Warfarin is used to decrease the tendency for thrombosis or as secondary prophylaxis (prevention of

further episodes) in those individuals who have already formed a blood clot (thrombus). Warfarin
treatment can help prevent formation of future blood clots and help reduce the risk
of embolism (migration of a thrombus to a spot where it blocks blood supply to a vital organ). [6]
Warfarin is best suited for anticoagulation (clot formation inhibition) in areas of slowly running blood
(such as in veins and the pooled blood behind artificial and natural valves) and in blood pooled in
dysfunctional cardiac atria. Thus, common clinical indications for warfarin use are atrial fibrillation,
the presence of artificial heart valves, deep venous thrombosis, and pulmonary embolism (where the
embolized clots first form in veins). Warfarin is also used in antiphospholipid syndrome. It has been
used occasionally after heart attacks (myocardial infarctions), but is far less effective at preventing
new thromboses in coronary arteries. Prevention of clotting in arteries is usually undertaken
with antiplatelet drugs, which act by a different mechanism from warfarin (which normally has no
effect on platelet function).[7]

Alternative anticoagulants[edit]
In some countries, other coumarins are used instead of warfarin, such
as acenocoumarol and phenprocoumon. These have a shorter (acenocoumarol) or longer
(phenprocoumon) half-life, and are not completely interchangeable with warfarin. Several types of
anticoagulant drugs offering the efficacy of warfarin without a need for monitoring, such
as dabigatran and rivaroxaban, have been approved in a number of countries for classical warfarin
uses like the more common types of atrial fibrillation, and others in the same drug classes are under
development.[8]

Dosing[edit]
Dosing of warfarin is complicated because it is known to interact with many commonly used
medications and certain foods.[3] These interactions may enhance or reduce warfarin's
anticoagulation effect. To optimize the therapeutic effect without risking dangerous side effects such
as bleeding, close monitoring of the degree of anticoagulation is required by a blood test measuring
an INR. During the initial stage of treatment, INR is checked daily; intervals between tests can be
lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose.
[7]

Newer point-of-care testing is available and has increased the ease of INR testing in the outpatient

setting. Instead of a blood draw, the point of care test involves a simple finger prick. [9]
When initiating warfarin therapy ("warfarinization"), the doctor will decide how strong the
anticoagulant therapy needs to be. The target INR level varies from case to case depending on the
clinical indicators, but tends to be 23 in most conditions. In particular, target INR may be 2.53.5 (or
even 3.04.5) in patients with one or more mechanical heart valves.[10]

In addition, for the first three days of "warfarinization", the levels of protein C and protein S
(anticoagulation factors) drop faster than procoagulation proteins such as factor II, VII, IX, and X.
Therefore, bridging anticoagulant therapies (usually heparin) are often used to reverse this
temporary hypercoagulable state.

Treatment and secondary prevention of venous thromboembolism (DVT and/or PE). 211500 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 23) 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 1005Long-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 1.51.9); however, therapeutic dosages may be required if recurrent thromboembolism occurs. 1013

Orthopedic Surgery
Prevention of postoperative venous thromboembolism in patients undergoing hip- or kneereplacement 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 1014 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/Atrial Flutter

Prevention of stroke and systemic embolism in patients with atrial
fibrillation.223 278 279 369 456 459 500 990999 1007 ACCP, the American College of Cardiology (ACC), American Heart
Association (AHA), and other experts recommend antithrombotic therapy (e.g., warfarin, aspirin) in
patients with persistent, permanent, or paroxysmal atrial fibrillation who are considered to be at
increased risk
Choice of antithrombotic therapy is based on patient's risk for stroke. 341 345 369 459 999 1007 In general, oral
anticoagulant therapy is recommended in patients with high risk for stroke; aspirin is recommended
in low-risk patients and those with contraindications to oral anticoagulant
therapy.211 330 335 341 344 345 349 456990 999 1007 Patients at increased risk of stroke generally include those with a history
of stroke, TIA, or systemic embolism, and those with 2 of the following risk factors: advanced age
(e.g., 75 years), history of hypertension, diabetes mellitus, or severely impaired left ventricular
systolic function and/or heart failure.500 999 1007
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
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/Atrial Flutter

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

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 23) 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 firstgeneration 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 342343 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 1008However, long-term
warfarin therapy (INR 2.5, range 23) 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 23) is suggested in patients with an aortic mechanical valve,
while target INR of 3 (range 2.53.5) 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., 50100 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 MI; 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 23) in conjunction
with low-dose aspirin (100 mg daily) for 3 months following acute MI in high-risk patients (e.g.,
those with large anterior MI, 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 MI and left ventricular thrombus).1010

Cerebral Embolism
Oral anticoagulation (e.g., warfarin) is recommended for secondary prevention of cerebral embolism
in patients with TIAs or ischemic stroke and concurrent atrial fibrillation.335 338 349 352 432 9991009
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
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.)

Coumadin Dosage and Administration

General

Carefully individualize dosage based on clinical and laboratory findings (i.e.,

INR).211 330Determine optimum dosage and duration of therapy by the condition being treated. 500

Adjust dosage in small increments and carefully monitor patient response.211 330

Dosage of warfarin does not vary with the route of administration. 211

Administration of large loading doses (i.e., >10 mg) not recommended;211 330 possible increased
risk of hemorrhage or necrosis.211 330 (See Hemorrhage under Cautions.)

Factors such as concomitant therapy with drugs or dietary or herbal supplements, changes in
diet, environment (prolonged hot weather), physical state, and genetic variations in warfarin
metabolism and/or sensitivity may alter an individuals response to warfarin
therapy.211 330 462 463 464 465 468 472 474 (See Factors Influencing Response under Cautions and see
Interactions.)

Laboratory Monitoring of Therapy

Determine INR regularly in all patients receiving warfarin. 211 330 Monitor INR daily following
initiation of therapy until it stabilizes in the therapeutic range. 211 330 Frequency of subsequent INR
determinations based on clinical judgment and patient response, but generally every 14
weeks.500

In patients with consistently stable INRs, ACCP has suggested an INR testing interval of up
to 12 weeks.1000

Perform additional INR testing when different warfarin preparations (e.g., proprietary versus
generic) are interchanged, and when concomitant drug therapy is added, discontinued, or taken
irregularly.211 330

Safety and efficacy may be improved by increasing the quality of laboratory

control.211 330Proportion of time in the therapeutic INR range is increased in patients managed by
anticoagulation clinics and in patients managed with the assistance of computer
programs.211330 452 462

ACCP suggests that self-management be considered as an alternative to outpatient

monitoring in appropriately selected, motivated patients who can demonstrate competency in
self-management strategies and techniques.1000

Pharmacogenomics

Variations in genes responsible for warfarin metabolism or pharmacodynamic response may

affect dosage requirements.211 330 378 462 463 464 465 466 467 468 469 470 471

Lower dosages may be required to avoid excessive anticoagulation (e.g., INR >3) and
bleeding in patients with variations in 2 genes (CYP2C9 and VKORC1).211 330 462 464 465 466 467 469 470474

Current lack of evidence to support benefit of routine genetic testing; ACCP currently
recommends against routine use of genetic testing to guide initial dosage selection. 1000

Transferring from Parenteral Anticoagulants to Warfarin

When warfarin is indicated for follow-up therapy after initial therapy with a parenteral
anticoagulant (e.g., heparin, LMWH), overlap therapy with parenteral anticoagulant and warfarin
until adequate oral anticoagulation obtained as indicated by INR monitoring. 1000 1005

Manufacturers recommend that heparin and warfarin be used concurrently for 45 days
until the desired INR has been achieved.211 330 500

In adults with acute DVT or PE, ACCP recommends that heparin, an LMWH, or fondaparinux
be used concurrently with warfarin for 5 days and until INR is 2 for 24 hours. 1005

In children with venous thromboembolism in whom long-term warfarin therapy is being

considered, ACCP recommends that warfarin be initiated on the same day as heparin or an
LMWH; overlap such therapy for 5 days and until the INR is therapeutic.1013

When warfarin is used for follow-up therapy after a nonheparin anticoagulant (e.g.,
argatroban, lepirudin) in patients with HIT, overlap therapy with warfarin and the nonheparin
anticoagulant for 5 days until an adequate response to warfarin is obtained as indicated by
INR.1006 Initiate warfarin therapy only after substantial recovery from acute HIT has occurred (i.e.,
platelet counts 150,000/mm3).1006

Conversion from argatroban to warfarin is more complex than with other nonheparin
anticoagulants since combined therapy with argatroban and warfarin prolongs the PT/INR
beyond that produced by warfarin alone.392 Consult manufacturer's prescribing information for
specific guidelines for conversion.392 Monitor INR daily during concurrent argatroban and warfarin
therapy.392

Interruption of Therapy for Invasive Procedures

Temporary interruption of warfarin therapy may be required in patients undergoing surgery or

other invasive procedures to minimize risk of perioperative bleeding.1004

Assess risk of thromboembolism versus risk of perioperative bleeding to determine whether

interruption of therapy is necessary.1004 Temporary interruption of therapy usually required for
major surgical or invasive procedures, but may not be necessary for minor procedures
associated with a low bleeding risk (e.g., minor dental procedures, minor dermatologic
procedures, cataract surgery).1004

If temporary interruption of warfarin necessary prior to surgery, discontinue approximately 5

days prior to procedure.1004 May resume approximately 1224 hours postoperatively when
adequate hemostasis is achieved.1004

May consider bridging anticoagulation (administration of an LMWH or IV heparin during the

period of warfarin interruption) in patients at particularly high risk of thromboembolism. 1004ACCP
states that bridging therapy generally unnecessary for patients other than those at highest risk
for stroke and/or venous thromboembolism (e.g., patients with mechanical heart valves, atrial
fibrillation, or a venous thromboembolic event with additional risk factors for venous
thromboembolism).1004

Administration
Administer orally.211 330 Administer by IV injection when therapy with a coumarin derivative is indicated
and oral therapy is not feasible.211
IM administration not recommended.211

Oral Administration
Administer in a single daily dose.211 330 Administer at the same time each day, with food or on an empty
stomach.453
If a dose is missed, contact clinician.445 453 Administer dose as soon as remembered on the same day;
do not take a double dose the next day to make up for the missed dose. 445 453

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

Reconstitution
Reconstitute lyophilized 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 12 minutes) into a peripheral vein.211

Dosage
Available as warfarin sodium; dosage expressed in terms of warfarin sodium. 211 330
Initial dosage varies widely among patients; individualize dosage based on factors such as age,
race, body weight, sex, genotype, concomitant drugs, and the specific indication being treated. 500
Adjust dosage based on INR; if a previously stable patient presents with a single subtherapeutic or
supratherapeutic INR (0.5 above or below the therapeutic range), ACCP suggests that current
dosage be continued and INR retested within 12 weeks. 1000

The manufacturers state that usual initial dosage is 25 mg daily in patients whose CYP2C9 and
VKORC1 genotypes are not known.211 500 For patients with known CYP2C9 and VKORC1 genotypes,
the manufacturers suggest that initial dosage may be determined by expectedmaintenance dosages
observed in clinical studies of patients with various combinations of these gene variants. 211 500 (See
Table.)
Manufacturers suggest using these expected maintenance dosage ranges to estimate initialdaily
dosage in patients with known CYP2C9 and VKORC1 genotypes. Dosage ranges derived from
multiple published clinical studies. VKORC1-1639G > A (rs9923231) variant is used in this table;
other co-inherited VKORC1 variants also may be important determinants of warfarin sodium dosage.

Table 1. Expected Daily Maintenance Dosages of Warfarin Sodium Based on CYP2C9 and
VKORC1 Genotypes211500

CYP2C9

VKORC1

*1/*1

*1/*2

*1/*3

*2/*2

*2/*3

*3/*3

GG

57 mg

57

34

34

34

0.52

mg

mg

mg

mg

mg

34

34

34

0.52

0.52

mg

mg

mg

mg

mg

34

0.52

0.52

0.52

0.52

mg

mg

mg

mg

mg

AG

AA

57 mg

34 mg

Routine use of warfarin loading doses not recommended by manufacturer;211 500 however, some
evidence suggests that use of a 10-mg loading dose may reduce time to therapeutic INR. 1000

Pediatric Patients
Warfarin dosage in pediatric patients varies based on age; infants generally have the highest, and
adolescents have the lowest dosage requirements.211 500 ACCP generally suggests a target INR range
of 23 for most indications in children except in the setting of prosthetic cardiac valves where
adherence to adult recommendations is suggested.1013

Adults
Treatment of DVT and PE
Oral or IV
Adjust dosage to achieve and maintain target INR of 2.5 (range 23). 332 500 1005
Patients with a proximal DVT or PE provoked by surgery or other transient risk factor: ACCP states
that 3 months of anticoagulation usually sufficient.1005
Patients with an unprovoked (idiopathic) thromboembolic event: Continue anticoagulant therapy for
3 months; after 3 months, evaluate risks and benefits of extended therapy.1005 In general, extended
anticoagulant therapy is recommended in patients with low risk of bleeding.1005
Cancer patients with acute venous thromboembolism: Extended anticoagulant therapy
recommended.1005
Patients with acute upper-extremity DVT involving the axillary or more proximal veins: Continue
anticoagulant therapy 3 months.1005 If upper-extremity DVT associated with a central venous catheter,
continue anticoagulation as long as the catheter remains in place; if catheter is removed, 3 months of
anticoagulation is sufficient.1005

Prevention of DVT and PE

Hip-Replacement, Knee-Replacement, or Hip-fracture Surgery
Oral or IV
Adjust dosage to INR range of 23.500 1000
ACCP recommends continuing thromboprophylaxis for at least 1014 days, and possibly for up to 35
days after surgery.1003

Embolism Associated with Atrial Fibrillation/Atrial Flutter

Oral or IV
Maintain target INR of 2.5 (range 23) long term.211 330 335 344 345 349 369 990 999 1007

Cardioversion of Atrial Fibrillation/Atrial Flutter

Oral or IV
Patients with atrial fibrillation lasting >48 hours or of unknown duration: Initiate warfarin 3 weeks
prior to cardioversion (target INR 23) and continue after the procedure until normal sinus rhythm
maintained for 4 weeks.999 1007

Embolism Associated with Valvular Heart Disease

Oral or IV
Patients with rheumatic mitral valve disease and concurrent atrial fibrillation, left atrial thrombus, or a
history of systemic embolism: Maintain target INR of 2.5 (range 23).1008
Patients with rheumatic mitral valve disease in normal sinus rhythm, but with left atrial hypertrophy
(left atrial diameter >5.5 cm): Target INR of 2.5 (range 23) suggested by ACCP.1008
Patients being considered for percutaneous mitral valvotomy with evidence of left atrial thrombus
(confirmed by TEE): Treat with warfarin (target INR of 3; range 2.53.5) and postpone procedure
until thrombus resolution.1008

Thromboembolism Associated with Prosthetic Heart Valves

Prophylaxis
Oral or IV
Base intensity of anticoagulation on the type of valve prosthesis.211 330 996 1008 In general, target INR of 2.5
(range 23) suggested in patients with a mechanical aortic valve; target INR of 3 (range 2.53.5)
recommended in those with a mechanical mitral valve.500 1008 996 Higher intensity of anticoagulation also
may be considered in patients with mechanical heart valves in both aortic and mitral positions. 1008
Patients with mechanical heart valves in any position: Long-term oral anticoagulation
required.9961008 ACCP recommends adding an antiplatelet agent such as low-dose aspirin (e.g., 50100
mg daily) to warfarin therapy in patients at low risk of bleeding. 1008

Patients with bioprosthetic mitral valves: 3 months of warfarin therapy suggested after valve
insertion; after 3 months, may switch to aspirin therapy, provided patient is in normal sinus rhythm. 1008
Patients with bioprosthetic heart valves and additional risk factors for thromboembolism (e.g., atrial
fibrillation, prior thromboembolism, left ventricular dysfunction, hypercoagulable states): Long-term
warfarin therapy may be warranted; may consider adding aspirin therapy. 996

STEMI
Treatment and Secondary Prevention
Oral or IV
Patients at high risk of systemic or pulmonary embolism (e.g., large anterior MI, a history of previous
thromboembolism, intracardiac thrombus, atrial fibrillation, or substantial heart failure): Long-term
(3 months) warfarin (INR 23) and aspirin therapy (100 mg daily) recommended following acute
MI.500 1010

Cerebral Thromboembolism
Secondary Prevention
Oral or IV
Patients with TIAs or ischemic stroke and concurrent atrial fibrillation: Maintain target INR of 2.5
(range 23) long term, provided no contraindications to therapy exist. 335 338 349 352 432 990 1009
Patients with risk of recurrent stroke from other cardiac sources (e.g., mechanical prosthetic heart
valves, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis,
extensive wall-motion abnormalities): Maintain target INR of 2.5 (range 23) with concomitant lowdose aspirin.335 338 349 432
Patients with a patent foramen ovale and cryptogenic stroke who have evidence of DVT: Target INR
2.5 (range 23) recommended.1008

HIT
Conversion to Warfarin Therapy
Oral or IV

Initiate warfarin only after substantial recovery from acute HIT has occurred (i.e., platelet counts
150,000/mm3).392 442 443 444 1006
Overlap therapy with a nonheparin anticoagulant for 5 days until desired INR is achieved. 387 392393 1006

Special Populations
Hepatic Impairment
Possible increased anticoagulant effect.211 330 May require lower initial and maintenance dosages.211 330

Renal Impairment
Possible increased anticoagulant effect in moderate to severe renal impairment. a No dosage
adjustments required.211 330

Geriatric Patients
Possible increased anticoagulant effect.211 330 Consider low initial dosages.500 Adjust dosage to maintain
INR at the lower end of the range of 23.211 330 344

Debilitated Patients
Possible increased anticoagulant effect.211 330 Consider low initial dosages.500

Asian Patients

Cautions for Coumadin

Contraindications

Pregnancy.211 330

Hemorrhagic tendencies or blood dyscrasias.211 330

Recent or contemplated eye, brain, or spinal cord surgery. 211 330

Recent or contemplated traumatic surgery resulting in open surgical wounds. 211 330

Active ulceration or bleeding of the GI, respiratory, or GU tracts.211 330

Cerebrovascular hemorrhage.211 330

Aneurysms (cerebral, dissecting aorta).211 330

Pericarditis and pericardial effusions.211 330

Bacterial endocarditis.211 330

Eclampsia, preeclampsia, or threatened abortion.211 330

Spinal puncture or other diagnostic or therapeutic procedures with potential for uncontrolled
bleeding.211 330

Major regional or lumbar block anesthesia.211 330

Severe, uncontrolled, or malignant hypertension.211 330

Unsupervised patients with senility, alcoholism, or psychosis or other lack of patient

cooperation.211 330

Inadequate laboratory facilities for monitoring anticoagulation. 211 330

Known hypersensitivity to warfarin or any ingredient in the formulation. 211 330

Warnings/Precautions
Warnings
Hemorrhage
Possible massive hemorrhage involving the GI tract, spinal cord, GU, cerebral, pericardial,
pulmonary, adrenal, or hepatic sites.a Hemorrhagic complications may be manifested by signs or
symptoms that do not indicate obvious bleeding, such as paralysis; headache; pain in the chest,
abdomen, joints, muscles, or other areas; dizziness; shortness of breath; difficulty breathing or
swallowing; unexplained swelling; weakness; hypotension; or unexplained shock. 211 330 Results
principally from overdosage or excessive PT/INR prolongation; however, may occur when the PT/INR
is in the usual therapeutic range and frequently results from the presence of occult lesions. a 211 330 More
likely to occur during the initiation of therapy and with higher dosages, resulting in higher INRs. 211 330

Increased risk of postoperative hemorrhage associated with an aPTT >50 seconds even if PT/INR in
desired range.211 330 a
Careful clinical management, including frequent PT/INR determinations, is required. 211 330 (See General
under Dosage and Administration.) Immediate critical evaluation recommended if any unexpected
bleeding occurs (e.g., microscopic or gross hematuria, melena, excessive uterine or menstrual
bleeding, petechiae, ecchymoses, bleeding from gums or other mucous membranes, oozing from
shaving nicks).a 211 330
In patients with major bleeding associated with warfarin therapy, ACCP suggests the use of 4-factor
prothrombin complex concentrate rather than fresh frozen plasma for rapid reversal of
anticoagulation; additional use of phytonadione (510 mg by slow IV infusion) recommended. 1000
Adrenal hemorrhage resulting in acute adrenal insufficiency reported with anticoagulant
therapy.409 410 411 417 In patients with manifestations of acute adrenal hemorrhage or insufficiency,
discontinue anticoagulant therapy, measure plasma cortisol concentrations immediately, and institute
prompt, vigorous therapy with IV corticosteroids; delay in initiating therapy may result in death. a

Necrosis
Rarely, possible potentially fatal necrosis and/or gangrene of skin or other
tissues.203 211 215 290 291 292293 298 330 Appears early (e.g., 110 days) after initiation of therapy principally at sites
of fat tissue (e.g., abdomen, breasts, buttocks, thighs).290 293 298 Increased risk in patients with
hereditary, familial, or clinical deficiencies of protein C or its cofactor, protein S. 211 213 290 330
Discontinue therapy if warfarin-induced necrosis is suspected211 213 215 290 330 354 and administer vitamin K
(phytonadione) or fresh frozen plasma.213 215 290 291 Consider heparin or LMWH therapy to treat the
underlying thromboembolic disease and possibly prevent additional microvascular
thrombosis.211 213 215 290 298 330 In severe cases, surgical debridement, skin grafting, or amputation may be
necessary.203 211 215 290 292 293 330
Possible limb ischemia, necrosis, and gangrene may occur in patients with HIT when warfarin is
substituted for or continued after heparin or LMWH treatment.387 388 389 395 Use with caution.211 330 391If
warfarin use necessary, delay initiation of therapy until thrombin generation is adequately controlled
and thrombocytopenia has resolved (i.e., platelet counts 150,000/mm3).354 442 443 444 1006
Initiation of anticoagulant therapy with heparin for 45 days before initiation of warfarin 211 330 or
overlapping therapy with the 2 drugs for 56 days 203 291 292 may minimize the risk of warfarin-induced
necrosis.203 211 330

Purple Toes Syndrome and Cholesterol Microembolization

Purple toes syndrome may result from possible increased release of atheromatous plaque fragments
from systemic cholesterol microemboli.211 216 221 284 285 286 287 288 330 May occur 310 weeks or later following
initiation of warfarin therapy.203 211 216 284 289 330
Discontinuance of warfarin therapy is recommended; some cases of purple toes syndrome have
progressed to gangrene or necrosis, requiring debridement and/or amputation. 211 284 288 330
Other possible manifestations of systemic atheroembolism include livedo reticularis, rash, gangrene,
abrupt and intense pain in the leg, foot, or toes, foot ulcers, myalgia, penile gangrene, abdominal
pain, flank or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord
infarction, pancreatitis, and symptoms simulating polyarteritis.211 216 221 285 287288 330

Fetal/Neonatal Morbidity and Mortality

Possible teratogenicity, fetal or neonatal hemorrhage, and intrauterine death. 211 330 1012 aDetectable in
fetal plasma at concentrations approaching maternal concentrations.211 330Generally contraindicated
during pregnancy, except in certain pregnant women (e.g., those with mechanical heart valves)
considered to be at high risk for thrombosis.211 330 341 342 343 386 500 1012
ACCP, ACC, and AHA suggest that warfarin might not be fetopathic when administered during the
first 6 weeks of pregnancy.341 1012 If decision made to use warfarin during pregnancy, ACCP
recommends avoiding administration during weeks 612 of gestation and close to term (to avoid
anticoagulation of the fetus).1012

General Precautions
Adequate Patient Evaluation and Monitoring
Closely supervise all patients medically and ensure availability of adequate laboratory facilities for
monitoring therapy (e.g., using PT/INR) and treating hemorrhage.211 330

Factors Influencing Response

Possible increased anticoagulant response (increased PT/INR and risk of hemorrhage) due to
vitamin K deficiency, scurvy, malnutrition or cachexia, small body size, hepatic dysfunction, moderate
to severe renal impairment, fever, hyperthyroidism, infectious disease, carcinoma, collagen disease,
CHF, diarrhea, biliary obstruction, old age, debility, menstruation and menstrual disorders, radiation
therapy, initial hypoprothrombinemia, and decreased clearance of warfarin as a result of variations in
genes responsible for warfarin metabolism.211 330 462 463 464 465 466467 468 469 470 473 (See Pharmacogenomics under
Dosage and Administration.)

Possible increased sensitivity to anticoagulant effect in Asian patients.211 378 465 469 (See Asian Patients
under Dosage and Administration.)
Possible decreased response (decreased PT/INR) due to increased intake or GI absorption of
vitamin K, diabetes mellitus, edema, hyperlipidemia, hypothyroidism, and visceral carcinoma. 211 a
Rarely, inherited familial coumarin resistance due to variations in the anticoagulant-vitamin K
receptor site.a May require 1020 times the usual dosage to achieve therapeutic effects. aResistance
also may result from an increased rate of drug metabolism and excretion. a Consider acquired or
inherited warfarin resistance if large daily doses are required to maintain the PT ratio/INR within a
normal therapeutic range.211 330

Surgery or Other Invasive Procedures

Generally contraindicated in patients with recent or contemplated surgery of the eye or CNS and in
those undergoing traumatic surgery resulting in large open surfaces. 211
Limit the operative site sufficiently to permit effective use of local procedures for hemostasis (e.g.,
absorbable hemostatic agents, sutures, pressure dressings) if necessary. 211 Maintain meticulous
surgical hemostasis (e.g., absorbable hemostatic agents, sutures, pressure dressings) if minor
dental and surgical procedures are performed.211 a
Administer IM injections of concomitantly administered therapy in an upper extremity to permit easy
access for manual compression, inspection for bleeding, and/or use of pressure bandages. 211

Specific Populations
Pregnancy
Category X.211 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation
Limited data indicate that warfarin is not distributed into breast milk or detectable in plasma of
nursing infants; prolonged PT/INRs reported in some infants, but substantial coagulation
abnormalities not observed.211 330 414 420 421 422 423 424 Although the manufacturer states to exercise
caution,500 experts generally consider warfarin therapy compatible with breast-feeding. 341 414 420 421422 423 424 1012
Neonates are particularly sensitive to the effects of warfarin as a result of vitamin K
deficiency.aMonitor infants at risk for bleeding with coagulation tests and evaluate their vitamin K
status before breast-feeding.211

Pediatric Use
Safety and efficacy not established in children <18 years of age.211 330 Has been used in pediatric
patients for prevention and treatment of thromboembolic events.211 330 More frequent determinations of
INR are recommended in pediatric patients.211 330 1013
ACCP states experience with warfarin in the pediatric population is mostly based on use in children
>3 months of age.1013

Geriatric Use
Increased anticoagulant response.a 211 Less warfarin required to produce a therapeutic level of
anticoagulation.a Cautious use recommended, particularly when the risk of hemorrhage is
present.211 330 335 Increased risk for hemorrhage in patients 75 years with atrial fibrillation who are at
high risk for thromboembolism.335 Close monitoring of INR recommended.335

Hepatic Impairment
Increased anticoagulant response due to decreased synthesis of coagulation factors and decreased
metabolism of warfarin.211 Weigh risks versus benefits of anticoagulant therapy in patients with
moderate to severe hepatic impairment.211

Renal Impairment
Increased anticoagulant response in patients with moderate or severe renal impairment. a Weigh risks
versus benefits of anticoagulant therapy in patients with moderate to severe renal impairment. 211

Common Adverse Effects

Hemorrhage.211

Interactions for Coumadin

Drug interactions with warfarin and other coumarin derivatives can occur via pharmacodynamic
interactions (e.g., impaired hemostasis; increased or decreased intestinal synthesis or absorption of
vitamin K; altered distribution or metabolism of vitamin K; increased warfarin affinity for receptor
sites; decreased synthesis and/or increased catabolism of functional blood coagulation factors II, VII,
IX, and X; interference with platelet function or fibrinolysis; ulcerogenic effects) or pharmacokinetic
interactions (e.g., increased or decreased rate of warfarin metabolism; increased or decreased

protein binding).211 a Such interactions may increase or decrease response to coumarin derivatives.
(See Tables 2 and 3.)
concurrent use probably should be avoided, if possible

Coumadin Pharmacokinetics
Absorption
Bioavailability
Essentially completely absorbed after oral administration; peak plasma concentration usually
attained within 4 hours.211

Onset
Synthesis of vitamin K-dependent coagulation factors is affected soon after absorption (e.g., within
24 hours).211 a Depletion of circulating functional coagulation factors must occur before therapeutic
effects of the drug become apparent.a

Duration
25 days after a single dose.211

Food
Decreased rate, but not extent, of absorption in the presence of food. 211

Distribution
Extent
The apparent volume of distribution is about 0.14 L/kg.211
Crosses the placental barrier; however, the drug has not been detected in human breast milk. 211

Plasma Protein Binding

Approximately 99%.211

Elimination
Metabolism
Almost entirely in the liver.211 Principally by CYP2C9; CYP2C19, 2C8, 2C18, 1A2, and 3A4 involved to
a lesser degree.211

Elimination Route
Excreted principally in urine as metabolites and to a lesser extent in bile. 211

Half-life
Effective half-life averages 40 hours (range: 2060 hours).211

Special Populations
Slightly decreased clearance of R-warfarin in geriatric patients compared with that in younger
individuals.211 330 However, similar pharmacokinetics of racemic warfarin and S-warfarin in geriatric and
younger individuals.211
Decreased metabolism in patients with hepatic dysfunction. 211

Stability
Storage
Oral
Tablets
1530C.211

Parenteral
Powder for Injection
1530C.211

Compatibility

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

Parenteral
Solution Compatibility

HID

Compatible

Dextrose 5% in Ringers injection, lactated

Dextrose 5% in sodium chloride 0.45 or 0.9%

Dextrose 5 or 10% in water

Incompatible

Ringers injection

Variable

Ringers injection, lactated

Sodium chloride 0.9%