Warfarin Sodium

The following serious adverse reactions to COUMADIN are discussed in greater detail in other sections of the labeling:

• Hemorrhage [see BOX WARNING, WARNINGS AND PRECAUTIONS and OVERDOSE]
• Tissue Necrosis [see WARNINGS AND PRECAUTIONS]
• Calciphylaxis [see WARNINGS AND PRECAUTIONS]
• Acute Kidney Injury [see WARNINGS AND PRECAUTIONS]
• Systemic Atheroemboli and Cholesterol Microemboli [see WARNINGS AND PRECAUTIONS]
• Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS [see WARNINGS AND PRECAUTIONS]
• Other Clinical Settings with Increased Risks [see WARNINGS AND PRECAUTIONS]

Other adverse reactions to COUMADIN include:

• Immune system disorders: hypersensitivity/allergic reactions (including urticaria and anaphylactic reactions)
• Vascular disorders: vasculitis
• Hepatobiliary disorders: hepatitis, elevated liver enzymes. Cholestatic hepatitis has been associated with concomitant administration of COUMADIN and ticlopidine.
• Gastrointestinal disorders: nausea, vomiting, diarrhea, taste perversion, abdominal pain, flatulence, bloating
• Skin disorders: rash, dermatitis (including bullous eruptions), pruritus, alopecia
• Respiratory disorders: tracheal or tracheobronchial calcification
• General disorders: chills

Mechanism Of Action

Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide [see Pharmacogenomics].

Pharmacodynamics

An anticoagulation effect generally occurs within 24 hours after warfarin administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of COUMADIN may become more pronounced as effects of daily maintenance doses overlap. This is consistent with the half-lives of the affected vitamin Kdependent clotting factors and anticoagulation proteins: Factor II - 60 hours, VII - 4 to 6 hours, IX - 24 hours, X - 48 to 72 hours, and proteins C and S are approximately 8 hours and 30 hours, respectively.

Pharmacokinetics

COUMADIN is a racemic mixture of the R- and S-enantiomers of warfarin. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.

Warfarin is essentially completely absorbed after oral administration, with peak concentration generally attained within the first 4 hours.

Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Approximately 99% of the drug is bound to plasma proteins.

The elimination of warfarin is almost entirely by metabolism. Warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP450) microsomal enzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols) with minimal anticoagulant activity. Identified metabolites of warfarin include dehydrowarfarin, two diastereoisomer alcohols, and 4’-, 6-, 7-, 8-, and 10-hydroxywarfarin. The CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9, a polymorphic enzyme, is likely to be the principal form of human liver CYP450 that modulates the in vivo anticoagulant activity of warfarin. Patients with one or more variant CYP2C9 alleles have decreased S-warfarin clearance [see Pharmacogenomics].

The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of Rwarfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown but may be due to a combination of pharmacokinetic and pharmacodynamic factors. Limited information suggests there is no difference in the clearance of S-warfarin; however, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation [see DOSAGE AND ADMINISTRATION].

Asian patients may require lower initiation and maintenance doses of warfarin. A non-controlled study of 151 Chinese outpatients stabilized on warfarin for various indications reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. Patient age was the most important determinant of warfarin requirement in these patients, with a progressively lower warfarin requirement with increasing age.

Pharmacogenomics

The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles, CYP2C9*2 and CYP2C9*3, result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these alleles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively.

Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9, and *11 alleles in Caucasians.

Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle through inhibition of VKOR, a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (e.g., .1639G>A) have been associated with variable warfarin dose requirements.

VKORC1 and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements.

CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the initial dose of warfarin [see DOSAGE AND ADMINISTRATION].

Clinical Studies

Atrial Fibrillation

In five prospective, randomized, controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 4). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (see Table 4).

Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF Patients *

Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with COUMADIN [see DOSAGE AND ADMINISTRATION].

Mechanical And Bioprosthetic Heart Valves

In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin-treated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05). The results of this study are presented in Table 5.

Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves

In a prospective, open-label, clinical study comparing moderate (INR 2.65) versus high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in Table 6.

Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves

In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively, and minor embolic events 10.8% vs. 10.2%, respectively). Major hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group.

Myocardial Infarction

WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. The primary endpoint was a composite of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in Table 7.

Table 7: WARIS . Endpoint Analys is of Separate Events

WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR 2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in Table 8.

Table 8: WARIS II . Distribution of Events According to Treatment Group

There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.

Follow your doctor's instructions about taking warfarin while you are pregnant. Warfarin can harm an unborn baby or cause birth defects. However, the benefits of preventing blood clots in certain women may outweigh any risks to the baby.

Never take a double dose of this medication.

You should not take warfarin if you have a bleeding or blood cell disorder, blood in your urine or stools, an infection of the lining of your heart, stomach bleeding, bleeding in the brain, recent or upcoming surgery, or if you need a spinal tap or spinal anesthesia (epidural).

Warfarin may cause you to bleed more easily, especially if you have: a history of bleeding problems, high blood pressure or severe heart disease, kidney or liver disease, cancer, surgery or a medical emergency, a disease affecting the blood vessels in your brain, a history of stomach or intestinal bleeding, if you are 65 or older, or if you are severely ill or debilitated.

Many drugs (including some over-the-counter medicines and herbal products) can cause serious medical problems or death if you take them with warfarin. It is very important to tell your doctor about all medicines you have recently used.

Ask your doctor before taking any medicine for pain, arthritis, fever, or swelling. These medicines may affect blood clotting and may also increase your risk of stomach bleeding.

Any doctor, dentist, surgeon, or other medical care provider who treats you should know that you are taking this medication.

Avoid making any changes in your diet without first talking to your doctor.

You should not take warfarin if you are allergic to it, or if you have:

• hemophilia or any bleeding disorder that is inherited or caused by disease;
• a blood cell disorder such as anemia (lack of red blood cells) or a low level of platelets in your blood;
• blood in your urine or stools, or if you have been coughing up blood;
• an infection of the lining of your heart (also called bacterial endocarditis);
• stomach or intestinal bleeding or ulcer;
• recent head injury, aneurysm, or bleeding in the brain;
• if you have recently had or will soon have any type of surgery (especially brain, spine, or eye surgery); or
• if you undergo a spinal tap or receive spinal anesthesia (epidural).

You should not take warfarin if you cannot be reliable in taking it because of alcoholism, psychiatric problems, dementia, or similar conditions.

Warfarin may cause you to bleed more easily, especially if you have:

• a history of bleeding problems;
• high blood pressure or severe heart disease;
• kidney or liver disease;
• cancer;
• surgery or a medical emergency;
• a disease affecting the blood vessels in your brain;
• a history of stomach or intestinal bleeding;
• if you are 65 or older; or
• if you are severely ill or debilitated.

To make sure you can safely take warfarin, tell your doctor if you have any of these other conditions:

• celiac sprue (an intestinal disorder);
• diabetes;
• congestive heart failure;
• overactive thyroid;
• a connective tissue disorder such as Marfan Syndrome, Sjogren syndrome, scleroderma, rheumatoid arthritis, or lupus; or
• if you have ever had low blood platelets after receiving heparin.

Follow your doctor's instructions about taking warfarin while you are pregnant. Warfarin can harm an unborn baby or cause birth defects. However, the benefits of preventing blood clots in certain women may outweigh any risks to the baby. Tell your doctor right away if you become pregnant during treatment. Use effective birth control while you are using this medication.

It is not known whether warfarin passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Your pharmacist can provide more information about warfarin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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DVT and PE

Treatment and secondary prevention of venous thromboembolism (DVT and/or PE).211 500 1005

Initiate concomitantly with a parenteral anticoagulant (e.g., a low molecular weight heparin [LMWH], heparin [referring throughout this monograph to unfractionated heparin], fondaparinux).1005 Overlap parenteral and oral anticoagulant therapy for ≥5 days and until a stable INR of ≥2 has been maintained for ≥24 hours, then discontinue parenteral anticoagulant.1000 1005

Anticoagulant therapy generally not recommended for treatment of isolated distal DVT unless symptoms are severe and there is a risk for thrombus extension.1005

The American College of Chest Physicians (ACCP) recommends a moderate intensity of anticoagulation (target INR 2.5, range 2–3) for most patients with DVT or PE.1000 1005

Appropriate duration of therapy determined by individual factors (e.g., location of thrombi, presence or absence of precipitating factors, presence of cancer, patient's risk of bleeding).1005 For most cases of venous thromboembolism, a minimum of 3 months of anticoagulant therapy is recommended.211 330 1005 Long-term anticoagulation (>3 months) may be considered in selected patients (e.g., those with idiopathic [unprovoked] DVT or PE who are at low risk of bleeding, cancer patients with DVT or PE).1005 (See Dosage under Dosage and Administration.)

Warfarin generally is the preferred anticoagulant for long-term treatment of venous thromboembolism in patients without cancer; however, in patients with cancer, ACCP suggests use of an LMWH over warfarin because of certain factors in such patients that may affect warfarin therapy (e.g., possible reduced response to warfarin, drug interactions, need for invasive procedures that require reversal of anticoagulation).1005

Used in select pediatric patients with DVT or PE†.1013 LMWHs or heparin generally recommended for both initial and ongoing treatment of venous thromboembolism in children; however, warfarin may be indicated in some situations (e.g., recurrent idiopathic venous thromboembolism).1013

Treatment and secondary prevention of venous thromboembolic events secondary to use of central venous access devices (CVAD) in children†.1013 Remove affected CVAD if no longer functioning or required; however, if CVAD required, ACCP suggests giving anticoagulants until catheter is removed.1013 After initial 3 months of therapy, may consider use of prophylactic-dose warfarin (target INR 1.5–1.9); however, therapeutic dosages may be required if recurrent thromboembolism occurs.1013

Orthopedic Surgery

Prevention of postoperative venous thromboembolism in patients undergoing hip- or knee-replacement surgery or hip-fracture surgery.1003

ACCP recommends routine thromboprophylaxis (with a pharmacologic and/or mechanical method) in all patients undergoing major orthopedic surgery (hip- or knee-replacement surgery, hip-fracture surgery).1003 Continue thromboprophylaxis for at least 10–14 days, and possibly for up to 35 days after surgery.1003

Several antithrombotic agents (e.g., LMWHs, fondaparinux, low-dose heparin, warfarin, aspirin) recommended by ACCP for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery.1003 Although LMWHs generally preferred, alternative agents (e.g., warfarin) may be considered if an LMWH is not available or cannot be used (e.g., in patients with heparin-induced thrombocytopenia [HIT] or in those who refuse or are uncooperative with sub-Q injections).1003

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, bleeding risk, logistics, and compliance.1003

Embolism Associated with Atrial Fibrillation

Prevention of stroke and systemic embolism in patients with atrial fibrillation.223 278 279 369 456 459 500 990 999 1007 1017 ACCP, ACC, AHA, the American Stroke Association (ASA), and other experts recommend antithrombotic therapy (e.g., warfarin, aspirin) in all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless such therapy is contraindicated.80 81 82 223 278 279 369 456 459 990 992 999 1007 1017

Choice of antithrombotic therapy is based on patient's risk for stroke and bleeding.80 81 82 341 345 369 459 999 1007 In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients who have a moderate to high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke.80 81 82 211 330 335 341 344 345 349 456 990 999 1007 1017 Patients considered to be at increased risk of stroke generally include those with advanced age (e.g., ≥75 years), history of hypertension, diabetes mellitus, or congestive heart failure.80 81 82 500 999 1007 In addition, population-based studies suggest that female sex is an important risk factor for stroke in patients with atrial fibrillation, particularly in patients ≥75 years of age.1017

AHA and ASA state that oral anticoagulation is not recommended in women ≤65 years of age with atrial fibrillation and no other risk factors; instead, antiplatelet therapy is a reasonable option in selected low-risk women.1017

In patients with atrial fibrillation at increased risk of stroke who cannot take or choose not to take oral anticoagulants for reasons other than concerns about major bleeding (e.g., those with difficulty maintaining stable INRs, compliance issues, dietary restrictions, cost limitations), combination therapy with clopidogrel and aspirin rather than aspirin alone is recommended.998 1007

Antiplatelet agents may be used in combination with warfarin therapy in selected patients who have coexisting conditions that warrant use of antiplatelet therapy (e.g., those with recent placement of an intracoronary stent, those with acute coronary syndrome).1007

AHA and ASA state that apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in selected women with paroxysmal or permanent atrial fibrillation and certain risk factors who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (creatinine clearance <15 mL/minute),1038 lower body weight (<50 kg), or advanced liver disease (impaired baseline clotting function).1017 Warfarin generally should remain the treatment of choice in patients with severe renal impairment pending clinical outcomes data with the non-vitamin K antagonist oral anticoagulants in such patients.86

Experts suggest managing antithrombotic therapy in patients with atrial flutter in the same manner as in patients with atrial fibrillation.999 1007

Cardioversion of Atrial Fibrillation

Prevention of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation.341 999 1007

ACCP and other experts recommend that patients with atrial fibrillation lasting >48 hours or of unknown duration who are to undergo elective cardioversion receive therapeutic anticoagulation (e.g., usually with warfarin) for ≥3 weeks prior to cardioversion; alternatively, a transesophageal echocardiography (TEE)-guided approach may be used.999 1007 After successful cardioversion, all patients should receive therapeutic anticoagulation for ≥4 weeks.999 1007

Experts suggest the same approach to thromboprophylaxis in patients undergoing cardioversion for atrial flutter as that used in patients with atrial fibrillation.999 1007

Embolism Associated with Valvular Heart Disease

Prevention of thromboembolism associated with various types of valvular heart disease, in combination with or as an alternative to low-dose aspirin; assess risk of thromboembolism versus risk of bleeding when determining choice of antithrombotic therapy.344 459 1008

Warfarin anticoagulation (INR 2–3) is recommended in patients with rheumatic mitral valve disease and concurrent atrial fibrillation, left atrial thrombus, or a history of systemic embolism.1007 1008

ACCP suggests warfarin anticoagulation in patients with rheumatic mitral valve disease and normal sinus rhythm who have a left atrial diameter >5.5 cm† because of their high risk of developing atrial fibrillation.1008

Warfarin also recommended by ACC and AHA for prevention of thromboembolic events in selected patients with mitral valve prolapse and a history of stroke who have concomitant atrial fibrillation, mitral valve regurgitation, or left atrial thrombus.996

Generally should not initiate antithrombotic therapy in patients with infective endocarditis involving a native valve because of the risk of serious (e.g., intracerebral) hemorrhage and lack of documented efficacy.1008 In patients with a prosthetic valve who are already receiving warfarin, ACCP suggests temporary discontinuance of the drug if infective endocarditis develops and reinitiation of therapy once invasive procedures no longer required and patient is stabilized without signs of neurologic complications.1008

Used in a limited number of patients undergoing percutaneous balloon mitral valvotomy† to prevent left atrial embolism.1008

Thromboembolism Associated with Prosthetic Heart Valves

Used to reduce the incidence of thromboembolism (e.g., stroke) in patients with prosthetic mechanical or biological heart valves.211 330 341 342 343 370 1008

Risk of systemic embolism higher with mechanical versus bioprosthetic valves, higher with first-generation mechanical (e.g., caged ball, caged disk) valves versus newer mechanical (e.g., bileaflet, Medtronic Hall tilting disk) valves, higher with >1 prosthetic valve, and higher with prosthetic mitral versus aortic valves; risk also increases in the presence of atrial fibrillation.341 342 343 370 1008

Long-term warfarin therapy required in all patients with mechanical heart valves because of associated high risk of thromboembolism.211 330 370 459 996 1008

Warfarin anticoagulation also suggested in patients with mitral bioprosthetic valves, at least for the first 3 months after valve insertion.1008 In patients with aortic bioprosthetic valves who are in sinus rhythm and have no other indications for warfarin therapy, aspirin generally suggested for initial (e.g., first 3 months after valve insertion) and long-term antithrombotic therapy.996 1008 However, long-term warfarin therapy (INR 2.5, range 2–3) may be indicated in some patients with bioprosthetic heart valves who have additional risk factors for thromboembolism (e.g., atrial fibrillation, prior thromboembolism, left ventricular dysfunction, hypercoagulable states).996

In general, target INR of 2.5 (range 2–3) is suggested in patients with an aortic mechanical valve, while target INR of 3 (range 2.5–3.5) is recommended in those with a mitral mechanical valve.500 1008 996 A higher intensity of warfarin anticoagulation also may be considered in patients with both aortic and mitral mechanical valves.1008

ACCP recommends adding low-dose aspirin (e.g., 50–100 mg daily) to warfarin therapy in all patients with mechanical heart valves who are at low risk of bleeding.1008 Combination therapy also may be warranted in some patients with bioprosthetic valves (e.g., those with additional risk factors for thrombosis).996

ST-Segment Elevation MI (STEMI)

Used as adjunctive therapy with antiplatelet agents (e.g., aspirin, clopidogrel) during and after successful coronary artery reperfusion for the prevention of early reocclusion and death in patients with acute STEMI.211 226 242 243 244 245 246 247 248 249 250 251 252 330 350 432 482 500 992 1010

In general, antiplatelet therapy is preferred to anticoagulants for secondary prevention and risk reduction in patients with atherosclerosis, including those with acute STEMI; however, warfarin (in combination with low-dose aspirin) may be indicated in selected patients (e.g., those with atrial fibrillation, prosthetic heart valve, left ventricular thrombus, or concomitant venous thromboembolic disease).992 1010

The manufacturer and other experts recommend warfarin therapy (target INR 2–3) in conjunction with low-dose aspirin (≤100 mg daily) for ≥3 months following acute STEMI in high-risk patients (e.g., those with large anterior STEMI, substantial heart failure, intracardiac thrombus visible on transthoracic echocardiography, atrial fibrillation, history of previous thromboembolic event).350 500 1010 Triple therapy with warfarin, low-dose aspirin, and clopidogrel is suggested in some patients (e.g., those with anterior STEMI and left ventricular thrombus).1010

Cerebral Embolism

Oral anticoagulation with warfarin or one of the non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran, rivaroxaban) is recommended for secondary prevention of cerebral embolism in patients with TIAs or ischemic stroke and concurrent atrial fibrillation, provided no contraindications exist.335 338 349 352 432 999 1009 1017

Warfarin also is used for prevention of recurrent stroke in patients at high risk for recurring cerebral embolism from other cardiac sources (e.g., prosthetic mechanical heart valves, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis, extensive wall-motion abnormalities).335 338 349 432 1008 1010

Antiplatelet agents generally preferred over oral anticoagulation for secondary prevention of noncardioembolic stroke in patients with a history of ischemic stroke or TIA.1009

ACCP, AHA, and ASA generally recommend oral anticoagulation with warfarin following initial therapy with heparin or an LMWH in patients with acute cerebral venous sinus thrombosis†.1009 1017 AHA and ASA recommend postpartum anticoagulation with warfarin (target INR of 2–3) as an alternative to LMWH for at least 6 weeks (for a total minimum duration of 6 months of anticoagulant therapy) following LMWH therapy during pregnancy in women with cerebral venous sinus thrombosis†.1017 Warfarin is suggested by ACCP as an option for long-term anticoagulation in children with arterial ischemic stroke† associated with dissection or a cardioembolic cause.1013 Warfarin also has been used in children with cerebral venous sinus thrombosis† who do not have substantial intracranial hemorrhage.1013

Arterial Occlusive Disease

Has been used in certain patients with peripheral arterial occlusive disease†.1011 However, ACCP generally recommends use of antiplatelet agents (aspirin or clopidogrel) for primary or secondary prevention of cardiovascular events in patients with peripheral arterial disease.1011

Indefinite anticoagulation with warfarin recommended by ACCP in all patients with chronic thromboembolic pulmonary hypertension†.1005

Heparin-Induced Thrombocytopenia

May be used as follow-up therapy after initial treatment with a nonheparin anticoagulant (e.g., lepirudin, argatroban) in patients with HIT.1006 Overlap therapy with warfarin and nonheparin anticoagulant for ≥5 days and until desired INR has been achieved.1006

Do not initiate warfarin in patients with HIT until substantial platelet recovery occurs (e.g., platelet count ≥150,000/mm3); in patients already receiving warfarin at the time of HIT diagnosis, ACCP suggests administration of vitamin K.1006 (See Necrosis under Cautions.)

Storage

Oral

15–30°C.211

Parenteral

15–30°C.211

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.