Apixaban Oral

Embolism Associated with Atrial Fibrillation

Nonvalvular Atrial Fibrillation

Apixaban is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.^{[1][3][5][8][40][42][1007]} The direct oral anticoagulants (DOACs; apixaban, dabigatran, edoxaban, rivaroxaban) have been shown in randomized controlled studies to be noninferior, and in some trials, superior to warfarin in reducing thromboembolic risk in patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of moderate-to-severe mitral stenosis or a mechanical heart valve), and are associated with reduced risk of serious bleeding.^[1][82][87]

Clinical Experience

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.^[1][3][4] 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, transient ischemic attack [TIA], or systemic embolism; age >=75 years; arterial hypertension requiring treatment; diabetes mellitus; symptomatic heart failure as defined by New York Heart Association [NYHA] class >=2; left ventricular ejection fraction of <=40%).^[1][3][4] 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 treated with warfarin or another vitamin K antagonist prior to study entry.^[1][3] 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: >=80 years of age, body weight of <=60 kg, serum creatinine concentration of >=1.5 mg/dL) or warfarin in a dosage adjusted to achieve an international normalized ratio (INR) of 2-3.^[1][3][4] Approximately 5% of patients in the apixaban group received the reduced dosage of the drug.^[3] 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.^[1][3][4] 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.^{[1][3][4][25]}

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.^[1][3][24] 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%).^[1][3] 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.^[1][3][20] 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%).^[1][3] 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.^[1][3][10] 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.^{[1][3][6][7][24]}

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).^{[1][3][10][12][13][25][66]} 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).^{[10][12][22][41][66]} 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).^[11][13][25]

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; >=75 years of age; arterial hypertension requiring treatment; diabetes mellitus requiring treatment; symptomatic heart failure as defined by NYHA class >=2; left ventricular ejection fraction <=35%; 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.^[1][5][30] Approximately 5600 patients were included; a major reason for warfarin unsuitability in these patients was difficulty or anticipated difficulty maintaining therapeutic INRs.^[5] 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.^[1][5] 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%).^[1][5][8] Although a modest increase in the risk of major bleeding was observed with apixaban versus aspirin, the difference was not statistically significant.^[1][5][21] The observed benefits of apixaban over aspirin in this study were consistent across major subgroups of patients.^[5][23][26]

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.^{[80][82][1007]}

DOACs including apixaban have been used for pharmacologic cardioversion^† in patients with atrial fibrillation or atrial flutter of >48 hours' duration or of unknown duration; DOACs are recommended as a safe and effective alternative to warfarin in this setting.^[87][1007]

Clinical Perspective

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.^{[80][81][82][989][990][999][1007][1017]} Although many risk stratification methods have been used, current guidelines recommend the use of the CHA₂DS₂-VASc risk stratification tool for assessing a patient's risk of stroke and need for anticoagulant therapy.^{[82][989][1007][1017]} Established clinical risk factors for stroke include prior ischemic stroke or TIA, advanced age (e.g., >=65 years), 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.^{[80][82][989][1007][1017]} 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-VASc score of 0 in males, or 1 in females), but should be considered in patients with one or more non-sex CHA₂DS₂-VASc stroke risk factors (CHA₂DS₂-VASc score of >=1 in males, or >=2 in females).^{[87][989][1007]} Patients also should be assessed for their risk of bleeding; those with a high risk of bleeding should be monitored more closely.^{[82][87][989][1007]}

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][1007]} A substantially greater benefit of DOACs versus warfarin has been observed when the INR was in the therapeutic range less than 66% of the time.^[82] If warfarin is used, patients should be optimally managed with well-controlled INRs (e.g., INR in therapeutic range more than 70% of the time).^[989][1007] A DOAC is recommended in patients unable to achieve optimal warfarin management.^{[82][87][989][1007]}

Patient age, body weight, and renal and hepatic function should be considered prior to treatment with DOACs.^[87][1007] There are limited data on the use of DOACs in obese patients and some experts have discouraged the use of these agents in the morbidly obese population (those with a body mass index [BMI] >40 kg/m² or body weight >120 kg).^[88][89] However, the various DOAC agents may have different outcomes.^[83][88][89] Because of limited data with DOACs in patients with morbid obesity, guidelines recommend considering warfarin over DOACs in morbidly obese patients with nonvalvular atrial fibrillation.^[83][88][89]

Because of the lack of direct, comparative studies, the relative efficacy and safety of apixaban compared to other DOACs for the prevention of stroke in patients with nonvalvular atrial fibrillation remain to be fully elucidated.^[84][85][87] Some evidence from indirect comparisons suggests that there may be important differences (e.g., bleeding risk) between these agents; 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).^[84][85][87] Selection of an appropriate anticoagulant for patients with nonvalvular atrial fibrillation should be individualized based on the absolute and relative risks of stroke and bleeding; costs; patient compliance, preference, tolerance, and comorbidities; and other clinical factors such as renal function and degree of INR control if the patient has been taking warfarin.^{[80][81][82][83][84][87][989][1007]}

Valvular Heart Disease

Safety and efficacy of apixaban have not been established in patients with prosthetic heart valves and the manufacturer states that use of apixaban is not generally recommended in such patients.^[1]

A subgroup of 156 patients with a history of bioprosthetic valve replacement or native valve repair from the ARISTOTLE trial was analyzed to assess safety and efficacy of apixaban compared with warfarin with regard to the occurrence of stroke/systemic embolism and major bleeding in these patients.^[1152] Results revealed overall clinical event rates to be low with no significant differences between apixaban and warfarin for any outcomes.^[1152]

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] Apixaban and other DOACs are an alternative to vitamin K antagonists in patients with atrial fibrillation and a bioprosthetic valve more than 3 months after implantation or with native valvular heart disease excluding rheumatic mitral stenosis.^[1143]

Prophylaxis of Venous Thromboembolism

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.^{[1][8][31][32][33][34][35][37][38][39][40][42][1003]}

Clinical Experience

Apixaban was evaluated for the prevention of venous thromboembolism (VTE) 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.^{[1][8][31][32][33][34][37]} 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).^{[1][31][32][33]} 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.^{[1][31][32][33]} 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.^[31][32][33] 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.^{[1][31][32][33]} 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).^{[1][31][32][33]} 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.^[31][32][33] These studies demonstrated that apixaban was more effective than enoxaparin sodium 40 mg once daily in reducing the risk of VTE without increasing the risk of bleeding; the improved efficacy of apixaban over enoxaparin was due principally to a reduction in asymptomatic proximal DVT.^{[1][8][32][33][37]} When compared with enoxaparin sodium 30 mg twice daily (the approved US regimen for enoxaparin thromboprophylaxis after knee-replacement surgery)^[47] 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.^[1][31][42]

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), American College of Chest Physicians (ACCP), and the American Society of Hematology (ASH).^{[1003][1108][1109]} Routine thromboprophylaxis is recommended in all patients undergoing major orthopedic surgery, including total hip- or knee-replacement surgery, because of the high risk of 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]

AAOS guidelines do not recommend any specific thromboprophylaxis agent, while the ACCP guidelines favor low molecular weight heparins (LMWHs) over DOACs.^[1003][1008] The ASH guidelines suggest the use of DOACs over LMWHs 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]

Acute Medical Illness

Apixaban has been used for VTE prevention in acutely ill medical patients^† .^[51] Evidence suggests that extended treatment with apixaban is not superior to short-term treatment with subcutaneous enoxaparin for thromboprophylaxis in such patients and is associated with a small but statistically significant increase in the risk of major bleeding.^[51]

Clinical Experience

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.^[51] The primary efficacy outcome was the 30-day composite of death related to VTE, PE, symptomatic DVT, or asymptomatic proximal-leg DVT (determined by systematic bilateral compression ultrasonography on day 30); the primary safety outcome was major bleeding.^[51] In approximately 4500 evaluable patients, the primary efficacy outcome occurred in 2.71% of those receiving apixaban and 3.06% who received enoxaparin; although this represented a 13% relative risk reduction with apixaban, the difference was not statistically significant.^[51] However, the rapid increase in the rate of thromboembolic events following discontinuance of enoxaparin treatment suggests the benefits of some type of extended thromboprophylaxis in this patient population; additional study and experience are needed.^[51] In the ADOPT study, apixaban therapy was associated with an increased risk of major bleeding; by day 30, major bleeding had occurred in 0.47% of patients in the apixaban group and 0.19% of enoxaparin-treated patients, representing a 2.58-fold increased risk with apixaban.^[51]

Clinical Perspective

Use of apixaban during hospitalization and post-discharge in acutely ill medical patients increases bleeding risk with no significant reduction in DVT, PE, and VTE death.^[51][1117]

Clinical trials evaluating extended-duration thromboprophylaxis in medically ill patients were carefully designed with strict patient inclusion and exclusion criteria and data suggesting a sufficient risk of VTE, based on a validated assessment tool, to offset the increased risk of bleeding.^[1117] However, these trials have varied in design, enrollment criteria, and patient selection, and therefore evidence from these trials is inconclusive.^[1117] Some clinicians suggest that decisions regarding extended-duration thromboprophylaxis should be based on the inclusion and exclusion criteria used in studies that provide available data.^[1117]

The American Society of Hematology (ASH) issued a strong recommendation to use LMWHs instead of DOACs for VTE prophylaxis in acutely ill hospitalized medical patients, and also strongly recommends inpatient VTE prophylaxis with LMWH only rather than inpatient and extended-duration outpatient VTE prophylaxis with DOACs.^[1116]

Cancer

Apixaban has been used for VTE prophylaxis in patients with active cancer^† .^[1157] Such patients are at an increased risk for VTE, and primary thromboprophylaxis with apixaban may be beneficial but carries a bleeding risk.^[1157]

Clinical Experience

The randomized, double-blind Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) trial compared the safety and efficacy of apixaban 2.5 mg twice daily with placebo for primary thromboprophylaxis in ambulatory cancer patients at intermediate-to-high risk for VTE.^[1157] The treatment period was 180 days with the initial dose of apixaban or placebo administered within 24 hours after chemotherapy initiation.^[1157] Cancer patients who were initiating a new course of chemotherapy with a minimum treatment intent of 3 months and a Khorana score >=2 were eligible.^[1157] Patients with a sole diagnosis of skin carcinoma, acute leukemia or myeloproliferative neoplasm, hepatic disease associated with coagulopathy, conditions associated with an increased bleeding risk, creatinine clearance <30 mL/minute per 1.73 m², planned stem-cell transplantation, or a life expectancy <6 months were excluded.^[1157]

The primary efficacy outcome was the initial occurrence of objectively confirmed symptomatic or incidentally detected proximal DVT of the lower or upper limbs, any nonfatal symptomatic or incidental PE, or fatal PE within the initial 180 (+/-3) days after randomization.^[1157] The main safety outcome, ISTH major bleeding, was defined as overt bleeding associated with a decrease in hemoglobin of >=2 g/dL, transfusion of >=2 units of packed red blood cells (or whole blood), bleeding in a critical site (e.g., intracranial, intraspinal, retroperitoneal), or bleeding contributing to a fatal outcome.^[1157] Results revealed the primary efficacy outcome occurred substantially less frequently in apixaban- versus placebo-treated patients (4.2% versus 10.2%).^[1157] Major bleeding occurred in more patients who received apixaban than those who received placebo (3.5% versus 1.8%).^[1157] The difference in the rate of major bleeding complications observed between the treatment groups was mainly due to higher rates of GI bleeding, hematuria, and gynecologic bleeding with apixaban.^[1157]

Clinical Perspective

Patients with cancer are substantially more likely to develop VTE than patients without cancer.^[1102][1103] Most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis throughout hospitalization; however, routine pharmacologic thromboprophylaxis is not recommended for all outpatients with cancer.^[1102] The patient's individual risk for thrombosis and risk of bleeding should be considered for all cancer patients when deciding whether to administer thromboprophylaxis.^[1102][1103]

The American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) have published guidelines for the management of VTE in cancer patients.^[1102][1103] The ASCO guideline states that high-risk outpatients with cancer (Khorana score >=2 prior to starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban, or a LMWH provided there are no significant risk factors for bleeding and no drug interactions.^[1102][1103] The ASH guideline suggests thromboprophylaxis with a DOAC (apixaban or rivaroxaban) in ambulatory cancer patients at intermediate to high risk for thrombosis; the decision to administer thromboprophylaxis versus no thromboprophylaxis should be based on the level of risk.^[1103]

Venous Thromboembolism - Treatment and Secondary Prevention

Apixaban is used for the treatment of acute DVT and/or PE and to reduce the risk of recurrent DVT and PE (secondary prevention) following initial anticoagulant therapy.^{[1][43][44][45][46][48]}

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.^[1]

Clinical Experience

Efficacy and safety of apixaban for the treatment of acute DVT and/or PE have 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.^[1][43][44] 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 therapeutic INR >=2, followed by daily warfarin therapy adjusted to maintain INR of 2-3 and continued for 6 months) in reducing the incidence of the primary efficacy outcome (composite of symptomatic recurrent VTE [defined as fatal or nonfatal PE and DVT] or death related to VTE) and superior to the conventional regimen in reducing the incidence of major bleeding.^[1][43][44] 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%).^[1][43][44]

Efficacy and safety of apixaban for reducing the risk of recurrent DVT and PE (i.e., secondary prevention) have been established in another randomized, placebo-controlled study (AMPLIFY-EXT) in approximately 2500 patients who had received 6-12 months of anticoagulant therapy for VTE.^[1][45][48] 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.^[1][45][48] 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 VTE [defined as fatal and nonfatal PE and DVT] or death from any cause) without increasing the rate of major bleeding.^[45][46] 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.^[45][46] The incidence of thromboembolism in the placebo group was 8.8%, indicating an appreciable continuing risk of recurrent VTE in the study population following an initial 6-12 months of anticoagulant therapy.^[45] Patients with provoked VTE 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 VTE, immobilization, history of or active cancer, known prothrombotic genotype).^[1][43][44] In addition, these studies included relatively few patients with cancer, low body weight (< 60 kg), or renal insufficiency (creatinine clearance <50 mL/minute); additional data on efficacy and safety of apixaban therapy in such patients with VTE are needed.^{[43][44][45][46]}

Patients with Cancer

Clinical Experience

In the open-label, noninferiority CARAVAGGIO trial, the efficacy and safety of apixaban for the prevention of recurrent VTE were evaluated in cancer patients with newly diagnosed symptomatic or incidental proximal lower limb DVT or PE.^[1150] Patients were randomized to apixaban 10 mg twice daily for the first 7 days, then 5 mg twice daily thereafter or dalteparin 200 units/kg once daily for the first 30 days, followed by 150 units/kg once daily.^[1150] The maximum dalteparin dosage was 18,000 units daily.^[1150] Both groups were treated for a total of 6 months.^[1150] Approximately 97% of patients had active cancer at baseline, and two-thirds of patients had recurrent locally advanced or metastatic lesions.^[1150] Approximately 60% of patients in both groups were receiving cancer treatment at enrollment.^[1150]

The primary outcome was objectively confirmed recurrent VTE, which included symptomatic upper limb DVT, symptomatic or incidental proximal DVT of the lower limbs, or symptomatic, incidental, or fatal PE.^[1150] Major bleeding, the principal safety outcome, was defined as clinically overt bleeding associated with at least one of the following: a decrease in hemoglobin >=2 g/dL, transfusion of >=2 units of packed red blood cells, bleeding that occurs at a critical site (e.g., intracranial, intraspinal, retroperitoneal), bleeding that necessitates surgical intervention, or fatal bleeding.^[1150]

The primary outcome occurred less frequently in the apixaban versus dalteparin group (5.6% versus 7.9%), meeting the criteria for noninferiority.^[1150] Major bleeding was not substantially different between the groups: 3.8% for apixaban- and 4% for dalteparin-treated patients.^[1150]

In the randomized, open-label, investigator-initiated ADAM VTE study, the efficacy and safety of apixaban were evaluated in the treatment of patients with active cancer and confirmed acute VTE.^[1151] In ADAM VTE, patients were randomized to apixaban 10 mg twice daily for the first 7 days, then 5 mg twice daily thereafter or dalteparin 200 units/kg once daily for the first 30 days, followed by 150 units/kg once daily.^[1151] Both groups were treated for 6 months.^[1156] At baseline, approximately 73% of patients were receiving concurrent systemic cancer treatment and two-thirds of patients had distant metastases.^[1151]

The primary safety outcome was the occurrence of major bleeding defined as overt bleeding plus a decrease in hemoglobin >=2 g/dL, transfusion of >=2 units of packed red blood cells, bleeding that occurs in at least one critical site (e.g., intracranial, intraspinal, retroperitoneal), or fatal bleeding.^[1151] VTE recurrence (defined as DVT, PE, fatal PE, or arterial thromboembolism) comprised the secondary efficacy endpoint.^[1151] Major bleeding was reported in 2 (1.4%) of 142 dalteparin-treated patients and 0 (0%) of 145 apixaban-treated patients.^[1151] In addition, VTE recurred in 0.7% of apixaban-treated patients and 6.3% of dalteparin-treated patients.^[1151]

Clinical Perspective

The DOACs are among several anticoagulants that can be used for the treatment of VTE.^[1005][1106] DOACs have similar efficacy to warfarin, but reduced bleeding (particularly intracranial hemorrhage) and greater convenience for patients and healthcare providers.^[1106] In addition to relative efficacy and safety, factors that should be considered when selecting an appropriate anticoagulant include convenience of administration, cost, patient preference, presence of renal impairment, and cancer or other comorbid conditions.^[1106]

Apixaban is recommended by ACCP, ASH, and the Anticoagulation Forum as an acceptable option for initial and long-term anticoagulant therapy in patients with acute proximal DVT of the leg and/or PE.^{[1005][1006][1008][1106]} 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 risk of bleeding).^{[1005][1006][1106]} Apixaban may offer some advantages over parenteral or vitamin K antagonist anticoagulants for the treatment of VTE (e.g., oral administration, no requirement for routine coagulation monitoring, minimal drug and food interactions) and guidelines recommend DOACs over vitamin K antagonist anticoagulants with a few exceptions based on risk factors (e.g., antiphospholipid syndrome).^{[1005][1006][1008][1106]} The relative efficacy and safety of apixaban versus other DOACs (e.g., rivaroxaban, dabigatran edoxaban) for the treatment of VTE remains to be fully elucidated due to the lack of head-to-head trials.^[1106][1107] ACCP does not recommend one DOAC over another as there are no published trials directly comparing these agents and indirect comparisons have not shown substantially different outcomes.^[1106]

DOACs generally should not be used in settings with high risk of bleeding (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, or GI complications affecting oral therapy (e.g., poor absorption, nausea and vomiting) because of the lack of safety data.^[1102][1106] There is some experience with the use of apixaban and rivaroxaban in patients with morbid obesity.^[88][89]

In patients with cancer and established VTE, LMWHs or oral factor Xa inhibitors (e.g., apixaban, rivaroxaban, edoxaban) are generally recommended over warfarin for long-term anticoagulation.^{[1102][1103][1106]} ACCP and ASH recommend the use of an oral factor Xa inhibitor over LMWH for the initiation and treatment phases of therapy in patients with cancer-associated thrombosis.^[1103][1106] Additional studies and experience are needed to further evaluate the efficacy and safety of apixaban for the treatment of cancer-related VTE. ^{[1005][1008][1102][1105][1106]}

General

Pretreatment Screening

Prior to initiating therapy with apixaban, assess renal function.^[1]Obtain body weight and serum creatinine to determine dosage in patients with nonvalvular atrial fibrillation.^[1]

Patient Monitoring

Periodically assess serum creatinine concentration as clinically indicated in patients with nonvalvular atrial fibrillation and adjust therapy accordingly.^[1]Periodically assess body weight in patients with nonvalvular atrial fibrillation who are at risk of decreasing to <=60 kg.^[1]If apixaban is administered in an epidural or spinal anesthesia/analgesia or lumbar puncture setting, frequently monitor for signs or symptoms of neurological impairment (e.g., numbness, tingling, weakness in lower limbs, bowel and/or bladder dysfunction).^[1]Monitor patients for any signs or symptoms of bleeding (e.g., unusual bruising) during therapy.^[1]Routine coagulation monitoring (e.g., prothrombin time [PT], activated partial thromboplastin time [aPTT], international normalized ratio [INR]) is not necessary with apixaban therapy because of the drug's predictable pharmacokinetic (PK) and pharmacodynamic (PD) effects.^{[8][19][22][30][40][989]} However, in certain situations, such as in the case of overdosage or in patients with hemorrhagic or thromboembolic complications or those requiring emergency surgery, it may be useful to assess the degree of anticoagulation.^{[8][19][22][40][42]} Although apixaban produces concentration-dependent increases in aPTT, PT, INR, and the Heptest (used to measure inhibition of exogenous activated factor X [factor Xa]), these tests generally are not useful for monitoring the anticoagulant effects of apixaban because of a high degree of inconsistency and variability in results.^{[1][8][19][28][40][42]} A chromogenic anti-factor Xa assay (Rotachrom^® Heparin chromogenic assay) was used during the apixaban development program to measure the effect of apixaban on factor Xa activity.^[1] Although the chromogenic assay appears to correlate well with apixaban activity and may produce less variable results than other coagulation tests, a standardized assay specifically calibrated for apixaban currently is not available in most healthcare facilities.^{[1][19][28][40][42]} The manufacturer does not recommend use of this chromogenic assay for assessing the anticoagulant effects of apixaban.^[1]

Dispensing and Administration Precautions

Based on the Institute for Safe Medication Practices (ISMP), apixaban is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.^[1169]

Oral Tablets

Administer orally twice daily without regard to food.^[1][17]

In patients who are unable to swallow whole tablets, crush apixaban 2.5- or 5-mg tablets and suspend in water, 5% dextrose in water, or apple juice, or mix with applesauce and promptly administer orally.^[1] Alternatively, crush apixaban tablets and suspend in 60 mL of water or 5% dextrose in water and promptly deliver through a nasogastric feeding tube.^[1] Crushed apixaban tablets are stable in water, dextrose 5% in water, apple juice, or applesauce for up to 4 hours.^[1]

If a dose is missed, take the missed dose as soon as possible on the same day, followed by resumption of the regular twice-daily dosing schedule; do not double the dose to make up for the missed dose.^[1]

Store apixaban tablets at 20°C to 25°C (excursions permitted to 15°C to 30°C).^[1]

Dosage

Embolism Associated with Atrial Fibrillation

For reducing the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation, the recommended dosage of apixaban for most patients is 5 mg orally twice daily.^[1]

Reduce dosage to 2.5 mg twice daily in patients with at least 2 of the following characteristics that can increase drug exposure and thus, increase the risk of bleeding: age >=80 years, body weight <=60 kg, or serum creatinine concentration >=1.5 mg/dL.^[1][42]

Thromboprophylaxis in Orthopedic Surgery

Hip or Knee-replacement Surgery

For the prevention of deep-vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adult patients who have undergone hip- or knee-replacement surgery, the recommended dosage of apixaban is 2.5 mg orally twice daily.^{[1][31][32][33]} Administer the initial dose at least 12-24 hours after surgery, provided hemostasis has been established.^[1] The recommended duration of apixaban therapy is 35 days for patients undergoing hip-replacement surgery and 12 days for patients undergoing knee-replacement surgery.^[1] In clinical studies, the initial dose of apixaban was administered 12-24 hours after wound closure, and treatment was continued postoperatively for 10-14 days after knee-replacement surgery and for 32-38 days after hip-replacement surgery.^[31][32][33]

Venous Thromboembolism - Treatment and Secondary Prevention

For the treatment of acute DVT and/or PE in adults, the recommended dosage of apixaban is 10 mg orally twice daily for 7 days, followed by 5 mg orally twice daily;^[1][43][44] in the principal efficacy trial, apixaban therapy was administered for 6 months.^[43][44] For reduction in the risk of recurrent DVT and PE (secondary prevention) in adult patients who have received at least 6 months of initial anticoagulant therapy, the recommended dosage of apixaban is 2.5 mg orally twice daily.^[1][45][46]

The optimum duration of anticoagulant therapy in patients with venous thromboembolism (VTE) should be determined by the individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors for thrombosis, presence of cancer, risk of bleeding).^[1005] In general, the American College of Chest Physicians (ACCP) states that anticoagulant therapy for VTE should be continued beyond the acute treatment period for at least 3 months and possibly longer in certain patients with a high risk of recurrence and low or moderate risk of bleeding.^[1005][1106]

Coadministration with Dual Inhibitors of Cytochrome P-450 Isoenzyme 3A4 and P-glycoprotein

In patients receiving apixaban dosages of 5 mg or 10 mg twice daily who are on concomitant therapy with drugs that are potent inhibitors of both cytochrome P-450 (CYP) isoenzyme 3A4 and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir), the dosage of apixaban should be reduced by 50% (e.g., from 5 mg twice daily to 2.5 mg twice daily).^[1] Patients who are already receiving an apixaban dosage of 2.5 mg twice daily should avoid concomitant use with such potent dual inhibitors of CYP3A4 and P-gp.^[1]

Transitioning from Other Anticoagulant Therapy

When transitioning from warfarin to apixaban therapy, the manufacturer states that warfarin should be discontinued and apixaban initiated as soon as the INR is <2.^[1]

When transitioning from therapy with anticoagulants other than warfarin, the manufacturer recommends discontinuing the current anticoagulant and initiating apixaban at the time of the next scheduled dose of the current anticoagulant.^[1][14]

Transitioning to Other Anticoagulant Therapy

When transitioning from apixaban to warfarin therapy, INR measurements may not be useful for determining an appropriate dose of warfarin because apixaban also can prolong the INR.^[1] The manufacturer suggests that apixaban be discontinued and a parenteral anticoagulant and warfarin initiated simultaneously at the time of the next scheduled dose of apixaban; the parenteral anticoagulant can then be discontinued once an acceptable INR is achieved with warfarin.^[1] Some clinicians have suggested other strategies for transitioning from non-vitamin K antagonist oral anticoagulants (e.g., apixaban, rivaroxaban) to warfarin based on the patient's creatinine clearance and the warfarin start date.^[78]

When transitioning from apixaban to anticoagulants other than warfarin, including parenteral anticoagulants or other direct oral anticoagulants (DOACs), apixaban should be discontinued and the other anticoagulant initiated at the time of the next scheduled apixaban dose.^[1] In patients taking apixaban or other factor Xa inhibitors (e.g., rivaroxaban), heparin anti-Xa assay accuracy may be affected; elevated heparin anti-Xa levels have been reported, which may impact monitoring of the transition from apixaban to IV heparin.^[1132]

Managing Anticoagulation in Patients Requiring Invasive Procedures

If temporary discontinuance of anticoagulation is necessary prior to surgery or other invasive procedures, the timing of discontinuance should be based upon procedural bleeding risk, the patient's thromboembolic risk, and renal function.^[1161]

To reduce the bleeding risk, the manufacturer recommends that apixaban be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding and at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or bleeding in a non-critical location that can be easily controlled.^[1]

Bridging anticoagulation generally is not required prior to the procedure or during the 24-48 hours after stopping apixaban.^[1] Apixaban therapy should be resumed postoperatively as soon as adequate hemostasis has been established.^[1][1161]

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A).^[1] Because of limited experience, the manufacturer states that dosage recommendations cannot be provided in patients with moderate hepatic impairment (Child-Pugh class B).^[1][77] Data are lacking on the use of apixaban in patients with severe hepatic impairment (Child-Pugh class C), and the manufacturer states that use of apixaban is not recommended in this population.^[1]

Renal Impairment

The manufacturer states that dosage adjustment of apixaban based solely on renal impairment (including patients with end-stage renal disease [ESRD] who are maintained on intermittent hemodialysis) is not necessary in patients with nonvalvular atrial fibrillation; however, a reduced dosage of 2.5 mg twice daily is recommended in those with at least 2 of the following characteristics: an elevated serum creatinine concentration >=1.5 mg/dL, age >=80 years, and/or weight <=60 kg.^[1][77] The manufacturer states that this recommendation is based on PK and PD (anti-factor Xa activity) data in ESRD patients maintained on hemodialysis; such patients were not studied in clinical efficacy and safety trials of apixaban.^[1]

No dosage adjustments are necessary in patients with renal impairment (including ESRD patients maintained on hemodialysis) who are receiving apixaban for the prevention of DVT and associated PE following hip- or knee-replacement surgery or for the treatment or secondary prevention of DVT or PE.^[1] The manufacturer states this recommendation is based on PK and PD (anti-factor Xa activity) data in ESRD patients maintained on hemodialysis; patients with ESRD on dialysis or with a creatinine clearance <15 mL/minute were not studied in apixaban clinical efficacy and safety trials.^[1]

Geriatric Patients

The manufacturer states that dosage adjustment based solely on age is not necessary in geriatric patients >=65 years of age; however, a reduced dosage of 2.5 mg twice daily is recommended in patients >=80 years of age with nonvalvular atrial fibrillation if they also weigh <=60 kg and/or have a serum creatinine concentration >=1.5 mg/dL.^[1]

Body Weight

The manufacturer states that dosage adjustment based solely on body weight is not necessary; however, a reduced dosage of 2.5 mg twice daily is recommended in patients with nonvalvular atrial fibrillation who weigh <=60 kg if they also are >=80 years of age and/or have a serum creatinine concentration >=1.5 mg/dL.^[1]

In the principal efficacy study, patients with high body weight (>120 kg) had decreased drug exposure (approximately 25% lower), but this did not result in loss of efficacy.^[77]

The International Society on Thrombosis and Haemostasis (ISTH) Subcommittee on Control of Anticoagulation issued consensus recommendations on VTE prevention and treatment with DOACs in patients with obesity.^[1129] Based upon the available PK/PD and clinical outcome data, apixaban at the standard dosage is an acceptable treatment and primary prevention option regardless of high body mass index (BMI) and body weight.^[1129] ISTH does not recommend regularly following peak or trough apixaban levels as there are insufficient data to influence management decisions.^[1129] Following surgical intervention for obesity, apixaban absorption may be reduced depending on the procedure.^[1129] Due to limited data, ISTH does not recommend the use of apixaban or other DOACs (e.g., rivaroxaban, edoxaban, dabigatran) for treatment or prevention of VTE in the acute setting after bariatric surgery due to concerns for decreased absorption.^[1129] In the early postsurgical phase, patients should be initiated on parenteral anticoagulation.^[1129] The use of a vitamin K antagonist or DOAC following at least 4 weeks of parenteral treatment may be considered and obtaining a DOAC trough level is suggested to check drug absorption.^[1129]

Contraindications

Active pathologic bleeding.^[1]Severe hypersensitivity reaction (e.g., anaphylactic reactions) to apixaban.^[1]

Warnings/Precautions

Warnings

Risk of Thrombosis Following Premature Discontinuance of Anticoagulation

Premature discontinuance of any oral anticoagulant, including apixaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events (e.g., stroke).^[1] A boxed warning about this risk is included in the prescribing information for apixaban.^[1] An increased incidence of stroke was observed during the transition from apixaban to warfarin in clinical trials in patients with atrial fibrillation.^[1] If discontinuance of apixaban is required for reasons other than pathologic bleeding or completion of a course of therapy, anticoagulant coverage with an alternative anticoagulant should be considered.^[1] When transitioning patients from one anticoagulant therapy to another, it is important to ensure continuous anticoagulation while minimizing the risk of bleeding.^[83] Particular caution is advised when switching patients from a factor Xa inhibitor to warfarin therapy because of the slow onset of action of warfarin.^[83]

Spinal/Epidural Hematoma

Patients receiving anticoagulants are at risk of developing an epidural or spinal hematoma when concomitant neuraxial (epidural/spinal) anesthesia or spinal puncture is employed; such complications can result in long-term or permanent paralysis.^[1] A boxed warning about this risk is included in the prescribing information for apixaban.^[1] The risk of these complications is increased by postoperative use of indwelling epidural catheters for administration of analgesia or by concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory agents (NSAIAs), platelet-aggregation inhibitors, or other anticoagulants.^[1] Risk also may be increased in patients with a history of traumatic or repeated epidural or spinal punctures, spinal deformity, or spinal surgery.^[1]

Removal of an indwelling epidural or intrathecal catheter should be delayed for at least 24 hours after a dose of apixaban, and at least 5 hours should elapse following removal of the catheter prior to administration of the next apixaban dose.^[1] If traumatic puncture occurs, the administration of apixaban should be delayed for 48 hours.^[1]

Patients receiving apixaban in the setting of epidural or spinal anesthesia should be monitored frequently for manifestations of neurologic impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction).^[1] If neurologic compromise is noted, urgent diagnosis and treatment are necessary.^[1] Clinicians should consider the potential benefits versus risks of neuraxial intervention in patients who are currently receiving or will receive anticoagulant prophylaxis.^[1]

Other Warnings and Precautions

Bleeding

Apixaban increases the risk of hemorrhage and can cause serious, potentially fatal, bleeding.^{[1][3][5][18][19][21]} The drug should be discontinued if active pathological hemorrhage occurs.^[1] However, minor or ''nuisance'' bleeding is a common occurrence in patients receiving any anticoagulant and should not readily lead to treatment discontinuance.^[83]

In the principal efficacy study of apixaban in patients with nonvalvular atrial fibrillation (ARISTOTLE), major bleeding occurred at an annual rate of 2.13% (327 out of 9088 patients) in patients who received the drug, although the rate was substantially lower with apixaban than with warfarin therapy (rate of 2.13% per year versus 3.09% per year).^[1][3][6] In this study, bleeding was assessed according to the International Society on Thrombosis and Hemostasis (ISTH) criteria, which defines major bleeding as clinically overt bleeding that is accompanied by one or more of the following events: decrease in hemoglobin >=2 g/dL, transfusion of >=2 units of packed red blood cells, bleeding at a critical site (i.e., intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal) or resulting in death.^[1] Concomitant use of aspirin increased the risk of bleeding in patients receiving apixaban from 1.8 to 3.4% per year, and concomitant use of aspirin and warfarin increased the bleeding risk from 2.7 to 4.6% per year.^[1]

Risk of bleeding may be increased in patients with renal impairment and in those receiving concomitant therapy with drugs that affect hemostasis (e.g., aspirin or other antiplatelet drugs, fibrinolytics, heparin or other anticoagulants, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, chronic use of NSAIAs) or drugs that are inhibitors of both P-glycoprotein (P-gp) and cytochrome P-450 (CYP) isoenzyme 3A4.^[1][6][42]

Apixaban therapy should be temporarily interrupted prior to any elective surgery or other invasive procedure to reduce the risk of bleeding.^[1]

Factor Xa (recombinant), inactivated-zhzo (also known as andexanet alfa), a recombinant modified human factor Xa protein, is a specific reversal agent for the anticoagulant effects of apixaban.^[90][91][92] Data from clinical trials indicate that factor Xa (recombinant), inactivated-zhzo is effective in rapidly reversing the anticoagulant effects of apixaban (as measured by anti-factor Xa activity, unbound anticoagulant concentration, and thrombin generation).^[90][91][92] The safety of factor Xa (recombinant), inactivated-zhzo has not been established in patients who have experienced a thromboembolic event or disseminated intravascular coagulation (DIC) within 2 weeks prior to the life-threatening bleeding event requiring treatment with the drug or in those who have received prothrombin complex concentrate (PCC), recombinant factor VIIa, or whole blood products within 7 days prior to the bleeding event.^[90] If a serious bleeding event occurs during therapy, apixaban should be discontinued and appropriate supportive measures provided.^{[1][13][22][989]}

Procoagulant reversal agents such as 4-factor PCC may be considered for immediate reversal of the anticoagulant effect of apixaban, when factor Xa (recombinant), inactivated-zhzo is not available.^{[1][43][68][1162]} In 2 prospective cohort studies, fixed dose 4-factor PCC was administered to patients with major bleeding due to factor Xa inhibitors.^[1162] In one study the dose of 4-factor PCC was weight-based (2000 units for patients weighing >65 kg and 1500 units for patients weighing <65 kg).^[1162] In the second study, the dose of 4-factor PCC was 2000 units.^[1162] Good or effective hemostasis was achieved in at least 65% of patients in both studies.^[1162] Embolic complications including ischemic stroke and thromboembolic events were reported in some patients who received the reversal agent.^[1162]

When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (prothrombin time [PT], international normalized ratio [INR], activated partial thromboplastin time [aPTT]) or anti-factor Xa activity is not useful and is not recommended.^[1]

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban.^[1] There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) or systemic hemostatics (desmopressin) in patients receiving apixaban, and such drugs are not expected to be effective as reversal agents.^[1] Because of high plasma protein binding, apixaban is not expected to be dialyzable.^[1] In the event of an overdosage, activated charcoal may be used to decrease plasma concentrations of apixaban more rapidly.^[1][19]

Patients with Prosthetic Heart Valves

Safety and efficacy of apixaban have not been established in patients with prosthetic heart valves and use of apixaban is not generally recommended in such patients.^[1]

Patients with Pulmonary Embolism

Apixaban is not recommended as initial therapy (as an alternative to unfractionated heparin) in patients with pulmonary embolism (PE) who have hemodynamic instability or who may receive thrombolytic therapy or undergo pulmonary embolectomy.^[1]

Thrombosis Risk in Triple Positive Antiphospholipid Syndrome

Apixaban and other DOACs are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS) (i.e., positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies).^[1] Treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with warfarin treatment in patients with APS, especially those with triple-positive disease.^[1] The International Society of Thrombosis and Hemostasis (ISTH) recommends the use of vitamin K antagonists over DOACs in patients with high-risk APS, including those with triple-positive disease.^[1163]

Specific Populations

Pregnancy

The manufacturer states the limited available data on apixaban use in pregnant women are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse developmental outcomes.^[1] Animal studies have not demonstrated any evidence of fetotoxic effects; however, increased maternal bleeding was observed when apixaban was administered to pregnant animals at doses ranging from 1-19 times the human exposure at the maximum recommended dose.^[1] All patients receiving anticoagulants, including pregnant women, are at risk for bleeding.^[1]

Consider use of a shorter acting anticoagulant as delivery approaches. Based on the pharmacologic activity of factor Xa inhibitors, bleeding may occur at any site in the fetus and/or neonate.^[1] Apixaban use during labor or delivery in women who are receiving neuraxial anaesthesia may result in epidural or spinal hematomas.^[1]

The American College of Chest Physicians (ACCP) and the American College of Obstetricians and Gynecologists (ACOG) recommend avoiding apixaban in pregnant women due to insufficient safety data; the American Society of Hematology (ASH) states that more data involving the DOACs are necessary in their most recent guidelines for the management of VTE in the context of pregnancy.^{[1012][1125][1126]}

Lactation

Apixaban is distributed into milk in rats; it is not known whether the drug is distributed into human milk.^[1] The effects of apixaban on the breast-fed infant or on milk production are unknown.^[1] The manufacturer states that breast-feeding is not recommended during treatment with apixaban.^[1] ACCP, ACOG, and ASH recommend that anticoagulants other than apixaban be used in nursing women.^{[1012][1125][1126]}

Females and Males of Reproductive Potential

Apixaban can cause significant uterine bleeding.^[1] Females of reproductive potential and those with abnormal uterine bleeding should be assessed for increased risk of clinically significant uterine bleeding, potentially requiring gynecologic surgical intervention.^[1]

Pediatric Use

Safety and efficacy of apixaban have not been established in pediatric patients.^[1][3][4]

Geriatric Use

No substantial differences in efficacy and safety were observed in geriatric patients >=65 years relative to younger adults in clinical trials.^[1] In clinical trials of apixaban in patients with nonvalvular atrial fibrillation or DVT/PE, no clinically important differences in efficacy or safety were observed among different age groups.^[1] Pharmacokinetic effects (systemic exposure and peak plasma concentrations) of apixaban were similar in patients >=65 years and younger adults (18-40 years of age) receiving the drug.^[1]

Hepatic Impairment

Pharmacokinetic (systemic exposure and peak plasma concentrations) and pharmacodynamic (inhibition of factor Xa activity) effects of apixaban do not appear to be substantially altered in patients with mild or moderate hepatic impairment.^[1][77] Patients with moderate hepatic impairment may have intrinsic coagulation abnormalities that can affect response to apixaban therapy; there are limited data and dosing recommendations cannot be provided.^[1][77] Data are lacking in patients with severe hepatic impairment, and the manufacturer recommends that apixaban not be used in such patients.^[1]

Renal Impairment

Pharmacokinetic (systemic exposure and peak plasma concentrations) and pharmacodynamic (inhibition of factor Xa activity) effects of apixaban do not appear to be substantially altered in patients with renal impairment (mild, moderate, or severe) compared with those with normal renal function.^[1][77]

Although results of a pharmacokinetic study showed an approximate 44% increase in systemic exposure to apixaban in patients with severe renal impairment (i.e., creatinine clearance <15 mL/minute) compared with those with normal renal function, this degree of change was considered to be modest.^[77]

In the principal clinical study of the drug, patients with moderate to severe renal impairment had higher rates of bleeding regardless of treatment (apixaban or warfarin).^[6][77]

End-stage renal disease (ESRD) patients on dialysis were not enrolled in apixaban clinical trials.^[1] The manufacturer states administration of apixaban in these patients at the usually recommended dosage results in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk.^[1]

In the settings of DVT prophylaxis following orthopedic surgery or VTE treatment and reduction in risk of recurrence, no dosage adjustment is recommended for patients with renal impairment including those with ESRD on dialysis.^[1] Clinical studies for these indications did not enroll patients with ESRD on dialysis or patients with a creatinine clearance <15 mL/minute.^[1] Dosing recommendations are based on pharmacokinetic and pharmacodynamic (anti-FXa activity) data from subjects with ESRD maintained on dialysis.^[1]

Dosage adjustment based on renal function alone does not appear to be necessary but is recommended in patients with nonvalvular atrial fibrillation and renal impairment who meet additional criteria for dosage modification.^[1][77]

Race/Ethnicity

Pharmacokinetics of apixaban do not appear to be substantially altered by race or ethnicity.^[1][42] In several studies in which healthy individuals of different ethnic or racial origins (Caucasian, Asian, and African-American) received apixaban, pharmacokinetic parameters (e.g., peak plasma concentrations, half-life, time to steady state) were similar regardless of race or ethnicity.^[1][8][42]

Common Adverse Effects

The most common adverse reactions reported with apixaban (>1%) are related to bleeding.^[1][3][5]

Apixaban is a substrate of cytochrome P-450 (CYP) 3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP).^[1]

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Apixaban is metabolized principally by CYP isoenzyme 3A4/5, and to a lesser extent by CYP isoenzymes 1A2, 2C8, 2C9, 2C19, and 2J2.^[1][15] Although pharmacokinetic interactions are possible with drugs that inhibit or induce CYP3A4/5, in vitro studies indicate that the potential may be low because of apixaban's multiple routes of elimination.^{[8][15][35][77]}

In vitro studies indicate that apixaban does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 3A4/5, or 2C19 nor induce CYP isoenzymes 1A2, 2B6, or 3A4/5; therefore, pharmacokinetic interactions are not expected with drugs that are metabolized by these isoenzymes.^[1][15]

Drugs Affecting P-glycoprotein Transport

Apixaban is a substrate of the efflux transporter P-gp; inhibitors or inducers of this transport protein may potentially alter apixaban exposure.^[1] Apixaban does not substantially inhibit P-gp.^[1]

Drugs Affecting P-glycoprotein Transport and CYP3A4

Since apixaban is a substrate of both P-gp and CYP3A4, concomitant use of drugs that inhibit P-gp and CYP3A4 can increase exposure (peak plasma concentrations and AUC) of apixaban and increase the risk of bleeding.^[1] In patients receiving apixaban dosages exceeding 2.5 mg twice daily (e.g., 5 mg twice daily), the dosage of apixaban should be reduced by 50% (e.g., from 5 mg twice daily to 2.5 mg twice daily) if concomitant therapy with potent dual inhibitors of P-gp and CYP3A4 (e.g., itraconazole, ketoconazole, ritonavir) is administered.^[1] In patients already receiving apixaban 2.5 mg twice daily, concomitant administration of potent dual inhibitors of P-gp and CYP3A4 should be avoided.^[1] While clarithromycin is an inhibitor of P-gp and a strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dosage adjustment is necessary with concomitant use of apixaban and clarithromycin.^[1] Concomitant administration of other, less potent inhibitors of CYP3A4 and P-gp (e.g., diltiazem, naproxen) also may increase exposure to apixaban.^[1][8]

Conversely, drugs that induce P-gp and CYP3A4 can reduce plasma concentrations of apixaban and increase the risk of stroke.^[1][8] Concomitant use of apixaban and potent dual inducers of P-gp and CYP3A4 (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [Hypericum perforatum]) should be avoided.^[1]

Diltiazem

Concomitant administration of apixaban and diltiazem (a moderate CYP3A4 and weak P-gp inhibitor) increased AUC and peak plasma concentrations of apixaban by 1.4- and 1.3-fold, respectively.^[8]

Ketoconazole

Concomitant administration of apixaban and ketoconazole (a strong inhibitor of both P-gp and CYP3A4) substantially increased the AUC and peak plasma concentration of apixaban by 2- and 1.6-fold, respectively.^[18] Dosage of apixaban should be reduced to 2.5 mg twice daily with such concomitant therapy.^[1] Concomitant use of apixaban and ketoconazole should be avoided in patients who have 2 or more of the following characteristics: age >=80 years, body weight <=60 kg, serum creatinine concentration >=1.5 mg/dL or in patients already requiring a 2.5 mg twice daily dosage regimen (e.g., prevention of VTE recurrence).^[1]

Naproxen

Concomitant administration of apixaban and naproxen (a P-gp inhibitor) increased AUC and peak plasma concentrations of apixaban by 1.5- and 1.6-fold, respectively.^[1][8]

Apixaban did not substantially alter the pharmacokinetics of naproxen; however, a 50-60% increase in anti-factor Xa activity was observed with such concomitant therapy.^[8]

Rifampin

Concomitant administration of apixaban and rifampin (a strong inducer of both P-gp and CYP3A4) decreased AUC and peak plasma concentrations of apixaban by 54 and 42%, respectively;^[8] concomitant use of these drugs should be avoided.^[1]

Drugs Affecting Hemostasis

Concomitant use of apixaban and drugs that affect hemostasis (e.g., aspirin or other antiplatelet drugs, heparin or other anticoagulants, fibrinolytics, selective serotonin-reuptake inhibitors [SSRIs], selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], nonsteroidal anti-inflammatory agents [NSAIAs]) increases the risk of bleeding.^[1][8][42]

Amiodarone

Efficacy and safety end points for apixaban compared with warfarin did not appear to be altered by concomitant administration of amiodarone in the principal efficacy study of apixaban in patients with nonvalvular atrial fibrillation.

Aspirin

In the principal efficacy study of apixaban, bleeding risk was increased in patients who received concomitant apixaban and aspirin therapy.^[1] Additionally, a placebo-controlled study of patients with acute coronary syndromes was terminated early after an increased risk of bleeding was observed in patients receiving apixaban in combination with aspirin and clopidogrel.^[1]

In drug interaction studies in healthy individuals, apixaban did not substantially alter the pharmacokinetics of aspirin, and a pharmacodynamic interaction was not observed with such concomitant therapy.^[1]

Atenolol

Concomitant administration of apixaban and atenolol in healthy individuals did not appreciably alter the pharmacokinetics of either drug.^[1]

Clopidogrel

No pharmacodynamic interactions (e.g., anti-factor Xa activity) were observed with concomitant apixaban and clopidogrel therapy.^[1] However, a placebo-controlled study (APPRAISE-2) of patients with acute coronary syndromes was terminated early after an increased risk of bleeding was observed in patients receiving apixaban in combination with aspirin and clopidogrel.^[1][50]

Digoxin

In drug interaction studies conducted in healthy individuals, apixaban did not substantially alter the pharmacokinetics of digoxin.^[1]

Enoxaparin

In a study in healthy individuals, concomitant administration of apixaban and enoxaparin had no effect on the pharmacokinetics of apixaban, but had an additive effect on anti-factor Xa activity.^[1][14] The increased pharmacodynamic effect was considered to be modest.^[14] When administration of apixaban and enoxaparin was separated by 6 hours in this study, the additive effect on anti-factor Xa activity was attenuated.^[14]

Famotidine

Famotidine did not substantially alter the pharmacokinetics of apixaban in healthy individuals.^[1]

Prasugrel

Concomitant administration of apixaban and prasugrel in healthy individuals did not appreciably alter the pharmacokinetics of either drug.^[1]

Apixaban is an oral, reversible, direct activated factor X (factor Xa) inhibitor.^{[1][3][5][8][28][31][32][33][35][39][42]} Factor Xa plays a central role in the blood coagulation cascade by serving as the convergence point for the intrinsic and extrinsic pathways; inhibition of coagulation factor Xa prevents conversion of prothrombin to thrombin, resulting in decreased thrombin generation and thrombus development.^[1][28][42] Unlike fondaparinux, heparin, and the low molecular weight heparins, apixaban binds directly to the active site of factor Xa with high affinity and selectivity, and does not require a cofactor (antithrombin III) for its antithrombotic activity.^[1][38][42] Apixaban inhibits free and clot-bound factor Xa and prothrombinase activity.^[1]

Apixaban exhibits linear, dose-proportional pharmacokinetics for oral doses up to 10 mg.^[1][17] The absolute bioavailability of the drug is approximately 50%, and peak plasma concentrations are reached approximately 3-4 hours after oral administration.^[1][17][28] Following oral administration of 10 mg of apixaban as 2 crushed 5-mg tablets suspended in 30 mL of water, bioavailability was similar to that after 2 intact 5-mg tablets taken orally.^[1] Following oral administration of 10 mg of apixaban as 2 crushed 5-mg tablets mixed with 30 g of applesauce, the peak plasma concentration and bioavailability of apixaban were decreased by 20 and 16%, respectively.^[1] Following administration via a nasogastric feeding tube of a single crushed 5-mg tablet suspended in 60 mL of 5% dextrose in water, bioavailability of the drug is similar to that of a whole tablet taken orally.^[1]

Apixaban has a total clearance of approximately 3.3 L/hour.^[1] Despite a short clearance half-life of about 6 hours, the apparent half-life of apixaban is longer (about 12 hours) following repeated administration because of prolonged absorption.^[1][17] Absorption of apixaban occurs throughout the GI tract, with about 55% of the drug absorbed in the distal small intestine and ascending colon.^[1] Food does not appear to affect the pharmacokinetics (systemic exposure and peak plasma concentrations) or pharmacodynamics of apixaban.^[1][17]

Apixaban is eliminated via multiple pathways, including hepatic metabolism by the cytochrome P-450 (CYP) enzyme system and through intestinal, biliary, and renal excretion; approximately 25% of an administered dose is eliminated renally.^{[1][15][16][42][77]} No active circulating metabolites have been identified.^[1] Approximately 87% of the drug is bound to plasma proteins.^[1][28] QT-interval prolongation has not been observed with apixaban doses up to 50 mg.^[1] Apixaban inhibits factor Xa activity, and prolongs prothrombin time (PT), activated partial thromboplastin time (aPTT), and the international normalized ratio (INR) in a concentration-dependent manner.^[1][8][28]

Take apixaban exactly as prescribed and do not discontinue therapy without first consulting a clinician.^[1]Advise patients on how to take the drug if they cannot swallow whole tablets or if they require a nasogastric tube.^[1]Instruct patients that if a dose is missed, to take it as soon as possible on the same day and then resume the regular twice-daily dosing schedule; do not take 2 doses at the same time.^[1]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 apixaban; advise patients on how to recognize signs and symptoms of bleeding.^[1]Inform clinicians immediately about any unusual bleeding or bruising during therapy, including menstrual or vaginal bleeding that is heavier than normal.^[1]Apixaban is generally not for patients with artificial heart valves; advise patients to inform their health care provider if they have had or will have heart valve surgery.^[1]Apixaban is not recommended for use in people with antiphospholipid syndrome (APS), especially with positive triple antibody testing; advise patients to inform their healthcare provider if they have APS.^[1]Advise patients who have had neuraxial anesthesia or spinal puncture to monitor for manifestations of spinal or epidural hematoma (e.g., numbness or weakness of legs, bowel or bladder dysfunction), particularly if they are receiving concomitant nonsteroidal anti-inflammatory agents (NSAIAs), platelet inhibitors, or other anticoagulants; inform the patient to seek emergency medical attention if any of these symptoms occur.^[1]Advise patients to inform clinicians (e.g., physicians, dentists) that they are receiving apixaban therapy before scheduling any surgery or invasive procedures, including dental procedures.^[1]Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.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.Advise patients of other important precautionary information. (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

†Use is not currently included in the labeling approved by the US Food and Drug Administration.

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