VA Class:BL110

AHFS Class:

• Coumarin Derivatives 20:12.04.08

Generic Name(s):

• Warfarin Sodium

Chemical Name:

• 3-(α-acetonylbenzyl)-4-hydroxycoumarin sodium salt

Warfarin sodium is a coumarin-derivative anticoagulant that alters the synthesis of vitamin-K dependent blood coagulation factors II, VII, IX, X, and the anticoagulants protein C and protein S.330

Warfarin is used for prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.330 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).330

Warfarin generally is used for follow-up anticoagulant therapy after the effects of an initial parenteral anticoagulant have been established and/or when long-term anticoagulant therapy is indicated.330,483,1000,1200 Therapy with warfarin and a parenteral anticoagulant should be overlapped for a short period of time until the therapeutic effects of warfarin are achieved for appropriate indications for use.330,483,1000,1200

Treatment of Venous Thromboembolism

Adults

Warfarin is used for the treatment of acute proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE) (i.e., venous thromboembolism [VTE]) in adults.330,1200 Because the effects of warfarin are delayed and early full-dose anticoagulant therapy reduces the risk of extension or recurrence of venous thrombosis, the American College of Chest Physicians (ACCP) recommends a rapid-acting parenteral anticoagulant (e.g., unfractionated heparin, low molecular weight heparin [LMWH], fondaparinux) for the initial treatment of VTE.330,483,1200 Therapy with warfarin and the parenteral anticoagulant should be overlapped for a short period of time until the therapeutic effects of warfarin are achieved.330,483,1000,1200

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.1000,1200 ACCP recommends a moderate intensity of warfarin anticoagulation (target INR of 2.5 [range 2-3]) for most patients.1000,1200 While use of either a lower (INR <2) or higher (INR 3-5) intensity of anticoagulation has been evaluated,399,400,407,1200 both 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.400,408,1014,1200

A systematic review with meta-analysis assessed the efficacy and safety of warfarin compared to direct oral anticoagulants (DOACs; apixaban, edoxaban, dabigatran, rivaroxaban) in patients with acute VTE.1164 The review included 5 good quality trials with a total of 24,455 patients.1164 Patients who received dabigatran or edoxaban were treated with an initial 5-10 days of parenteral anticoagulant therapy.1164 Warfarin patients initially received overlapping parenteral anticoagulation therapy for a minimum of 6 days and were treated to a goal INR of 2-3; the reported time in therapeutic range during warfarin therapy was 58-64%.1164 Efficacy outcomes included recurrent VTE, fatal PE, and overall mortality.1164 Recurrent VTE occurred in 2% and 2.2% of DOAC- and warfarin-treated patients, respectively.1164 Fatal PE (0.07%) and overall mortality rates (2.4%) were not different between the treatment groups.1164 The safety outcome of major bleeding occurred in 1.1% and 1.7% of DOAC- and warfarin-treated patients, respectively.1164 When compared to DOAC-treated patients, overall results of this study showed that warfarin had similar efficacy, but a higher rate of major bleeding.1164

Pediatric Patients

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 VTE. 1013,1118 Data are primarily derived from observational studies that do not include a comparator group.1118 Experience with warfarin in the pediatric population is mostly based on use of the drug in children ≥3 months of a there is little efficacy or safety information in neonates.1013 Unfractionated heparin or LMWH generally is recommended in children for initial VTE treatment for at least 5 days; ongoing therapy may occur with heparin, LMWH, or warfarin.1013,1118 Transition to warfarin therapy is the same in children as in adults where warfarin is initiated on the same day that the parenteral anticoagulant is started, and such therapy is overlapped for at least 5 days and until a stable INR ≥2 has been maintained for ≥24 hours.1013,1118 Duration of therapy decisions should be based on an evaluation of clinical risk factors (e.g., location of thrombi, presence or absence of precipitating factors, presence of cancer, patient's risk of bleeding).1013,1118

Warfarin has been used in children with central venous catheter-related thromboembolism†.1013 In these situations, 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 removal.1013 If the central venous access device is required, ACCP suggests that anticoagulants be given until the catheter is removed.1013 After the initial 3 months of therapy, use of prophylactic dosages of warfarin (target INR 1.5-1.9) or a LMWH is suggested until the catheter is removed; however, if recurrent thromboembolism occurs, therapeutic-dose anticoagulation may be necessary.1013

Clinical Perspective

Warfarin remains an option for the treatment of VTE; however, the DOACs (e.g., dabigatran, rivaroxaban, apixaban, edoxaban) are preferred in most cases by experts such as the American College of Chest Physicians (ACCP), American Society of Hematology (ASH), and the Anticoagulation Forum.1006,1106,1200 DOACs have similar efficacy to warfarin for treatment of VTE, but reduced bleeding (particularly intracranial hemorrhage) and greater convenience for patients and healthcare providers.1006,1106,1200 In addition to relative efficacy and safety, factors that should be considered when selecting an appropriate anticoagulant include convenience of administration, need for INR monitoring, drug-drug or drug-food interactions, cost, patient preference, presence of renal impairment, and cancer or other comorbid conditions.1200

Warfarin can be recommended in clinical situations where DOACs are generally not used.1200,1102 These include settings with high bleeding risk (e.g., hemorrhagic lesion, renal/hepatic impairment, thrombocytopenia, GI or genitourinary malignancy, mucosal lesion, CNS malignancy or bleeding, recent surgery), or in patients with morbid obesity (body weight >120 kg or body mass index [BMI] ≥40 mg/m²), drug-drug interactions (e.g., potent dual inducers of p-glycoprotein [P-gp] and cytochrome P-450 [CYP]3A4 [e.g., carbamazepine, phenytoin, rifampin]), or GI complications affecting oral therapy (e.g., poor absorption, nausea and vomiting).1102,1200 Warfarin is also preferred in patients with antiphospholipid syndrome and those with significant valvular heart disease, including patients with mechanical heart valves.1006,1106,1143

In patients with cancer and established VTE, LMWHs or oral factor Xa inhibitors are generally recommended over warfarin for long-term anticoagulation.1200,1102,1103

In patients with acute VTE, therapy should 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 bleeding risk).1200,1006,1106 While several randomized, controlled studies indicate that recurrence of VTE is less frequent with longer periods of anticoagulation (exceeding 6 months) compared with shorter periods (3-6 months),401,402,405 particularly in patients with idiopathic (i.e., unprovoked) VTE, prolonged therapy with warfarin (in addition to increased intensity of anticoagulation) is associated with an increased risk of bleeding complications.401,402,1200

The incidence of VTE in pediatric patients is very low.1013,1118 Several organizations (ACCP, ASH) have published guidelines on the use of antithrombotic therapy in pediatric patients.1013,1118

Prophylaxis of Venous Thromboembolism

Major Orthopedic Surgery

Warfarin is used for the prevention of VTE in adults undergoing major orthopedic surgery (hip- or knee-replacement surgery or hip-fracture surgery).330,1003

Clinical Perspective

Several major guidelines for thromboprophylaxis following hip- or knee-replacement surgery have been published, including guidelines from the American Academy of Orthopedic Surgeons (AAOS), ACCP, and ASH.1003,1108,1109 Routine thromboprophylaxis is recommended 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 VTE.1003 According to ACCP, thromboprophylaxis with an appropriate antithrombotic agent or an intermittent pneumatic compression device should be continued for at least 10-14 days and possibly for up to 35 days after surgery.1003 Although ACCP suggests that a LMWH 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 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 subcutaneous injections).1003 AAOS guidelines do not recommend any specific thromboprophylaxis agent.1108 The ASH guidelines suggest the use of DOACs over LMWH if anticoagulants are used; however, this recommendation is considered conditional based on moderate certainty in the evidence of harms versus benefits.1109

Drug selection and duration of therapy should be individualized based on type of surgery, patient risk factors for embolism and bleeding, as well as costs, patient compliance, preference, tolerance, and comorbidities, and other clinical factors such as renal function.1003,1108

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†).1013,1165,1166,1167

Embolism Associated with Atrial Fibrillation

Warfarin is used for the prevention of stroke and systemic embolism in patients with atrial fibrillation.223,278,279,330,369,456,459,999,1017,1201 In several randomized controlled studies in patients with 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.217,218,222,223,224,276,277,278,279,280,281,282,330,1201

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.217,223,224,279,280,281,346,349,990,999,1201 In addition, warfarin therapy appears to have a therapeutic advantage over aspirin in preventing nonfatal stroke.1201 Nonfatal extracranial bleeding occurred more frequently in warfarin patients.1201

Dual antiplatelet therapy with clopidogrel and aspirin was evaluated as a potential alternative to warfarin in a randomized controlled study in patients with atrial fibrillation at high risk of stroke.995,1201 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.995,1201 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.997,1201 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.990

Warfarin therapy with a goal INR of 2-3 was compared to a DOAC for stroke prevention in atrial fibrillation in 4 phase 3 randomized controlled trials (dabigatran in RE-LY, rivaroxaban in ROCKET-AF, apixaban in ARISTOTLE, and edoxaban in ENGAGE AF-TIMI 48).1201 In these trials, the DOAC was noninferior or superior to warfarin for the primary efficacy endpoint of the occurrence of stroke and systemic embolism and was associated with significantly less intracranial hemorrhage and similar or less frequent major bleeding.1201 A meta-analysis of the studies combined endpoints from 42,411 DOAC- and 29,272 warfarin-treated patients.1201 Stroke or systemic embolism was substantially reduced by 19% with DOAC therapy; this endpoint was primarily driven by a reduction in hemorrhagic stroke.1201 There was also a nonsignificant 14% reduction in major bleeding and a significant 52% reduction in intracranial hemorrhage with DOAC therapy.1201

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 is strongly recommended in such patients based on results of studies in patients who have atrial fibrillation without these coexisting conditions.330,341,349,370,459,999,1201,1202 The intensity of anticoagulation in patients with prosthetic heart valves should be based on the particular type of prosthesis330,999 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 2.5.999,1143

The risk of stroke in patients with atrial flutter is similar to the risk in those with atrial fibrillation.82 Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.82,87,1201

Clinical Perspective

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.81,82,989,990,1017,1201 Although many risk stratification methods have been used, current guidelines recommend the use of the CHA₂DS₂-VAS_c risk stratification tool for assessing a patient's risk of stroke and need for anticoagulant therapy. 82,989,1017,1201 Established clinical risk factors for stroke include prior ischemic stroke or transient ischemic attack (TIA), advanced age (e.g., ≥65 years of age), history of hypertension, diabetes mellitus, vascular disease, and congestive heart failure; in addition, female sex has been identified as a factor that can modify the risk of stroke.82,87,989,1017,1201 The presence of stroke or TIA places a patient in the high-risk category regardless of other risk factors.82 Experts state that antithrombotic therapy generally is not necessary in low-risk patients (CHA₂DS₂-VAS_c score of 0 in males, or 1 in females), but should be considered in patients with one or more non-sex CHA₂DS₂-VAS_c stroke risk factors (CHA₂DS₂-VAS_c score of ≥1 in males, or ≥2 in females).87,989,1201 Patients also should be assessed for their bleeding risk; those with a high risk of bleeding should be monitored more closely.82,87,989,1201

In patients with nonvalvular atrial fibrillation who are eligible for oral anticoagulant therapy, DOACs are recommended over warfarin based on improved safety and similar or improved efficacy in clinical trials and meta-analyses.82,87,989,1201 A substantially greater safety benefit of DOACs versus warfarin has been observed when the INR is in the therapeutic range <66% of the time.82 A DOAC is also recommended in patients unable to achieve optimal warfarin management.82,87,989,1201 Because of limited data on the use of DOACs in obese patients, some experts have discouraged the use of these agents in the morbidly obese population (those with a BMI ≥40 kg/m² or body weight >120) and recommend considering warfarin instead in such patients with nonvalvular atrial fibrillation.83,88,89

If warfarin is used, patients should be optimally managed with well-controlled INRs (e.g., INR in therapeutic range >70% of the time).989,1201 The therapeutic range for atrial fibrillation without a mechanical heart valve is 2 - 3.1143,1201 Factors influencing individual time in the therapeutic range include age, sex, diet, ethnicity, socioeconomic status, medical comorbidities, genetics, length of time on warfarin, nonadherence, polypharmacy, frequency of INR monitoring, and how therapy is managed (e.g., physician practice, anticoagulation clinic, home INR testing).1201 ACCP suggests use of the SAMe-TT₂R₂ tool to identify patients who are likely to do well on warfarin; the tool generates a score based on clinical factors known to influence time in therapeutic range.1201 One point is generated for sex (female), age (<60 years old), medical history (≥2 from hypertension, diabetes mellitus, coronary artery disease/MI, peripheral arterial disease, congestive heart failure, previous stroke, pulmonary disease, and hepatic or renal disease), and treatment with interacting drugs (e.g., amiodarone), and 2 points for tobacco use (current or within 2 years) and race (non-white) for a maximum score of 8.1201 Patients with scores of 0-2 are more likely to achieve an appropriate time in the therapeutic ran scores >2 suggest the patient will need more frequent INR monitoring, frequent follow-ups, and additional education.1201

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.341,999,1201

Because the risk of thromboembolism appears to be greatest when atrial fibrillation has been present for ≥48 hours, recommendations for the use of anticoagulant therapy in such patients vary based on the duration of the arrhythmia.999,1201 ACCP and other experts recommend that patients with atrial fibrillation of unknown or ≥48 hours' duration who are to undergo elective cardioversion receive therapeutic anticoagulation (e.g., warfarin, apixaban, dabigatran, edoxaban, rivaroxaban) for at least 3 weeks prior to cardioversion; alternatively, a transesophageal echocardiography (TEE)-guided approach with abbreviated anticoagulation before cardioversion may be used.999,1201 In patients who have atrial fibrillation of short duration (e.g., ≤48 hours), cardioversion usually is performed with full dose heparin or LMWH, without prolonged warfarin anticoagulation or TEE prior to the procedure.1201 After successful cardioversion to sinus rhythm, all patients should receive therapeutic anticoagulation for at least 4 weeks.999,1201

Experts suggest that patients with atrial flutter undergoing cardioversion be managed according to the same approach as that used in patients with atrial fibrillation.999,1201

Embolism Associated with Valvular Heart Disease

Warfarin is used for the prevention of thromboembolic complications in patients with valvular heart disease, including those with mechanical and bioprosthetic heart valves.330,341,342,343,370,1143,1202

Clinical Experience in Patients with Prosthetic Heart Valves

In a prospective, randomized, open-label study in 254 patients with mechanical prosthetic heart valves, thromboembolic events occurred significantly less frequently in patients treated with warfarin than in those treated with dipyridamole/aspirin or pentoxifylline/aspirin.330 In a prospective, open-label study, moderate-intensity warfarin therapy was compared with high-intensity warfarin in 258 patients with mechanical prosthetic heart valves.330 There was no difference in incidence of thromboembolism, but a higher rate of major bleeding was reported in the high-intensity group.330 In another study that compared 2 different intensities of warfarin therapy (INR 2-2.25 versus INR 2.5-4), thromboembolism occurred with similar frequency, but major hemorrhage occurred more frequently in the higher-intensity INR group.330

Dabigatran was compared to warfarin following mechanical valve replacement in the RE-ALIGN trial.1171 In this study, selection of the initial dabigatran dosage (150, 220, or 300 mg twice daily) was based on kidney function with dosages adjusted to a trough level of at least 50 ng/mL.1171 Warfarin dosage was adjusted to an INR of 2-3 or 2.5-3.5 based on thromboembolic risk.1171 Bridging anticoagulation was allowed based on investigator discretion.1171 In population A (adults undergoing implantation of a mechanical bileaflet valve in the aortic or mitral position or both), the first dose of study drug was administered in 6 days and 5 days following surgery in patients randomly assigned to dabigatran and warfarin, respectively.1171 The trial was terminated early due to an excess rate of thromboembolic and bleeding events in the dabigatran group.1171 The thromboembolic composite endpoint, defined as the occurrence of death, stroke, systemic embolism, or MI, occurred in 8% of dabigatran-treated patients compared to 3% of patients in the warfarin group.1171 Major bleeding with a pericardial location occurred in 5% versus 3% of dabigatran and warfarin patients, respectively; the rate of any bleeding was also higher (26% versus 12%).1171

Clinical Experience in Patients with other Valvular Heart Conditions

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.1201,1202

Vitamin K antagonist therapy was compared with a DOAC (rivaroxaban) in INVICTUS, a prospective, open-label study that was conducted in 4531 adults with echocardiographically confirmed rheumatic heart disease and documented atrial fibrillation or atrial flutter and at least one additional criteria (e.g., mitral stenosis, CHA₂DS₂VASc ≥2); patients with a mechanical heart valve or need for one within the next 6 months were excluded.1169 The primary efficacy outcome was the composite of stroke, systemic embolism, MI, or death from vascular or unknown causes.1169 The primary safety outcome was the occurrence of International Society of Thrombosis and Hemostasis (ISTH)-defined major bleeding.1169 Patients received rivaroxaban 20 mg daily (15 mg daily if creatinine clearance <50 mL/minute) or a vitamin K antagonist (predominantly warfarin) with dosage adjusted to maintain an INR of 2-3.1169 The mean age of patients enrolled in the study was 50.5 years, 72.3% were female, 85.3% had mitral-valve stenosis, and 39.5% had both moderate to severe mitral stenosis and a CHA₂DS₂VAS_c score ≥2.1169 Time in therapeutic range of vitamin K antagonist therapy ranged from 56.1 to 65.3% at various study time points; mean rivaroxaban adherence was 83.7%.1169 The primary composite outcome occurred significantly more frequently in the rivaroxaban group than in the vitamin K antagonist group (8.21% versus 6.49% per year).1169 There was no significant difference in major bleeding between the treatment groups (0.67% per year with rivaroxaban and 0.83% per year with the vitamin K antagonist).1169

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.1202 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.1143,1202

Clinical Perspective

All patients with mechanical heart valves require long-term warfarin therapy because of the high risk of thromboembolism with these valves.330,370,459,996,1143,1202 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.341,342,343,370,1143,1202 In patients with mechanical aortic valve replacement who have additional risk factors (e.g., older generation valve, atrial fibrillation, previous thromboembolism, hypercoagulable state, left ventricular systolic dysfunction), a target INR of 3 (range 2.5-3.5) is recommended; in the absence of these risk factors, a target INR of 2.5 (range 2-3) is recommended.330,1143 In patients with mechanical mitral valve replacement, a target INR of 3 (range 2.5-3.5) is recommended.330,1143 Due to the increased risk of major bleeding, the addition of aspirin 75-100 mg is no longer routinely recommended in patients with mechanical valve replacement; the decision to add aspirin should be based on thromboembolism risk, bleeding risk, and presence of an indication for antiplatelet therapy.82,1143

Warfarin is recommended during the initial 3-6 months following surgical bioprosthetic valve replacement, regardless of position, aortic or mitral.82,330,1143 Following transcatheter aortic valve implantation, the decision to select antiplatelet therapy or warfarin during the first 3-6 months should be individualized.1143 The target INR is 2.5 (range 2-3) following either valve replacement approach.1143 Following the initial period of warfarin prophylaxis, patients may be switched to aspirin 75-100 mg provided they are in normal sinus rhythm and have no other indication for therapeutic anticoagulation (e.g., atrial fibrillation, previous thromboembolism, hypercoagulable state, left ventricular dysfunction).330,1143

In prosthetic valve patients who experience a thromboembolic event despite achievement of target INR or while adhering to aspirin therapy, antithrombotic therapy may be escalated after a thorough investigation of other causative factors (e.g., medication adherence, new onset atrial fibrillation or other hypercoagulable state, infective endocarditis) and after an assessment of the patient's bleeding risk.1143 Aspirin 75-100 mg daily may be added in patients with mechanical aortic or mitral valves, or warfarin therapy may be adjusted to a target INR of 3 (range 2.5-3.5) for aortic and 4 (range 3.5-4.5) for mitral positions.1143 Patients with a bioprosthetic valve who experience a thromboembolic event on antiplatelet therapy may be converted to warfarin.1143

The 2020 AHA/ACC guideline for the management of patients with valvular heart disease states that patients with valvular heart disease and atrial fibrillation should be evaluated for risk of thromboembolic events and treated with oral anticoagulation if at high risk.1143 Vitamin K antagonists are the anticoagulants of choice for patients with rheumatic mitral stenosis and mechanical heart valves.1143 DOACs are an alternative to vitamin K antagonists in patients with atrial fibrillation and with bioprosthetic valves >3 months after implantation or with native valvular heart disease, excluding rheumatic mitral stenosis.1143

ST-Segment Elevation Myocardial Infarction

Secondary Prevention

Warfarin has been used for secondary prevention to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolism after an acute ST-segment-elevation MI (STEMI).330,527,992,1010 The manufacturer of warfarin states that 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), the use of warfarin (target INR 2-3) in conjunction with low-dose aspirin (not exceeding 100 mg daily) for at least 3 months is recommended.330 However, antiplatelet therapy is preferred over warfarin for secondary prevention and risk reduction in patients with atherosclerosis, including those with acute STEMI unless there is a separate indication (e.g., atrial fibrillation, prosthetic heart valve, left ventricular thrombus or high risk for such thrombi, concomitant venous thromboembolic disease).527,992,1010,1172

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.269,270,271,272,330 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).299,330 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.330,451 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.330,451

Clinical Perspective

An AHA Scientific Statement on the management of patients at risk for and with left ventricular thrombus was published in 2022.527,1199 Due to the lack of data supporting routine prophylactic anticoagulation in the current era of reperfusion, coronary stenting, and dual antiplatelet therapy (DAPT), prophylactic anticoagulation to prevent left ventricular thrombus post-STEMI is not routinely recommended for all patients, but may be considered on an individual basis.1199 Therapeutic anticoagulation (e.g., with warfarin, DOACs) for the treatment of left ventricular thrombus after acute MI is appropriate.1199

Cerebral Embolism

Antiplatelet agents are considered preferable to oral anticoagulation for secondary prevention of noncardioembolic stroke in patients with a history of ischemic stroke or TIA.82,1009 However, oral anticoagulation with warfarin or a DOAC (e.g., apixaban, dabigatran, rivaroxaban, edoxaban) is recommended for secondary prevention in patients with TIAs or ischemic stroke and concurrent atrial fibrillation, provided no contraindications to therapy exist.82,335,338,349,352,373,999,1009,1017 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).82,1010,1199,1202

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.1013

The American Heart Association Stroke Council states that warfarin is recommended following initial therapy with heparin or a LMWH in patients with acute cerebral venous thrombosis (CVT)†.1175 Target INR is 2-3 and the recommended duration of therapy is based on known or unknown provocation and the presence or absence of thrombophilia.1175 One randomized, open-label, prospective study (RE-SPECT CVT) and one retrospective cohort study (ACTION-CVT) compared the use of DOACs (e.g., dabigatran, apixaban, rivaroxaban) with warfarin in adults with CVT following the acute treatment phase.1173,1174 Similar rates of VTE recurrence, bleeding, and recanalization were observed between warfarin and the DOACs; additional prospective studies are in progress (NCT04660747, NCT03178864).1173,1174

Heparin-Induced Thrombocytopenia

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.330,1168,1203 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.330,1168 ACCP and ASH recommend 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/mm³); for patients already receiving warfarin at the time of diagnosis of HIT, use of vitamin K is suggested.1168,1203

ACCP and ASH state that HIT should be treated initially with a parenteral nonheparin anticoagulant (e.g., argatroban, bivalirudin, fondaparinux).1168,1203 Conversion to warfarin therapy should be initiated with low dosages (maximum 5 mg daily) and only after substantial recovery from acute HIT has occurred.1203 To avoid prothrombotic effects and ensure continuous anticoagulation, ACCP recommends that therapy with the parenteral nonheparin anticoagulant and warfarin be administered concurrently for at least 5 days and until the desired INR has been achieved.1203

Thrombotic Antiphospholipid Syndrome†

The International Society of Thrombosis and Hemostasis (ISTH) recommends the use of warfarin over DOACs in patients with high-risk antiphospholipid syndrome (APS), including those with triple-positive APS and patients non-adherent to warfarin or with recurrent thrombosis while on therapeutic intensity warfarin.1163

General

Pretreatment Screening

• Obtain baseline international normalized ratio (INR).330,1176,1177
• Obtain baseline complete blood count (CBC).330,1176,1177
• Verify pregnancy status in females of reproductive potential.330
• Perform other relevant baseline laboratory tests as needed based upon the patient's clinical condition (e.g., liver function tests [LFTs]).330,1176,1177
• Assess patient for active bleeding and bleeding risk.330,1176
• Assess patient for comorbid conditions (e.g., heart failure, diarrhea) and drug-drug interactions (e.g., amiodarone, metronidazole) that may influence warfarin dose selection.330,1176,1177
• Pharmacogenomic testing for cytochrome P-450 (CYP)2C9 and vitamin K epoxide reductase (VKORC)1 genotypes is available and recommended, but not required.330,1178

Patient Monitoring

• Perform INR assessments regularly during therapy.330,1176
• Perform an INR assessment daily after warfarin initiation until the INR stabilizes in the therapeutic range.330,1176,1177
• The American College of Chest Physicians (ACCP) states that INR assessments usually are performed daily in hospitalized patients until the INR is in the therapeutic range for at least 2 consecutive days; in nonhospitalized patients, initial INR assessments may be reduced from daily to every few days until a stable response has been achieved.1014,1176,1177
• The frequency of INR assessments should be based on clinical judgment and patient response, but generally are performed every 1-4 weeks.330 In patients with consistently stable INRs, ACCP has suggested an INR testing interval of up to 12 weeks.1000,1176,1177
• Monitor for signs and symptoms of bleeding (e.g., bruising, gum or nose bleeding, blood in stool).330,1176
• Monitor for signs and symptoms of thrombosis (e.g., leg swelling).330,1176
• Monitor CBC regularly and other laboratory tests based upon the patient's clinical condition.330,1176
• Monitor comorbid conditions (e.g., heart failure, diarrhea) for clinical changes that may influence the patient's INR response to warfarin (e.g., diarrhea, resolved or decompensated heart failure).330,1176,1177
• Monitor for drug-drug interactions and drug therapy that is added, discontinued, or taken irregularly, that may influence the patient's INR response.330,1176,1177
• Perform additional INR assessments when differing warfarin preparations (e.g., proprietary versus nonproprietary [generic]) are interchanged.330,1177

Dispensing and Administration Precautions

• Personnel who are pregnant should avoid exposure to crushed or broken tablets. 330
• Procedures for proper handling and disposal of potentially hazardous drugs should be considered.1206
• Per the Institute for Safe Medication Practices (ISMP), warfarin is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.1205

Other General Considerations

• In patients managed by anticoagulation clinics, compared with patients receiving usual monitoring by their primary care clinician, available data indicate that the proportion of time in the therapeutic INR range and patient satisfaction is increased, but clinical outcomes such as bleeding, thrombosis, and mortality are not significantly different.1180
• Self-testing with or without self-monitoring may be an option for some patients.1179 A Cochrane systematic review with meta-analysis reported no difference in bleeding or mortality, and reduced thromboembolic events, when patient self-testing or self-monitoring was compared to standard therapy; however, the risk of bias downgraded the quality of evidence.1179
• Self-management of warfarin therapy is suggested by ACCP as an alternative to outpatient INR monitoring in patients who are motivated and can demonstrate competency in self-management strategies, including the use of self-testing equipment.1000

Administration

Administer warfarin sodium orally as a single daily dose without regard to food.330 Adhere strictly to the prescribed dosage and schedule of warfarin.330 Take warfarin tablets at the same time each day.330

If a dose of warfarin is missed at the intended time of day, take the dose as soon as possible on the same day.330 A double dose of warfarin should not be taken the next day to make up for the missed dose.330

Warfarin is discolored by light; warfarin preparations should be stored at controlled room temperature (20-25°C) in tight, light-resistant containers.330

Dosage

Warfarin dosage is expressed in terms of warfarin sodium.330

Nonproprietary (generic) preparations of warfarin sodium are available, and the manufacturers warn that patients should be carefully instructed about the preparation they are receiving so that overdosage from inadvertent simultaneous use of equivalent preparations is avoided.330,1177

Warfarin sodium dosage requirements vary greatly among individual patients, and dosage must be carefully individualized based on the patient's INR in order to obtain optimum therapeutic effects while minimizing the risk of hemorrhage.330 Factors influencing initial dose selection include clinical factors (e.g., age, sex, comorbidities, concomitant medications) and genetic factors (e.g., CYP2C9 and VKORC1 genotypes).330,1176,1177,1178

Duration and intensity of anticoagulation (i.e., INR) is based on the indication for use.330 Pharmacogenomic factors (e.g., genetic variations in enzymes that metabolize warfarin or modulate its effect on clotting factor synthesis) also may be considered in determining the warfarin dosage.330,463,465,467,469,474,1178

Initial Dosage

The appropriate initial dosage of warfarin varies widely among different patients; dosage must be individualized taking into account factors such as age, race, body weight, sex, genotype, concomitant drugs, and the specific indication for use.330,1176,1177

Routine use of warfarin loading doses is not recommended as such practice may increase the risk of hemorrhage or other complications and does not offer more rapid protection against clot formation.330 However, there is some evidence suggesting that use of a 10-mg loading dose may be a safe and effective approach in reducing the time to therapeutic INR.1000 ACCP therefore suggests that in sufficiently healthy, nonhospitalized patients, an initial dosage of 10 mg daily for the first 2 days may be administered, with subsequent dosing based on INR determinations.1000

Smaller initial dosages (e.g., 2-5 mg of warfarin sodium daily) result in less fluctuation in the degree of anticoagulation and decrease the risk of hemorrhage.1000 Low initial dosages should be considered for geriatric and/or debilitated patients.330 Lower initial dosages also should be considered in patients with certain genetic variations in CYP2C9 and/or VKORC1 gene(s), which are associated with reduced warfarin clearance or altered pharmacodynamic response.330,465,467,469,1178 Individuals of Asian descent also appear to require lower initial dosages than white patients, resulting in part from such genetic variations.330,378,463,465,469

In patients whose CYP2C9 and VKORC1 genotypes are not known, the usual initial dosage of warfarin sodium is 2-5 mg daily or the expected maintenance dosage, adjusted based on patient factors (e.g., age, race).330

For patients with known CYP2C9 and VKORC1 genotypes, the manufacturers suggest that initial dosage may be determined by expected maintenance dosages observed in clinical studies of patients with various combinations of these gene variants.330 (See Pharmacogenomic Considerations in Dosing under Dosage and Administration.)

Maintenance Dosage

Maintenance dosage of warfarin varies greatly among patients and should be based on INR assessments.330 The manufacturer states that the usual maintenance dosage of warfarin is 2-10 mg daily for patients in whom CYP2C9 and VKORC1 genotypes are not known.330

For patients with known CYP2C9 and VKORC1 genotypes, the manufacturer suggests expected maintenance dosages observed in clinical studies of patients with various combinations of these gene variants.330 Lower maintenance dosages should be considered for geriatric and/or debilitated patients.330,1177 Because of inherited increased sensitivity and/or reduced metabolism of warfarin,463,469 individuals of Asian descent also appear to require lower maintenance dosages of warfarin than white patients.330,378,463,465,469

Acquired or inherited warfarin resistance is rare but should be suspected if large daily dosages are required to maintain INR within a normal therapeutic range.330,1178 Changes in anticoagulant dosage should be made in small increments, and patient response should be carefully monitored with clinical observation and INR determinations; warfarin dosing nomograms may be utilized.330,1176,1177

If a previously stable patient presents with a single subtherapeutic or supratherapeutic INR, consider transient risk factors (e.g., missed dose, acute alcohol ingestion) before making a dosage chan ACCP suggests that the current dosage of warfarin may be continued and the INR retested within 1-2 weeks for outlier INR results not exceeding 0.5 above or below the therapeutic range.1000,1176,1177 If an unexpected result that does not fit the patient's clinical picture occurs, consider repeating the INR.1176,1177

Warfarin maintenance dosages were analyzed prospectively and retrospectively in atrial fibrillation and venous thromboembolism (VTE) cohorts with a target INR of 2-3.1181 Analysis was performed based on indication, sex, and age.1181 Warfarin dosage in the prospective cohort was higher in younger patients compared to older patients.1181 The median (25th, 75th percentile) daily warfarin dosage in male patients with atrial fibrillation was 5.4 mg (4, 6.4 mg) in those 50-59 years of age and 3.9 mg (2.5, 5 mg) in those 80-89 years of age compared to females of the same age (5 mg [3.9, 6 mg] and 3.2 mg [2.5, 4.3 mg], respectively).1181 The weekly warfarin dosage declined by 0.4 mg per year of age, and women required 4.5 mg less per week than men.1181 The weekly warfarin dosage was 7.3 mg per week lower among those taking amiodarone and was also lower in patients with coronary artery disease or heart failure, but higher in those with diabetes.1181 Based on these results, initial warfarin doses >5 mg per day would be expected to be too high for a majority of women over the age of 60 and men over the age of 70.1181

The manufacturer states that warfarin dosage in pediatric patients varies based on age, with infants generally having the highest, and adolescents having the lowest dosage requirements to maintain therapeutic INRs.330

Target INR and Duration of Therapy

Duration and intensity of warfarin anticoagulation (i.e., INR) is based on the indication for use.330

Table 1 contains the indication-based target INR and duration of therapy for adults as described by manufacturers and experts.82,330,999,1003,1017,1143,1102,1103,1106,1168,1176,1200,1201

Patients with more than 1 indication for warfarin should have a target INR consistent with the greatest thrombotic risk.1017,1106,1200,1201 For example, a patient with atrial fibrillation and mechanical heart valve in the mitral position would have a target INR of 3 (2.5-3.5).1017,1143,1201

Patients with more than 1 indication for warfarin should have a duration consistent with the greatest thrombotic risk.1200,1201,1017,1106 For example, a patient with a provoked VTE due to surgery and atrial fibrillation would receive long-term warfarin therapy rather than 3 months of treatment.1017,1106,1200,1201

Targeting an INR >4 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding complications.330

When warfarin is used in pediatric patients†, a target INR range of 2-3 generally is suggested by ACCP for most indications except in the setting of prosthetic cardiac valves where adherence to adult recommendations is suggested.1013,1143

Consensus statements specific to pediatric patients treated with ventricular assist devices†, large or giant coronary aneurysms following Kawasaki disease†, and primary pulmonary hypertension† should be consulted for further information regarding target INR and duration of warfarin therapy.1165,1166,1167

Pharmacogenomic Considerations in Dosing

Variations in the genes responsible for warfarin metabolism or pharmacodynamic response may affect warfarin dosage requirements.330,378,462,463,464,465,466,467,469,1178 Over 30% of European and white populations have one or more variant alleles encoding CYP2C9, the enzyme principally responsible for metabolism of S -warfarin, and such alleles are associated with reduced clearance of warfarin.330,462,464,465,469,1178 Patients with one or more variant CYP2C9 alleles (e.g., CYP2C9*2, CYP2C9*3) are at increased risk of excessive anticoagulation (e.g., INR exceeding 3) and bleeding and require lower dosages of warfarin, particularly during initiation of therapy.330,462,464,465,466,467,469,474,1178

Warfarin inhibits vitamin K epoxide reductase, which is a vitamin K-cycle enzyme complex controlling the regeneration of reduced vitamin K from vitamin K epoxide.330,464,467 Reduced vitamin K is an essential cofactor involved in the formation of vitamin K-dependent clotting factors.464,1178 Limited evidence suggests that variations in the gene that encodes vitamin K epoxide reductase, VKORC1, may have an even larger impact on warfarin dosage than CYP2C9 genetic variations, and differing average dosage requirements between patients of white, Black, and Asian ancestry may be explained by VKORC1 variant frequency.463,464,465,467,1178

The availability and reliability of genetic tests vary, and clinicians should check with their local or reference clinical laboratory to obtain more information about specific tests.474 Additional information about pharmacogenetic testing can be found at the Genetic Testing Registry ([Web]). 1178 Genetic information does not replace regular INR monitoring and results of genetic testing should not delay initiation of warfarin therapy.473

The 2017 update of the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing suggests use of pharmacogenetic algorithm-based warfarin dosing over the genetics-based dosing (Table 2) found in the FDA-approved warfarin label.330,1178

The 2 recommended pharmacogenetic algorithms (Gage and International Warfarin Pharmacogenetics Consortium [IWPC]) consider age, sex, race or self-identified ancestry, weight, height, smoking status, warfarin indication, target INR, interacting drugs (e.g., amiodarone, phenytoin) and genetic variables (e.g., CYP2C9, VKORC1 genotypes).1178 CPIC recommends the Gage over the IWPC algorithm because it can adjust for CYP4F2, CYP2C9*5 and *6, if those genotypes are known.1178

CPIC considers initial use of a loading dose to be controversial.1178 If a loading dose is used, a genetically informed approach is suggested with an understanding of the limitations of the loading dose trials (e.g., majority of experience in those of European ancestry).1178

In patients whose CYP2C9 and VKORC1 genotypes are known, the manufacturer suggests that initial warfarin dosage may be determined based on expected maintenance dosages observed in clinical studies of patients with various combinations of these gene variants.330 (See Table 2.)

Transferring from Parenteral Anticoagulation to Warfarin

When warfarin is indicated for follow-up therapy after initial treatment with a parenteral anticoagulant (e.g., heparin, LMWH, fondaparinux), therapy with the parenteral anticoagulant is usually continued until an adequate response to warfarin is obtained as indicated by INR determinations.330,1000,1200 The manufacturer recommends that heparin and warfarin be used concurrently for at least 4-5 days until the desired INR has been attained, after which the parenteral anticoagulant may be discontinued.330 In adults with acute deep-vein thrombosis (DVT) or pulmonary embolism (PE), ACCP and ASH recommend that heparin, LMWH, or fondaparinux be used concurrently with warfarin for at least 5 days and until the INR is ≥2 for 24 hours or longer.1006,1200

In children with VTE in whom long-term warfarin therapy is being considered, warfarin should be initiated on the same day as heparin or LMWH, and such therapy should be overlapped for ≥5 days and until the INR is therapeutic.1013

Heparin prolongs the INR, and caution should be observed in evaluating the INR in patients receiving concomitant therapy with warfarin and heparin.330 Valid INR determinations can usually be made during concurrent heparin therapy if blood samples for the test are drawn at least 5 hours after an IV injection of heparin, 4 hours after cessation of a continuous heparin IV infusion, or 24 hours after a subcutaneous injection of heparin. 330 Warfarin may prolong the activated partial thromboplastin time (aPTT), even in the absence of heparin.330 However, during initial therapy with warfarin, the interference with heparin anticoagulation is of minimal clinical importance.330

When warfarin is indicated for follow-up therapy after a nonheparin anticoagulant (e.g., argatroban, fondaparinux, bivalirudin) in the treatment of heparin-induced thrombocytopenia (HIT), therapy with warfarin and the nonheparin anticoagulant should be overlapped for a minimum of 5 days until an adequate response to warfarin is obtained as indicated by INR determinations.1203 Warfarin therapy should be initiated only after substantial recovery from acute HIT has occurred (i.e., stable platelet counts ≥150,000/mm³ or platelet recovery >50% of baseline).1168,1203 Do not use a warfarin loading dose in HIT patients.392,1168,1203

Conversion from anticoagulation with argatroban to warfarin is more complex than with other anticoagulants since combined therapy with argatroban and warfarin prolongs the INR beyond that produced by warfarin alone.392 The INR should be determined daily during concurrent argatroban and warfarin therapy.392 For an argatroban infusion rate of 2 mcg/kg per minute, argatroban therapy should be temporarily discontinued when the INR on combined therapy is >4.392 Overshooting the target INR should be avoided, as supratherapeutic INRs during concomitant therapy with direct thrombin inhibitors and warfarin have been associated with necrosis or gangrene of the skin or limbs.442,444,1203 The INR should be determined 4-6 hours after discontinuance of argatroban infusion during warfarin monotherapy.392 If INR is below the desired therapeutic range, argatroban infusion should be resumed.392 Attempts to discontinue argatroban should be repeated daily and until the INR (4-6 hours after discontinuance of argatroban) on warfarin alone is in therapeutic range.392

For argatroban infusion rates exceeding 2 mcg/kg per minute, the infusion rate should be reduced temporarily to 2 mcg/kg per minute, and the INR should be repeated 4-6 hours later.392 If the INR is >4, temporarily discontinue argatroban and repeat the INR 4-6 hours later.392 If the INR is below the desired therapeutic range, the argatroban infusion should be resumed.392 Attempts to discontinue argatroban should be repeated daily and until the INR on warfarin alone is in therapeutic range.392

Transferring from Other Anticoagulants to Warfarin

The manufacturer suggests consulting the labeling of other anticoagulants for instructions on conversion to warfarin.330

Managing Anticoagulation in Patients Requiring Invasive Procedures

Temporary interruption of long-term warfarin therapy may be required in patients undergoing surgical or other invasive procedures to minimize the risk of perioperative bleeding.330,1004 The decision whether to interrupt therapy should be based on an assessment of the patient's risk for thromboembolism versus risk of perioperative bleeding, taking into account individual patient- and surgery-related factors.1004 ACCP issued clinical practice guidelines that include recommendations for standardized surgical bleed and thromboembolic risk assessments, discontinuance and resumption of warfarin therapy, and bridging anticoagulation (e.g., heparin, LMWH).1004 Temporary discontinuance of warfarin usually is required for major surgical or invasive procedures.330,1004 Warfarin discontinuance for minor procedures associated with a low risk of bleeding (e.g., minor dental procedures, minor dermatologic procedures, cataract surgery) may not be necessary; however, the manufacturer recommends targeting the low end of the INR therapeutic range in these situations.330,1004

In patients who require temporary interruption of warfarin prior to surgery, ACCP recommends that the drug be discontinued ≥5 days prior to surgery; elderly patients with comorbidities, patients with low dose warfarin requirements, and those with a higher target INR range are among those who may require >5 days of warfarin interruption prior to surgery.1004 Determine the INR immediately prior to any invasive procedure.330 Routine use of pre-operative vitamin K when the INR is >1.5 1 to 2 days before the elective surgery or procedure is not recommended.1004 ACCP recommends warfarin resumption within 24 hours, usually on the evening of the surgery or procedure; warfarin resumption may be delayed in those with inadequate hemostasis, need for additional procedures, or those unable to receive enteral medications.1004 Warfarin should be resumed at the patient's established maintenance dosa loading doses (e.g., double the established maintenance dose) are not recommended.1004

Heparin bridging is defined as administration of LMWH or IV heparin during the period of interruption of warfarin therapy.1004 The decision to administer heparin bridging should be individualized based on the patient's risk of thromboembolism versus risk of bleeding.1004 ACCP recommends against heparin bridging in patients with mechanical heart valves, atrial fibrillation, or VTE who are not classified as high-risk for thromboembolism when warfarin is interrupted for an elective surgery or procedure.1004 ACCP states that heparin bridging is recommended for patients at the highest risk for thromboembolism (e.g., patients with older-generation [e.g., tilting-disc] mechanical heart valves, any mechanical mitral valve, thromboembolic event within the last 3 months, atrial fibrillation patients with a CHA₂DS₂VAS_c score ≥7 or CHADS₂ score ≥5).1004 During the early postoperative period following insertion of a mechanical heart valve, ACCP suggests bridging anticoagulation with heparin or a LMWH until the patient is stable on warfarin therapy.1202

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment; however, more frequent monitoring for bleeding is recommended.330

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment; however, more frequent INR monitoring may be required.330

Geriatric Patients

In patients >60 years of age, the manufacturer recommends considering lower initial and maintenance warfarin dosages and more frequent monitoring for bleeding.330

Asian Patients

A lower initiation and maintenance warfarin dosage may be required in Asian patients.330 Asian patients appear to be more sensitive than white patients to the anticoagulant effect of warfarin and may require lower initial and maintenance dosages.330,378,465,469,1178 In an uncontrolled study in Chinese patients receiving warfarin for various indications and on a stable warfarin sodium dosage for at least 1 month, the average daily dosage required to maintain an INR of 2-2.5 was 3.3 mg.330,378 Age also was an important determinant of warfarin dosage (inverse correlation) in these patients, as were body weight and underlying disease (positive correlations).330,378,463,465 A single nucleotide polymorphism of VKORC1 that identifies a low-dose and a high-dose warfarin phenotype has been found to associate with optimal warfarin dosage in both European and Asian patients.464,1178 The reduced average warfarin maintenance dosage requirement in Asian individuals is largely related to the relatively rare occurrence of the high-dose allele in this ethnic group.463,464,465,469,1178

Black Patients

The CYP2C9 *5, *6, *8, and *11 alleles associated with reduced enzymatic activity and warfarin metabolism occur in 45-50% of patients with self-reported African ancestry.330,1178

The 2017 update of the CPIC guideline for pharmacogenetics-guided warfarin dosing suggests a 15-30% warfarin dosage reduction when CYP2C9 *5, *6, *8, and *11 variant alleles are detected, regardless of self-reported ancestry.1178

Contraindications

• Pregnancy, except in patients with mechanical heart valves.330
• Patients with hemorrhagic tendencies or blood dyscrasias.330
• Recent or contemplated surgery of the eye or CNS and in those undergoing traumatic surgery resulting in large open surfaces.330
• Bleeding tendencies associated with active ulceration or overt bleeding of the GI, respiratory, or genitourinary tract; CNS hemorrha aneurysms (cerebral, dissecting aorta); pericarditis and pericardial effusions; bacterial endocarditis.330
• Threatened abortion, eclampsia, and preeclampsia.330
• Unsupervised patients with conditions associated with a potential high level of non-compliance with therapy (e.g., dementia/senility).330
• Known hypersensitivity (e.g., anaphylaxis).330
• Spinal puncture and other diagnostic or therapeutic procedures associated with the potential for uncontrollable bleeding.330
• Major regional or lumbar block anesthesia.330
• Malignant hypertension.330

Warnings/Precautions

Warnings

Bleeding Risk

Warfarin increases bleeding risk and can cause serious, potentially fatal, bleeding.330 A boxed warning about the risk of major or fatal bleeding is included in the prescribing information for warfarin.330 Patients should be promptly evaluated if any manifestations of blood loss occur during therapy; discontinue warfarin if active pathological bleeding occurs.330

Bleeding is more likely to occur within the first month during the initiation of warfarin therapy. 330 Risk factors for bleeding include higher dosages, high intensity of anticoagulation (INR >4), age ≥65 years, highly variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal or liver impairment, alcohol abuse, prior stroke, certain genetic factors, concomitant drugs that may increase INR response, and a long duration of warfarin therapy.330,462,466,474,1014 Regular monitoring of INR should be performed in all patients receiving warfarin therapy.330 Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, or when significant dietary changes occur.330 Patients at high risk of bleeding may benefit from more frequent monitoring, use of lower dosages with careful dosage adjustment to the desired INR, and a shorter duration of therapy appropriate for the clinical condition. 330 Bleeding may still occur when INR is maintained in the therapeutic range.330

Patients should be instructed to immediately report any signs and symptoms of bleeding (e.g., pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness).330 Bleeding from the GI or urinary tract may warrant investigation of underlying malignancy or other correctable lesions.1014

Warfarin-induced anticoagulation may be reversed by discontinuing the drug, administering oral or parenteral vitamin K, and/or administering replacement factors with fresh frozen plasma (FFP) or 4-factor prothrombin complex concentrate (PCC).330,1182 Several hours are usually required for the effects of vitamin K to occur whether the drug is administered orally or parenterally.1182 FFP and 4-factor PCC will result in more rapid warfarin reversal; 4-factor PCC may be administered in a smaller volume and at a more rapid infusion rate and is therefore preferred.1000,1182 In patients with a significantly elevated INR and no evidence of bleeding, the American College of Chest Physicians (ACCP) states that use of vitamin K is not recommended for INR values of 4.5-10 but may be used when the INR >10. 1000

In warfarin patients with a bleed, regardless of INR, therapy should be determined following assessment of bleed severity (e.g., hemodynamic instability, critical site [e.g., intracranial], nonmajor [e.g., not in a critical site, hemodynamically stable, stable hemoglobin]), the urgency of the need to restore normal hemostasis, and whether or not therapy with the anticoagulant is to be maintained, temporarily held, or discontinued.1000,1182

In patients with major bleeding requiring urgent warfarin reversal, ACCP and the Expert Consensus Decision Pathway from the American College of Cardiology (ACC) suggest the use of IV 4-factor PCC (INR-based dose [e.g., 25, 35, or 50 units/kg] or fixed dose [e.g., 1000 units, 1500 units]) rather than FFP 10-15 mL/kg, with additional use of vitamin K administered at a dosage of 5-10 mg by slow IV infusion.1000,1182 Activated factor VII reversal is not recommended; FFP may be used when 4-factor PCC is not available.1000,1182

Other Warnings and Precautions

Tissue Necrosis

Tissue necrosis and/or gangrene of skin or other tissues have occurred rarely (<0.1%).203,215,290,291,292,293,298,330,1183 This reaction, which can occur on the first exposure to warfarin or during a subsequent course of therapy, usually appears within 1-10 days after initiation of therapy; tissue damage occurs principally at sites of fat tissue such as the abdomen, breasts, buttocks, hips, and thighs.290,293,298,330,1183 Cases of warfarin-induced necrosis have been reported more frequently in women.203,290,1183

Patients with hereditary or acquired deficiencies of protein C, or its cofactor protein S, appear to have an increased risk of developing necrosis during warfarin therapy; however, necrosis can occur in the absence of this deficiency.290,330,1183 Concomitant heparin for 5-7 days during warfarin initiation may minimize the incidence of tissue necrosis in these patients.330,1183

The necrotic lesions generally begin as painful, erythematous patches on the skin that progress rapidly to dark, hemorrhagic areas.203,290,1183 In severe cases, surgical debridement of the affected tissue, skin grafting, or amputation of the affected tissue, limb, breast, or penis has been required.203,215,290,292,293,330,1183

To determine whether necrosis is caused by underlying disease, careful clinical evaluation is required.330 Discontinue warfarin if necrosis occurs; although guidelines do not exist, suggested treatments include supportive care, surgical debridement, aggressive wound care, and topical bactericidal agents.330,1183 Alternative anticoagulants should be considered.330

Patients should be instructed to immediately inform their clinician if they experience pain, temperature change, or discoloration of the skin (a purple bruise-like rash), especially on areas of the body with a high fat content, such as breasts, thighs, buttocks, hips, and abdomen.330

Systemic Atheroemboli and Cholesterol Microemboli

Some evidence suggests that warfarin anticoagulation may enhance the release of atheromatous plaque emboli and increase the risk of complications; some cases have progressed to necrosis and death.216,221,284,285,286,287,288,330 The most common visceral organs involved are the kidneys, followed by the pancreas, spleen, and liver.330 Signs and symptoms will vary depending on the site of embolization.330

A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome”.330 Purple toes syndrome usually occurs 3-10 weeks or later following warfarin initiation or related compounds (e.g., dicumarol [no longer commercially available in the US])203,216,284,289 This syndrome typically is characterized by a purplish or mottled discoloration of the plantar surfaces and sides of the toes, which blanches on moderate pressure and fades with elevation of the legs; other characteristics may include pain and tenderness of the toes and waxing and waning of the color over time.216,284,289

Patients should be instructed to immediately inform their clinician if they experience sudden cool, painful, purple discoloration of the toe(s) or forefoot, or any unusual symptom (e.g., pain, color, or temperature change to any other area of the body).330 If signs and symptoms are observed, discontinue warfarin and consider an alternative anticoagulant.330

Calciphylaxis

Potentially serious and/or fatal calciphylaxis or calcium uremic arteriolopathy has been reported in warfarin-treated patients with and without end stage renal disease.330,1184 The time course and presentation differ from warfarin-induced necrosis.1184 Warfarin-induced necrosis occurs typically within the first 10 days, whereas warfarin-associated calciphylaxis results after a prolonged duration of warfarin therapy.1184

If calciphylaxis occurs during therapy, discontinue warfarin, treat the patient as appropriate, and consider alternative anticoagulants.330,1184

Acute Kidney Injury

Warfarin-induced acute kidney injury may occur in patients with altered glomerular integrity or with a history of kidney disease, possibly in relation to episodes of excessive anticoagulation and hematuria.330 Monitor patients with compromised renal function more frequently.330

Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS

Do not use warfarin as initial therapy for heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia with thrombosis syndrome (HITTS).330,1168,1203 Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when warfarin was initiated or continued after heparin discontinuance.330,387,388,389,395,1168 In some patients, amputation of the involved area and/or death have occurred.330,1168 Delay warfarin initiation until thrombin generation is adequately controlled and thrombocytopenia has resolved (i.e., platelet counts ≥150,000/mm³ and stable).330,442,444,1168,1203

Use in Pregnant Women with Mechanical Heart Valves

Warfarin can cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy.330 If warfarin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.330

Major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality may occur as a result of warfarin exposure during pregnancy.330

In women with mechanical heart valves at high risk of thromboembolism, the potential benefits of using warfarin may outweigh the fetal risks.330 The manufacturer states that the decision to initiate or continue warfarin should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient's situation, as well as the most current medical guidelines.330

Other Clinical Settings with Increased Risks

The decision to use warfarin in patients with the following conditions should be based on clinical judgment after weighing the increased risks against the benefits: moderate to severe hepatic or renal impairment, infectious diseases (e.g., patients receiving antibiotic therapy) or disturbances of intestinal flora (e.g., sprue), patients with indwelling catheters, moderate to severe hypertension, acquired or hereditary protein C or protein S deficiencies, polycythemia vera, diabetes mellitus, eye surgery, and vasculitis.330 Although diabetes mellitus is also included in the list of conditions, this should be interpreted with caution because diabetes is a prominent factor in stroke scoring tools (e.g., CHA₂DS₂-VASc, ATRIA), but is a less consistent risk factor for bleeding.330,1187,1186,1190 With the exception of the modified Outpatient Bleeding Risk Index (mOBRI), diabetes is not included in contemporary bleeding scoring tools (e.g., HAS-BLED, HEMORR2HAGES).1186,1187,1190

The manufacturer states that cataract surgery in patients taking warfarin has resulted in minor complications of sharp needle and local anesthesia block but has not been associated with potentially sight-threatening operative hemorrhagic complications.330,1004 The decision to discontinue or reduce the warfarin dosage prior to less invasive or less complex eye surgery (e.g., lens surgery) should be based on the patient's risk of thromboembolism.330,1004

Endogenous Factors Affecting INR

Endogenous factors such as diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency may be responsible for an increased INR response.330 Other factors have been reported in the literature (e.g., decompensated heart failure, non-euthyroid hyperthyroidism).1014

Endogenous factors that may result in a decreased INR response include increased vitamin K intake or hereditary warfarin resistance.330 Other factors have been reported in the literature (e.g., alcoholism following chronic ingestion, non-euthyroid hypothyroidism).1014

Specific Populations

Pregnancy

Warfarin can cause fetal harm and is contraindicated during pregnancy except in women with mechanical heart valves who are at high risk of thromboembolism and for whom the benefits of warfarin may outweigh the risks.330

Major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality may occur as a result of warfarin exposure during pregnancy.330 Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight).330 CNS and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy.330 Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters.330 Teratogenicity risk is highest during the first trimester, at 6-12 weeks of gestation.1126,1143 However, risk of pregnancy loss or fetal hemorrhage still exists for warfarin exposure in the second and/or third trimester.1143

The risk of valve thrombosis is much higher with mechanical heart valves because of the hypercoagulable state.1143 Pregnant women with mechanical heart valves should receive therapeutic anticoagulation with frequent monitoring during pregnancy.330,1143 Despite the risks of warfarin to the fetus, the drug has been used in pregnant women with prosthetic heart valves who are at an increased risk for valve thrombosis.1143,1185 The manufacturer states in these situations, the decision to initiate or continue warfarin should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to that individual patient's medical situation, as well as the most current medical guidelines.330,1143 If warfarin is used during pregnancy, or if the patient becomes pregnant while taking warfarin, the patient should be apprised of the potential hazard to a fetus.330

The American College of Cardiology/American Heart Association (ACC/AHA) issued guidelines for the management of patients with valvular heart disease, which includes recommendations for the management of women with mechanical heart valves who are pregnant or plan to become pregnant.1143 Multiple strategies to reduce, as well as balance, the maternal (e.g., valve thrombosis, death) and fetal risks (e.g., fetal loss, teratogenicity) are based on factors such as daily warfarin dosage (≤ or >5 mg/day), ability to utilize heparin or low molecular weight heparin (LMWH), ability to conduct frequent laboratory monitoring (e.g., INR, anti-Xa levels), and the patient's values and priorities.1143,1185 No single anticoagulation strategy is optimally safe for both the mother and the fetus; maternal and fetal risks can be reduced, but not eliminated.1143 Options include warfarin continuation throughout pregnancy, dose-adjusted heparin or LMWH with frequent anti-Xa level monitoring throughout pregnancy, or sequential therapy with dose-adjusted heparin or LMWH with frequent anti-Xa level monitoring during the first trimester and warfarin during the second and third trimesters.1143 Heparin and LMWH therapy have been associated with an increased maternal risk for valve thrombosis, death, and major bleeding complications in women with prosthetic heart valves.386,1143,1185

Other guidance documents (e.g., American College of Obstetricians and Gynecologists [ACOG], American Society of Hematology [ASH]) should be consulted for the management of other warfarin indications in the context of pregnancy.1125,1126,1188

The timing of anticoagulation discontinuance in anticipation of labor and delivery is important to reduce the risk of maternal and fetal bleeding; women should have an individualized plan that addresses obstetrical, anesthetic, and thrombotic concerns.1125,1126,1143,1188

Lactation

Limited data suggest that warfarin is not significantly distributed into human milk, is not detectable in plasma of nursing infants, and has not produced substantial coagulation abnormalities in such infants.330,414,1125,1126,1188,1189 Based on limited available data, it is considered unlikely that maternal warfarin therapy would pose a substantial risk to healthy, full-term infants receiving human milk, and ACOG, ASH, American Academy of Pediatrics (AAP), ACCP and other experts consider maternal warfarin therapy to be compatible with breast-feeding.414,1012,1125,1126,1188 Women should inform their clinician if they are breast-feeding or plan to breast-feed.330 The manufacturers state that the decision to breast-feed while receiving warfarin anticoagulation should be made only after careful consideration of the mother's clinical need for warfarin, the developmental and health benefits of breastfeeding, and potential adverse effects.330

Neonates are particularly sensitive to the effects of warfarin as a result of vitamin K deficiency; monitor infants receiving human milk for bruising and bleeding.330 The effects of warfarin in premature infants have not been evaluated.330

Females and Males of Reproductive Potential

Females of reproductive potential who are receiving warfarin therapy should be counseled on effective contraception, about the risks of therapy before pregnancy occurs, as well as pre- and post-conception strategies to reduce the risks to the mother and the fetus.330 Continue effective contraception during treatment and for at least 1 month after the final warfarin dose in such patients.330

Pediatric Use

The manufacturer of warfarin states that the optimum dosing, safety, and efficacy in pediatric patients are unknown due to a lack of adequate, well-controlled studies.330 Pediatric use of warfarin is based on adult data and recommendations, as well as limited pediatric data from observational studies and patient registries.330,1013,1118 However, the drug has been used in pediatric patients for prevention and treatment of thromboembolic events.1013,1118

Difficulty achieving and maintaining therapeutic INRs has been reported in pediatric patients, and more frequent assessments of INR are recommended in such patients because of possible changing warfarin requirements due to age, concomitant medications, diet, and comorbid conditions.330,1013 Variable bleeding rates have been observed in pediatric patients; therefore, such patients should avoid activities or sports that may result in traumatic injury.330,1013

Infants may have the highest and adolescents the lowest mg per kg dosage requirements.330,1013 Human milk-fed children may be more sensitive to warfarin compared to those receiving vitamin-K supplemented nutrition.330,1013

Geriatric Use

Age does not appear to substantially affect the pharmacokinetics of racemic warfarin, and the manufacturer states that the clearance of S -warfarin is similar in geriatric versus younger individuals.330 However, the clearance of R -warfarin appears to be slightly reduced in geriatric patients compared with that in younger individuals.330 Patients >60 years of age appear to exhibit a greater than expected INR response to warfarin, and a lower dosage is required to produce a therapeutic level of anticoagulation.330 Increasing age has been shown to confer a greater risk for bleeding outcomes, and advanced age has been included as a risk factor in both disease and bleeding risk stratification tools.1186,1187,1190,1191 The cause for increased sensitivity in geriatric patients is unknown but may be due to a combination of pharmacokinetic and pharmacodynamic factors.330 Consider lower initial and maintenance doses for elderly and/or debilitated patients.330 Conduct more frequent monitoring for bleeding in any situation or with any physical condition where added risk of hemorrhage is present. 330

A systematic review with meta-analysis of 11 clinical trials involving warfarin and direct oral anticoagulants (DOACs; e.g., dabigatran, apixaban, rivaroxaban, edoxaban) for atrial fibrillation and venous thromboembolism (VTE) compared the benefits and harms of these therapies in patients ≥75 years of age.1191 Of the 102,479 patients within the 11 trials, 31,418 were ≥75 years of age.1191 In these patients, DOACs were shown to be at least as effective as warfarin in reducing the recurrence of stroke, systemic embolism, and VTE; however, DOAC therapy was associated with a significantly lower risk of intracranial bleeding.1191 When stratified by major bleeding, GI bleeding, and clinically relevant bleeding, comparisons were limited due to trial design and data availability; warfarin or a specific DOAC was favored depending upon the specific bleeding outcome.1191

Hepatic Impairment

Patients with hepatic impairment should be monitored more frequently for bleeding due to impaired synthesis of clotting factors and decreased warfarin metabolism that can potentiate the anticoagulation response.330

Renal Impairment

No dosage adjustment is necessary in patients with renal impairment; renal clearance is considered a minor determinant of anticoagulant response to warfarin.330 The manufacturer suggests increased INR monitoring in warfarin patients with renal impairment.330

Common Adverse Effects

Most common adverse effects: fatal and nonfatal hemorrhage from any tissue or organ.330

Concurrent administration of numerous drugs or dietary or herbal supplements has been reported to affect patient response to warfarin.330,1192,1193

Drugs may increase patient sensitivity to warfarin by decreasing intestinal synthesis or absorption of vitamin K or affecting distribution of the vitamin; decreasing the rate of anticoagulant metabolism by competing for sites of metabolism or inhibiting the function or synthesis of metabolic enzymes; increasing affinity of the anticoagulant for receptor sites; decreasing synthesis and/or increasing catabolism of functional blood coagulation factors II, VII, IX, and X; interfering with other components of normal hemostasis such as platelet function or fibrinolysis; and by producing ulcerogenic effects.330,1192,1193

Certain drugs may decrease patient response to warfarin by decreasing absorption1192 of the anticoagulant; increasing the rate of metabolism of the anticoagulant by enzyme induction; or by increasing synthesis of functional blood coagulation factors II, VII, IX, and X.330,1193

Some dietary or herbal supplements contain naturally occurring coumarins or salicylates that may have anticoagulant, antiplatelet, or fibrinolytic effects; these supplements would be expected to increase the anticoagulant effects of concomitantly administered warfarin.330,379,1192,1197

Certain dietary or herbal supplements also may decrease response to warfarin, possibly as a result of induction of hepatic microsomal enzymes (e.g., St. John's wort)381,1197 or because of procoagulant effects (e.g., coenzyme Q10).330,380,1192,1197

Drugs Affecting Hepatic Microsomal Enzymes

Warfarin is metabolized by cytochrome P-450 (CYP) isoenzymes CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4; the S -enantiomer is metabolized principally by CYP2C9, while the R -enantiomer is metabolized by CYP1A2 and 3A4.330 Because the S -enantiomer of warfarin is about 2-5 times more potent than R -warfarin, drugs that preferentially increase or decrease the metabolism of S -warfarin are more likely to be associated with alterations in INR.322,1192,1193 Drugs that inhibit CYP2C9, CYP1A2, or CYP3A4 can potentially increase exposure and response to warfarin; conversely, drugs that induce CYP2C9, CYP1A2, or CYP3A4 can potentially decrease exposure and response to warfarin.330 (See Table 3.) INR should be closely monitored in patients who initiate, discontinue, or change dosages of concomitant drugs that affect these CYP isoenzymes.330,1192,1193

Protein-bound Drugs

Drugs may competitively or noncompetitively interfere with protein binding of warfarin, producing increased concentrations of unbound drug and potentiation of anticoagulant effects.1192,1193 In most instances, this is only a temporary effect with marginally increased INR and the INR may return to therapeutic levels after several days of concomitant therapy.1192

Drugs That Can Increase Bleeding Risk

Risk of bleeding may be increased when warfarin is used concomitantly with other drugs that can also increase bleeding risk.330,1192,1193 (See Table 4.) The interacting drug should be initiated only after weighing the risk-benefit of the combination, including other risk factors which may impact bleeding risk (e.g., advanced age, history of bleeding), and should be used for the shortest duration possible; patients should be monitored closely whenever such drugs are used concomitantly with warfarin.330,1192,1193

Nonsteroidal anti-inflammatory agents (NSAIAs) can inhibit platelet aggregation and cause GI bleeding and peptic ulceration and/or perforation, in addition to specific drug interactions that may affect the INR.1192 While the manufacturer of warfarin suggests close monitoring in those receiving NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors, and others recommend the use of gastroprotective agents when the combination cannot be avoided, some experts (e.g., the American College of Chest Physicians [ACCP]) suggest that such concomitant therapy be avoided.1000,1192,1193

Concomitant administration of warfarin and antiplatelet agents should be avoided unless the benefit is known or is highly likely to be greater than the potential harm from bleeding; patients in whom benefit may potentially outweigh risk include those with mechanical heart valves, acute coronary syndrome, or patients who have undergone recent coronary artery stent placement or bypass surgery.1000,1192,1193

Antibiotics and Antifungals

Changes in INR have been reported in patients receiving certain antibiotics or antifungal agents concomitantly with warfarin; however, clinical pharmacokinetic studies have not shown consistent effects of these drugs on plasma concentrations of warfarin.330,1192 The manufacturer states that INR should be monitored closely whenever any antibiotic or antifungal agent is initiated or discontinued in patients receiving warfarin.330,1192,1193

Cholestyramine

Concurrent administration of cholestyramine with warfarin results in decreased absorption of the anticoagulant.322,1192,1194 In addition, cholestyramine has been shown to decrease the plasma half-life of warfarin by interfering with enterohepatic circulation of the drug.1195,1197 However, because vitamin K absorption may also be decreased by cholestyramine, the net effect of concurrent anticoagulant and cholestyramine therapy is difficult to predict.1194 If concurrent use of cholestyramine and warfarin cannot be avoided, administer warfarin 1 hour before or at least 4 to 6 hours after cholestyramine.1194

Acetaminophen

Chronic ingestion of large doses of acetaminophen has been reported to potentiate the effects of coumarin-derivative anticoagulants (e.g., warfarin).307,310,312,313,1196 Conflicting data exist and the clinical importance of such an interaction has been questioned.90,304,305,306,308,311,1014,1196 Large dosages of acetaminophen (exceeding 1.5 g per day) may augment the anticoagulant effect of warfarin.1014,1192,1196 In addition, results of an observational study in patients stabilized on warfarin therapy indicate an association between ingestion of even low to moderate dosages of acetaminophen (7 or more 325-mg tablets weekly) and excessively high INR values.307 In a 4-week, randomized controlled trial comparing the addition of placebo, acetaminophen 2 g/day, or acetaminophen 4 g/day in stable chronic warfarin-treated patients, both groups of acetaminophen patients experienced significantly elevated INR values.1196 The average weekly change in INR from baseline was -0.1 to 0.1, 0.1 to 0.3, and 0 to 0.6 for the placebo, 2 g/day, and 4 g/day groups, respectively; 54% of patients in the acetaminophen groups had an INR of 0.3 or more above the upper limit of their therapeutic range.1196 Some clinicians suggest that additional monitoring of INR values may be prudent in patients receiving warfarin therapy following initiation of, and during sustained therapy with, large doses of acetaminophen.322,1196

Miconazole

Concomitant administration of vaginal miconazole creams or suppositories with acenocoumarol or warfarin for approximately 3 days has resulted in an increased PT/INR and/or bleeding.330,362,363,364,1192 Additional monitoring of INR values and appropriate dosage adjustments may be required in patients receiving concomitant intravaginal miconazole therapy.363,364

Alcohol

Some clinicians state that alcohol ingestion should be avoided in patients receiving warfarin.485,486 However, other clinicians suggest that patients receiving warfarin therapy may consume alcohol in small amounts (e.g., 1-2 drinks occasionally)487 but that chronic heavy consumption (e.g., defined as greater than 720 mL of beer, 300 mL of wine, or 60 mL of liquor daily) should be avoided. The effects of moderate alcohol consumption (e.g., 1-2 drinks daily)486 on adverse events or anticoagulation control in patients receiving long-term therapeutic anticoagulation with warfarin has not been well studied.486,490,491,495 In 2 studies in a small number of healthy young men, daily ingestion of 300-600 mL of wine in the fasting or unfasting state on a short-term basis (21 days) did not affect plasma warfarin concentrations or therapeutic hypoprothrombinemia (maintained at 25-35% of normal prothrombin activity as measured by one-stage prothrombin time).492,493 However, numerous patient-specific factors affect response to warfarin, including age, vitamin K status, concomitant disease (e.g., hepatic dysfunction, fat malabsorption, hyperthyroidism, fever), and hereditary resistance; therefore, lack of evidence of a warfarin-alcohol interaction in healthy individuals may not preclude such interactions in individual patients.494 Acute ingestion of alcohol has been reported to enhance hypoprothrombinemia and prolong INR by inhibiting warfarin metabolism, reducing its clearance, and/or displacing it from plasma proteins, while long-term use of alcohol (e.g., chronic alcoholism) may reduce anticoagulant effects by inducing CYP isoenzymes (e.g., CYP2E1, CYP3A4, CYP1A2) and warfarin metabolism.486,490,494,495,1197 Alcohol also has antiplatelet effects that may increase bleeding risk with warfarin without affecting INR.487

Dietary or Herbal Supplements

Dietary and herbal supplements also have been reported to increase or decrease the effects of warfarin, in some cases through CYP-mediated interactions (e.g., echinacea, grapefruit juice, gingko, goldenseal, St. John's wort).330,1197,1192 (See Tables 5 and 6.) In general, caution should be exercised when dietary or herbal supplements are used in patients receiving warfarin, and additional INR monitoring is recommended whenever these products are initiated or discontinued; limited information is available regarding the interaction potential of these products with warfarin.330,1192,1197

Cranberry Products

Several case reports have suggested a possible interaction between warfarin and cranberry juice; in these reports, the effects of warfarin appeared to be potentiated by cranberry juice or a cranberry product, in some cases resulting in clinically important bleeding events.501,502,503,504,505,506,510,1197,1198 However, confounding factors were present in many of these cases and prospective controlled studies generally have not been able to confirm this interaction.501,502,504,505,507,508,509,510,1197 Results of several studies, including a randomized, double-blind trial evaluating the effects of daily consumption of 240 mL of cranberry juice over a 2-week period in 30 patients stabilized on warfarin therapy, showed no evidence of any clinically important pharmacokinetic or pharmacodynamic interaction.502,505,507,508,509,510 The amounts of cranberry juice ingested varied among these studies, but generally were lower than those described in the case reports.502,503,504,505,510 It is possible that this interaction may be dose dependent, with response elicited by ingestion of large quantities (approximately 1-2 L) of cranberry juice.501,508,510,511,1198 In a study of healthy volunteers who were administered concentrated cranberry extract (3 g/day) and warfarin 25 mg daily, the area under the INR-time curve was increased by approximately 30% compared to warfarin treatment alone, a result that was both statistically and clinically significant.1198 Although available data do not appear to support a clinically important interaction between warfarin and moderate amounts of cranberry juice (240-480 mL) or cranberry extract (≤1350 mg/day) consumption, clinicians should be aware of the possibility of such an interaction and monitor closely for changes in INR and manifestations of bleeding.501,502,507,508,509,510,1198

Description

Pharmacology

Warfarin sodium is a coumarin-derivative anticoagulant that alters the synthesis of vitamin-K dependent blood coagulation factors II, VII, IX, X, and the anticoagulant proteins C and protein S.330

The mechanism of vitamin-K interference is thought to be inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex and reduction of vitamin K1 epoxide regeneration.330 Reduced vitamin K is an essential cofactor involved in the formation of vitamin K-dependent clotting factors.464,1178

Warfarin decreases clotting factor synthesis by inhibiting the regeneration of reduced vitamin K from vitamin K epoxide via inhibition of warfarin's target enzyme, vitamin K epoxide reductase.464,1176 Without reduced vitamin K as a cofactor for γ-glutamyl carboxylase, carboxylation of glutamic acid residues on coagulation factors II, VII, IX, and X cannot proceed and these proteins do not become fully functional coagulation factors.467 Certain variations in the gene VKORC1 that encodes vitamin K epoxide reductase may be associated with lower hepatic expression of the gene and lower concentrations of reduced vitamin K.465,467,469 Patients with such variant genes are at increased risk of excessive anticoagulation (e.g., supratherapeutic INRs) and/or bleeding and require lower dosages of warfarin.330,465,467,469,474,1178 Other genetic variations in the VKORC1 gene may contribute to warfarin resistance and increased warfarin dosage requirements.463,464,467,469,1178 (See Pharmacogenomics under Description.)

Because warfarin does not alter catabolism of blood coagulation factors, depletion of circulating functional vitamin K-dependent coagulation factors must occur before effects of the drug become apparent.1176 Depletion of functional coagulation factor II, factor VII, Protein C, factor IX, Protein S, and factor X occurs in a sequential manner; the rate of depletion of these coagulation factors depends on their individual rates of degradation.1176

Warfarin therapy inhibits thrombus formation when stasis is induced and may prevent extension of existing thrombi.330 The drug has no direct effect on established thrombi and appears to have little if any effect on the pathogenesis of arterial thrombi that result from interaction of platelets with an abnormal vessel wall.330,1176 Because warfarin affects synthesis of blood coagulation factors that are involved in both extrinsic and intrinsic coagulation, the drug prolongs both the prothrombin time (PT), which measures the integrity of the extrinsic system, and the activated partial thromboplastin time (aPTT), which measures the integrity of the intrinsic system.330,1176

Commercially available warfarin sodium is a racemic mixture of the R - and S -enantiomers of the drug.330 The enantiomers have different half-lives, potencies, routes of administration, and rates of elimination.330 The S -enantiomer of warfarin has 2-5 times the anticoagulant activity of the R -enantiomer.330 An anticoagulant effect generally occurs within 24 hours following administration of warfarin, but peak anticoagulant effects may be delayed for 72-96 hours.330 Antithrombogenic effects of warfarin generally occur only after concentrations of functional coagulation factors IX and X are diminished, which may not occur until 5-10 days following initiation of therapy.1176,1177

Plasma concentrations of vitamin K-dependent coagulation factors are physiologically decreased in neonates compared with adults, and the capacity of plasma from children receiving warfarin to generate thrombin is delayed and reduced compared with adults.496,497,1013

Pharmacokinetics

Warfarin sodium is rapidly and extensively absorbed from the GI tract.330 Peak plasma concentrations of warfarin usually are attained within 4 hours.330 Following initiation of warfarin therapy, blood concentrations of functional coagulation factor VII (plasma half-life of 4-6 hours) are depressed first, followed by those of factors IX (plasma half-life of 24 hours) and X (plasma half-life of 48-72 hours), and finally factor II (plasma half-life of 60 hours).330 When warfarin therapy is discontinued or phytonadione is administered, blood concentrations of functional vitamin K-dependent coagulation factors return to pretreatment concentrations.330

Warfarin is 99% bound to plasma proteins, principally albumin.330,1177 Warfarin crosses the placenta, and fetal plasma drug concentrations may be equal to maternal plasma concentrations.330 The estimated volumes of distribution for R - and S -warfarin and racemic warfarin are similar.330 Limited data suggest that warfarin is not significantly distributed into milk in humans.330 In one study, warfarin was not detected in the milk of 15 nursing women; prothrombin times measured in 6 of the infants (PT not obtained in the other 9) were within the expected range.330

The effective elimination half-life of warfarin averages about 40 hours and shows considerable interindividual variation (range: 20-60 hours).330 The clearance of the R -enantiomer of warfarin is about 50% that of the S -enantiomer; since the volumes of distribution of the enantiomers are similar, the half-life of R -warfarin (e.g., 37-89 hours) is longer than that of S -warfarin (e.g., 21-43 hours).330 Up to 92% of the drug is excreted in the urine and very little is unchanged drug.330 Racemic warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP) microsomal enzymes to inactive metabolites.330 The CYP isoenzymes involved in warfarin metabolism include CYP2C9, CYP2C19, CYP2C8, CYP2C18, CYP1A2, and CYP3A4.330

Pharmacogenomics

Variations in the genes responsible for warfarin metabolism or pharmacodynamic response may affect warfarin dosage requirements.330,378,462,463,464,465,466,467,469,1178 The enzyme principally responsible for metabolism of S -warfarin is CYP2C9; the degree of activity of the CYP2C9 isoenzyme is under genetic control and is subject to individual variation.330,462,464,465,469,474,1178 Patients who are homozygous for the CYP2C9*1 (wild-type) allele (about 80% of white patients)462,463 have normal enzyme activity (i.e., extensive metabolizers).1176 However, approximately 11 or 7% of white patients are intermediate (e.g., CYP2C9*2 allele) or poor (e.g., CYP2C9*3 allele) metabolizers of warfarin, respectively;330,462,463,464,465,466,474 clearance of S -warfarin, the predominant active form of the drug, is reduced in such patients.330 Therefore, patients with variant CYP2C9 alleles are at increased risk of bleeding and excessive anticoagulation (e.g., INR exceeding 3) and require lower dosages of warfarin, particularly during initiation of therapy.330,462,464,465,466,467,469,474 The CYP2C9*2 and CYP2C9*3 alleles reduce metabolism of warfarin by about 30-50 and 90%, respectively.462 Other CYP2C9 variant alleles associated with reduced enzymatic activity occur less frequently, including CYP2C9*5, CYP2C9*6, and CYP2C9*11 alleles in African populations and CYP2C9*5, CYP2C9*9, and CYP2C9*11 alleles in white patients.330,464,465,469,1176

Warfarin inhibits vitamin K epoxide reductase, which is a vitamin K-cycle enzyme complex controlling the regeneration of reduced vitamin K from vitamin K epoxide.330,464,467 Limited evidence suggests that variations in the gene that encodes vitamin K epoxide reductase, vitamin K epoxide reductase complex subunit 1 (VKORC1), may have an even larger impact on warfarin dosage than CYP2C9 genetic variations, and differing average dosage requirements between patients of white, Black, and Asian ancestry may be explained by VKORC1 variant frequency.463,464,465,467,1178 Common polymorphisms in non-coding regions of the VKORC1 gene contribute substantially to warfarin dosage variability across the normal dosage range.464 Asian patients appear to be more sensitive than white patients to the anticoagulant effect of warfarin and may require lower initial and maintenance dosages.330,378,465,469 A single nucleotide polymorphism of VKORC1 that identifies a low-dose and a high-dose warfarin phenotype has been found to associate with optimal warfarin dosage in both European and Asian patients.464 The reduced average warfarin maintenance dosage requirement in Asian individuals is largely related to the relatively rare occurrence of the high-dose allele in this ethnic group.463,464,465,469,1178

Several dosing algorithms for warfarin have been developed that take into account genetic variations in CYP2C9 and VKORC1 genes and individual clinical factors (e.g., age, height, body weight, interacting drugs, indication for warfarin therapy).463,467,469

The 2017 update of the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing suggests pharmacogenetic algorithm-based warfarin dosing over the genetics-based dosing table found in the FDA approved warfarin label.1178 The two recommended algorithms (Gage or International Warfarin Pharmacogenetics Consortium [IWPC]) consider age, sex, race or self-identified ancestry, weight, height, smoking status, warfarin indication, target INR, interacting drugs (e.g., amiodarone, phenytoin) and genetic variables (e.g., CYP2C9, VKORC1 genotypes).1178 CPIC recommends the Gage over the IWPC algorithm because it can adjust for CYP4F2, CYP2C9*5, and *6, if those genotypes are known.1178 The availability and reliability of genetic tests vary, and clinicians should check with their local or reference clinical laboratory to obtain more information about specific tests.474,1178

Advice to Patients

• Inform patients to strictly adhere to the prescribed dosage schedule and to not discontinue therapy without first consulting a healthcare provider.330
• Inform patients that if a dose is missed, it should be taken as soon as possible on the same day; resume the regular dosing schedule the following day.330 Do not double a dose to make up for a missed dose.330
• Inform patients that INR tests must be obtained based on their healthcare provider's recommendations and regular visits are necessary.330 Instruct patients that their healthcare provider will decide what INR goal is appropriate and adjust the warfarin dosage based on the INR results.330
• Advise patients that if warfarin is discontinued, the anticoagulant effects may persist for 2-5 days.330
• Inform patients that they may bruise and/or bleed more easily and that a longer than normal time may be required to stop bleeding when taking warfarin.330 Instruct patients to tell their healthcare provider about any unusual bleeding (e.g., nose bleeds, bleeding gums, heavier than normal menstrual bleeding, unexpected vaginal bleeding, pink or brown urine, red or black stools, coughing up blood, vomiting blood or material that looks like coffee grounds) or bruising during therapy.330
• Advise patients to avoid any activity or sport that may result in traumatic injury and to tell their healthcare provider if they fall often as this may increase their risk for complications.330
• Advise patients to eat a normal, balanced diet to maintain a consistent intake of vitamin K.330 Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables.330
• Advise patients to report any serious illness, such as severe diarrhea, infection, or fever to their healthcare provider.330
• Advise patients to inform all healthcare providers, including dentists, about their warfarin therapy including before scheduling any medical, surgical, dental, or other invasive procedure.330
• Advise patients to carry identification notifying others of their current warfarin therapy.330
• Advise patients to immediately contact their healthcare provider if they experience pain and discoloration of the skin (a purple bruise-like rash) that primarily occurs on areas of the body with high fat content, such as breasts, thighs, buttocks, hips, and abdomen.330
• Advise patients to immediately contact a healthcare provider if they experience any unusual symptoms or pain since warfarin may cause small cholesterol or atheroemboli.330 When this occurs in the feet, symptoms may include sudden cool, painful, purple discoloration of the toe(s) or forefoot.330
• Advise patients to immediately contact a healthcare provider if any of the following occur: pain, swelling, discomfort, headache, dizziness, weakness, and fall or injury, especially if they hit their head.330
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.330 Effective measures to avoid pregnancy should be used while taking warfarin and for 1 month after the last dose.330
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses. Instruct patients not to take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other OTC drugs, and botanical (herbal) products except on advice of a healthcare provider.330
• Advise patients of other important precautionary information.330

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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