Download Update on novel anticoagulants

Stephanie M. Dentoni, MD,FSVM
California Vein & Vascular Institute
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Introduce Novel Anticoagulant
Review Practice Pharmacokinetics
Outline Indications with Respect to VTE
Warnings and Side Effects
Discuss Practical Usage
Clinical Pearls
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Heparin was first discovered in 1916 by Jay Mc Lean and
William Harry Howell
Use of heparin in clinical practice was 20 years later
Low molecular weight heparin was discovered in 1976 with
clinical trials starting in the early 1980’s
Sweet clover disease lead to the discovery of the first oral
anticoagulant: dicourmarol
Now, the turn of the century there are several oral
anticoagulants available for use
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Subcutaneous administration
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Long half-life
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Warfarin/food and drug interactions
Accumulation with renal insufficiency
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warfarin
Variable dosing
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Bleeding complications
Monitoring
Slow Onset
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Difficult to administer - subcutaneous
Limits long term use
LMWH
Heparin Induced Thrombocytopenia
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Specific target in the coagulation cascade
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Factor II
Factor X
Predictable dose response
Ease of administration
No monitoring required
Short half life
No significant food interactions
Less drug interactions
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
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Prodrug – dabigatran etexilate
Reversibly inhibits the active site of thrombin
Bioavailability of 6%
Peak plasma levels = 2 hours
Half-life 14 - 17 hours
Renal excretion
Concomitant use of quinidine is contraindicated due to
increasing plasma levels of dabigatran by reducing clearance
Reduced dose recommended with co-administration of
amiodarone and verapamil
Nonvalvular Atrial Fibrillation
 Prevention of venous thromboembolism
 Treatment of venous thromboembolism
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150mg po twice daily
110mg po twice daily for special populations
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Greater than 80 years old
Concomitant use of verapamil
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Oral
With or without food
Swallowed with water
Capsule should not be broken or opened
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Increased bioavailability
Increased risk of bleeding
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Can take dose up to 6 hours prior to next
scheduled dose
Do not double dose
Do not take missed dose within 6 hours of the
next dose
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aPTT is elevated
aTT is elevated
ECT is elevated
INR is abnormal
Cannot determine the amount of anticoagulant or the level
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TT and ECT may be useful for monitoring but studies are needed
5 days of LMWH
 Start dabigatran 0-2 hours prior
to next dose of LMWH
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CrCl less than 30
Clinically significant bleeding
Lesion or medical condition considered high risk
for bleeding
Concomitant administration with other
anticoagulants
Hepatic or liver impairment that will have an
impact on survival
Concomitant treatment with ketaconazole,
itraconizole, cyclosporin, dronedrone
Prosthetic heart valves
Pregnancy or breast feeding
Stop Warfarin
When INR falls below 2, start
dabigatran
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Direct Xa inhibitor
Oral bioavailability of 80%
Rapid onset with half-life of 7-11 hours
Elimination:
1/3 unchanged through renal excretion
 1/3 via the liver CYP3A4 dependent and independent pathways with
fecal excretion
 1/3 metabolized in the liver with inactive metabolites and excreted
through the kidneys
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Active, severe bleeding
Severe hypersensitivity reaction to
rivaroxaban
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Not approved for prosthetic heart valves
Combined P-gp and strong CYP3A4 inhibitors
and inducers significantly alter the
anticoagulant effect
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ketaconazole and ritonavir
Use with caution in pregnancy due to bleeding
risk
Avoid concomitant use of other anticoagulants
Nonvalvular atrial fibrillation
 Treatment of DVT or PE
Prevention of DVT or PE in hip and knee
replacement surgery patients
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10mg tablets – prophylactic dose
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With or without food
15mg tablets – treatment dose
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With food
20mg tablets – treatment dose
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With food
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LMWH is not needed initially
 15mg po BID for 3 weeks
then 20 mg po QD
for the proper length
of treatment
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Hip replacement
10 mg po qd for 35 days
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Knee replacement
10mg po qd for 12 days
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Discontinue warfarin and start rivaroxaban when the INR is
below 3.
No data on switching from rivaroxaban to warfarin
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Recommended: discontinue warfarin and start parenteral
anitcoagulation and warfarin at the next scheduled dose to avoid periods
of inadequate anticoagulation
Transitioning to another rapid onset anticoagulant, start at the
next scheduled dose
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Those taking 15mg twice daily
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Take the missed dose as soon as possible for a total of 30mg a day
May double the dose and take 30mg at once to achieve 30mg daily dose
Those taking 20mg once daily
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Take the next dose immediately and continue on a daily dose (every 24
hours)
Do not double dose
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PT is elevated and may be useful in monitoring
aPTT is prolonged
There is no reliable correlation between
elevation of these values and therapeutic effect
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No Antidote or reversal agent
Activated Charcoal to reduce absorption
Not expected to be dialyzable due to high
protein binding
Prothrombin Complex Concentrate (PCC) may
be considered in severe hemorrhage
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Factor Xa inhibitor
Peak plasma concentration 2-4 hours
Half life 5 – 6 hours and 12 hours with repeated
dosing
No active circulating metabolites
Excretion
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Renal – 27%
25% in urine, biliary and intestinal
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Severe hypersensitivity to Apixaban
Active, pathalogical bleeding
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Not recommended in hemodynamic instability with PE or
thrombolysis or embolectomy
Not recommended with prosthetic heart valves
Not to be used with neuroaxial anesthesia
Not to be used with strong inhibitors or inducers of CYP3A4 and
P-gp
Not to be used with other anticoagulants
Category B in pregnancy
In animal models, 12% of maternal dose is excreted during
lactation
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Nonvalvular Atrial Fibrillation
DVT and PE treatment
VTE prophylaxis in hip and knee replacement
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Postoperative prophylaxis
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Hip – 2.5mg po BID x 35 days
Knee – 2.5 mg po BID x 12 days
DVT/PE
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10mg po BID x 7 days then
5mg po BID
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Apixaban affects INR
If converting from apixaban to warfarin, start Heparin or LMWH
at next scheduled dose of apixaban and discontinue LMWH
when INR reaches the target range
Converting from warfarin to apixaban
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Start apixaban when the INR is less than 2.
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Take with or without food
May crush tablet
If missed dose, take immediately and then every 12 hours there
after
Do no double dose for missed doses
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Carbamazapine
Dexamethasone
Fosphenytoin
Phenytoin
Prothrombin Complex Concentrate
Rifabutin
Rifampin
St. John’s Wort
Warfarin
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Increases INR
Increases PT
Increase aPTT
Not reliable for monitoring
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No specific antidote or reversal agent
Bleeding effects last 24 hours
Due to high plasma protein binding, it is not expected to be
dialyzable
PCC or recombinant factor VIIa may be considered but no
evidence for efficacy
Activated charcoal reduces absorption
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Factor Xa inhibitor
Plasma availability 62%
Half life 10 -14 hours
Peak plasma concentration 1 - 2 hours
Excretion primarily unchanged in the urine
with a minority from the biliary and intestinal
system
Take with or without food
No data on the effect of crushing
Do not double dose if missed
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Active, prolonged bleeding
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Prosthetic heart valves
Neuroaxial anesthesia
Pregnancy Category C, discontinue with breast feeding
No medications are contraindicated
Avoid the use of rifampin (strong inducer of P-gp)
Avoid the use of concomitant anticoagulants, thrombolytics and
antiplatelet agents
Coadministration of P-gp inhibitors during treatment for VTE should
reduce dose to 30mg
Reduce dose in renal insufficiency
Not recommended in moderate to severe liver dysfunction/disease
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Nonvalvular atrial fibrillation
Treatment of DVT and PE
Parenteral anticoagulation for 5-10 days then
 Greater than 60kg: 60mg po QD
 Less than or equal to 60kg: 30 mg po QD
 Renal impairment with GFR 15-15ml/min: 30mg po QD
 Not recommended in moderate to severe liver disease
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Stop warfarin and start edoxaban when the INR is less than or
equal to 2.5
Other oral anticoagulants except warfarin, start at the next
scheduled dose
To parenteral anticoagulants, stop anticoagulant and start
edoxaban at the next scheduled dose
To warfarin: decrease dose of edoxaban by 50% and start
warfarin. Discontinue edoxaban when the INR is >2
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To warfarin: decrease to 30mg a day and start warfarin.
Discontinue edoxaban when INR is greater than 2 (if takeing
30mg then decrease to 15mg)
Discontinue edoxaban and start parenteral AC and warfarin at
the next scheduled dose
To another short acting agent: discontinue edoxaban and start
new agent at the next scheduled dose
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Dabigatran tablet/capsule cannot be altered – significantly
increases bioavailability
Dabigatran increases the TT and ECT
Rivaroxaban in doses of 15mg and 20mg must be taken with
food
Rivaroxaban can be used as monotherapy without initial use of
parenteral anticoagulation
PCC may be useful for bleeding complications with rivaroxaban
Apixaban is pregnancy category B
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Tablet may be crushed for administration with Apixaban
9 medications contraindicated with Apixaban
When transitioning edoxaban to warfarin, parenteral
anticoagulation may not be needed, may overlap a lower dose of
edoxaban with warfarin until the INR is in target range
Edoxaban is not approved for VTE prophylaxis in hip and knee
replacement surgical patients