1. An Update on Reversal Agents for NOACs: Where Are We Now?
NOAC = non-vitamin K antagonist oral anticoagulant
Moderator
Christian T. Ruff, MD, MPH
Assistant Professor of Medicine
TIMI Study Group
Brigham and Women's Hospital
Harvard Medical School
Boston, Massachusetts

2. Joshua N. Goldstein, MD, PhD Arash Afshinnik, MD
Panelists
Joshua N. Goldstein, MD, PhD
Associate Professor of Surgery
Harvard Medical School
Director
Center for Neurologic Emergencies
Massachusetts General Hospital
Boston, Massachusetts
Arash Afshinnik, MD
Director of Neurocritical Care
Assistant Clinical Professor
Department of Neurologic Surgery
Division of Neurology
University of California, San Francisco
Fresno, California
Carmelo Graffagnino, MD
Medical Director
Duke Comprehensive Stroke Center
Professor and Chief
Division of Vascular Neurology, Stroke and Neurocritical Care
Department of Neurology
Duke University Medical Center
Durham, North Carolina
Panelists Layout (Title slide layout)

3. This program will include discussion of investigational drugs not approved by the FDA for use in the United States.
FDA = US Food and Drug Administration

4. Overview
NOACs are at least as effective as warfarin in the prevention of stroke in patients with atrial fibrillation and in VTE treatment and prevention
Easier to administer
Safer with respect to bleeding, particularly serious bleeding
Overall, an approximate 50% reduction in fatal and life-threatening bleeding (particularly ICH) events across trials
NOACs were developed without a reversal agent
Many eligible patients are still not receiving NOACs partially because of perceived fear of bleeding, lack of antidote
ICH = intracranial hemorrhage 
VTE = venous thromboembolism
Ruff CT, et al. Lancet. 2014;383:

5. X Better to Prevent Than Treat
Most bleeding events can be effectively managed with supportive care and are not associated with any bad long-term outcomes
Serious bleeding is a lot less common with NOACs
Avoid concomitant use of antiplatelet agents, NSAIDs
Monitor renal function and dose appropriately
Due to short half-lives of NOACs, temporarily stopping them may be all that is required X
Also available at
NSAID = nonsteroidal anti-inflammatory drug
Characteristic
Rivaroxaban[a]
Apixaban[b]
Dabigatran[c]
Edoxaban[d]
Half-life, h
5-9
~12
12-17
10-14
Renal clearance, %
33* 27 80 50
*33% renally cleared; 33% excreted unchanged in urine.
a. Xarelto® PI 2016; b. Eliquis® PI 2015; c. Pradaxa® PI 2015; d. Savaysa™ PI 2015.

6. Coagulation Cascade Warfarin Apixaban Edoxaban Rivaroxaban Dabigatran
Clot
XII
XIIa XI
XIa IX
IXa
VIIa
VII Xa X
VIIIa TF Va
Prothrombin II
Thrombin IIa
Fibrinogen I
Fibrin Ia
Warfarin
Apixaban
Edoxaban
Rivaroxaban
No permissions budget.
Dabigatran
Makaryus JN, et al. Nat Rev Cardiol. 2013;10:

7. Is Testing Helpful? Dabigatran Factor Xa inhibitors
APTT, dilute TT, ECA, ECT can determine if drug levels are present
Normal TT likely excludes relevant dabigatran level
Factor Xa inhibitors
Anti-Xa can detect drug levels
PT may detect if drug is present
APTT = activated partial thromboplastin time
ECA = ecarin chromogenic assay ECT = ecarin clotting time
PT = prothrombin time
TT = thrombin time
Cuker A, et al. J Am Coll Cardiol. 2014;64:

8. Reversal Agents Idarucizumab Andexanet alfa Ciraparantag Structure
Idarucizumab
Andexanet alfa
Ciraparantag
Structure
Humanized Fab fragment
Recombinant factor Xa variant
Synthetic small molecule
Target
Dabigatran
Factor Xa inhibitors
UFH, LMWH, NOACs (not warfarin)
Mechanism
Binds dabigatran with high affinity
Competes with factor Xa for inhibitor binding
Noncovalent hydrogen bond (exact mechanism unclear)
Reconstitution
None
Add 10 mL sterile water
Administration
2 × 2.5 g/50 mL IV bolus, may require repeat dose
400 mg IV bolus plus 2-hour infusion*
Single 100 mg IV dose (dose under investigation)
Status
FDA-Approved
10/16/2015
Not yet approved
IV = intravenous
LMWH = low-molecular-weight heparin
UFH = unfractionated heparin
*Dose being studied in ANNEXA-4; dosing will depend on which FXa inhibitor was taken, and when it was taken.
Hu TY, et al. Vasc Health Risk Manag. 2016;12:35-44.

9. REVERSE-AD: Trial Design
Group A (n = 298) Patients taking dabigatran with uncontrolled bleeding
0-15 min
90 days follow-up
Hospital arrival
5 g idarucizumab (2 ×2.5 g IV)
Pre-2nd vial
2 h
4 h
12 h
24 h
30 d
90 d
Pre-1st vial
1 h
Blood
samples
Group B (n = 196) Patients taking dabigatran requiring emergency surgery
dTT = diluted thrombin time
Primary endpoint: Maximum reversal within 4 h based on dTT, ECT
Pollack CV, et al. Thromb Haemost. 2015;114:

10. REVERSE-AD: Mortality
Patients had life-threatening conditions
Deaths:
Group A (bleeding, n = 298): 12.3% (30 days); 18.7% (90 days)
Group B (surgery, n = 196): 12.4% (30 days); 18.5% (90 days)
Idarucizumab
Given two 2.5 g loading doses, 15 minutes apart = 5 g total
Rapidly eliminates dabigatran from circulation
Allows the body to establish hemostasis
There were 18 deaths overall, with 9 in each study group; 10 deaths were due to vascular
causes, including 5 fatal bleeding events.
Pollack CV. ESC 2016.

11. ANNEXA-4: Andexanet Alfa
Recombinant modified human factor Xa decoy protein 
Multicenter, prospective, open-label, single-group study
N = 67 (interim analysis)
Patients with acute major bleeding ≤18 hours after the administration of a fXa inhibitor
Bolus of andexanet followed by a 2-hour infusion
Patients were evaluated for changes in measures of anti-fXa activity and clinical hemostatic efficacy during a 12-hour period
All the patients were followed for 30 days
fXa = factor Xa
Connolly SJ, et al. N Engl J Med. 2016;375:

12. ANNEXA-4: Mortality Interim Analysis Safety group, n = 67
All patients who received andexanet
Death = 15%
Patients with ICH: 6/28 died = 21%
Efficacy group, n = 47
Patients with baseline anti-fXa activity ≥ 75 ng/mL (or ≥ 0.5 IU/mL for enoxaparin)
Table 2 page 1136
The prespecified safety population included all the patients who received andexanet, and the efficacy population included only patients in
whom the baseline anti–factor Xa activity was later determined to be 75 ng per milliliter or more (or ≥0.5 IU per milliliter for those receiving enoxaparin) and the acute major bleeding
episode was later adjudicated to meet the study criteria.
Connolly SJ, et al. N Engl J Med. 2016;375:

13. The Bleeding Has Stopped -- What's Next?
Reversal agents rapidly and safely remove the anticoagulant from the body
When to restart anticoagulation is patient specific, but should be as early as possible due to high risk of thrombosis
Reversal agents are not associated with immune reactions
Reversal agents remove the anticoagulant rapidly without serious adverse events

14. Ciraparantag (PER977) Universal reversal agent
Synthetic molecule binds:
Direct Xa inhibitors (apixaban, rivaroxaban, and edoxaban)
Direct thrombin inhibitors (dabigatran)
UFH, LMWH
Hu TY, et al. Vasc Health Risk Manag. 2016;12:35-44.

15. Supply and Distribution
How will reversal agents be incorporated into protocols?
Where will the drugs be kept?
Emergency department?
Pharmacy?
Blood bank?
How are they stored?
Need for refrigeration?
Need for reconstitution?
Who gives approval for use?
Where are they needed?
ICU, ED
ED = emergency department
ICU = intensive care unit

16. Summary
Reversal agents will provide reassurance and hopefully improve use of anticoagulation in at-risk patients
NCDR PINNACLE Registry demonstrated that approximately half of eligible patients with AF do not receive anticoagulation[a]
Patients on NOACs are less likely to have serious bleeding events than patients on warfarin
Idarucizumab is available across the United States[b]
Approval of andexanet alfa for fXa inhibitors expected soon
Hospitals should be developing protocols to enable rapid and effective use of reversal agents
Find Praxbind. Accessed December 26, 2016.
a. Hsu JC, et al. JAMA Cardiol. 2016;1:55-62.
b. Praxbind (idarucizumab) website.

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