NUOVI ANTICOAGULANTI ORALI
DIRETTI: COME NEUTRALIZZARE LA
ATTIVITA’ ANTICOAGULANTE
DAVIDE IMBERTI
CENTRO EMOSTASI E TROMBOSI
MEDICINA INTERNA
DIPARTIMENTO DI MEDICINA GENERALE
OSPEDALE GUGLIELMO DA SALICETO
PIACENZA
Nuovi anticoagulanti: pratica clinica
 Monitoraggio laboratoristico
 “Reverse” dell’effetto anticoagulante
 Gestione complicanze emorragiche
 Gestione perioperatoria
 Switch da VKA (e viceversa)
 Quali pazienti
ESC 2012 guidelines: management of bleeding
with new oral anticoagulants
Patient on a new OAC presenting with bleeding
Check haemodynamic status, basic coagulation tests
to assess anticoagulation effect
Minor
• Delay next dose or discontinue treatment
Moderate
•
•
•
•
•
Very severe
• Consider rFVIIa or PCC
• Charcoal filtration
• Dabigatran only: haemodialysis
Symptomatic/supportive treatment
Mechanical compression
Fluid replacement
Blood transfusion
Oral charcoal if recently ingested
Camm, Eur Heart J, 2012
Emivita media dei farmaci attuali

Warfarin: 36-42 ore

Rivaroxaban: 7-11 ore

Apixaban: 12 ore

Dabigatran: 12-14 ore

Edoxaban 6-12 ore

EBPM: 3-6 ore

Fondaparinux: 13-21 ore
NAO e EMORRAGIE
Informazioni cliniche importanti

Tipo di farmaco

Dose
 Ora dell’ultima assunzione
 Eventuale coesistenza di insufficienza renale
Monitoring and Antidotes
Monitoring
Antidote
Warfarin
INR
TTR
Vitamin K
Dabigatran
TT - Hemoclot®
Monoclonal Ab
ECT (aPTT)
FXa Inhibitors
Factor Xa activity
(PT)
Universal antidote in ph 2 (FX
analogue: PRT4445)
All
Hb concentrations
HAS-BLED #
Fresh frozen plasma
Prothrombin complex concentrate
FEIBA
rFVIIa
Weitz , Hematology Am Soc Educ Program, 2012
Concentrati di Complesso Protrombinico
(PCC)
• Rivaroxaban: significativo
allungamento del PT
– Allungamento revertito
immediatamente e
completamentre dal PCC
• Dabigatran: significativo
allungamento dell‘aPTT
– Nessun effetto sull‘aPTT del PCC
• Conclusioni
– PCC reverte in vivo nell‘uomo
l‘effetto anticoagulante di
rivaroxaban
Eeremberg, Circulation, 2011
Reversal of rivaroxaban by PCC
A randomized, placebo-controlled, crossover study in healthy
subjects
Eerenberg, Circulation, 2011
Marlu, Thromb Haemost, 2012
Apixaban Reversal with PCC, aPCC and rFVIIa
In Vitro with Circulating Human Blood
Objective
Study Design
In vitro analysis to test the reversibility of the alterations in hemostasis caused by apixaban using different
coagulation factor concentrates
Whole
Blood from
Healthy
Donors
Apixaban
200 ng/ml
added to
blood
Coagulation
Factors Added
Measurement of Apixaban Anticoagulant
Activity
rFVIIa:
Novoseven® 270
µg/kg
Platelet function at high shear rates
(IMPACT-R)
aPCC: Feiba® 75
U/kg
PCC: Beriplex® 50
IU/kg
Thrombin generation
(TECHNOTHROMBIN)
Viscoelastic parameters (ROTEM)
Studies under flow conditions
Aliquots of plasma for further testing
In vitro analysis demonstrated that apixaban
Results

Did not interfere with the reactivity of platelets

Inhibited thrombin generation

Caused moderate reduction in thromboelastometry parameters (TEM)
Apixaban-induced alterations of hemostasis were variably compensated or even reversed by the different factor
concentrates used in this analysis, including PCCs, active PCCs, and rFVIIa.
Effects of these concentrates were not homogeneous in all the tests

PCCs demonstrated greater efficacy in reversing apixaban effect measured by thrombin generation

rFVIIa demonstrated greater effectiveness in reversing apixaban effect in TEM and perfusion chamber analyses
Adapted from Escolar G, Arellano-Rodrigo E, Reverter JC, et al. Reversal of apixaban induced alterations of hemostasis by different coagulation factor concentrates:
studies in vitro with circulating human blood. Presented during the American Heart Association-Emerging Science Series webinar; June 20, 2012. Available at:
http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@smd/documents/downloadable/ucm_441679.pdf
Prothrombin complex
concentrate, activated
prothrombin complex
concentrate (Feiba),
and recombinant factor
VIIa (rFVIIa)
significantly reversed
the anticoagulant effect
of edoxaban in vitro.
186
Fukuda, Thromb Haemost, 2012
Use of PCCs for urgent reversal of dabigatran in the
Emergency Department
Quintana-Diaz, Haematologica, 2013
Use of PCCs for urgent reversal of dabigatran in the
Emergency Department
Quintana-Diaz, Haematologica, 2013
Reversing the NOACs with
PCCs: what is the evidence ?
- Systematic review about dabigatran, rivaroxaban,
apixaban, edoxaban.
-
PCCs (including activated PCCs) show promise
for reversing the anticoagulant effects of the new
oral anticoagulants.
- Conventional laboratory assays do not correlate
well with bleeding or reversal of anticoagulation in
this setting; thrombin generation assays appear to
have the best predictive value.
Dickneite , Thromb Haemost, 2014
Dabigatran antidote: characteristics
• Fully humanized antibody fragment (Fab)
• Potently binds dabigatran
• No prothrombotic or anti-thrombotic effects
• Short half-life
• No endogenous targets
• Allows for intravenous administration
van Ryn J, Circulation, 2012;126:A9928
Reversal of anticoagulation ex vivo: results
• Antidote reverses the anticoagulant activity of dabigatran
within 1 min of i.v. bolus injection to rats
Plasma levels
Dabigatran (nM)
125
100
75
50
25
8000
7000
6000
5000
4000
3000
2000
1000
0
8000
7000
6000
5000
4000
3000
2000
1000
0
Fab Level (nM)
Thrombin time (seconds)
Thrombin clotting time
0
-20
-20
0
5
10
15
20
25
30
Time (min)
0.3 + 0.1 mol/kg/hr BIBR 953
BI 655075 0.3 µmol/kg
Control + BI00655075 0.3 µmol
Control
0
5
10
15
20
25
30
Time (min)
Dabi 0.3 + 0.1 umol/kg/hr
Dabi+Fab
Vehicle+Fab
Dabi (+0.3 umol Fab)
Dabigatran: bolus (0.3 mol/kg) + infusion (0.1 mol/kg/hr)
(0.141mg/kg) +
(0.047mg/kg/hr)
 SE, n=4.
Schiele,
Blood, 2013
Dabigatran bolus (0.3 mol/kg) + infusion (0.1 mol/kg/hr)Data expressed as mean
Thrombin time: 3.0 U/ml thrombin used in the assay
A specific antidote for dabigatran: immediate,
complete and sustained reversal of dabigatran
induced anticoagulation in healthy male volunteers
Glund, OC17765, AHA, Dallas, 2013
r- Antidote (PRT064445) has a high affinity
for Xa inhibitors
Antidoto: ANDEXANET ALFA (Portola)
• Analogo ricombinante del FXa
• Non partecipa alla formazione del complesso della
protrombinasi e all’attivazione del FII
– Elevata capacità legante per gli inibitori del FXa (rivaroxaban,
apixaban, betrixaban, ecc.)
Management of major bleeding events in patients tretaed
with rivaroxaban vs warfarin: results from the ROCKET AF
Pharmacologic management post-major bleed (0-24 hours)
Rivaroxaban
Warfarin
(n=431)
(n=409)
Vitamin K
32 (7.4%)
54 (13.2%)
Protamine
0 (0.0%)
0 (0.0%)
Desmopressin
0 (0.0%)
0 (0.0%)
Epsilon-aminocaproic acid
2 (0.5%)
3 (0.7%)
Tranexamic acid
2 (0.5%)
11 (2.7%)
Prothrombin complex concentrates
4 (0.9%)
9 (2.2%)
Recombinant factor VIIa
0 (0.0%)
1 (0.2%)
Factor VIII concentrate
1 (0.2%)
1 (0.2%)
Factor IX concentrate
0 (0.0%)
3 (0.7%)
Piccini, Eur Heart J, 2014
Outcomes following ISTH major bleeding
Stroke or systemic embolism
Events
Riva
Warfarin
(N=431)
(N=409)
20 (4.7%)
22 (5.4%)
Interaction
P Value
0.888 (0.420, 1.876) 0.5135
HR (95% CI)
Composite of all stroke,
non-CNS embolism, MI/UA,
and all-cause death
104 (24.8%) 120 (29.9%)
0.758 (0.530, 1.082)
0.0975
All-cause death
86 (20.4%) 105 (26.1%)
0.688 (0.455, 1.042)
0.1098
MI/UA
11 (2.6%)
1.848 (0.572, 5.971)
0.5597
7 (1.7%)
0.1
Favors rivaroxaban
1
10
Favors warfarin
Piccini, Eur Heart J, 2014
Strategies used for management of major bleeding: RE-LY®
trial – results
Dabigatran*
Warfarin
741 (100)
421 (100)
Blood transfusion, n (%)
439 (59.2)
210 (49.9)
0.002
Fresh frozen plasma, n (%)
147 (19.8)
127 (30.2)
<0.001
70 (9.4)
115 (27.3)
<0.001
Prothrombin complex concentrate, n (%)
5 (0.7)
5 (1.2)
0.36
Recombinant Factor VIIa, n (%)
8 (1.1)
3 (0.7)
0.53
Patients with major bleeds, n (%)
Vitamin K, n (%)
P value
Major bleeds in the dabigatran groups were more frequently treated with blood
transfusions than those on warfarin but less frequently with plasma
Data derived based on the randomized set of RE-LY®
*Data combined from dabigatran 150 mg and 110 mg BID treatment groups
Mayeed, Blood, 2012
Short-term consequences of major bleeding:
RE-LY® trial – results
Dabigatran*
Warfarin
P value
Patients with major bleeds, n (%)
741 (100)
421 (100)
Patients with hospitalization,† n (%)
456 (61.5)
254 (60.3)
0.68
Length of stay, days, mean (SD)
8.4 (9.1)
8.9 (9.8)
0.48
Nights in ICU/CCU, mean (SD)
1.6 (4.3)
2.7 (6.6)
0.01
Nights in step-down unit, mean (SD)
1.0 (2.5)
1.0 (2.7)
0.84
Patients with major bleed requiring surgery,
n (%)
90 (12.1)
63 (15.0)
0.17
Length of stay in ICU is shorter with
dabigatran treatment than with comparator
Data derived based on the randomized set of RE-LY®; *Data combined from dabigatran 150 mg and 110 mg BID treatment
groups; †First reported hospitalization is given for a major bleeding event, if admission to hospital was between 1 day before
event and 7 days after event
Length of stay, night in ICU/CCU, night in step-down unit was obtained from all hospitalization events (dabigatran = 510;
warfarin = 273)
CCU = coronary care unit; ICU = intensive care unit; SD = standard deviation
Mortality after a major bleed:
five Phase III trials – results
Warfarin
Dabigatran
Mortality rate (%)
0.2
0.1
0.3
0
5
10
15
20
Time (days)
25
30
35
The Kaplan–Meier analysis indicated a reduced risk for death with dabigatran* vs
warfarin during 30 days from the bleeding (P=0.052)
*Data combined from dabigatran 150 mg and 110 mg BID treatment groups. Only first major
bleed included. Analysis not adjusted for covariates
Major Bleeding in Patients with Atrial Fibrillation Receiving Apixaban or
Warfarin in the ARISTOTLE Trial: Predictors, Characteristics, and Clinical
Outcomes
Characteristics of major extracranial hemorrhage
Characteristics of ISTH Major
Extracranial Hemorrhage
Overall
Apixaban
Warfarin
Hazard Ratio
(95% CI)
Event
Rate
(%/yr)
Event
Rate
(%/yr)
Event
Rate
(%/yr)
Apixaban vs.
Warfarin
Led to hospitalization
1.23 (374)
1.05 (162)
1.41 (212)
0.75 (0.609–0.917)
0.0052
Fall in hemoglobin 2 g/dL
1.25 (381)
1.06 (164)
1.44 (217)
0.74 (0.603–0.905)
0.0035
Led to transfusion
1.06 (325)
0.89 (137)
1.25 (188)
0.71 (0.571–0.887)
0.0025
Required a medical or
surgical consultation
1.74 (527)
1.54 (236)
1.94 (291)
0.79 (0.668–0.941)
0.008
Required a medical or
surgical intervention to stop
0.77 (236)
0.65 (100)
0.90 (136)
0.72 (0.555–0.930)
0.012
Associated with
hemodynamic compromise
0.32 (97)
0.26 (40)
0.38 (57)
0.69 (0.459–1.029)
0.069
Caused changed in
antithrombotic therapy
1.31 (398)
1.14 (176)
1.47 (222)
0.78 (0.636–0.945)
0.012
P Value
Hylek, JACC, 2014
Major Bleeding in Patients with Atrial Fibrillation Receiving Apixaban or
Warfarin in the ARISTOTLE Trial: Predictors, Characteristics, and Clinical
Outcomes
Major bleeding followed by death within 30 days
237
Hylek, JACC, 2014
Hemorrhagic complications in ED patients
receiving dabigatran compared with warfarin
Berger, Ann Emerg Med, 2013
Emorragie minori in corso di NAO
- Considerare sede e severità della emorragia;
eventuale valutazione laboratoristica della attività
anticogulante del NAO
- Misure locali
- Antifibrinolitici
- Rimandare, ridurre oppure temporaneamente
sospendere la dose successiva del NAO,evitando
peraltro prolungate riduzioni o sospensioni della stessa
- Identificare e se possibile trattare la causa della
emorragia