New oral pharmacotherapeutic agents for venous thromboprophylaxis after total hip arthroplasty

Table 1 Target specific oral anticoagulant pharmacokinetics

	Dabigatran etexilate[17,32-36]	Rivaroxaban[19,27,39,40]	Apixaban[21,27,41,42]	Edoxaban[43-45]
Half Life (t1/2)	(1) Healthy subjects: 12-15 h (2) Mild renal impairment (50–80 mL/min) : 15 h (3) Moderate renal impairment (30-50 mL/min): 18 h (4) Severe renal impairment (15-30 mL/min): 27 h	(1) Healthy subjects: – 5-9 h (2) Elderly: 11-19 h (3) Mild to moderate hepatic impairment: 10.1-10.4 h (4) Mild renal impairment (50–79 mL/min): 8.7 h (5) Moderate renal impairment (30-49 mL/min): 9 h (6) Severe renal impairment (15-29 mL/min): 9.5 h	(1) 2.5 mg: 6.8 h (2) 5 mg: 15.2 h (3) 10 mg: 11.1 h	8.75-10.4 h
Distribution	Vd: 50-70 L	Vd: 50 L	Vd: 21 L	Vd: > 300 L
Protein binding	35%	92%-95%	87%	40%-59%
Metabolism	(1) Hepatic: dabigatran etexilate is hydrolyzed to dabigatran (active form). (2) Dabigatran undergoes hepatic glucouronidation to 4 active acyl glucuronides, each accounting for < 10% of total dabigatran in plasma.	Hepatic: oxidative metabolism via CYP3A4/5 and CYP2J2	Hepatic: mainly via CYP3A4/5 with minor contribution from CYP1A2, CYP2C8/9/19, and CYP2J2	Hepatic: minimal hepatic contribution from CYP3A4
Bioavailability	3%-7%	Dose dependent (absolute bioavailability) (1) 10 mg 80%-100% in fasted state (2) 20 mg approximately 66% in fasted state	50%	62%
Onset (TCmax)	1-6 h (1) Healthy subjects in fasted state–1 h (2) Healthy subjects following high fat meal–3 h (3) Subjects undergoing elective hip surgery–6 h	2-4 h	2.5 mg: 1.5 h 5 mg: 3.3 h 10 mg: 3-4 h	1-2 h
Excretion	80% renal clearance	(1) 66% renal clearance (36% unchanged and 30% as inactive metabolite); (2) 28% fecal excretion (7% unchanged and 21% as inactive metabolite)	(1) 27% renal clearance unchanged (2) 25% fecal excretion unchanged	49% renal clearance

Table 2 Effects on target specific oral anticoagulants plasma concentrations from drug-drug interactions and dosing recommendations

	Drug interaction via	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Verapamil	P-gp inhibition and weak CYP3A4 inhibition	+ 12%-180% (take simultaneously and reduce dose)	Minor effect (use caution with CrCl 15-50 mL/min	No data yet	+ 53% (SR verapamil) (reduce dose by 50%)
Diltiazem	P-gp inhibition	No effect	Minor effect (use caution with CrCl 15-50 mL/min	+ 40%	No data yet
Quinidine	P-gp inhibition	+ 50%	+ 50%	No data yet	+ 80% (reduce dose by 50%)
Amiodarone	P-gp inhibition	+ 12%-60%	Minor effect (use caution with CrCl 15-50 mL/min	No data yet	No effect
Dronedarone	P-gp and CYP3A4 inhibition	+ 70%-100% (75 mg BID)	No data yet	No data yet	+ 85% (reduce dose by 50%)
Azole antifungals (1) Voriconazole (2) Ketoconazole (3) Itraconazole (4) Posaconazole	Strong P-gp and CYP3A4 inhibition	+ 140%-150% (75 mg BID)	Up to + 160%	+ 100%	No data yet
Fluconazole	Moderate CYP3A4 inhibition	No data yet	+ 42%	No data yet	No data yet
Clarithromycin Erythromycin	Strong P-gp and CYP3A4 inhibition	-0.05	+ 30%-54%	No data yet	No data yet
HIV Protease Inhibitors	Strong P-gp and CYP3A4 inhibition	No data yet	Up to + 153%	Strong increase	No data yet
Rifampin St. John’s Wort Carbamazepine Phenytoin Phenobarbital	Strong P-gp and CYP3A4 induction	- 66%	Up to - 50%	- 54%	- 35%

Table adapted from EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation[46]. Grey boxes indicate drug contraindicated or not recommended. AUC: Area under the curve; TSOA: Target specific oral anticoagulant; P-gp: Permeability glycoprotein; BID: Twice daily.

Table 3 Phase III clinical trials of target specific oral anticoagulants (target specific oral anticoagulants)

Clinical trial	TSOA regimen(duration)	Enoxaparinregimen(duration)	Composite of total venous thromboembolism and death		P-value,non-inferiority (superiority)	Major bleeding		P-value
			TSOA %(n/N)	Enoxaparin %(n/N)		TSOA %(n/N)	Enoxaparin %(n/N)
RE-NOVATE[54] (N = 3494)	Dabigatran 220 mg daily (28-35 d) Dabigatran 150 mg daily (28-35 d)	40 mg daily (28-35 d)	220 mg; 3.1% (28/909) 150 mg; 8.6% (75/874)	6.0% (53/880)	< 0.0001 (n/a) < 0.0001 (n/a)	220 mg; 2.0% (23/1146) 150 mg; 1.3% (15/1163)	1.6% (18/1154)	0.44 0.6
RE-NOVATE II[47] (N = 2055)	Dabigatran 220 mg daily (28-35 d)	40 mg daily (28-35 d)	7.7% (61/792)	8.8% (69/785)	< 0.0001 0.43	1.4% (14/1010)	0.9% (9/1003)	0.4
RECORD 1[62] (N = 4541)	Rivaroxaban 10 mg daily (31-39 d)	40 mg daily (31-39 d)	1.1% (18/1595)	3.7% (58/1558)	n/a (< 0.001)	0.3% (6/2209)	0.1% (2/2224)	0.18
RECORD 2[63] (N = 2509)	Rivaroxaban 10 mg daily (31-39 d)	40 mg daily (10-14 d)	2.0% (17/864)	9.3% (81/869)	n/a (< 0.0001)	0.08% (1/1228)	0.08% (1/1229)	n/a
ADVANCE 3[73] (N = 5407)	Apixaban 2.5 mg BID (32-38 d)	40 mg daily (32-38 d)	1.4% (27/1949)	3.9% (74/1917)	< 0.001 (< 0.001)	0.8% (22/2673)	0.7% (18/2659)	0.54
STARS J-5[75] (N = 610)	Edoxaban 30 mg daily (11-14 d)	20 mg BID (11-14 d)	2.4% (6/255)1	6.9% (17/248)1	< 0.001 0.016	2.6% (8/303)2	3.7% (11/301)2	0.48

¹All events were asymptomatic DVT.

²Rate of major and clinically relevant non-major bleeding. TSOA: Target specific oral anticoagulant; RE-NOVATE: The extended thromboembolism prevention after hip surgery; RECORD: Regulation of Coagulation in Orthopedic Surgery to Prevent DVT and PE; STARS: Studying thrombosis after replacement surgery.