Apixaban: A Novel Oral Inhibitor of Factor Xa

Edith Nutescu, Pharm.D., FCCP

Disclosures

Am J Health Syst Pharm. 2012;69(13):1113-1126. 

In This Article

Abstract and Introduction

Abstract

Purpose The pharmacology, pharmacokinetics, efficacy, and safety of apixaban are reviewed.
Summary Apixaban is an oral, direct, selective factor Xa inhibitor with a rapid onset of action. It has a plasma elimination half-life of 12 hours and has been administered in a twice-daily dosing regimen in clinical trials without the need for anticoagulation monitoring or dosage adjustment. Apixaban has multiple elimination pathways, and its pharmacokinetics is not substantially altered by patient age, sex, race, or ethnicity. The results of three Phase III trials indicated that apixaban was similar to or more effective than enoxaparin for preventing venous thromboembolism (VTE) in patients undergoing total hip or knee replacement, with similar or lower rates of bleeding. Two Phase III trials found that apixaban was more effective for stroke prevention than either aspirin or warfarin in patients with atrial fibrillation (AF), with a similar (versus aspirin) or improved (versus warfarin) safety profile. A Phase III trial evaluating apixaban plus antiplatelet monotherapy or dual-antiplatelet therapy in patients with acute coronary syndrome ended early due to clear evidence of a clinically important increase in bleeding among patients randomized to apixaban without any meaningful reduction in ischemic events. The adverse-event profiles for apixaban and comparators have been similar in studies conducted to date.
Conclusion Apixaban, a new anticoagulant, appears to offer an efficacy and safety profile comparable with that of enoxaparin for preventing VTE after orthopedic surgery, with the advantage of oral administration. In patients with AF, apixaban is more effective than either warfarin or aspirin for stroke prevention, with an acceptable safety profile.

Introduction

Thromboembolic diseases are a common cause of mortality and morbidity. Venous thromboembolism (VTE) (deep vein thrombosis and pulmonary embolism) occurs in 1–2 adults per 1000 in the United States each year.[1,2] VTE also is a deadly disease, mostly owing to pulmonary embolism. The one-month mortality rate for patients with pulmonary embolism has been reported to be 12.9%.[3] In 2006, 733,000 people in the United States experienced acute coronary syndrome (ACS), including myocardial infarction and unstable angina. Six percent of Medicare recipients age 65 years and older have been diagnosed with atrial fibrillation (AF), an arrhythmia that accounts for 15–20% of all ischemic strokes.[4] An estimated 2.2% of all strokes are attributable to AF, meaning that approximately 17,500 of the 795,000 strokes that occur annually in the United States are a result of AF.[5]

Anticoagulants are effective for the prevention and treatment of thromboembolic disorders; however, conventional agents have several limitations. Parenteral anticoagulants such as unfractionated heparin, low-molecular-weight heparins (LMWHs), and the indirect factor Xa inhibitor fondaparinux are effective in the prevention and initial treatment of VTE and the management of ACS, but their need for subcutaneous injection is inconvenient for long-term use. Nevertheless, injected LMWHs are used for long-term treatment in some patients (e.g., those with cancer or who are receiving broad-spectrum antibiotics).[6] The inconvenience of parenteral anticoagulant administration may contribute to inadequate provision of VTE prophylaxis in many settings (e.g., after discharge from the hospital after major orthopedic surgery).[7] Vitamin K antagonists have disadvantages, such as variability in dose response, a low therapeutic index, monitoring requirements, and numerous drug and dietary interactions, but until recently they have been the only effective option for oral therapy in most patients requiring long-term anticoagulation.[8,9] Vitamin K antagonists tend to be underutilized, mainly due to their complexity of use, concerns about complications, and the amount of time patients' anticoagulation- related laboratory test values are outside the target range when these drugs are used.[10,11,12] This is a concern to providers and patients, as poor anticoagulation control has been associated with bleeding and thrombotic complications.[13,14,15,16] There has long been an unmet need for a convenient, orally administered, rapidly acting, reversible, safe, and effective anticoagulant with a high therapeutic index, little or no requirement for monitoring, pharmacokinetics that limits the requirement for dose adjustments in special patient populations, and limited potential for clinically important drug–drug interactions.

Several novel oral anticoagulants have been recently approved or are in clinical development. These include the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, edoxaban, and apixaban.[7] Rivaroxaban and dabigatran are approved in Europe and Canada for the prevention of VTE in patients undergoing hip or knee replacement surgery.[17,18] Dabigatran was approved in October 2010 in the United States and Canada for the prevention of stroke in patients with AF and is also approved in Europe for this indication.[19] Rivaroxaban was approved for the prevention of VTE in the United States in July 2011 and for stroke prevention in AF in November 2011.[20] This review focuses on the pharmacokinetics and pharmacodynamic properties of apixaban (a pix' a ban) (Eliquis, Bristol-Myers Squibb/Pfizer) and the clinical efficacy and safety results from studies of its use in patients with or at risk for VTE, patients with ACS, and patients with AF who are at risk for cerebrovascular events. This review is timely since new results from Phase III trials of apixaban have recently been reported in patients undergoing total knee replacement or total hip replacement and in patients with AF receiving prophylaxis against ischemic stroke. Apixaban was approved by the European Medications Agency for the prevention of VTE in patients undergoing total knee replacement or total hip replacement in May 2011.[21] A new drug application for apixaban for stroke prophylaxis in patients with nonvalvular AF was submitted to the Food and Drug Administration (FDA) in 2011.[22]

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