Antiagregantes Plaquetarios en Pacientes con SCA

Presentación del tema: "Antiagregantes Plaquetarios en Pacientes con SCA"— Transcripción de la presentación:

1 Antiagregantes Plaquetarios en Pacientes con SCA
Dr Ramón Corbalán Departamento Enfermedades Cardiovaculares Pontificia Universidad Cátolica de Chile

2 Atherothrombosis and Microcirculation
Plaque rupture Microvascular obstruction Embolization Through the development of new imaging modalities and specific therapeutics that serve as probes, microvascular obstruction, owing to embolization, has become increasingly recognized as an important sequelae of atherosclerotic and atherothrombotic vascular disease.1 Thrombus formation on an atherosclerotic plaque is a dynamic process in which platelets aggregate but also spontaneously disaggregate, leading to embolization of platelet aggregates from an evolving thrombus, which can lead to inflammation or microvascular obstruction.2 Additionally, particulate matter may also shed from the ruptured atherosclerotic lesion.2 Altogether, the release of microemboli, which occurs while a plaque is active and can last for hours, days or weeks, leads to microvascular obstruction in the myocardium, brain or peripheral tissues, resulting for example in cardiac insufficiency or vascular dementia.2 Adapted from: Topol EJ, Yadav JS. Circulation 2000; 101: 570–80, and Falk E et al. Circulation 1995; 92: 657–71. References: 1. Topol EJ, Yadav JS. Circulation 2000; 101: 570–80. 2. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6.

3 Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
3

4 Clotting Cascade

5 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? Background on antiplatelet therapy Pharmacological inhibition of platelets with a combination of aspirin (ASA) and a thienopyridine is a currently recommended approach to prevent recurrent ischemic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI).1-3 The goals of antiplatelet therapy are to provide rapid and consistent high levels of inhibition of platelet activation and aggregation. Important clinical benefits have been demonstrated with current antiplatelet treatments in large, multinational trials over the last decade resulting in clinical guidelines for antiplatelet therapy. ASA=Acetylsalicylic Acid; ACS=Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention 1Anderson JL et al. Circulation 2007;116:e Antman EM et al. Circulation 2008;117: King SB et al. Circulation 2008;117: 4Hochholzer W et al. Circulation 2005;111: Wiviott SD et al. Rev Cardiovasc Med 2006;7: 1Anderson JL et al. Circulation 2007;116:e Antman EM et al. Circulation 2008;117: King SB et al. Circulation 2008;117: Hochholzer W et al. Circulation 2005;111: Wiviott SD et al. Rev Caridovasc Med 2006;7: 5

6 Los Estudios que avalan Terapia Antiplaquetarias Dual:
CURE CREDO CREDO-PCI CLARITY COMIT

7 Limitaciones de Clopidogrel
Latencia de su efecto Variantes genéticas Resistencia a la droga ¿Alternativas?

8 Meta-análisis de 10 estudios (11,959 pacientes)
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 Portador de gen LOF (%) No portador (%) OR (95% IC) p MACE 9,7 7,8 1,29 (1,12-1,49) <0,001 Trombosis Intrastent 2,9 0,9 3,45 (2,14-5,57) Muerte 1,8 1,0 1,79 (1,10-2,91) 0,019 Hulot JS et al. JACC 2010; 56:

9 The First Clopidogrel Resistance Study (300 mg): A “Fingerprint” of Clopidogrel Response
Variability 2 Hours 24 Hours 24 Resistance Resistance = 63% Resistance Resistance = 31% 20 Patients (%) Patients (%) 12 10 ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60 ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60  Aggregation (%) (-30,-20] (-10,0] (10,20] (30,40] (50,60] (-30,-20] (-10,0] (10,20] (30,40] (50,60]  Aggregation (%) 5 Days 30 Days 22 Resistance Resistance = 31% 28 Resistance = 15% Patients (%) 11 Patients (%) 14 Resistance ≤ -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60 ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60  Aggregation (%) (-30,-20] (-10,0] (10,20] (30,40] (50,60]  Aggregation (%) Gurbel PA et al. Circulation. 2003;107: 9

10 5 µM ADP-induced Platelet Aggregation
Clopidogrel Response Variability and Increased Risk of Ischemic Events Primary PCI for STEMI (N = 60) 5 µM ADP-induced Platelet Aggregation Death/ACS/CVA by 6 mo 120 Clop resist 40 40 100 Q1 P = 0.007 30 80 Q2 Baseline (%) Percent 60 20 Q3 40 Q4 10 6.7 20 Quartiles of response Q1 Q2 Q3 Q4 1 2 3 4 5 6 Days Matetzky S et al. Circulation ;109: Wiviott SD, Antman EM. Circulation. 2004;109: 10

11 D Aggregation (5 µM ADP-induced Aggregation) at 24 Hr
Variabilidad de Respuesta a Clopidogrel: Aumento de la Dosis (300 mg vs. 600 mg) 33 300 mg Clopidogrel 30 600 mg Clopidogrel 27 24 Resistance = 28% (300 mg) Resistance = 8% (600 mg) 21 18 Patients (%) 15 12 9 6 3 ≤-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: 11

12 Death/MI/Stroke at 30 days
ASA Dose Comparison Death/MI/Stroke at 30 days 25,087 ACS Patients with planned PCI 0.04 0.03 HR 0.97 ( ) P = 0.61 Cumulative Hazard 0.02 0.01 ASA mg ASA mg 0.0 3 6 9 12 15 18 21 24 27 30 Days CURRENT-OASIS 7. NEJM 2010;363:930 12

13 CURRENT-OASIS 7: Eventos Primarios y Dosis de Clopidogrel /AAS a 30 Días
Mehta SR, et al, ESC; September 2009; Barcelona, Spain.

14 CURRENT-OASIS 7: Muerte CV, IM, AVE a 30 Días
Mehta SR, et al, ESC; September 2009; Barcelona, Spain.

15 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

16 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?

17 Platelet P2 Receptors/Inhibitors
Ticlopidine Clopidogrel Prasugrel Cangrelor Ticagrelor ADP Receptor subtype X P2Y1 P2Y12 P2X1 G protein G protein Molecular structure Intrinsic ion channel GPCR Gq GPCR Gj Secondary Messenger system [Na+/Ca2+]i PLC/IP3 [Ca2+]j AC [cAMP] Shape change Transient aggregation Sustained aggregation Secretion Functional response Shape Change Aggregation Adapted From Bhatt and Topol, Nature Reviews Drug Disc 2:15-28, 2003

18 Inhibidores Receptor P2Y12
Indirectos (Tienopiridinas) Ticlopidina Clopidogrel Prasugrel Directos (No Tienopiridinas) Cangrelor Ticagrelor Elinogrel Necesidad de nuevos agentes antiplaquetarios: Prodroga Variabilidad Interindividual Bloqueador Irreversible Resistencia Interacción medicamentos

19 Inhibidores Receptor P2Y12
Clopidogrel Prasugrel Ticagrelor Clase Tienopiridina Análogo ATP Reversibilidad irreversible reversible Administración oral Efecto peak 2-3 hrs 1 hr 1,5 hrs Eliminación 3 hrs 3,7 hrs 12 hrs Duración 5-8 días 5-10 días 24 hrs Trials CURE TRITON PLATO

20 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

21 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 TRITON-TIMI 38 was a phase 3, randomized, double-blind, parallel-group, multinational, clinical trial. Approximately patients with moderate to high-risk ACS undergoing PCI (9500 unstable angina/non–ST-segment elevation myocardial infarction [MI], 3500 ST-segment elevation MI) were randomized to prasugrel 60 mg loading dose followed by 10 mg daily or clopidogrel 300 mg loading dose followed by 75 mg daily for up to 15 months. The primary end point was the time of the first event of cardiovascular death, MI, or stroke. Analyses were performed first in the unstable angina/non–ST-segment elevation MI cohort and, conditionally, on the whole ACS population. Major safety end points included TIMI major and minor bleeding unrelated to coronary artery bypass graft surgery. 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 ;152: 21 21 21 21

22 TIMI Major Non-CABG Bleeds
TRITON TIMI-38: Balance of Efficacy and Safety End Point (%) 12.1 9.9 1.8 2.4 5 10 15 30 60 90 180 270 360 450 CV Death/MI/Stroke TIMI Major Non-CABG Bleeds Clopidogrel Prasugrel HR 0.81 ( ) P = .0004 HR 1.32 ( ) P = .03 138 events NNT = 46 NNH = 167 35 events To compare prasugrel, a new thienopyridine, with clopidogrel, the authors randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. Results: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). The authors also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002). Figure: Cumulative Kaplan–Meier estimates of the rates of key study end points during the follow-up period showing data for the primary efficacy end point (death from cardiovascular causes, nonfatal myocardial infarction [MI], or nonfatal stroke). In the overall cohort, a total of 781 patients (12.1%) in the clopidogrel group had the primary end point, as compared with 643 patients (9.9%) in the prasugrel group (hazard ratio, 0.81; 95% CI, 0.73 to 0.90; P<0.001), supporting the primary hypothesis of superior efficacy. Conclusions: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. Days HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm Wiviott SD, et al. N Engl J Med. 2007;357: 22 22

23 Any Stent at Index PCI N = 12,844
TRITON TIMI-38: Stent Thrombosis (ARC Definite + Probable) 1 2 3 30 60 90 180 270 360 450 HR 0.48 P < .0001 Prasugrel Clopidogrel 2.4 (142) 74 events NNT = 77 1.1 (68) End Point (%) Any Stent at Index PCI N = 12,844 To compare prasugrel, a new thienopyridine, with clopidogrel, the authors randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. Results: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). The authors also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002). Figure: The rate of definite or probable stent thrombosis, as defined by the Academic Research Consortium, was significantly reduced in the prasugrel group as compared with the clopidogrel group, with 68 patients (1.1%) and 142 patients (2.4%), respectively, having at least one occurrence (hazard ratio, 0.48; 95% CI, 0.36 to 0.64; P<0.001). Conclusions: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. Days ARC = Academic Research Consortium; PCI = percutaneous coronary intervention Wiviott SD, et al. N Engl J Med. 2007;357: 23 23

24 TIMI Major NonCABG Bleeds
Diabetic Subgroup N=3146 18 Clopidogrel 17.0 16 CV Death / MI / Stroke 14 12.2 12 HR 0.70 P<0.001 Endpoint (%) Prasugrel 10 NNT = 21 8 Patients with diabetes are of particular interest since they are known to have increased rates of events and more aggregable platelets. PRASUGREL REDUCED THE RATE OF THE PRIMARY ENDPOINT IN DIABETIC PATIENST FROM 17% with clopidogrel to 12.2% of prasugrel patients. 68 events were prevented. There was a 30% reduction in the HR with P < 0.001 As shown at the bottom of the slide these striking benefits in a high risk subgroup were achieved with prasugrel with a virtually identical rate of major non CABG bleeding compared with clopidogrel. 6 TIMI Major NonCABG Bleeds 4 Clopidogrel 2.6 2.5 2 Prasugrel 30 60 90 180 270 360 450 Days 24

25 TRITON TIMI-38 Net Clinical Benefit: Bleeding Risk Subgroups
Yes + 37 Prior Stroke / TIA -16 No Pint = 0.006 ≥75 -1 Age -16 Pint = 0.18 <75 <60 kg +3 Weight To compare prasugrel, a new thienopyridine, with clopidogrel, the authors randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. Results: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). The authors also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002). Figure: There were three specific groups of interest; patients who had a previous stroke or transient ischemic attack had net harm from prasugrel (hazard ratio, 1.54; 95% CI, 1.02 to 2.32; P = 0.04), patients 75 years of age or older had no net benefit from prasugrel (hazard ratio, 0.99; 95% CI, 0.81 to 1.21; P = 0.92), and patients weighing less than 60 kg had no net benefit from prasugrel (hazard ratio, 1.03; 95% CI, 0.69 to 1.53; P = 0.89). In both treatment groups, patients with at least one of these three risk factors had higher rates of bleeding than those without them. Conclusions: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. ≥60 kg -14 Pint = 0.36 -13 Overall 0.5 1 2 Prasugrel Better Clopidogrel Better HR Post-hoc analysis Wiviott SD, et al. N Engl J Med. 2007;357: 25 25

26 Subgrupos de Riesgo de Hemorragias Consideraciones terapeuticas
Reduced MD Guided by PK Age > 75 or Wt < 60 kg Avoid Prasugrel Prior CVA/TIA 16% 4% Significant Net Clinical Benefit with Prasugrel 80% MD 10 mg 26 26

27 Terapia Antiplaquetaria en SCA
ASA ASA + Clopidogrel ASA + Prasugrel - 22% Reduction in Ischemic Events - 20% - 19% Increase in Major Bleeds + 60% + 38% + 32% Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA 27

28 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 28

29 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

30 PLATO main endpoints* Primary efficacy endpoint
Primary safety endpoint 13 15 12 Clopidogrel 11.7 11 Ticagrelor 10 9.8 11.58 11.20 9 10 Ticagrelor Clopidogrel 8 7 K-M estimated rate (%) 6 K-M estimated rate (%) 5 5 4 3 2 1 HR 0.84 (95% CI 0.77–0.92), p=0.0003 HR 1.04 (95% CI 0.95–1.13), p=0.434 2 4 6 8 10 12 2 4 6 8 10 12 Months from randomization Months from randomization No. at risk 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 30

31 PLATO Ticagrelor: Impacto en Mortalidad Cardiovascular
7 Disminución de mortalidad cardiovascular 6 Clopidogrel 5.1 5 4 4.0 Cumulative incidence (%) Ticagrelor 3 2 1 HR 0.79 (95% CI 0.69–0.91), p=0.001 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:

32 PLATO Ticagrelor: Trombosis del Stent
Trombosis Stent (%) Ticagrelor (n=6.732) Clopidogrel (n=6.676) HR (95% IC) p Definitiva 1,0 1,6 0,62 (0,45-0,85) 0,003 Probable o Definitiva 1,7 2,3 0,72 (0,56-0,93) 0,01 Posible, Probable o Definitiva 2,2 3,1 (0,58-0,90) Cannon et al. Lancet 2010;375:

33 PLATO: Dosis de AAS y eficacia:

34 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

35 Platelet Receptors Platelet Platelet PAR-1 Thrombin PAR-4 GP IIb/IIIa
Fibrinogen GP IIb/IIIa P2Y1 ADP P2Y12 GP IIb/IIIa TBX A2 TBXA2-R Epinephrine EPI-R Serotonin 5HT2A GP VI Collagen Anionic phospholipid surfaces GP Ia

36 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

37 Thrombin generation After MI (N=319)
Ardissino D. Blood 2003,102:

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

39 TRACER SCH 530348 (Vorapaxar) en SCA
Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome SCA SIN SDST N = 10,000 SCH 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 •

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

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

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

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

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

45

46

47

48 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 (??)

49 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?

50 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 Ticagrelor 90 mg bid 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 50

51 Protocol Synopsis Presented by Helene Petitjean, MD Daiichi-Sankyo
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

52 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 52

53 Study Design 9326 patients in 8 regions, 52 countries (Primary: 7243 patients < 75 years old) Medically Managed UA/NSTEMI Patients Clopidogrel1 75 mg MD Prasugrel1 5 or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, Stroke Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort — Age < 75 years) Clopidogrel1 300 mg LD + Prasugrel1 30 mg LD 5 or 10 mg MD 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 Median Time to Enrollment = 4.5 Days Source: Q113, Q111, Q331 [Source: Figure 1 on page 19] Reference: Chin CT, Roe MT, Fox KA, Prabhakaran D, Marshall DA, Petitjean H, Lokhnygina Y, Brown E, Armstrong PW, White HD, Ohman EM; TRILOGY ACS Steering Committee. Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J 2010;160(1):16-22.e1. 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 53 Pras

54 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

55 Incidence of Outcomes by Angiography Status (Age < 75 years)

56 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): (0.61, 0.98) 16.3% vs 16.7% P = 0.954 HR (95% CI): (0.84, 1.20) P interaction = 0.08

57 Myocardial Infarction
Angio No Angio 7.2% vs 10.3% P = 0.042 HR (95% CI): (0.55, 1.00) 9.2% vs 10.6% P = 0.989 HR (95% CI): (0.79, 1.26) P interaction = 0.12

58 Stroke Angio No Angio P interaction = 0.02 0.6% vs 2.4% P = 0.004
HR (95% CI): (0.13,0.71) 2.2% vs 2.0% P = 0.933 HR (95% CI): (0.58,1.83) P interaction = 0.02

59 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. 59