Kelly-DOAC_overview_2017_fo.pptx

Warfarin, Your Days are
Numbered!
Linda R. Kelly PharmD PhC CACP
Pharmacy Anticoagulation Specialist
Presbyterian Healthcare System

Objectives
• Identify and classify the available oral
anticoagulants
• Evaluate patient characteristics that would
suggest using one product over another
• Design a plan for switching from one oral
anticoagulant to another
• Manage oral anticoagulants in the peri-
procedural period

Terminology
• VKA-Vitamin K Antagonist (warfarin)
• DOAC-Direct Oral Anticoagulant
• TSOAC-Target Specific Oral Anticoagulant
• NOAC-Novel (or New or Non-vitamin K) Oral
Anticoagulant

Available Direct Acting Oral
Anticoagulants (DOACs)
• Dabigatran
• Rivaroxaban
• Apixaban
• Edoxaban

DOAC Mechanism of Action
Inhibits Factor Xa
Rivaroxaban
Apixaban
Edoxaban
Direct Thrombin Inhibitor
Dabigatran

Focus on Venous Thromboembolism
and Non-valvular Atrial Fibrillation

Marge is a 72 year old female with non-valvular
atrial fibrillation (NVAF). She has been taking
warfarin for stroke prevention. Her history also
includes hypertension. What is her CHA2DS2-
VASc score?
Meet Marge

Marge comes to see you about starting a new
product, bringing you a souvenir from her
latest excursion.
What factors should be considered when
planning to start or switch a patient to a
DOAC?
Marge

DOAC Indications and Dosing
NVAF
DVT
PE
Rivaroxaban Apixaban
20 mg once daily with
evening meal
5mg twice daily
Rivaroxaban Apixaban
15 mg twice daily x 21 days 10 mg twice daily x 7 days
20 mg once daily with evening
meal
5 mg twice daily

DOAC Indications and Dosing
NVAF
DVT
PE
Dabigatran Edoxaban
150 mg twice daily 60 mg daily
Dabigatran Edoxaban
LMWH lead in x 5-10 days LMWH lead in x 5-10 days
150 mg twice daily 60 mg daily

DOAC Renal Dosing
Rivaroxaban
NVAF
CrCl 15-50 mL/min 15 mg once daily
CrCl < 15 mL/min Use warfarin
DVT/PE CrCl < 30 mL/min Use warfarin
2.5 mg Apixaban twice daily**
NVAF
Must meet 2 of the following
Age 80 years or older
Actual body weight 60 kg or less
Serum Creatinine 1.5 mg/dL or
greater
**No dose reduction in DVT/PE patients. However, patients with SCr > 2.5 or CrCl < 25 mL/min
not studied

DOAC Renal Dosing
Dabigatran
NVAF
CrCl 15-30 mL/min 75mg bid
CrCl < 15 mL/min Use warfarin
DVT/PE CrCl < 30 mL/min Use warfarin
Edoxaban
NVAF
CrCl >95 mL/min DO NOT USE
CrCl 15-50 mL/min 30mg daily
CrCl < 15mL/min Use warfarin
DVT/PE
CrCl 15-50 mL/min 30mg daily
CrCl < 15mL/min Use warfarin

DOAC Hepatic Dosing
Child- Pugh Class Rivaroxaban Apixaban
A No Adjustment No Adjustment
B Use warfarin
Use with caution-
limited clinical
experience
C Use warfarin Use warfarin
Child- Pugh Score calculator can be found at PresNet Anticoagulation Oral
Anticoagulants Rivaroxaban (Xarelto) Child-Pugh Classification Score

DOAC Hepatic Dosing
Child- Pugh Class Dabigatran Edoxaban
A No Adjustment No Adjustment
B No Adjustment Use Warfarin
C Use warfarin Use warfarin
Child- Pugh Score calculator can be found at PresNet Anticoagulation Oral
Anticoagulants Rivaroxaban (Xarelto) Child-Pugh Classification Score

Drug Interactions
• Dabigatran:
▫ Substrate for p-glycoprotein
• Rivaroxaban:
▫ 51% CYP 3A4 metabolism
• Apixaban:
▫ 25% CYP 3A4 metabolism
• Edoxaban
▫ Minimal CYP 3A4 metabolism

Drug Interactions
Common Interacting Classes
▫ Anticonvulsants including barbiturates
▫ Antiretrovirals
▫ Antifungals
▫ Antiplatelet drugs and NSAIDS
Your favorite drug interaction program is
your best friend

Is a DOAC a Good Choice For Marge?
What should we consider before prescribing a DOAC?

DOAC Selection
• DVT of leg or PE with active
cancer
• Pregnant
• DVT of leg or PE without
active cancer

Anticoagulant Selection
• Valvular atrial fibrillation
• Valve replacement
• Myocardial infarction requiring
dual antiplatelet therapy
• Breast feeding

Does patient have
CrCl < 30, mechanical
heart valve, moderate
to severe hepatic
impairment (Child-
Pugh B or C),
significant drug-drug
interactions6?
Will the patient
have trouble
paying for a
DOAC?
Yes
Yes
No
No
• Valvular atrial fibrillation
• Valve replacement
• Myocardial infarction
requiring dual antiplatelet
therapy
• Pregnant or breast feeding
• Non-valvular atrial
fibrillation
• Secondary VTE
prevention
• VTE prophylaxis
following knee/hip
replacement
surgery

Does patient have
CrCl < 30, mechanical
heart valve, moderate
to severe hepatic
impairment (Child-
Pugh B or C),
significant drug-drug
interactions6?
Yes
Patient Characteristics Favoring DOAC
• Highly like to be adherent with DOAC therapy and follow up plan
• Reliable to notify health care provider about changes to health and pertinent
medical issues
• Confirmed ability to obtain DOAC on a longitudinal basis from a financial,
insurance coverage and retail availability standpoint
• Unstable diet or malnutrition
• Frequent illness or health status changes
• Frequent medicine changes or need for medications that interact with warfarin
but not with DOAC
• Frequent medical procedures with bleeding risk
No
Patient/ Family Preference

Patient/ Family
Preference
Drug 2
• Newer, less familiar
• No diet interaction and fewer interactions with
other medications
• Cannot easily monitor level of anticoagulation
and reversal agent may not be readily available
• Frequent monitoring and dose changes not
required
• Bridging NOT required around procedures
• Lower risk of intracranial hemorrhage
Drug 1
• Older, more established
• Strong interaction with diet and other
medications
• Reversible and easily monitored
• Frequent monitoring and dose changes
often required
• Bridging may be required around
procedures
• Higher risk of intracranial hemorrhage

Drug affordability
• Warfarin $
• Rivaroxaban, Apixaban, Dabigatran, Edoxaban $$$$
• Commercial plans (not Medicare/ Medicaid)
▫ Patient copay
• Medicare
▫ Consider coverage gap
▫ TrOOP vs. Drug spend
• Use sample card and/or coupon Sample clinic
Patient pay

Drug affordability- Medicare
• Medicare coverage gap or “Donut Hole”
• Must pay deductible (PHS plan deductible= $0)
• Copay ~$45 per month
• Gap starts at $3700 total cost or “drug spend”
▫ This is copay + balance insurance pays
▫ In 2017, when in the gap patient pays ~51% cost for generic,
~40% for brand.
▫ Out of gap at $4,950 paid in out of pocket expenses
• True out of pocket cost= “TrOOP”
▫ Cost the patient sees, copay, coinsurance, spending during the
coverage gap

Drug Affordability- Medicare
• Example- Rivaroxaban alone
▫ Rivaroxaban total cost= $431.4
▫ Rivaroxaban copay = $45
▫ Will meet gap in 8.6 months ($3700)
▫ After gap, drugs cost = $172.56 per month
▫ TrOOP ($4950 to get out of gap)
 $360 (on copays) before gap with no deductible
 $690.24 (4 months in gap)
▫ Drug spend for catastrophic = $4950
 After gap $21.57 (5%) (if patient is on other medications)

Drug Affordability- Medicare
• Example – Warfarin alone
▫ Warfarin total cost $6 (5 mg per day x 30 days. )
▫ Warfarin copay= $4
▫ Will not meet gap with warfarin
▫ In the gap, warfarin cost approx $3
▫ After gap will pay $1.60 per month

Patient Assistance
• Utilize patient savings cards
▫ Sample Cards
 1st month free! Regardless of insurance plan.
▫ Copy Card
 $0 copay for commercial insurance
▫ Samples may be available

Patient selections takeaway
• LMWH preferred in patients with active cancer
• DOAC preferred in patients with DVT/ PE
• NVAF -2016 European and Canadian guidelines
recommend DOAC over warfarin, 2014
AHA/ACC/HRS guidelines do not recommend
one over the other
• Must consider patient co-morbidities and ability
to afford therapy

Is a DOAC a Good Choice For Marge?

Enoxaparin TO/FROM DOAC
Stop old medication and start new
medication when the next dose is due
Abo-Salem J Thromb Thrombolysis (2014)

DOAC TO DOAC
Stop DOAC 1 and start DOAC 2 when the
next dose is due

DOAC to Warfarin/Warfarin to DOAC

Warfarin to DOAC
• Discontinue warfarin
• Begin rivaroxaban when INR below 3.0
• Begin dabigatran or apixaban when INR
below 2.0

DOAC to warfarin
• Need overlap therapy until INR equal or above 2.0
1. DOAC
• May interfere with INR reading
• Must use DOAC trough for INR draw
• Make clear to the patient that they MUST go in for an INR
draw right before next DOAC dose is due.
OR
2. LMWH
• Transition like normal LMWH bridge per PMG policy.
• Start LMWH when next DOAC dose due.

Anticoagulant Transitions
• Warfarin to DOAC, DOAC to Warfarin
** INR < 3.0 for Rivaroxaban

How Does Marge Switch from Warfarin
to Rivaroxaban?

Peri-procedural bridging
• Avoid overlapping LMWH and DOACS
1. Can the procedure be delayed until patient is not on
anticoagulation therapy?
2. Is the bleeding risk of procedure high enough to warrant
DOAC interruption?
1. Consult bleed risk tables.
3. Can we delay procedure to increase time for elimination?
1. DOAC elimination based on renal function.
4. Resume DOAC after hemostasis is achieved
1. Low bleed risk: 24 hours
2. High bleed risk: 48-72 hours.

MAPPP Online and App
www.mappp.ipro.org

Drug
Renal
Function
Low
Bleeding
Risk
Surgery
High
Bleeding
Risk
Surgery
Resumption of
Therapy
Low
Bleeding
Risk
High
Bleeding
Risk
Rivaroxaban
T ½ = 8-9
hrs
CrCl >50
mL/min
Last dose: 2
days before
procedure
*Skip 2 doses
Last dose: 3
days before
procedure
*Skip 3 doses
Resume on
day after
procedure
(24 h
postop)
Resume 2-3
days after
procedure
(48-72 h
postop)
T ½ = 9 hrs
CrCl 30-50
mL/min
Last dose: 2
days before
procedure
*Skip 2 doses
Last dose: 3
days before
procedure
*Skip 3 doses
T ½ = 9-10
hrs
CrCl 15-
29.9
mL/min
Last dose: 3
days before
procedure
*Skip 3 doses
Last dose: 4
days before
procedure
*Skip 4 doses
Peri-Operative Management

Drug
Renal
Function
Low Bleeding
Risk Surgery
High Bleeding
Risk Surgery
Resumption of Therapy
Low
Bleeding
Risk
High
Bleeding
Risk
Apixaban
T ½ = 7-8
hrs
CrCl >50
mL/min
Last dose: 2
days before
procedure
*Skip 4 doses
Last dose: 3
days before
procedure
*Skip 6 doses
Resume on
day after
procedure
(24h
postop)
Resume 2-3
days after
procedure
(48–72h
postop)
T ½ = 17-
18 hrs
CrCl 30-50
mL/min
Last dose: 3
days before
procedure
*Skip 6 doses
Last dose: 4
days before
procedure
*Skip 8 doses

Drug
Renal
Function
Low
Bleeding
Risk Surgery
High Bleeding
Risk Surgery
Low
Bleeding
Risk
High
Bleeding
Risk
Dabigatran
T ½ = 14-17
hrs
CrCl >50
mL/min
Last dose: 2
days before
procedure
*Skip 4 doses
Last dose: 3 days
before procedure
*Skip 6 doses
Resume on
day after
procedure
(24h
postop)
Resume 2-3
days after
procedure
(48-72h
postop)
T ½ = 16-18
hrs
CrCl 30-
50
mL/min
Last dose: 3
days before
procedure
*Skip 6 doses
Last dose: 4–5
days before
procedure
*Skip 8-10 doses

Drug
Renal
Function
Low
Bleeding
Risk Surgery
High
Bleeding
Risk Surgery
Low Bleeding
Risk
High
Bleeding
Risk
Edoxaban
T ½ = 6-11
hrs
CrCl >50
mL/min
Last dose: 2
days before
procedure
*Skip 2 doses
Last dose: 3
days before
procedure
*Skip 3 doses
Resume on
day after
procedure
(24h postop)
Resume 2-3
days after
procedure
(48-72h
postop)

DOAC temporary interruption
1. Allow for 95% drug elimination prior to procedure (~5 drug half lives)
2. Resume DOAC 24-72 hours post procedure based on bleeding risk

Case Study: MR. JF
• Creatinine Clearance is about 60ml/min

Overview
• DOACS used for DVT/PE and NVAF
▫ Double check dosing for drug/ indication
• DOACS may not be the best option for everyone
▫ Consider your patient and their preferences
• DOACS come with added cost, but help is available
• We can transition between drug classes with monitoring
• DOAC temporary interruption AKA “peri-procedural
bridging” is possible.
▫ Be aware of procedure bleeding risk and patient risk factors.
▫ Do not overlap LMWH with DOACS

References
• www.xarelto.com
• Antithrombotic Therapy For Vte Disease: Chest Guideline And Expert Panel
ReportKearon C, Akl EA, Ornelas J, et al.Chest. 2016;149(2):315-352.
doi:10.1016/j.chest.2015.11.026
• Abo-salem E, Becker R. Transitioning to and from the novel oral anticoagulants:
a management strategy for clinicians. J Thromb Thrombolysis. 2014;37(3):372-
9.
• Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet Alfa for Acute Major
Bleeding Associated with Factor Xa Inhibitors. N Engl J Med.
2016;375(12):1131-41.
• Burnett AE, Mahan CE, Vazquez SR, Oertel LB, Garcia DA, Ansell J. Guidance
for the practical management of the direct oral anticoagulants (DOACs) in VTE
treatment. J Thromb Thrombolysis. 2016;41(1):206-32.
• Rechenmacher SJ, Fang JC. Bridging Anticoagulation: Primum Non Nocere. J
Am Coll Cardiol. 2015;66(12):1392-403.
• www.drugsafety.ipro.org Management of Anticoagulation in the Peri-Procedural
Period
• Thrombosis Canada. New/ Novel oral anticoagulants (NOACS): Peri-Operative
Management

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