Transcript (dabigatran, rivaroxaban, apixaban)…

Bleeding Management in
the NOAC era
Eddy Lang
Senior Researcher
Alberta Health Services
Associate Professor
University of Calgary
Disclosures
• Member of Thrombosis Interest Group of
Canada
• Sponsored presentations Boeringher
Ingleheim / Bayer
• Research support BI – studentship grant
• Failed heme exam in med school
Objectives
(Q’s you will be able to answer)
1. What should my approach be to NOAC
related bleeding?
2. How can I tell if the drug’s on board?
3. What do I do when the patient is spiralling?
Key Points
NOACs demand different
approaches
PTT / Thrombin time will point
you the presence of
dabigitran
PT/INR will tell you if
rivaroxaban is at play
Key Points
Half-lives are a
consideration
There are no full
reversal agents
Dialysis is an option
for one of the agents
Pharmacological advantages of the new
OAC compared with warfarin include:
1. More rapid onset & offset of
action
2. Easily reversible anticoagulant
effect
3. No need for routine laboratory
monitoring
4. All of the above
5. 1 and 3
Case Scenario
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•
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82 year old female
Rivaroxaban 20 mg OD
Started 3 mos ago for AF, CHADs 2
Syncope, melena this am
No liver disease
BP 90/60; HR 115
OB +ve; BUN 16; Hgb 95 (145)
GI: Stabilize first
New OACs: Advantages vs. VKAs
Feature
Warfarin
New OACs
Onset
Slow
Rapid
Dosing
Variable
Fixed
Food effect
Yes
No
Interactions
Many
Few
Monitoring
Yes
No
Offset
Long
Shorter
New OACs: Disadvantages vs. VKAs
Features
Warfarin
New Agents
Frequency
once-daily
twice-daily*
Monitoring
INR
uncertain
Clearance
non-renal
renal 25-80%
Antidote
vitamin K
none
Familiarity
extensive
minimal
*dabigatran and apixaban
Pharmacology of New OACs
Feature
IIa Inhibitors
Xa Inhibitors
factor IIa
factor Xa
Prodrug
Yes
No
Bioavailability
6%
50-80%
12-18 hrs
7-13 hrs
Renal
80%
25-35%
Monitoring
No
No
Interactions
P-gp
3A4/P-gp
Target
Half-life
Three new drugs have been studied in
AF (dabigatran, rivaroxaban,
apixaban)…
1. All 3 are as efficacious as warfarin to
reduce stroke/SE
2. All 3 are associated with less overall
bleeding
3. All 3 are associated with less
intracranial bleeding
4. All of above
5. 1 and 3 are correct
Feature
Dabigatran
(150 bid)
Rivaroxaban
(20 mg od)
Apixaban
(5mg bid)
Stroke
-36%
-12%
-21%
Ischemic stroke
-24%
-1%
-8%
ICH
-60%
-33%
-58%
Death
-12%
-8%
-11%
Bleeding
-7%
+3%
-31%
GI Bleeding
+36%
+40%
-11%
MI
+27%
-9%
-12%
dyspepsia
-
-
Other
Pharmacokinetics
Property
Conventional Anticoagulants
New Anticoagulants
warfarin
UFH
LMWH
fondaparinux
dabigatran
rivaroxaban
apixaban
vitamin K
antagonist
indirect fIIa
+ Xa
inhibitor
indirect fXa
(minor IIa)
inhibitor
indirect fXa
inhibitor
direct factor
IIa inhibitor
direct factor
Xa inhibitor
direct factor
Xa inhibitor
100%
100%
100%
100%
6-7%
80%
80%
Peak action
(tmax)
4-5 days
immediate
(IV); 0.5
hrs (SC)
2-4 hrs
2-4 hrs
1-3 hrs
1-3 hrs
1-3 hrs
Elimination
half-life (t 1/2)
36-42 hrs
1-1.5 hrs
3-4 hrs
17-21 hrs
14-17 hrs
9-15 hrs
9-14 hrs
Route of
clearance
multiple
reticuloendotheial
>80% renal
100% renal
80% renal
35% renal
25% renal
yes
no
no
no
minor
minor
minor
Mode of
action
Bioavailability
(Frel)
Involvement
of CYP
Douketis JD. Curr Pharm Des 2010;16:3436
Dabigatran and the aPTT
- non-linear dose-response
- median peak aPTT is approximately 2-fold of control
- 12 hrs after the last dose (trough level), median aPTT 1.5-fold of
control
Measuring Anticoagulant Effect of Dabigatran: INR?
- dose-dependent and short-lived (1-4 hrs after dose)
prolongation of INR
Thrombin Time
- linear dose-response over therapeutic concentrations of
dabigatran
- directly measures plasma thrombin activity
Laboratory Monitoring of Dabigatran
• PT (INR)
– Dabigatran has MINIMAL or NO EFFECT on effect
on PT
– Apixiban and Rivaroxiban do effect PT
– not reliable to measure anticoagulant effect
• aPTT
– dabigatran HAS EFFECT on aPTT
– Apix and Dabi no effect on aPTT
– trough level (10-16 hrs post-ingestion) >80 sec = ABNORMAL
– trough level >1.5-times control aPTT = EXPECTED
– prolongation reflects thrombin (factor II) inhibition
NOT factor deficiency
Laboratory Monitoring of Dabigatran
• Thrombin clotting time (TCT)
– normal TCT (<30 sec) likely reflects absence of significant
anticoagulant effect
– too sensitive for routine monitoring (to distinguish different levels of
anticoagulation) but determines if any dabigatran present
• Dilute thrombin clotting time (Hemoclot assay)
– 1/16th dilution of TCT
– peak (2 hr post-ingestion levels): 125-175 ng/mL
– trough (10-16 hrs post-ingestion levels): 65-90
ng/mL
Laboratory Monitoring of Dabigatran: Use in
Practice
• Step 1: aPTT
– qualitative test (for screening)
– if elevated aPTT (and no other cause), likely some dabigatran
effect
– if normal aPTT, no clinically significant dabigatran effect
– for extra reassurance that no residual anticoagulant effect…
• Step 2: TCT (or Hemoclot test)
– quantitative test
– if normal TCT (<30 sec) or if normal Hemoclot test, no
detectable dabigatran anticoagulant effect
Laboratory Monitoring of Rivaroxaban (and
Apixaban)
• Step 1: PT
– qualitative test (for screening)
– if elevated PT (and no other cause), likely some
rivaroxaban effect BUT, highly assay-dependent
– if normal PT, no clinically significant rivaroxaban
effect
– for extra reassurance that no residual anticoagulant
effect…
• Step 2: anti-factor Xa assay
– ‘LMWH-calibrated’ anti-factor Xa assay
– can develop rivaroxaban (apixaban) – calibrated
assays
Dabigatran
(Pradaxa®)
Clinical Indications and
Doses
- atrial fibrillation (indefinite
duration)
- acute VTE treatment (3 to 6
months)
150 mg or 110
twice-daily
150 mg twicedaily†
Rivaroxaban
(Xarelto®)
20 mg once-daily
20 mg once-daily
(15 mg twice-daily
for initial 7-10 d)
Apixaban
(Eliquis®)
5 mg twicedaily†
5 mg twicedaily†
10 mg once-daily
- VTE prevention after hip or
knee replacement surgery (14 to
35 days)
Laboratory Measurement
of Anticoagulant Effect
110 mg or 220 mg
once-daily
aPTT or TT
dilute TT
(Hemoclot
assay)
2.5 mg twicedaily
PT
anti-factor
Xa assay
PT
anti-factor
Xa assay
General Management
1. Stop offending drug + general supportive
measures
2. Baseline tests: CBC, aPTT, INR, TCT, creat
3. Investigate and treat bleeding: ulcer
electrocautery, polyp clipping, embolization,
etc.
4. Antidote
- vitamin K for VKAs
- others for new anticoagulants in
development
General Management
5. Transfuse pRBCs as required
- dilutional coagulopathy after 8 units pRBCs
- consider cryoprecipitate (especially if low fibrinogen)
6. Use non-specific “blood thickeners” ???
- DDAVP
- Amicar/Tranexamic acid
- platelet transfusion
7. Consider dialysis to remove drug (dabigatran)
8. By the time all this is done…most drugs will
have been cleared
Crowther M, et al. Blood 2008
Prothrombin complex concentrates
Contain all vitamin K-dependent coagulation factors
Non-activated:
– ‘4-factor-concentrates’ contain Factors II, VII, IX, and X
(e.g. Beriplex, Octaplex, Proplex T, Cofact)
– ‘3-factor-concentrates’ contain lower amounts of Factor VII
(e.g. Prothrombinex-HT, Profilnine and BEBULIN)
Activated:
– FEIBA VH contains Factors II, IX, X and protein C mainly
in non-activated forms and Factor VII mainly in the activated
form
Van Ryn J et al. Thromb Hemost 2010;103:1116–27
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Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph
The content of this slide may contain information not reviewed by Health Canada
Apr 2012
Studies evaluating reversal with new oral
anticoagulants
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Adsorbs and
neutralizes,
in vitro data1
Adsorbs and
neutralizes
Adsorbs and
neutralizes,
in vivo data10
No data
Haemodialysis
Human volunteers,
case report2
Not possible
Not possible
No data
Fresh frozen plasma
Mouse ICH3 model
No data
No data
No data
Activated FVIIa
Mouse3, rat4 model
Baboon8, rabbit
trauma9 models
3-factor PCC
No data
No data
4-factor PCC
Mouse3, rat4, rabbit
trauma5 model,
human volunteers6
Oral activated charcoal
Rabbit
Rat12 model
trauma11 model
No data
No data
Rat7, baboon8,
Rabbit
12 model
rabbit trauma9,
11 model Rat
trauma
human volunteers6
ICH = intracranial haemorrhage; OAC = oral anticoagulant; PCC = prothrombin complex concentrate
1. van Ryn J et al. Blood (ASH Annual Meeting Abstracts) 2009;114;Abs 1065; 2. Warkentin TE et al. Blood 2012;119:2172–4;
3. Zhou W et al. Stroke 2011;42:3594–9; 4. van Ryn J et al. Blood (ASH Annual Meeting Abstracts) 2011;118:Abs 2316; 5. van Ryn J
et al. Pathophysiol Haemost Thromb 2010;37:A94–P486; 6. Eerenberg ES et al. Circulation 2011;124:1573–9; 7. Perzborn A et al. J
Thromb Haemost 2009;7(suppl 2):Abs PP-MO-183; 8. Gruber A et al. Haematologica 2009;94(suppl 2):181 Abs 0449; 9. Godier A et
al. Anesthesiology 2012;116:94–102. 10. Wang X et al. Clin Pharmacol Ther 2012;91(suppl 1):Abs PI-90; 11. Martin A-C et al. ACC
2012; 24-27 March, Chicago, IL, USA: Abs 904-8; 12. Fukuda T et al. Thromb Haemost 2012;107:253–9
•
•
Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph
The content of this slide may contain information not reviewed by Health Canada
26
Apr 2012
Administer antidote…?
• There are no “antidotes” for dabigatran or
rivaroxaban (apixaban)
• Hemodialysis (…and patience!) are the only
methods to remove dabigatran
• Hemodialysis does NOT work for rivaroxaban
(apixaban) since these are highly proteinbound (…can’t dialyse out)
• No blood product (FFP, PCC) has been
shown to reverse the anticoagulant effect of
the new agents in bleeding patients
27
Agent
4-Factor Prothrombinase
Dabigatran
Rivaroxaban or Apixabanb
Possibly beneficial
Probably beneficial
Probably beneficial
Probably beneficial
Possibly beneficial
Possibly beneficial
Fresh frozen plasma
Probably ineffective
Probably ineffective
Cryoprecipitate
Probably ineffective
Probably ineffective
3-Factor Prothrombinase
No available evidence
No available evidence
Antifibrinolytic agents
No available evidence.
No available evidence.
(Aminocaproic acid – Amicar;
Potentially harmful
Potentially harmful
Complex Concentrate (PCC;
Beriplex, Octaplex)
Activated 4-Factor
Prothrombinase Complex
Concentrate (FEIBA)
Recombinant activated Factor VII
(Novoseven, Niastase)
Complex Concentrate
Tranexamic acid – Cyklokapron)
Administer coagulation factor
replacement…?
• Replacement of clotting factors
– does NOT reverse effect of dabigatran or rivaroxaban
– existing drug will simply inhibit ADDED clotting
factors…BUT
– adding factor II (or X) may ‘overwhelm’ this inhibitory effect
• No agent has been shown to reverse the
anticoagulant effect of the new agents in bleeding
patients
– ? 4-factor PCC (contains: II, VII, IX, X) – Octaplex, Beriplex
– ? activated 4-factor PCC – Feiba
– ? recombinant (activated) factor VII – Novoseven
Reversal of dabigatran activity by coagulation
factor concentrates: van Ryn et al.
Prolonged bleeding time induced by dabigatran was rapidly reversed within
5 min of concentrate administration
Mean (standard error)
bleeding time, seconds
–
Effect maintained during study period (120 min)
Dabigatran etexilate 30 mg/kg
+ Beriplex 35 U/kg
+ Octaplex 40 U/kg
+ FEIBA 100 U/kg
+ NovoSeven 500 µg/kg
500
Bleeding time prolonged with
dabigatran (vs control)
400
300
200
Control
Effect of dabigatran reversed by
concentrate administration
0
5
15
30
120
Time post concentrate addition (min)
n=4
van Ryn J et al. Blood (ASH Annual Meeting Abstracts) 2011;118:Abs 2316
•
•
Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph
The content of this slide may contain information not reviewed by Health Canada
31
Apr 2012
Reversal of rivaroxaban and dabigatran activity by
PCC in healthy subjects: Eerenberg et al.
Effects of a single dose of concentrate were assessed in a
randomized, double-blind, placebo-controlled, crossover trial
– Healthy male volunteers (n=12)
– Single dose of PCC (Cofact* 50 U/kg)
Rivaroxaban
20 mg BID
(n=6)
Rivaroxaban
20 mg BID
(n=6)
PCC or
PCC or
placebo
placebo
Dabigatran
150 mg BID
(n=6)
Dabigatran
150 mg BID
(n=6)
2.5 days
Washout period
(11 days)
2.5 days
Assessments were coagulation parameters only
*Non-activated PCC derived from human plasma containing a high concentration of the procoagulation Factors II,
VII, IX, and X, as well as the natural anticoagulants protein C and S and antithrombin
BID = twice daily; PCC = prothrombin complex concentrate
Eerenberg ES et al. Circulation 2011;124:1573–9
•
•
Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph
The content of this slide may contain information not reviewed by Health Canada
32
Apr 2012
Reversal of rivaroxaban and dabigatran activity by
PCC in healthy subjects: Eerenberg et al.
Rivaroxaban significantly prolonged PT and significantly decreased ETP
Effects were normalized by subsequent PCC infusion
Effect of
rivaroxaban
Effect of
rivaroxaban
Effect of subsequent PCC or
placebo infusion
18
200
Placebo
PCC
Placebo
PCC
150
ETP (%)
PT (seconds)
16
Effect of subsequent PCC or
placebo infusion
14
100
12
50
10
0
1h
Time
2h
4h
6h
24 h
0
1h
2h
4h
6h
24 h
Time
Data are mean ± standard deviation
ETP = endogenous thrombin potential; PCC = prothrombin complex concentrate; PT = prothrombin time
Eerenberg ES et al. Circulation 2011;124:1573–9
•
•
Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph
The content of this slide may contain information not reviewed by Health Canada
33
Apr 2012
Reversal of rivaroxaban and dabigatran activity by
PCC in healthy subjects: Eerenberg et al.
Dabigatran significantly prolonged aPTT, TT, and ECT
Effects not reversed by subsequent infusion of PCC
Effect of
dabigatran
Effect of
dabigatran
Effect of subsequent
PCC or placebo infusion
100
>120
150
60
40
20
ECT (seconds)
TT (seconds)
aPTT (seconds)
Effect of subsequent
PCC or placebo infusion
100
80
0
Effect of
dabigatran
Effect of subsequent
PCC or placebo infusion
80
60
40
100
50
20
1h
Time
2h
4h
6h
24 h
0
1h
Time
2h
4h
6h
24 h
0
1h
2h
4h
6h
24 h
Time
Data are mean ± standard deviation
aPTT = activated partial thromboplastin time; ECT = ecarin clotting time; PCC = prothrombin complex concentrate;
TT = thrombin time
Eerenberg ES et al. Circulation 2011;124:1573–9
•
•
Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph
The content of this slide may contain information not reviewed by Health Canada
34
Apr 2012
Reversing the effects of dabigatran by coagulation
factor concentrates: summary
There is some experimental evidence to support the role of coagulation
factor concentrates in reversing the anticoagulant effect of dabigatran
However, limited clinical evidence is available
–
Guidance regarding reversal of dabigatran activity (e.g. in cases of overdose or major
bleeding) highlights that the usefulness of CFCs in clinical settings has not yet been
demonstrated
Patient with bleeding on dabigatran therapy
Mild bleeding
Delay next dose or
discontinue treatment as
appropriate
Moderate to severe bleeding
•
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•
•
Symptomatic treatment
Mechanical compression
Surgical intervention
Fluid replacement and haemodynamic support
Blood product transfusion
Oral charcoal application*
Life-threatening bleeding
• Consideration of rFVlla or
PCC*
• Charcoal filtration*
(if dabigatran etexilate ingested <2 hrs before)
• Haemodialysis
*Recommendation based only on limited non-clinical data; there is no experience in volunteers or patients
CFCs = coagulation factor concentrates; PCC = prothrombin complex concentrate;
van Ryn J et al. Thromb Haemost 2010;103:1116-1127.
rFVIIa = recombinant activated Factor VIIa
•
•
Boehringer-Ingelheim (Canada) Ltd cannot recommend the use of any product outside the Canadian approved Product Monograph
The content of this slide may contain information not reviewed by Health Canada
35
Apr 2012
Reversal of rivaroxaban activity by coagulation
factor concentrates: Perzborn et al.
Bleeding time (seconds)
Rivaroxaban significantly increased bleeding time vs baseline
PCC reversed rivaroxaban-induced bleeding (dose-dependent)
Baseline
After treatment
1400
1200
1000
*
*
U/kg
800
600
400
200
0
Rivaroxaban
2 mg/kg
+ vehicle
Rivaroxaban
2 mg/kg
+ PCC 25 U/kg
Rivaroxaban
2 mg/kg
+ PCC 50 U/kg
*P<0.01 vs baseline
PCC = prothrombin complex concentrate; PT = prothrombin time
Perzborn E et al. ISTH XXII Congress, July 11–16 2009, Boston, MA, USA: PP-MO-183
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Apr 2012
Take-home Messages
•
New OACs use increasing but warfarin will
remain
–
–
warfarin in users with good results and INR
monitoring
patients with impaired renal function
…more Take-home Messages
•
Laboratory monitoring
–
–
•
rivaroxaban/apixaban: PT (screen), anti-Xa
(quantitative)
dabigatran: aPTT (screen), TT (more sensitive)
Bleeding in patients receiving new OACs
–
–
–
–
–
supportive care (fluids, pRBCs) is most relevant
FFP and PCC do NOT eliminate anticoagulant effect
no full antidotes yet BUT short drug half-lives
HD for dabigatran but NOT rivaroxaban/apixaban
Fab for Dabigitran
Case Scenario
•
•
•
•
•
•
•
•
82 year old female
Rivaroxaban 20 mg QD
Started 3 mos ago for AF, CHADs 2
Syncope, melena this am
No liver disease
BP 90/60; HR 115
OB +ve; BUN 16; Hgb 95 (145)
GI: Stabilize first
Q and A…