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Warfarin


Pronunciation

 (WAR far in)


U.S. Brand Names

 Coumadin®; Jantoven™


Synonyms

 Warfarin Sodium


Generic Available

 Yes: Tablet


Canadian Brand Names

 Apo-Warfarin®; Coumadin®; Gen-Warfarin; Taro-Warfarin


Use

 Prophylaxis and treatment of venous thrombosis, pulmonary embolism and thromboembolic disorders; atrial fibrillation with risk of embolism and as an adjunct in the prophylaxis of systemic embolism after myocardial infarction


Use - Unlabeled/Investigational

 Prevention of recurrent transient ischemic attacks and to reduce risk of recurrent myocardial infarction


Pregnancy Risk Factor

 X


Pregnancy Implications

 Oral anticoagulants cross the placenta and produce fetal abnormalities. Warfarin should not be used during pregnancy because of significant risks. Adjusted-dose heparin can be given safely throughout pregnancy in patients with venous thromboembolism.


Lactation

 Does not enter breast milk, only metabolites are excreted (AAP rates "compatible")


Contraindications

 Hypersensitivity to warfarin or any component of the formulation; hemorrhagic tendencies; hemophilia; thrombocytopenia purpura; leukemia; recent or potential surgery of the eye or CNS; major regional lumbar block anesthesia or surgery resulting in large, open surfaces; patients bleeding from the GI, respiratory, or GU tract; threatened abortion; aneurysm; ascorbic acid deficiency; history of bleeding diathesis; prostatectomy; continuous tube drainage of the small intestine; polyarthritis; diverticulitis; emaciation; malnutrition; cerebrovascular hemorrhage; eclampsia/pre-eclampsia; blood dyscrasias; severe uncontrolled or malignant hypertension; severe hepatic disease; pericarditis or pericardial effusion; subacute bacterial endocarditis; visceral carcinoma; following spinal puncture and other diagnostic or therapeutic procedures with potential for significant bleeding; history of warfarin-induced necrosis; an unreliable, noncompliant patient; alcoholism; patient who has a history of falls or is a significant fall risk; pregnancy


Warnings/Precautions

 Use care in the selection of patients appropriate for this treatment. Ensure patient cooperation especially from the alcoholic, illicit drug user, demented, or psychotic patient. Use with caution in trauma, acute infection (antibiotics and fever may alter affects), renal insufficiency, prolonged dietary insufficiencies (vitamin K deficiency), moderate-severe hypertension, polycythemia vera, vasculitis, open wound, active TB, history of PUD, anaphylactic disorders, indwelling catheters, severe diabetes, thyroid disease, severe renal disease, and menstruating and postpartum women. Use with caution in protein C deficiency.

Hemorrhage is the most serious risk of therapy. Patient must be instructed to report bleeding, accidents, or falls. Patient must also report any new or discontinued medications, herbal or alternative products used, significant changes in smoking or dietary habits. Necrosis or gangrene of the skin and other tissues can occur (rarely) due to early hypercoagulability. "Purple toes syndrome," due to cholesterol microembolization, may rarely occur (often after several weeks of therapy). Women may be at risk of developing ovarian hemorrhage at the time of ovulation. The elderly may be more sensitive to anticoagulant therapy.


Adverse Reactions

 As with all anticoagulants, bleeding is the major adverse effect of warfarin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility.

Additional adverse effects are often related to idiosyncratic reactions, and the frequency cannot be accurately estimated.

Cardiovascular: Vasculitis, edema, hemorrhagic shock

Central nervous system: Fever, lethargy, malaise, asthenia, pain, headache, dizziness, stroke

Dermatologic: Rash, dermatitis, bullous eruptions, urticaria, pruritus, alopecia

Gastrointestinal: Anorexia, nausea, vomiting, stomach cramps, abdominal pain, diarrhea, flatulence, gastrointestinal bleeding, taste disturbance, mouth ulcers

Genitourinary: Priapism, hematuria

Hematologic: Hemorrhage, leukopenia, unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulation, retroperitoneal hematoma, agranulocytosis

Hepatic: Hepatic injury, jaundice, transaminases increased

Neuromuscular & skeletal: Paresthesia, osteoporosis

Respiratory: Hemoptysis, epistaxis, pulmonary hemorrhage, tracheobronchial calcification

Miscellaneous: Hypersensitivity/allergic reactions

Skin necrosis/gangrene, due to paradoxical local thrombosis, is a known but rare risk of warfarin therapy. Its onset is usually within the first few days of therapy and is frequently localized to the limbs, breast or penis. The risk of this effect is increased in patients with protein C or S deficiency.

"Purple toes syndrome," caused by cholesterol microembolization, also occurs rarely. Typically, this occurs after several weeks of therapy, and may present as a dark, purplish, mottled discoloration of the plantar and lateral surfaces. Other manifestations of cholesterol microembolization may include rash; livedo reticularis; gangrene; abrupt and intense pain in lower extremities; abdominal, flank, or back pain; hematuria, renal insufficiency; hypertension; cerebral ischemia; spinal cord infarction; or other symptom of vascular compromise.


Overdosage/Toxicology

 Symptoms of overdose include internal or external hemorrhage and hematuria. Avoid emesis and lavage to avoid possible trauma and incidental bleeding. When an overdose occurs, the drug should be immediately discontinued and vitamin K1 (phytonadione) may be administered, up to 25 mg I.V. for adults. When hemorrhage occurs, fresh frozen plasma transfusions can help control bleeding by replacing clotting factors. In urgent bleeding, prothrombin complex concentrates may be needed.

Management of elevated INR: See table.


or

Management of Elevated INR

INR Patient Situation Action
>3 and <5 No bleeding or need for rapid reversal (ie, no need for surgery) Omit next few warfarin dose and/or restart at lower dose when INR approaches desired range. If only minimally above range, then no dosage reduction may be required.
>5 and <9.0 No bleeding or need for rapid reversal Omit next 1-2 doses, monitor INR more frequently, and restart at lower dose when INR approaches target range or omit dose and give 1-2.5 mg vitamin K1 orally (use this if patient has risk factors for bleeding).
No bleeding but reversal needed for surgery or dental extraction within 24 hours 2-4 mg vitamin K1 orally (expected reversal within 24 hours); give additional 1-2 mg if INR remains high at 24 hours.
>9.0 and <20.0 No bleeding Stop warfarin, give 3-5 mg vitamin K1 orally; follow INR closely; repeat vitamin K1 if needed. Reassess need and dose of warfarin when INR approaches desirable range.
Rapid reversal required
(ie, INR >20)		 Serious bleeding or major warfarin overdose Stop warfarin, give 10 mg vitamin K1 by slow I.V. infusion. May repeat vitamin K1 every 12 hours and give fresh plasma transfusion or prothrombin complex concentrate as needed. When appropriate, heparin can be given until the patient becomes responsive to warfarin.

Drug Interactions

 Substrate of CYP1A2 (minor), 2C8/9 (major), 2C19 (minor), 3A4 (minor); Inhibits CYP2C8/9 (moderate), 2C19 (weak)

See tables.


Ethanol/Nutrition/Herb Interactions

Decreased Anticoagulant Effects

Induction of Enzymes Increased Procoagulant Factors Decreased Drug Absorption Other
Antithyroid drugs
Barbiturates
Bosentan
Carbamazepine
Glutethimide
Griseofulvin		 Nafcillin
Phenytoin
Rifampin		 Estrogens
Oral contraceptives
Vitamin K (including nutritional supplements)		 Aluminum hydroxide
Cholestyramine 1
Colestipol 1 		Ethchlorvynol
Griseofulvin
Spironolactone 2
Sucralfate
Decreased anticoagulant effect may occur when these drugs are administered with oral anticoagulants.
1 Cholestyramine and colestipol may increase the anticoagulant effect by binding vitamin K in the gut; yet, the decreased drug absorption appears to be of more concern.
2 Diuretic-induced hemoconcentration with subsequent concentration of clotting factors has been reported to decrease the effects of oral anticoagulants.

Ethanol/Nutrition/Herb Interactions

Increased Bleeding Tendency

Inhibit Platelet Aggregation Inhibit Procoagulant Factors Ulcerogenic Drugs
Cephalosporins
Clopidogrel
Dipyridamole
Indomethacin
Penicillin, parenteral
Salicylates
Sulfinpyrazone
Ticlopidine		 Antimetabolites
Quinidine
Quinine
Salicylates		 Adrenal corticosteroids
Indomethacin
Potassium products
Salicylates
Use of these agents with oral anticoagulants may increase the chances of hemorrhage.

Ethanol/Nutrition/Herb Interactions

Enhanced Anticoagulant Effects

Decrease Vitamin&nbsp;K Displace Anticoagulant Inhibit Metabolism Other
Oral antibiotics:
Can / INR.
Check INR 3 days after a patient begins antibiotics to see the INR value and adjust the warfarin dose accordingly		 Chloral hydrate
Clofibrate
Diazoxide
Ethacrynic acid
Miconazole (including
intravaginal use)
Nalidixic acid
Salicylates
Sulfonamides
Sulfonylureas		 Allopurinol
Amiodarone
Azole antifungals
Capecitabine
Chloramphenicol
Chlorpropamide
Cimetidine
Ciprofloxacin
Co-trimoxazole
Disulfiram
Ethanol
(acute ingestion) 1
Flutamide
Isoniazid
Metronidazole
Norfloxacin
Ofloxacin
Omeprazole
Phenytoin
Propafenone
Propoxyphene
Quinidine
"Statins" 2
Sulfinpyrazone
Sulfonamides
Tamoxifen
Tolbutamide
Zafirlukast
Zileuton		 Acetaminophen
Anabolic steroids
Capecitabine
Celecoxib
Clarithromycin
Clofibrate
Danazol
Erythromycin
Fenofibrate
Gemfibrozil
Glucagon
Influenza vaccine
Propranolol
Propylthiouracil
Ranitidine
Rofecoxib
SSRIs
Sulindac
Tetracycline
Thyroid drugs
Vitamin E
( 400 int. units)
1 The hypoprothrombinemic effect of oral anticoagulants has been reported to be both increased and decreased during chronic and excessive alcohol ingestion. Data are insufficient to predict the direction of this interaction in alcoholic patients.
2 Particularly lovastatin and fluvastatin; others (atorvastatin, pravastatin) rarely associated with increased PT.

CYP2C8/9 inducers: May decrease the levels/effects of warfarin. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8/9 inhibitors: May increase the levels/effects of warfarin. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.

CYP2C8/9 substrates: Warfarin may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, and sertraline.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol. Acute ethanol ingestion (binge drinking) decreases the metabolism of warfarin and increases PT/INR. Chronic daily ethanol use increases the metabolism of warfarin and decreases PT/INR.

Food: The anticoagulant effects of warfarin may be decreased if taken with foods rich in vitamin K. Vitamin E may increase warfarin effect. Cranberry juice may increase warfarin effect.

Herb/Nutraceutical: St John's wort may decrease warfarin levels. Alfalfa contains large amounts of vitamin K as do many enteral products. Coenzyme Q10 may decrease response to warfarin. Avoid cat's claw, dong quai, bromelains, evening primrose, feverfew, red clover, horse chestnut, garlic, green tea, ginseng, ginkgo (all have additional antiplatelet activity).


Stability

 Protect from light; injection is stable for 4 hours at room temperature after reconstitution with 2.7 mL of sterile water (yields 2 mg/mL solution)


Compatibility

 Stable in D5LR, D5 1 /2NS, D5NS, D5W, D10W, variable stability (consult detailed reference) in LR, NS

Y-site administration: Compatible: Amikacin, ascorbic acid injection, cefazolin, ceftriaxone, dopamine, epinephrine, heparin, lidocaine, metaraminol, morphine, nitroglycerin, oxytocin, potassium chloride, ranitidine. Incompatible: Aminophylline, bretylium, ceftazidime, cimetidine, ciprofloxacin, dobutamine, esmolol, gentamicin, labetalol, metronidazole, promazine, Ringer's injection. Variable (consult detailed reference): Ammonium chloride, vancomycin

Compatibility in syringe: Incompatible: Heparin


Mechanism of Action

 Interferes with hepatic synthesis of vitamin K-dependent coagulation factors (II, VII, IX, X)


Pharmacodynamics/Kinetics

Onset of action: Anticoagulation: Oral: 36-72 hours

Peak effect: Full therapeutic effect: 5-7 days; INR may increase in 36-72 hours

Duration: 2-5 days

Absorption: Oral: Rapid

Metabolism: Hepatic

Half-life elimination: 20-60 hours; Mean: 40 hours; highly variable among individuals


Dosage

Oral:

Infants and Children: 0.05-0.34 mg/kg/day; infants <12 months of age may require doses at or near the high end of this range; consistent anticoagulation may be difficult to maintain in children <5 years of age

Adults: Initial dosing must be individualized. Consider the patient (hepatic function, cardiac function, age, nutritional status, concurrent therapy, risk of bleeding) in addition to prior dose response (if available) and the clinical situation. Start 5-10 mg daily for 2 days. Adjust dose according to INR results; usual maintenance dose ranges from 2-10 mg daily (individual patients may require loading and maintenance doses outside these general guidelines).

Note : Lower starting doses may be required for patients with hepatic impairment, poor nutrition, CHF, elderly, or a high risk of bleeding. Higher initial doses may be reasonable in selected patients (ie, receiving enzyme-inducing agents and with low risk of bleeding).

I.V. (administer as a slow bolus injection): 2-5 mg/day

Dosing adjustment/comments in hepatic disease: Monitor effect at usual doses; the response to oral anticoagulants may be markedly enhanced in obstructive jaundice (due to reduced vitamin K absorption) and also in hepatitis and cirrhosis (due to decreased production of vitamin K-dependent clotting factors); prothrombin index should be closely monitored


Administration

Oral: Do not take with food. Take at the same time each day.

I.V.: Administer as a slow bolus injection over 1-2 minutes; avoid all I.M. injections


Monitoring Parameters

 Prothrombin time, hematocrit, INR


Reference Range

Therapeutic: 2-5 mcg/mL (SI: 6.5-16.2 mol/L)

Prothrombin time should be 1 1 /2 to 2 times the control or INR should be increased 2 to 3 times based upon indication

Normal prothrombin time: 10-13 seconds

INR ranges based upon indication: See table.


Test Interactions

INR Ranges Based Upon Indication

Indication Targeted INR Range Targeted INR
Acute myocardial infarction with risk factor 1 2.0-3.0 2.5
Atrial fibrillation (moderate- to high-risk patients) 2.0-3.0 2.5
Bileaflet or tilting disk mechanical aortic valve
(NSR, NL LA)		 2.0-3.0 2.5
Bileaflet mechanical aortic valve with atrial fibrillation 2.5-3.5 3
Bileaflet mechanical aortic valve with atrial fibrillation with ASA 80-100 mg/day 2.0-3.0 2.5
Bileaflet or tilting disk mechanical mitral valve 2.5-3.5 3
Bileaflet or tilting disk mechanical mitral valve with ASA 80-100 mg/day 2.0-3.0 2.5
Bioprosthetic mitral or aortic valve 2 2.0-3.0 2.5
Bioprosthetic mitral or aortic valve with atrial fibrillation 2.0-3.0 2.5
Cardioembolic cerebral ischemic events 2.0-3.0 2.5
Mechanical heart valve (caged ball, caged disk) with ASA 80-100 mg/day 2.5-3.5 3
Mechanical prosthetic valve with systemic embolism despite adequate anticoagulation 3 2.5-3.5 3
Rheumatic mitral valve disease and NSR
(left atrial diameter >5.5 cm)		 2.0-3.0 2.5
Venous thromboembolism 2.0-3.0 2.5
1 Up to 3 months of therapy following heparin or LMWH in patients with anterior Q-wave infarction, severe left-ventricular dysfunction, mural thrombus on 2D echo, atrial fibrillation, history of systemic or pulmonary embolism, congestive heart failure.
2 Maintained for 3 months; chronic low-dose aspirin (80 mg/day) after warfarin therapy.
3 Add ASA 80-100 mg/day.
For complete discussion, Chest, 2001, 119 (Suppl):1S-370S

Warfarin levels are not used for monitoring degree of anticoagulation. They may be useful if a patient with unexplained coagulopathy is using the drug surreptitiously or if it is unclear whether clinical resistance is due to true drug resistance or lack of drug intake.

Normal prothrombin time (PT): 10.9-12.9 seconds. Healthy premature newborns have prolonged coagulation test screening results (eg, PT, aPTT, TT) which return to normal adult values at approximately 6 months of age. Healthy prematures, however, do not develop spontaneous hemorrhage or thrombotic complications because of a balance between procoagulants and inhibitors

The World Health Organization (WHO), in cooperation with other regulatory-advisory bodies, has developed system of standardizing the reporting of PT values through the determination of the International Normalized Ratio (INR). The INR involves the standardization of the PT by the generation of two pieces of information: the PT ratio and the International Sensitivity Index (ISI)

Therapeutic ranges are now available or being developed to assist practicing physicians in their treatment of patients with a wide variety of thrombotic disorders


Test Interactions

 Increased aPTT


Dietary Considerations

 Foods high in vitamin K (eg, beef liver, pork liver, green tea and leafy green vegetables) inhibit anticoagulant effect. Do not change dietary habits once stabilized on warfarin therapy; a balanced diet with a consistent intake of vitamin K is essential; avoid large amounts of alfalfa, asparagus, broccoli, Brussels sprouts, cabbage, cauliflower, green teas, kale, lettuce, spinach, turnip greens, watercress decrease efficacy of warfarin. It is recommended that the diet contain a CONSISTENT vitamin K content of 70-140 mcg/day. Check with healthcare provider before changing diet.


Patient Education

 It is imperative that you inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed; if dose is missed, take as soon as possible. Do not double dose. Follow diet and activity as recommended by prescriber; check with prescriber before changing diet. Avoid alcohol. You will have a tendency to bleed easily while taking this drug (use soft toothbrush, waxed dental floss, electric razor, and avoid scissors or sharp knives and potentially harmful activities). May cause nausea, vomiting, disturbed taste (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report any unusual bleeding or bruising (eg, bleeding gums, nosebleed, blood in urine, dark stool, bloody emesis); skin rash or irritation; unusual fever; persistent nausea or GI upset; pain in joints or back; or swelling or pain at injection site. Pregnancy precautions: Do not get pregnant while taking this medication. Consult prescriber for appropriate barrier contraceptive measures.


Anesthesia and Critical Care Concerns/Other Considerations

 Tube-feeding formulas are often a rich source of vitamin K.

Management of oral anticoagulation prior to surgery: Patients with low risk of thromboembolism (eg, patients without venous thromboembolism for >3 months or patients who have experienced atrial fibrillation who do not have a history of stroke): Stop warfarin therapy approximately 4 days before surgery, allow the INR to return to a near normal level, briefly administer postoperative prophylaxis (if the intervention itself creates a higher risk of thrombosis) using low-dose heparin and simultaneously begin warfarin therapy after surgery.

Patients with intermediate risk of thromboembolism: Stop warfarin therapy approximately 4 days before surgery, allow the INR to fall. Initiate low-dose heparin or prophylactic dose of LMWH beginning 2 days before surgery. Then commence low-dose heparin (or LMWH) and warfarin therapy after surgery.

Patients with high risk of thromboembolism (eg, a recent [<3 months] history of venous thromboembolism, a mechanical cardiac valve in the mitral position; or an old model of cardiac valve [ball/cage]): Stop warfarin therapy approximately 4 days before surgery, allow the INR to return to a normal level, begin therapy with full-dose heparin or full-dose LMWH as the INR falls (approximately 2 days before surgery). Heparin can be administered as a SubQ injection on an outpatient basis, can then be given as a continuous I.V. infusion after hospital admission in preparation for surgery, and can be discontinued 5 hours before surgery with the expectation that the anticoagulant effect will have worn off at the time of surgery. It is also possible to continue the administration of SubQ heparin or LMWH and to stop therapy 12-24 hours before surgery with the expectation that the anticoagulant effect will be very low or will have worn off by the time of surgery.

Patients with low risk of bleeding: Continue warfarin therapy at a lower dose and operate at an INR of 1.3-1.5, an intensity that has been shown to be safe in randomized trials of gynecologic and orthopedic surgical patients. The dose of warfarin can be lowered 4-5 days before surgery. Warfarin therapy then can be restarted after surgery and supplemented with low-dose heparin if necessary.

Heparin-induced Thrombocytopenia (HIT) or Heparin-induced Thrombotic Thrombocytopenia Syndrome (HITTS): When a patient develops HIT/HITTS, do not start warfarin. Rather, a direct thrombin inhibitor should be initiated and continued until platelets return. Warfarin anticoagulation should be postponed in the patient with HIT until substantial recovery of the platelet count has occurred.


Cardiovascular Considerations

Factor VII half-life: 4-6 hours

Factor X half-life: 27-48 hours

Factor II half-life: 42-72 hours

Overlapping heparin and warfarin therapy by at least 5 days is necessary in treatment of DVT/PE even if the INR is therapeutic earlier. Although an elevation in INR (factor VII depletion) may be seen early (first 24-48 hours) in warfarin therapy, it does not represent adequate anticoagulation. Factors II and X must be depleted which takes considerably longer.

Vitamin K Rich Foods: Significant changes in vitamin K intake can upset warfarin stability. The list of usual foods with high vitamin K content are well known, however, unique ones continue to appear like green tea, chewing tobacco, a variety of oils (canola, corn, olive, peanut, safflower, sesame seed, soybean, and sunflower). Snack foods containing Olestra have 80 mcg of vitamin K added to each ounce. Some natural products may contain hidden sources of vitamin K.

Heparin-induced Thrombocytopenia (HIT) or Heparin-induced Thrombotic Thrombocytopenia Syndrome (HITTS): When a patient develops HIT/HITTS, do not start warfarin. Rather, a direct thrombin inhibitor should be initiated and continued until platelets return. Warfarin anticoagulation should be postponed in the patient with HIT until substantial recovery of the platelet count has occurred.

ST-Elevation Myocardial Infarction: The 2004 ACC/AHA guidelines for the management of patients with acute myocardial infarction suggest considering warfarin as a secondary prevention alternative to clopidogrel in aspirin allergic patients. If used alone, an INR of 2.5-3.5 is recommended.


Dental Health: Effects on Dental Treatment

 Signs of warfarin overdose may first appear as bleeding from gingival tissue; consultation with prescribing physician is advisable prior to surgery to determine temporary dose reduction or withdrawal of medication.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 None reported


Mental Health: Effects on Psychiatric Treatment

 May cause leukopenia; use caution with clozapine and carbamazepine; barbiturates and carbamazepine may decrease the anticoagulant effect of warfarin; chloral hydrate, alcohol, disulfiram, and SSRIs may enhance the anticoagulant effect


Dosage Forms

Injection, powder for reconstitution, as sodium (Coumadin®): 5 mg

Tablet, as sodium (Coumadin®, Jantoven™): 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg


References

Anand SS, Yusuf S, Pogue J, et al, "Long-Term Oral Anticoagulant Therapy in Patients With Unstable Angina or Suspected Non-Q-Wave Myocardial Infarction: Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study Results," Circulation , 1998, 98(11):1064-70.

Antman EM, Anbe SC, Alpert JS, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction)," Circulation, 2004, 110:588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed October 26, 2004.

"Effect of Long-Term Oral Anticoagulant Treatment on Mortality and Cardiovascular Morbidity After Myocardial Infarction. Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group," Lancet , 1994, 343(8896):499-503.

Kovacs MJ, Rodger M, Anderson DR, et al, "Comparison of 10-mg and 5-mg Warfarin Initiation Nomograms Together With Low-Molecular-Weight Heparin for Outpatient Treatment of Acute Venous Thromboembolism. A Randomized, Double-Blind, Controlled Trial," Ann Intern Med , 2003, 138(9):714-9.

"Randomised Double-Blind Trial of Fixed Low-Dose Warfarin With Aspirin After Myocardial Infarction. Coumadin Aspirin Reinfarction Study (CARS) Investigators," Lancet , 1997, 350(9075):389-96.

"Sixth ACCP Consensus Conference on Antithrombotic Therapy," Chest , 2001, 119(Suppl):1-370.

Smith P, Arnesen H, and Holme I, "The Effect of Warfarin on Mortality and Reinfarction After Myocardial Infarction," N Engl J Med , 1990, 323(3):147-52.

Smythe MA, Warkentin TE, Stephens JL, et al, "Venous Limb Gangrene During Overlapping Therapy With Warfarin and a Direct Thrombin Inhibitor for Immune Heparin-Induced Thrombocytopenia," Am J Hematol , 2002, 71(1):50-2.

Suvarna R, Pirmohamed M, and Henderson L, "Possible Interaction Between Warfarin and Cranberry Juice," BMJ , 2003, 327(7429):1454.


International Brand Names

 Apo-Warfarin® (CA); Coumadin® (CA); Gen-Warfarin (CA); Taro-Warfarin (CA)


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