Eliquis (apixaban) - 3 indications

Scroll down for more information on each indication:

• to reduce the risk of stroke and systemic embolism resulting from nonvalvular atrial fibrillation; approved December 2012
• for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; approved March of 2014
• for the treatment of DVT and PE and the reduction in risk of DVT and PE following initial therapy; approved August of 2014

General Information

Eliquis (apixaban) is an orally available Factor Xa antagonist. 

Eliquis is specifically indicated for the following:

• to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery
• for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following initial therapy

Eliquis is supplied as a tablet for oral administration. Scroll down for recommended dosing/administration for each indication.

Mechanism of Action

Eliquis (apixaban) is an orally available Factor Xa antagonist. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development.

Side Effects

The most common adverse reactions to the use of Eliquis for all indications are related to bleeding.

The Eliquis drug label comes with the following Black Box Warning: Premature discontinuation of any oral anticoagulant, including Eliquis, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if Eliquis is discontinued for a reason other than pathological bleeding or completion of a course of therapy. Epidural or spinal hematomas may occur in patients treated with Eliquis who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. 

Indication 1 - to reduce the risk of stroke and systemic embolism resulting from nonvalvular atrial fibrillation

approved December 2012

Dosing/Administration

The recommended dose is 5 mg orally twice daily. In patients with at least 2 of the following characteristics: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or serum creatinine greater than or equal to 1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily

Clinical Trial Results

ARISTOTLE
This multinational, double-blind study enrolled 18,201 subjects with nonvalvular atrial fibrillation (AF). The subjects were randomized to Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in subjects meeting certain parameters- see above) or to warfarin . The trial was designed to compare the effects of Eliquis and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. The primary endpint was the non-inferiority of Eliquis to warfarin in reducing the risk of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of Eliquis to warfarin was also examined for the primary endpoint (rate of stroke and systemic embolism), major bleeding, and death from any cause. The subjects were followed for a median of 89 weeks. Eliquis was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Eliquis: 212 subjects (1.27%) versus warfarin (265 subjects (1.60%); p=0.01). Eliquis also showed significantly fewer major bleeds than warfarin. Eliquis also resulted in a significantly lower rate of all-cause death (p = 0.046) than did treatment with warfarin, primarily because of a reduction in cardiovascular death, particularly stroke deaths. Non-vascular death rates were similar in the treatment arms.
AVERROES
This trial enrolled 5,598 subjects with nonvalvular atrial fibrillation thought not to be candidates for warfarin therapy. Subjects were randomized to treatment with Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in selected patients) or aspirin 81 to 324 mg once daily. The primary objective of the study was to determine if Eliquis was superior to aspirin for preventing the composite outcome of stroke or systemic embolism. AVERROES was stopped early on the basis of a prespecified interim analysis showing a significant reduction in stroke and systemic embolism for Eliquis compared to aspirin that was associated with a modest increase in major bleeding.

Indication 2 - for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery

approved March of 2014

Dosing/Administration

The recommended dose is 2.5 mg orally twice daily.

Clinical Trial Results

FDA approval was based on the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical trials in adult patients undergoing elective hip (ADVANCE-3) or knee (ADVANCE-2 and ADVANCE-1) replacement surgery. A total of 11,659 patients were randomized in 3 double-blind, multi-national studies. Included in this total were 1866 patients age 75 or older, 1161 patients with low body weight (≤60 kg), 2528 patients with Body Mass Index ≥33 kg/m2, and 625 patients with severe or moderate renal impairment. In the ADVANCE-3 study, 5407 patients undergoing elective hip replacement surgery were randomized to receive either Eliquis 2.5 mg orally twice daily or enoxaparin 40 mg subcutaneously once daily. The first dose of Eliquis was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Treatment duration was 32 to 38 days. In patients undergoing elective knee replacement surgery, Eliquis 2.5 mg orally twice daily was compared to enoxaparin 40 mg subcutaneously once daily (ADVANCE-2, N=3057) or enoxaparin 30 mg subcutaneously every 12 hours (ADVANCE-1, N=3195). In the ADVANCE-2 study, the first dose of Eliquis was given 12 to 24 hours post surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. In the ADVANCE-1 study, both Eliquis and enoxaparin were initiated 12 to 24 hours post surgery. Treatment duration in both ADVANCE-2 and ADVANCE-1 was 10 to 14 days. In all 3 studies, the primary endpoint was a composite of adjudicated asymptomatic and symptomatic DVT, nonfatal PE, and all-cause death at the end of the double-blind intended treatment period. In ADVANCE-3 and ADVANCE-2, the primary endpoint was tested for noninferiority, then superiority, of Eliquis to enoxaparin. In ADVANCE-1, the primary endpoint was tested for noninferiority of Eliquis to enoxaparin.

Indication 3 - for the treatment of DVT and PE and reduction in the risk of recurrent DVT and PE following initial therapy

approved August of 2014

Dosing/Administration

Treatment of DVT and PE:

• the recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.

Reduction in the risk of recurrent DVT and PE following initial therapy:

• the recommended dose is 2.5 mg taken orally twice daily

Clinical Trial Results

FDA approval was based on the AMPLIFY and AMPLIFY-EXT studies. Both studies were randomized, parallel-group, double-blind trials in patients with symptomatic proximal DVT and/or symptomatic PE. All key safety and efficacy endpoints were adjudicated in a blinded manner by an independent committee. 

AMPLIFY: The primary objective of AMPLIFY was to determine whether Eliquis was noninferior to enoxaparin/warfarin for the incidence of recurrent VTE (venous thromboembolism) or VTE-related death. Patients with an objectively confirmed symptomatic DVT and/or PE were randomized to treatment with Eliquis 10 mg twice daily orally for 7 days followed by Eliquis 5 mg twice daily orally for 6 months, or enoxaparin 1 mg/kg twice daily subcutaneously for at least 5 days (until INR ≥2) followed by warfarin (target INR range 2.0-3.0) orally for 6 months. A total of 5244 patients were evaluable for efficacy and were followed for a mean of 154 days in the Eliquis group and 152 days in the enoxaparin/warfarin group. Eliquis was shown to be noninferior to enoxaparin/warfarin in the AMPLIFY study for the primary endpoint of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy.