Levoleucovorin Intravenous and Warfarin Sodium

• Generic Name: levoleucovorin
• Dosage Forms: n.a.
• Other Brand Names: Fusilev, Khapzory

Levoleucovorin injection is used as an antidote to the harmful effects of methotrexate (a cancer medicine) that is given in high doses in patients with bone cancer (osteosarcoma). It is also used to treat overdosage of certain medicines. Levoleucovorin acts the same way in the body as folic acid (vitamin B9).

Levoleucovorin injection is also used in combination with 5-fluorouracil (Adrucil®) to relieve and prevent symptoms of patients with advanced metastatic (cancer that has already spread) cancer of the colon and rectum.

Levoleucovorin is to be given only by or under the direct supervision of a doctor.

• Generic Name: warfarin
• Dosage Forms: n.a.
• Other Brand Names: Coumadin, Jantoven

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

Initiate concomitantly with a parenteral anticoagulant (e.g., a low molecular weight heparin [LMWH], heparin [referring throughout this monograph to unfractionated heparin], fondaparinux). 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.

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

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.

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). For most cases of venous thromboembolism, a minimum of 3 months of anticoagulant therapy is recommended. 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). (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).

Used in select pediatric patients with DVT or PE. 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).

Treatment and secondary prevention of venous thromboembolic events secondary to use of central venous access devices (CVAD) in children. Remove affected CVAD if no longer functioning or required; however, if CVAD required, ACCP suggests giving anticoagulants until catheter is removed. 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.

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

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). Continue thromboprophylaxis for at least 10–14 days, and possibly for up to 35 days after surgery.

Several antithrombotic agents (e.g., LMWHs, fondaparinux, low-dose heparin, warfarin, aspirin) recommended by ACCP for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery. 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).

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

Prevention of stroke and systemic embolism in patients with atrial fibrillation. 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.

Choice of antithrombotic therapy is based on patient's risk for stroke and bleeding. 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. 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. 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.

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.

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.

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).

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), lower body weight (<50 kg), or advanced liver disease (impaired baseline clotting function). 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.

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

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

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. After successful cardioversion, all patients should receive therapeutic anticoagulation for ≥4 weeks.

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

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.

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.

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.

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.

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. 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.

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

Used to reduce the incidence of thromboembolism (e.g., stroke) in patients with prosthetic mechanical or biological heart valves.

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.

Long-term warfarin therapy required in all patients with mechanical heart valves because of associated high risk of thromboembolism.

Warfarin anticoagulation also suggested in patients with mitral bioprosthetic valves, at least for the first 3 months after valve insertion. 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. 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).

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. A higher intensity of warfarin anticoagulation also may be considered in patients with both aortic and mitral mechanical valves.

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. Combination therapy also may be warranted in some patients with bioprosthetic valves (e.g., those with additional risk factors for thrombosis).

Used for secondary prevention to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after acute STEMI.

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).

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 MI, substantial heart failure, intracardiac thrombus visible on transthoracic echocardiography, atrial fibrillation, history of previous thromboembolic event). Triple therapy with warfarin, low-dose aspirin, and clopidogrel is suggested in some patients (e.g., those with anterior MI and left ventricular thrombus who undergo coronary artery stent placement).

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.

Warfarin anticoagulation also is recommended for the prevention of recurrent stroke in patients at high risk for recurring cerebral embolism from other cardiac sources (e.g., prosthetic mechanical heart valves, anterior MI and left ventricular thrombus).

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

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. 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. 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. Warfarin also has been used in children with cerebral venous sinus thrombosis who do not have substantial intracranial hemorrhage.

Has been used in certain patients with peripheral arterial occlusive disease. 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.

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

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

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. (See Necrosis under Cautions.)