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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

A Scientific Statement From the American Heart Association - 2017

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.

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