Transcript Slide 1
Practical Approach to
Warfarin Therapy
Craig Ernst MHS, PA-C
Richard Freeman MD MPH
Lock Haven University
2013
Anticoagulation
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
ANTICOAGULANTS
Prevention:-Prophylactic intensity
Require Risk stratification
Examples:
immobilized patient (hospitalized)
Atrial fibrillation
Orthopedic surgery
Genetic coagulation anomalies
Treatment: -=Therapeutic intensity
Examples
DVT
PE
Arterial thromboembolisms
FDA approved ANTICOAGULANTS
Unfractionated Heparin
Low molecular weight heparin-Enoxaparin
Fondaparinux (Arixta)
Oral Inhibitorof production of Vit K dependent factors
Dabigatran (Pradaxa)
Factor Xa inhibitor-Subcutaneous
Warfarin (Coumadin)
activates antithrombin III
oral direct thrombin inhibitor
Rivaoxaban (Xarelto)
Oral direct factor Xa inhibitor
WARFARIN
Historical Background
Spoiled clover silage caused bleeding in
cattle
Causative agent: dicoumarol
Warfarin is a derivative of dicoumarol
Primarily used as a rodenticide-Decon
Clinical Trials: warfarin safe for human use
EXCEPT IN PREGNANCY-Category Xcrosses placenta
Mechanism of Action
Warfarin partially blocks the re-use of Vit Kliver
Vitamin K dependent procoagulants:
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
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
Bleeding complications- frequent
Slow onset of action-- 3-5 days
Requires ongoing monitoring—PT INR
MULTIPLE drug interactions
Effected by diet-Vit K containing
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
Broad spectrum -antibiotics inhibit
Pharmacokinetics
Many Therapeutic challenges
Delayed optimal anticoagulant effect
Has no effect on currently circulating clotting factors
No anticoagulant effect until these decay
Warfarin half-life of 36 to 48 hours
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
Patient’s liver stasis
hepatitis, cirrhosis, and cancers that degrade liver
function already result in a deficiency of clotting
factors
Providers – not knowledgeable in usage
WARFARIN CLINICS
Oral Formulations
Warfarin
Jantoven
~13 different generic companies
Generic name brand
Coumadin
Most widely used formulation of warfarin
Contraindications to warfarin
very similar to thrombolytic contraindications
history of hemorrhagic stroke < 2 months
CNS neoplasm, AV malformation, or aneurysm, or
CNS surgery < 2months
Severe uncontrolled hypertension
(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
Drugs That May
Lengthen PT
Antibiotics
azithromycin
Antiarrhythmics
Others
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
Prothrombin Time
a.k.a—Protime, PT, INR
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
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
ASSESS FOR CONTRAINDICATIONS
HISTORY AND PHYSICAL EXAM
Initiating a Plan:
Pt Education
Diet- do not vary – see slide
Timing- EVENING
Warning signs- abnormal bleeding:
bowel/bladder, epistaxis, gum, petechia/ purpura
Laboratory findings
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.
Metabolic alterations can affect the prothrombin time.
Expect a longer prothrombin time in ELDERLY patients.
Dietary Interactions
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
Initiate therapy with the estimated daily
maintenance dose
2-5 mg daily
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)
Check daily PT- INR
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
2-5 mg daily
Check INR on days 3, 4, 5
Insure anticoagulation therapeutic range and stable
If therapeutic -- Recheck one week from initiation
Additional anticoagulant?
Urgent anticoagulation needed-DVT
Concurrent LMWH or Heparin UNTIL INR THERAPUETIC
Non-urgent anticoagulation
Start with anticipated daily dose
Case 1
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???.
Case 1
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.
Day 3 INR is 2.0
What do you do?
Day 4 INR is 3.2
What do you do?
Case 2
70 y/o male with new dx atrial fibrillation.
Hemodynamically stable, HR 70 bpm.
PMH: CAD
Habits: occasional beer, eats a healthy diet.
What do you do?
Case 3
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
What do you do?
Altering Chronic Therapy
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.
Recheck PT INR
Patients are confused by multiple dosages of
pills.
Case 2
70 y/o male with new dx atrial fibrillation.
Hemodynamically stable, HR 70 bpm.
PMH: CAD
Habits: occasional beer, eats a healthy diet.
Pt returns for monthly “protime”
Coumadin 4 mg daily (28 mg/week)
INR history within therapeutic range for last 3
months
INR today: 1.8
Case 3
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
HEMORRHAGE
Warfarin necrosis
Protein C deficiency
Massive thrombosis
Osteoporosis
Purple toe syndrome
Embolic cholesterol deposits
Hemorrhage management
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
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
Direct Factor Xa inhibitor- onset 4 hours
Oral
Indications:
Prevention and treatment of DVT
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
ACC foundation guide to therapy
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