ORAL ANTICOAGULANTS IN THE 21ST CENTURY: A PRACTICAL GUIDE TO USING NEWER AGENTSKatherine Vogel Anderson, Pharm.D., BCACPUniversity of Florida Colleges of Pharmacy and Medicine

DisclosuresI have nothing to disclose

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

an2012

apixaban

2013…What do I choose?

*All are FDA approved for stroke prevention secondary to a. fib

warfarinrivaroxaban and apixaban

dabigatran

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

In a nutshell…

Katsnelson M et al. Circulation 2012;125: 1577-1583

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.

But…

Which oral anticoagulant do you recommend?

A. ApixabanB. DabigatranC. RivaroxabanD. Warfarin

Prodrug? YesFood? No effectDrug 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

But…

Which oral anticoagulant do you recommend?

A. ApixabanB. DabigatranC. RivaroxabanD. Warfarin

Prodrug? NoFood? MandatoryDrug 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 requirementHeidbuchel H et al. Europace 2013;15: 625-651

But…

Which oral anticoagulant do you recommend?

A. ApixabanB. DabigatranC. RivaroxabanD. Warfarin

Pros renal dose prospectively studiedCons twice daily dosing; newest of the new

Prodrug? NoFood? No effectDrug 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?

Let’s get started…

Heidbuchel H et al. Europace 2013;15: 625-651

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 RivaroxabanPlasma 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 ProlongedINR Increase Increase IncreaseaPTT >2xULN @

trough suggests risk

N/A N/A

Anti-Xa N/A No data YET QuantitativeECT >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

Management of bleeding

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

My answer I’m old school…

But, if pressed to choose a new one….

Thanks for your

attention!