DROGAS ANTITROMBÓTICAS

Presentación del tema: "DROGAS ANTITROMBÓTICAS"— Transcripción de la presentación:

1 DROGAS ANTITROMBÓTICAS
CONGRESO PARAGUAYO DE HEMATOLOGÍA 2011 Dra. Ana María Otero

2 HEPARINA 1916 HOWEL Y MACFARLAIN 1935 TRATAMIENTO DE LA ETV
SALVÓ MUCHAS VIDAS PROVOCÓ MUCHAS MUERTES HASTA HOY SE EMPLEA Y ES ACEPTADA POR ORGANISMOS INTERNACIONALES

3 WARFARINA 1945 ANTICOAGULANTE COMPLEJO SALVÓ MUCHAS VIDAS
PROVOCÓ MUCHAS MUERTES AÚN HOY SE USA POR ESTUDIOS DE EVIDENCIA COMO EFECTIVA PREVENCIÓN SECUNDARIA DE LA ETV PREVENCIÓN DE LA EMBOLIA SISTÉMICA

4 HBPM Lancet 1972; 2: 1972 ESTUDIO DE KAKKAR SEPARACIÓN ACTIVIDAD ANTI Xa DE LA ANTI TROMBINA (IIa) 1980 DESARROLLO DE LAS DIFERENTES HBPM NUMEROSOS ESTUDIOS DE EVIDENCIA EFECTIVA SEGURA EN LA PREVENCIÓN Y EL TRATAMIENTO

5 HBPM HAN CAMBIADO LOS TRATAMIENTOS ANTITROMBÓTICOS
HAN DESARROLLADO LA PREVENCIÓN PRIMARIA DE LA ETE SON MUY SEGURAS, SON EFECTIVAS LLEVAN MAS DE 20 AÑOS DE USO MASIVO A NIVEL MUNDIAL

6 EPÍDEMIOLOGÍA TROMBOSIS PRIMERA CAUSA DE MUERTE E INCAPACIDAD
REPERCUSIÓN PERSONAL REPERCUSIÓN FAMILAR REPERCUSIÓN SOCIAL

7 PREVENCIÓN DE LA TROMBOSIS
SE PUEDE SE DEBE NO SIEMPRE SE HACE SITUACIONES DE RIESGO MAYOR RIESGO CIRUGÍA ORTOPÉDICA MAYOR EMBOLIA POR FA ETV EN PACIENTE MEDICOS HOSPITALIZADOS CIRUGÍA MAYOR ASOCIACIÓN DE FACTORES

8 DROGA ANTITROMBOTICA IDEAL
EFECTIVA SEGURA NO REQUIERA CONTROLES VIA ORAL NO INTERFERENCIAS BAJO COSTO SIN EFECTOS SECUNDARIOS POSEA ANTÍDOTO PARA CASO DE SANGRADO

9 DROGA ANTITROMBOTICA IDEAL
NO EXISTE

10 NUEVAS DROGAS SINTÉTICAS VIA ORAL
ACCIÓN ESPECÍFICA SOBRE UN FACTOR DE LA COAGULACIÓN RELACIÓN DIRECTA DOSIS EFECTO NO NECESIDAD DE CONTROL BIOLÓGICO ….(?)

11 NUEVAS DROGAS LAS MAS ESTUDIADADAS (2011)
ETEXILATO DE DABIGATRAN RIVAROXABAN APIXABAN OTRAS DROGAS VIENEN LLEGANDO

12 COMPARACION DE LA WARFARINA CON LOS NUEVOS ANTICOAGULANTES ORALES
ETEXILATO DABIGATRAN RIVAROXABAN APIXABAN INHIBE VITAMINA K E-REDUCTASA TROMBINA FACTOR X ABSORCIÓN ORAL 99% 67% 60-80% 80% T (max) 72-96 h 2 h 2.5-4 h 3 h VIDA MEDIA 40 h 14-17 h 5-9 h SANOS, 9-13 h VIEJOS 8-15 h MONITOREO INR- NO NECESITA? ADMINIST. 1/D 1/D o 2 /D 2/D MET/ELIMIN. CYTOCHOMO P450 80% RENAL 20% BILIAR 66% RENAL 33% BILIAR 25% RENAL 75% BILIAR ANTÍDOTO O TRAT.SANGRADO VIT. K PLASMA CONSIDERAR PCC O rVIIa LABORAT. PT/INR ECARIN CLOTTING TIME ANTI FACTOR Xa ANTI-FACTOR XA INTERACCIÓN CON DROGAS CYP 2C9, 1A2, and 3A4 Potent P-gp inhibiDORs/inducers; PPIs decrease absorción Potent P-gp inhibitors/inducers; CYP3A4 inhibitors 12 12

13 ESTUDIOS CLÍNICOS PREVEN. PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR
DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELY RECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AF EINSTEIN PE EINSTEIN DVT EINSTEIN-EXT MAGELLAN RECORD 1 RECORD 2 RECORD 3 RECORD 4 APIXABAN INHIBIDOR FACTOR Xa AVERROES (ASA) ARISTOTLE (W) AMPLIFY AMPLIFY-EXT ADVANCE 1 ADVANCE 2 ADVANCE 3 13

14 Dabigatran approved for VTE prophylaxis post TJR in Canada June 2008
Critical Care Meeting March 19,2010 Dabigatran in Orthopedics RR Dabigatran etexilate 220 mg QD n/N Enoxaparin n/N dose Study or sub-category RR [95% CI] RE-MOBILIZE 188/ / mg BID RE-MODEL 183/ / mg QD RE-NOVATE 53/ / mg QD 1.23 [1.03, 1.47] 0.97 [0.82, 1.13] 0.90 [0.63, 1.29] Random Effects Analysis Total (95% CI) Test for overall effect: Z = 0.47 (P = 0.64) 1.05 [0.87, 1.26] Analysis is based on the 220 mg QD dose of dabigatran etexilate. Dabigatran approved for VTE prophylaxis post TJR in Canada June 2008 y en Europa Favours Dabigatran Favours Enoxaparin Wolowacz et al. Thromb Haemost 2009. 14 14

15 Rivaroxaban in Orthopedics RECORD 1 - 4
Endpoint Rivaroxaban (%) Enoxaparin HR or RR (95% CI) Total VTE (DVT, PE, death) 4.26 9.43 RR 0.46 (0.39, 0.54) Major VTE (proximal DVT, PE, VTE death) 0.68 2.74 RR 0.25 (0.17, 0.37) Symptomatic VTE or death 0.57 1.32 HR 0.42 (0.29, 0.63) Major bleeding event 0.39 0.21 HR 1.84 (0.94, 3.62) Major or CRNM bleeding event 3.19 2.55 HR 1.25 (1.01, 1.54) Major bleeding combined with surgical-site bleeding events 1.80 1.37 HR 1.31 (0.99, 1.73) Rivaroxaban approved for VTE prophylaxis post TJR in Canada 2008 y en Europa Levitan et al. ASH 2009. 15

16 APIXABAN 2.5 MG PO BID FOR 10 – 14 DAYS VS ENOXAPARIN 30 MG SC
Apixaban in Orthopedics ADVANCE 1 – 3 ~10,000 patients randomized ADVANCE 1 ADVANCE 2 ADVANCE 3 KNEE REPLACEMENT1 APIXABAN 2.5 MG PO BID FOR 10 – 14 DAYS VS ENOXAPARIN 30 MG SC BID STARTING POST-OP FOR DAYS FOLLOW-UP: 60 DAYS KNEE REPLACEMENT2 APIXABAN 2.5 MG PO BID FOR 10 – 14 DAYS VS ENOXAPARIN 40 MG SC QD FOR 10–14 DAYS FOLLOW-UP: 60 DAYS HIP REPLACEMENT3 APIXABAN 2.5 MG PO BID FOR 10 – 14 DAYS VS ENOXAPARIN 40 MG SC QD FOR 35 DAYS FOLLOW-UP: 60 DAYS N=3195 N=3057 N=3866 1. Lassen, et al. N Engl J Med Lassen et al. Lancet Lassen et al. Intl Congress on Thrombosis 2010. 16 16

17 Apixaban in Orthopedics ADVANCE 1 – 3
All VTE/Death Major VTE Major Bleed Apix Enox ADVANCE 1 (TKR) 9.0% 8.9% 2.1% 1.6% 0.7% 1.4% ADVANCE 2 (TKR) 15.1% 24.4% 1.1% 2.2% 0.6% 0.9% ADVANCE 3 (THR) 3.9% 0. 5% 0.8% Did not meet prespecified criterion for noninferiority vs enoxaparin 30 mg BID in TKR (ADVANCE 1) Superior to enoxaparin 40 mg once daily in THR and TKR (ADVANCE 2 & 3) Lassen, et al. N Engl J Med Lassen et al. Lancet 2010. 3. Lassen et al. Intl Congress on Thrombosis 2010.

18 Apixaban in Orthopedics ADVANCE 2 & 3
Enoxaparin Abs. Risk Diff. Outcome- n/N (%) Apixaban 40 mg QD (95% CI) Major VTE 23/ / (0.7) (1.5) (-1.23 to -0.30) VTE Death 2/ / (0.05) (0) (-0.02 to 0.11) Non-Fatal PE 5/ / (0.12) (0.12) (-0.15 to 0.15) Sx Proximal DVT 2/ / (0.05) (0.12) (-0.19 to 0.05) Asx Proximal DVT 14/ / (0.41) (1.21) (-1.00 to -0.24) Sx Distal DVT Only 2/ / (0.05) (0.17) (-0.26 to 0.02) Favors Apixa Favors Enox -1.5 -1.0 -0.5 0.5 Raskob et al. ASH 2010 Abstract #192. 18

19 Apixaban in Orthopedics ADVANCE 2 & 3
Apixaban Enoxaparin Absolute Outcome- N (%) (n=4,174) (n=4,167) Diff (95% CI) MAJOR BLEED 31 (0.74) 32 (0.77) (-0.40 to 0.35) Non-Surgical Site 5 (0.12) 5 (0.12) Surgical Site 26 (0.62) 27 (0.65) (-0.37 to 0.32) Before 1st Post-Op Dose 17 (0.41) 11 (0.26) After 1st Post-Op Dose 9 (0.22) 16 (0.38) (-0.40 to 0.07) MAJOR BLEED OR CRNM 182 (4.36) 206 (4.94) (-1.49 to 0.32) Non-Surgical Site 47 (1.13) 51 (1.22) Surgical Site 135 (3.23) 155 (3.72) (-1.27 to 0.30) Before 1st Post-Op Dose 42 (1.01) 33 (0.79) After 1st Post-Op Dose 93 (2.23) 122 (2.93) (-1.38 to -0.02) Raskob et al. ASH 2010 Abstract #192. 19

20 PROFILAXIS EN CIRUGÍA ORTOPEDICA MAYOR. CONCLUSI0NES
Los nuevos anticoagulantes orales son similares a la enoxaparina en eficacia y en riesgo de sangrado en prevención de la ETV en cirugía de cadera y rodilla. Dabigatran 220 mg once daily Rivaroxaban 10 mg once daily Apixaban 2.5 mg twice daily Ninguno fue aprobado en EEUU por la FDA pero SI están aprobados por la EMEA y en Canadá. 20

21 ESTUDIOS CLÍNICOS PREVEN. PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR
DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELY RECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AF EINSTEIN PE EINSTEIN DVT EINSTEIN-EXT MAGELLAN RECORD 1 RECORD 2 RECORD 3 RECORD 4 APIXABAN INHIBIDOR FACTOR Xa AVERROES (ASA) ARISTOTLE (W) AMPLIFY AMPLIFY-EXT ADVANCE 1 ADVANCE 2 ADVANCE 3 21

22 NUEVOS ANTICOAGULANTES EN LA PREVENCIÓN DEL STROKE
Fibrilación Auricular NO valvular

23 ESTUDIOS CLÍNICOS PREVEN. PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR
DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELY RECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AF EINSTEIN PE EINSTEIN DVT EINSTEIN-EXT MAGELLAN RECORD 1 RECORD 2 RECORD 3 RECORD 4 APIXABAN INHIBIDOR FACTOR Xa AVERROES (ASA) ARISTOTLE (W) AMPLIFY AMPLIFY-EXT ADVANCE 1 ADVANCE 2 ADVANCE 3 23

24 stroke DABIGATRAN (RELY) RIVAROXABAN (ROCKET AF)
150 mg dos veces por día es tan eficáz como la warfarina pero, al precio de un mayor riesgo de sangrado-. 110 mg dos veces al día es comparable la eficacia pero menor riesgo de sangrado Menos HC que con la warfarina RIVAROXABAN (ROCKET AF) 20 mg una vez al día, es comparable a la warfarina sin necesidad de monitoreo. Menos riesgo de HC comparado a la wafarina. APIXABAN (ABERROES ARISTÓTELES) Aberroes: 5 mg dos veces por dia es más eficáz que la aspirina en pacientes que no toleran la warfarina. Aristoteles: Comparación con la warfarina está pendiente Connolly et al. NEJM Mahaffey et al AHA Connolly et al ESC 2010. 24

25 FA y Stroke DABIGATRAN (APROVADO POR LA FDA) RIVAROXABAN APIXABAN
150 mg dos veces por día es tan eficáz como la warfarina pero, al precio de un mayor riesgo de sangrado-. 110 mg dos veces al día es comparable pero menor riesgo de sangrado. Menos HC RIVAROXABAN 20 mg una vez al día es comparable a la warfarina sin necesidad de monitoreo Menos riesgo de HC comparado a la wafarina APIXABAN 5 mg dos veces por dia es más eficáz que la aspirina en pacientes que no toleran la warfarina. Aristotle: August 28 at the European Society of Cardiology 2011 meeting in Paris, France. Connolly et al. NEJM Mahaffey et al AHA Connolly et al ESC 2010. 25

26 FDA APPROVES DABIGATRAN FOR AF
Indication Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation Dosing 150 mg BID for all patients except in renal impairment 75 mg BID if Cr Cl 15 – 30 mL/min No adjustment for hepatic impairment Guidelines Take with or without meals Do not chew, break or open capsules

27 TRATAMIENTO DE LA ENFERMEDAD TROMBOEMBÓLICA VENOSA
NUEVAS DROGAS

28 ESTUDIOS CLÍNICOS PREVEN. PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR
DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELY RECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AF EINSTEIN PE EINSTEIN DVT EINSTEIN-EXT MAGELLAN RECORD 1 RECORD 2 RECORD 3 RECORD 4 APIXABAN INHIBIDOR FACTOR Xa AVERROES (ASA) ARISTOTLE (W) AMPLIFY AMPLIFY-EXT ADVANCE 1 ADVANCE 2 ADVANCE 3 28

29 Dabigatran in VTE Treatment
RECOVER Dabigatran in VTE Treatment 2539 patients with acute DVTor PE treated initially with UFH/LMWH for a mean of 10 days Randomized to dabigatran 150 mg BID vs warfarin x 6 months Non-inferiority study Routine therapy with UFH or LMWH Dabigatran 150 mg BID x 6 months Follow-up 1 month Dx of VTE Double blind Primary Efficacy: Recurrent, symptomatic VTE Primary Safety: Major bleeding Routine therapy with UFH or LMWH Warfarin INR 2.0 – 3.0 x 6 months Follow-up 1 month Schulman et al. New Engl J Med 2009. 29

30 Dabigatran is non-inferior to warfarin for prevention of
Dabigatran in VTE Treatment RECOVER INR in range 60% above range 19% below range 21% P<0.001 for noninferiority Dabigatran is non-inferior to warfarin for prevention of recurrent or fatal VTE with comparable major bleeding risk (1.6% vs 1.9%) Schulman et al. New Engl J Med 2009. 30

31 ESTUDIOS CLÍNICOS PREVEN. PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR
DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELY RECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AF EINSTEIN PE EINSTEIN DVT EINSTEIN-EXT MAGELLAN RECORD 1 RECORD 2 RECORD 3 RECORD 4 APIXABAN INHIBIDOR FACTOR Xa AVERROES (ASA) ARISTOTLE (W) AMPLIFY AMPLIFY-EXT ADVANCE 1 ADVANCE 2 ADVANCE 3 31

32 Rivaroxaban in DVT Treatment EINSTEIN
3,449 patients with acute DVT Randomized to rivaroxaban or enoxaparin/warfarin for 3 to 12 months Non-inferiority study Rivaroxaban, 15 mg BID x 21 days then 20 mg QD x 3, 6 or 12 months (1,731) Dx of DVT Primary Efficacy: Recurrent, symptomatic VTE Primary Safety: Major bleeding Open Label Enoxaparin 1 mg/kd BID > 5 d, then warfarin with INR 2 – 3 x 3, 6 or 12 months (1,718) Buller et al. ASH 2010 Abstract #187. New Engl J Med 2010. 32

33 Rivaroxaban in DVT Treatment EINSTEIN
INR in range 58% above range 16% below range 24% 4.0 Enoxaparin/VKA (3.0%; 51/1,718) 3.0 Cumulative event rate (%) 2.0 Rivaroxaban (2.1%; 36/1,731) 1.0 P<0.001 for noninferiority 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Rivaroxaban is non-inferior to warfarin for prevention of recurrent or fatal VTE with comparable major bleeding risk (0.8% vs 1.2%) Buller et al. ASH 2010 Abstract #187. New Engl J Med 2010. 33

34 ESTUDIOS CLÍNICOS PREVEN. PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR
DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELY RECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AF EINSTEIN PE EINSTEIN DVT EINSTEIN-EXT MAGELLAN RECORD 1 RECORD 2 RECORD 3 RECORD 4 APIXABAN INHIBIDOR FACTOR Xa AVERROES (ASA) ARISTOTLE (W) AMPLIFY AMPLIFY-EXT ADVANCE 1 ADVANCE 2 ADVANCE 3 34

35 Rivaroxaban in Extended Treatment EINSTEIN EXT
1197 patients with acute DVT treated for 6 – 12 months with standard Rx or rivaroxaban Randomized to rivaroxaban 20 mg QD vs placebo x 6 – 12 months Superiority Study Rivaroxaban 20 mg QD x 6 – 12 months (mean duration 190 d) Dx of VTE and treatment for 6 – 12 months (routine Rx or rivaroxaban) Double blind Primary Efficacy: Recurrent, symptomatic VTE Primary Safety: Major bleeding Placebo x 6 – 12 months (mean duration 190 d) Buller et al. ASH 2010 Abstract #187. New Engl J Med 2010. 35

36 Cumulative event rate (%)
Rivaroxaban in Extended Treatment EINSTEIN EXT 13 Number needed to treat to prevent 1 primary efficacy outcome: 15 12 11 Placebo (7.1%; 42/594) 10 9 8 7 Cumulative event rate (%) 6 HR=0.18; p<0.0001 5 4 3 2 Rivaroxaban (1.3%; 8/602) 1 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Rivaroxaban is superior to placebo for prevention of recurrent or fatal VTE with comparable bleeding risk (0.7% vs 0%) Buller et al. ASH 2010 Abstract #187. New Engl J Med 2010. 36

37 Treatment of Acute VTE Summary
Dabigatran Can replace warfarin for treatment of acute PE/DVT without need for monitoring Does not eliminate the need for initial UFH/LMWH Comparable to warfarin in major bleeding risk Rivaroxaban Can replace heparin/warfarin for treatment of acute DVT without need for monitoring Effective in reducing recurrent VTE up to 1 yr Studies of other agents are pending None of the new agents have received regulatory approval for this indication to date 37

38 ESTUDIOS CLÍNICOS PREVEN. PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR
DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELY RECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AF EINSTEIN PE EINSTEIN DVT EINSTEIN-EXT MAGELLAN RECORD 1 RECORD 2 RECORD 3 RECORD 4 APIXABAN INHIBIDOR FACTOR Xa AVERROES (ASA) ARISTOTLE (W) AMPLIFY AMPLIFY-EXT ADVANCE 1 ADVANCE 2 ADVANCE 3 38

39 ESTUDIO MAGELLAN

40 Bleeding Results at Days 1–10
MAGELLAN Bleeding Results at Days 1–10 Outcome Rivaroxaban, n=3997 Enoxaparin, n=4001 (%) (%) Clinically relevant bleeding* 2.8 1.2 Major bleeding 0.6 0.3 Fall in hemoglobin >2g/dL 0.4 0.2 Transfusions >2 units blood 0.1 Critical site bleeding Fatal bleeding <0.1 HR=2.3; p<0.0001

41 Primary Efficacy Outcome at Day 35
MAGELLAN Outcome Rivaroxaban, n=2967 (%) Enoxaparin, n=3057 (%) Composite efficacy outcome* 4.4 5.7 Asymptomatic proximal DVT 3.5 Symptomatic lower extremity DVT 0.4 0.5 Symptomatic nonfatal PE 0.3 VTE-related death 0.6 1 HR=0.77 (95% CI 0.62–0.96); p=0.02

42 Primary Efficacy Outcome at Day 10 Outcome Rivaroxaban, n=2939 (%)
MAGELLAN Outcome Rivaroxaban, n=2939 (%) Enoxaparin, 2993 (%) Composite efficacy outcome* 2.7 Asymptomatic proximal DVT 2.4 Symptomatic lower extremity DVT 0.2 Symptomatic nonfatal PE 0.1 VTE-related death *p for noninferiority=0.0025

43 Bleeding Results at Days 11–35
MAGELLAN Bleeding Results at Days 11–35 Outcome Rivaroxaban, n=3997 (%) Enoxaparin, n=4001 (%) Clinically relevant bleeding* 1.4 0.5 Major bleeding 0.1 Fall in hemoglobin >2g/dL 0.4 <0.1 Transfusions >2 units blood 0.2 Critical site bleeding Fatal bleeding HR=3.0; p<0.0001

44 RESULTADOS ESTUDIO MAGELLAN (prevencion de le etv en pacientes internados por cuadros médicos agudos) Rivaroxaban, No inferior a la Enoxaparina a los 10 días de internación. Superior al placebo a los 35 días. Nivel de sangrado superior a la enoxaparina no aceptable. Dr Alexander Cohen (King's College, London, UK) American College of Cardiology 2011 Scientific Sessions,