Download Warfarin - Lock Haven University

Practical Approach to
Warfarin Therapy
Craig Ernst MHS, PA-C
Richard Freeman MD MPH
Lock Haven University
2013
Anticoagulation
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Definition:
Use of a medication to directly or indirectly
inhibit the action of one or more of the clotting
factors

Medication are called
ANTICOAGULANTs or ANTITHROMBOTICs

NOT THROMBOLYTICS
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ANTICOAGULANTS
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Prevention:-Prophylactic intensity
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Require Risk stratification
Examples:
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immobilized patient (hospitalized)
Atrial fibrillation
Orthopedic surgery
Genetic coagulation anomalies
Treatment: -=Therapeutic intensity
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Examples
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DVT
PE
Arterial thromboembolisms
FDA approved ANTICOAGULANTS

Unfractionated Heparin
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Low molecular weight heparin-Enoxaparin
Fondaparinux (Arixta)
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Oral Inhibitorof production of Vit K dependent factors
Dabigatran (Pradaxa)
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Factor Xa inhibitor-Subcutaneous
Warfarin (Coumadin)
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activates antithrombin III
oral direct thrombin inhibitor
Rivaoxaban (Xarelto)
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Oral direct factor Xa inhibitor
WARFARIN
Historical Background
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Spoiled clover silage caused bleeding in
cattle
Causative agent: dicoumarol
Warfarin is a derivative of dicoumarol
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Primarily used as a rodenticide-Decon
Clinical Trials: warfarin safe for human use
EXCEPT IN PREGNANCY-Category Xcrosses placenta
Mechanism of Action
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Warfarin partially blocks the re-use of Vit Kliver
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Vitamin K dependent procoagulants:
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Prothrombin (Factor II)
Factor VII
Factor IX
Factor X
Vitamin K dependent Anticoagulants:

Proteins S and C.
Indications

Long-term thrombosis prophylaxis
 Atrial
fibrillation
 Prosthetic heart valves
 Deep venous thrombosis
 Pulmonary emboli

Warfarin is not a thrombolytic!
Warfarin- positives
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Well studied- been around a LONG time
Relatively inexpensive (covered by most 3
party payers)
Given ORALLY
Comes in multiple strengths
Effects “Can” be Reversed
Warfarin-Negatives
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Bleeding complications- frequent
Slow onset of action-- 3-5 days
Requires ongoing monitoring—PT INR
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MULTIPLE drug interactions
Effected by diet-Vit K containing
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May require frequent dosage changes
Dark green leafy; fish oils
Reversing effects with Vit K may take days
Normal gut flora needed for Vit K
conversion/absorption
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Broad spectrum -antibiotics inhibit
Pharmacokinetics
Many Therapeutic challenges

Delayed optimal anticoagulant effect
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Has no effect on currently circulating clotting factors
No anticoagulant effect until these decay

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Warfarin half-life of 36 to 48 hours
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5-7 days until clotting factors are at a minimal level
Persistent anticoagulant effect after warfarin is
discontinued
THERAPUETIC INDEX- NARROW
Initial Prothrombotic effect-slight problem

Protein C and S are Vit K dependent
Other Considerations
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Patient’s liver stasis
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hepatitis, cirrhosis, and cancers that degrade liver
function already result in a deficiency of clotting
factors
Providers – not knowledgeable in usage
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WARFARIN CLINICS
Oral Formulations
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Warfarin
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Jantoven
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~13 different generic companies
Generic name brand
Coumadin
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Most widely used formulation of warfarin
Contraindications to warfarin
very similar to thrombolytic contraindications
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history of hemorrhagic stroke < 2 months
CNS neoplasm, AV malformation, or aneurysm, or
CNS surgery < 2months
Severe uncontrolled hypertension
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(over 200/130 or complicated by retinovascular disease or
encephalopathy)
ongoing (active/current) bleeding
s/p recent significant surgery, pending surgery
Pregnancy
MI due to aortic dissection
allergy
many relative contraindications
Drug Interactions
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Drugs That May
Lengthen PT
Antibiotics
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azithromycin
Antiarrhythmics
Others
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Anabolic steroids
Omeprazole
Cimetidine
Phenytoin
Clofibrate
Tamoxifen
Disulfiram
Thyroxine
Statins- lovastatin
Vitamin E (large doses)
Drugs That May Shorten
PT
 Alcohol
 Antacids
 Antihistamines
 Spironolactone
 Barbiturates
 Sucralfate
 Carbamazepine
 Trazodone
 others
Monitoring
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Prothrombin Time
a.k.a—Protime, PT, INR
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Used to assess Extrinsic Pathway Factor VII
Normal range 12-15 seconds
Normal range NOT SAME as therapeutic range
INR-Standardized Test
Must use INR for Coumadin Dosing

“normal” range for the INR is 0.8-1.2
Monitoring
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Warfarin is a narrow therapeutic index drug (NTI).
When the INR falls below 2.0 thrombosis risk increases and
when the INR rises above 4.0 serious bleeding risk increases.
Target INR ranges:
Disease
INR Range
DVT/PE
2.0-3.0
Atrial Fibrillation
2.0-3.0
Myocardial Infarction
2.0-3.0
Mechanical Heart Valves
2.5-3.5
Initiating Therapy
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ASSESS FOR CONTRAINDICATIONS
HISTORY AND PHYSICAL EXAM
Initiating a Plan:
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Pt Education
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Diet- do not vary – see slide
Timing- EVENING
Warning signs- abnormal bleeding:
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bowel/bladder, epistaxis, gum, petechia/ purpura
Laboratory findings
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Baseline PT INR, aPTT, platelet count
Arrange schedule for Follow-up PT INR

If patient can not comply reconsider using warfarin
Co-morbid Conditions

Expect a LONGER baseline prothrombin time in patients with:
CHF,
hepatitis, liver failure,
diarrhea,
extensive cancer
connective tissue disease.
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Metabolic alterations can affect the prothrombin time.
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Expect a longer prothrombin time in ELDERLY patients.
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Dietary Interactions
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Patients taking warfarin should eat a diet that
is CONSTANT in vitamin K.
MINIMIZE CHANGES in intake of green
leafy vegetables (spinach, greens, and
broccoli), green peas, and oriental green
tea
Initiating Warfarin Therapy
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Initiate therapy with the estimated daily
maintenance dose
2-5 mg daily
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Large loading doses do not markedly shorten the
time to achieve a full therapeutic effect.
Elderly or debilitated patients often require
lower daily doses of warfarin (2-4 mg daily).
Initiating Warfarin Therapy
Inpatient (hospitalized)
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Check daily PT- INR
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5mg Day 1
5mg Day 2
2-5mg Day 3
2-5 mg Day 4
Concurrent LMWH or Heparin management
Initiating Warfarin Therapy
Out patient
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2-5 mg daily
Check INR on days 3, 4, 5
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Insure anticoagulation therapeutic range and stable
If therapeutic -- Recheck one week from initiation
Additional anticoagulant?
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Urgent anticoagulation needed-DVT
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Concurrent LMWH or Heparin UNTIL INR THERAPUETIC
Non-urgent anticoagulation
 Start with anticipated daily dose
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Case 1
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80 y/o female with SOB, tachypnea,
tachycardia, hypoxia. Found to have PE on
CT angiogram.
PMH: Prior DVT- no workup, DM, HTN

WHAT DO YOU DO???.
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Case 1
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80 y/o female with SOB, tachypnea, tachycardia,
and mild hypoxia. Found to have large PE on CT
angiogram.
PMH: Prior DVT no workup, DM, HTN.
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Day 3 INR is 2.0
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What do you do?
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Day 4 INR is 3.2
What do you do?
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Case 2
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70 y/o male with new dx atrial fibrillation.
Hemodynamically stable, HR 70 bpm.
PMH: CAD
Habits: occasional beer, eats a healthy diet.
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What do you do?
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Case 3
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55 y/o healthy female. Recently returned
from visiting France . Found to have
unilateral R leg swelling, U/S comes back
confirming R DVT.
PMH: G2 P2 not currently pregnant
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What do you do?
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Altering Chronic Therapy
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Significant changes in INR can usually be
achieved by small changes in dose (15% or
less).
4-5 days are required after any dose change
or any new diet or drug interaction to reach
the new antithrombotic steady state.
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Recheck PT INR
Patients are confused by multiple dosages of
pills.
Case 2
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70 y/o male with new dx atrial fibrillation.
Hemodynamically stable, HR 70 bpm.
PMH: CAD
Habits: occasional beer, eats a healthy diet.
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Pt returns for monthly “protime”
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Coumadin 4 mg daily (28 mg/week)
INR history within therapeutic range for last 3
months
INR today: 1.8
Case 3
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55 y/o healthy female. Recently returned from
visiting France . Found to have unilateral R leg
swelling, U/S comes back confirming R DVT.
PMH: G2 P2
Coumadin 5 mg daily (35 mg/week)
Stable INR history for past 6 weeks
INR today 3.5
1 mg
2mg
5mg
3 mg
10 mg
4mg
Complications
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HEMORRHAGE
Warfarin necrosis
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Protein C deficiency
Massive thrombosis
Osteoporosis
Purple toe syndrome
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Embolic cholesterol deposits
Hemorrhage management
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Stop Warfarin
Fresh Frozen Plasma
Administer Packed Red Blood cells- if
indicated
Aqua-Mephyton(Vit K)
difficult to re-establish a therapeutic INR
Dr. Freeman & PAdeath of a patient
DABIGATRAN-Pradaxa
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Direct Thrombin inhibitor
Oral
Indications:
 Stroke prevention AF patients
 DVT prophy- hip and knee surgeries
 Used as an alternative to poorer controlled Warfarin
users (nothing gained if controlled)
DOES NOT REQUIRE INR MONITORING
Complications:
 Higher risk for GI bleeding BUT overall life threatening
bleeds are less
RIVAROXABAN-Xarelto
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Direct Factor Xa inhibitor- onset 4 hours
Oral
Indications:
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Prevention and treatment of DVT
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Orthopedic hip and knee replacements
Long term DVT recurrence prevention
Nonvalular Atrial fib-stroke prophylaxis
Resources
Clotting Cascade
 Web based aid to help determine dose
http://warfarindosing.org/Source/Home.aspx
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ACC foundation guide to therapy
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http://circ.ahajournals.org/cgi/content/full/107/12/169
2?eaf
Excellent Resource for managing Warfarin
http://www.med.umich.edu/cvc/services/site_anticoa
g/healthprof.html