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
Vitamin K Mechanism of Action Antagonism of Vitamin K VII IX X II Synthesis of Non Functional Coagulation Factors Warfarin
Mechanism of Action Clotting Cascade
Indications & Recommended Therapeutic Range Indication Therapeutic Range (INR) 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 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 Chest 2004;126(3):204S-233S
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 < 1.5
1.5 – 1.9
Dosage Adjustment Recheck INR
Weekly dose by 10-20%, consider extra dose
4 to 8 days Weekly dose by 5-10%^ 7 to 14 days 2.0 – 3.0 No change # of consecutive in-range INRs x 1 week (max:4 wks) 3.1 – 3.9
Weekly dose by 5-10%* 4.0 - 4.9 Hold 0-1 dose,
weekly 7 to 14 days 4 to 8 days ≥ 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
INR < 1.5
1.5 – 2.4
2.5 - 3.5
3.6 - 4.5
4.5 - 6.0
> 6.0
Warfarin Maintenance Target INR 2.5 - 3.5
Dosage Adjustment
Weekly dose by 10-20%, consider extra dose
Weekly dose by 5-10%^ No change Recheck INR 4 to 8 days 7 to 14 days # of consecutive in-range INRs x 1 week (max:4 wks)
Weekly dose by 5-10%*, consider holding one dose Hold 1-2 doses,
by 5-15% weekly dose 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
10%
15% 2 2 Warfarin Dosing Schedule Mon 3 Tue 3 Wed 3 Thu 3 Fri 3 Sat 3 Sun 3 Total Weekly Dose 21 mg 3 3 2 3 2 3 2 3 3 3 3 3 19 mg 18 mg
10%
15% 4 4 Warfarin Dosing Schedule Mon 3 Tue 3 Wed 3 Thu 3 Fri 3 Sat 3 Sun 3 Total Weekly Dose 21 mg 3 3 4 3 4 3 4 3 3 3 3 3 23 mg 24 mg
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 units of blood Life-threatening bleeding
Intracranial hemorrhage, retroperitoneal bleed, leading to cardiac arrest, surgical/angiographic intervention, or irreversible sequelae
Warfarin Management
INR 5.0 – 8.9
Dosage Adjustment 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
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