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.