Jornada IV Jornada V ¿Cuál, cuándo, a quién y por qué?

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
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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