New Oral Anticoagulants in
Peri-operative Medicine
Teresa L. Carman, MD
Director, Vascular Medicine
University Hospitals Case Medical Center
Associate Professor of Medicine
Case Western Reserve University School of Medicine
Objectives
• Review the new anticoagulants and
clinical indications
• Discuss the pharmacology of the drugs
• Review available surgical and trauma
guidelines for reversing and monitoring the
new anticoagulants
Historical Perspective
Lepirudin
Argatroban
Bivalirudin
Desirudin
1916
Heparin
1950s
1990s
Warfarin
LMWHs
Enoxaparin
Dalteparin
Tinzaparin
DTIs
Dabigatran
Rivaroxaban
Apixaban
2002
Indirect
Factor Xa
Inhibitors
Fondaparinux
2010
2012
Endoxaban
Betrixaban
Ideal Anticoagulant
•
•
•
•
•
•
•
•
Oral administration
Rapid and predictable anticoagulant effect
Broad therapeutic window
Efficacious with a low bleeding risk
No food-drug and drug-drug interactions
No need for laboratory monitoring
Easily reversible
Affordable (acceptable cost-benefit ratio)
Mechanisms of Anticoagulation
Intrinsic system
(surface contact)
Extrinsic system
(tissue damage)
XIIa
XII
Tissue factor
XIa
XI
IX
VIIa
IXa
VIII
Heparins
Vitamin K antagonists
Factor Xa inhibitors
VII
VIIIa
Xa
X
V
Va
II
IIa
IIa
(Thrombin)
Direct thrombin inhibitors
Fibrinogen
Fibrin
New Terminology
• DOAs – Direct oral anticoagulants
• NOAs – New oral anticoagulants
• TSOAs – Target specific oral
anticoagulants
TSAs
Emerging Therapies
• Pentasacchaide anti-Xa
– Idrabioptraparinux**
• Oral DTIs
–
–
–
–
–
Ximelagatran**
Dabigatran
AZD0837
SB-424323
TGN-167
• Oral direct Anti-Xa
–
–
–
–
–
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
Otamixaban
• FVIIa inhibitors
– rNAP-c2
– TFPI
TSOAs
Dabigatran
VTE prevention
RE-MODEL
RE-NOVATE
RE-MOBILIZE
RE-SOLVE
VTE treatment
RE-COVER
RE-MEDY
RE-SONATE
Rivaroxaban
RECORD 1
RECORD 2
RECORD 3
RECORD 4
MAGELLAN
EINSTEIN-DVT
EINSTEIN-PE
EINSTEIN-EXT
Stroke prevention in AF
RE-LY
ROCKET-AF
ARISTOTLE
AVERROES
ATLAS 2
APPRAISE 2
Prevention of secondary
events
in ACS
—
Apixaban
ADVANCE I
ADVANCE 2
ADVANCE 3
ADOPT
AMPLIFY
AMPLIFY-EXT
TSOA
• Phase III trials of new/emerging
anticoagulants demonstrate promise
– Ease of dosing
– Bioeffective
– Safe compared to conventional therapies
– Monitoring and dose adjustments are typically
not required
• Apply caution in renal insufficiency
Dabigatran
• Oral direct thrombin inhibitor (DTI)
• Rapidly converted from dabigatran
etexilate to dabigatran
• Binds clot-bound and free thrombin with
high affinity and specificity
• Predictable anticoagulant effect
• Low plasma protein binding
• No liver toxicity based on available clinical
data
Dabigatran
•
•
•
•
•
Onset is immediate with peak activity at 2-3 hrs
Plasma t ½ 12-17 hours
Excreted renally (80%); eliminated in bile
No significant food-drug
Few drug-drug interactions (amiodarone,
quinidine, verapamil – dose once daily)
• Bottled product has a 4-month shelf life once
opened
• Needs acidic environment for best absorption
Dabigatran
• Approved for NONVALVULAR AFIB
– Fixed dose CrCl>30 ml/min - 150 mg BID
• Once daily dosing with verapamil, quinidine, and amiodarone
• Dose adjustment or avoidance with other strong P-gp agents
– Caution with CrCl < 30 ml/min
– CrCl 15-30 ml/min - 75 mg BID
• FDA recommended based on pharmacology (no trial data)
• No monitoring is required
• NOT for use in patients with valves
• Approved in Europe and Canada for orthopedic
prophylaxis
Rivaroxaban
• Direct factor-Xa inhibitor
• Inhibits free factor-Xa as well as prothrombinase-bound
and clot bound factor-Xa
• Circulates primarily bound to albumin
• 80-100% oral bioavailability
• Peak activity at 2-4 hours
• T ½ - 7 to 11 hours
• Hepatic metabolism with renal and fecal excretion
• Avoid with CrCl <15 ml/min; caution when CrCl 1530ml/min
• No food and few drug interactions
Riveroxaban
• VTE prophylaxis in THA/TKA
– 10 mg daily (w/ or w/o food)
• Nonvalvular Afib
– 20 mg daily w/ evening meal
– 15 mg daily with CrCl 15-50 mg/ml w/ evening meal
• VTE dosing
– 15 mg BID x 21 days then 20 mg daily with food
• VTE extended prophylaxis
– 20 mg daily with food
• Approved in European Union for VTE prophylaxis after TKA/THA,
nonvalvular afib, and VTE
• Approved in Canada for VTE prophylaxis after TKA/THA
Apixaban
• Direct factor-Xa inhibitor
• Inhibits free factor Xa as well as clot bound
Xa and activated prothrombinase bound Xa
• Peak activity at 3 hours
• T ½ - 8 to 11 hours
• Non-renal metabolism with renal (25-30%)
and fecal (65%) excretion
• Reduce dosing with ketoconazole,
itraconazole, ritonair, clarithromycin
Apixaban Dosing
• Nonvalvular Afib
– 5 mg BID
– With 2 or more risk factors – dose 2.5 mg BID
• age >80
• Cr > 1.5
• wt < 60 kg
TSOAs



J Thromb Thrombolysis 2013;36:133-140.
New Anticoagulants
• Benefits
– Efficacy similar in to present therapy in many clinical settings
– Large trials support relative safety compared to VKA
– Wide therapeutic window
• Problems
–
–
–
–
Inability to accurately monitor the agents
NO antidotes
Short t ½ may leave patients unprotected with missed doses
No clear indication of patients that may benefit most from the
new therapies
– $$$
Special Clinical Situations
• Peri-procedural management
– Determining the need for bridging
• Acute reversal for surgery or bleeding
Pre-procedural Interruption
J Thromb Thrombolysis 2013;36:212-222.
Pre-procedural Interruption
Cleve Clin J Med 2013;80:443-451.
Bridging algorithm for vitamin K antagonists and new oral anticoagulants.
Gallego P et al. Circulation 2012;126:1573-1576
Copyright © American Heart Association
Pre-op Management
• If surgery cannot be delayed, there is an increased risk
of bleeding in patients receiving anticoagulants.
• Risk of bleeding should be weighed against the urgency
of intervention.
• Discontinue drugs minimum 1 to 2 days (CrCl ≥ 50
mL/min)
• Patients with the highest risk of bleeding hold for 2-4
days
– major surgery, spinal puncture, or placement of a spinal or
epidural catheter or port, in whom complete hemostasis may be
required
• CrCl< 50 mL/min hold 2 to 5 days before elective
invasive or surgical procedures
van Ryn et al. Thromb Haemost 2010;103:1116-1127.
Need for Bridging
Estimated that >250,000 patients interrupt AC annually for procedures
>10% risk
5-10% risk
< 5% risk
Bridging Therapy
•
Bridging -- transitioning warfarin to a short-acting
anticoagulant for a temporary interruption of
anticoagulation, especially for surgery or a potential
invasive procedure (colonic polyp removal).
•
Pro
– avoid thromboembolism
– avoid prolonged hospitalization
•
Con
–
–
–
–
–
May increase bleeding complications
Creates miscommunications, logistical nightmares
Prolongs the hospital stay in some cases
Lack of evidence (no RCTs)
Published reports are cohort studies, without tight protocols
Periprocedural Heparin Bridging in Patients Receiving
Vitamin K Antagonists
Systematic Review and Meta-Analysis of Bleeding and
Thromboembolic Rates
Circulation 2012; 126:1630
Vitamin K antagonist–treated patients receiving periprocedural heparin
bridging appear to be at increased risk of overall (OR 5.4) and major
bleeding (OR 3.6)
and at similar risk of thromboembolic events compared to nonbridged
patients (0.9% vs. 0.6%).
Bridging Decisions
•
•
•
•
•
Does AC need interrupted?
Is bridging required (risk assessment)?
“Bridge in”– Preop strategy
“Bridge out”– Postop strategy
Anticoagulation Intensity
– (risk/bleeding assessment)
“full” or “therapeutic”
(e.g., Enoxaparin 1 mg/kg BID or UFH gtt)
“prophylactic”
(e.g., Enoxaparin 40 mg/day or SQ UFH)
Bridging Protocol
Arch Cardiovasc Dis 2011;104:669-676.
Basic Recommendations
1. “Bridging” is becoming more selective
because of the high bleeding risks,
logistical problems, and communication
mishaps.
2. The higher the risk the tighter the
management.
3. Don’t forget about the option of
“bridging-in” with LMWH (OP) or IV UFH
in-hospital when necessary.
4. “Bridging-out” may be unnecessary in
many patients.
Regional Anesthesia
Anesthesiology 2013;118:1466-1474.
Why Monitor?
Monitoring
• Requires understanding of the available
coagulation tests
• Should not be done “routinely” but limited
to clinical situations a specific goal in mind
– Urgent pre-op assessment
– Active bleeding assessment
• Presently – do not quantitatively assess
the degree of anticoagulation but can
make a qualitative assessment
Cautions - Monitoring
•
Do not have reliable
laboratory monitoring
– 150 mg BID dose
• Peak - 184 ng/ml
• Trough - 90 ng/ml
– PT is insensitive to
dabigatran
• INR rarely exceeds 1.2
– aPTT is more sensitive with
less variability
– Very high dabigatran levels
are underestimated by
aPTT values
van Ryn et al. Thromb Haemost 2010;103:1116-1127.
Cautions - Monitoring
PT/INR and aPTT are variable based on the coagulometer and the reagent
Thromb Haemost 2010;105 (epub)
Cautions - Monitoring
• For DTIs - ECT is the
best lab monitor – not
widely available/not
FDA approved
• Chromogenic antifactor II – FDA
approved but not for
monitoring DTIs
• Thrombin time is too
sensitive
van Ryn et al. Thromb Haemost 2010;103:1116-1127.
Cautions - Monitoring
Limited data a best are available for rivaroxaban
and apixaban for monitoring or reversal
•
Rivaroxaban and Apixaban influences
prothrombin time (PT) > aPTT
Rivaroxaban and apixaban should be able to be
monitored by chromogenic Anti-Xa assays
•
Standards have not been set/reported
Monitoring Guidelines
J Thromb Thrombolysis 2013;36:187-194.
Dabigatran
Arch Cardiovasc Dis 2013;106:382-393.
Riveroxaban
Arch Cardiovasc Dis 2013;106:382-393.
Managing Bleeding
•
•
•
•
•
•
Hold the drug
Local hemostatic measures
Supportive PRBC/PLT transfusions
FFP unlikely to be useful
Initiate a hematology consult early
Institutional protocols are recommended*
Managing Bleeding
• Specific reversal agents (“antidotes”) not yet available
• Protamine sulfate and vitamin K should not be expected to affect the
anticoagulant activity
• With overdose – when given within 1-2 hours of ingestion activated
charcoal can adsorb dabigatran (in vitro data)
• Maintain adequate diuresis given renal elimination
• Dabigatran can be dialyzed with removal of about 60% of drug over
2-3 hrs.
• Rivaroxaban is not expected to be dialyzable (high plasma protein
binding).
• Consider transfusion of fresh frozen plasma, platelets or red blood
cells for supportive management
Reversal Agents
Effect of PCC infusion (vs placebo)
on the Protime after administration of
Rivaroxaban 20 mg BID x 2.5 days
Note: PCC infusion also reversed the effect of
rivaroxaban on new thrombin generation as
measured by the endogenous thrombin potential
Erenberg ES et al. Circ 2011:124:1573-9
Effect of PCC infusion (vs placebo) on the
Ecarin Clotting Time after administration
of Dabigatran 150 mg BID x 2.5 days
Note: PCC infusion did NOT reverse the
anticoagulant effect of dabigatran on aPTT
or Thrombin Time
Managing Bleeding
• Some evidence supports use of activated prothrombin complex
concentrates (FEIBA) for rivaroxaban, recombinant factor VIIa
(Novoseven) for dabigatran or concentrates of coagulation factors II,
IX, or X (PCC) but data are limited.
• 4-factor PCC recently approved in the US.
– Best data available for the DTIs
• Always concerns about the “potentially” prothrombotic state created
with bypassing agents.
• Xa recombinant reversing agent is under investigation. Phase II data
was encouraging
– Phase III in development
Conclusions
• Available anticoagulants successfully inhibit
thrombin formation and the interactions of
thrombin within the coagulation cascade
• There is no antidote yet available.
• Mechanisms to bypass the anticoagulant effect
are available.
• In the appropriate patient the half-life is typically
short. Withholding therapy may be sufficient
Conclusions
• Reversibility still need to be addressed
• Monitoring is problematic
– Common/familiar coagulation assays are
helpful but not the most accurate
• Be wary in high risk clinical settings
• Advise the use of Med-alert devices for
patients using the drugs
Ongoing Clinical Challenges
• No validated tests to measure anticoagulation
effect
• No established therapeutic range
• No true antidote for most agents
• Assessment of compliance more difficult than
with vitamin K antagonists
• Potential for unknown long-term adverse events
• Balancing cost against efficacy
• Lack of head-to-head studies comparing new
agents
Questions