The role of factor Xa inhibitors in venous thromboembolism treatment

Figures & data

Table 1 Factor-Xa inhibitor’s pharmacokinetic and pharmacodynamic characteristics

	Rivaroxaban	Apixaban	Edoxaban
VTE dose	15 mg BID ×3 weeks, then 20 mg once daily	10 mg BID ×7 days, then 5 mg BID	60 mg QD after 7–10 days heparin
Renal dose adjustment	Yes, CrCl <30 mL/min	Yes, CrCl <25 mL/min or Scr >2.5	Assumed 50% reduction if CrCl <50 mL/min
Tmax (h)	2–4	3–4	1–2
VD (L)	50	~23*	>300
Half-life (h)	5–9	9–14	10–14
Bioavailability	>80%	>50%	62%
Protein binding	92%–95%	87%	40%–59%
Metabolism	CYP3A4, CYP2J2	CYP3A4	CYP3A4
Elimination	33% renal	25% renal	35% renal
Effects of food	Cmax and AUC increased; take with food	Cmax and AUC unchanged	Cmax and AUC unchanged
CYP3A4 substrate	Yes	Yes	Yes
P-gp substrate	Yes	Yes	Yes

Notes:

* VD =0.3 L/kg and assuming a 75 kg patient. The HOKUSAI-VTE trial²⁰ reduced dose by 50% in those patients with a CrCl of 30 to 50 mL/min, or a body weight ≤60kg, or in patients receiving concomitant treatment with potent P-gp inhibitor.

Abbreviations: AUC, area under the curve; BID, twice daily; Cmax, maximum peak concentration; CrCl, creatinine clearance; CYP, cytochrome P450; h, hours; min, minutes; P-gp, P-glycoprotein; QD, every day; Scr, serum creatine; Tmax, time to maximum concentration; VD, volume of distribution; VTE, venous thromboembolism.

Table 2 Phase III clinical trial results for the treatment of acute venous thromboembolism

Phase III trials	Major outcomes	Oral Xa inhibitor (% of events)	Standard therapy (% of events)	Hazard ratio, 95% confidence interval
Acute VTE treatment
EINSTEIN-DVT^Citation17	Symptomatic recurrent VTE	2.1%	3.0%	HR 0.68 (95% CI 0.44–1.04); P<0.001
	1st M/CRNMB	8.1%	8.1%	HR 0.97 (95% CI 0.76–1.22); P=0.77
EINSTEIN-PE^Citation18	Recurrent VTE	2.1%	1.8%	HR 1.12 (95% CI 0.75–1.68); P=0.003
	1st M/CRNMB	10.3%	11.4%	HR 0.90 (95% CI 0.76–1.07); P=0.23
AMPLIFY^Citation19	1st recurrent VTE or VTE-related death	2.3%	2.7%	HR 0.84 (95% CI 0.6–1.8); P<0.001
	Major bleed	0.6%	1.8%	HR 0.31 (95% CI 0.17–0.55); P<0.001
HOKUSAI-VTE^Citation20	Symptomatic recurrent VTE	3.2%	3.5%	HR 0.89 (95% CI 0.70–1.13); P<0.001
	Clinically relevant bleeding	8.5%	10.3%	HR 0.81 (95% CI 0.71–0.94); P=0.004
Extended VTE treatment
EINSTEIN-Ext^Citation17	Symptomatic recurrent VTE	1.3%	7.1%	HR 0.18 (95% CI 0.09–0.39); P<0.001
	1st M/CRNMB	6.0%	1.2% (placebo)	HR 5.19 (95% CI 2.3–11.7); P<0.001
AMPLIFY-Ext^Citation21,*	Recurrent VTE/death from any cause	4.2% (5 mg)	11.6% (placebo)	HR 0.36 (95% CI 0.25–0.53); P<0.001
		3.8% (2.5 mg)		HR 0.33 (95% CI 0.22–0.48); P<0.001
	Major bleeding	0.1% (5 mg)	0.5% (placebo)	HR 0.25 (95% CI 0.03–2.24); NS
		0.2% (2.5 mg)		HR 0.49 (95% CI 0.09–2.64); NS

Notes:

* This study included two doses of Xa inhibitor and only one placebo. Data from.^17–20,21

Abbreviations: CI, confidence interval; HR, hazard ratio; M/CRNMB, major or clinically relevant nonmajor bleeding; VTE, venous thromboembolism; NS, not significant.

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