New Oral Anticoagulants in the Treatment of Pulmonary Embolism: Efficacy, Bleeding Risk, and Monitoring

Table 1

Comparison of the pharmacokinetic and pharmacodynamic features of oral anticoagulant therapies [15, 18, 21, 23–31].

Characteristic	Warfarin	Apixaban	Dabigatran	Rivaroxaban
Mechanism of action	VKORC1 enzyme inhibitor	Direct^∧ Factor Xa inhibitor	Direct^∧ Factor IIa (Thrombin) inhibitor	Direct^∧ Factor Xa inhibitor
Prodrug	No	No	Yes	No
Approved indications	VTE prevention; VTE treatment; Atrial fibrillation; Valvular heart disease; (all approved in EMA, HC, FDA)	VTE prevention; (EMA, HC); Nonvalvular AF; (EMA, HC, FDA)	VTE prevention; (EMA, HC); Nonvalvular AF; (EMA, HC, FDA)	VTE prevention; (EMA, HC, FDA); Nonvalvular AF; (EMA, HC, FDA); VTE treatment; (EMA, HC, FDA)
FDA black box warnings	Agent can cause major or fatal bleeding; Regular INR monitoring is necessary; drugs, dietary changes, and other factors affect INR levels (FDA)	Discontinuation in patients without adequate continuous anticoagulation increases the risk of stroke (FDA)	None to date	Discontinuing places patients at an increased risk of thrombotic events; Risk of spinal/epidural hematoma during neuraxial anesthesia/spinal puncture (FDA)
Dosing	Variable, patient specific	Fixed, twice daily; With dose reduction in two of the following patients: (per FDA); (1) Age ≥ 80 years; (2) Weight ≤ 60 kg; (3) Serum creatinine ≥1.5 mg/dL	Fixed, twice daily; With dose reduction in patients with renal dysfunction (per FDA)	VTE prevention and nonvalvular AF: Fixed, once daily; With dose reduction in patients with renal dysfunction (per FDA); VTE treatment: Fixed, twice daily × 3 weeks then fixed, once daily; Not to be used if ClCr <30 mL/min
𝑇max (h)	4	1–3	1–3	2–4
Half-life (h)	20–60	12	12–17	5–9
Bioavailability (F)	100%	50%	6%; (~75% if capsule opened)	10 mg: 80–100%; (regardless of food); 20 mg: 66% (without food).; Food increases absorption^#
Renal Clearance	>90% as inactive metabolites	25%	80%*	36% unchanged drug*; 33% as inactive metabolites; Mostly via secretion not glomerular filtration
CYP metabolism^+	>90%; (S-enantiomer is a substrate for 2C9 and 2C19 while R-enantiomer is a substrate for 1A1, 1A2, and 3A4 )	15%; (primary substrate for CYP3A4; minor contributions by others, without active metabolites)	No	30%; (substrate for CYP3A4, CYP2J2)
P-glycoprotein (P-gp)^+	No	Yes	Yes	Yes
Dietary considerations	Dietary vitamin K	None	None	VTE prevention dose: does not specify; AFIB: Take with evening meal; VTE treatment: Take with food
Influence on routine coagulation assay
Protime (PT)	↑	↑	↑	↑
aPTT	No/↑	↑	↑	↑
Thrombin time (TT)	No	No	↑↑	No
Coagulation assay; used to monitor efficacy	INR (Protime)	None	None	None
Clinically validated; Reversal agent	Vitamin K, FFP, PCC, Factor VIIa, aPCC	None	None	None

EMA: European Medicines Agency; HC: Health Canada; FDA: U.S. Food and Drug Administration
AF: Atrial Fibrillation; CYP: cytochrome P450; VKORC1: C1 subunit of the vitamin K epoxide reductase enzyme; FFP: Fresh Frozen Plasma; PCC: Prothrombin Complex Concentrate.
^∧Does not bind to antithrombin.
^#Rivaroxaban 15 mg tablet, if available, should be taken with food.
*Dose adjustment for level of renal dysfunction required.
⁺Potential source for drug-drug interactions—review full package insert for details.