Antiagregantes Plaquetarios en Pacientes con SCA

Transcripción

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

2 Atherothrombosis and Microcirculation Plaque rupture Embolization Microvascular obstruction Adapted from: Topol EJ, Yadav JS. Circulation 2000; 101: , and Falk E et al. Circulation 1995; 92:

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

4 Clotting Cascade

5 Terapia Antiplaquetaria Dual La inhibición de las plaquetas es una estrategia clave en el tratmiento de pacientes con sindromes coronarios agudos 1,2, sometidos a PCI 3 Las metas de este tratamiento son la inhibición rápida, consistente y efectiva de la activación y agregación plaquetaria 3-5 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 1 Anderson 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 Cardiovasc Med 2006;7:

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 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) <0,001 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 24 2 Hours Resistance Variability 24 Hours Resistance = 63% Resistance Resistance = 31% 20 Patients (%) 12 Patients (%) (-20,-10] (-30,-20] (-10,0] (0,10] (20,30] (40,50] (10,20] (30,40] Aggregation (%) (50,60] >60-30 (-20,-10] (-30,-20] (-10,0] (0,10] (20,30] (40,50] (10,20] (30,40] Aggregation (%) (50,60] >60 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 Aggregation (%) -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60] Aggregation (%) Gurbel PA et al. Circulation. 2003;107:

10 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 Baseline (%) Clop resist Q1 Q2 Q3 Q Quartiles of response Days Percent P = Q1 Q2 Q3 Q4 Matetzky S et al. Circulation. 2004;109: Wiviott SD, Antman EM. Circulation. 2004;109:

11 Variabilidad de Respuesta a Clopidogrel: Aumento de la Dosis (300 mg vs. 600 mg) Patients (%) Resistance = 28% (300 mg) Resistance = 8% (600 mg) -30 (-30,-20] (-20,-10] (-10,0] (0,10] (10,20] (20,30] (30,40] 300 mg Clopidogrel 600 mg Clopidogrel (40,50] (60,70] (50,60] > 70 D Aggregation (5 µm ADP-induced Aggregation) at 24 Hr Gurbel PA et al. J Am Coll Cardiol. 2005;45:

12 ASA Dose Comparison Death/MI/Stroke at 30 days Cumulative Hazard ,087 ACS Patients with planned PCI HR 0.97 ( ) P = 0.61 ASA mg ASA mg Days CURRENT-OASIS 7. NEJM 2010;363:930

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 ADP Ticlopidine Clopidogrel Prasugrel Cangrelor Ticagrelor Receptor subtype P2X 1 P2Y 1 P2Y 12 X G protein G protein Molecular structure Intrinsic ion channel GPCR G q GPCR G j Secondary Messenger system [Na + /Ca 2+ ] i PLC/IP 3 [Ca 2 +] j AC [camp] Functional response Shape Change Aggregation Shape change Transient aggregation Sustained aggregation Secretion 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: 1. Prodroga 2. Variabilidad Interindividual 3. Bloqueador Irreversible 4. Resistencia 5. Interacción medicamentos

19 Inhibidores Receptor P2Y12 Clopidogrel Prasugrel Ticagrelor Clase Tienopiridina Tienopiridina Análogo ATP Reversibilidad irreversible irreversible reversible Administración oral oral 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 (20 µm ADP) Inhibition of Platelet Aggregation (%) Response to Clopidogrel Background Variability 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 Median duration of therapy: 12 months PRASUGREL 60 mg LD/ 10 mg MD 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:

22 TRITON TIMI-38: Balance of Efficacy and Safety End Point (%) CV Death/MI/Stroke Clopidogrel Prasugrel events HR 0.81 ( ) P =.0004 NNT = 46 5 TIMI Major Non-CABG Bleeds Prasugrel Clopidogrel Days HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm events HR 1.32 ( ) P =.03 NNH = 167 Wiviott SD, et al. N Engl J Med. 2007;357:

23 TRITON TIMI-38: Stent Thrombosis (ARC Definite + Probable) End Point (%) Any Stent at Index PCI N = 12,844 Clopidogrel 2.4 (142) 74 events Prasugrel 1.1 (68) HR 0.48 P <.0001 NNT = Days ARC = Academic Research Consortium; PCI = percutaneous coronary intervention Wiviott SD, et al. N Engl J Med. 2007;357:

24 Diabetic Subgroup N=3146 Endpo oint (%) CV Death / MI / Stroke Clopidogrel Prasugrel HR 0.70 P<0.001 NNT = TIMI Major NonCABG Bleeds Days Clopidogrel 2.6 Prasugrel 2.5

25 TRITON TIMI-38 Net Clinical Benefit: Bleeding Risk Subgroups Risk (%) Prior Stroke / TIA Yes No P int = Age 75 < P int = 0.18 Weight <60 kg 60 kg P int = 0.36 Overall Prasugrel Better HR Clopidogrel Better -13 Post-hoc analysis Wiviott SD, et al. N Engl J Med. 2007;357:

26 Subgrupos de Riesgo de Hemorragias Consideraciones terapeuticas 16% 4% MD 10 mg Significant Net Clinical Benefit with Prasugrel 80%

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

28 Ticagrelor (AZD 6140): an oral reversible P2Y 12 antagonist HO HO O N N N N N H N F Ticagrelor is a cyclo-pentyl-triazolopyrimidine (CPTP) S F OH Direct acting Not a pro-drug; does not require metabolic activation Rapid onset of inhibitory effect on the P2Y 12 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

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 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 K-M estimated rate (%) Clopidogrel Ticagrelor estimated rate (%) K-M 10 5 Ticagrelor Clopidogrel HR 0.84 (95% CI ), p= HR 1.04 (95% CI ), p= No. at risk Ticagrelor Clopidogrel Months from randomization 9,333 8,628 8,460 8,219 6,743 5,161 4,147 9,291 8,521 8,362 8,124 6,743 5,096 4, Months from randomization 9,235 7,246 6,826 6,545 5,129 3,783 3,433 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:

31 PLATO Ticagrelor: Impacto en Mortalidad Cardiovascular Disminución de mortalidad cardiovascular Clopidogrel 5.1 Cumulativ ve incidence (%) Ticagrelor 0 HR 0.79 (95% CI ), p= Days after randomisation 9,333 8,294 8,822 8, ,482 4,419 9,291 8,865 8,780 8, ,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 0,72 (0,58-0,90) 0,003 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 Thrombin ADP PAR-4 P2Y 1 P2Y 12 PAR-1 TBX A 2 TBXA 2 -R Fibrinogen GP IIb/IIIa GP IIb/IIIa Epinephrine Serotonin Collagen EPI-R 5HT 2 A GP VI GP Ia Anionic phospholipid surfaces

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 (Vorapaxar) en SCA Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome SCA SIN SDST N = 10,000 SCH mg carga, 2.5 mg/día n=5000 STOP!!!! Placebo (y terapia usual) n=5000 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

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46

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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 N ~ 21,000 Stable pts with history of MI 1-3 yrs prior + 1 additional atherothrombosis risk factor* RANDOMIZE DOUBLE BLIND * Age >65 yrs, diabetes, 2 nd prior MI, multivessel CAD, or chronic non-end stage renal dysfunction Planned treatment with ASA mg & Standard background care Ticagrelor 90 mg bid Ticagrelor 60 mg bid Placebo Follow-up Visits Q4 mos for 1 st 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

51 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 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

53 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 Time to 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 Clopidogrel mg LD + 75 mg MD Prasugrel 1 30 mg LD + 5 or 10 mg MD Clopidogrel 1 75 mg MD Prasugrel 1 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

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

55 Incidence of Outcomes by Angiography Status (Age < 75 years) P < P < P = 0.09

56 Primary Efficacy Endpoint to 30 Months (Age < 75 years) Angio N=3085 No Angio N= % vs 14.9% P = HR (95% CI): 0.77 (0.61, 0.98) 16.3% vs 16.7% P = HR (95% CI): 1.01 (0.84, 1.20) P interaction = 0.08

57 Myocardial Infarction Angio No Angio 7.2% vs 10.3% P = HR (95% CI): 0.74 (0.55, 1.00) 9.2% vs 10.6% P = HR (95% CI): 1.00 (0.79, 1.26) P interaction = 0.12

58 Stroke Angio No Angio 0.6% vs 2.4% P = HR (95% CI): 0.30 (0.13,0.71) 2.2% vs 2.0% P = HR (95% CI): 1.03 (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.