460
8,124
Months from randomization
6,743
6,743
5,096
5,161
4,047
4,1478,219
0 2 4 6 8 10 12
12
11
10
9
8
7
6
5
4
3
2
1
0
13
K-M
est
imat
ed ra
te (
%)
9.8
11.7
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., New Eng J Med. 2009;361:1045–1057
0 2 4 6 8 10 12
10
5
0
15
Clopidogrel
Ticagrelor
11.2011.58
HR 1.04 (95% CI 0.95–1.13), p=0.434
K-M
est
imat
ed ra
te (
%)
Months from randomization
Primary safety endpointPrimary efficacy endpoint
9,186
9,235
7,305
7,246
6,930
6,826
6,670 5,209
5,129
3,841
3,783
3,479
3,4336,545
PLATOTicagrelor: Impacto en Mortalidad Cardiovascular
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
Days after randomisation
7079
7119
5,441
5,482
4,364
4,4198,626
Cum
ulat
ive in
ciden
ce (%
)
Disminución de mortalidad cardiovascularDisminución de mortalidad cardiovascular
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
► 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
ThrombinThrombin
ADPADP
EpinephrineEpinephrine
CollagenCollagen Anionicphospholipid
surfaces
GPGPIIb/IIIaIIb/IIIa
Platelet
Fibrinogen
GP Ia
P2Y1
GP VI
PAR-4
TBX ATBX A22 TBXA2-R
SerotoninSerotonin 5HT2A
P2Y12
PAR-1
GPGPIIb/IIIaIIb/IIIa
EPI-R
SCA se caracterizan por formación aumentada de trombina que persiste SCA se caracterizan por formación aumentada de trombina que persiste incluso luego del evento agudoincluso luego del evento agudo
Trombina es el principal activador de la plaquetaTrombina es el principal activador de la plaqueta
Actúa a través de receptor PAR-1 Actúa a través de receptor PAR-1
El bloqueo de los receptores PAR-1 tendría ventajas potenciales en el corto El bloqueo de los receptores PAR-1 tendría ventajas potenciales en el corto y largo plazoy largo plazo
Estudios iniciales en pacientes sometidos a PCI electiva han mostrado Estudios iniciales en pacientes sometidos a PCI electiva han mostrado
resultados alentadores: resultados alentadores: TRA-PCI TRA-PCI
Estudios Terminados: Estudios Terminados: TRACER y TRA 2PTRACER y TRA 2P
Antagonista de los receptores de Trombina (TRA) y Triple Inhibición Plaquetaria
Morrow et al. ACC 2012, Chicago, March 24, 2012
TRACERSCH 530348 (Vorapaxar) en SCA
• • Muerte cardiovascular a 1 año, IAM, Stroke, Isquemia recurrente con Rehosp, Muerte cardiovascular a 1 año, IAM, Stroke, Isquemia recurrente con Rehosp, Revascularización Coronaria Urgente •Revascularización Coronaria Urgente •
• • Muerte cardiovascular a 1 año, IAM, Stroke, Isquemia recurrente con Rehosp, Muerte cardiovascular a 1 año, IAM, Stroke, Isquemia recurrente con Rehosp, Revascularización Coronaria Urgente •Revascularización Coronaria Urgente •
SCA SIN SDSTSCA SIN SDSTN = 10,000N = 10,000
SCH 530348SCH 53034840 mg carga, 2.5 mg/día40 mg carga, 2.5 mg/día
n=5000n=5000
PlaceboPlacebo(y terapia usual)(y terapia usual)
n=5000n=5000
TThrombin hrombin RReceptor eceptor AAntagonist for ntagonist for CClinical linical EEvent vent RReduction in Acute eduction in Acute Coronary SyndromeCoronary Syndrome
STOP !!!! STOP !!!!
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 (??)
► 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?
► 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
Stable pts with history of MI 1-3 yrs prior+ 1 additional atherothrombosis risk factor*N ~ 21,000
Ticagrelor90 mg bid
Placebo
RANDOMIZEDOUBLE BLIND
Follow-up VisitsQ4 mos for 1st yr, then Q6 mos
Planned treatment with ASA 75 – 150 mg &Standard background care
Primary Efficacy Endpoint: CV Death, MI, or StrokePrimary Safety Endpoint: TIMI Major Bleeding
* Age >65 yrs, diabetes, 2nd prior MI, multivessel CAD, or chronic non-end stage renal dysfunction
Min 12 mos and median 26 mos follow-upEvent-driven trial
Ticagrelor60 mg bid
TRILOGY ACS:TRILOGY ACS: TTaaRRgeted platelet geted platelet IInhibition nhibition to cto cLLarify the arify the OOptimal strateptimal strateGGy to medically to medicallYY
manage manage AAcute cute CCoronary oronary SSyndromesyndromesProtocol Synopsis
Presented byHelene Petitjean, MD
Daiichi-Sankyo
An Unmet Medical Need:An Unmet Medical Need:Medically-Managed UA/NSTEMI PatientsMedically-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 co-morbidities
• Less commonly studied in randomized clinical trials
Study DesignStudy Design
Roe Mt et al NEJM 2012
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.
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.
Medically Managed UA/NSTEMI PatientsMedically Managed UA/NSTEMI Patients
Clopidogrel1
75 mg MD
Clopidogrel1
75 mg MD
Prasugrel1
5 or 10 mg MD
Prasugrel1
5 or 10 mg MD
Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 monthsMinimum Rx Duration: 6 months; Maximum Rx Duration: 30 months
Primary Efficacy Endpoint: CV Death, MI, Stroke Primary Efficacy Endpoint: CV Death, MI, Stroke
Randomization Stratified by:Age, Country, Prior Clopidogrel Treatment(Primary analysis cohort — Age < 75 years)
Randomization Stratified by:Age, Country, Prior Clopidogrel Treatment(Primary analysis cohort — Age < 75 years)
Clopidogrel1
300 mg LD+
75 mg MD
Clopidogrel1
300 mg LD+
75 mg MD
Prasugrel1
30 mg LD+
5 or 10 mg MD
Prasugrel1
30 mg LD+
5 or 10 mg MD
Medical Management Decision ≤ 72 hrs(No prior clopidogrel given) — 4% of totalMedical Management Decision ≤ 72 hrs(No prior clopidogrel given) — 4% of total
Medical Management Decision ≤ 10 days(Clopidogrel started ≤ 72 hrs in-hospital OR
on chronic clopidogrel) — 96% of total
Medical Management Decision ≤ 10 days(Clopidogrel started ≤ 72 hrs in-hospital OR
on chronic clopidogrel) — 96% of total
Median Timeto Enrollment
= 4.5 Days
9326 patients in 8 regions, 52 countries9326 patients in 8 regions, 52 countries(Primary: 7243 patients < 75 years old)(Primary: 7243 patients < 75 years old)
Primary Efficacy Endpoint and Primary Efficacy Endpoint and TIMI Major Bleeding Through 30 MonthsTIMI Major Bleeding Through 30 Months(Age < 75 years; 7243)(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
En
dp
oin
t (%
)
Roe MT et al NEJM 2012
Incidence of Outcomes Incidence of Outcomes by Angiography Statusby Angiography Status(Age < 75 years)(Age < 75 years)
P < 0.001
P < 0.001
P = 0.09
Primary Efficacy Endpoint to 30 MonthsPrimary Efficacy Endpoint to 30 Months(Age < 75 years)(Age < 75 years)
P interaction = 0.08
10.7% vs 14.9%P = 0.031
HR (95% CI): 0.77 (0.61, 0.98)
AngioN=3085
No AngioN=4158
16.3% vs 16.7%P = 0.954
HR (95% CI): 1.01 (0.84, 1.20)
P interaction = 0.12
7.2% vs 10.3%P = 0.042
HR (95% CI): 0.74 (0.55, 1.00)
Angio No Angio
9.2% vs 10.6%P = 0.989
HR (95% CI): 1.00 (0.79, 1.26)
Myocardial InfarctionMyocardial Infarction
StrokeStroke
P interaction = 0.02
0.6% vs 2.4%P = 0.004
HR (95% CI): 0.30 (0.13,0.71)
Angio No Angio
2.2% vs 2.0%P = 0.933
HR (95% CI): 1.03 (0.58,1.83)
ConclusionsConclusions
Overall, in the TRILOGY ACS Trial Overall, in the TRILOGY ACS Trial prasugrelprasugrel did not reduce did not reduce cardiovascular events among patients managed medically cardiovascular events among patients managed medically for ACS.for ACS.
When treated with When treated with prasugrel prasugrel compared to compared to clopidogrelclopidogrel, , patients patients triaged to medical therapy following angiography triaged to medical therapy following angiography tended to have: tended to have: • Lower rates of the combined endpoint of CVD/MI/CVALower rates of the combined endpoint of CVD/MI/CVA
• Lower rates of MI, CVA alone, and recurrent ischemic eventsLower rates of MI, CVA alone, and recurrent ischemic events
• A trend to higher rates of TIMI major bleeding. A trend to higher rates of TIMI major bleeding.
Though hypothesis generating, these results are consistent Though hypothesis generating, these results are consistent with previous trials and suggest that when angiography is with previous trials and suggest that when angiography is performed and coronary disease is confirmed, the benefits performed and coronary disease is confirmed, the benefits and risks of intensive antiplatelet therapy exist whether and risks of intensive antiplatelet therapy exist whether medical therapy or PCI is elected.medical therapy or PCI is elected.