Apixaban for the prophylaxis and treatment of deep vein thrombosis and pulmonary embolism: an evidence-based review

Figures & data

Table 1 Apixaban pharmacokinetics and pharmacodynamics^13,15–17

Mechanism of action	Factor Xa inhibitor
Bioavailability	50%, gastrointestinal
T (max)	3–4 hours
Distribution	87% protein bound
Half-life	8–13 hours (prolonged in renal impairment)
Monitoring	None required. Anti-Xa assay useful in determining if anticoagulant effect present
Dosing	Nonvalvular atrial fibrillation: 5 mg twice daily
	THR prophylaxis: 2.5 mg twice daily for 35 days
	TKR prophylaxis: 2.5 mg twice daily for 12 days
	VTE treatment: 10 mg twice daily for 7 days, then 5 mg twice daily
	Prophylaxis of recurrent VTE: 2.5 mg twice daily after at least 6 months of treatment
Dose adjustments	In patients with nonvalvular atrial fibrillation and at least two of the following: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, recommended dose is 2.5 mg twice daily
Metabolism	Hepatic CYP3A4 system
Elimination	25% renal, 75% biliary
Drug interactions	Potent P-gp and CYP3A4 inhibitors or inducers

Abbreviations: THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism; P-glycoprotein.

Table 2 Apixaban clinical trial data for VTE

Study	Year	Design	Study population	Intervention	Comparator	Primary efficacy outcome (apixaban vs comparator)	Primary safety outcome	Follow-up (years)	Authors conclusions
ADVANCE-1^Citation19	2009	Multicenter, randomized, double-blind, double-dummy, noninferiority and superiority	TKR	Apixaban 2.5 mg twice daily	Enoxaparin 30 mg every 12 hours	Composite of all cause VTE (symptomatic and asymptomatic DVT, nonfatal PE) and all-cause death: 9.0% vs 8.8% (RR 1.02, 95% CI 0.78–1.32)	Major bleeding: 0.7% vs 1.4% (P=0.05) Composite (major bleeding and clinically relevant nonmajor bleeding): 2.9% vs 4.3% (P=0.03)	60 days after cessation of study drug	Efficacy: noninferiority not established Safety: lower rates of clinically relevant bleeding compared to LMWH
ADVANCE-2^Citation20	2010	Multicenter, randomized, double-blind, noninferiority and superiority	TKR	Apixaban 2.5 mg twice daily	Enoxaparin 40 mg daily	Composite of all VTE and all-cause death: 15.1% vs 24.4% (RR 0.62, 95% CI 0.51–0.74)	Major bleeding: 0.6% vs 0.9% (P=0.3014)	60 days after cessation of study drug	Efficacy: noninferiority established; superiority established compared to LMWH Safety: no difference in major bleeding between the two treatment groups
ADVANCE-3^Citation23	2010	Multicenter, randomized, double-blind, double-dummy, noninferiority and superiority	THR	Apixaban 2.5 mg twice daily	Enoxaparin 40 mg daily	Composite of all VTE and all-cause death: 1.4% vs 3.9% (RR 0.36, 95% CI 0.22–0.54)	Major bleeding: 0.8% vs 0.7% (P=0.54) Composite (major bleeding and clinically relevant nonmajor bleeding): 4.8% vs 5.0% (P=0.72)	60 days after cessation of study drug	Efficacy: noninferiority established; superiority established compared to LMWH Safety: no difference in major bleeding between the two treatment groups
AMPLIFY^Citation24	2013	Multicenter, randomized, double-blind, noninferiority and superiority	Acute VTE	Apixaban 10 mg bid for 7 days followed by 5 mg bid	Enoxaparin 1.0 mg/kg every 12 hours for ≥5 days plus VKA initiated ≤48 hours after randomization	Composite of recurrent symptomatic VTE or VTE-related death: 2.3% vs 2.7% (RR 0.84, 95% CI 0.60–1.18)	Major bleeding: 0.6% vs 1.8% (RR 0.31, 95% CI 0.17–0.55)	6 months	Efficacy: noninferiority Established Safety: superiority established compared to LMWH
AMPLIFY-EXT^Citation25	2013	Multicenter, randomized, double-blind, superiority	VTE after 6–12 months of treatment	Apixaban 2.5 mg or 5 mg twice daily	Placebo	Composite of recurrent symptomatic VTE or death from any cause: 3.8% (apixaban 2.5 mg) vs 4.2% (apixaban 5 mg) vs 11.6% (placebo); RR Apixaban 2.5 mg vs placebo: 0.33 (95% CI 0.22–0.48); RR Apixaban 5 mg vs placebo: 0.36 (95% CI 0.25–0.53)	Major bleeding: 0.2% (2.5 mg) vs 0.1% (5 mg) vs 0.5% (placebo); RR Apixaban 2.5 mg vs placebo: 0.49 (95% CI 0.09–2.64); RR Apixaban 5 mg vs placebo: 0.25 (95% CI 0.03–2.24); RR Apixaban 2.5mg vs 5 mg 1.93 (95% CI 0.18–21.25)	1 year	Efficacy: superiority established compared to placebo for both doses of apixaban Safety: no increased rate of major bleeding

Abbreviations: THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; RR, relative risk; CI, confidence interval; LMWH, low molecular weight heparin; VKA, vitamin K antagonist; bid, twice daily.

Table 3 Effect of apixaban on coagulation assays^26,27

Measurement	Effect
PT	Prolonged, dose-dependent
PTT	Prolonged, dose-dependent
INR	Increased, dose-dependent
PTT-based lupus anticoagulant	Prolonged, dose-dependent
dRVVT	Prolonged, dose-dependent
Thrombin time	No effect
Protein C activity	No effect
Free protein S antigen	No effect
Fibrinogen	No effect
Antithrombin	Potential effect depending upon specific assay
Factor Xa assay	Linear correlation, high sensitivity

Abbreviations: PT, prothrombin time; PTT, partial thromboplastin time; INR, international normalized ratio; dRVVT, dilute Russell’s viper venom time.

Table 4 Perioperative recommendations^13,28–31

	Renal function	Low bleeding risk or minor surgery	High bleeding risk or major surgery
Preoperative management	CrCl >50 mL/min	Hold 24 hours prior to surgery (skip two doses)	Hold 48 hours prior to surgery (skip four doses)
	CrCl 30–50 mL/min	Hold 48 hours prior to surgery (skip four doses)	Hold 72 hours prior to surgery (skip six doses)
Postoperative management	CrCl >50 mL/min or CrCl 30–50 mL/min	Resume 24 hours postoperative	Resume 48–72 hours postoperative

Abbreviation: CrCl, creatinine clearance.

Table 5 Risk stratification for perioperative arterial or venous thromboembolism^29,30

Risk stratification	High	Intermediate	Low
	• Any mechanical mitral valve • Mitral/aortic caged ball or tilting disc valve • MHV with history of stroke or TIA in previous 6 months • CHADS2 >5 • Atrial fibrillation with history of stroke or TIA in previous 3 months • Recent (within 3 months) VTE • Deficiency of protein C, protein S, or antithrombin • Presence of antiphospholipid antibodies	• Bileaflet AVR plus major risk factors for stroke • CHADS2 score of 3 or 4 • VTE within 3–12 months • Heterozygous factor V Leiden, prothrombin gene mutation • Active cancer (treatment within 6 months or palliative) • Recurrent VTE	• Bileaflet AVR without major risk factors for stroke • CHADS2 score of 0–2 • No prior stroke or TIA • No VTE in previous 12 months
Anticoagulation recommendations	Bridging anticoagulation recommended	Bridging anticoagulation if low bleeding risk	Bridging anticoagulation not required

Abbreviations: VTE, venous thromboembolism; ATE, arterial thromboembolism; AVR, aortic valve replacement; MHV, mechanical heart valve; CHADS₂, congestive heart failure, hypertension, age >75 years, diabetes mellitus, stroke history; TIA, transient ischemic attack.

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