warfarin (Rx)

Venous Thrombosis

Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE)

Initial dose: 2-5 mg PO/IV qDay for 2 days, OR 10 mg PO for 2 days in healthy individuals

Initiate warfarin on day 1 or 2 of LMWH or unfractionated heparin therapy and overlap until desired INR, THEN discontinue heparin

Check INR after 2 days and adjust dose according to results

Typical maintenance dose ranges between 2 and 10 mg/day

Consider dosage based on genotype (see Genomic Considerations)

DVT and PE treatment

• Initiate warfarin on day 1 or 2 of parenteral anticoagulation therapy (eg, LMWH or unfractionated heparin)
• Overlap warfarin and parenteral anticoagulant for at least 5 days until desired INR (>2.0) maintained for 24 hours, then discontinue parenteral therapy

INR range and treatment duration

• Maintain an INR of 2.0-3.0
• Surgery-provoked DVT or PE: Treatment duration of 3 months
• Transient (reversible) risk factor-induced DVT or PE: Treatment duration of 3 months
• First unprovoked proximal DVT or PE with low or moderate bleeding risk: Extended treatment consideration with periodic (ie, annual) risk-benefit analysis
• First unprovoked proximal DVT or PE with high bleeding risk: Treatment duration of 3 months
• First unprovoked distal DVT regardless of bleeding risk: Treatment duration of 3 months
• Second unprovoked DVT or PE with low or moderate bleeding risk: Extended treatment
• Second unprovoked DVT or PE with high bleeding risk: Treatment duration of 3 months
• DVT/PE and active cancer: Extended treatment, with periodic risk-benefit analysis (ACCP recommends LMWH over vitamin K antagonist therapy)
• Prevention of venous thromboembolism for total knee arthroplasty, total hip arthroplasty, and hip fracture surgery: Minimum treatment duration of 10-14 days, with a recommendation to extend outpatient therapy to 35 days (ACCP recommends LMWH over vitamin K antagonist therapy)

Stroke & Thromboembolism

Prophylaxis and treatment of systemic embolic complications (eg, stroke) associated with atrial fibrillation (AF)

Initial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individuals

Check INR after 2 days and adjust dose according to results

Typical maintenance dose ranges between 2-10 mg/day

Consider dosage based on genotype (see Genomic Considerations)

ACCP guidelines recommend dabigatran 150 mg PO BID over adjusted-dose warfarin therapy for AF unless both AF and mitral stenosis are present

INR range and treatment duration

• Nonvalvular AF: Maintain an INR of 2.0-3.0
• AF and stable CAD: Adjusted-dose warfarin therapy (INR 2.0-3.0) without aspirin
• AF with high stroke risk and placement of stent: Triple therapy of dose-adjusted warfarin (INR 2.0-3.0), clopidogrel, and aspirin; for 1 month if bare metal stent; for 3-6 months for drug-eluting stent
• AF with intermediate to high stroke risk without stent placement: 12 months of warfarin therapy (INR 2.0-3.0) with single antiplatelet regimen
• AF for more than 48 hours to undergo cardioversion: Warfarin therapy (INR 2.0-3.0) for 3 weeks prior to and 4 weeks after cardioversion

Indications for indefinite treatment duration

• Persistent or paroxysmal nonvalvular AF in patients with a high risk of stroke: Ie, patients who have risk factors for stroke, such as prior ischemic stroke, transient ischemic attack, or systemic embolism or who have 2 of the following risk factors--age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus
• Persistent or paroxysmal nonvalvular AF in patients with an intermediate risk of ischemic stroke: Ie, patients who have 1 of the following risk factors--age >75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus
• AF and mitral stenosis
• ≥2 episodes of documented DVT or PE

Cardiac Valve Replacement

Prophylaxis and treatment of thromboembolic complications associated with cardiac valve replacement

Initial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individuals

Check INR after 2 days and adjust dose according to results

Typical maintenance dose ranges between 2 and 10 mg/day

Consider dosage based on genotype (see Genomic Considerations)

INR and treatment duration

• Mitral bioprosthetic valve: INR 2.0-3.0 for a 3-month treatment duration; if other risk factors for thromboembolism are present (ie, AF, previous thromboembolism, left ventricular dysfunction), a longer duration may be necessary
• Aortic mechanical valve: INR 2.0-3.0 for indefinite treatment duration
• Mitral mechanical valve, caged ball or caged disk valve, or both aortic and mitral mechanical valves: INR 2.5-3.5 for indefinite treatment duration
• Mechanical valves include bileaflet mechanical valves and Medtronic Hall tilting disk valves

Post-Myocardial Infarction

Reduction in the risk of death, recurrent MI, and thromboembolic events (eg, stroke, systemic embolization) after MI

Initial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individuals

Check INR after 2 days and adjust dose according to results

Typical maintenance dose ranges between 2 and 10 mg/day

Consider dosage based on genotype (see Genomic Considerations)

INR and treatment duration

• Maintain INR between 2.0 and 3.0
• In patients who have not had stenting and who have anterior MI and left ventricular (LV) thrombus or high risk of LV thrombus (ie, ejection fraction <40%, anteroapical wall-motion abnormality), treatment involves dual therapy of warfarin (INR 2.0-3.0) and low-dose aspirin 75-100 mg, daily; treatment duration is 3 months, after which warfarin is discontinued
• In patients who have had bare-metal stent placement and who have anterior MI and LV thrombus or high risk of LV thrombus (ejection fraction <40%, anteroapical wall-motion abnormality), treatment involves triple therapy of warfarin (INR 2.0-3.0), low-dose aspirin, and clopidogrel 75 mg, daily for 1 month, followed by warfarin (INR 2.0-3.0) and single antiplatelet therapy for second and third month, after which warfarin is discontinued
• In patients who have had drug-eluting stent placement and who have anterior MI and LV thrombus or high risk of LV thrombus (ejection fraction <40%, anteroapical wall-motion abnormality), treatment involves triple therapy of warfarin (INR 2.0-3.0), low-dose aspirin, and clopidogrel 75 mg, daily for 3-6 months, after which warfarin is discontinued

Rheumatic Valve Disease (Off-label)

Rheumatic valve disease with any of the following: Atrial diameter >55 mm, left atrial thrombus, atrial fibrillation, and previous systemic embolism

Maintain INR 2.0-3.0 indefinitely

Cryptogenic Stroke and Patent Foramen Ovale With DVT (Off-label)

Maintain INR between 2.0 and 3.0 for 3 months

Cardioembolic Stroke or TIA (Off-label)

Maintain INR between 2.0 and 3.0 indefinitely

ACCP guidelines recommend dabigatran 150 mg PO twice daily over dose-adjusted warfarin therapy

Systolic LV Dysfunction (Off-label)

Systolic LV dysfunction without established CAD but with identified acute LV thrombus (eg, Takotsubo cardiomyopathy)

Maintain INR between 2.0 and 3.0 for at least 3 months

Antiphospholipid Antibody Syndrome (Off-label)

Antiphospholipid antibody syndrome with previous arterial or venous thromboembolism

Maintain INR between 2.0 and 3.0 indefinitely

Genomic Considerations

ACCP 2012 guidelines recommend against using pharmacogenetic testing for guiding doses

CYP2C9 and vitamin K epoxide reductase complex, subunit 1 (VKORC1) genotype information can assist in selecting starting dose

If genotype information unavailable, usual starting dose is 2-5 mg/day (modify based on other patient factors)

Range of expected therapeutic doses based on CYP2C9 and VKORC1 genotypes are listed below

VKORC1-GG

• CYP2C9 *1/*1: 5-7 mg
• CYP2C9 *1/*2: 5-7 mg
• CYP2C9 *1/*3: 3-4 mg
• CYP2C9 *2/*2: 3-4 mg
• CYP2C9 *2/*3: 3-4 mg
• CYP2C9 *3/*3: 0.5-2 mg

VKORC1-AG

• CYP2C9 *1/*1: 5-7 mg
• CYP2C9 *1/*2: 3-4 mg
• CYP2C9 *1/*3: 3-4 mg
• CYP2C9 *2/*2: 3-4 mg
• CYP2C9 *2/*3: 0.5-2 mg
• CYP2C9 *3/*3: 0.5-2 mg

VKORC1-AA

• CYP2C9 *1/*1: 3-4 mg
• CYP2C9 *1/*2: 3-4 mg
• CYP2C9 *1/*3: 0.5-2 mg
• CYP2C9 *2/*2: 0.5-2 mg
• CYP2C9 *2/*3: 0.5-2 mg
• CYP2C9 *3/*3: 0.5-2 mg

Dosing Considerations

Indication determines intensity and duration of therapy

Individualized doses and monitoring of PT/INR are necessary

Monitoring frequency should be daily or once every few days until stabilized; once stable, q4-6 weeks or longer may be appropriate (eg, 12 weeks)

Not all factors causing warfarin dose variability are known, but they include age, race, sex, body weight, concomitant medications, and comorbidities, in addition to genetic factors

Lower starting doses (ie, 2-5 mg/day × 2 days) recommended with the elderly, hepatic impairment, poor nutrition, CHF, high bleeding risk, debilitated patients, heart valve replacement, concomitant medications known to increase warfarin effect, or individuals suspected of having genomic variants

Perioperative management recommendations: Hold warfarin therapy approximately 5 days before surgery; resume warfarin 12-24 hr after surgery; bridge anticoagulation during interruption in patients at high thromboembolism risk

Minor procedures and dental procedures: See ACCP guidelines for specific recommendations

Warfarin has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage

Systemic atheroemboli and cholesterol microemboli; some cases have progressed to necrosis or death; discontinue therapy if such emboli occur

Pregnant women with mechanical heart valves: Therapy may cause fetal harm; however, benefits may outweigh the risks

Dosage Modifications

Hepatic impairment: May potentiate warfarin response because of decreased metabolism and impaired synthesis of clotting factors

Thrombosis

Prevention/treatment: If baseline INR is 1.0-1.3, administer loading dose of 0.1-0.2 mg/kg PO qDay × 1 day; check INR on days 2-4 and adjust daily dose to maintain INR between 2.0 and 3.0 (unless valve replacement indicates a higher range)  

Use 0.1 mg/kg to initiate therapy with liver impairment or in patients who have had a Fontan procedure

Typical maintenance dose: 0.09-0.33 mg/kg/day, with infants <12 months old often requiring doses at high end of range

Dosing considerations

• Consistent anticoagulation in children is difficult and requires close supervision and frequent dose adjustments
• Refer to ACCP recommendations or institutional protocol for treatment duration dependent on indication
• Infants and children receiving vitamin K-supplemented nutrition (including infant formulas): May be resistant to warfarin therapy
• Infants with human-milk diet: May be sensitive to warfarin therapy

Dosing Considerations

Hepatic impairment

• Hepatic impairment may potentiate warfarin response because of decreased metabolism and impaired synthesis of clotting factors
• Load: 0.1 mg/kg PO qDay × 2 days
• Typical maintenance dose: 0.1 mg/kg PO qDay; adjust dose to achieve desired INR
• Common maintenance dose range: 0.05-0.34 mg/kg PO qDay

Anticoagulation

Lower doses required to produce therapeutic level of anticoagulation

Initial: ≤5 mg PO qDay

Maintenance: 2-5 mg PO qDay

Dosing Considerations

Elderly show greater than expected PT/INR response to anticoagulant effects of warfarin, possibly because of decreased hepatic function resulting in decreased warfarin metabolism and impaired synthesis of clotting factors

Caution should be used in elderly individuals who have increased risk of hemorrhage