Apixaban: A Novel Oral Inhibitor of Factor Xa

Edith Nutescu, Pharm.D., FCCP

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

Pharmacology and Monitoring

Pharmacology

Apixaban is an oral, direct, selective factor Xa inhibitor.^[23] In vitro, apixaban is potent and selective, with an equilibrium dissociation constant of 0.08 nm for human factor Xa. It also inhibits clot-bound factor Xa in vitro.^[23,24] Apixaban has been shown to be effective in the prevention of experimental venous and arterial thrombosis at doses that preserved hemostasis in rabbits.^[25] Results from additional studies have shown that bleeding times were lower with apixaban compared with dabigatran at equivalent antithrombotic doses^[26] and that the combination of apixaban and aspirin or of apixaban, aspirin, and clopidogrel reduced the formation of occlusive arterial thromboses without excessive increases in bleeding time in rabbits.^[27]

Monitoring

When tested in human plasma, apixaban produced concentration-dependent increases in the activated partial thromboplastin time (aPTT), modified pro-thrombin time, and Heptest.^[27] The modified prothrombin time and the Heptest (Heptest Laboratories, St. Louis, MO) appear to be 10- to 20-fold more sensitive than the aPTT or prothrombin time for assessing the anticoagulant effect of apixaban; however, commercially available tests for prothrombin time or the International Normalized Ratio (INR) are not appropriate for monitoring factor Xa inhibitors as these values are highly variable and inconsistent. Results from a study using human plasma samples to which bovine factor Xa had been added and evaluated using a Rotachrom assay (Diagnostica Stago, Parsippany, NJ) indicated that apixaban 100 ng/mL resulted in an approximately 45% decrease in factor Xa activity, and apixaban 1000 ng/mL inhibited factor Xa activity by about 90%.^[28]

Apixaban does not require routine laboratory monitoring in the majority of patients. However, like other novel anticoagulants, there may be special patient circumstances or clinical scenarios where knowing the patient's anticoagulant status may be beneficial or necessary (e.g., serious bleeding into critical organs, potential overdose, emergency surgery).^[28,29]

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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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