Basics of Warfarin Management

Objectives
Discuss warfarins mechanism of action Review indications for warfarin and corresponding INR ranges Differentiate between a prothrombin time (PT) and an international normalized ratio (INR) Review most common side effects of warfarin Summarize diet/drug/herbal interactions and other influences on INR Discuss important patient interview questions Describe how dosing adjustments are made and when to order another INR
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Warfarin (Coumadin)
History
In 1939, bishydroxycoumarin was discovered from spoiled sweet clover and found to have anticoagulant properties In 1948, warfarin was discovered and used as an effective rodenticide In 1954, warfarin was approved by the FDA as a human oral anticoagulant

Warfarin (Coumadin)
Warfarin is an antagonist of the conversion of vitamin K epoxide to vitamin K Vitamin K is required for the synthesis of clotting factors (II, VII, IX, X) and endogenous anticoagulant proteins C and S Without vitamin K, the rate at which these factors are produced greatly decreases and produces a state of anticoagulation

Warfarin (Coumadin)
Pharmacodynamics/Pharmacokinetics
Each clotting factor differs in half-life
Longest is factor II (60 hours) factor VII (5 hours) Shortest is protein C (8 hours)

Mean plasma half-life is approximately 40 hrs Maximal effect of a dose occurs up to 48 hours after it is administered

Common Indications for Warfarin

INR goal: 2-3
Prophylaxis of venous thrombosis for high risk surgery Treatment of deep venous thrombosis (DVT) Treatment of pulmonary embolism (PE) Treatment of cardiac thrombus (i.e. mural) Treatment of severe congestive heart failure (CHF) Treatment of atrial fibrillation Bioprosthetic heart valves (3 months post placement) Hypercoagulable states (Protein C and S deficiency, Antithrombin III deficiency, Factor V Leiden)

Common Indications for Warfarin

Goal INR 2.5-3.5
Mechanical Valves (exceptions St. Judes in the aortic position with no other structural heart abnormalities 2-3 and cagedball/caged disk benefit from high level of anticoagulation)

Goal INR 3-4

Thrombus associated with antiphospholipid antibody

Difference Between INR and PT

Prothrombin Time (PT)
Measure of time to clotting Stimulated by thromboplastin (which comes from mammalian tissue) Choice of thromboplastin can vary from lab to lab

International Normalized Ratio (INR)

Adjusts for the variable sensitivities of the different thromboplastins The standard for evaluation of effect with coumadin therapy INR = (PTpt / PT ref )ISI
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Side Effects of Warfarin

Bleeding
Related to intensity, length of therapy, comorbidities, and other medications Risk dramatically increases when INR >4

Purple Toe Syndrome

Cholesterol microembolization Occurs 3-10 weeks after initiation Discontinuation is recommended

Side Effects of Warfarin

Skin Necrosis
Associate with a thrombosis Uncommon, occurs 3-8 days after initiation More frequent in women and patients with protein C or S deficiency Discontinue, may reinitiate at low dose once heparin is therapeutic

Teratogenic

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Diet Interactions
Food/herbs/vitamins/nutritional supplements which contain vitamin K will decrease the effect of warfarin In general, leafy green vegetables and oils contain high amounts of vitamin K
Broccoli, brussels sprouts, cabbage, collard greens, endive, green scallion, kale, lettuce, mustard greens, spinach, turnip greens, watercress, large quantities of mayonnaise, canola, salad, and soybean oils Liver

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Diet Interactions

Patients do not have to cut all dark greens out of their diet!

The key is consistency.

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Drug Interactions
Warfarin has many drug interactions which can make the INR elevate or decrease It is difficult to remember them all, so it is important to look up every medication change that occurs and manage appropriately
Starting a new drug Stopping an old drug Increase/decrease in dose

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Drug Interactions
Advise patients not to take any aspirin (unless directed by their physician) or NSAIDs over the counter for pain, recommend Tylenol. All other OTC medications should be reviewed with their physician/pharmacist before administering.

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Herbal/Nutritional Supplement Interactions

Always ask it a patient is taking herbals, they will not always think about them as a medication change. Many herbal interactions have occurred with warfarin, but many are still unknown. More frequent monitoring should be implemented when they are initiated.

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Other influences on INR

Increase INR
Compliance Decreased Exercise Diarrhea Fever Hyperthyroidism Hepatic Disorders Prolonged hot weather Vomiting

Decrease INR
Compliance Increased Exercise Edema Hypothyroidism

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Important Interview Questions

Have you stopped your warfarin for any reason? Any unusual bruising or bleeding? Any unusual leg pain, chest pain, dizziness, numbness or tingling? Any changes in you medications? Any OTC or herbals started?

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Important Interview Questions

Any changes in your diet with regard to dark green vegetables, oils, or liver? Any missed doses? How are you taking your warfarin? What strength tablet do you have?

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Managing Warfarin Patients

Dosing adjustments
Look at trends and other causes for change in INR Adjustments are made from 5-20% per week depending on clinical judgement Patients should be monitored closely during initiation and when the INR is not therapeutic. Once therapeutic, may check weekly, q2week, q3week, q4week after 2 consecutive INRs are in range.

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Vitamin K Administration
Vitamin K reverses the effects of warfarin If INR < 5 without significant bleeding
Rapid reversal is not necessary Omit next dose and resume at lower dose

INR >5 and < 9 without significant bleeding

Rapid reversal not necessary Omit 1-2 doses Could give 2.5mg Vit K orally and omit a dose

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Vitamin K Administration
INR > 9 without clinically significant bleeding
2.5 - 5mg Vit K orally and omit dose

If rapid reversal is required, due to serious bleeding or INR > 20

Give 10mg Vit K IV FFP

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Compliance
Obviously, the importance of compliance cannot be over-looked! Aids for compliance
Involvement of family Pill boxes Notebooks Alarm watches

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Resources
Managing Oral Anticoagulation Therapy - Clinical and Operational Guidelines. 2nd edition Ansell, Oertel, Wittkowsky. 2003, Aspen. Anticoagulation Forum - www.acforum.org www.coumadin.com

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Questions?

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