Antiagregantes Plaquetarios en Pacientes con SCA
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Antiagregantes Plaquetarios en Pacientes con SCA. Dr Ramón Corbalán Departamento Enfermedades Cardiovaculares Pontificia Universidad Cátolica de Chile. Terapia Antiplaquetaria Dual.

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Antiagregantes plaquetarios en pacientes con sca

Antiagregantes Plaquetarios en Pacientes con SCA

Dr Ramón Corbalán

Departamento Enfermedades Cardiovaculares

Pontificia Universidad Cátolica de Chile


Terapia antiplaquetaria dual

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 SCAdesde 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

4Hochholzer W et al. Circulation 2005;111:2560-2564 5Wiviott SD et al. Rev Cardiovasc Med 2006;7:214-225

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


Antiagregantes plaquetarios en pacientes con sca

Los Estudios que avalan

Terapia Antiplaquetarias Dual:

  • CURE

  • CREDO

  • CREDO-PCI

  • CLARITY

  • COMIT


Antiagregantes plaquetarios en pacientes con sca

Limitaciones de Clopidogrel

  • Latencia de su efecto

  • Variantes genéticas

  • Resistencia a la droga

  • ¿Alternativas?


Antiagregantes plaquetarios en pacientes con sca

Inhibidores Receptor P2Y12Riesgo de eventos CV en portadores de gen CYP2C19*2 LOF tratados con clopidogrel

Meta-análisis de 10 estudios (11,959 pacientes)

Hulot JS et al. JACC 2010; 56:134-143.


Antiagregantes plaquetarios en pacientes con sca

Clopidogrel Response Variability andIncreased Risk of Ischemic Events Primary PCI for STEMI (N = 60)

5 µM ADP-induced Platelet Aggregation

Death/ACS/CVA by 6 mo

Clop resist

40

120

40

100

Q1

P = 0.007

30

80

Q2

Baseline (%)

Percent

60

20

Q3

40

Q4

6.7

10

20

Quartiles of response

0

0

0

0

Q1

Q2

Q3

Q4

1

2

3

4

5

6

Days

Matetzky S et al. Circulation. 2004;109:3171-3175. Wiviott SD, Antman EM. Circulation. 2004;109:3064-3067.


Antiagregantes plaquetarios en pacientes con sca

Variabilidad de Respuesta a Clopidogrel: Aumento de la Dosis (300 mg vs. 600 mg)

33

300 mg Clopidogrel

30

600 mg Clopidogrel

27

Resistance = 28% (300 mg)

24

Resistance = 8% (600 mg)

21

18

Patients (%)

15

12

9

6

3

0

≤-30

(-20,-10]

(0,10]

(20,30]

(40,50]

(60,70]

(-30,-20]

(-10,0]

(10,20]

(30,40]

(50,60]

> 70

D Aggregation (5 µM ADP-induced Aggregation) at 24 Hr

Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.


Antiagregantes plaquetarios en pacientes con sca

CURRENT-OASIS 7: Eventos Primarios y Dosis de Clopidogrel /AAS a 30 Días

Mehta SR, et al, ESC; September 2009; Barcelona, Spain.


Antiagregantes plaquetarios en pacientes con sca

CURRENT-OASIS 7: Muerte CV, IM, AVE a 30 Días

Mehta SR, et al, ESC; September 2009; Barcelona, Spain.


Antiagregantes plaquetarios en pacientes con sca

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


Antiagregantes plaquetarios en pacientes con sca

Novedades en Antiplaquetarios...

  • “ArmamentarioTerapeútico” másallá del Clopidogrel: ¿quétenemos?

  • Bloqueoplaquetario Triple: ¿realidad o ficción?

  • Cuales son los antiplaquetarios con mejoresperspectivasfuturas?


Platelet p2 receptors inhibitors

Platelet P2 Receptors/Inhibitors

G protein

G protein

Ticlopidine

Clopidogrel

Prasugrel

Cangrelor

Ticagrelor

ADP

X

Receptor subtype

P2Y12

P2Y1

P2X1

Intrinsic ion

channel

GPCR

Gj

GPCR

Gq

Molecular structure

Secondary

Messenger system

PLC/IP3

[Ca2+]j

[Na+/Ca2+]i

AC

[cAMP]

Shape change

Transient

aggregation

Sustained

aggregation

Secretion

Shape Change

Aggregation

Functional response

Adapted From Bhatt and Topol, Nature Reviews Drug Disc 2:15-28, 2003


Antiagregantes plaquetarios en pacientes con sca

  • Necesidad de nuevosagentesantiplaquetarios:

  • Prodroga

  • VariabilidadInterindividual

  • Bloqueador Irreversible

  • Resistencia

  • Interacciónmedicamentos

Inhibidores Receptor P2Y12

  • Indirectos (Tienopiridinas)

    • Ticlopidina

    • Clopidogrel

    • Prasugrel

  • Directos (No Tienopiridinas)

    • Cangrelor

    • Ticagrelor

    • Elinogrel


Antiagregantes plaquetarios en pacientes con sca

Comparing Response of Clopidogrel (300 mg) and Prasugrel (60 mg) by IPA at 24 Hours

100.0

(20 µM ADP)

80.0

60.0

40.0

Inhibition of Platelet Aggregation (%)

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


Antiagregantes plaquetarios en pacientes con sca

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 InfarctionFDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading dosePrasugrel is not yet approved for use

Wiviott SD, et al. Am Heart J. 2006;152:627-635.


Antiagregantes plaquetarios en pacientes con sca

138 events

15

Clopidogrel

CV Death/MI/Stroke

12.1

HR 0.81(0.73-0.90)P = .0004

9.9

10

NNT = 46

Prasugrel

End Point (%)

TIMI Major Non-CABG Bleeds

5

Prasugrel

2.4

HR 1.32(1.03-1.68)P = .03

1.8

Clopidogrel

0

NNH = 167

0

30

60

90

180

270

360

450

TRITON TIMI-38: Balance of Efficacy and Safety

35 events

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.


Antiagregantes plaquetarios en pacientes con sca

TRITON TIMI-38 Net Clinical Benefit: Bleeding Risk Subgroups

Risk (%)

+ 37

Yes

Prior Stroke / TIA

-16

Pint = 0.006

No

-1

≥75

Age

-16

Pint = 0.18

<75

+3

<60 kg

Weight

-14

Pint = 0.36

≥60 kg

-13

Overall

0.5

1

2

Prasugrel Better

Clopidogrel Better

HR

Post-hoc analysisWiviott SD, et al. N Engl J Med. 2007;357:2001-2015.


Subgrupos de riesgo de hemorragias consideraciones terapeuticas

Subgrupos de Riesgo de Hemorragias Consideraciones terapeuticas

Reduced MDGuided by PKAge > 75 or Wt < 60 kg

Avoid PrasugrelPrior CVA/TIA

16%

4%

Significant Net Clinical Benefit with Prasugrel80%

MD 10 mg


Terapia antiplaquetaria en sca

Terapia Antiplaquetaria en SCA

ASA

ASA + Clopidogrel

ASA + Prasugrel

Reduction inIschemicEvents

- 22%

- 20%

- 19%

Increase in Major Bleeds

+ 32%

+ 38%

+ 60%

Single Antiplatelet Rx

Dual Antiplatelet Rx

Higher IPA


Ticagrelor azd 6140 an oral reversible p2y 12 antagonist

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


Plato study design

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 interventionCV = cardiovascular


Plato main endpoints

PLATO main endpoints*

Primary safety endpoint

Primary efficacy endpoint

13

15

12

11.7

Clopidogrel

11

Ticagrelor

10

11.58

9.8

11.20

9

10

Clopidogrel

Ticagrelor

8

7

K-M estimated rate (%)

K-M estimated rate (%)

6

5

5

4

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

2

4

6

8

10

12

0

2

4

6

8

10

12

Months from randomization

Months from randomization

No. at risk

9,235

7,246

6,826

6,545

5,129

3,783

3,433

Ticagrelor

9,333

8,460

4,147

8,628

8,219

6,743

5,161

9,186

7,305

6,930

6,670

5,209

3,841

3,479

Clopidogrel

9,291

8,362

4,047

8,521

8,124

6,743

5,096

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

* Wallentin, L et al., New Eng J Med. 2009;361:1045–1057


Antiagregantes plaquetarios en pacientes con sca

PLATOTicagrelor: Impacto en Mortalidad Cardiovascular

7

  • Disminución de mortalidad cardiovascular

6

Clopidogrel

5.1

5

4.0

4

Ticagrelor

Cumulative incidence (%)

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.


Antiagregantes plaquetarios en pacientes con sca

PLATO: Dosis de AAS y eficacia:


Antiagregantes plaquetarios en pacientes con sca

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

PAR-1

PAR-4

P2Y1

P2Y12

TBX A2

TBXA2-R

Serotonin

5HT2A

GP VI

Platelet Receptors

Platelet

Platelet

Thrombin

Fibrinogen

GP

IIb/IIIa

ADP

GP

IIb/IIIa

EPI-R

Epinephrine

Collagen

Anionic

phospholipid

surfaces

GP Ia


Antiagregantes plaquetarios en pacientes con sca

Antagonista de los receptores de Trombina (TRA) y Triple Inhibición Plaquetaria

  • SCA se caracterizanporformaciónaumentada de trombinaquepersisteinclusoluego del eventoagudo

  • Trombinaes el principal activador de la plaqueta

  • Actúa a través de receptor PAR-1

  • El bloqueo de los receptores PAR-1 tendríaventajaspotenciales en el corto y largo plazo

  • Estudiosiniciales en pacientessometidos a PCI electivahanmostradoresultadosalentadores: TRA-PCI

  • EstudiosTerminados: TRACER y TRA 2P


Antiagregantes plaquetarios en pacientes con sca

Morrow et al. ACC 2012, Chicago, March 24, 2012


Antiagregantes plaquetarios en pacientes con sca

TRACERSCH 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 •


Antiagregantes plaquetarios en pacientes con sca

Morrow et al. ACC 2012, Chicago, March 24, 2012


Antiagregantes plaquetarios en pacientes con sca

Morrow et al. ACC 2012, Chicago, March 24, 2012


Antiagregantes plaquetarios en pacientes con sca

Morrow et al. ACC 2012, Chicago, March 24, 2012


Antiagregantes plaquetarios en pacientes con sca

Morrow et al. ACC 2012, Chicago, March 24, 2012


Antiagregantes plaquetarios en pacientes con sca

Morrow et al. ACC 2012, Chicago, March 24, 2012


Antiagregantes plaquetarios en pacientes con sca

Conclusiones

  • Actualmente importante “armamentario” de antiagregantesplaquetarios 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 (??)


Antiagregantes plaquetarios en pacientes con sca

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

Trial Schema

Stable pts with history of MI 1-3 yrs prior

+ 1 additional atherothrombosis risk factor*

N ~ 21,000

* Age >65 yrs, diabetes, 2nd prior MI, multivessel CAD, or chronic non-end stage renal dysfunction

RANDOMIZE

DOUBLE BLIND

Planned treatment with ASA 75 – 150 mg &

Standard background care

Ticagrelor90 mg bid

Ticagrelor60 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


Antiagregantes plaquetarios en pacientes con sca

TRILOGY ACS:TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes

Protocol Synopsis

Presented byHelene Petitjean, MD

Daiichi-Sankyo


An unmet medical need medically managed ua nstemi patients

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 co-morbidities

Less commonly studied in randomized clinical trials


Study design

Study Design

9326 patients in 8 regions, 52 countries(Primary: 7243 patients < 75 years old)

Medically Managed UA/NSTEMI Patients

Randomization Stratified by:

Age, Country, Prior Clopidogrel Treatment

(Primary analysis cohort — Age < 75 years)

Median Timeto Enrollment = 4.5 Days

Medical 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

Clopidogrel1300 mg LD

+

75 mg MD

Prasugrel130 mg LD

+

5or 10 mg MD

Clopidogrel1

75 mg MD

Prasugrel15or 10 mg MD

Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months

Primary Efficacy Endpoint: CV Death, MI, Stroke

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 age 75 years 7243

Primary Efficacy Endpoint and TIMI Major Bleeding Through 30 Months(Age < 75 years; 7243)

HR (95% CI):

0.91 (0.79, 1.05)

P = 0.21

Endpoint (%)

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

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

Primary Efficacy Endpoint to 30 Months(Age < 75 years)

Angio

N=3085

No Angio

N=4158

10.7% vs 14.9%P = 0.031

HR (95% CI):0.77 (0.61, 0.98)

16.3% vs 16.7%P = 0.954

HR (95% CI):1.01 (0.84, 1.20)

P interaction = 0.08


Myocardial infarction

Myocardial Infarction

Angio

No Angio

7.2% vs 10.3%P = 0.042

HR (95% CI):0.74 (0.55, 1.00)

9.2% vs 10.6%P = 0.989

HR (95% CI):1.00 (0.79, 1.26)

P interaction = 0.12


Stroke

Stroke

Angio

No Angio

0.6% vs 2.4%P = 0.004

HR (95% CI):0.30 (0.13,0.71)

2.2% vs 2.0%P = 0.933

HR (95% CI):1.03 (0.58,1.83)

P interaction = 0.02


Conclusions

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.


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