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Reversal of DOACs
Breakthroughs and Their Aftermath
Geno J Merli, MD, MACP, FSVM, FHM
Professor Medicine & Surgery
Co-Director Jefferson Vascular Center
Sidney Kimmel Medical College
Thomas Jefferson University Hospitals
Disclosure
Financial Relationships Geno J. Merli, MD, MACP, FHM, FSVM
• Jannsen: Research (Medically ill)
• Bristol-Meyer Squibb: Research ADIOS Study
• Portola: Research
• LoweRisk LLC, Co-Chief Development Officer
Reversal of DOACs Breakthroughs and Aftermath
1. Has the emergence of reversal agents for DOACs
impacted on prescribing behavior or improved
clinical outcomes?
2. What education needs to be disseminated about
reversal agents and how should that be done
effectively?
3. How should reversal strategies be used
appropriately and what can the ACC do to
encourage appropriate use?
4. What is the expectation of availability for emerging
reversal agents for DOACs? At minimum, should all
stroke and trauma centers be required to carry all
reversal agents?
Assess Patient
Anticoagulant LABs Imaging Consultation
Drug Class
Indication
Last Dose
½ Life
Clearance
CBC
PTT/PT
SCr
LFTs
Thrombin Time
As Indicated
By H&P
As Indicated
By H&P
History & Physical
Target Specific Anticoagulants
Key Points Rivaroxaban Apixaban Edoxaban Dabigatran
Target Factor Xa Factor Xa Factor Xa Factor IIa
T ½ 7-11 hrs 12 hrs 6-11 hrs
single doses
9-10 hrs
multiple
doses
12-17 hrs
Clearance 30% Renal
60% Liver
25% Renal
75% Liver
33% Renal
60% Liver
80% Renal
Metabolism
CYP 450
CYP3A4
CYP2J2
CYP3A4 No No
P-GP Yes Yes Yes Yes
Dialysis removes 60% Dabigatran
Intervention
Warfarin IIa Inhibitor
DOAC
Xa Inhibitor
DOAC
Vit K + 4 PCC
Vit K + 3 PCC
FFP
rF VIIa
Vit K + 4 PCC
Vit K + 3 PCC Idarucizumab
Goals of Intervention
1. Fluid Resuscitation
2. Provide Rescue Clotting Factors
3. Increase Production of Normal Clotting Factors
4. Provide Anticoagulant Reversing Factor
Andexanet
Andexanet
Idarucizmab
Reversal Agents Target Mechanism
Ruff C et al Circ 2016;134:248
Ciraparantag (PER977)
Ruff C et al Circ 2016;134:248
DOAC Reversing Agents
Key Points Idarucizumab Andexanet
Chemical structure Human Monoclonal
Antibody fragment
Recombinant truncated
human Factor Xa
variant (decoy)
Onset < 5 min 2 min
Half-Life Initial 47 minutes
Terminal 10.3 hrs
Terminal 6hrs
Elimination Kidney Not reported
Binding Non-competitive
binding to dabigatran
Competitive binding to
direct Factor Xa
inhibitors or to indirect
Factor Xa inhibitors-
activated AT III
Target Affinity 350 greater affinity for
dabigatran than IIa
Affinity for Direct FXa
inhibitors similar to
that of native FXa
Storage Refrigerate Refrigerate
Pollack C, et al N Engl J Med 2015;373:511
51 Patients Serious Bleeding 39 Patients Urgent Surgery
Conclusion:
Idarucizumab completely reversed the anticoagulant effect of
Dabigatran within minutes.
Idarucizumab Major Bleeding Criteria
Group A
Overt, uncontrollable, or life-threatening bleeding that
was judged by the treating clinician to require a
reversal agent.
Group B
who required surgery or other invasive procedures
that could not be delayed for at least 8 hours and for
which normal hemostasis was required.
Pollack C, et al N Engl J Med 2015;373:511
Idarucizumab Dosing Schedule
1. Prior to administration, flush preexisting IV line with sodium
chloride 0.9%.
2. Administer dose undiluted as an IV bolus either via syringe or
as an infusion by hanging the vials. Infusion of each vial
should take no longer than 5 to 10 minutes with the second
vial of 2.5 g administered no later than 15 minutes after the
end of the first 2.5 g vial.
3. Do not administer any other infusion in the same IV line.
4. Baseline aPTT (at presentation), repeat at 2 hours
postexposure (if exposure time is known) or post-presentation
(if exposure time is unknown) and every 12 hours thereafter
until aPTT returns to normal. 2.5 gm/50 mL (50 mL): $2100.00
Pollack C, et al N Engl J Med 2015;373:511
Thrombotic Events or Death 30 Days Idarucizumab
5 Patients DVT/PE
2 days post Rxment: DVT/PE
9 days post Rxment: DVT/PE/Left Atrial thrombus
7 days post Rxment: DVT
13 days post Rxment: NSTEMI
26 days post Rxment: Stroke
Pollack C, et al N Engl J Med 2015;373:511
Connolly S, et al N Engl J Med 2016;375:1131
67 patients acute major bleeding within 18 hours after the administration
of a factor Xa inhibitor.
Conclusion:
andexanet substantially reduced anti–factor Xa activity in patients with
acute major bleeding associated with factor Xa inhibitors, with effective
hemostasis occurring in 79%.
Andexanet Major Bleeding Criteria
1. Potentially life-threatening
2. Acute overt bleeding with signs or symptoms of hemodynamic
compromise (e.g., severe hypotension hypotension, poor skin
perfusion, mental confusion, or low cardiac output that could
not otherwise be explained)
3. Acute overt bleeding associated with a decrease in
hemoglobin of at least 2 g or a hemoglobin level of 8 g or less
if no baseline hemoglobin level was available
4. Acute symptomatic bleeding in a critical area or organ (e.g.,
retroperitoneal, intraarticular, pericardial, intracranial, or
intramuscular with the compartment syndrome).
Connolly S, et al N Engl J Med 2016;375:1131
Andexanet Dosing Schedule
Apixaban or Rivaroxaban > 7 hours before Rxment
Bolus dose: 400 mg [15-30 min]
Infusion dose: 480 mg [over 2 hrs]
Enoxaparin, Edoxaban, or Rivaroxaban < 7 hours or
less before Rxment or an Unknown time.
Bolus dose: 800 mg [15-30 min]
Infusion dose: 960 mg [over 2 hrs]
Connolly S, et al N Engl J Med 2016;375:1131
Thrombotic Events or Death 30 Days
Connolly S, et al N Engl J Med 2016;375:1131
Thrombotic Event 18% (12/67)
1 Myocardial Infarction
5 Strokes
7 DVTs
1 PE
Some patient more than 1 event
4 Thrombotic Event within 3 days
8 Thrombotic Events within 4-30 days
Team Alert
Patient Eval
Labs
Imaging
Define
Major Bleeding
Reversal Agent
Post Reversal
Management
Approach to Bleeding
Ruff C et al Circ 2016;134:248
Serious Bleeding
Urgent Surgery or Procedure
Bleeding
Anticoagulation
ICH GI/GU Emergent
Surgery
Emergent
Procedure Trauma
Assess Patient
Anticoagulant LABs Imaging Consultation
Intervention
Warfarin IIa Inhibitor
DOAC
Xa Inhibitor
DOAC
Connolly S, et al N Engl J Med 2016;375:1131
Rivaroxaban
Connolly S, et al N Engl J Med 2016;375:1131
Apixaban
Connolly S, et al N Engl J Med 2016;375:1131
Connolly S, et al N Engl J Med 2016;375:1131
Geno.Merli@Jefferson.edu
DEVELOPMENT
• Monoclonal antibody then humanized and
directly expressed as a Fab fragment in hamster
cells
PROPERTIES
• Potent binding affinity ~350 times higher than
binding of dabigatran to thrombin
• No procoagulant or anticoagulant effects
expected
• Short half life
• Intravenous administration, immediate onset of
action
EXPECTED LOW RISK OF ADVERSE REACTIONS
• No Fc receptor binding
• No endogenous targets
Idarucizumab
Fully humanized
antibody fragment (Fab)
Glund S et al. AHA 2013. Abstr 17765; Schiele F et al. Blood 2013;121:3554–62
Idarucizumab Healthy Volunteers
Glund S et al. AHA 2013. Abstr 17765
Dabigatran plus:
Placebo (n=9)
2 g idarucizumab (day 4) (n=9)
4 g idarucizumab (day 4) (n=8)
Normal upper reference limit (n=86)
Mean baseline (n=86)
End of idarucizumab injection (5-min infusion)
Dabigatran + placebo
–2
Time after end of infusion (hours)
dT
T (
s)
Dabigatran Antidote
70
65
60
55
50
45
40
35
30
0 2 4 6 8 10 12 24 36 48 72 60
Pollack C, et al NEJM 2015
51 Serious Bleeding 51 Serious Bleeding
Dilute Thrombin Time Ecrin Clotting Time
Two 2.5 Gram IV, 15 mins apart
S S
Andexanet Alfa Recombinant Modified Version Human FXa
Acts as a FXa decoy and retains high affinity for all FXa inhibitors
GLA
S419
A419
GLA domain removed to prevent
anticoagulant effect
N-terminal residues retained
to reduce immunogenicity
Catalytic Domain Activity eliminated to prevent
thrombin generation
FXa Inhibitor High affinity retained
Ansell J. Nat Med. 2013;19(4)402.
Andexanet Alfa: Apixaban Phase II
• Apixaban 5mg bid x 6 d prior to
andexanet/placebo bolus
• 420mg bolus + 4mg/min
infusion over 2 hours:
– > 90 % reversal at 2 minutes
– > 90 % reversal at 2 hours
– Highly statistically significant
• Reversal sustained throughout
antidote infusion
– Anti-FXa activity returns to
normal decay curve after
termination of infusion
• Well tolerated; no thrombotic
events or serious adverse
events reported
• No antibodies to FXa or FX
detected
• Similar activity against
rivaroxaban and enoxaparin
Crowther MA, et al. J Thromb Haemost. 2013;11:AS20.
Anti-FXa Activity
420mg bolus only (n=6)
Placebo (Cohorts 1-3, n=9)
420mg bolus + 480mg
infusion (n=6)
End of Bolus End of Infusion
An
ti-F
Xa (
ng
/mL
)
0
50
100
150
200
250
Time after bolus in hours
0.0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10
Rivaroxaban 20mg qd x 6 d prior
to andexanet/placebo
800mg bolus + 8mg/min infusion
over 2 hours: - > 90% reversal at 2 minutes
- > 90 % reversal at 2 hours
- Highly statistically significant
Reversal sustained throughout
antidote infusion - Anti-FXa activity returns to
normal decay curve after
termination of infusion
Well tolerated; no thrombotic
events or serious adverse events
reported
No antibodies to FXa or FX
detected
Crowther MA, et al. Blood. 2013;122:A3636.
Andexanet Alfa: Rivaroxaban Phase II
Anti-FXa Activity
800mg bolus + 960mg
infusion (n=6)
Placebo (Cohorts 1-3, n=9)
End of Infusion End of Bolus
An
ti-F
Xa (
ng
/mL
)
0
100
200
300
400
Time after bolus in hours
0.0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10
Andexanet Alfa: Enoxaparin Phase II
Crowther MA, et al. J Thromb Haemost. 2014;12(suppl 1):7. 41
Hit clinical threshold for
enoxaparin reversal
(≤ 0.2 IU/ml)
Restoration of thrombin
generation within normal
range
Well tolerated; no
thrombotic events or
serious adverse events
reported
No antibodies to FXa or FX
detected
Anti-FXa Activity
End of Bolus
An
ti-F
Xa (
IU/m
L)
Time after bolus in hours AnXa vs. Placebo
*p<0.0001; **p<0.005
Placebo (Cohorts 1-3, n=9)
210mg bolus only (Cohort 1, n=6)
420mg bolus only (Cohort 2, n=6)
210mg (Lyo) bolus only (Cohort 3, n=6)
0.0
0.1
0.2
0.3
0.4
0.5
0.0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10
Lower limit of
detection
Thrombotic Events or Death 30 Days
Connolly S, et al N Engl J Med 2016;375:1131
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