"May 31, 2013 -- More than 2 million Americans have an abnormal heart rhythm known as atrial fibrillation, raising their risk of blood clots leading to stroke. For many years, the blood thinner Coumadin (warfarin) was the only game in town to help"...
Mechanism Of Action
Apixaban is an oral, reversible, and selective active site inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. 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.
As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose, however, are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of apixaban.
The Rotachrom®Heparin chromogenic assay was used to measure the effect of apixaban on FXa activity in humans during the apixaban development program. A concentration-dependent increase in anti-FXa activity was observed in the dose range tested and was similar in healthy subjects and patients with AF.
This test is not recommended for assessing the anticoagulant effect of apixaban.
Pharmacodynamic Drug Interaction Studies
Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin and clopidogrel, prasugrel, enoxaparin, and naproxen were conducted. No pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel [see WARNINGS AND PRECAUTIONS]. A 50% to 60% increase in anti-FXa activity was observed when apixaban was coadministered with enoxaparin or naproxen.
Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across renal function categories.
Hepatic impairment: Changes in anti-FXa activity were similar in patients with mild-tomoderate hepatic impairment and healthy subjects. However, in patients with moderate hepatic impairment, there is no clear understanding of the impact of this degree of hepatic function impairment on the coagulation cascade and its relationship to efficacy and bleeding. Patients with severe hepatic impairment were not studied.
Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.
The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of ELIQUIS. Food does not affect the bioavailability of apixaban. Maximum concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration of ELIQUIS. Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 mg. At doses ≥ 25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability.
Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
Approximately 25% of an orally administered apixaban dose is recovered in urine and feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation.
Unchanged apixaban is the major drug-related component in human plasma; there are no active circulating metabolites.
Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces.
Apixaban has a total clearance of approximately 3.3 L/hour and an apparent half-life of approximately 12 hours following oral administration.
Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance protein.
Drug Interaction Studies
In vitro apixaban studies at concentrations significantly greater than therapeutic exposures, no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of CYP1A2, CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp.
Figure 2: Effect of Coadministered Drugs on the Pharmacokinetics of Apixaban
* Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations. Dosing recommendations were also informed by clinical considerations [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, and enoxaparin did not meaningfully alter the pharmacokinetics of apixaban.
In studies conducted in healthy subjects, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid.
The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of apixaban are summarized in Figure 3.
Figure 3: Effect of Specific Populations on the
Pharmacokinetics of Apixaban
* ESRD subjects maintained with
chronic and stable hemodialysis; reported PK findings are following single dose
of apixaban post hemodialysis.
† Creatinine clearance 15 to 29 mL/min.
‡ Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations.
A study in healthy subjects comparing the pharmacokinetics in males and females showed no meaningful difference.
The results across pharmacokinetic studies in normal subjects showed no differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/African American subjects. No dose adjustment is required based on race/ethnicity.
In subjects with ESRD, a 4-hour hemodialysis session with a dialysate flow rate of 500 mL/min and a blood flow rate in the range of 350 to 500 mL/min started 2 hours after administration of a single 5 mg dose of apixaban, the AUC of apixaban was 17% greater compared to those with normal renal function. The dialysis clearance of apixaban is approximately 18 mL/min resulting in a 14% decrease in exposure due to hemodialysis compared to off-dialysis period.
Protein binding was similar (92%-94%) between healthy controls and the on-dialysis and off-dialysis periods.
Evidence for the efficacy and safety of ELIQUIS was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular AF comparing the effects of ELIQUIS and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. In ARISTOTLE, patients were randomized to ELIQUIS 5 mg orally twice daily (or 2.5 mg twice daily in subjects with at least 2 of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL) or to warfarin (targeted to an INR range of 2.0-3.0). Patients had to have one or more of the following additional risk factors for stroke:
- prior stroke or transient ischemic attack (TIA)
- prior systemic embolism
- age ≥ 75 years
- arterial hypertension requiring treatment
- diabetes mellitus
- heart failure ≥ New York Heart Association Class 2
- left ventricular ejection fraction ≤ 40%
The primary objective of ARISTOTLE was to determine whether ELIQUIS 5 mg twice daily (or 2.5 mg twice daily) was effective (noninferior 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.
A total of 18,201 patients were randomized and followed on study treatment for a median of 89 weeks. Forty-three percent of patients were vitamin K antagonist (VKA) “naive,” defined as having received ≤ 30 consecutive days of treatment with warfarin or another VKA before entering the study. The mean age was 69 years and the mean CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk) was 2.1. The population was 65% male, 83% Caucasian, 14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 19% of patients. Concomitant diseases of patients in this study included hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular ejection fraction ≤ 40%) 35%, and prior myocardial infarction 14%. Patients treated with warfarin in ARISTOTLE had a mean percentage of time in therapeutic range (INR 2.0-3.0) of 62%.
ELIQUIS was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Table 3 and Figure 4). Superiority to warfarin was primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs.
ELIQUIS also showed significantly fewer major bleeds than warfarin [see ADVERSE REACTIONS].
Table 3: Key Efficacy
Outcomes in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE
|Hazard Ratio (95% CI)||P-value|
|Stroke or systemic embolism||212 (1.27)||265 (1.60)||0.79 (0.66, 0.95)||0.01|
|Stroke||199 (1.19)||250 (1.51)||0.79 (0.65, 0.95)|
|Ischemic without hemorrhage||140 (0.83)||136 (0.82)||1.02 (0.81, 1.29)|
|Ischemic with hemorrhagic conversion||12 (0.07)||20 (0.12)||0.60 (0.29, 1.23)|
|Hemorrhagic||40 (0.24)||78 (0.47)||0.51 (0.35, 0.75)|
|Unknown||14 (0.08)||21 (0.13)||0.65 (0.33, 1.29)|
|Systemic embolism||15 (0.09)||17 (0.10)||0.87 (0.44, 1.75)|
The primary endpoint was based on the time to first event (one per subject). Component counts are for subjects with any event, not necessarily the first.
Figure 4: Kaplan-Meier
Estimate of Time to First Stroke or Systemic Embolism in ARISTOTLE
All-cause death was assessed using a sequential testing strategy that allowed testing for superiority if effects on earlier endpoints (stroke plus systemic embolus and major bleeding) were demonstrated. ELIQUIS treatment 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.
In ARISTOTLE, the results for the primary efficacy endpoint were generally consistent across most major subgroups including weight, CHADS2 score (a scale from 0 to 6 used to predict risk of stroke in patients with AF, with higher scores predicting greater risk), prior warfarin use, level of renal impairment, geographic region, ELIQUIS dose, type of AF, and aspirin use at randomization (Figure 5).
Figure 5: Stroke and Systemic Embolism Hazard Ratios
by Baseline Characteristics – ARISTOTLE Study
At the end of the ARISTOTLE study, warfarin patients who completed the study were generally maintained on a VKA with no interruption of anticoagulation. ELIQUIS patients who completed the study were generally switched to a VKA with a 2-day period of coadministration of ELIQUIS and VKA, so that some patients may not have been adequately anticoagulated after stopping ELIQUIS until attaining a stable and therapeutic INR. During the 30 days following the end of the study, there were 21 stroke or systemic embolism events in the 6791 patients (0.3%) in the ELIQUIS arm compared to 5 in the 6569 patients (0.1%) in the warfarin arm [see DOSAGE AND ADMINISTRATION].
In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates for warfarin therapy 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 (Table 4) [see ADVERSE REACTIONS].
Table 4: Key Efficacy
Outcomes in Patients with Nonvalvular Atrial Fibrillation in AVERROES
|Hazard Ratio (95% CI)||P-value|
|Stroke or systemic embolism||51 (1.62)||113 (3.63)||0.45 (0.32, 0.62)||< 0.0001|
|Ischemic or undetermined||43 (1.37)||97 (3.11)||0.44 (0.31, 0.63)||-|
|Hemorrhagic||6 (0.19)||9 (0.28)||0.67 (0.24, 1.88)||-|
|Systemic embolism||2 (0.06)||13 (0.41)||0.15 (0.03, 0.68)||-|
|MI||24 (0.76)||28 (0.89)||0.86 (0.50, 1.48)||-|
|All-cause death||111 (3.51)||140 (4.42)||0.79 (0.62, 1.02)||0.068|
|Vascular death||84 (2.65)||96 (3.03)||0.87 (0.65, 1.17)||-|
Last reviewed on RxList: 2/10/2014
This monograph has been modified to include the generic and brand name in many instances.
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