J Jornada IV 1 Jornada IV 16:00 h 16:30 h 1 Infección piel y partes blandas ¿Cómo seleccionar el tratamiento antibiótico? Dr. Juan González del Castillo Servicio de Urgencias. HCSC 1 1 ¿Debemos abordar igual la NAC del anciano que la del paciente joven? Dr. Javier Martín Sánchez Servicio de Urgencias HCSC 1 ¿Cuál, cuándo, a quién y por qué? 17:00 h ¿Cuáles son los errores más frecuentes 17:30 h ¿Cómo hacer más efectivo el tramiento antibiótico? Dra. Mercedes Nieto Cabrera Servicio de Cuidados Intensivos. HCSC tes 27 en la prescipción de antibiótico? Dr. Javier Candel González Servicio de Microbiología Clínica. HCSC Dr. Pedro Ruiz Artacho 18:00 h Descanso Servicio de Urgencias. HCSC Grupo ETV-SEMES CLASE PRACTICA Ventilación mecánica no invasiva Dr. Álvaro Martín Ruíz Limitaciones del tratamiento con AVK Margen terapéutico estrecho (Intervalo de INR 2-3) Respuesta impredecible Numerosas interacciones farmacológicas Numerosas interacciones con fármacos y alimentos El tratamiento con AVK tiene diversas limitaciones que conducen a su infrautilización, por lo que los pacientes están expuestos al riesgo de TEV o hemorragias Resistencia a la warfarina Lento inicio/final de la acción Vigilancia sistemática de la coagulación Frecuentes ajustes de la dosis 1. Ansell J, et al. Chest 2008;133;160S-198S; 2. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008; 22:129-137; 2. Nutescu EA, et al. Cardiol Clin 2008; 26:169-187. 2 AVK vs ACODs ACODs Indicaciones en Ficha Técnica Indicaciones terapéuticas (MENOS EDOXABAN): ► Prevención del tromboembolismo venoso (TEV) en pacientes adultos sometidos a cirugía electiva de reemplazo de cadera o rodilla Indicaciones terapéuticas (TODOS): ► Prevención del ictus y de la embolia sistémica en pacientes adultos con fibrilación auricular novalvular (FANV) con uno o más factores de riesgo, tales como ictus o ataque isquémico transitorio (AIT) previos, edad ≥ 75 años, hipertensión, diabetes mellitus e insuficiencia cardíaca sintomática (≥ clase 2 escala NYHA) ► Tratamiento fase aguda y a largo plazo de ETV. Indicaciones terapéuticas (RIVAROXABAN): ► Prevención secundaria del SCA (2,5 mg/12 h) and when not available, we report estimates from our calculations based on data from the primary publications or from the FDA The ROCKET AF investigators reported that, in the ITT analysis, rivaroxaban 20 mg daily (15 mg daily in patients with a calcu- Ensayos Clínicos con NACOs en FA Table 1: Study characteristics. Studies RE-LY (1) ROCKET AF (2) ARISTOTLE (3) ENGAGE AF-TIMI 48 (4) Trial size (n) 18,113 14,264 18,201 21,105 Patient Mean age characteristics (years) 71.5 73 70 72 Male (%) 63.5% 59.3% 64.5% 61.9% Mean CHADS2 2.1 3.5 2.1 2.8 Two intervention arms: Rivaroxaban 20 mg daily 1. Dabigatran 150 mg bid 2. Dabigatran 150 mg bid Apixaban 5 mg bid Two intervention arms: 1. Edoxaban 30 mg daily 2. Edoxaban 60 mg daily Dose modification No Yes, at randomisation Yes, at randomisation and during study Criteria for modified dose N/A Comparators Open label warfarin Intervention Intervention vs Comparator Outcomes 71.683 Primary efficacy Stroke or systemic embolism Primary safety Major bleeding Yes, at randomisation 15 mg daily in patients with 2.5 mg bid in patients who CrCI 30–49 ml/min met 2 of the 3 following criteria: • age >80 years, • weight <60 kg, • creatinine >133 µmol/l Half dose in patients with any of the following criteria: • CrCl 30–50 ml/min, • weight <60 kg, • concomitant use of potent p-glycoprotein inhibitors such as verapamil, quinidine, dronaderone. Standard dose resumed once these medications ceased. Blinded warfarin Blinded warfarin Blinded warfarin Stroke or systemic embolism Stroke or systemic embolism Stroke or systemic embolism Major bleeding + clinically Major bleeding relevant non major bleeding Major bleeding Bid = twice-daily dose; CrCl = creatinine clearance as per Cockcroft Gault formulas; kg = kilogram; mg = milligram. Thromb Haemost 2014; 111: 798–807 EFICACIA: Ictus/Embolia sistémica Chaninetatrial al. NOACs in Chan et al. NOACs fibrillat N Engl J Med 2009; 361: 1139-1151. N Engl J Med 2011; 365: 883-891. N Engl J Med 2011; 365: 981-992. N Engl J Med 2013; 369: 2093-2104. Thromb Haemost 2014; 111: 798–807 SEGURIDAD: Ictus hemorrágico N Engl J Med 2009; 361: 1139-1151. N Engl J Med 2011; 365: 883-891. N Engl J Med 2011; 365: 981-992. N Engl J Med 2013; 369: 2093-2104. Thromb Haemost 2014; 111: 798–807 SEGURIDAD: HEMORRAGIA INTRACRANEAL g outcomes. A) Major bleeding: All fourbleeding: new oralAllanti150oral mg,antiedoxaban mgedoxaban and rivaroxaban caused more major gastroin N60 Englmg J Med 2009; 361: 1139-1151. ure 2: Bleeding outcomes. A) Major four new 15060 mg, and rivaroxaban caused mor were at(NOACs) least aswere safe as warfarin in patients with in atrial nalwith bleeding Intracranial haemorrhage: All four N gulants at least as safe as warfarin patients atrial than nal warfarin. bleeding C) than warfarin. C)2011; Intracranial haemorrh N Engl J Med 365: 883-891. an, dabigatran 110 dabigatran mg and both of caused less of caused haemorrhage than warfarin. Note: constr illation. Apixaban, 110doses mg and both doses causedless lessintracranial caused less intracranial haemorrhage than Plots warfarin. N N Engl J Med 2011; 365: 981-992. Major gastrointestinal Dabigatran different RRwith scales on theRR x-axis. orwarfarin. bleedingB)than warfarin. B) Major bleeding: gastrointestinal bleeding:with Dabigatran different scales on the x-axis. N Engl J Med 2013; 369: 2093-2104. Thromb Haemost 2014; 111: 798–807 Ensayos Clínicos con NACOs en ETV Table 1 Baseline characteristics. Trial Randomized intervention (n) Overall treatment duration d (SD) RECOVER-II N = 2589 Dabigatran 150 mg BID × 6 m (n = 1279) NR Enoxaparin 1 mg/kg BID × 5d + VKA daily for 6 m (n = 1289) AMPLIFY N = 5395 Apixaban 10 mg BID × 7d then 5 mg BID × 6 m (n = 2691) NR Enoxaparin 1 mg/kg BID × 5d + VKA daily for 6 m (n = 2704) Hokusai-VTE N = 8240 EINSTEIN-PE N = 4832 EINSTEIN-DVT N = 3449 RECOVER N = 2564 27.069 Males N (%) Age y (SD) Index event N (%) Un Ind N( 781 (61) 54.7 (16.2) NR 776 (60.2) 55.1 (16.3) 1569 (58.3) 57.2 (16.0) 1598 (59.1) 56.7 (16.0) 105 108 993 (57.4) 55.8 (16.4) DVT: 877 (68.5) PE: 298 (23.3) Both: 104 (8.1) DVT: 873 (67.8) PE: 297 (23.1) Both: 117 (9.1) DVT: 1749 (65.0) PE: 678 (25.2) Both: 252 (9.4) DVT: 1783 (65.9) PE: 681 (25.2) Both: 225 (8.3) DVT:2468 (59.9) PE: 1240 (30.1) Both: 410 (10.0) DVT: 2453 (59.5) PE: 1265 (30.7) Both: 404 (9.8) DVT: 0 PE: 1813 (74.9) Both: 606 (25.1) DVT: 0 PE: 1823 (75.5) Both: 590 (24.5) DVT: 1731 (100) 967 (56.3) 56.4 (16.3) DVT: 1718 (100) 738 (58) 55.0 (15.8) 746 (58.9) 54.4 (16.2) Edoxaban 30 mg or 60 mg daily for 3-12 m (n = 4118) 250 (111.8) 2360 (57.3) 55.7 (16.3) Enoxaparin or heparin × 5d + warfarin daily for 3-12 m (n = 4122) Rivaroxaban 15 mg BID × 3w then 20 mg daily for 3, 6, or 12 m (n = 2419) Enoxaparin 1 mg/kg BID × 5d + VKA daily for 3, 6, or 12 m (n = 2413) Rivaroxaban 15 mg BID × 3w then 20 mg daily for 3, 6, or 12 m (n = 1731) Enoxaparin 1 mg/kg BID × 5d + VKA daily for 3, 6, or 12 m (n = 1718) Dabigatran 150 mg BID × 6 m (n = 1273) 248.4 (112.6) 2356 (57.2) 55.9 (16.2) 216 (NR) 1309 (54.1) 57.9 (7.3) 214 (NR) 1247 (51.7) 57.5 (7.2) Enoxaparin 1 mg/kg BID × 5d + VKA daily for 6 m (n = 1266) NR NR DVT: PE: Both: DVT: PE: Both: 880 270 121 869 271 124 (69.1) (21.2) (9.5) (68.6) (21.4) (9.8) 241 242 271 26 156 155 NR Effectiveness and safety of novel ora Outcome Study Recurrent VTE R R Lower limit Upper limit Weight (%) Re-Cover (dabigatran) Einstein-DVT (rivaroxaban) Einstein-PE (rivaroxaban) Amplify (apixaban) Hokusai (edoxaban) Subtotal (I2 = 0%, P = 0.46) 1.10 0.70 1.13 0.84 0.83 0.88 EFICACIA Fatal PE Outcome Study Recurrent VTE Re-Cover (dabigatran) 0.33 Einstein-DVT (rivaroxaban) 2.98 2.00 Einstein-PE (rivaroxaban) 0.50 Amplify (apixaban)R R Lower limit Hokusai (edoxaban) 1.33 Subtotal (I2 = 0%, P = 0.71) 1.02 Re-Cover (dabigatran) 1.10 Overall mortality 0.70 Einstein-DVT (rivaroxaban) Re-Cover (dabigatran) 1.13 Einstein-PE (rivaroxaban) Einstein-DVT (rivaroxaban) Einstein-PE (rivaroxaban) 0.84 Amplify (apixaban) Amplify (apixaban)0.83 Hokusai (edoxaban) Hokusai (edoxaban) Subtotal (I2 = 0%, P = 0.46) Subtotal (I2 = 0%,0.88 P = 0.50) Fatal PE 0.66 0.46 0.99 0.76 0.77 1.16 0.60 0.79 0.60 1.05 0.74 0.97 0.66 0.46 0.76 0.60 0.60 0.74 1.84 1.07 1.69 1.18 1.14 1.05 11.2 16.7 18.4 25.4 28.3 100 18.0 0.03 3.18 73.04 9.0 0.12 16.0 21.99 0.18 5.57 0.05 Upper limit Weight16.0 (%) 41.1 5.96 0.30 5.96 100 0.39 1.84 1.07 0.55 1.69 0.51 0.80 1.18 0.53 1.14 0.82 1.05 0.83 11.2 1.8116.7 1.1718.4 1.6825.4 1.19 28.3 1.33 1.14100 R R (95% CI) Effectiveness and safety of novel o R R (95% CI) 7.1 14.6 18.3 15.6 44.4 100 18.0 0.1 1 0.03 Re-Cover (dabigatran) 0.33 3.18 Favors VKAs Favors NOACs 73.04 9.0 0.12 Einstein-DVT (rivaroxaban) 2.98 16.0 21.99 0.18 2.00 Einstein-PE (rivaroxaban) 3. Efficacy outcomes. 5.57 NOACs, 16.0 new direct oral anticoagulants; PE, pulmonary embolism; VKA 0.50CI, confidence 0.05 interval; AmplifyFig. (apixaban) nist; VTE, venous thromboembolism. Hokusai (edoxaban) 41.1 5.96 0.30 1.33 2 Subtotal (I = 0%, P = 0.71) 1.02 5.96 100 0.39 Overall mortality Outcome Study R R Lower limit Upper limit Weight (%) Major(dabigatran) bleeding 0.99 Re-Cover 0.83 Re-Cover (dabigatran) 0.77 Einstein-DVTEinstein-DVT (rivaroxaban) (rivaroxaban) 0.70 0.50 Einstein-PE (rivaroxaban) 1.16 Einstein-PE Amplify (rivaroxaban) (apixaban) 0.31 Hokusai (edoxaban) 0.85 Amplify (apixaban) 0.79 Subtotal (I = 62%, P = 0.03) 0.60 bleeding at a critical site 1.05 HokusaiNon-fatal (edoxaban) 2 0.46 0.35 0.31 0.17 0.60 0.41 0.55 1.49 0.51 1.38 0.80 0.80 0.55 1.21 0.53 0.88 0.82 1.81 18.2 15.91.17 21.8 18.61.68 25.5 1.19 100 1.33 R R (95% CI) 7.1 14.6Van der Hulle et al. J Thromb Haemost 2014; 12: 320-8. 18.3 15.6 44.4 Effectiveness and safety of novel oral anticoagulants 325 Outcome Study Recurrent VTE Outcome Study Re-Cover Recurrent VTE (dabigatran) Einstein-DVT (rivaroxaban) Re-Cover (dabigatran) Einstein-PE (rivaroxaban) Einstein-DVT (rivaroxaban) Amplify (apixaban) Einstein-PE (rivaroxaban) Hokusai (edoxaban) Amplify (apixaban) Subtotal (I2 = 0%, P = 0.46) Hokusai (edoxaban) R R Lower limit Upper limit Weight (%) R R (95% CI) R R Lower limit Upper limit Weight (%) R R (95% CI) 1.10 0.70 1.10 1.13 0.70 0.84 1.13 0.83 0.84 0.88 0.83 0.66 0.46 0.66 0.76 0.46 0.60 0.76 0.60 0.60 0.74 0.60 1.84 1.07 1.84 1.69 1.07 1.18 1.69 1.14 1.18 1.05 11.2 16.7 11.2 18.4 16.7 25.4 18.4 28.3 25.4 100 28.3 EFICACIA Fatal PE 2 0.88 0.74 1.14 1.05 0.33 2.98 0.33 2.00 2.98 0.50 2.00 1.33 0.50 1.02 0.03 0.12 0.03 0.18 0.12 0.05 0.18 0.30 0.05 0.39 3.18 73.04 3.18 21.99 73.04 5.57 21.99 5.96 5.57 5.96 100 18.0 9.0 18.0 16.0 9.0 16.0 16.0 41.1 16.0 100 Einstein-DVT (rivaroxaban) 0.77 Overall mortality 0.51 0.80 0.55 0.53 0.51 0.82 0.80 0.83 0.53 1.17 1.68 1.81 1.19 1.17 1.33 1.68 1.14 1.19 14.6 18.3 7.1 15.6 14.6 44.4 18.3 100 15.6 Subtotal (I(dabigatran) = 0%, P = 0.46) Re-Cover Fatal PEEinstein-DVT (rivaroxaban) Re-Cover (dabigatran) Einstein-PE (rivaroxaban) Einstein-DVT (rivaroxaban) Amplify (apixaban) Einstein-PE (rivaroxaban) Hokusai (edoxaban) 2 Amplify (apixaban) Subtotal (I = 0%, P = 0.71) Hokusai (edoxaban) 1.33 Overall mortality 2 Subtotal (I(dabigatran) = 0%, P = 0.71) 0.99 Re-Cover 1.02 Einstein-PE (rivaroxaban) Re-Cover (dabigatran) Amplify (apixaban) Einstein-DVT (rivaroxaban) Hokusai (edoxaban) Einstein-PE (rivaroxaban) Subtotal (I2 = 0%, P = 0.50) Amplify (apixaban) 1.16 0.99 0.79 0.77 1.05 1.16 0.97 0.79 Hokusai (edoxaban) 1.05 2 Subtotal (I = 0%, P = 0.50) 0.97 0.30 0.55 0.39 0.82 0.83 5.96 5.96 1.81 1.33 1.14 41.1 7.1 100 44.4 100 0.1 Favors NOACs 0.1 1 1 Favors VKAs 10 10 Favors VKAs Fig. 3. Efficacy outcomes. CI, confidence interval; NOACs, new direct oral anticoagulants;Favors PE, NOACs pulmonary embolism; VKA, vitamin-K antagonist; VTE, venous thromboembolism. Fig. 3. Efficacy outcomes. CI, confidence interval; NOACs, new direct oral anticoagulants; PE, pulmonary embolism; VKA, vitamin-K antagoVan der Hulle et al. J Thromb Haemost 2014; 12: 320-8. nist; VTE, venous thromboembolism. Outcome Study Lower limit Upper limit Weight (%) Major bleeding Re-Cover (dabigatran) RR 0.83 R R (95% CI) 0.46 1.49 18.2 0.50 Einstein-PE (rivaroxaban) Amplify (apixaban) 0.31 Hokusai (edoxaban) 0.85 2 Subtotal (I = 62%, P = 0.03) 0.60 Non-fatal bleeding at a critical site Re-Cover (dabigatran) 0.11 Outcome Study (rivaroxaban) 1.00 Einstein-DVT MajorEinstein-PE bleeding (rivaroxaban) 0.27 Amplify (apixaban) 0.29 Hokusai (edoxaban) 0.520.83 Re-Cover (dabigatran) 2 Subtotal (I = 13%, P = 0.33) 0.38 Einstein-DVT (rivaroxaban) 0.70 Clinically relevant non-major bleeding Einstein-PE (rivaroxaban) 0.580.50 Re-Cover (dabigatran) Outcome Study R0.31 R 1.05 Einstein-DVT (rivaroxaban) Amplify (apixaban) Einstein-PE (rivaroxaban) 0.97 Major bleeding Hokusai (edoxaban) 0.85 Amplify (apixaban) 0.48 0.83 2 Re-Cover (dabigatran) 0.81 Hokusai (edoxaban) Subtotal 2 (I = 62%, P = 0.03) 0.60 0.70 Einstein-DVT (rivaroxaban) P < 0.01) 0.76 Subtotal (I = 88%, Non-fatal bleedingbleeding at(rivaroxaban) a critical site 0.50 Non-fatal intracranial Einstein-PE Re-Cover (dabigatran) Re-Cover(apixaban) (dabigatran) 0.140.31 0.11 Amplify Einstein-DVT (rivaroxaban) 4.98 1.00 Einstein-DVT (rivaroxaban)0.100.85 Einstein-PE (rivaroxaban) Hokusai (edoxaban) 2 Amplify (apixaban) 0.50 0.27 Einstein-PE Subtotal (I =(rivaroxaban) 62%, P = 0.03) 0.60 0.42 Hokusai (edoxaban) 2 Amplify = 20%, P = 0.29) Subtotal (I (apixaban) Non-fatal bleeding at a critical site0.390.29 Major gastrointestinal bleeding Hokusai (edoxaban) 0.52 Re-Cover (dabigatran) 0.11 Re-Cover (dabigatran) 1.79 2 1.00 Einstein-DVT =(rivaroxaban) 13%, P = 0.33) Subtotal (I(rivaroxaban) 0.75 Einstein-DVT 0.38 0.56 Einstein-PE (rivaroxaban) 0.27 Einstein-PE (rivaroxaban) Clinically relevant non-major bleeding Amplify (apixaban) 0.39 2 Amplify 0.29 0.58 Subtotal (I (apixaban) = (dabigatran) 37%, P = 0.19) 0.68 Re-Cover Hokusai (edoxaban) 0.52 Fatal bleeding 1.05 Einstein-DVT 2 (rivaroxaban) Re-Cover (dabigatran) 0.99 = 13%, P = 0.33) Subtotal (I 0.38 Einstein-PE(rivaroxaban) (rivaroxaban) 0.200.97 Einstein-DVT Clinically relevant non-major 0.66 Einstein-PE (rivaroxaban) Amplify (apixaban) bleeding 0.48 0.50 Amplify (apixaban) 0.58 Re-Cover (dabigatran) Hokusai (edoxaban) 0.81 0.20 Hokusai (edoxaban) 2 1.05 Einstein-DVT 2 (rivaroxaban) P = 0.75) 0.36 Subtotal (I = 0%, 0.31 0.17 0.60 0.41 0.80 0.55 1.21 0.88 21.8 18.6 25.5 100 0.01 0.20 0.12 0.09 0.46 0.27 0.23 0.35 0.87 4.93 0.62 0.87 1.49 1.02 0.62 1.38 5.5 9.0 28.4 17.4 18.2 39.7 100 15.9 Fig. 3. Efficacy outcomes. CI, confidence interval; NOACs, new direct oral anticoagulants; PE, pulmonary e R R Lower limit Upper limit Weight (%) R R (95% CI) nist; VTE, venous thromboembolism. SEGURIDAD = 88%, P < 0.01) 0.97 Subtotal (I (rivaroxaban) 0.76 Einstein-PE Non-fatalAmplify intracranial bleeding (apixaban) 0.48 0.14 Re-Cover(edoxaban) (dabigatran) 0.81 Hokusai 2 4.98 Einstein-DVT 88%, P < 0.01) 0.76 Subtotal (I = (rivaroxaban) Fig.Non-fatal 4. Safety outcomes. CI, 0.10 Einstein-PE intracranial(rivaroxaban) bleeding Amplify (apixaban) 0.50 0.14 Re-Cover (dabigatran) 0.42 Hokusai (edoxaban) Einstein-DVT (rivaroxaban) 4.98 2 Einstein-PE = 20%, P = 0.29) 0.10 Subtotal (I (rivaroxaban) 0.39 0.31 0.820.80 17.121.8 0.42 Lower Weight 0.83 1.34 0.55limit 19.7 18.6 (%) 0.17limit Upper 0.81 1.15 21.3 1.21 25.5 0.60 0.38 0.46 0.61 1.49 20.0 18.2 0.70 0.94 21.9 0.41 0.99 0.88 100 100 15.9 1.38 0.35 0.58 0.31 0.80 21.8 0.01 0.01 0.17 0.24 0.01 0.20 0.60 0.13 0.12 0.41 0.15 0.09 0.16 2.75 0.87 0.55 103.65 0.78 4.93 1.21 2.01 0.62 0.88 1.18 0.87 0.94 8.0 5.5 18.6 7.7 15.3 9.0 25.5 28.3 28.4 100 40.8 17.4 100 0.60 0.20 0.17 0.23 0.25 0.12 0.16 0.09 0.42 0.36 5.33 4.93 3.33 0.62 1.27 0.62 0.93 0.87 0.82 0.30 22.9 9.0 14.5 100 32.4 28.4 30.1 17.4 17.1 100 0.83 1.34 15.88 0.62 1.70 1.15 3.97 0.61 5.54 0.82 0.91 0.94 1.34 0.87 19.7 10.3 100 17.1 21.3 24.7 20.0 13.7 17.1 34.2 21.9 19.7 100 0.27 0.01 0.27 0.06 0.23 0.02 0.81 0.11 0.38 0.05 0.42 0.04 0.70 0.83 0.15 0.58 0.81 0.38 0.01 0.70 0.24 0.58 1.02 0.87 1.02 0.99 1.15 0.61 2.75 0.94 103.65 0.99 R R (95% CI) 39.7 5.5 39.7 100 21.3 20.0 0.1 8.0 21.9 7.7 100 Favors NOACs 1 Favors VKAs confidence 0.01 0.78 interval; 15.3 NOACs, new direct oral anticoagulants; VKA, vitamin-K 0.13 0.01 0.15 0.24 0.01 0.16 2.01 2.75 1.18 103.65 0.78 0.94 rointestinal bleeding (Table 2; 28.3 8.0 40.8 7.7 15.3 Fig.1004). Van der Hulle et al. J Thromb Haemost 2014; 12: 320-8. Major bleeding difference was ! 0.38% Subtotal P = site 0.03) 0.60 Major bleeding Non-fatal bleeding(I at= a62%, critical Re-Cover (dabigatran) Non-fatalRe-Cover bleeding(dabigatran) at a critical site 0.11 0.83 1.00 Einstein-DVT (rivaroxaban) Re-Cover (dabigatran) 0.11 Einstein-DVT (rivaroxaban) 0.70 Einstein-PE (rivaroxaban) 0.27 1.00 Einstein-DVT (rivaroxaban) 0.29 0.50 Einstein-PE (rivaroxaban) Amplify (apixaban) 0.27 Einstein-PE (rivaroxaban) 0.52 Amplify (apixaban) 0.31 Hokusai (edoxaban) 2 Amplify (apixaban) 0.29 Hokusai (edoxaban) Subtotal (I = 13%, P = 0.33) 0.38 0.85 2 (edoxaban) 0.52 ClinicallyHokusai relevant non-major bleeding Subtotal (I2 = 62%, P = 0.03) 0.60 0.58 Re-Cover P = 0.33) Subtotal Non-fatal bleeding(I(dabigatran) at= 13%, a critical site 0.38 (rivaroxaban) ClinicallyEinstein-DVT relevant(dabigatran) non-major bleeding1.05 Re-Cover 0.11 Einstein-PE (rivaroxaban) 0.97 0.58 Re-Cover (dabigatran) 1.00 Einstein-DVT (rivaroxaban) 0.48 Amplify (apixaban) 1.05 Einstein-DVT (rivaroxaban) 0.81 Hokusai (edoxaban) 0.27 Einstein-PE (rivaroxaban) 2 Einstein-PE 0.97 88%, P < 0.01) 0.29 Subtotal (I =(rivaroxaban) 0.76 Amplify (apixaban) (apixaban) Non-fatalAmplify intracranial bleeding 0.48 Hokusai (edoxaban) 0.52 2 0.14 Re-Cover (dabigatran) 0.81 Hokusai (edoxaban) = 13%, P = 0.33) Subtotal (I 0.38 2 Einstein-DVT (rivaroxaban) 4.98 = 88%, P <bleeding 0.01) 0.10 Subtotal 0.76 ClinicallyEinstein-PE relevant(I non-major (rivaroxaban) Non-fatalAmplify intracranial bleeding 0.50 (apixaban) 0.58 Re-Cover (dabigatran) 0.14 Re-Cover (dabigatran) 0.42 Hokusai (edoxaban) Einstein-DVT 2 (rivaroxaban) 1.05 4.98 20%, P = 0.29) 0.39 Subtotal (I =(rivaroxaban) Einstein-DVT (rivaroxaban) Einstein-PE 0.97 Major gastrointestinal bleeding 0.10 Einstein-PE (rivaroxaban) Amplify (apixaban) 0.48 Re-Cover (dabigatran) 1.79 Amplify (apixaban) 0.50 0.81 Hokusai (edoxaban) Einstein-DVT (rivaroxaban) 0.75 0.42 2 Hokusai (edoxaban) Einstein-PE = 88%, P < 0.01) 0.56 Subtotal (I2 (rivaroxaban) 0.76 Subtotal(apixaban) (I = 20%, P = 0.29) 0.39 0.39 Amplify Non-fatal intracranial bleeding 2 Major gastrointestinal bleeding Subtotal (I = 37%, P = 0.19) 0.68 0.14 Re-Cover (dabigatran) Fatal bleeding Re-Cover (dabigatran) 1.79 Einstein-DVT (rivaroxaban) 4.98 Re-Cover (dabigatran) 0.75 Einstein-DVT (rivaroxaban) 0.99 0.10 Einstein-PE (rivaroxaban) Einstein-DVT (rivaroxaban) 0.20 Einstein-PE (rivaroxaban) 0.56 Amplify (apixaban) Einstein-PE (rivaroxaban) 0.66 0.50 Amplify (apixaban) (apixaban) 0.39 0.50 Amplify 0.42 2 Hokusai (edoxaban) Subtotal(edoxaban) (I 2 = 37%, P = 0.19) 0.20 Hokusai 0.68 Subtotal (I2 = 20%, P = 0.29) 0.39 Fatal bleeding Subtotal (I = 0%, P = 0.75) 0.36 0.41 0.01 0.46 0.20 0.01 0.35 0.12 0.20 0.31 0.09 0.12 0.17 0.27 0.09 0.60 0.23 0.27 0.41 0.42 0.23 0.83 0.01 0.81 0.42 0.20 0.38 0.83 0.70 0.12 0.81 0.58 0.09 0.38 0.27 0.01 0.70 0.23 0.24 0.58 0.01 0.88 1.02 0.88 0.82 0.62 1.34 0.87 1.15 0.82 4.93 0.61 1.34 0.94 0.62 1.15 0.99 0.87 0.61 1.02 2.75 0.94 0.62 103.65 0.99 0.78 0.13 0.42 0.01 0.15 0.83 0.24 0.16 0.81 2.01 0.82 2.75 1.18 1.34 103.65 0.94 1.15 0.87 1.49 4.93 0.87 1.38 0.62 4.93 0.80 0.87 0.62 0.55 1.02 0.87 1.21 0.62 100 5.5 18.2 9.0 15.9 5.5 28.4 21.8 9.0 17.4 28.4 18.6 39.7 17.4 25.5 100 39.7 100 17.1 100 19.7 5.5 21.3 17.1 9.0 20.0 19.7 21.9 28.4 21.3 100 17.4 20.0 39.7 8.0 21.9 100 7.7 100 15.3 SEGURIDAD 0.01 0.38 0.60 0.13 0.70 0.17 0.15 0.25 0.58 0.16 0.16 0.78 0.61 5.33 2.01 0.94 3.33 1.18 1.27 0.99 0.94 0.93 28.3 17.1 8.0 40.8 19.7 7.7 100 21.3 15.3 20.0 22.9 28.3 21.9 14.5 40.8 32.4 100 100 30.1 0.36 0.01 0.30 100 2.75 8.0 5.33 22.9 0.60 0.24 103.65 7.7 10.3 0.06 3.33 14.5 0.17 15.88 0.01 0.78 15.3 17.1 1.70 0.02 1.27 32.4 0.25 24.7 3.97 0.11 0.13 2.01 28.3 0.93 30.1 0.16 13.7 5.54 0.05 0.15 1.18 40.8 34.2 0.91 0.04 0.36 0.30 100 0.16 0.94 100 100 0.15 0.87 Major gastrointestinal bleeding 0.99 0.06 15.88 10.3 Re-Cover (dabigatran) Re-Cover (dabigatran) 1.79 0.02 5.33 22.9 0.60 17.1 1.70 Einstein-DVT (rivaroxaban) 0.20 1 0.75 0.11 3.33 14.5 0.1 0.17 Einstein-DVT(rivaroxaban) (rivaroxaban) 0.66 24.7 3.97 Favors NOACs Favors VKAs Einstein-PE 0.56 1.27 Einstein-PE (rivaroxaban) 32.4 0.25 13.7 5.54 0.50 0.05 Amplify (apixaban) Van der Hulle et al. J Thromb Haemost 2014; 12: 320-8. Amplify (apixaban) 0.39 0.93 30.1 0.16 34.2 Hokusai (edoxaban) 0.91 0.20 0.04 2 outcomes. CI, confidence interval; NOACs, new direct oral anticoagulants; VKA, vitamin-K antagonists. Fig. 4.Subtotal Safety 2 37%, P = 0.19) 0.68 0.36 0.30 100 0.15 0.87 100 P = 0.75) 0.36 Subtotal (I(I == 0%, Fatal bleeding Re-Cover (dabigatran) 0.99 0.06 15.88 10.3 10 *Number 2. In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist (VKA) therapy (all Grade 2B). Chest. 2016;149(2):315-352 Dabigatran en “vida real” Invited Editorial Focus A Thromb Haemost. 2015 Nov 25;114(6):1093-8. 1095 1096 Invited Editorial Focus C Thromb Haemost. 2015 Nov 25;114(6):1093-8. C D Thromb Haemost. 2015 Nov 25;114(6):1093-8. Figure 1 ◆ To analyse baseline demographics and hospitalization rates for rivaroxaban andand standard anticoagulation groups versus in XALIAstandard Safety effectiveness of oraltherapy rivaroxaban anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study Methods Special license agreement to Bayer Pharma AG for commercial e-Reprints until 08.12.2016 Walter Ageno, Lorenzo G Mantovani, Sylvia Haas, Reinhold Kreutz, Danja Monje, Jonas Schneider, Martin van Eickels, Martin Gebel, Elizabeth Zell, Alexander G G Turpie ◆ XALIA included patients presenting with acute, objectively confirmed DVT who were treated with rivaroxaban or standard anticoagulation therapy for a period of ≥3 months (Figure 1)1 Summary Background The efficacy and safety of the anticoagulant rivaroxaban for the treatment and secondary prevention of deep-vein thrombosis and pulmonary embolism has been shown in phase 3 trials. However, data about rivaroxaban use in routine clinical practice are needed. Lancet Haematol 2015 Published Online December 7, 2015 http://dx.doi.org/10.1016/ S2352-3026(15)00257-4 Methods XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism See Online/Comment (XALIA) was a multicentre, international, prospective, non-interventional study of patients with deep-vein http://dx.doi.org/10.1016/ thrombosis, done in hospitals and community care centres in 21 countries. The study investigated the safety and S2352-3026(15)00282-3 effectiveness of rivaroxaban compared with standard anticoagulation therapy (initial with unfractionated Department of Clinical and Rivaroxaban fortreatment ≥3 months heparin, low-molecular-weight heparin, or fondaparinux, usually overlapping with and followed by a vitamin K Experimental Medicine, n=2460 antagonist) for at least 3 months. Eligible patients were adults (aged ≥18 years) with an objectively confirmed University of Insubria, Varese, Italy (W Ageno MD); diagnosis of deep-vein thrombosis, and an indication to receive anticoagulation treatment for at least 3 months. CESP-Center for Public Health Population: Objectively Drug type, Following approval of rivaroxaban for the pulmonary embolism indication, patients with deep-vein thrombosis and Research, University of Milan concomitant pulmonary embolism were also eligible; not Bicocca, Milan, Italy confirmed, acute dose and however, those with isolated pulmonary embolism(1were month included. Type, dose, and duration of therapy for each patientData were collection at the physician’s discretion. The primary (L G Mantovani DSc); Vascular at initial visit, Munich, Germany DVT + indication for duration at after end ofCentre, effectiveness and safety outcomes were major bleeding, recurrent venous thromboembolism, and all-cause mortality. (Prof S Haas MD); Institute of 1 month and then quarterly anticoagulant physician’s Propensity score-adjusted therapy analyses were done to account for potential imbalances between groups. This study is Clinical Pharmacology and treatment) Toxicology, registered with ClinicalTrials.gov, number NCT01619007. for ≥3 months discretion Charité-Universitätsmedizin, Berlin, Germany (Prof R Kreutz MD); Bayer Vital GmbH, Leverkusen, Germany (D Monje Dipl Biol); Bayer Pharma AG, Berlin, Germany (J Schneider MD, M van Eickels #MD); Bayer Pharma AG, Wuppertal, Germany (M Gebel PhD); Stat-Epi Associates Inc, Ponte Vedra Beach, FL, USA (E Zell MStat); and Department of Medicine, Hamilton Health Sciences, General Division, Hamilton, ON, Canada (Prof A G G Turpie MD) Findings Between June 26, 2012, and March 31, 2014, 5142 patients were enrolled. The safety population (all patients N=4744* Standard anticoagulation who received at least one dose of the anticoagulant of interest) comprised 2619 patients in the rivaroxaban group and 2149 in the standard anticoagulant therapy group. Patients in the rivaroxaban younger and fewer had therapy: e.g.group initialwere treatment active cancer or concomitant pulmonary embolism than those in the standard anticoagulation group. In the Final with was LMWH fondaparinux, propensity score-adjusted population, the frequency of major bleeding 0·8%or (19/2505) in the rivaroxaban group and 2·1% (43/2010) in the standard anticoagulation group, with a propensity score-adjusted hazard ratio (HR)assessment of followed by VKA for ≥3 months 0·77 (95% CI 0·40–1·50); p=0·44. The frequency of recurrent venous thromboembolism was 1·4% (36/2505) in the rivaroxaban group and 2·3% (47/2010) in the standard anticoagulation groupn=1972 (propensity score-adjusted HR 0·91 [95% CI 0·54–1·54], p=0·72). The all-cause mortality frequency was 0·4% (11/2505) in the rivaroxaban group and 3·4% (69/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·51 [95% CI 0·24–1·07], p=0·074). The incidence of treatment-emergent adverse events in the safety population was similar between the two *This number includes 312 early switchers, defined as patients who received parenteral anticoagulation groups (944 [36·0%] of 2619 in the rivaroxaban group vs 805 [37·5%] of 2149 in the standard anticoagulation group). # and/or VKA for >2–14 days before being switched to rivaroxaban; final data collection for the primary Correspondence to: Interpretation In routine clinical practice, rivaroxaban-treated had a lower risk profile at baseline than those Dr Walter Ageno, Department of outcome will occur approximately 30 days after the end of patients antithrombotic treatment. treated with standard anticoagulation. Propensity score-adjusted results confirm that rivaroxaban is a safe and Clinical and Experimental Tha Lancet Haematology: December 7, 2015 http://dx.doi.org/10.1016/S2352-3026(15)00257-4 effective alternative to standard anticoagulation therapy in a broad range of patients. Rates of major bleeding and Medicine, University of Insubria, Hemorragia mayor A 4 Rivaroxaban Standard anticoagulation Cumulative incidence (%) 100 Cumulative incidence of major bleeding (%) 90 80 70 60 50 3 HR 0·41 (95% CI 0·24–0·70) 2 1 0 0 Rivaroxaban Patients at risk 2619 0 Patients with events Standard anticoagulation Patients at risk 2149 0 Patients with events 40 30 20 60 120 180 240 300 360 420 480 2386 10 1650 14 1348 17 797 18 664 18 566 18 262 19 173 19 1870 22 1458 30 1226 33 842 37 710 42 612 45 317 46 197 47 10 0 0 60 120 180 B 240 Time to event (days) 300 360 420 480 4 100 Tha Lancet 3Haematology: December 7, 2015 http://dx.doi.org/10.1016/S2352-3026(15)00257-4 idence (%) ) 90 HR 0·67 (95% CI 0·44–1·03) Cumulati 0 Patients with events Standard anticoagulation Patients at risk 2149 0 Patients with events 30 20 10 14 17 18 18 18 19 19 1870 22 1458 30 1226 33 842 37 710 42 612 45 317 46 197 47 10 Recurrencia 0 0 60 120 180 B 240 Time to event (days) 300 360 420 480 4 Cumulative incidence (%) 100 80 70 60 50 3 HR 0·67 (95% CI 0·44–1·03) 2 1 0 0 Rivaroxaban Patients at risk 2619 0 Patients with events Standard anticoagulation Patients at risk 2149 0 Patients with events 40 30 20 60 120 180 240 300 360 420 480 2380 23 1642 31 1340 32 789 34 658 34 560 34 263 36 174 37 1858 30 1444 37 1212 40 828 46 695 52 603 52 313 53 193 54 10 0 0 60 120 180 C 7 100 6 90 ence (%) Cumulative incidence of recurrent VTE (%) 90 5 240 Time to event (days) 300 360 420 480 0 Patients with events Standard anticoagulation Patients at risk 2149 0 Patients with events 20 10 0 Mortalidad 0 60 120 C 7 100 6 90 Cumulative incidence of all-cause morality (%) 180 Cumulative incidence (%) Cumulati 30 80 70 60 50 20 10 0 0 60 120 32 34 34 34 36 37 1858 30 1444 37 1212 40 828 46 695 52 603 52 313 53 193 54 240 Time to event (days) 300 360 4 420 480 HR 0·26 (95% CI 0·14–0·49) 3 2 1 0 Rivaroxaban Patients at risk 2619 0 Patients with events Standard anticoagulation Patients at risk 2149 0 Patients with events 30 31 5 0 40 23 180 60 120 180 2389 4 1652 7 1349 9 797 9 1878 26 1467 47 1232 63 847 75 240 Time to event (days) 240 300 Time to event (days) 300 360 420 480 664 10 566 10 263 12 174 12 716 79 619 83 322 84 200 85 360 420 480 www.thelancet.com/haematology PublishedDecember online December 2015 http://dx.doi.org/10.1016/S2352-3026(15)00257-4 Tha Lancet Haematology: 7, 2015 7, http://dx.doi.org/10.1016/S2352-3026(15)00257-4 patients in both treatment groups were male (52.6%). Clinical characteristics of with moderate to high risk of stroke. This study compared major bleeding risk associated costs among NVAF patientswith with high risk of stroke who were apixaban and warfarin and patients differed at baseline, warfarin patients # ACC Scientific Session Program Planner Home ! Print Pa newly anticoagulated with apixaban or warfarin. having higher prevalence of majority of the comorbidities. Major bleeding Data for this retrospective cohort study was drawn from the PharMetrics Plus " Share Pa between 01/2012 NVAF patients were selected incidence rate per 100database person-years were and 8.509/2014. for apixaban and 16.9 for for Session 1268 - World Discussion of Anticoagulation for Atrial Fibrillation inclusion if they newly filled a prescription for apixaban or warfarin. After controlling for patients’ characteristics, patients treated with warfarin, had a CHA ≥ 3 over the prior 12 months, and were ≥ 18 1268-343 / 343 - Compare Major Bleeding Risk 2DS2-VASc warfarin had higher risk of atmajor bleeding (HR: 1.66, 95% CI: years the time of the prescription fill. A minimum of 11.13 month- 2.44; and Associated Costs Among NVAF Patients of follow-up was required and follow-up ended upon treatment P=0.0096). Mean monthly costs With CHA2DS2-VASc Score(≥30 ≥ day 3 Newly discontinuation gap in treatment), switch to a different anticoagulant, associated with majorWith bleeding was enrollment, also higher warfarin patients compared end of continuous 1 yearfor after the index date, or end of study. Anticoagulated Apixaban Versus evaluated major bleeding and major bleeding medical with apixaban patientsOutcomes ($872 vs $347;included P<0.0001). Warfarin costs. Multivariable Cox proportional hazards model was used to evaluate the Among high risk NVAF impact patient who wereonnewly of anticoagulant the risk anticoagulated, of major bleeding and major GLM wasbleeding used to $ April 2016, 9:45 - 10:30 AMwere %reduced Posteron Area, South Hall A1with major evaluate thesignificantly impact of anticoagulant costs associated bleeding. and the4,associated costs with apixaban compared There were 6,699 patients meeting the study criteria; of these 1,275 (19.0%) to warfarin. received apixaban and 5,424 (81.0%) received warfarin. The mean age of apixaban and warfarin patients was 69.7 and 71.2, respectively. The majority of Authors patients in both treatment groups were male (52.6%). Clinical characteristics of Steven Deitelzweig, Kiran Gupta, Augustina Ogbonnaya, Manan Shah, Eileen apixaban and warfarin patients differed at baseline, with warfarin patients Farrelly, Tasneem Lokhandwala, Michael Eaddy, Bristol-Myers Squibb, having higher prevalence of majority of the comorbidities. Major bleeding Princeton, NJ, USA, Pfizer, New York, NY, USA incidence rate per 100 person-years were 8.5 for apixaban and 16.9 for Abstract warfarin. After controlling for patients’ characteristics, patients treated with Current studies evaluating outcomes associated with- direct warfarin had higher risk of majorclinical bleeding (HR: 1.66, 95% CI: 1.13 2.44; oral anticoagulants have costs focused on non-valvular atrial fibrillation (NVAF) patients P=0.0096). Mean monthly with moderate high riskwas of stroke. This study compared major bleeding ris associated with majortobleeding also higher for warfarin patients compared and associated among NVAF patients with high risk of stroke who were with apixaban patientscosts ($872 vs $347; P<0.0001). Casoclínico • Varón de 72 años 4 horas tras la toma de 20 mg de rivaroxaban (por FA) presenta… Hematemesis franca con hipotensión INR de 1,8 y Hb de 8,6 g/dL Level 1A evidence for reversal strategies for direct anticoagulants 5 Systematic review of REVISIÓN SISTEMÁTICA DOACs vs Warfarin ACODs VS AVK 102.707 pacientes de 13 EECC de FA y ETV Case-fatality rate HEMORRAGIA MAYOR: 7,57% VS 11,05% HEMORRAGIA FATAL: 0,16 VS 0,32 por 100 pacientes-año J Thromb Haem 2015;13:2012-20. 8 • Dabigatran might increase bleeding with surgery/procedures • 4591 patients undergoing at least 1 invasive procedure: – 24.7% of patients receiving dabigatran 110 mg – 25.4% of patients receiving dabigatran 150 mg – 25.9% of patients receiving warfarin • No significant difference in the rates of periprocedural major bleeding: – dabigatran 110 mg (3.8%) or dabigatran 150 mg (5.1%) or warfarin (4.6%) • Urgent surgery: – 17.8% with dabigatran 110 mg, 17.7% with dabigatran 150 mg, and 21.6% with warfarin • Despite a lack of an antidote there was no evidence of increased bleeding with Dabigatran 10 PCCs are recommended as the treatment of choice in PCCs• are recommended as the treatment of choice in warfarin-related coagulopathy. warfarin-related coagulopathy. • Meta-analysis to estimate of thromboembolic Meta-analysis to estimate the ratethe of rate thromboembolic (TE) (TE) complications in patients receiving PCCs for bleeding or complications in patients receiving PCCs for bleeding or before before urgent urgent surgerysurgery • 27 studies patients) were included 27 studies (1,032 (1,032 patients) were included • 12 patients had a TE (1.4%; CI 0.8-2.1) 12 patients had a TE (1.4%; 95% CI95% 0.8-2.1) – 2 fatal– 2 fatal • isThere a low but quantifiable risk of thromboembolism in There a lowisbut quantifiable risk of thromboembolism in VKA-treated patients receiving PCCs for anticoagulation VKA-treated patients receiving PCCs for anticoagulation reversalreversal 11 Internal use only L.GB.MKT.08.2015.12297L Aug 2015 Internal use only L.GB.MKT.08.2015.12297L Aug 2015 11 KEY POINTS No existe una epidemia de sangrados con los nuevos anticoagulantes El sangrado es menos frecuente y menos grave que en los pacientes con AVK La cirugía urgente se asocia a menos sangrados que en los pacientes con AVK La reversión del efecto anticoagulante tiene riesgos: • El paciente pasa a tener un estado procoagulante • Los agentes reversores incrementan el riesgo de trombosis ¿Son necesarias las estrategias de reversión? • Pueden reducir la severidad del sangrado y las consencuencias del mismo • Proporcionan confort al médico que prescribe el anticoagulante Managing Bleeding Complications in Patients Treated with NOACs Initial Assessment Hemodynamic stability Source of bleeding Time elapsed since last dose Renal function Risk Stratification Minor Bleeding Moderate Bleeding Severe/Life-threatening Bleeding • Local hemostatic measures • Consider anticoagulant withdrawal (balance thrombotic and bleeding risks) General measures • Anticoagulant withdrawal • Mechanical Compression • Monitor hemodynamic status • Volume Replacement • Definitive Interventions Blood product transfusion • RBC transfusion for anemia • FFP for coagulopathy (e.g., DIC, dilutional coagulopathy) • Consider platelets for patients on antiplatelet agents Patient with bleeding on novel oral anticoagulant * Preferred agent for rivaroxaban/apixaban ** Preferred agent for dabigatran */**Recommendation based only on limited non-clinical data. PCC: prothrombin complex concentrates (non-activated or activated). DIC: disseminated intravascular coagulation. Siegal DM, Crowther MA. Eur Heart J. 2012;34:489-498b. General measures and blood product transfusion as per moderate bleeding • Intensive care setting • Hemodynamic support • Consider: • 4-factor PCC (50U/kg)* • Activated PCC (80U/kg)** Adjunctive therapies • Oral charcoal for dabigatran ingestion within 2 hours • Hemodialysis for dabigatran removal (if feasible) • Desmopressin • Antifibrinolytic agents Manejo general del paciente con hemorragia en tratamiento con NOACs *Dosis concentrado de complejo protrombínico (CCP): 50 UI/kg; Dosis CCP activado (FEIBAR): 80 UI/kg, en los casos de hemorragia severa con amenaza para la vida del paciente. Guías SETH. http://www.seth.es/images/files/guia-nuevos-anticoagulantes-orales.pdf Sánchez M. et al. Emergencias 2013; 25: 482-490 ¿Está la droga presente cuantitativamente de forma significativa? ¿Necesita el tratamiento anticoagulante ser revertido? ¿Cómo se revierte el efecto del fármaco? 'Caracterís*cas'farmacológicas ' PKPD de los NACOs Parámetro Diana Biodisponibilidad oral Fijación a proteínas plasmáticas Dosis (para la indicación en prevención del ictus en FA) Profármaco Vida media (h) Dabigatran Rivaroxaban Apixaban Edoxaban Trombina Factor Xa Factor Xa Factor Xa 6.5% 80–100%* ~66% 50% 34–35% 92–95% 87% 40–59% Fija, Fija, Fija, Fija, dos veces día una vez al día dos veces día una vez al día Sí No No No 8–13 9–11 12–14 5–9 (jóvenes sanos) 11–13 (ancianos) Tmax (h) ~62 2–4 1–3 1–2 Monitorización rutinaria *After oral ingestion de la coagulación No No No No *15–20 mg deben tomarse con alimentos Eriksson BI et al, 2011; Frost et al, 2007; Kubitza D et al, 2005; Kubitza D et al, 2005; Ogata K et al, 2010; Stangier et al, 2005; Raghavan N et al, 2009; 7' SmPC 2011; Xarelto PI 2011; Pradaxa SmPC 2011; Eliquis SmPC 2011; Xarelto Dabigatran PI; ROCKET AF Investigators 2010; Lopes et al, 2010; Ruff et al, 2010. 16 Tests Siegal & Crowther. Eur H J ePub Dec 7 ¿Está la droga presente cuantitativamente de forma significativa? ¿Necesita el tratamiento anticoagulante ser revertido? ¿Cómo se revierte el efecto del fármaco? ¿Necesita el tratamiento anticoagulante ser revertido? • En sangrado menor o fácilmente controlable con otras medidas o si la cirugía es diferible: • Los ACODs tienen vida media corta con pacientes con función renal normal • Mejor esperar • Si el paciente está estable en hemorragias más importantes es mejor “watched and waited” mientras la droga se elimina • En caso de cirugía urgente necesaria • Incremento del riesgo de sangrado a tener en cuenta ¿Cómo se revierte el efecto del fármaco? Estrategias de manejo del sangrado • Endoscopia, radiología intervencionista, cirugía • Considerar PFC, ácido tranexámico, desmopresina, etc • Considerar CCP, CCPa en pacientes con sangrado de riesgo vital (FVIIar parece inefectivo) • Hemodiálisis si dabigatran • Antídotos en DESARROLLO • Andexanet: Designed to Reverse Activity of Factor Xa Inhibitors Nature Medicine (2013),19(4): 446-51 Recombinant engineered version of human factor Xa produced in CHO cells • Acts as a fXa decoy and retains high affinity for all direct fXa inhibitors • Change of serine to alanine to eliminate catalytic activity and prevent prothrombin cleavage • GLA domain removed to prevent anticoagulant effect S419 Gla Gla Factor Xa inhibitor Factor Xa inhibitor A419 Catalytic Domain S S Factor Xa S S Andexanet Alfa • No known interaction with other coagulation factors except Tissue Factor Pathway Inhibitor (TFPI) • Retains high affinity for Antithrombin III-inhibitor complex and can reverse ATIII- Phase 4 Outcomes Study in Bleeding Patients: ANNEXA™-4 on Apixaban, Rivaroxaban and Enoxaparin ▸ An open-label, multinational study in patients receiving fXa inhibitors presenting with acute major bleeding ▸ Two Primary Endpoints ▸ First primary: Percent change from baseline in anti-fXa activity ▸ Second primary: Occurrence of patients achieving “effective hemostasis” as adjudicated by an Independent Endpoint Adjudication Committee ▸ Study is ongoing; to be conducted at over 50 sites in North America and Europe ▸ Plan to add edoxaban to study in 2016 • Specific, short half-life agent that binds to an inactivates a variety of Xa inhibiting anticoagulants • Administered as either bolus or bolus + infusion • Does not change underlying PK of the anticoagulant Cirparantag (PER977) Experimental Data Cirparantag tested in 2 animal models and in human blood ex vivo: • Rat-tail transection models using a 100x overdose of dabigatran, rivaroxaban, apixaban, and edoxaban, 12.5 mg of cirparantag decreased bleeding by > 90% vs. control1,2 • Bleeding reduced to normal range of non-anticoagulated rats • In rats, 20 mg/kg cirparantag reversed the anticoagulant activity of edoxaban (0.5 mg/kg) within 30 minutes of administration, measured using thromboelastography assays1,3 • In a human plasma model, cirparantag reversed anti-FXa activity of rivaroxaban, apixaban, and enoxaparin dose-dependently across a range of concentrations1,2 1. Lauw MN, et al. Can. J. Cardiol. 2014;30:381-84; 2. Laulicht B, et al. Circulation. 2012;126:A11395; 3. Laulicht B, et al. J Thromb Haemost. 2013;11:AS47.1 (abstr). Ciraparantag (PER977) is being developed for the universal inhibition of anticoagulant therapies. The efficacy and safety of this agent has not been established and it is not available for sale in Canada. DOI: 10.1056/NEJMc1412266 Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban correspondence Percent Change from Baseline in Whole-Blood Clotting Time To the Editor: New target-specific oral anticoag- was used to measure the anticoagulant effect of ulants are limited by the lack of a proven reversal edoxaban and its reversal by PER977. In clinical agent. PER977 50(Perosphere) is a small, synthetic, trials of PER977, whole-blood clotting time PER977 60 mg edoxaban administered water-soluble, cationic molecule that is designed showed low variability (interobserver variation, Pooled placebo 25 mg PER977 to bind specifically to unfractionated heparin 3.0%) and high reproducibility (intersubject vari40 100 mg PER977 and low-molecular-weight heparin through non- ation, 3.6%), and correlated well with edoxaban 300 mg PER977 covalent hydrogen bonding and charge–charge plasma concentrations (Fig. S3 in the Supple30 *P<0.05 vs. placebo interactions (Fig. S1 in the Supplementary Ap- mentary Appendix). pendix, available with the full text of this letter at After the administration of edoxaban, the 20 NEJM.org).1,2 PER977 binds in a similar way to mean whole-blood clotting time increased by 37% the new oral factor Xa *inhibitors, edoxaban, riva- over the baseline value (Fig. 1). In patients re10 * roxaban and apixaban, ***and ceiving a single intravenous dose of PER977 (100 to * to the oral thrombin ** * * * * thromboelastographic inhibitor, dabigatran. In 300 mg) 3 hours after the administration of 0 studies and rat-tail–transection bleeding assays, edoxaban, the whole-blood clotting time decreased PER977 has been shown to reverse anticoagula- to within 10% above the baseline value in 10 min1,2 In non- utes or less, whereas in patients receiving placebo, tion with each−10of0 the new oral agents. 3 6 9 12 15 18 21 24 27 clinical studies, PER977 did not bind to plasma the time to reach that level was much longer Hours after Edoxaban Administration proteins, including albumin, and showed no (approximately 12 to 15 hours). The whole-blood Figure 1. Effect of PER977 on Whole-Blood Clotting Time. bindingShown when tested against several common clotting time remained within 10% above or are the mean whole-blood clotting times after administration of a single oral 60-mg dose of edoxaban, followed 3 hours later by a single intravenous of 25 mg, 100 mg, or 300 mg PER977 or placebo. cardiovascular, antiepileptic, and doseanesthetic below theof baseline value for 24 hours after the drugs. In this study, we assessed the safety, side- administration of a single dose of PER977. ScanRobert J. Noveck, M.D. effect was profile, and effect on anticoagulation ning electron micrographs clots 2014;370:390. obtained durno evidence of procoagulant activity after reN Engl JofMed Duke University Medical Center PER977, as assessed by measureversaladministration of PER977 ofwhen administered alone and ing measurement of the whole-blood clotting time Durham, NC ment of levels of d-dimer, prothrombin fragafter a 60-mg dose of the factor Xa inhibitor were analyzed with a computer algorithm to Idarucizumab: a specific reversal agent for dabigatran 34 Approved in the US Friday October 15th 2015 35 Idarucizumab está aprobado por EMA. En España no está comercializado a espera de condiciones de precio y reembolso Estudio de fase III, de un solo brazo, abierto y multicéntrico Grupo A: hemorragia incontrolada + tto. con dabigatrán Grupo B: cirugía o procedimientos de urgencia + tto. con dabigatrán 5 g idarucizumab (dos infusiones separadas de 2,5 g) 0–15 min N=300 90 d. seguimiento 0–24 h Llegada al hospital Pre1er. vial Pre2º vial ~20 min 1 h 2 h 4 h 12 h 24 h 30 d 90 d Muestras de sangre Pollack C, et al. Thromb Haemost. 2015 May 28;114 [Epub ahead of print]. RESULTADOS: variable principal • TTd normalizado en el 98% y 93% de los pacientes del Grupo A y B, respectivamente* • TCE normalizado en el 89% y 88% de los pacientes del Grupo A y B, respectivamente* Resultados similares en TTPa y TT de laboratorio central *Calculado para pacientes con niveles basales elevados. ¿Cuál, cuándo, a quién y por qué? CUÁL: CUALQUIERA CUÁNDO: DIAGNÓSTICO DE FANV O ETV EN PACIENTE NO ONCOLÓGICO A QUIÉN: A TODOS SALVO INSUFICIENCIA RENAL O HEPÁTICA GRAVES POR QUÉ: PORQUE LO DICEN DAVID JIMÉNEZ Y ALFONSO MARTÍN