Sandbox: NOAC

Template:NOAC Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Associate Editor(s)-in-Chief: Arzu Kalayci, M.D. [2]

Management of Patients on Non–Vitamin K Antagonist Oral Anticoagulants (NOACs) in the Acute Care and Periprocedural Setting

Comparison Among NOACs

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Approved indications	Nonvalular AF ↓ Risk of stroke and systemic embolism	Nonvalular AF ↓ Risk of stroke and systemic embolism	Nonvalular AF ↓ Risk of stroke and systemic embolism	Nonvalular AF ↓ Risk of stroke and systemic embolism. Limitation: should not use in patients with CrCl >95 mL/min as a result of ↑ risk of ischemic stroke compared with warfarin at 60 mg
	DVT,PE Treatment after 5–10 d parenteral AC ↓ Recurrence Prophylaxis after hip replacement	DVT,PE Treatment ↓ Recurrence Prophylaxis after hip or knee replacement	DVT,PE Treatment ↓ Recurrence Prophylaxis after hip replacement	DVT,PE ↓ Recurrence Treatment after 5–10 d initial parenteral AC
Mechanism of action	Direct thrombin inhibitor	Factor Xa inhibitor	Factor Xa inhibitor	Factor Xa inhibitor
Time to peak	1 h; delayed to 2 h with food	2–4 h	3–4 h	1–2 h
Bioavailability	3%–7%	10-mg dose: 80%–100% ; 20-mg dose: 66% ; ↑ With food	~50%	62%
Plasma protein binding	35%	92%–95%	~87%	55%
Volume of distribution	50–70 L	50 L	21 L	107 L
Plasma t½	12–17 h; Elderly 14–17 h; Mild to moderate renal impairment 15–18 h; Severe renal impairment 28 h	5–9 h; Elderly 11–13 h	~12 h (8–15 h)	10–14 h
Metabolism	Hepatic and plasma hydrolysis to active dabigatran; Hepatic glucuronidation to active metabolites (<10%); P-gp substrate	Hepatic: oxidation by CYP3A4/5, CYP2J2; hydrolysis to inactive metabolites (51%); P-gp substrate; No major or active circulating metabolites; Substrate of P-gp and ABCG2 (BCRP)	Hepatic: 25% mainly by CYP3A4/5; lesser by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2J2; O-demethylation and hydroxylation; No active circulating metabolites; Substrate of CYP3A4, P-gp, BCRP	Minimal CYP3A4 hydrolysis, conjugation, oxidation; Active metabolite (M-4, <10% of parent); P-gp substrate
Excretion	Renal (~80%) after IV administration; After oral, 7% recovered in urine, 86% in feces	Feces (28%): 7% active, 21% inactive metabolites	Biliary and direct intestinal excretion	Metabolism and biliary/ intestinal excretion accounts for the rest
Dosing
Nonvalvular AF	CrCl >30 mL/min: 150 mg BID; CrCl 15–30 mL/min: 75 mg BID; CrCl <15 mL/min or on dialysis: Not recommended; CrCl 30–50 mL/min with concomitant P-gp inhibitors: 75 mg BID; CrCl <30 mL/min with concomitant P-gp inhibitors: Avoid coadministration	CrCl >50 mL/min: 20 mg daily with evening meal; CrCl 15–50 mL/min: 15 mg daily with evening meal; Not recommended for CrCl <15 mL/min or on dialysis in patients with AF	5 mg BID; 2.5 mg BID, if 2 of 3 characteristics: Cr ≥1.5 mg/dL, age ≥80 y, weight ≤60 kg	CrCl >50 to ≤95 mL/min: 60 mg daily; CrCl 15–50 mL/min: 30 mg daily; NOT recommended for CrCl >95 mL/min
DVT or PE treatment	CrCl >30 mL/min: 150 mg BID after 5-10 d parenteral anticoagulation; CrCl ≤30 mL/min or on dialysis: Not recommended	15 mg BID with food rst 21 d for initial treatment, then 20 mg once daily with food; Not recommended for CrCl <30 mL/min in patients with DVT or PE	10 mg BID x 7 d, then 5 mg BID	60 mg once daily; CrCl 15–50 mL/min or weight ≤60 kg or on certain P-gp inhibitors: 30 mg once daily
↓ in recurrent DVT/PE	CrCl >30 mL/min: 150 mg BID after 5–10 d parenteral anticoagulation; CrCl ≤30 mL/min or on dialysis: Not recommended	20 mg daily with food	2.5 mg BID
DVT, PE prophylaxis after hip or knee replacement	After hip replacement surgery: CrCl >30 mL/min after achievement of hemostasis: If given day of surgery, 110 mg 1–4 h postop; after day of surgery 220 mg once daily x 28–35 d CrCl ≤30 mL/min or on dialysis: Not recommended CrCl <50 mL/min with concomitant P-gp inhibitors: Avoid coadministration	Initial dose 6–10 h after surgery provided homeostasis established; 10 mg daily with or without food x 35 d for hip replacement, x 12 d for knee replacement	2.5 mg BIDx35 d after hip replacement surgery or x 12 d after knee replacement surgery
Additional dosing comments		Avoid use with patients with moderate-severe hepatic impairment (Child- Pugh class B/C) or hepatic disease with coagulopathy; 15-20 mg taken with food; 10 mg with or without food	Not recommended in patients with severe hepatic impairment (Child-Pugh class C)	Not recommended with CrCl <15 mL/min; Not recommended in patients with moderate-severe hepatic impairment (Child-Pugh class B/C)
Therapeutic measurement	Routine not required, To detect presence: aPTT, ECT (if available), TT; aPTT >2.5 times control may indicate over anticoagulation; Renal function, CBC periodically, at least annually	Routine not required; To detect presence: PT, aPTT, antifactor Xa activity; Renal function, CBC periodically, at least annually; Hepatic function	Routine not required; To detect presence: PT, aPTT, antifactor Xa activity; Renal function, CBC periodically, at least annually	Routine not required; Prolongs PT, aPTT, antifactor Xa activity; Renal function, CBC periodically, at least annually
AC indicates anticoagulant; AF, atrial brillation; aPTT, activated partial thromboplastin time; BID, twice daily; CBC, complete blood count; CrCl, creatinine clearance; DVT, deep vein thrombosis; ECT, ecarin clotting time; IV, intravenous; NOACs, non–vitamin K antagonist oral anticoagulants; PE, pulmonary embolism; P-gp, P-glycoprotein; PT, prothrombin time; and TT, thrombin time.

NOAC Drug Interactions

NOAC	Interacting Medications	Effect on NOAC	Labeled Guidance; Comments
Dabigatran	P-gp inducer: rifampin	↓ Dabigatran exposure	Concomitant use should generally be avoided.
	P-gp inhibitors: ketoconazole, dronedarone	↑ Dabigatran exposure if concomitant moderate renal impairment	If moderate renal impairment (CrCl 30–50 mL/min) ↓ to 75 mg BID during concomitant use
	P-gp inhibitors: ketoconazole, dronedarone, verapamil, amiodarone, quinidine, clarithromycin, ticagrelor	↑ Dabigatran exposure if concomitant severe renal impairment	If severe renal impairment (CrCl 15–30 mL/ min) avoid concomitant use
Apixaban	Strong dual P-gp and CYP3A4 inducers: rifampin, carbamazepine, phenytoin, St. John’s wort	↓ Apixaban exposure	Avoid concomitant use
	Strong dual P-gp and CYP3A4 inhibitors: ketoconazole, itraconazole, ritonavir, clarithromycin	↑ Apixaban exposure	In patients on 5 mg or 10 mg BID, ↓ dose by 50% when coadministered; Avoid coadministration on 2.5 mg BID
Rivaroxaban	Combined P-gp and strong CYP3A4 inducers: rifampin, carbamazepine, phenytoin, St. John’s wort	↓ Rivaroxaban exposure	Avoid concomitant use; may decrease rivaroxaban efficacy
	Combined P-gp and strong CYP3A4 inhibitors: ketoconazole, itraconazole, HIV protease inhibitors (ritonavir, lopinavir/ ritonavir, indinavir), conivaptan	↓ Rivaroxaban exposure	Avoid concomitant use
	Combined P-gp and moderate CYP3A4 inhibitors: diltiazem, verapamil, amiodarone, dronedarone, erythromycin	↑ Rivaroxaban exposure in patients with renal impairment	- In patients with CrCl 15 to <80 mL/min, rivaroxaban should not be used concomitantly unless the potential benefit justifies the potential risks - No evidence of interaction observed in ROCKET AF between treatment assignment and outcomes in patients using ≥1 combined P-gp and moderate 3A4 inhibitors (including amiodarone, diltiazem, and verapamil)
Edoxaban	P-gp inducer: rifampin	↓ Edoxaban exposure	Avoid concomitant use
	Strong P-gp inhibitors: ritonavir, nelfinavir, saquinavir, indinavir, cyclosporine	↑ Edoxaban exposure	Avoid concomitant use in patients taking edoxaban for treatment of VTE
	P-gp inhibitors: verapamil, quinidine, azithromycin, clarithromycin, itraconazole, ketoconazole	↑ Edoxaban exposure	- ↓ to 30 mg daily during concomitant administration for patients taking edoxaban for the treatment of VTE - Dose reduction is not recommended for AF indications - In ENGAGE AF, a ↓ dose of edoxaban as a result of concomitant P-gp inhibitor use (verapamil, quinidine, dronedarone) was associated with ↓ edoxaban exposure and a relative ↑ in risk of stroke or systemic embolism with edoxaban relative to warfarin
AF, atrial fibrillation; BID, twice daily; CrCl, creatinine clearance; ENGAGE AF, Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation trial; NOAC, non–vitamin K antagonist oral anticoagulant; P-gp, P-glycoprotein; ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; and VTE, venous thromboembolism.