Warfarin

Warfarin is taken by mouth to inhibit vitamin K. This vitamin is essential for effective production of clotting factors II, VII, IX, X, and anticoagulant proteins C&S. Warfarin is given once daily. It is monitored by the prothrombin time and the international normalized ratio (INR).

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.

Test your knowledge in a real life case simulation of patient J.B., scheduled to under go left hip replacement surgery.

Therapeutic Recommendations For Warfarin

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

Duration of Action

Warfarin takes 4-7 days to have its optimum effect. Large loading doses do not markedly shorten the time to achieve a full therapeutic effect but cause rapid falls in the level of protein C, which may precipitate paradoxical thrombosis in the first few days of warfarin therapy. The following general recommendations for warfarin use are made.

Initiate therapy with the estimated daily maintenance dose (2-5 mg.).
Elderly or debilitated patients often require low daily doses of warfarin (2-4 mg.).
Patients are confused by alternating daily doses (e.g. 7.5 and 5.0 mg).
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.

Frequency of Dosing

Daily

Monitoring

Warfarin is monitored by the one stage prothrombin time. Prothrombin times are reported in seconds, as a ratio of the prothrombin time in seconds to the mean normal prothrombin time of the laboratory, and as the international normalized ratio (INR). The INR is the most reliable way to monitor the prothrombin time.

Some Drug Interactions With Warfarin

Drugs That May Lengthen PT		Drugs That May Shorten PT
(higher INR; increased warfarin effect)		(lower INR; decreased warfarin effect)
Antibiotics	Anti-inflammatories	Alcohol	Penicillin
Carbenicillin	Allopurinol	Antacids	Rifampin
Erythromycin	Fenoprofen	Antihistamines	Spironolactone
Fluconazole	Ibuprofen	Barbiturates	Sucralfate
Isoniazid	Indomethacin	Carbamazepine	Trazodone
Ketoconazole	Naproxen	Cholestyramine	Vitamin C (large doses)
Metronidazole	Phenylbutazone	Griseofulvin
Moxalactam	Piroxicam	Haloperidol
and other cephalosporins	Sulfinpyrazone	Oral contraceptives
Trimethoprimsulfa	Zileuton
Antiarrhythmics
Amiodarone
Quinidine
Others
Anabolic steroids	Omeprazole
Cimetidine	Phenytoin
Clofibrate	Tamoxifen
Disulfiram	Thyroxine
Lovastatin	Vitamin E (large doses)

Remember: Drug interactions with warfarin are not always known or predictable. Repeat an INR 5-7 days after adding, subtracting or changing the dose of any drug in a patient receiving warfarin.

Dietary And Other Interactions With Warfarin

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.

Conditions that interfere with vitamin K uptake or interfere with liver function will increase the warfarin effect.

Expect a longer prothrombin time in patients with CHF, jaundice, hepatitis, liver failure, diarrhea, or extensive cancer or connective tissue disease.
Expect a longer prothrombin time when patients receiving warfarin are hospitalized for any reason.

Metabolic alterations can affect the prothrombin time.

Expect a longer prothrombin time in patients with hyperthyroidism or high fever.
Expect a shorter prothrombin time in patients with hypothyroidism.

Initiating Warfarin Therapy

Are there any contra-indications?

Pregnancy
History of warfarin-induced purpura
Active Bleeding

Has the patient been instructed on drug interactions and a diet of constant vitamin K intake?

Has a baseline PT, APTT, and platelet count been obtained?

		Day 1	Day 2	Day 3	Day 4 & after
In-patient Anticoagulation	Warfarin Dose	5 mg	5 mg	2-5 mg	2-5 mg
				INR**	INR

* Should be overlapped for 3-5 days with heparin in cases with active thrombosis

		Day 1	Day 2	Day 3	Day 4 & after
Out-patient Anticoagulation	Warfarin Dose	2-5 mg	2-5 mg	2-5 mg	2-5 mg
				INR**	INR

** Starting on day 3, adjust subsequent doses as outlined below based on INR. Obtain INR 3-4 times in week 1; twice in 2nd week; then weekly until stable; then monthly. Elderly or debilitated patients often require low daily doses of warfarin (2-3 mg).

Initiating Therapy: Dose Adjustment

Day	INR	Dosage
3	<1.5 1.5-1.9 2.0-3.0 >3.0	5.0 - 10.0 mg 2.5 - 5.0mg 0.0 - 5.0 mg 0.0
4	<1.5 1.5-1.9 2.0-3.0 >3.0	10.0 mg 5.0 - 7.5 mg 0.0 - 5.0 mg 0.0
5	<1.5 1.5-1.9 2.0-3.0 >3.0	10.0 mg 7.5 - 10.0 mg 0.0 - 5.0mg 0.0
6	<1.5 1.5-1.9 2.0-3.0 >3.0	7.5 - 12.5 mg 5.0 - 10.0 mg 0.0 - 7.5 mg 0.0

Stable Patients: Dosing Algorithm To Achieve INR Of 2.0 - 3.0

Warfarin Sodium¹: Monitoring and Dosage Adjustment in Stable Anticoagulated Patients (based on a starting dose of 4 mg/d)

INR²	Action
>10.0	Stop warfarin. Contact patient for examination.
7.0-10.0	Stop warfarin for 2 days; decrease weekly dosage by 25% or by 1 mg/d for next week (7 mg total); repeat PT³ in 1 week.
4.5-7.0	Decrease weekly dosage by 15% or by 1 mg/d for 5 days of next week (5 mg total); repeat PT in 1 week.
3.0-4.5	Decrease weekly dosage by 10% or by 1 mg/d for 3 days of next week (3 mg total); repeat PT in 1 week.
2.0-3.0	No change.
1.5-2.0	Increase weekly dosage by 10% or by 1 mg/d for 3 days of next week (3 mg total); repeat PT in 1 week.
<1.50	Increase weekly dose by 15% or by 1 mg/d for 5 days of next week (5 mg total); repeat PT in 1 week.

¹ - Coumadin®, 1mg tablet

² - INR: International Normalized Ratio = (x/y)^z , where:

x = Prothrombin Time of sample (sec)

y = Mean Normal Prothrombin Time (sec)

z = [ ISI of Thromboplastin]

Evaluation Of Atrial Fibrillation

Atrial fibrillation on ECG (constant or intermittent)

Obtain history and physical exam (valvular, ischemic or hypertensive heart disease present? Diabetes or thyrotoxicosis present?)

Obtain surface echocardiogram (valvular heart disease, atrial or appendegeal thrombus or LV dysfunction present?)

Valvular, ischemic, or hypertensive heart disease present; diabetes, previous stroke or TIA present; or patient 65 years or older.	Thrombosis? Consider TEE	No heart, or systemic disease detected and patient less than 65 Years old.

Anticoagulate with Warfarin to INR of 2.0-3.0		No anticoagulation ("Lone atrial fibrillator")

If low intensity anticoagulation is contraindicated, aspirin at 325 mg daily may offer some benefit, but warfarin has performed better in most comparisons to aspirin.