Reversal of DOACs Breakthroughs and Their Aftermath

39 Pages·2016·1.6 MB·English

by  Geno Merli

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
History & Physical
Anticoagulant LABs Imaging Consultation
 Drug Class  CBC As Indicated
As Indicated
 Indication  PTT/PT By H&P
By H&P
 Last Dose  SCr
 ½ Life  LFTs
 Clearance  Thrombin Time
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 12-17 hrs
single doses
9-10 hrs
multiple
doses
Clearance 30% Renal 25% Renal 33% Renal 80% Renal
60% Liver 60% Liver
75% Liver
Metabolism CYP3A4 CYP3A4 No No
CYP 450
CYP2J2
P-GP Yes Yes Yes Yes
Dialysis removes 60% Dabigatran
Intervention
IIa Inhibitor Xa Inhibitor
Warfarin
DOAC DOAC

Vit K + 4 PCC

Idarucizumab Vit K + 4 PCC

Vit K + 3 PCC

Vit K + 3 PCC

FFP
 Andexanet
rF VIIa
Goals of Intervention
1. Fluid Resuscitation
2. Provide Rescue Clotting Factors
3. Increase Production of Normal Clotting Factors
4. Provide Anticoagulant Reversing Factor
Reversal Agents Target Mechanism
Idarucizmab
Andexanet
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 Recombinant truncated
Antibody fragment human Factor Xa
variant (decoy)
Onset < 5 min 2 min
Half-Life Initial 47 minutes Terminal 6hrs
Terminal 10.3 hrs
Elimination Kidney Not reported
Binding Non-competitive Competitive binding to
binding to dabigatran direct Factor Xa
inhibitors or to indirect
Factor Xa inhibitors-
activated AT III
Target Affinity 350 greater affinity for Affinity for Direct FXa
dabigatran than IIa inhibitors similar to
that of native FXa
Storage Refrigerate Refrigerate
51 Patients Serious Bleeding 39 Patients Urgent Surgery
Conclusion:
Idarucizumab completely reversed the anticoagulant effect of
Dabigatran within minutes.
Pollack C, et al N Engl J Med 2015;373:511