Warfarin is used for prophylaxis and/or treatment of venous thrombosis and its extension, prophylaxis and treatment of pulmonary embolism, prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement, and as an adjunct in the treatment of coronary occlusion. The drug also is used to reduce the risk of death, reinfarction, and thromboembolic events such as stroke or systemic embolization following myocardial infarction (MI).
The most widely accepted indications for anticoagulant therapy include the treatment of venous thrombosis and pulmonary embolism and prevention of these conditions in high-risk patients, such as those with a history of thromboembolism, those undergoing certain types of major surgery, or those who require prolonged immobilization. Because the effects of warfarin are delayed and early full-dose anticoagulant therapy reduces the risk of extension or recurrence of venous thrombosis, a rapid-acting parenteral anticoagulant such as heparin (referring throughout this monograph to unfractionated heparin), a low molecular weight heparin, or fondaparinux is used for the initial treatment of venous thromboembolism. Warfarin generally is used for follow-up anticoagulant therapy after the effects of the initial parenteral anticoagulant have been established and when long-term anticoagulant therapy is indicated. Therapy with warfarin and the parenteral anticoagulant should be overlapped for a short period of time until the therapeutic effects of warfarin are achieved.
Deep-Vein Thrombosis and Pulmonary Embolism
Treatment and Secondary Prevention
In the treatment of acute proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE) (i.e., venous thromboembolism) in adults, the American College of Chest Physicians (ACCP) recommends that warfarin therapy be initiated concomitantly with a parenteral anticoagulant (heparin, a low molecular weight heparin, or fondaparinux). Warfarin should be initiated on the same day that the parenteral anticoagulant is started, and such therapy should be overlapped for at least 5 days and until a stable international normalized ratio (INR) of at least 2 has been maintained for 24 hours or longer. Anticoagulant therapy generally is not recommended for the treatment of isolated distal DVT unless symptoms are severe and there is a risk for thrombus extension. ACCP recommends a moderate intensity (target INR of 2.5, range 2-3) of warfarin anticoagulation in most patients for the treatment of DVT and PE. While use of either a lower intensity of anticoagulation (INR <2) or a higher intensity of anticoagulation (INR of 3-5) has been evaluated for these indications, both low-intensity and high-intensity anticoagulation appear to be less optimal than moderate-intensity warfarin; low-intensity warfarin is no safer than moderate-intensity warfarin, and high-intensity warfarin is associated with an increased incidence of bleeding complications.
In patients with venous thromboembolism, ACCP recommends that anticoagulant therapy be continued beyond the acute treatment period for at least 3 months, and possibly longer depending on the individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors, presence of cancer, patient's risk of bleeding). Warfarin generally is the preferred anticoagulant for long-term treatment of venous thromboembolism in patients without cancer; however, in patients with cancer, ACCP suggests the use of a low molecular weight heparin 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). While several randomized, controlled studies of patients receiving warfarin indicate that recurrence of venous thromboembolism is less frequent with longer periods of anticoagulation (exceeding 6 months) compared with shorter periods (3-6 months), particularly in patients with idiopathic (i.e., unprovoked) venous thromboembolism, prolonged therapy with warfarin (in addition to increased intensity of anticoagulation) is associated with an increased risk of bleeding complications. Therefore, the shortest period of anticoagulant therapy deemed to be effective should be used, keeping in mind the high morbidity and mortality of undertreated venous thromboembolism. ACCP states that 3 months of anticoagulant treatment usually is sufficient in patients experiencing a proximal DVT or PE provoked by surgery or other transient risk factor. For those with an unprovoked thromboembolic event, anticoagulant therapy should be continued for at least 3 months; after this time, the risks versus benefits of extended therapy (defined by ACCP as treatment beyond 3 months without a scheduled stop date) should be evaluated in individual patients. In general, extended anticoagulant therapy is suggested in patients with unprovoked (idiopathic) DVT or PE who are at low risk of bleeding. Extended therapy is recommended by ACCP in cancer patients with acute venous thromboembolism because of the high risk of recurrence in these patients. Patients with acute upper-extremity DVT involving the axillary or more proximal veins also should receive anticoagulant therapy for at least 3 months. If the upper-extremity DVT is associated with a central venous catheter, anticoagulation should be continued as long as the catheter remains in place; if the catheter is removed, ACCP states that 3 months of anticoagulation is sufficient. For additional information on treatment of venous thromboembolism, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.
Although warfarin therapy can be problematic in children for several reasons (e.g., dietary differences, compliance issues, monitoring difficulty, lack of a commercially available liquid preparation), the drug has been used in selected pediatric patients with venous thromboembolism. Experience with warfarin in the pediatric population is mostly based on use of the drug in children older than 3 months of age; there is little efficacy or safety information in neonates. Heparin or a low molecular weight heparin generally is recommended for both the initial and ongoing treatment of venous thromboembolism in children. However, ACCP recommends that children with recurrent idiopathic venous thromboembolism receive indefinite treatment with warfarin. Unlike in adults, most episodes of venous thromboembolism in children are secondary to an identifiable risk factor such as the presence of a central venous access device (e.g., central venous catheter or umbilical venous catheter). In children with central venous catheter-related thromboembolism, ACCP recommends that the catheter be removed if no longer functioning or required; at least 3-5 days of therapeutic anticoagulation is suggested prior to its removal. If the central venous access device is required, ACCP suggests that anticoagulants be given until the catheter is removed. After the initial 3 months of therapy, use of prophylactic dosages of warfarin (target INR 1.5-1.9) or a low molecular weight heparin is suggested until the catheter is removed; however, if recurrent thromboembolism occurs, therapeutic-dose anticoagulation may be required.
ACCP recommends routine thromboprophylaxis (with a pharmacologic and/or mechanical method [e.g., intermittent pneumatic compression]) in all patients undergoing major orthopedic surgery, including total hip-replacement, total knee-replacement, and hip-fracture surgery, because of the high risk for postoperative venous thromboembolism; thromboprophylaxis should be continued for at least 10-14 days, and possibly for up to 35 days after surgery. Several antithrombotic agents (e.g., low molecular weight heparins, fondaparinux, low-dose heparin, warfarin, aspirin) are recommended by ACCP for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery. Although ACCP suggests that a low molecular weight heparin generally is preferred because of its relative efficacy and safety and extensive clinical experience, alternative agents such as warfarin may be a reasonable choice in situations in which a low molecular weight heparin is not available or cannot be used (e.g., in patients with heparin-induced thrombocytopenia or in those who refuse or are uncooperative with subcutaneous injections). ACCP states that when selecting an appropriate thromboprophylaxis regimen, factors such as relative efficacy and bleeding risk as well as logistics and compliance issues should be considered. For additional information on the prevention of venous thromboembolism in patients undergoing major orthopedic surgery, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.
Thromboprophylaxis in Pediatric Patients
Warfarin also has been used for primary thromboprophylaxis in children with ventricular assist devices or with an arteriovenous fistula undergoing hemodialysis and in children with certain medical conditions associated with a high risk of thrombosis (e.g., moderate or giant coronary aneurysms following Kawasaki disease, primary pulmonary hypertension).
Embolism Associated with Atrial Fibrillation
Warfarin is used for the prevention of stroke and systemic embolism in patients with atrial fibrillation. In several randomized, controlled studies in patients with chronic atrial fibrillation unrelated to rheumatic fever (i.e., nonvalvular atrial fibrillation), the incidence of thromboembolic events (e.g., transient ischemic attack [TIA], ischemic stroke) in patients anticoagulated with warfarin was substantially reduced compared with that in patients receiving placebo. ACCP, the American College of Cardiology (ACC), the American Heart Association (AHA), the American Stroke Association (ASA), and other experts currently recommend that antithrombotic therapy be administered to 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.
Recommendations regarding choice of antithrombotic therapy in patients with atrial fibrillation are based on the patient's risk for stroke and bleeding. In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients with atrial fibrillation 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. Although many risk stratification methods have been used, patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or TIA, advanced age (e.g., 75 years or older), 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 or older, and AHA and the American Stroke Association (ASA) recommend the use of risk stratification tools that account for age- and sex-specific differences in stroke risk. One such tool is the CHA2DS2-VASc score, an extension of the CHADS2 system (which considers the risk factors congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and prior stroke/TIA) that adds extra points for female sex (1 point); previous MI, peripheral arterial disease, or aortic plaque (1 point); and age 65-74 years (1 point) or 75 years or older (2 points). In a large drug registry study in Sweden, women had a greater reduction in stroke (60%) than men (40%) with warfarin therapy while the risk of major hemorrhage was similar between groups.
Although warfarin traditionally has been used for oral anticoagulation in patients with atrial fibrillation at increased risk of stroke, some experts suggest that non-vitamin K antagonist oral anticoagulants such as apixaban, dabigatran, or rivaroxaban may provide certain advantages over warfarin (e.g., rapid onset of action, predictable anticoagulant effect, no requirement for coagulation monitoring, less potential for drug-drug and drug-food interactions) and may be considered as alternative therapy in selected patients. 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. AHA and ASA state that while clinical trials of non-vitamin K antagonist oral anticoagulants were not designed to determine differences in efficacy compared with warfarin in men versus women, apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in women with paroxysmal or permanent atrial fibrillation and prespecified risk factors (according to CHA2DS2-VASc) who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (creatinine clearance less than 15 mL/minute), lower body weight (less than 50 kg), or advanced liver disease (impaired baseline clotting function). When selecting an appropriate anticoagulant for patients with atrial fibrillation, experts recommend that the risks versus benefits of such therapy be considered for individual patients based on the absolute and relative risks of stroke and bleeding; patient compliance, preference, tolerance, and comorbidities; cost; availability of agents to reverse anticoagulant effects in case of bleeding complications; and other clinical factors such as renal function, availability of facilities to monitor INR, and degree of current INR control in patients already receiving warfarin.
Pooled analysis of data from a number of comparative studies evaluating therapy with warfarin and aspirin in patients with chronic atrial fibrillation demonstrate that warfarin therapy is more effective than aspirin (e.g., 75-325 mg daily) in reducing thromboembolic complications. In addition, warfarin therapy appears to have a therapeutic advantage over aspirin in preventing nonfatal stroke. However, the anticipated greater benefits of warfarin compared with aspirin must be weighed against the greater risk of bleeding and inconvenience of monitoring oral anticoagulation. Because the net clinical benefit with warfarin relative to aspirin appears to be greatest in patients with a high (and possibly also intermediate) risk of stroke, ACCP and other experts generally recommend the use of oral anticoagulation (e.g., warfarin targeted to an INR of 2-3) over aspirin in such patients. For patients at low risk of stroke, the expected benefits of warfarin may not outweigh the risks of bleeding, and thus, aspirin is preferred. AHA and ASA state that oral anticoagulation is not recommended in women 65 years of age or younger with atrial fibrillation and no other risk factors (CHADS2 = 0 or CHA2DS2-VASc = 1); instead, antiplatelet therapy is a reasonable option in selected low-risk women.
Dual antiplatelet therapy with clopidogrel and aspirin was evaluated as a potential alternative to oral anticoagulation in a randomized controlled study in patients with atrial fibrillation at high risk of stroke. The study was terminated early because of clear evidence of superiority of warfarin over antiplatelet therapy for the primary outcome of stroke, systemic embolism, MI, or vascular death. Results of another study comparing dual antiplatelet therapy (clopidogrel and aspirin) with aspirin monotherapy in patients with atrial fibrillation who had an increased risk of stroke but were unable to take warfarin showed that the combination of clopidogrel and aspirin was more effective than aspirin in reducing the risk of nonfatal stroke; however, dual antiplatelet therapy was associated with an increased risk of bleeding. Based on these findings, ACCP and other experts recommend the use of clopidogrel and aspirin rather than aspirin alone as an alternative to oral anticoagulation 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, or cost limitations). Because the risk of bleeding with combination aspirin and clopidogrel therapy is similar to the risk of bleeding with warfarin, such combination therapy is not recommended in patients with a hemorrhagic contraindication to warfarin.
Antiplatelet agents may be used in addition to warfarin in certain patients with atrial fibrillation who have coexisting conditions that warrant the use of antiplatelet therapy (e.g., patients with recent placement of an intracoronary stent or those experiencing an acute coronary syndrome).
While randomized clinical trials evaluating warfarin anticoagulation in patients with atrial fibrillation and prosthetic heart valves or rheumatic mitral valve disease have not been conducted, long-term warfarin therapy also is strongly recommended in such patients based on results of studies in patients who have atrial fibrillation without these coexisting conditions. The intensity of anticoagulation in patients with prosthetic heart valves should be based on the particular type of prosthesis but should not be less than that required to maintain an INR of 2.5; patients with prosthetic mechanical heart valves should have a target INR of at least 2.5.
(See Uses: Thromboembolism Associated with Prosthetic Heart Valves.)
In patients with atrial fibrillation who have ischemic stroke or systemic embolism during warfarin anticoagulation at an INR of 2-3, ACC, AHA, and the European Society of Cardiology (ESC) suggest that it may be reasonable to increase the intensity of anticoagulation to a maximum target INR of 3-3.5; however, other experts state that data are lacking regarding the efficacy of increasing anticoagulation in providing future protection against thromboembolic events, and higher INRs are associated with an increased risk of bleeding.
The risk of thromboembolism in patients with atrial flutter is not as well established as it is in those with atrial fibrillation. In addition, many patients with atrial flutter have alternating periods of atrial fibrillation. Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.
Cardioversion of Atrial Fibrillation
Use of warfarin is recommended to decrease the risk of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation.
Because the risk of thromboembolism appears to be greatest when atrial fibrillation has been present for more than 48 hours, recommendations for the use of anticoagulant therapy in such patients vary based on the duration of the arrhythmia. ACCP and other experts recommend that patients with atrial fibrillation of unknown or greater than 48 hours' duration who are to undergo elective cardioversion receive therapeutic anticoagulation (e.g., usually with warfarin) for at least 3 weeks prior to cardioversion; alternatively, a transesophageal echocardiography (TEE)-guided approach may be used. In patients who have atrial fibrillation of short duration (e.g., 48 hours or less), cardioversion usually is performed without prolonged warfarin anticoagulation or TEE prior to the procedure. After successful cardioversion to sinus rhythm, all patients should receive therapeutic anticoagulation for at least 4 weeks.
Experts suggest that patients with atrial flutter undergoing cardioversion be managed according to the same approach as that used in patients with atrial fibrillation.
Embolism Associated with Valvular Heart Disease
Warfarin and/or aspirin is used to prevent thromboembolism associated with various types of valvular heart disease; the choice of antithrombotic therapy depends on balancing the risk of thromboembolism with the risk of hemorrhagic complications from antithrombotic therapy.
Analysis of data from trials evaluating thromboembolism in patients with nonvalvular atrial fibrillation indicate that oral anticoagulants are most effective in patients at highest risk for embolic events. Among the common types of valvular heart disease, rheumatic mitral valve disease is associated with the greatest risk of systemic thromboembolism, and the risk is further increased in patients with concurrent atrial fibrillation, left atrial thrombus, or a history of systemic embolism. Therefore, ACCP recommends warfarin anticoagulation (INR of 2-3) in such patients.
Patients with rheumatic mitral valve disease and in normal sinus rhythm who have a left atrial diameter exceeding 5.5 cm also may be considered for oral anticoagulation with warfarin (target INR 2.5, range 2-3) because of their high likelihood of developing atrial fibrillation. Antithrombotic therapy usually is not required in patients with rheumatic mitral valve disease who are in normal sinus rhythm and have a left atrial diameter of less than 5.5 cm.
In selected patients with mitral valve prolapse who have atrial fibrillation (i.e., those 65 years of age or older or those with a mitral valve regurgitation murmur, hypertension, or a history of heart failure), prophylaxis with warfarin is recommended by ACC and AHA. Warfarin (INR of 2-3) also is recommended by ACC and AHA for prevention of thromboembolic events in patients with mitral valve prolapse and a history of stroke who have concomitant mitral valve regurgitation, atrial fibrillation, or left atrial thrombus.
Warfarin has been used in a limited number of patients undergoing percutaneous balloon mitral valvotomy to prevent left atrial embolism. In patients who are being considered for percutaneous balloon mitral valvotomy who have TEE-confirmed left atrial thrombus, ACCP recommends postponing the procedure and administering warfarin (target INR 3, range 2.5-3.5) until confirmed thrombus resolution occurs. The procedure should not be performed if thrombus resolution does not occur with warfarin therapy.
Antithrombotic therapy generally should not be initiated in patients with infective endocarditis involving a native valve because of the risk of serious hemorrhage, including intracerebral hemorrhage, and lack of documented efficacy in such patients. In patients with a prosthetic valve who are already receiving warfarin therapy, ACCP suggests temporary discontinuance of the drug if infective endocarditis develops, and reinitiation of therapy once invasive procedures no longer are required and the patient is stabilized without signs of neurologic complications.
Thromboembolism Associated with Prosthetic Heart Valves
Warfarin is used to reduce the incidence of thromboembolism (e.g., stroke) in patients with prosthetic mechanical or biological heart valves. The risk of systemic embolism is higher with 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 is higher in the first few days and months after valve insertion (before full endothelialization) and increases in the presence of atrial fibrillation.
All patients with mechanical heart valves require long-term warfarin therapy because of the high risk of thromboembolism with these valves, which appears to average 1-2% annually even with the use of warfarin. During the early postoperative period following insertion of a mechanical heart valve, ACCP suggests bridging anticoagulation with heparin or a low molecular weight heparin until the patient is stable on warfarin therapy.
(See Initial Dosage under Dosage and Administration: Dosage.)Warfarin therapy also is suggested by ACCP in patients with bioprosthetic heart valves in the mitral position, at least for the first 3 months after valve insertion; after the first 3 months, patients may be switched to aspirin therapy provided they are in normal sinus rhythm. In patients with aortic bioprosthetic valves who are in sinus rhythm and have no other indications for warfarin therapy, aspirin generally is 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, a target INR of 2.5 (range 2-3) is suggested with warfarin therapy in patients with a mechanical heart valve in the aortic position, while a higher intensity of anticoagulation (target INR of 3; range 2.5-3.5) is recommended in those with a mechanical heart valve in the mitral position. A higher intensity of warfarin anticoagulation also may be considered in patients with mechanical heart valves in both the aortic and mitral positions.
(See Initial Dosage under Dosage and Administration: Dosage.)
Because warfarin therapy alone does not completely prevent thrombosis in patients with prosthetic heart valves, aspirin or dipyridamole has been used in conjunction with warfarin to reduce the incidence of thrombosis in these patients. The combination of warfarin and aspirin appears to be more effective than warfarin alone but may increase the risk of bleeding. In 2 studies comparing treatment with warfarin alone or in combination with 500-mg or 1-g daily doses of aspirin, patients receiving 1 g of aspirin daily had an increased risk of GI bleeding. In another study comparing treatment with warfarin alone or in combination with aspirin (500 mg daily) or dipyridamole (400 mg daily), the combination regimen with aspirin was associated with an increased risk of bleeding complications compared to the other regimens. In a randomized, placebo-controlled study in patients with prosthetic heart valves who were at high risk for systemic embolism, addition of delayed-release, enteric-coated aspirin (100 mg daily) to warfarin therapy (adjusted to maintain an INR of 3-4.5) resulted in a substantial reduction in major systemic embolism or death, particularly from vascular causes, compared with warfarin therapy alone. Although the risk of hemorrhagic complications with combined aspirin-warfarin therapy was considerably higher than that with warfarin alone (55% increase, principally in minor bleeding), combined therapy was associated with a 61% reduction in relative risk (compared with warfarin alone) for the combined end point of major systemic embolism, nonfatal intracranial hemorrhage, death from hemorrhage, and death from vascular causes. Based on the current evidence, ACCP recommends the addition of an antiplatelet agent such as 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. In addition, combination therapy with aspirin and warfarin also is recommended by ACC/AHA in patients with bioprosthetic valves who have additional risk factors for thrombosis (e.g., atrial fibrillation, previous thromboembolism, left ventricular dysfunction, hypercoagulable condition).
ST-Segment Elevation Myocardial Infarction
Current treatment of acute ST-segment elevation MI (STEMI) includes the use of thrombolytic therapy for lysis of coronary artery thrombi, and adjunctive therapy with anticoagulants (e.g., heparin, low molecular weight heparin, fondaparinux, warfarin) and/or platelet-aggregation inhibitors (e.g., aspirin, clopidogrel) has been used during and after successful coronary artery reperfusion for the prevention of early reocclusion and death.
Current evidence suggests that treatment with full-dose heparin followed by short-term therapy with an oral anticoagulant (e.g., warfarin) may reduce the risk of early recurrence or extension of infarction in selected patients with acute STEMI.
ACC and AHA recommend continuation of full-dose IV heparin, low molecular weight heparin, or fondaparinux for at least 48 hours, followed by conversion to warfarin therapy (dosage adjusted to maintain an INR of 2-3) and low-dose aspirin at hospital discharge in patients at high risk for systemic emboli.
Warfarin is used for secondary prevention to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after an acute STEMI. In general, antiplatelet therapy is preferred to the use of anticoagulants for secondary prevention and risk reduction in patients with atherosclerosis, including those with acute STEMI; however, warfarin in conjunction with low-dose aspirin is recommended in patients who have other compelling indications for anticoagulation therapy (e.g., atrial fibrillation, prosthetic heart valve, left ventricular thrombus or high risk for such thrombi, concomitant venous thromboembolic disease). Anticoagulant therapy with warfarin has been shown to reduce the risk of left ventricular thrombus formation and systemic embolization in patients with Q-wave (transmural) anterior STEMI.
Results of a few prospective studies and analysis of pooled data from other controlled trials suggest that long-term therapy (1-2 years or longer) with a coumarin derivative (e.g., warfarin) may be useful in selected patients for secondary prevention of death and/or nonfatal recurrent STEMI. In a randomized, placebo-controlled study in patients with acute STEMI, therapy with warfarin, initiated 2-4 weeks postinfarction and continued for an average of 37 months, was associated with reductions in the risk of death (24% reduction), nonfatal or fatal reinfarction (34% reduction), and total cerebrovascular events (55% reduction). In another placebo-controlled study in patients randomized to treatment with a coumarin anticoagulant (nicoumalone or phenprocoumon, not currently available in the US) within 6 weeks (usually within 2 weeks) after hospital discharge following acute STEMI, anticoagulant therapy was associated with statistically significant reductions in the risks of reinfarction (53% reduction) and cerebrovascular events (40% reduction); a reduction in the risk of death from any cause (10%) also occurred but was not statistically significant. In an open-label, randomized, comparative study in hospitalized patients with recent acute STEMI, long-term (approximately 4 years) therapy with warfarin alone or in combination with aspirin was more effective than aspirin therapy alone in reducing the incidence of the composite end point of death, nonfatal reinfarction, or thromboembolic stroke. The benefit of warfarin (dosage adjusted to achieve an INR of 2-2.5) in combination with aspirin (75 mg daily) or warfarin alone (dosage adjusted to achieve an INR of 2.8-4.2) compared with aspirin alone (160 mg daily) was restricted to reduction of nonfatal reinfarction and thromboembolic stroke; overall mortality was similar among the treatment groups.
The manufacturers and other experts currently recommend the use of warfarin (target INR 2-3) in conjunction with low-dose aspirin (not exceeding 100 mg daily) for at least 3 months following an acute STEMI in high-risk patients (e.g., those with a large anterior STEMI, substantial heart failure, intracardiac thrombus visible on transthoracic echocardiography, atrial fibrillation, history of previous thromboembolic event). For patients with an anterior STEMI and left ventricular thrombus (or at high risk for such thrombi) who undergo coronary artery stent placement, some experts suggest the use of warfarin in combination with low-dose aspirin and clopidogrel; the recommended duration of such triple antithrombotic therapy is dependent on whether the patient has a bare-metal or drug-eluting stent.
Other Cardiovascular Disease
ACC and AHA recommend the use of anticoagulation in patients with heart failure who have persistent or paroxysmal atrial fibrillation or a prior thromboembolic event.
(See Uses: Embolism Associated with Atrial Fibrillation.)However, routine use of aspirin or warfarin for prevention of thromboembolic events is not recommended by ACC and AHA in patients who have heart failure without an ischemic etiology (e.g., idiopathic, hypertensive) or in those who do not have atrial fibrillation or previous thromboembolism.
Antiplatelet agents are considered preferable to oral anticoagulation for secondary prevention of noncardioembolic stroke in patients with a history of ischemic stroke or TIA. However, oral anticoagulation with warfarin or one of the non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran, rivaroxaban) is recommended for secondary prevention in patients with TIAs or ischemic stroke and concurrent atrial fibrillation, provided no contraindications to therapy exist.
(See Uses: Embolism Associated with Atrial Fibrillation.)Warfarin anticoagulation (target INR 2-3) 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, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis, extensive wall-motion abnormalities).
For arterial ischemic stroke associated with dissection or a cardioembolic cause in children, ACCP suggests the use of warfarin as an option for long-term anticoagulation.
In patients with cryptogenic stroke and a patent foramen ovale or atrial septal aneurysm, ACCP recommends aspirin therapy for secondary prophylaxis of such events; however, if recurrent events occur despite aspirin therapy or another condition requiring anticoagulation (e.g., DVT) exists in such patients, warfarin (target INR 2.5; range 2-3) is suggested over aspirin.
ACCP, AHA, and ASA state that oral anticoagulation with warfarin usually is recommended following initial therapy with heparin or a low molecular weight heparin in patients with acute cerebral venous sinus thrombosis. Following low molecular weight heparin therapy during pregnancy in women with cerebral venous sinus thrombosis, AHA and ASA recommend postpartum anticoagulation with warfarin (target INR of 2-3) as an alternative to low molecular weight heparin for at least 6 weeks (for a total minimum duration of 6 months of anticoagulant therapy). ACCP recommends initial therapy with heparin or a low molecular weight heparin followed by conversion to warfarin or continued therapy with a low molecular weight heparin for at least 3 months in children with cerebral venous sinus thrombosis without substantial intracranial hemorrhage. If symptoms persist or there is continued occlusion of the cerebral venous sinuses, another 3 months of anticoagulant therapy is suggested. For additional information on the use of anticoagulants in pediatric patients with cerebral venous sinus thrombosis, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.
Arterial Occlusive Disease
Warfarin has been used in certain patients with peripheral arterial occlusive disease. However, ACCP generally recommends the use of antiplatelet agents (aspirin or clopidogrel) rather than anticoagulants for the primary or secondary prevention of cardiovascular events in patients with peripheral arterial disease.
Extended anticoagulant therapy (e.g., with warfarin) is recommended by ACCP in all patients with chronic thromboembolic pulmonary hypertension.
While warfarin should not be used for initial treatment of heparin-induced thrombocytopenia (HIT), the manufacturers and other clinicians state that therapy with the drug may be considered after platelet counts have normalized. Cases of venous limb ischemia, necrosis, and gangrene, sometimes resulting in amputation or death, have occurred in patients with HIT when heparin was discontinued and warfarin was initiated or continued. ACCP recommends against initiating warfarin in patients with strongly suspected or confirmed HIT until substantial platelet recovery occurs (e.g., platelet count of at least 150,000/mm); for patients already receiving warfarin at the time of diagnosis of HIT, use of vitamin K is suggested.
ACCP states that HIT should be treated initially with a nonheparin anticoagulant (e.g., lepirudin, argatroban). Conversion to warfarin therapy should be initiated with low dosages (maximum 5 mg daily) and only after substantial recovery from acute HIT has occurred. To avoid prothrombotic effects and ensure continuous anticoagulation, ACCP recommends that therapy with the nonheparin anticoagulant and warfarin be administered concurrently for at least 5 days and until the desired INR has been achieved.
(See Initial Dosage under Dosage and Administration: Dosage)