Apixaban: A Novel Oral Inhibitor of Factor Xa

Edith Nutescu, Pharm.D., FCCP

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

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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Next Section

Abstract and Introduction
Pharmacology and Monitoring
Pharmacokinetics
Efficacy and Safety
Comparison of Apixaban With Other New Oral Anticoagulants
Place in Therapy
Conclusion
References

Table 1. Summary of Clinical Trial Design for Phase III Trials of Apixaban for Prevention of Venous Thromboembolism in Patients Undergoing Total Knee or Total Hip Replacement ^a
Study Characteristic	ADVANCE-1⁴⁹ (n = 3195)	ADVANCE-2⁵⁰ (n = 3057)	ADVANCE-3⁵¹ (n = 5407)
Type of surgery	Total knee replacement	Total knee replacement	Total hip replacement
Dosage of s.c. enoxaparin sodium	30 mg twice daily	40 mg once daily	40 mg once daily
Time after surgery of first study dose (hr)	12–24	12	12
Treatment duration (days)	10–14	10–14	35

^a The dosage of apixaban in all trials was 2.5 mg orally twice daily, starting 12–24 hours after surgery.

Table 2. Phase III Trials of Apixaban for Indications Other Than Prevention of Venous Thromboembolism After Total Knee or Total Hip Replacement ^a
Study	n	Indication	Treatment
ADOPT⁵⁶	6,524	Prevention of VTE or VTE-related death in acutely ill medical patients during and following hospitalization	Apixaban 2.5 mg orally twice daily for 30 days Enoxaparin sodium 40 mg s.c. once daily for 6–14 days
AMPLIFY⁵⁷	4,816	Treatment of symptomatic DVT or PE	Apixaban 10 mg orally twice daily for 7 days followed by 5 mg twice daily for 6 mo S.C. enoxaparin, followed by oral warfarin for 6 mo
AMPLIFY-EXT⁵⁸	2,430	Extended treatment for patients who have completed their usual treatment for DVT or PE	Apixaban 2.5 or 5 mg orally twice daily for 12 mo Placebo
AVERROES⁵⁹	5,599	Prevention of stroke and systemic embolism in patients with nonvalvular AF and ≥1 stroke risk factor who are not candidates for vitamin K antagonists	Apixaban 5 mg orally twice daily (2.5 mg twice daily in selected patients) Aspirin 81–324 mg orally once daily Duration determined by events
ARISTOTLE^60,61	18,206	Prevention of stroke and systemic embolism in patients with nonvalvular AF and ≥1 stroke risk factor	Apixaban 5 mg orally twice daily Warfarin orally Duration determined by events
APPRAISE-2⁶²	10,800	Prevention of cardiovascular death, nonfatal myocardial infarction, or ischemic stroke in patients with a recent ACS event	Apixaban 5 mg twice daily plus standard care Placebo plus standard care Duration determined by events

^a VTE = venous thromboembolism, DVT = deep vein thrombosis, PE = pulmonary embolism, AF = atrial fibrillation, ACS = acute coronary syndrome.

Table 3. Comparative Frequencies of Adverse Events in Two Clinical Trials Involving Apixaban ^a
Variable	Apixaban (n = 2673)	Comparator (n = 2659)
ADVANCE-3 ^51,b
No. (%) pts with adverse event	1752 (65.5)	1811 (68.1)
No. (%) pts with serious adverse events^c	184 (6.9)	172 (6.5)
No. (%) pts with treatment discontinued due to adverse events	91 (3.4)	111 (4.2)
No. (%) pts with bleeding	268 (10.0)	268 (10.1)
Fraction (%) pts with ALT and AST of >3 × ULN on same date	37/2635 (1.4)	46/2620 (1.8)
Fraction (%) pts with TSB of >2 × ULN	27/2635 (1.0)	13/2620 (0.5)
Fraction (%) pts with ALT or AST of >3 × ULN and TSB of >2 ×ULN on same date	10/2634 (0.4)	4/2619 (0.2)
No. (%) pts with myocardial infarction	9 (0.3)	4 (0.2)
No. (%) pts with stroke	1 (<0.1)	5 (0.2)
No. (%) pts with thrombocytopenia^d	3 (0.1)	5 (0.2)
ARISTOTLE ^61,e
No. (%) pts with adverse event	7406 (81.5)	7521 (83.1)
No. (%) pts with serious adverse event	3182 (35.0)	3302 (36.5)
No. (%) pts with atrial fibrillation^f	301 (3.3)	287 (3.2)
No. (%) pts with pneumonia^f	202 (2.2)	231 (2.6)
No. (%) pts with treatment discontinued due to adverse events	688 (7.6)	758 (8.4)
Fraction (%) pts with ALT or AST of >3 × ULN and TSB of >2 × ULN	30/8788 (0.3)	31/8756 (0.4)
Fraction (%) pts with ALT or AST of >3 × ULN, TSB of >2 × ULN, and ALP of >2 × ULN	17/8786 (0.2)	19/8755 (0.2)
Fraction (%) pts with ALT of >3 × ULN	100/8790 (1.1)	89/8759 (1.0)
Fraction (%) pts with ALT of >5 × ULN	45/8790 (0.5)	47/8759 (0.5)
Fraction (%) pts with ALT of >10 × ULN	16/8790 (0.2)	20/8759 (0.2)
Fraction (%) pts with ALT of >20 × ULN	8/8790 (<0.1)	12/8759 (0.1)

^a ALT = alanine transaminase, AST = aspartate transaminase, ULN = upper limit of normal range, TSB = total serum bilirubin, ALP = alkaline phosphatase.
^b Comparator was enoxaparin. Unless otherwise noted, n = 2673 for the apixaban group and 2659 for the enoxaparin group.
^c No category of serious adverse event occurred in ≥1% of patients.
^d Thrombocytopenia was defined as a decline in the platelet count to <100,000 platelets/mm³ in patients with a postoperative count of >150,000 platelets/mm³ or a >50% decline in platelet count if the postoperative count was ≤150,000 platelets/mm³.
^e Comparator was warfarin. Unless otherwise noted, n = 9088 for the apixaban group and 9052 for the warfarin group; included the safety population of patients who received at least one dose of the study drug.
^f Among adverse events reported in ≥1% of patients in either treatment group (other than events collected on the case report form).

Table 4. Pharmacokinetics of Apixaban, Rivaroxaban, and Dabigatran ^{17,18,30,31,39,75–80}
Drug	Class	Prodrug	Oral Bioavailability (%)	Excretion (%)	Half-life (hr)
Rivaroxaban	Direct anti-Xa, selective, reversible	No	100	Renal, 67; fecal, 33	6–9; 12–13 in elderly
Apixaban	Direct anti-Xa, selective, reversible	No	66	Renal, 25; fecal, 56	12; 12–15 in elderly
Dabigatran	Direct anti-IIa, selective, reversible	Yes	6.5	Renal, 80	14–17⁷⁵ or 12–14¹⁷; 12–14 in elderly

Table 5. Findings and Approval Status of Apixaban, Dabigatran, and Rivaroxaban for Indications Considered for Apixaban ^a
Indication	Approval Status
Indication	Apixaban	Dabigatran	Rivaroxaban
Total knee or hip replacement	Approved in Europe	Approved in Europe	Approved in Europe and United States
Stroke	Superior to aspirin with no significant increase in risk for major bleeding in AVERROES⁵⁹; superior to warfarin with significantly lower risk for major bleeding in ARISTOTLE⁶¹	Approved in Europe and United States	Approved in United States
Acute coronary syndrome	Abandoned	Not currently being pursued^b	In ATLAS-ACS TIMI 46, trend toward superiority over placebo for decreasing risk for primary composite endpoint of death, MI, stroke, and severe recurrent ischemia requiring revascularization. Also increased risk of bleeding¹⁰⁵ Currently in ATLAS-ACS 2 TIMI 51¹⁰⁶
Treatment of symptomatic VTE	No significant difference in efficacy or safety vs. LMWH followed by vitamin K antagonist in Botticelli DVT study⁶⁴; currently being evaluated in AMPLIFY^57,58,100	Noninferior to warfarin for the treatment of acute VTE and no significant between-treatment difference for all bleeding events¹⁰⁰	No significant difference in efficacy or bleeding risk vs. patients treated with rivaroxaban vs. enoxaparin followed by vitamin K antagonist¹⁰⁷ No significant difference in efficacy or bleeding risk vs. patients treated with rivaroxaban vs. LMWH followed by vitamin K antagonist¹⁰⁸ Noninferior and no significant difference in bleeding risk vs. LMWH followed by warfarin in EINSTEIN trial^101,109
Prevention of VTE in acutely ill hospitalized patients	Currently being evaluated in ADOPT⁵⁶	Not currently being pursued^b	Currently being evaluated in MAGELLAN study¹¹⁰

^a MI = myocardial infarction, VTE = venous thromboembolism, LMWH = low-molecular-weight heparin.
^b Based on review of studies listed on ClinicalTrials.gov.

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