Reversal of DOACs Breakthroughs and Their Aftermath

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)


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.


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


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


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).


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]


Thrombotic Events or Death 30 Days


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


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


Rivaroxaban


Apixaban



[email protected]

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)


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


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


Documents

Reversal of DOACs Breakthroughs and Their Aftermath