Transcript Management of Oral Anticoagulant Therapy

Margaret Jin, BScPHM, PharmD, CGP
November 2007
Learning Objectives
 To
review the mechanism of action, indications,
contraindications, adverse reactions, &
common drug interactions of warfarin
 To provide effective patient education
 To understand general concepts in warfarin
dosing
 To be able to use vitamin K1 appropriately
Mechanism of Action
Vitamin K
Antagonism
of
Vitamin K
VII
IX
X
II
Warfarin
Synthesis of
Non Functional
Coagulation
Factors
Mechanism of Action
Clotting Cascade
Indications &
Recommended Therapeutic Range
Therapeutic
Range (INR)
Indication
Treatment of venous thrombosis
Treatment of pulmonary embolism
Prevention of systemic embolism
Tissue heart valves
Valvular heart disease
Atrial fibrillation
Bileaflet mechanical valve in aortic position
Mechanical prosthetic valves
Acute Myocardial infarction
2.0 – 3.0
Target = 2.5
2.5 – 3.5
Target = 3.0
Chest 2004;126(3 Suppl):204S-233S
Contraindications
 Pregnancy
 Risk
of hemorrhage > clinical benefits
Active hemorrhage (e.g., GI bleed)
Uncontrolled alcohol/drug abuse
Unsupervised dementia/psychosis
 Unable to monitor INR
Adverse Effects
A/E to report to MD:
 Blood in stools or urine
 Excessive menstrual
bleeding
 Bruising
 Excessive nose
bleeds/bleeding gums
 Persistent oozing from
superficial injuries
 Intracranial Hemorrhage
Chest 2004;126(3):204S-233S
Factors that may influence
bleeding risk:
 Intensity of anticoagulation
 Concomitant clinical
disorders
 Hx of bleeding
 Hx of stroke
 Renal/Liver insufficiency
 Anemia
 Hypertension
 Concomitant use of other
medications
Adverse Effects




Skin necrosis – 0.01-0.1%
 Day 3 – 8
 Painful skin lesions
Purple toe syndrome
 Week 3 – 8
 Blue/purple toes/fingers
Allergic Dermatitis
 Skin rash, hives, itching
Vasculitis
 Fever, itching, skin
sores or blisters
Pharmacokinetics
 Absorption
Rapid
absorption
Food does not
affect absorption
 Distribution
99%
protein
bound
 Metabolism
Liver
Cytochrome
P450 2C9
Drug Interactions
Increase Warfarin Response
 NSAIDS, ASA
 Acetaminophen > 2g/d
 Amiodarone
 Quinolones (e.g., Cipro),
sulfonamides,
metronidazole
 Fibrates
 Ginkgo, Garlic, Ginseng
 Grapefruit
Decrease Warfarin
Response
 Phenobarbital
 Carbamazepine
 Phenytoin
 Vitamin K rich foods
Green leafy
vegetables
Effective Patient Education
 Teach basic
concepts of safe, effective
anticoagulation
 Discuss importance of regular INR monitoring
 Counsel on use of other medications, alcohol
 Develop creative strategies for improving
compliance
Evening, same time
Dosettes, blisterpacks
Warfarin Tablets









1mg – pink
2mg – lavendar
2.5mg – green
3mg – tan
4mg – blue
5mg – peach
6mg – teal
7.5mg – yellow
10mg - white
Warfarin Maintenance
Target INR 2.0 - 3.0
INR
Dosage Adjustment
Recheck INR
 Weekly dose by 10-20%,
< 1.5
4 to 8 days
consider extra dose
1.5 – 1.9  Weekly dose by 5-10%^ 7 to 14 days
# of consecutive in-range
2.0 – 3.0 No change
INRs x 1 week (max:4 wks)
3.1 – 3.9  Weekly dose by 5-10%* 7 to 14 days
Hold 0-1 dose, weekly
4.0 - 4.9
4 to 8 days
dose by 10%
≥ 5.0
Consult PHM or MD
^If INR is 1.8 to 1.9, consider no change with repeat INR in 7 to 14 days
*If INR is 3.1 to 3.2, consider no change with repeat INR in 7 to 14 days
Warfarin Maintenance
Target INR 2.5 - 3.5
INR
1.5 – 2.4
Dosage Adjustment
 Weekly dose by 10-20%,
consider extra dose
 Weekly dose by 5-10%^
2.5 - 3.5
No change
< 1.5
3.6 - 4.5
4.5 - 6.0
> 6.0
 Weekly dose by 5-10%*,
consider holding one dose
Hold 1-2 doses, weekly dose
by 5-15%
Recheck INR
4 to 8 days
7 to 14 days
# of consecutive in-range INRs
x 1 week (max:4 wks)
7 to 14 days
2 to 8 days
Consult PHM or MD
^If INR is 2.3 to 2.4, consider no change with repeat INR in 7 to 14 days
*If INR is 3.6 to 3.7, consider no change with repeat INR in 7 to 14 days
Warfarin Dosing Schedule
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Total
Weekly
Dose
3
3
3
3
3
3
3
21 mg
3
3
3
3
19 mg
3
3
18 mg
 10%
2
3
 15%
2
3
2
2
3
2
Warfarin Dosing Schedule
Mon
Tue
Wed
Thu
Fri
Sat
Sun
Total
Weekly
Dose
3
3
3
3
3
3
3
21 mg
3
3
3
3
23 mg
3
3
24 mg
 10%
4
3
 15%
4
3
4
4
3
4
Types of Bleeds

No significant bleeding = Minor bleeding
 Bruises
 Reported, but does not require additional testing, referrals or
visits

Serious bleeding = Major bleeding
 Black tarry stools, blood in urine, hematoma
 Requiring treatment, medical evaluation or at least 2
blood

Life-threatening bleeding
units of
 Intracranial hemorrhage, retroperitoneal bleed, leading to
cardiac arrest, surgical/angiographic intervention, or
irreversible sequelae
Warfarin Management
INR
Dosage Adjustment
5.0 –
8.9
If low risk of bleeding, omit 1-2 doses,
monitor INR more frequently, resume
warfarin at 10-20% lower than original dose
when INR is at therapeutic range
If high risk* of bleeding, omit 1 dose and give
vitamin K1 1-2.5mg orally. Check INR in 24
hours; if still high, administer additional
vitamin K1 1-2mg PO.
*High risk = factors that may influence bleeding risk - Hx of bleeding, stroke, renal & liver
insufficiency, anemia, hypertension, other medications
Warfarin Management
INR
 9.0
Dosage Adjustment
With no significant bleeding:
Hold warfarin
Administer vitamin K1 5-10mg PO
Check INR in 24 hours
If still high, administer vitamin K1 1-2mg PO
Resume warfarin at lower dose when INR is
therapeutic
Warfarin Management

Serious bleeding, any INR
 Hold Warfarin
 Give
Vitamin K1 10mg slow IV plus fresh plasma or
prothrombin complex concentrate, depending on urgency
 Repeat Vitamin K1 every 12 hours as needed

Life-threatening bleeding, any INR
 Hold warfarin
 Give
prothrombin complex concentrate (or recombinant factor
VIIa as an alternative) supplemented with vitamin K1 10mg
slow IV; repeat as needed
Vitamin K1, Phytonadione
 Injection Formulation
10mg/mL – 1mL vial
2mg/mL – 1mL vial
 Tablets
are not available in Canada
 Administer PO or IV
 Do not administer SC
 Elimination Half-life = 26-193 hours
Summary
 Use
clinical judgment
 Educate patient
 Adjusting warfarin dose is better than adjusting
patient’s quality of life
 Monitor INR appropriately
 Refer to Thrombosis Clinic if necessary
References
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The Thrombosis Interest Group of Canada (www.tigc.org)
Vitamin K diet
 www.gicare.com/pated/edtot39.htm
 http://www.drgourmet.com/warfarin/vitaminkcontent.pdf
Ansell J, et al. The pharmacology and management of the
vitamin K antagonists. Chest 2004;126:204S-233S
Singer DE, et al. Antithrombotic therapy in atrial fibrillation.
Chest 2004;126:429S-456S
http://www.ccs.ca/download/consensus_conference/consens
us_conference_archives/2004_Atrial_Fib_full.pdf
Questions