Since their first approval, nonvitamin K antagonist oral anticoagulants (NOACs; also known as direct oral anticoagulants or DOACs) have become a common treatment for stroke prophylaxis in patients with nonvalvular atrial fibrillation (NVAF).1 Current US Food and Drug Administration-approved NOACs include an antithrombin agent (dabigatran) and 3 anti-factor Xa agents (rivaroxaban, apixaban, and edoxaban), with more agents in development.1-5

Indications for NOACs have expanded to include the treatment and prevention of deep vein thrombosis (DVT), pulmonary embolism (PE), and as an adjunct to aspirin therapy in the prevention of further cardiac events associated with coronary artery disease (CAD). More recently, researchers have evaluated their use as venous thromboembolism (VTE) prophylaxis in patients with cancer, critically ill hospitalized patients, and patients with peripheral artery disease (PAD).6,7

Atrial Fibrillation and NOACs: The Basics

The use of NOACs has revolutionized the treatment of patients with NVAF for the prevention of ischemic stroke. The term nonvalvular refers to patients without mechanical heart valves or severe valvular disease such as mitral stenosis.1 In contrast to warfarin, a vitamin K antagonist that had been the mainstay of treatment of NVAF, patients can be treated with NOACs without concern about blood levels and medication or dietary interactions.  In multiple clinical trials, NOACs were not inferior to warfarin for stroke prophylaxis and equal or superior in reducing bleeding risk.2-5

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The onset of action for NOACs is 1 to 4 hours; thus, therapeutic levels are quickly achieved compared with warfarin, which may take days to reach a therapeutic level.8-11 This rapid onset and offset of action eliminates the need for costly bridging therapy with subcutaneous low-molecular-weight heparin (LMWH) and faster interventions such as cardioversions.12 NOACs also reduce the amount of time patients are off anticoagulation for specific procedures, which in turn reduces the risk of blood clot formation.1

The risk of stroke in patients with atrial fibrillation is stratified using the CHA2DS2-VASc scoring method, which replaced CHADS2 (Table 1).13 A score of 0 for men and 1 for women indicates low risk of stroke; 1 for men and 2 for women indicates moderate risk; and a score of 2 or higher for men and 3 or higher for women indicates high risk. Any patient with a score above 2 should be on anticoagulation therapy for stroke prophylaxis.  One exception is women younger than 65 years without other risk factors; antithrombotic therapy should not be given to these patients.13 The updated recommendations from the American Heart Association (AHA), American College of Cardiology (ACC), and Heart Rhythm Society (HRS) no longer support the use of aspirin for low-risk atrial fibrillation patients, citing no clinical benefit and an increased risk of bleeding.14

Table 1.  CHA2DS2-VASc Score13

Congestive heart failure/left ventricle dysfunction+1          
HHypertension (>140/90 mm Hg), treated hypertension+1
Age >75 y+2
DDiabetes mellitus+1
SHistory of stroke, TIA, cerebral ischemia+2
VVascular disease (MI, carotid artery disease, PAD, etc)+1
A  Age 65-74 y+1
ScSex category:  female+1
MI, myocardial infarction; PAD, peripheral artery disease; TIA, transient ischemic attack

Specific Populations and NOAC Dosing

Practitioners need to consider specific dosing for each NOAC based on creatinine clearance (CrCL), and/or weight and patient age (Table 2).8-11 Renal adjustment is extremely important because if the NOAC dose is too low, patients are at risk for stroke and if the dose is too high, they have an increased risk of bleeding.15

Table 2. NOAC Dosing for Nonvalvular Atrial Fibrillation8-11

Apixaban65 mg twice a day• Reduce dose to 2.5 mg twice a day if 2 of the following are present: age ≥80 y, creatine ≥1.5 mg/dL, weight ≤60 kg, or if taking drugs that are combined P-gp and strong CYP34A inhibitors
Dabigatran150 mg twice a day for CrCL ≥30 mL/min
AVOID if P-gp inducer and CYP34a inducer (carbamazepine, phenytoin, rifampin, St. John’s wart) are prescribed
• Reduce dose to 75 mg twice a day if CrCL is 15-30 mL/min or if CrCL is 30-50 mL/min and taking P-gp inhibitor (dronedarone or ketoconazole), avoid if CrCL is ≤30 mL/min
• AVOID if taking P-gp inducer (eg, rifampin), or CrCL is ≤15 mL/min
• Dabigatran comes in a bottle or blister pack and should be kept dry and not be placed in pillboxes but kept in packaging. It is only stable for 4 months after opening the bottle.
Edoxaban60 mg/dif CrCL is ≥50 mL/min or ≤95 mL/min• Reduce doseto 30 mg/d if CrCL is 15-50 mL/min
• AVOID if CrCL is >95 mL/min or if taking P-gp inducers (eg, rifampin)
Rivaroxaban15 or 20 mg/dif CrCL is ≥50 mL/min with food• Reduce dosageto 15 mg/d if CrCL is 15-50 mL/min
• AVOID if CrCL is ≤15 mL/min  
CrCL, creatinine clearance; P-gp, P-glycoprotein

Given the short half-life of NOACs, these agents should be discontinued 24 to 48 hours prior to surgery depending on the bleeding risk associated with the procedure.8-11 In contrast, warfarin should be discontinued 5 days before surgery.12 Patients at high risk for bleeding from procedures like spinal or epidural procedures need special consideration due to the risk of a spinal hematoma, which could result in permanent paralysis. New guidelines from the American Society of Regional Anesthesia and Pain Medicine(ASRA) recommend stopping dabigatran for 4 days (or 5 to 6 days for patients with impaired renal function) and holding rivaroxaban, apixaban, and edoxaban for 3 days prior to neuraxial pain and spinal interventions; all agents can be resumed after 24 hours.16 The use of NOACs is not recommended in patients with triple-positive antiphospholipid syndrome because of an increased risk of recurrent thrombosis.1,8-11