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

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Presentación del tema: "DROGAS ANTITROMBÓTICAS CONGRESO PARAGUAYO DE HEMATOLOGÍA 2011 Dra. Ana María Otero."— 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 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 Lancet 1972; 2:

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 12 WARFARINAETEXILATO DABIGATRANRIVAROXABAN APIXABAN INHIBE VITAMINA K E-REDUCTASA TROMBINAFACTOR X ABSORCIÓN ORAL 99%67%60-80%80% T (max)72-96 h2 h2.5-4 h3 h VIDA MEDIA40 h14-17 h 5-9 h SANOS, 9-13 h VIEJOS 8-15 h MONITOREOINR-NO NECESITA? ADMINIST.1/D1/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.SANGRA DO 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/induce rs; PPIs decrease absorción Potent P-gp inhibitors/inducer s; CYP3A4 inhibitors COMPARACION DE LA WARFARINA CON LOS NUEVOS ANTICOAGULANTES ORALES

13 ESTUDIOS CLÍNICOS DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELYRECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AFEINSTEIN 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

14 Wolowacz et al. Thromb Haemost Favours Enoxaparin Favours Dabigatran RE-MOBILIZE188/ /643 30mg BID RE-MODEL183/ /512 40mg QD RE-NOVATE 53/880 60/897 40mg QD Study or sub-category Dabigatran etexilate 220 mg QD n/N Enoxaparin n/N dose RR [95% CI] 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] RR Analysis is based on the 220 mg QD dose of dabigatran etexilate. Dabigatran in Orthopedics Dabigatran approved for VTE prophylaxis post TJR in Canada June 2008 y en Europa

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

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

17 All VTE/Death Major VTEMajor Bleed ApixEnoxApixEnoxApixEnox 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) 1.4%3.9%0. 5%1.1%0.8%0.7% Apixaban in Orthopedics ADVANCE 1 – 3 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) 1.Lassen, et al. N Engl J Med Lassen et al. Lancet Lassen et al. Intl Congress on Thrombosis 2010.

18 EnoxaparinAbs. Risk Diff. Outcome- n/N (%) Apixaban 40 mg QD(95% CI) Major VTE23/ / (0.7) (1.5) (-1.23 to -0.30) VTE Death2/4236 0/ (0.05) (0) (-0.02 to 0.11) Non-Fatal PE5/4236 5/ (0.12) (0.12) (-0.15 to 0.15) Sx Proximal DVT2/4236 5/ (0.05) (0.12) (-0.19 to 0.05) Asx Proximal DVT14/ / (0.41) (1.21) (-1.00 to -0.24) Sx Distal DVT Only2/4236 7/ (0.05) (0.17) (-0.26 to 0.02) Favors Enox Favors Apixa Apixaban in Orthopedics ADVANCE 2 & 3 Raskob et al. ASH 2010 Abstract #192.

19 Apixaban Enoxaparin Absolute Outcome- N (%)(n=4,174)(n=4,167) Diff (95% CI) MAJOR BLEED31 (0.74)32 (0.77)-0.02 (-0.40 to 0.35) Non-Surgical Site5 (0.12)5 (0.12) Surgical Site26 (0.62)27 (0.65)-0.02 (-0.37 to 0.32) Before 1 st Post-Op Dose17 (0.41)11 (0.26) After 1 st Post-Op Dose9 (0.22)16 (0.38)-0.17 (-0.40 to 0.07) MAJOR BLEED OR CRNM182 (4.36)206 (4.94)-0.58 (-1.49 to 0.32) Non-Surgical Site47 (1.13)51 (1.22) Surgical Site135 (3.23)155 (3.72)-0.49 (-1.27 to 0.30) Before 1 st Post-Op Dose42 (1.01)33 (0.79) After 1 st Post-Op Dose93 (2.23)122 (2.93)-0.70 (-1.38 to -0.02) Apixaban in Orthopedics ADVANCE 2 & 3 Raskob et al. ASH 2010 Abstract #192.

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.

21 ESTUDIOS CLÍNICOS DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELYRECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AFEINSTEIN 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

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

23 ESTUDIOS CLÍNICOS DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELYRECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AFEINSTEIN 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

24 DABIGATRAN (RELY) 150 mg dos veces por día es tan eficáz como la warfarina pero, al precio de un mayor riesgo de sangrado 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 stroke Connolly et al. NEJM Mahaffey et al AHA Connolly et al ESC 2010.

25 DABIGATRAN (APROVADO POR LA FDA) 150 mg dos veces por día es tan eficáz como la warfarina pero, al precio de un mayor riesgo de sangrado 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. FA y Stroke Connolly et al. NEJM Mahaffey et al AHA Connolly et al ESC 2010.

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 DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELYRECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AFEINSTEIN 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

29 Routine therapy with UFH or LMWH Warfarin INR 2.0 – 3.0 x 6 months Dabigatran 150 mg BID x 6 months Routine therapy with UFH or LMWH Follow- up 1 month Double blind Primary Efficacy: Recurrent, symptomatic VTE Primary Safety: Major bleeding 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 RECOVER Dabigatran in VTE Treatment Schulman et al. New Engl J Med Dx of VTE

30 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 Dabigatran in VTE Treatment RECOVER INR in range 60% above range 19% below range 21% P<0.001 for noninferiority

31 ESTUDIOS CLÍNICOS DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELYRECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AFEINSTEIN 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

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

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

34 ESTUDIOS CLÍNICOS DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELYRECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AFEINSTEIN 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

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

36 Cumulative event rate (%) Time to event (days) Number needed to treat to prevent 1 primary efficacy outcome: 15 HR=0.18; p< Placebo (7.1%; 42/594) Rivaroxaban (1.3%; 8/602) Rivaroxaban in Extended Treatment EINSTEIN EXT Buller et al. ASH 2010 Abstract #187. New Engl J Med Rivaroxaban is superior to placebo for prevention of recurrent or fatal VTE with comparable bleeding risk (0.7% vs 0%)

37 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 Comparable to warfarin in major bleeding risk Studies of other agents are pending None of the new agents have received regulatory approval for this indication to date Treatment of Acute VTE Summary

38 ESTUDIOS CLÍNICOS DROGA PREVEN. STROKE FA ETV y PREV TRATAMIENTO PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR DABIGATRAN I. DE LA TROMB RELYRECOVER REMEDY RE-MOBILIZE RE-MODEL RE-NOVATE RIVAROXABAN INHIBIDOR FXa ROCKET AFEINSTEIN 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

39 ESTUDIO MAGELLAN

40 Outcome Rivaroxaban, n=3997 Enoxaparin, n=4001 (%) (%) Clinically relevant bleeding* Major bleeding Fall in hemoglobin >2g/dL Transfusions >2 units blood Critical site bleeding0.1 Fatal bleeding0.1 <0.1 MAGELLAN HR=2.3; p< Bleeding Results at Days 1–10

41 OutcomeRivaroxaban, n=2967 (%) Enoxaparin, n=3057 (%) Composite efficacy outcome* Asymptomatic proximal DVT Symptomatic lower extremity DVT Symptomatic nonfatal PE VTE-related death0.61 HR=0.77 (95% CI 0.62–0.96); p=0.02 Primary Efficacy Outcome at Day 35 MAGELLAN

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

43 OutcomeRivaroxaban, n=3997 (%) Enoxaparin, n=4001 (%) Clinically relevant bleeding* Major bleeding Fall in hemoglobin >2g/dL 0.4<0.1 Transfusions >2 units blood 0.2<0.1 Critical site bleeding0.1<0.1 Fatal bleeding<0.10 Bleeding Results at Days 11–35 MAGELLAN 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,


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