Download An Update on Reversal Agents for NOACs: Where Are

An Update on Reversal Agents for
NOACs: Where Are We Now?
Moderator
Christian T. Ruff, MD, MPH
Assistant Professor of Medicine
TIMI Study Group
Brigham and Women's Hospital
Harvard Medical School
Boston, Massachusetts
Panelists
Joshua N. Goldstein, MD, PhD
Arash Afshinnik, MD
Associate Professor of Surgery
Harvard Medical School
Director
Center for Neurologic Emergencies
Massachusetts General Hospital
Boston, Massachusetts
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
This program will include discussion of
investigational drugs not approved by the
FDA for use in the United States.
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
Ruff CT, et al. Lancet. 2014;383:955-962.
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
X
• Due to short half-lives of NOACs, temporarily stopping
them may be all that is required
Rivaroxaban[a]
Apixaban[b]
Dabigatran[c]
Edoxaban[d]
Half-life, h
5-9
~12
12-17
10-14
Renal clearance, %
33*
27
80
50
Characteristic
*33% renally cleared; 33% excreted unchanged in urine.
a. Xarelto® PI 2016; b. Eliquis® PI 2015; c. Pradaxa® PI 2015; d. Savaysa™ PI 2015.
Coagulation Cascade
XII
XIIa
XI
Warfarin
XIa
IX
IXa
VIIa
VIIIa
Apixaban
Edoxaban
Rivaroxaban
X
Warfarin
VII
TF
Xa
X
Va
Warfarin
Prothrombin II
Thrombin IIa
Fibrinogen I
Makaryus JN, et al. Nat Rev Cardiol. 2013;10:397-409.
Fibrin Ia
Dabigatran
Clot
Is Testing Helpful?
• Dabigatran
– 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
Cuker A, et al. J Am Coll Cardiol. 2014;64:1128-1139.
Reversal Agents
Idarucizumab
Humanized Fab
fragment
Andexanet alfa
Recombinant factor Xa
variant
Ciraparantag
Synthetic small
molecule
Dabigatran
Factor Xa inhibitors
UFH, LMWH, NOACs
(not warfarin)
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
None
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)
FDA-Approved
10/16/2015
Not yet approved
Not yet approved
Structure
Target
Mechanism
Status
*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.
REVERSE-AD: Trial Design
Group A (n = 298)
Patients taking
dabigatran with
uncontrolled
bleeding
5 g idarucizumab
(2 ×2.5 g IV)
Group B (n = 196)
Patients taking
dabigatran requiring
emergency surgery
Hospital
arrival
0-15 min
Pre-1st vial
Pre-2nd vial
90 days follow-up
1 h 2 h 4 h 12 h
24 h
30 d
90 d
Primary endpoint: Maximum reversal within 4 h
based on dTT, ECT
Pollack CV, et al. Thromb Haemost. 2015;114:198-205.
Blood
samples
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
Pollack CV. ESC 2016.
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
Connolly SJ, et al. N Engl J Med. 2016;375:1131-1141.
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)
– Death = 15%
Connolly SJ, et al. N Engl J Med. 2016;375:1131-1141.
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
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.
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
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
a. Hsu JC, et al. JAMA Cardiol. 2016;1:55-62.
b. Praxbind (idarucizumab) website.
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