We Now Moderator Christian T Ruff MD MPH Assistant Professor of Medicine TIMI Study Group Brigham and Womens Hospital Harvard Medical School Boston Massachusetts Arash Afshinnik MD ID: 558299
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Slide1
An Update on Reversal Agents for NOACs: Where Are We Now?
ModeratorChristian T. Ruff, MD, MPHAssistant Professor of MedicineTIMI Study GroupBrigham and Women's HospitalHarvard Medical SchoolBoston, MassachusettsSlide2
Arash Afshinnik, MDDirector of Neurocritical Care
Assistant Clinical ProfessorDepartment of Neurologic SurgeryDivision of Neurology University of California, San FranciscoFresno, California Joshua N. Goldstein, MD, PhDAssociate Professor of Surgery
Harvard Medical School
Director
Center
for Neurologic EmergenciesMassachusetts General HospitalBoston, Massachusetts
Carmelo Graffagnino, MD Medical DirectorDuke Comprehensive Stroke Center Professor and ChiefDivision of Vascular Neurology, Stroke and Neurocritical CareDepartment of Neurology Duke University Medical Center Durham, North Carolina
PanelistsSlide3
This program will include discussion of investigational drugs not
approved by the FDA for use in the United States. Slide4
OverviewNOACs are
at least as effective as warfarin in the prevention of stroke in patients with atrial fibrillation and in VTE treatment and preventionEasier to administerSafer with respect to bleeding, particularly serious bleedingOverall, an approximate 50% reduction in fatal and life-threatening bleeding (particularly ICH) events across trialsNOACs were developed without a reversal agentMany 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. Slide5
Characteristic
Rivaroxaban[a]
Apixaban
[b]
Dabigatran
[c]
Edoxaban[d]Half-life, h5-9
~12
12-17
10-14
Renal clearance, %
33*
27
80
50
a. Xarelto® PI 2016; b. Eliquis® PI 2015; c. Pradaxa® PI 2015; d. Savaysa™ PI 2015.
*33% renally cleared; 33% excreted unchanged in urine.
Most bleeding events can be effectively managed with supportive care and are not associated with any bad long-term outcomesSerious bleeding is a lot less common with NOACs Avoid concomitant use of antiplatelet agents, NSAIDs Monitor renal function and dose appropriatelyDue to short half-lives of NOACs, temporarily stopping them may be all that is required
X
Better to Prevent
Than
TreatSlide6
Coagulation Cascade
Makaryus JN, et al. Nat Rev Cardiol. 2013;10:397-409.
Clot
XII
XIIa
XI
XIa
IX
IXa
VIIa
VII
Xa
X
VIIIa
TF
Va
X
Prothrombin II
Thrombin IIa
Fibrinogen I
Fibrin Ia
Warfarin
Warfarin
Apixaban
Edoxaban
Rivaroxaban
Warfarin
DabigatranSlide7
Is Testing Helpful?Dabigatran
APTT, dilute TT, ECA, ECT can determine if drug levels are presentNormal TT likely excludes relevant dabigatran levelFactor Xa inhibitorsAnti-Xa can detect drug levelsPT may detect if drug is present Cuker A, et al. J Am Coll Cardiol. 2014;64:1128-1139.Slide8
Reversal Agents
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
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)
Status
FDA-Approved
10/16/2015
Not
yet approved
Not yet approved
Hu TY,
et al.
Vasc
Health Risk Manag.
2016;12:35-44.
*Dose being studied in ANNEXA-4; dosing will depend on which FXa inhibitor was taken, and when it was taken.Slide9
REVERSE-AD: Trial Design
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
Primary endpoint:
Maximum reversal within 4
h based on dTT
, ECT
Pollack CV, et al.
Thromb Haemost
.
2015;114:198-205.
Group A (n = 298)
Patients taking dabigatran with uncontrolled bleeding
Group B (n = 196)
Patients taking dabigatran requiring emergency surgerySlide10
REVERSE-AD: MortalityPatients 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) IdarucizumabGiven 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
.Slide11
ANNEXA-4: Andexanet Alfa
Recombinant modified human factor Xa decoy protein Multicenter, prospective, open-label, single-group studyN = 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. Slide12
Safety group, n = 67All patients
who received andexanet Death = 15%Patients with ICH: 6/28 died = 21%Efficacy group, n = 47Patients with baseline anti-fXa activity ≥ 75 ng/mL (or ≥ 0.5 IU/mL for enoxaparin)
Death = 15%
ANNEXA-4: Mortality
Interim Analysis
Connolly SJ, et
al. N Engl J Med. 2016;375:1131-1141. Slide13
The Bleeding Has Stopped -- What's Next?
Reversal agents rapidly and safely remove the anticoagulant from the bodyWhen 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 Slide14
Ciraparantag (PER977)Universal reversal
agentSynthetic molecule binds:Direct Xa inhibitors (apixaban, rivaroxaban, and edoxaban)Direct thrombin inhibitors (dabigatran)UFH, LMWHHu TY,
et al. Vasc
Health Risk Manag.
2016;12:35-44.Slide15
Supply and DistributionHow 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, EDSlide16
SummaryReversal 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 warfarinIdarucizumab is available across the United States[b]Approval of andexanet alfa for fXa inhibitors expected soonHospitals 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.Slide17
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