What is the recommended dosage and selection of Direct Oral Anticoagulants (DOACs) for patients requiring anticoagulation?

Direct Oral Anticoagulant (DOAC) Dosing and Selection

DOACs are the preferred anticoagulants over warfarin for most indications, with specific dosing determined by the indication (atrial fibrillation versus venous thromboembolism) and patient-specific factors including renal function, age, weight, and concomitant medications. 1, 2

Standard Dosing by Indication

Atrial Fibrillation (Stroke Prevention)

• Apixaban: 5 mg twice daily; reduce to 2.5 mg twice daily ONLY if patient meets two or more of these criteria: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (≥133 μmol/L) 1, 2

• Rivaroxaban: 20 mg once daily with food; reduce to 15 mg once daily if creatinine clearance (CrCl) 15-49 mL/min 1, 3

• Dabigatran: 150 mg twice daily; reduce to 110 mg twice daily if age ≥80 years or receiving concomitant verapamil 1, 2

• Edoxaban: 60 mg once daily; reduce to 30 mg once daily if CrCl 15-50 mL/min, weight ≤60 kg, or concomitant use of P-glycoprotein inhibitors (ciclosporin, dronedarone, erythromycin, ketoconazole) 1, 2

Venous Thromboembolism (DVT/PE) Treatment

Critical distinction: VTE requires higher initial dosing than atrial fibrillation—using AF doses for VTE is inadequate and dangerous. 2

• Rivaroxaban: 15 mg twice daily with food for 21 days, then 20 mg once daily with food 1, 2, 3

• Apixaban: 10 mg twice daily for 7 days, then 5 mg twice daily 1, 2

• Dabigatran: Requires at least 5 days of parenteral anticoagulation (LMWH or UFH) first, then 150 mg twice daily 1, 2

• Edoxaban: Requires at least 5 days of parenteral anticoagulation first, then 60 mg once daily (30 mg once daily if weight <60 kg, CrCl 30-50 mL/min, or concomitant P-gp inhibitors) 1, 2

Extended VTE Prevention (After 6 Months of Treatment)

For patients requiring indefinite anticoagulation beyond the initial 6-month treatment period:

• Rivaroxaban: 10 mg once daily 1
• Apixaban: 2.5 mg twice daily 1

These reduced-intensity regimens balance continued thrombosis prevention against bleeding risk. 1

DOAC Selection Algorithm

First-Line Choice by Indication

For non-cancer-associated VTE: DOACs are preferred over warfarin and LMWH 1

For cancer-associated VTE:

• DOACs are preferred over warfarin and LMWH for most patients due to superior compliance and ease of use 1
• Exception: Patients with gastric or gastroesophageal malignancies have higher bleeding risk with DOACs; LMWH (dalteparin 200 units/kg daily for 30 days, then 150 units/kg daily) is preferred in this population 1
• If DOAC is used in gastric/gastroesophageal cancer, apixaban may be safer than rivaroxaban or edoxaban 1

For atrial fibrillation: All four DOACs (apixaban, dabigatran, edoxaban, rivaroxaban) are preferred over warfarin 1

Renal Function Considerations

CrCl 30-59 mL/min:

• All DOACs can be used with dose adjustments as specified above 1
• Dabigatran: 150 mg twice daily (or 110 mg twice daily in non-US countries) 1
• Rivaroxaban: 15 mg once daily for AF 1
• Apixaban: 5 mg twice daily (or 2.5 mg twice daily if meets two additional criteria) 1
• Edoxaban: 30 mg once daily 1

CrCl 15-29 mL/min:

• Apixaban: 2.5 mg twice daily (most data support use) 1
• Rivaroxaban: 15 mg once daily (limited data, use with caution) 1
• Dabigatran: 75 mg twice daily (US only; not studied in trials) 1
• Edoxaban: Not recommended by FDA; some guidelines suggest 30 mg once daily 1

CrCl <15 mL/min or dialysis:

• Apixaban: 2.5-5 mg twice daily (most experience, though not studied in trials) 1
• All other DOACs: Not recommended 1
• Dabigatran is 50-60% dialyzable, but still not recommended 1

Monitor renal function: Check CrCl at baseline, then at least annually; more frequently (every 3-6 months) if CrCl <60 mL/min or age >75 years 1

Hepatic Impairment

• Child-Pugh A: All DOACs can be used 1
• Child-Pugh B or C: Avoid all DOACs; use warfarin instead 1
• Elevated transaminases >2x upper limit of normal with coagulopathy: Avoid DOACs 1

Drug-Drug Interactions

Contraindicated combinations:

• Strong dual inhibitors of both CYP3A4 and P-glycoprotein: ketoconazole, itraconazole, HIV protease inhibitors, ciclosporin (with dabigatran) 1, 3
• Strong CYP3A4 inducers: rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort 1, 3

Dose adjustments required:

• Verapamil with dabigatran: reduce dabigatran to 110 mg twice daily 1, 2
• Moderate P-gp inhibitors (amiodarone, dronedarone, quinidine) with edoxaban: reduce to 30 mg once daily 2

Mechanical Heart Valves and Mitral Stenosis

Absolute contraindication: Do not use DOACs; warfarin is required 1, 2

Triple Positive Antiphospholipid Syndrome

Do not use DOACs: Increased thrombosis risk observed; warfarin is preferred 1

Practical Considerations

Food Requirements

• Rivaroxaban 15 mg and 20 mg doses: Must be taken with food (increases bioavailability from 66% to 80-100%) 1, 3
• Rivaroxaban 10 mg, apixaban, dabigatran, edoxaban: Can be taken with or without food 1

Missed Dose Management

Once-daily regimens (rivaroxaban, edoxaban): Missing a single dose creates a longer period without anticoagulation (up to 48 hours if next dose also delayed) 4

Twice-daily regimens (apixaban, dabigatran): Provide more consistent anticoagulation; if one dose missed, next dose provides coverage within 12 hours 4

Comparative Safety Data

Real-world evidence from 527,226 patients with atrial fibrillation showed:

• Apixaban had lower gastrointestinal bleeding compared to dabigatran (HR 0.81), edoxaban (HR 0.77), and rivaroxaban (HR 0.72) 5
• No substantial differences in ischemic stroke, intracranial hemorrhage, or mortality between DOACs 5
• This GI bleeding advantage for apixaban was consistent in patients ≥80 years, those with chronic kidney disease, and across both standard and reduced doses 5

Perioperative Management

• Low bleeding risk procedures: Hold DOAC the night before 2
• High bleeding risk procedures:
  • Rivaroxaban, apixaban, edoxaban: Hold for 3 days before 2
  • Dabigatran: Hold for 4 days if CrCl >50 mL/min; 5 days if CrCl 30-50 mL/min 2
• Resumption: Restart at least 6 hours after procedure if adequate hemostasis achieved 2

Common Pitfalls to Avoid

1. Do not use atrial fibrillation doses for VTE treatment—VTE requires higher initial dosing 2

2. Do not reduce apixaban dose based on single criterion—requires two out of three criteria (age ≥80, weight ≤60 kg, creatinine ≥1.5 mg/dL) 1, 2

3. Do not forget food requirement for rivaroxaban 15-20 mg doses—significantly affects absorption 3

4. Do not use DOACs in mechanical valves or moderate-severe mitral stenosis—warfarin only 1, 2

5. Do not initiate dabigatran or edoxaban immediately after acute VTE—requires 5 days of parenteral anticoagulation first 1, 2

6. Monitor renal function regularly—all DOACs have renal clearance (dabigatran 80%, edoxaban 50%, rivaroxaban 35%, apixaban 27%) 1