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ORAL ANTICOAGULANTS IN THE 21ST CENTURY: A PRACTICAL GUIDE TO USING NEWER AGENTSKatherine Vogel Anderson, Pharm.D., BCACP
University of Florida Colleges of Pharmacy and Medicine
Case
BV is a 75 year old white male who has just been diagnosed with a. fib. His past medical history is significant for hypertension (taking chlorthalidone) and seasonal allergies.Which oral anticoagulant do you
recommend?A. ApixabanB. DabigatranC. RivaroxabanD. Warfarin
Objectives
Identify new oral anticoagulants (OACs) Determine the current place in therapy
for OACs Review appropriate transitions between
parenteral anticoagulants and OACs (and vice versa)
Highlight pharmacotherapy scenarios when changing between OACs
Identify OAC options peri-procedure
A History Lesson…
1930s heparin
1950s warfarin
1990sLMWH
2001 fondapari
nux
2010dabigatra
n
2011 rivaroxab
an
2012apixaban
FDA-Approved Doses
Apixaban Dabigatran Rivaroxaban
Warfarin
Mechanism Activated factor Xa inhibitor
Direct thrombin inhbitor
Activated factor Xa inhibitor
Vitamin K antagonist
Dose for stroke prevention secondary toa. fib
5mg twice daily
150mg twice daily
20mg once daily
Dosed to achieve an INR between 2 and 3
Renal dose adjustment
2.5mg twice daily
75mg twice daily
15mg once daily
Not requiredAlso approved for VTE treatment and prevention
If it isn’t broken, why fix it?
What’s wrong with warfarin? Monthly monitoring Drug interactions Takes lots of time…
New OACs • Don’t
require monitoring
• Fewer interactions
• Quicker onset of action
BUT new OACs…• Lack
antidotes• Require
renal adjustment
• Are expensive
A wise man once said…
“Inferiors revolt in order that they may be equal, and equals that they may be superior. Such is the state of mind, which creates revolutions.”
—Aristotle. In: Politics. Book V; Part II; 350 B.C.E.
anticoagulation
Nedeltchev K. Stroke 2012;43: 922-923
Back to our case…
Which oral anticoagulant do you recommend?
A. ApixabanB. DabigatranC. RivaroxabanD. Warfarin
Warfarin
Pharmacogenomic dosing?
Regardless – treat to an INR between 2 and 3 You JJ et al. Chest 2012;141(2)(Suppl): e531S-e575SCoumadin (warfarin) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2011 Oct.
Prodrug? Yes
Food? No effect
Drug interactions
P-gp substrate:Verapamil decrease dabigatran doseDronedarone decrease/don’t use
Renal adjustment
CrCL < 30ml/min 75mg twice dailyPros the oldest of the new
Cons GI intolerance; renal dose not prospectively studied
Heidbuchel H et al. Europace 2013;15: 625-651
Prodrug? No
Food? Mandatory
Drug interactions
P-gp AND CYP3A4 substrate:Amiodarone, diltiazem, verapamil – caution if CrCL is less than 50ml/minAVOID with strong inhibitors
Renal adjustment
CrCL 15 – 50ml/min 15mg once dailyPros once daily dosing; renal adjustments
Cons once daily dosing; food requirement
Heidbuchel H et al. Europace 2013;15: 625-651
Pros renal dose prospectively studiedCons twice daily dosing; newest of the new
Prodrug? No
Food? No effect
Drug interactions
CYP3A4 substrate:Reduce dose to 2.5mg/avoid with strong CYP3A4 and P-gp inhibitors
Renal adjustment
If SCr is greater than 1.5mg/dl, patient is greater than 80 years old, patient weighs less than 60Kg 2.5mg twice daily
Heidbuchel H et al. Europace 2013;15: 625-651
Some considerations
Although new OACs are substrates for P-gp and CYP, they are not inhibitors
PPI use does not have a clinical effect on efficacy
Bleeding risk increases with antiplatelet agents
Compliance is key effectiveness fades fast 12 – 24 hours after last dose = no anticoagulation
The decision is made...
… A new OAC will be prescribed for BV
So – what’s next?Do we really NOT monitor?What if BV has a procedure?What if BV wants to switch to
warfarin?
Patient anticoagulation cards: www.noacforaf.eu
PPI: No prospective evidence, but consider a PPI for high risk patients (i.e. history of GI bleed)
Follow up visits: Compliance S/Sx thromboembolism and/or bleeding Side effects Medication reconciliation Labs: 3, 6, 12 months and as neededHeidbuchel H et al. Europace 2013;15: 625-651
Coagulation Monitoring
Dabigatran Apixaban Rivaroxaban
Plasma peak (after ingestion)
2 hours 1 – 4 hours 2 – 4 hours
Plasma trough (after ingestion)
12 – 24 hours 12 – 24 hours 16 – 24 hours
PT N/A N/A Prolonged
INR Increase Increase Increase
aPTT >2xULN @ trough suggests risk
N/A N/A
Anti-Xa N/A No data YET Quantitative
ECT >3xULN @ trough suggests risk
N/A N/A
Heidbuchel H et al. Europace 2013;15: 625-651
Transitions in Therapy
To a new OAC… From heparin upon discontinuation (~2
hours) From low molecular weight heparin (LMWH)
when the next dose of LMWH is due From a new OAC…
To warfarin similar to “bridging” The new OAC is taken simultaneously with
warfarin until the INR is within the appropriate therapeutic range
To LMWH when the next dose of OAC is dueHeidbuchel H et al. Europace 2013;15: 625-651
Transitions in Therapy
From warfarin to a new OAC: As soon as the INR is less than 2 If INR is between 2 and 2.5 start the next
day For INR greater than 2.5 It depends
How high is the INR? Wait and hold Draw a new INR
If INR is less than 2.5, proceed as above
Heidbuchel H et al. Europace 2013;15: 625-651
Peri-procedural management of OAC
Evaluate Patient factors = age,
renal function, history of bleeding
AND Procedure factors
No bleeding risk Minor bleeding risk Major bleeding risk
When do you stop the new OAC?
No need to hold the OAC
Heidbuchel H et al. Europace 2013;15: 625-651
Peri-procedural management of OAC
Hold the OAC 24 hours prior
Hold the OAC 48 hours prior
Resume OAC 6 – 8 hours after the procedure IF immediate and complete hemostasis is achieved AND re-bleeding risk
is minimal.If invasive procedure, resumption of OAC may be deferred
for 48 - 72 hours Heidbuchel H et al. Europace 2013;15: 625-651
Two Clinical Questions
What about aspirin? Post-ACS:
ASA or clopidogrel + new OAC = increased bleeding
apixaban or rivaroxaban may be preferred Within the first year ASA + decreased OAC
dose After the first year OAC alone
What about valves? NOT for valvular atrial fibrillation NOT for mechanical valve replacement
Heidbuchel H et al. Europace 2013;15: 625-651
Back to our case…
Which oral anticoagulant do you recommend?
A. ApixabanB. DabigatranC. RivaroxabanD. Warfarin