Embolism Associated with Atrial Fibrillation
Apixaban is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Current evidence suggests that apixaban is more effective than aspirin or warfarin in reducing the risk of these thromboembolic events in patients with atrial fibrillation and at least one additional risk factor for stroke, with a similar risk of bleeding complications as aspirin and a lower risk than with warfarin.
Data are lacking on the use of apixaban in patients with prosthetic heart valves, and the manufacturer recommends that the drug not be used in such patients.
(See Patients with Prosthetic Heart Valves under Warning/Precautions: Other Warnings/Precautions, in Cautions.)
The American College of Chest Physicians (ACCP), the American College of Cardiology (ACC), the American Heart Association (AHA), the American Stroke Association (ASA), and other experts currently recommend that antithrombotic therapy be administered to all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless such therapy is contraindicated. Recommendations regarding choice of antithrombotic therapy are based on the patient's risk for stroke and bleeding. In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients with atrial fibrillation who have a moderate to high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke. Although many risk stratification methods have been used, patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or transient ischemic attack (TIA), advanced age (e.g., 75 years or older), history of hypertension, diabetes mellitus, or congestive heart failure. In addition, population-based studies suggest that female sex is an important risk factor for stroke in patients with atrial fibrillation, particularly in patients 75 years of age or older, and AHA and ASA recommend the use of risk stratification tools that account for age- and sex-specific differences in stroke risk. One such tool is the CHA2DS2-VASc score, an extension of the CHADS2 system (which considers the risk factors congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and prior stroke/TIA) that adds extra points for female sex (1 point); previous myocardial infarction, peripheral arterial disease, or aortic plaque (1 point); and age 65-74 years (1 point) or 75 years or older (2 points).
The risk of thromboembolism in patients with atrial flutter is not as well established as it is in those with atrial fibrillation. In addition, many patients with atrial flutter have alternating periods of atrial fibrillation. Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.
Although warfarin traditionally has been used for oral anticoagulation in patients with atrial fibrillation at increased risk of stroke, some experts suggest that non-vitamin K antagonist oral anticoagulants such as apixaban may provide certain advantages over warfarin (e.g., rapid onset of action, predictable anticoagulant effect, no requirement for coagulation monitoring, less potential for drug-drug and drug-food interactions) and may be considered as alternative therapy in selected patients. The non-vitamin K antagonist oral anticoagulants may be particularly useful in patients at moderate to high risk of stroke who are unable to comply with warfarin monitoring requirements or in whom a consistent therapeutic response to warfarin has not been achieved (e.g., because of drug or food interactions), while warfarin may continue to be preferred in patients who have well-controlled international normalized ratios (INRs) (e.g., INR in therapeutic range more than 70% of the time) and are compliant with regular laboratory monitoring. Warfarin generally should remain the treatment of choice in patients with severe renal impairment pending clinical outcomes data with the non-vitamin K antagonist oral anticoagulants in these patients. Because of the lack of direct, comparative studies, the relative efficacy and safety of apixaban and other non-vitamin K antagonist oral anticoagulants (e.g., dabigatran, edoxaban, rivaroxaban) used for the prevention of stroke in patients with nonvalvular atrial fibrillation remains to be fully elucidated. Some evidence from indirect comparisons suggests that there may be important differences (e.g., bleeding risk) among the non-vitamin K antagonist oral anticoagulants; however, results of such analyses should be interpreted with caution because of possible confounding factors (e.g., differences in study design and methods, patient populations, and anticoagulation control). AHA and ASA state that while clinical trials of non-vitamin K antagonist oral anticoagulants were not designed to determine differences in efficacy compared with warfarin in men versus women, apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in women with paroxysmal or permanent atrial fibrillation and prespecified risk factors (according to CHA2DS2-VASc) who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (creatinine clearance less than 15 mL/minute), lower body weight (less than 50 kg), or advanced liver disease (impaired baseline clotting function). When selecting an appropriate anticoagulant for patients with atrial fibrillation, experts recommend that the risks versus benefits of such therapy be considered for individual patients based on the absolute and relative risks of stroke and bleeding; patient compliance, preference, tolerance, and comorbidities; cost; availability of agents to reverse anticoagulant effects in case of bleeding complications; and other clinical factors such as renal function, availability of facilities to monitor INR, and degree of current INR control in patients already receiving warfarin.
Efficacy and safety of apixaban for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation were evaluated in a multinational, randomized, double-blind study (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]) that was designed to demonstrate noninferiority of apixaban compared with warfarin. The study included a total of 18,201 adults with nonvalvular atrial fibrillation and at least one additional risk factor for stroke (i.e., prior stroke, TIA, or systemic embolism; age 75 years or older; arterial hypertension requiring treatment; diabetes mellitus; symptomatic heart failure as defined by New York Heart Association [NYHA] class 2 or higher; left ventricular ejection fraction of 40% or less). At baseline, patients had a mean Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke (doubled) (i.e., CHADS2) score of 2.1; 19% had a history of a previous embolic event (stroke, TIA, or non-CNS systemic embolism), and 57% had been previously treated with warfarin or another vitamin K antagonist prior to study entry. Patients received apixaban at a dosage of 5 mg orally twice daily (or a reduced dosage of 2.5 mg twice daily in patients with at least 2 of the following characteristics: age of 80 years or older, body weight of 60 kg or less, serum creatinine concentration of 1.5 mg/dL or higher) or warfarin in a dosage adjusted to achieve an INR of 2-3. Approximately 5% of patients in the apixaban group received the reduced dosage of the drug. The primary efficacy outcome of the study was a composite of stroke (ischemic or hemorrhagic) or systemic embolism, and the primary safety end point was major bleeding as defined by the International Society of Thrombosis and Hemostasis (ISTH) criteria; all-cause mortality was evaluated as a secondary outcome. Although the study was designed principally to test for noninferiority of apixaban compared with warfarin in reducing the rate of stroke or systemic embolism, a sequential testing strategy was employed where superiority testing was performed on the key outcome measures if noninferiority was achieved; all efficacy analyses were conducted in the intent-to-treat (per randomization) population.
Results of the study indicated that apixaban was not only noninferior, but also was superior to warfarin in reducing the risk of stroke and systemic embolism. After a median follow-up of 1.8 years, the rate of the primary outcome of stroke or systemic embolism was substantially lower in patients receiving apixaban than in those receiving warfarin (annual rate of 1.27 and 1.6%, respectively; relative risk reduction of 21%). Superiority of apixaban over warfarin was largely attributed to a reduction in the risk of hemorrhagic stroke and ischemic stroke with hemorrhagic conversion; there was no difference in the incidence of purely ischemic strokes between the treatment groups. With respect to the primary safety outcome, apixaban also demonstrated superiority over warfarin; major bleeding, including intracranial hemorrhage, occurred at a substantially lower rate in patients receiving apixaban than in those receiving warfarin (annual rate of 2.13 and 3.09%, respectively; relative risk reduction of 31%). In addition, a significant reduction in all-cause mortality was observed with apixaban versus warfarin therapy (annual rate of 3.52 and 3.94%, respectively), which was primarily due to a reduction in cardiovascular-related deaths. The beneficial effects of apixaban over warfarin on stroke risk reduction, major bleeding, and all-cause mortality were consistent across a variety of patient subgroups defined by geographic region, prior warfarin use, age, baseline body weight, CHADS2 scores, renal function, apixaban dosage, type of atrial fibrillation, history of stroke or TIA, and aspirin use at randomization.
Patients who received warfarin in the ARISTOTLE study had an INR within therapeutic range 62% of the time, which is comparable to or better than that reported in other trials of non-vitamin K antagonist oral anticoagulants (e.g., dabigatran, rivaroxaban). Some clinicians have criticized this level of INR control as not being reflective of current practice and suggest that the benefits of apixaban may be less pronounced when compared with patients who achieve better warfarin control (e.g., INR in therapeutic range at least 70% of the time). However, in a subanalysis of the ARISTOTLE study, the benefits of apixaban relative to warfarin appeared to be consistent regardless of the quality of INR control (based on center-level comparison).
Apixaban was evaluated in another randomized double-blind study (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke [AVERROES]) for the prevention of stroke in patients with atrial fibrillation and at least one additional risk factor for stroke (i.e., prior stroke or TIA; age 75 years or older; arterial hypertension requiring treatment; diabetes mellitus requiring treatment; symptomatic heart failure as defined by NYHA class 2 or higher; left ventricular ejection fraction of 35% or less; documented peripheral arterial disease); the study compared apixaban (5 mg twice daily or 2.5 mg twice daily in selected patients) with aspirin (81-324 mg daily) in such patients who had failed or were considered unsuitable for vitamin K antagonist therapy by their clinician. Approximately 5600 patients were included; a major reason for warfarin unsuitability in these patients was difficulty or anticipated difficulty maintaining therapeutic INRs. The AVERROES study was terminated early after a planned interim analysis demonstrated a clear benefit of apixaban over aspirin in reducing the risk of stroke without substantially increasing the risk of bleeding. After a mean follow-up of 1.1 years, the rate of the primary outcome of stroke (ischemic or hemorrhagic) or systemic embolism was substantially lower in patients receiving apixaban than in those receiving aspirin (annual rate of 1.6 and 3.7%, respectively; relative risk reduction of 55%). Although a modest increase in the risk of major bleeding was observed with apixaban versus aspirin, the difference was not statistically significant. The observed benefits of apixaban over aspirin in this study were consistent across major subgroups of patients.
Deep-Vein Thrombosis and Pulmonary Embolism
Major Orthopedic Surgery
Apixaban is used for the prevention of postoperative deep-vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone total hip- or knee-replacement surgery. Evidence from randomized, controlled studies suggests that apixaban (2.5 mg twice daily) is more effective than once-daily subcutaneous enoxaparin sodium (40 mg once daily) in reducing the risk of venous thromboembolism in patients undergoing total hip- or knee-replacement surgery, without increasing bleeding risk. Noninferiority of apixaban (2.5 mg twice daily) and the currently recommended US dosing regimen for subcutaneous enoxaparin sodium in knee-replacement surgery (30 mg twice daily) was not established in a controlled study comparing these 2 anticoagulant regimens, although clinically relevant bleeding rates in this study were lower with apixaban. Data currently are lacking on the efficacy and safety of apixaban in patients undergoing hip-fracture surgery.
ACCP recommends routine thromboprophylaxis in all patients undergoing major orthopedic surgery, including total hip- or knee-replacement surgery, because of the high risk of postoperative venous thromboembolism. 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 potentially for up to 35 days after surgery in all patients undergoing major orthopedic surgery. Apixaban is considered by ACCP and other clinicians to be an acceptable option for pharmacologic thromboprophylaxis in patients undergoing total hip- or knee-replacement surgery. Although ACCP states a low molecular weight heparin generally is preferred for this use because of relative efficacy and safety and extensive clinical experience, apixaban may be a reasonable choice in situations in which a low molecular weight heparin is not available or cannot be used (e.g., in patients with a history of heparin-induced thrombocytopenia or in those who refuse or are uncooperative with subcutaneous injections). When selecting an appropriate thromboprophylaxis regimen for patients undergoing major orthopedic surgery, factors such as relative efficacy and bleeding risk as well as logistics and compliance issues should be considered. For additional details on prevention of venous thromboembolism in patients undergoing major orthopedic surgery, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.
Apixaban was evaluated for the prevention of venous thromboembolism following total hip- or knee-replacement surgery in 3 multicenter randomized double-blind studies known as the ADVANCE (Apixaban Dose Orally versus Anticoagulation with Enoxaparin) studies. In these studies, apixaban was compared with subcutaneous enoxaparin therapy in patients undergoing elective total knee-replacement (ADVANCE 1 and 2) or total hip-replacement surgery (ADVANCE 3). The primary efficacy end point in all 3 studies consisted of a composite of asymptomatic and symptomatic DVT, nonfatal PE, and all-cause mortality; the primary safety outcome was bleeding. These studies were designed principally to test for noninferiority of apixaban compared with enoxaparin in reducing the rate of the primary efficacy end point; superiority testing was performed if noninferiority was achieved. In all 3 studies, apixaban was administered orally at the same dosage (2.5 mg twice daily, initiated 12-24 hours after surgery), but dosage and timing of enoxaparin sodium administration varied between the studies. In ADVANCE 1, enoxaparin sodium was administered at a dosage of 30 mg twice daily (initiated 12-24 hours after surgery), while in ADVANCE 2 and 3, enoxaparin sodium was administered at a dosage of 40 mg once daily (initiated 12 hours before surgery and continued after surgery according to the investigator's standard of care). Anticoagulant prophylaxis (with apixaban or enoxaparin) was continued postoperatively for 10-14 days in the knee-replacement studies and for 32-38 days in the hip-replacement study. These studies demonstrated that apixaban was more effective than enoxaparin sodium 40 mg once daily in reducing the risk of venous thromboembolism without increasing the risk of bleeding; the improved efficacy of apixaban over enoxaparin was due principally to a reduction in asymptomatic proximal DVT. When compared with enoxaparin sodium 30 mg twice daily (the approved US regimen for enoxaparin thromboprophylaxis after knee-replacement surgery) in the ADVANCE 1 study, apixaban did not meet the noninferiority criteria for the primary efficacy outcome, although apixaban was associated with lower rates of clinically relevant bleeding.
Treatment and Secondary Prevention
Apixaban is used for the treatment of acute DVT and/or PE and for reduction in the risk of recurrent DVT and PE (secondary prevention) following initial anticoagulant therapy.
Efficacy and safety of apixaban for the treatment of acute DVT and/or PE has been established in a randomized, controlled study (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy [AMPLIFY]) in more than 5000 adults with symptomatic proximal DVT and/or PE. In this study, therapy with apixaban (10 mg orally twice daily for 7 days, followed by 5 mg twice daily for 6 months) was noninferior to conventional anticoagulant therapy (subcutaneous enoxaparin sodium 1 mg/kg every 12 hours for at least 5 days with overlapping warfarin therapy until INR was therapeutic (2 or greater), followed by daily warfarin therapy adjusted to maintain an INR of 2-3 and continued for 6 months) in reducing the incidence of the primary efficacy outcome (composite of symptomatic recurrent venous thromboembolism [defined as fatal or nonfatal PE and DVT] or death related to venous thromboembolism) and superior to the conventional regimen in reducing the incidence of major bleeding. The primary efficacy outcome occurred in 2.3% of patients receiving apixaban and 2.7% of those receiving the conventional regimen, and major bleeding occurred in 0.6 and 1.8% of patients in these respective groups (relative risk reduction of 69%).
Efficacy and safety of apixaban for reducing the risk of recurrent deep-vein thrombosis and pulmonary embolism (i.e., secondary prevention) has been established in another randomized, placebo-controlled study (AMPLIFY-EXT) in approximately 2500 patients who had received 6-12 months of anticoagulant therapy for venous thromboembolism. Some patients in the AMPLIFY-EXT study (approximately one-third) were participants in the AMPLIFY study who had received apixaban or enoxaparin and warfarin therapy and in whom clinicians were uncertain about the need for continuing anticoagulation. In the AMPLIFY-EXT study, extended treatment with apixaban 2.5 or 5 mg twice daily for 1 year reduced the incidence of the primary efficacy outcome (composite of symptomatic recurrent venous thromboembolism [defined as fatal and nonfatal PE and DVT] or death from any cause) without increasing the rate of major bleeding. The 2.5-mg (thromboprophylactic) and 5-mg (treatment) dosages of apixaban used in the extension study showed similar efficacy, and rates of adverse events in the 2 treatment groups were similar to those with placebo. The incidence of thromboembolism in the placebo group in the extension study was 8.8%, indicating an appreciable continuing risk of recurrent venous thromboembolism in the study population following an initial 6-12 months of anticoagulant therapy. Patients with provoked venous thromboembolism related to a transient risk factor (e.g., surgery) were not enrolled in the AMPLIFY and AMPLIFY-EXT studies unless they had another irreversible risk factor requiring 6 months of anticoagulant treatment (e.g., prior venous thromboembolism, immobilization, history of or active cancer, known prothrombotic genotype). In addition, these studies included relatively few patients with cancer, low body weight (less than 60 kg), or renal insufficiency (creatinine clearance less than 50 mL/minute); additional data on efficacy and safety of apixaban therapy in such patients with venous thromboembolism are needed. The relative efficacy and safety of apixaban versus other non-vitamin K antagonist oral anticoagulants (e.g., dabigatran, rivaroxaban) for the treatment of venous thromboembolism remains to be established in controlled, comparative trials.
The manufacturer states that apixaban is not recommended as initial therapy (as an alternative to heparin) in patients with PE who have hemodynamic instability or who may receive thrombolytic therapy or undergo pulmonary embolectomy.
Acute Medical Illness
Current evidence suggests that extended treatment with apixaban is not superior to short-term treatment with subcutaneous enoxaparin for thromboprophylaxis in patients with acute medical illness and is associated with a small but statistically significant increase in the risk of major bleeding. In a randomized, double-dummy placebo-controlled study (Apixaban Dosing to Optimize Protection from Thrombosis [ADOPT]), patients with an acute medical illness (e.g., congestive heart failure, respiratory failure) and moderately to severely restricted mobility received apixaban 2.5 mg twice daily for 30 days or subcutaneous enoxaparin sodium 40 mg once daily for 6-14 days or until hospital discharge; treatment was initiated within 72 hours of hospital admission. The primary efficacy outcome was the 30-day composite of death related to venous thromboembolism, PE, symptomatic DVT, or asymptomatic proximal-leg DVT (determined by systematic bilateral compression ultrasonography on day 30); the primary safety outcome was major bleeding. In approximately 4500 evaluable patients, the primary efficacy outcome occurred in 2.71% of those receiving apixaban and 3.06% who received enoxaparin (13% relative risk reduction with apixaban), a difference that was not statistically significant. However, the rapid increase in the rate of thromboembolic events following discontinuance of enoxaparin treatment suggests the benefits of some type of extended thromboembolism prophylaxis in this patient population; additional study and experience are needed. Apixaban therapy was associated with an increased risk of major bleeding; by day 30, major bleeding had occurred in 0.47% of the patients in the apixaban group and in 0.19% of the enoxaparin-treated patients (2.58-fold risk increase with apixaban).
Acute Coronary Syndrome
Current evidence suggests that addition of apixaban to standard antiplatelet therapy (e.g., aspirin, clopidogrel) does not substantially reduce the rate of recurrent ischemic events in patients with acute coronary syndrome (ACS) and may increase the risk of major, sometimes fatal, bleeding. In a randomized, phase 2, dose-ranging study (Apixaban for Prevention of Acute Ischemic and Safety Events [APPRAISE]), approximately 1700 patients with recent ST-segment elevation or non-ST-segment elevation ACS received apixaban (2.5 mg twice daily, 10 mg once daily, 10 mg twice daily, or 20 mg once daily) or placebo. Nearly all patients also received aspirin (up to 165 mg daily), and 76% of patients also received clopidogrel according to clinician discretion. The primary outcome of the study was major bleeding or clinically relevant nonmajor bleeding. The 2 higher-dose arms of apixaban therapy were discontinued early because of excess total bleeding events. Compared with placebo, apixaban (2.5 mg twice daily or 10 mg once daily for approximately 6 months) increased bleeding in a dose-dependent fashion. There was a trend toward fewer ischemic events (cardiovascular death, myocardial infarction, severe recurrent ischemia, ischemic stroke) in patients given apixaban; overall ischemic event rates and bleeding events in the apixaban group were greater in patients receiving dual antiplatelet therapy (adjunctive aspirin plus clopidogrel) compared with those receiving only adjunctive aspirin. In a follow-up randomized, phase 3 trial (APPRAISE-2), high-risk patients with ACS received apixaban (5 mg twice daily or a reduced dosage of 2.5 mg twice daily in those with a creatinine clearance less than 40 mL/minute) or placebo as adjuncts to antiplatelet therapy with aspirin with or without a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) for prevention of recurrent ischemic events. The trial was stopped early because of excess bleeding, including intracranial and fatal bleeding events, when apixaban was given in conjunction with dual antiplatelet therapy, without evidence of efficacy.