Dose Changes in Stable Patients
Management of Serious Bleeding
Warfarin is taken by mouth to
inhibit vitamin K. This vitamin is essential for effective production of
clotting factors V, 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. When the INR falls below 2.0
thrombosis risk increases and when the INR rises above 4.0 serious bleeding
risk increases.
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
Dosage Initiation and Duration
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).
• In stable patients, 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.
Daily
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 (higher INR; increased warfarin effect)
Antibiotics
Carbenicillin
Erythromycin
Fluconazole
Isoniazid
Ketoconazole
Metronidazole
Moxalactam and other cephalosporins
Trimethoprim sulfa
Anti-inflammatories
Allopurinol
Fenoprofen
lbuprofen
Indomethacin
Naproxen
Phenylbutazone
Piroxicam
Sulfinpyrazone
Zileuton
Antiarrhythmics
Amiodarone
Quinidine
Others
Anabolic
steroids
Cimetidine
Clofibrate
Disulfiram
Lovastatin
Omeprazole
Phenytoin
Tamoxifen
Thyroxine
Vitamin
E (large doses)
Drugs That May Shorten PT (lower INR; decreased warfarin effect)
Alcohol
Antacids
Antihistamines
Barbiturates
Carbamazepine
Cholestyramine
Griseofulvin
Haloperidol
Oral
contraceptives
Penicillin
Rifampin
Spironolactone
Sucralfate
Trazodone
Vitamin
C (large doses)
Remember: Drug interactions
with warfarin are not always known or predictable. Repeat an INR 5 to 7 days
after adding, subtracting or changing the dose of any drug in a patient
receiving warfarin.
Dietary and Other Interactions with Warfarin
1. 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.
2. Conditions that interfere with vitamin K uptake or
interfere with liver function will increase the warfarin effect.
3. 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.
4. Metabolic alterations can affect prothrombin time.
Expect a longer prothrombin time in patients with hyperthyroidism or
fever.
Are there any contraindications?
1. Pregnancy
2. History of warfarin - induced purpura
3. 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?
Inpatient Anticoagulation Warfarin Dose *
Day 1 5 mg.
Day 2 5 mg.
Day 3 2 to 5 mg. Do INR
Day 4 2 to 5 mg. Do INR
* Should be overlapped for 3 to 5 days with heparin in cases with
active thrombosis. The INR should be in
therapeutic range for 2 consecutive days to allow
for depletion of factors in the intrinsic clotting pathway.
Outpatient Anticoagulation Warfarin Dose
Day 1 2 to 5 mg.
Day 2
2 to 5 mg.
Day 3
2 to 5 mg. Do INR
Day 4
2 to 5 mg. Do INR
** Starting on day 3, adjust subsequent doses as outlined below
based on INR. The INR should be in therapeutic range
for 2 consecutive days to allow for depletion of factors in the intrinsic
clotting pathway. 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 to 3 mg).
Initiating Therapy: Dose Adjustment
Day INR Dose mg.
3 <1.5 5.0 – 10.0
1.5 – 1.9 2.5 – 5.0
2.0 - 3.0 0.0 – 5.0
>3.0 0.0
4 <1.5 10.0
1.5 - 1.9 5.0 – 7.5
2.0 - 3.0 0.0-5.0
>3.0 0.0
5 <1.5 10.0
1.5 - 1.9 7.5 – 10.0
2.0 - 3.0 0.0 – 5.0
>3.0 0.0
6 <1.5 7.5 – 12.5
1.5 - 1.9 5.0 – 10.0
2.0 - 3.0 0.0 – 7.5
>3.0 0.0
Stable Patients: Dosing Algorithm To Achieve INR Of 2.0 to 3.0
Warfarin
Sodium*: Monitoring and Dosage Adjustment in Stable Anticoagulated Patients With No or Minimal Bleeding.
INR>9.0
·
Stop warfarin
temporarily.
·
Daily INR
·
Oral vitamin K 5-10
mg. If not available, IV preparation
can be used
·
INR should drop in 24-48
hr
·
Resume warfarin once INR
in therapeutic range at 20% reduced dosage
INR 5.0-9.0
·
Stop warfarin for 2 days
·
Daily INR
·
Resume warfarin at
10-20% reduced dosage once INR in therapeutic range.
·
If high risk for serious
bleeding consider oral vitamin K 2-3 mg.
If not available, IV preparation can be used
INR 4.0-5.0
·
Omit 1 dose
·
INR in 2-5 days
·
Resume warfarin at
10-20% lower dose once INR in therapeutic range.
INR 3.0-4.0
·
No change in dose. Recheck in 1 week.
·
If no change in INR,
reduce warfarin dosage by 10-20%
INR 2.0 - 3.0 No change.
INR 1.5 - 2.0 Increase weekly dosage by 10% and repeat INR in 1
week.
INR <1.50 Increase weekly dose by 15% and repeat INR in 1 week.
Management of Elevated INR with Serious Bleeding:
1. Admit to acute care
2. Stop warfarin
3. Attempt local hemostasis if possible.
4. Give Vitamin K 5-10 mg. by Slow IV infusion over 20-60 min.
5. Give Fresh Frozen Plasma 2-3 units initially, and more
if subsequently indicated.
6. Obtain consultation.
1. Treatment of patients overanticoagulated with
warfarin.
2. Initiation and maintenance of warfarin therapy.
3. Valentine KA, et al. Correcting excess anticoagulation
after warfarin. In: UpToDate, Basow, DS (Ed), UpToDate,
** INR:
international Normalized Ratio = (x/y)z, where: x = Prothrombin Time
of sample (sec) y = Mean Normal Prothrombin Time (sec) z = [ ISI of
Thromboplastin]