Warfarin Sodium

Class: Coumarin Derivatives
CAS Number: 129-06-6
Brands: Coumadin

Special Alerts:

[Posted 08/16/2007] FDA approved updated labeling to include pharmacogenomics information to the CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for the widely used blood-thinning drug, warfarin (Coumadin). This new information explains that people’s genetic makeup may influence how they respond to the drug. Specifically, people with variations in two genes may need lower warfarin doses than people without these genetic variations. The two genes are called CYP2C9 and VKORC1. The CYP2C9 gene is involved in the breakdown (metabolism) of warfarin and the VKORC1 gene helps regulate the ability of warfarin to prevent blood from clotting.

The dosage and administration of warfarin must be individualized for each patient according to the particular patient’s prothrombin time (PT) / International Normalized Ratio (INR) response to the drug. The specific dose recommendations are described in the warfarin product labeling, along with the new information regarding the impact of genetic information upon the initial dose and the response to warfarin. Ongoing warfarin therapy should be guided by continued INR monitoring. For more information visit the FDA website at: .

[Posted 10/06/2006] FDA and Bristol-Myers Squibb notified pharmacists and physicians of revisions to the labeling for warfarin (Coumadin), to include a new patient Medication Guide as well as a reorganization and highlighting of the current safety information to better inform providers and patients.

The FDA regulation 21CFR 208 requires a Medication Guide to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. Information about all currently approved Medication Guides is available at: . For more information visit the FDA website at: , and .

Introduction

Anticoagulant; a coumarin derivative.²¹¹

Uses for Warfarin Sodium

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Treatment/Secondary Prevention of Venous Thrombosis and Pulmonary Embolism

Used as follow-up to initial heparin anticoagulation for treatment of proximal DVT or nonmassive acute pulmonary embolism; initiate concomitantly with full-dose IV or adjusted-dose sub-Q unfractionated heparin or a weight-based dosage of sub-Q low molecular weight (LMW) heparin.^{365 407 427 446} May consider thrombolytic therapy in those with massive pulmonary embolism with hemodynamic instability or severe ileofemoral thrombosis.^{332 427}

LMW heparin or sub-Q unfractionated heparin used as alternative therapy for secondary prevention of DVT and pulmonary embolism when warfarin is contraindicated or inconvenient.^{429 446}

Secondary prevention of DVT and pulmonary embolism in patients with concurrent cancer; LMW heparin preferred in such patients.⁴²⁷

Secondary prevention of venous thromboembolism or pulmonary embolism associated with reversible or time-limited risk factors (e.g., transient immobilization, trauma, surgery, pharmacologic doses of estrogen, central venous catheter).^{365 437 446}

Secondary prevention of venous thromboembolism associated with thrombophilic conditions (e.g., combined factor V Leiden and prothrombin 20210 gene mutations).^{427 429}

Secondary prevention of venous thromboembolism in children with ongoing risk factors such as active nephrotic syndrome, ongoing asparaginase therapy, or lupus anticoagulant.⁴⁴⁶

Prophylaxis in General Surgery

American College of Chest Physicians (ACCP) prefers other drug therapies (LMW heparin or low-dose unfractionated heparin) or non-drug therapies (intermittent pneumatic compression, elastic stockings) in most moderate- to high-risk general surgery patients†.^{333 366 430}

Prophylaxis in Hip-Replacement Surgery

Short-term prophylaxis in patients undergoing hip-replacement surgery as one of several therapeutic options (fondaparinux, LMW heparin).^{366 430 200 208 333 366 430}

Consider extended prophylaxis (≤28–35 days) in patients undergoing hip-replacement surgery who have ongoing risk factors for venous thromboembolism (e.g., obesity, delayed mobilization, cancer, history of venous thromboembolism).⁴³⁰

Prophylaxis in Hip-fracture Surgery

Short-term prophylaxis in patients undergoing hip-fracture surgery†, as one of several therapeutic options (fondaparinux, LMW heparin).^{200 208 333 366 430}

Consider extended prophylaxis (≤28–35 days) in patients undergoing hip-fracture surgery who have ongoing risk factors for venous thromboembolism (e.g., obesity, delayed mobilization, cancer, history of venous thromboembolism).⁴³⁰

Prophylaxis in Knee-replacement Surgery

Short-term prophylaxis in patients undergoing knee-replacement surgery† as one of several therapeutic options (LMW heparin, fondaparinux, intermittent pneumatic compression).^{200 208 333 366 430}

Prophylaxis in Trauma

Prevention of thromboembolism in the rehabilitation phase of acute spinal cord injury†, as an alternative to continued therapy with an LMW heparin.^{366 430}

Prevention of thromboembolism in other types of trauma† after initial treatment with an LMW heparin in patients with an ongoing risk of venous thromboembolism requiring extended hospital stays.⁴³⁰

Continued prophylaxis with warfarin or an LMW heparin after hospital discharge suggested by ACCP in selected patients with impaired mobility.⁴³⁰

Embolism Associated with Atrial Fibrillation/Flutter

Prophylaxis of thromboembolic episodes in patients with persistent or paroxysmal atrial fibrillation who are at high risk for stroke (e.g., history of stroke, TIA, or systemic embolism; poor left ventricular systolic function and/or CHF; hypertension; diabetes mellitus; >75 years of age) or as alternative to aspirin in patients with persistent or paroxysmal atrial fibrillation and no other high-risk factors.^{211 431 434 e}

Prevention of thromboembolism in patients with atrial flutter† with or without mitral valve stenosis.^{a 431} Use alone or in combination with aspirin in patients with atrial flutter and prosthetic heart valves.⁴³¹

Patients with “lone” atrial fibrillation should be offered aspirin rather than warfarin because of their relatively low risk of stroke.^{223 279 283 335 339 344 346 367 368 369 431} ACCP, ACC, and AHA state that patients who decline therapy with warfarin or who are extremely poor candidates for oral anticoagulation also should be offered aspirin, except when contraindicated.^{335 339 349 367 368 431}

Short-term prevention of thromboembolism in patients with atrial fibrillation (>48 hours) who are at high risk for stroke after open-heart surgery.⁴³¹

Thromboprophylaxis during Cardioversion of Atrial Fibrillation/Flutter

Prevention of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation/flutter†.^{a 431}

Embolism Associated with Valvular Heart Disease

Prevention of thromboembolism associated with various types of valvular heart disease†, in combination with or as alternative to low-dose aspirin; choice of antithrombotic therapy depends on risks of thromboembolism versus hemorrhagic complications from such therapy.^{340 344 371 c}

Many experts recommend long-term oral anticoagulation with warfarin therapy in patients with rheumatic mitral valve disease† and atrial fibrillation or a history of systemic embolism (e.g., stroke).^{340 341 371 c} Add low-dose aspirin therapy in patients with atrial fibrillation or history of systemic embolism who have a breakthrough embolic event despite prophylactic anticoagulation; may use another oral platelet-aggregation inhibitor (e.g., dipyridamole, clopidogrel) if aspirin not tolerated.^{371 433 c}

Consider long-term anticoagulation in patients with rheumatic mitral valve disease† and normal sinus rhythm who have a left atrial diameter >5.5 cm (high risk of atrial fibrillation).^{340 371 c}

Prophylaxis with warfarin (target INR 2.5, range 2–3) recommended by ACC/AHA in selected high-risk patients with mitral valve prolapse† and atrial fibrillation (i.e., those ≥65 years of age or those with mitral valve regurgitation, hypertension, or a history of heart failure).³⁴¹ Patients <65 years of age with mitral valve prolapse and atrial fibrillation who do not have these risk factors for thromboembolism and those with mitral valve prolapse and unexplained TIAs should be considered for low-dose aspirin therapy.^{340 341 371 c} Also consider long-term warfarin prophylaxis in patients with mitral valve prolapse who have atrial fibrillation, a history of systemic embolism (e.g., stroke), or recurrent TIAs despite aspirin therapy.^{340 341 371 c}

Adjusted-dose warfarin also recommended by some clinicians for prevention of thromboembolic events in patients with mitral valve regurgitation and concomitant atrial fibrillation or a history of systemic embolism.^{341 371}

Long-term antithrombotic therapy generally not recommended in patients with mitral annular calcification who lack a history of thromboembolism or atrial fibrillation.^{340 371 c} However, ACCP suggests that long-term warfarin therapy be given to patients with mitral annular calcification complicated by systemic embolism not documented to be calcific embolism or in those who have atrial fibrillation.^{340 371 c}

Generally should not initiate anticoagulant therapy in patients with uncomplicated infective endocarditis involving a native valve because of the risk of hemorrhage and lack of documented efficacy.^{340 371}

Oral anticoagulant therapy recommended in patients undergoing mitral valvuloplasty beginning 3 weeks prior to the procedure and continuing for 4 weeks following the procedure.^c

Generally should not initiate long-term anticoagulant therapy in patients with aortic arch valve disease unless warranted by a coexisting condition.^{371 c} However, ACCP states that patients with mobile aortic atheromas and aortic plaques >4 mm (as measured by transesophageal echocardiography) should receive long-term anticoagulation with warfarin.^{371 c}

Thromboembolism Associated with Prosthetic Heart Valves

Follow-up anticoagulation after unfractionated heparin or an LMW heparin for prevention of thromboembolic complications associated with heart valve replacement.^{211 341 347 370 433 c}

Risk of systemic embolism is higher with prosthetic mechanical than with bioprosthetic heart valves, higher with first-generation mechanical (e.g., caged ball, caged disk) valves than with newer mechanical (e.g., bileaflet, Medtronic Hall tilting disk) heart valves, higher with more than one prosthetic valve, and higher with prosthetic mitral than with aortic valves; risk also increases in the presence of atrial fibrillation.^{341 342 343 347 370 431 433} Lifelong prophylaxis required in all patients with mechanical heart valves because of associated high risk of thromboembolism.^{341 347 370}

Combination therapy with aspirin recommended in patients with mechanical heart valves and additional risk factors (e.g., atrial fibrillation, left atrial enlargement, endocardial damage, low ejection fraction).⁴³³

Combination therapy with aspirin recommended in patients with first-generation mechanical heart valves.⁴³³

Short-term (3 months) prophylaxis in patients with a bioprosthetic valve in the mitral position; follow-up with long-term aspirin therapy in patients with no continuing risk factors who are in normal sinus rhythm.⁴³³

Short-term (3 months) prophylaxis with warfarin or aspirin in patients with a bioprosthetic valve in the aortic position; follow-up with aspirin in patients with no continuing risk factors who are in normal sinus rhythm.⁴³³

Short-term prophylaxis in patients with a bioprosthetic valve and evidence of a left atrial thrombus.⁴³³

Long-term prophylaxis in patients with a bioprosthetic valve and other risk factors (e.g., atrial fibrillation, prior thromboembolism, left ventricular dysfunction, hypercoagulable states).^{341 347 370 433}

Generally should not initiate anticoagulant therapy in patients with uncomplicated infective endocarditis involving a bioprosthetic heart valve because of the risk of hemorrhage and lack of documented efficacy.^{340 371 433} However, ACCP states that patients with mechanical prosthetic valves receiving long-term anticoagulation who develop infective endocarditis generally should remain on anticoagulant therapy unless there are specific contraindications, keeping in mind the substantial risk of intracranial hemorrhage.^{340 371 c}

Treatment of “breakthrough” thromboembolic events in patients with prosthetic heart valves receiving thromboprophylaxis.^{211 341 433 c} Combination therapy with aspirin recommended in patients with breakthrough embolic event despite warfarin therapy.^{433 341 370 433 c}

Thromboembolism Following ST-Segment Elevation MI

Used as adjunctive therapy with platelet-aggregation inhibitors (e.g., aspirin, clopidogrel) after coronary artery reperfusion for the prevention of early reocclusion and death.^{211 226 242 243 244 245 246 247 248 249 250 251 252 348 350 372 432 440}

Used short-term with an LMW heparin in the treatment of DVT or pulmonary embolism following MI in hospitalized patients.⁴³²

Used in selected patients to reduce the incidence of thromboembolic events such as stroke or systemic embolization following MI.^{211 226 256 268 269 270 271 272 348 432 440} ACC and AHA recommend follow-up anticoagulation (3 months) at hospital discharge and adjunctive aspirin after initiation of unfractionated heparin or an LMW heparin in patients at high risk for systemic emboli.⁴³² ACCP suggests oral anticoagulation and aspirin following MI for 3 months in those at high risk for embolism.^{348 350 372 437}

ACC and AHA recommend long-term anticoagulation alone or with aspirin at hospital discharge in patients without stent implantation who have coexisting conditions (i.e., atrial fibrillation, left ventricular thrombus, cerebral emboli, extensive wall motion abnormality) that warrant such therapy.⁴³²

Used as an alternative to clopidogrel in patients who are unable to take daily aspirin therapy and who do not have a stent implanted.⁴³²

Primary Prevention of Thromboembolic Events in CAD

Used to reduce the incidence of cardiovascular events and mortality† in patients at high risk for CAD.^{372 437}

Thromboembolism Associated with Other Cardiovascular Diseases

Used in conjunction with aspirin to prevent thrombi and infarction in children with Kawasaki disease†.⁴⁴⁶

Used as primary prophylaxis for thrombotic complications in children with dilated cardiomyopathy† awaiting a cardiac transplant.⁴⁴⁶

May be used as primary prevention of thromboembolic events in children undergoing Fontan surgery for congenital univentricular heart lesions†; use with aspirin (5 mg/kg daily) as follow-up to heparin therapy.⁴⁴⁶

Cerebral Thromboembolism

Secondary prevention in patients with TIAs† or mild ischemic stroke and concurrent atrial fibrillation, provided no contraindications to therapy exist.^{335 338 349 352 373 432 434}

Used in conjunction with aspirin for prevention of recurrent stroke in patients at high risk for recurring cerebral embolism from other cardiac sources (e.g., mechanical prosthetic heart valves, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis, extensive wall-motion abnormalities).^{335 338 349 352 432} Follow-up anticoagulation after heparin or an LMW heparin in patients with recent MI and acute ischemic stroke and cardiac sources of embolism.⁴³²

Has been used as follow-up anticoagulation after heparin therapy for the prevention of embolism in paralyzed or immobile patients with progressive stroke† (when the suspected mechanism is thromboembolic) or stroke-in-evolution†.^{212 373} However, use of heparin or an LMW heparin not recommended by ACCP in patients with a stroke-in-evolution because of lack of conclusive data on efficacy and safety.⁴³⁴

Short-term (3–6 months) follow-up anticoagulation with warfarin or an LMW heparin after heparin or an LMW heparin in children with arterial ischemic stroke from cardiac sources† or vascular dissection.⁴⁴⁶ May initiate aspirin following completion of anticoagulation.⁴⁴⁶

Long-term antithrombotic therapy generally not recommended in asymptomatic patients with a patent foramen ovale or atrial septal aneurysm unless such patients have unexplained system embolism or TIAs and demonstrable venous thrombosis or pulmonary embolism.^{340 371} Treatment of suspected DVT in patients with cryptogenic stroke and patent foramen ovale†.⁴³⁴ ACCP suggests use of antiplatelet agents over warfarin in patients with cryptogenic stroke and patent foramen ovale without DVT.⁴³⁴

ACCP suggests either oral anticoagulation or antiplatelet agents for secondary prophylaxis in patients with cryptogenic stroke and mobile arch thrombi†.⁴³⁴

Oral anticoagulation (3–6 months) recommended by ACCP as follow-up to unfractionated heparin or an LMW heparin in patients with acute cerebral venous sinus thrombosis†.

Thrombosis Associated with CABG

Prevention of saphenous vein or internal mammary artery graft occlusion following CABG†.^{376 448} ACCP recommends use in combination with aspirin when other coexisting conditions (e.g., heart valve replacement) warrant such therapy.^{376 448}

Prevention of Stent Thrombosis and Restenosis Following PCI

Has been used short-term for prevention of stent thrombosis after stent placement† or long-term (1–6 months) for prevention of restenosis following PCI†.⁴⁴⁷ Since warfarin has no apparent advantages over antiplatelet therapy, not routinely recommended by ACCP after PCI if no other indications for anticoagulation exist.⁴⁴⁷

Arterial Occlusive Disease

Has been used in selected patients with peripheral arterial occlusive disease†, but ACCP currently recommends against use of anticoagulants for intermittent claudication.^{377 449}

Treatment/Secondary Prevention in Arterial Vascular Surgery

ACCP recommends long-term follow-up oral anticoagulation after initial heparin treatment in patients undergoing embolectomy†.^{377 449}

ACCP recommends long-term oral anticoagulation in postsurgical patients following pulmonary thromboendarterectomy† and in patients ineligible for such a procedure.⁴²⁷

Prevention (combined with aspirin therapy) of embolism in selected (high risk for graft thrombosis and limb loss) patients after infrainguinal femoropopliteal or distal vein bypass†.^{377 449}

Heparin-Induced Thrombocytopenia^{387 392 393}

Has been administered as follow-up treatment of heparin-induced thrombocytopenia† when substantial recovery has occurred (i.e., platelet counts ≥ 100,000–150,000/mm³ and are stable) after therapy with a direct thrombin inhibitor (e.g., lepirudin, bivalirudin, argatroban).^{392 441 442 443 444} Overlap therapy for approximately 5 days until an adequate response to warfarin is obtained.^{387 392 393}

Warfarin Sodium Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Carefully individualize dosage based on clinical and laboratory findings (i.e., determination of INR and/or PT ratios).²¹¹ Adjust dosage in small increments and carefully monitor patient response.^a Determine optimum duration of therapy by the condition being treated and its severity.^a

  
  


• 
  

  Determine PT prior to and 24 hours after initiation of therapy.^{211 a 426} Determine PT daily until the PT/INR is in the therapeutic range.²¹¹ Intervals between subsequent PT determinations based on clinician’s judgment and patient’s response.²¹¹ Determine PT/INR generally every 1–4 weeks after a stable dosage has been determined.^{211 426}

  
  


• 
  

  Determine PT when different warfarin preparations (e.g., proprietary versus generic) are interchanged.^{211 a} Determine PT when concomitant drug therapy is added, discontinued, or taken irregularly.^{211 a}

  
  


• 
  

  Dosage does not vary with the route of administration.²¹¹

  
  


• 
  

  Administration of large loading doses (i.e., >20 mg) not recommended.^{211 426} Possible increased risk of hemorrhage or necrosis.²¹¹ (See Hemorrhage under Cautions.)

  
  


• 
  

  For follow-up therapy after heparin, the manufacturer recommends that therapy with heparin and warfarin be used concurrently for at least 4–5 days or until the desired PT/INR has been achieved.²¹¹ Some clinicians recommend that unfractionated heparin or an LMW heparin be used concurrently with warfarin for about 5–7 days or until the desired INR has been achieved for 2 consecutive days.⁴²⁷

  
  


• 
  

  Increased risk of thrombosis or rebound thromboembolism has been suggested following abrupt discontinuance of warfarin therapy; some manufacturers recommend gradually decreasing dosage (e.g., over 3–4 weeks) when withdrawing therapy.^a

  
  

Transferring from Anticoagulation with Direct Thrombin Inhibitors

• 
  

  For follow-up therapy after most direct thrombin inhibitors, overlap therapy with direct thrombin inhibitors for ≥5 days until desired INR has been achieved for 2 consecutive days.^{441 443}

  
  


• 
  

  Combined therapy with argatroban and warfarin prolongs the PT and INR beyond that produced by warfarin alone.^{392 441} Determine PT and INR daily during concurrent argatroban and warfarin therapy.³⁹² Continue to monitor the effects of argatroban using aPTT during conversion to warfarin.³⁹²

  
  


• 
  

  For an argatroban infusion rate ≤2 mcg/kg per minute, discontinue argatroban therapy when INR on combined therapy >4.³⁹² Avoid overshooting target INR, as supratherapeutic INRs during concomitant therapy with direct thrombin inhibitors and warfarin have been associated with necrosis or gangrene of the skin or limbs.^{441 442 444}

  
  


• 
  

  Determine INR 4–6 hours after discontinuance of argatroban infusion during warfarin monotherapy.³⁹² If INR is below the desired therapeutic range, resume argatroban infusion.³⁹² Repeat attempts to discontinue argatroban daily and until INR (4–6 hours after discontinuance of argatroban) on warfarin alone is in therapeutic range.³⁹²

  
  


• 
  

  For argatroban infusion rates >2 mcg/kg per minute, reduce infusion rate temporarily to 2 mcg/kg per minute, and reinstitute the procedure just described for conversion to oral therapy.³⁹² Repeat INR determination 4–6 hours after reduction of the argatroban infusion and reinstitute procedure just described for conversion to oral therapy.³⁹²

  
  

Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Administer orally.^a Administer by IV injection when a coumarin derivative is indicated and oral therapy is not feasible.²¹¹

IM administration not recommended.²¹¹

Oral Administration

Administer orally in a single, daily dose.^a

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute powder for injection with 2.7 mL of sterile water for injection to a final concentration of 2 mg/mL.²¹¹

Rate of Administration

Inject slowly (over 1–2 minutes) into a peripheral vein.²¹¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as warfarin sodium; dosage expressed in terms of the salt.^{211 330}

Pediatric Patients

Venous Thrombosis and Pulmonary Embolism

Treatment or Secondary Prevention

Oral

Neonates with homozygous protein C deficiency and associated purpura fulminans: Maintenance of an INR of 2.5–4.5 long-term suggested.⁴⁴⁶

Children >2 months of age with first episode idiopathic thromboembolic event: Follow-up anticoagulation after heparin or an LMW heparin with dosage adjusted to maintain a target INR of 2.5 (range 2–3) for at least 6 months.⁴⁴⁶

Children >2 months of age with first episode thromboembolic event secondary to precipitating factors: Maintenance of a target INR of 2.5 (range 2–3) is suggested for 3 months or until resolution of such factors.⁴⁴⁶ Such factors include cancer, trauma/surgery, congenital heart disease, or systemic lupus erythematosus.⁴⁴⁶

Children >2 months of age with recurrent thromboembolic events secondary to precipitating factors after previous 3 months of oral anticoagulation: Continued maintenance of a target INR of 2.5 (range 2–3) is suggested for another 3 months or until resolution of such factors.⁴⁴⁶

Children with recurrent idiopathic thromboembolic events: Indefinite oral anticoagulation at low (INR of 1.3–1.8) to moderate intensity (INR of 2–3) suggested.^{426 446}

Children >2 months of age with central venous catheter-associated venous thromboembolic events: Adjust dosage to maintain target INR of 2.5 (range 2–3) for 3 months.⁴⁴⁶

Children >2 months of age with first DVT associated with a central venous catheter after previous 3 months of oral anticoagulation for catheter-related thrombosis: Continue anticoagulation at a lower intensity (INR 1.5–1.8) until the central venous catheter is removed.⁴⁴⁶

Children >2 months of age with recurrent thrombosis associated with a central venous catheter after previous 3 months of oral anticoagulation: Continue anticoagulation at a lower intensity (INR 1.5–1.8) until the central venous catheter is removed.⁴⁴⁶

Children >2 months of age with breakthrough thrombosis associated with central venous catheters despite low-intensity oral anticoagulation: Increase of the anticoagulation to an INR of 2–3 until the catheter is removed or for a minimum of 3 months.⁴⁴⁶

Children >2 months of age receiving long-term total parenteral nutrition via a central venous catheter: Continuous dosage at INR 2–2.5 suggested or alternatively, for the first 3 months after each central venous catheter is inserted.⁴⁴⁶

Cardiovascular Conditions†

Oral

Giant coronary aneurysms following Kawasaki disease†: Adjustment of dosage to maintain an INR of 2–3 with aspirin (3–5 mg/kg daily) is suggested to reduce subsequent thrombosis and infarction.⁴⁴⁶

Neonates and children with dilated cardiomyopathy†: Primary prophylaxis at INR of 2–3 suggested while the child is awaiting a cardiac transplant.⁴⁴⁶

Fontan surgery for congenital univentricular heart lesions†: Maintenance of an INR of 2–3 following full-dose heparin suggested for primary prevention of thromboembolic events; the optimal duration of therapy unknown.⁴⁴⁶

Cerebral Thromboembolism

Acute Cerebral Venous Sinus Thrombosis†

Oral

Secondary prevention†: Follow-up oral anticoagulation at a target INR of 2.5 (range 2–3) for 3–6 months after therapy with unfractionated heparin or an LMW heparin.⁴⁴⁶

Adults

Venous Thrombosis and Pulmonary Embolism

Treatment or Secondary Prevention

Oral

As follow-up to therapy with heparin or an LMW heparin, initial dose is 5–10 mg daily.^{211 332 334 365 407 426} Adjust subsequent daily dosage to achieve and maintain a target INR of 2.5 (range 2–3) for ≥3 months.^{211 332 334 365 407}

Individualize length of treatment of DVT or pulmonary embolism based on age, comorbid conditions, and the likelihood of recurrence.^{365 427}

DVT or pulmonary embolism with reversible or time-limited risk factors for venous thromboembolism: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for at least 3 months.^{365 427}

First episode of idiopathic DVT: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for at least 6–12 months.^{332 365 427 446}

First episode of DVT or pulmonary embolism and continuing risk factors: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for at least 6–12 months.^{365 427} Such factors include cancer, antithrombin III or protein C or S deficiencies, antiphospholipid antibody syndrome, factor V Leiden or prothrombin 20210A gene mutations, homocysteinemia, and high levels of factor VII.^{365 427}

First episode of DVT or pulmonary embolism with antiphospholipid antibodies or ≥2 thrombophilic conditions: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for 12 months.⁴²⁷ Indefinite anticoagulation suggested in these patients.⁴²⁷

Consider long-term therapy in patients with risk factors for recurrent thromboembolism, including venous insufficiency, idiopathic venous thromboembolism, and history of thrombotic events (≥2 episodes).^{211 427 446}

Prophylaxis in Hip-replacement Surgery

Oral

Initially, 5–10 mg daily with dosage adjusted to achieve a target INR of 2.5 (range 2–3) for ≥10 days.^{333 366 430}

Initiate prophylaxis for venous thromboembolism perioperatively (the evening before or after surgery).^{203 208 333 366 430}

Extended prophylaxis for ≤28–35 days with warfarin, fondaparinux, or LMW heparin recommended.⁴³⁰

Prophylaxis in Hip-fracture Surgery

Oral

Initially, 5–10 mg daily with dosage adjusted to achieve a target INR of 2.5 (range 2–3) for ≥10 days.^{333 366 430}

Initiate prophylaxis for venous thromboembolism preoperatively with heparin or a LMW heparin if surgery is delayed or after surgery once hemostasis has been demonstrated.⁴³⁰ Continue prophylactic anticoagulant therapy with warfarin, a LMW heparin, or fondaparinux following surgery for 28–35 days.⁴³⁰

Prophylaxis in Knee-replacement Surgery

Oral

Initially, 5–10 mg daily with dosage adjusted to achieve a target INR of 2.5 (range 2–3) for 10 days.^{333 366 430}

Initiate prophylaxis for venous thromboembolism perioperatively (the evening before or after surgery).^{203 208 333 366 430}

Prophylaxis in Trauma

Oral

Acute spinal cord injury: Following initial therapy with an LMW heparin, adjust warfarin sodium dosage to a target INR of 2.5 (range 2–3) in the rehabilitation phase.^{366 430} Continue prophylactic anticoagulant therapy following trauma for a minimum of 3 months or until completion of the inpatient phase of rehabilitation.⁴³⁰

Trauma patients with impaired mobility: Adjust dosage to a target INR of 2.5 (range 2–3) after hospital discharge.⁴³⁰

Embolism Associated with Atrial Fibrillation/Flutter

Oral

Adjust dosage for long-term oral anticoagulation to a target INR of 2.5 (range 2–3) in patients who are at high risk for stroke.^{335 339 344 345 349 368 431 434}

For atrial fibrillation persisting for >48 hours after open-heart surgery: Maintain a target INR of 2.5 (range 2–3) in patients at high risk for stroke for several weeks following reversion to normal sinus rhythm.⁴³¹

Atrial flutter and mitral stenosis: Adjust dosage to maintain a target INR of 2.5 (range 2–3).⁴³¹

Thromboprophylaxis during Cardioversion of Atrial Fibrillation/Flutter

Oral

Initiate at least 3–4 weeks prior to cardioversion (target INR of 2.5, range 2–3) and continue after the procedure until normal sinus rhythm has been maintained for 3–4 weeks.^{334 335 336 339 367 368 431} For emergency cardioversion, administer for ≥4 weeks as follow-up anticoagulation after initiating periprocedural IV heparin.^{335 336 339 341 367 368 431}

Embolism Associated with Valvular Heart Disease

Oral

Mitral valve disease associated with rheumatic fever or mitral valve regurgitation: Adjust dosage to prolong the INR to a target of 2.5 (range 2–3) in patients who have either concurrent paroxysmal or chronic persistent atrial fibrillation or a history of systemic embolism (e.g., stroke).^{340 371 433} Add aspirin (75–100 mg daily) to therapy in patients who have a breakthrough embolic event.^{371 433}

Rheumatic mitral valve disease with left atrial hypertrophy (left atrial diameter exceeding 5.5 cm) and normal sinus rhythm: Long-term anticoagulation at a target INR of 2.5 (range 2–3).^{340 371 433}

Mitral valve prolapse and a history of systemic embolism (e.g., stroke), or recurrent TIAs despite aspirin therapy: Maintain a target INR of 2.5 (range 2–3).^{340 341 371 433}

Mitral annular calcification complicated by systemic embolism (noncalcific systemic embolism): Long-term prophylaxis at a target INR of 2.5 (range 2–3) suggested.^{340 371 433}

Patients undergoing percutaneous mitral valvuloplasty: Maintain a target INR of 2.5 (range 2–3) for 3 weeks prior to the procedure and for 4 weeks after the procedure.⁴³³

Thromboembolism Associated with Prosthetic Heart Valves

Prophylaxis

Oral

Bioprosthetic valve in the aortic position: Adjust dosage to maintain a target INR of 2.5 (range 2–3) during the first 3 months.⁴³³

Bioprosthetic valve in the mitral position: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for the first 3 months.⁴³³

Mitral bioprosthetic heart valve and additional risk factors (atrial fibrillation, left ventricular dysfunction, prior thromboembolism, hypercoagulable states³⁴¹ ): Maintenance of a target INR of 3 (range 2.5–3.5) for ≥3 months recommended by ACC and AHA.³⁴¹

Bioprosthetic valves with evidence of a left atrial thrombus at valve replacement surgery: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for the first 3 months.⁴³³

Patients with bioprosthetic valves who have a history of systemic embolism: Maintenance of a target INR of 2.5 (range 2–3) for 3–12 months recommended by ACCP.⁴³³

Patients with newer (e.g., bileaflet, Medtronic disk) mechanical heart valves in the aortic position with no additional risk factors: Adjust dosage to a target INR of 2.5 (range 2–3) long-term.^{341 347 370 433}

Tilting disk valves and bileaflet mechanical heart valves i