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Warfarin Management

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Andrew Miesner

on 24 January 2014

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Transcript of Warfarin Management

Warfarin Management
• Choose an appropriate starting dose of warfarin and identify factors that might impact this decision.

• Recommend appropriate dosing adjustment for patients with subtherapeutic or supratherapeutic INR values including appropriate use of vitamin K for critical INRs.

• Identify drug-drug, drug-food, and drug-disease interactions that occur with warfarin in a patient case and strategies to minimize their expected effects.

• Create an appropriate monitoring schedule for patients recently started on warfarin or on chronic warfarin therapy.

Initiating Therapy
Pharmacokinetic Interactions
Micromedex’s Drugdex

CHEST 2012;141(Suppl):e44S–e88S

Cleveland Clinic Journal of Medicine 2003;70:361-71



Andrew Miesner, PharmD, BCPS
Assistant Professor of Pharmacy Practice
Drake University College of Pharmacy & Health Sciences

One of the most common clinical services offered by pharmacists in any setting
Up to 60% of anticoagulation management services

WHY? The evidence:
We’re the best at it… Chest 2005; 125:1515-22.
It saves money… Ann Pharmacother. 2007;41:496-501.
Patients like us... J Am Pharm Assoc. 2003;43:630-6.
If the patient goes back to their physician, they do worse… Pharmacotherapy. 2008; 28:20-6.

What else?
Narrow therapeutic window
MANY drug interactions
Dietary interactions
Requires an understanding of pharmacokinetics and pharmacodynamics
Good communications with patients
Reimbursable service for pharmacists!

“The ability of the health-care provider to make appropriate dosage and follow-up decisions can have a major impact on therapeutic effectiveness. The comprehensive management of the VKAs requires a knowledgeable health-care provider, an organized system of followup, reliable PT monitoring, and good patient communication and education.”

Chest 2008;133;160-198

email: andrew.miesner@drake.edu

Pathophysiology and Physiology
Adjustment of Maintenance Doses
Pharmacodynamic Interactions
Dietary Interactions
Disease State Interactions
Other Interactions
Intravascular thrombus formation can problematic

Common Indications
Treatment / secondary prevention of venous thromboembolism (VTE)
Deep vein thrombosis
Pulmonary embolism
Longer term VTE prophylaxis
Knee and hip replacement surgeries
Embolic stroke prevention
Atrial Fibrillation
Mechanical Heart Valves (Mitral > Aortic)
Previous embolic stroke
Et cetera…

A delicate balance exists between the formation and breakdown of clots on a normal physiologic level

Clotting Cascade 

...of mice and
A narrow therapeutic window

High amount of INTERpatient variability
Genetics, race, weight, sex, medications, liver, etc

High amount of INTRApatient variability
Drug interactions, diet, illness, etc

Inhibits vitamin K epoxide reductase (VKORC1)
Reduced vitamin K is a required cofactor for carboxylation
II, VII, IX, X, Protein C & S

Slows the rate of SYNTHESIS of functional clotting factor

No effect on circulating factors or formed thrombus

Creates a delayed anticoagulant effect due to reduced functional status of Vitamin K dependent clotting factors
Initial prothrombotic state due to inhibition of Protein C and S

Factor VII

Protein C

Factor IX

Factor X

Protein S

Factor II
6 - 8 hours

8 - 10 hours

20 - 30 hours

24 - 40 hours

40 - 60 hours

60 - 100 hours
Anticoagulation (as it pertains to warfarin) is measured by the prothrombin time (PT)
Standardized to the International Normalized Ratio (INR)

INR measures activity of VII, X, and II

Typical baseline is 1.0 (0.8 – 1.2)

Empiric goal is 2.0 to 3.0 for most indications
2.5 to 3.5 for higher risk indications (mechanical mitral valve, some mechanical aortic valves)
Lower intensity may not adequately treat / prevent thrombi
Higher intensity places patient at higher risk for bleeding
Slightly higher day-to-day bleed risks >3.0
No net clinical benefit to INRs >4.0

Warfarin exhibits a high amount of variability making this small therapeutic window difficult to achieve

99% plasma protein bound
Allows for displacement interactions to occur

Extensively hepatically metabolized by CYP450
S is 5x more potent than R
Stereoselective metabolism:
S = 2C9 R = 3A4, 1A2
Interactions with 2C9 are often more significant

T 1/2 = ~40 hrs
Clearance may be slightly reduced in the elderly
Actual T 1/2 mostly dependent on genetics

Genetic variations in metabolism are thought to be the major driver of variation in requirements

VKORC1 genotype: explains ~25% of variation
AA: very sensitive
GG: more resistant

2C9 genotype: explains ~6-10% of variation
CYP2C9*1/*2 are slow metabolizers
CYP2C9*2/*2, CYP2C9*3, CYP2C9*5, CYP2C9*6, CYP2C9*9, CYP2C9*11 are very slow metabolizers
CYP2C9*2 and CYP2C9*3 associated with increased risk of overanticoagulation and bleeding

Others identified
GGCX genotype, CYP4F2 genotype, CALU genotype

Warfarin is the single most personalized medication… the initial dose is at best an educated guess

Most patients are started on 5mg to 10mg empirically
CHEST AT9: 10mg for first 2 doses recommended for “patients healthy enough to be treated as outpatients”

Nomograms have been used with variable success
Most are useless after 5 days of therapy

Considerations for baseline factors:

– requirements tend to decrease with age
4mg is a common starting dose in the elderly

– males tend to require more than females

– heavier patients tend to have higher requirements

– probably related to genetics
Blacks > Whites > Hispanics & Asians

– tend to have higher requirements

– tend to have lower requirements
Usually reliant on baseline INR

Amiodarone, Statins, TMP/SMX, Azoles all decrease initial requirements

… if available
Not widely used (yet) clinically due to lab availability and long term utility
CHEST AT9: currently recommends against routine use

Other Initiation Issues
Follow daily INRs inpatient
A baseline INR should be drawn prior to initiation of therapy

Given the half-life of clotting factors, inpatient titration is expensive… and may lead to hasty dose increases
Empiric dose increases may be necessary if no response after 3 doses

Outpatient initiation is possible for some indications
Minimum of 2-3 INRs per week

Overlapping parenteral anticoagulation with LMWH / UFH
Necessary initially for indications with suspected clot burden
Depletion of Protein C & S places the patient at a hypercoaguable state

Monitor rate of increase versus expected time to full effect
The “Rule of 7:” if therapeutic before steady state

EXAMPLE: 10mg x2, then 5mg x2 does not equal 5mg daily
20mg / 7 = less than 3mg daily

INRs out of range
ALWAYS attempt to determine why
Missed doses, medication changes, dietary changes

Do not always require adjustment
INRs slightly out of range (+/- 0.5) often return to normal in 1-2 weeks without intervention
Missed doses

• Sample protocol
• No protocol could possibly account for all the variables
Consider holding doses for INRs 4.5 and higher
Do not consider in your dose adjustment calculation

Vitamin K (phytonadione) administration
Is the patient actively bleeding?
Yes? Give vitamin K
No? Give vitamin K only if INR is >10
PO > IV > SubQ > IM
2.5 to 5mg is usually adequate in non-severe bleeds
Must also hold/decrease the dose

Not good practice to increase maintenance dose of a nonadherent patient
May consider a one-time bolus dose to expedite a therapeutic INR
Some high risk indications may require coverage with LMWH to prevent embolism until therapeutic again (~5 days)
Minimal evidence to support this practice
Follow up INR schedule
No one best way to do this… must be individualized based on response and pharmacokinetics

My typical approach:
Initiation: daily if inpatient or
2-3 times per week until a stable dose response is achieved outpatient
Then once weekly
Obtain 1-2 therapeutic INRs at this frequency
Then every 2 weeks
Obtain 1-2 therapeutic INRs at this frequency
Then every 4 weeks
If 12 weeks of consistently stable INRs, may recheck every 12 weeks
Follow ups should never be beyond every 12 weeks (or every 4 weeks for most patients)
Must return earlier if medication changes, missed doses, etc

Other follow up issues
Generally follow up on any dose changes within 7 to 10 days
See >75% of the change
BUT… must consider when change is ACTUALLY made

Many possible strategies after changes are made…
Follow up at 1 week in range x2
Then at 2 weeks x1
Then at 4 weeks

If an interaction is expected, early follow up is typically indicated
Must consider when you would expect an effect

Other Monitoring Issues
Bruising is common

Possible in range (and below range!), but suggest self-monitoring strategies for supratherapeutic patients

Fall prevention

Self monitoring for thromboembolism

Surgical procedures may (or may not) require interruption and bridging with LMWH
Should be stopped 5 days prior to invasive procedures with high bleeding risks

Hundreds of interactions, each places a patient at possible hemorrhagic or embolic risk
IMPOSSIBLE to avoid, but most can be managed

Can be fixed “prospectively,” but most interacting medications will have already been started
Earlier follow up is always indicated

Probably not possible to know all, but certain trends should be recognized
2C9 > 3A4 > 1A2
Most are “built in” to the maintenance dose
Typically occur upon initiation or withdrawal of therapies
Documented / Theoretical interaction vs. clinical relevance
Recommended resource: Micromedex’s DrugDex

The 8 A’s
Acetaminophen (high dose)
Alternative Therapies (herbals)
Antiinflamatories (NSAIDs, steroids)

Protein displacement
Displacement from albumin increases free warfarin concentrations
Often a transient effect

Examples: Phenytoin, fluoxetine, TMP/SMX, valproic acid

Management often depends on additional interactions with the given drug

Inhibition of metabolism – INCREASES INR
Represents a majority of common interactions
Effects seen within a few days
2C9 > 3A4 > 1A2 > others
High level of effect variability between drugs

Examples: Amiodarone*, TMP/SMX*, macrolides, azole antifungals, metronidazole*, cimetidine, some statins, corticosteroids (?), etc…
*May require preemptive dose reductions

Enzymatic competition for metabolism– INCREASES INR
Theoretical concern with actual clinical interactions

Examples: Some statins, ropinirole, tolterodine

Induction of metabolism – DECREASES INR
Much less common clinically
Not immediate; occurs over time (several days to weeks)

Examples: Phenytoin, rifampin, phenobarbital, carbamazapine, nafcillin, dicloxicillin, St. John’s Wort

NSAIDs/Celecoxib, Aspirin, clopidogrel
Antiplatelet effects increase bleeding risk
COX inhibition increases GI bleeds
Does NOT affect the INR

Avoid if possible!
Suggest Acetaminophen (It’s one of the 8A’s… I know, I know)
Short courses of less GI toxic NSAIDs
Consider PPI
Low dose aspirin (if antiplatelet activity is required)

Levothyroxine, PTU, Methimazole
Thyroid hormone increases metabolism of clotting factors

Dietary supplements, Vitamin K
Multivitamins will decrease the INR

Inhibition of cyclic conversion of vitamin K
All antibiotics to some extent

Vitamin K – “green, leafy veggies”
Decrease the INR by increasing the amount of available clotting factor
Consistency is key… Do NOT advise patients to avoid!

High protein diets may decrease the INR

Others known to increase the INR
Cranberry, grapefruit, mango, papaya

Large decreases in overall intake (sickness, fasting) may increase the INR

Often very difficult patients to treat with warfarin
Problems with metabolism of warfarin and synthesis of clotting factors
Typically require very low doses

Heart Failure Exacerbations
Decreased perfusion to the liver resulting in marked increases in INR

Changes in metabolism of clotting factors, not the drug
Monitor frequently when titrating antithyroid or thyroid replacement therapy

Increases the metabolism of clotting factors
Acute illness generally causes INR variability

Prolonged diarrhea often leads to increased INR
Poor oral intake

Smoking is a 1A2 inducer
Cessation may increase INR

Smoking may acutely increase INR

2 servings/day are unlikely to affect the INR
Acute binges increase the INR and fall risk

Generally adjustments should be in the range of 5-20%
Larger changes the further away you are from goal

Add up weekly dose

Make REALISTIC changes using the patients home supply
Often work in half tablet increments

EXAMPLE: 5mg daily = 35mg/week
2.5mg (half tablet) / 35mg = 7.1%
5mg / 35mg = 14.2%
7.5mg / 35mg = 21.3%

Bi-phasic (alternating day dosing) is possible given the long T 1/2½
Higher amount of errors
Consider when you are actually making the dose change

Other strategies
Adjust by about 10%
See what doses the patient has previously responded well to
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