Comprehensive DOAC Guide
Direct oral anticoagulants (DOACs) are first-line anticoagulants for most indications, preferred over vitamin K antagonists except in mechanical heart valves and moderate-to-severe mitral stenosis. 1
Standard Dosing by Indication
Atrial Fibrillation (Stroke Prevention)
Apixaban: 5 mg twice daily 2
- Reduce to 2.5 mg twice daily if ≥2 of: age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL
Dabigatran: 150 mg twice daily 2
- 110 mg twice daily option (not FDA-approved in US, but available in Canada for age ≥75 with bleeding risk factors)
Rivaroxaban: 20 mg once daily with food 2
Edoxaban: 60 mg once daily 2
- Critical: Only use if CrCl <95 mL/min (FDA restriction due to reduced efficacy at higher renal function)
Betrixaban: Not approved for AF
VTE Treatment (Initial Phase)
Apixaban: 10 mg twice daily × 7 days, then 5 mg twice daily 3
Dabigatran: 150 mg twice daily after 5-10 days parenteral anticoagulation 3
Rivaroxaban: 15 mg twice daily with food × 21 days, then 20 mg once daily with food 3
Edoxaban: 60 mg once daily after 5-10 days parenteral anticoagulation 3
VTE Secondary Prevention (After 6 months)
- Apixaban: 2.5 mg twice daily (reduced dose option) 3
- Rivaroxaban: 10 mg once daily (reduced dose option) 3
VTE Prophylaxis Post-Orthopedic Surgery
- Dabigatran: 220 mg once daily (or 150 mg if CrCl 30-50 mL/min, age ≥75, or P-gp inhibitors) 4
- Rivaroxaban: 10 mg once daily 4
- Apixaban: 2.5 mg twice daily 4
- Edoxaban: 30 mg once daily 4
Renal Dose Adjustments
Critical Thresholds by Drug 2, 5
Dabigatran (most renally dependent - 80% renal elimination):
- CrCl 30-50 mL/min: Consider 110 mg twice daily (or 75 mg twice daily in US if also on dronedarone/ketoconazole)
- CrCl 15-30 mL/min: 75 mg twice daily (US only)
- CrCl <15 mL/min: Contraindicated
Rivaroxaban:
- CrCl 30-50 mL/min (AF): 15 mg once daily
- CrCl 15-30 mL/min: 15 mg once daily
- CrCl <15 mL/min: Contraindicated
Apixaban (safest in renal impairment):
- Dose reduction criteria already incorporated in standard dosing
- Can use in dialysis: 5 mg twice daily (reduce to 2.5 mg if age ≥80 or weight ≤60 kg)
Edoxaban:
- CrCl 51-95 mL/min: 60 mg once daily
- CrCl 15-50 mL/min: 30 mg once daily
- CrCl <15 mL/min: Contraindicated
- Weight ≤60 kg or P-gp inhibitors: 30 mg once daily
Betrixaban (least renally dependent):
- Safest option in severe renal impairment 6
Hepatic Impairment 5
All DOACs contraindicated in:
- Child-Pugh C cirrhosis
- Active liver disease with coagulopathy
Rivaroxaban: Also contraindicated in Child-Pugh B (>2-fold drug exposure)
Dabigatran, Apixaban, Edoxaban: May use with caution in Child-Pugh B with multidisciplinary team (hepatologist + hematologist)
Avoid if:
- ALT/AST ≥2-3× ULN
- Total bilirubin ≥1.5× ULN
Drug Interactions
P-glycoprotein (P-gp) Inhibitors 4, 7
Strong P-gp inhibitors (affect all DOACs, especially dabigatran):
- Dronedarone, ketoconazole, cyclosporine, itraconazole, tacrolimus
Management:
- Dabigatran: Reduce to 75 mg twice daily if CrCl 30-50 mL/min + P-gp inhibitor
- Edoxaban: Reduce to 30 mg once daily with P-gp inhibitors
- Apixaban/Rivaroxaban: Use with caution
CYP3A4 Inhibitors/Inducers 7
Affect: Rivaroxaban, Apixaban (not Dabigatran or Edoxaban)
Strong dual P-gp/CYP3A4 inhibitors: Contraindicated or avoid
- Examples: Ketoconazole, ritonavir, clarithromycin
Strong inducers (reduce DOAC levels): Avoid
- Rifampin, phenytoin, carbamazepine, St. John's wort
Perioperative Management
Preoperative Interruption 4, 8, 4
Low Bleeding Risk Procedures (aim for 12-25% residual anticoagulant):
Xabans (Rivaroxaban, Apixaban, Edoxaban):
- CrCl >30 mL/min: Stop 2 days before (skip 1-2 doses)
Dabigatran:
- CrCl ≥50 mL/min: Stop 2 days before (skip 2-4 doses)
- CrCl 30-50 mL/min: Stop 3 days before (skip 4 doses)
High Bleeding Risk Procedures (aim for <6% residual anticoagulant):
Xabans:
- CrCl >30 mL/min: Stop 3 days before (skip 2-4 doses)
Dabigatran:
- CrCl ≥50 mL/min: Stop 3 days before (skip 4 doses)
- CrCl 30-50 mL/min: Stop 4-5 days before (skip 6-8 doses)
Very High Risk (Neuraxial anesthesia, intracranial surgery):
- All DOACs: Stop 5 days before 4
- Never perform spinal/epidural with possible DOAC levels, especially dabigatran in elderly or renal impairment
Bridging 4
No bridging needed except very high thrombotic risk (e.g., mechanical valve, recent VTE <3 months)
Postoperative Resumption 4, 8
Low Bleeding Risk:
- Resume 24 hours postoperatively at full dose
High Bleeding Risk:
- Resume 48-72 hours postoperatively
- Consider reduced dose first 1-2 days (e.g., dabigatran 150 mg once daily, rivaroxaban 10 mg, apixaban 2.5 mg twice daily) for very high thrombotic risk
With epidural catheter: Use heparin until catheter removed, then resume DOAC 12 hours after last prophylactic LMWH dose
Monitoring
Routine Monitoring Not Required 5
However, measure DOAC levels in:
- Life-threatening bleeding
- Emergency surgery
- Suspected overdose/accumulation
- Extremes of body weight
- Renal/hepatic dysfunction
- Drug interactions
- Thrombosis on therapy
Specific Assays 5, 9
Dabigatran:
- Dilute thrombin time (dTT) or ecarin clotting time (ECT): Most accurate
- aPTT: Qualitative only (normal aPTT does NOT exclude clinically relevant levels)
Xa Inhibitors (Rivaroxaban, Apixaban, Edoxaban):
- Anti-Xa assay with drug-specific calibrator: Required
- PT/INR: Not reliable (varies by reagent)
Clinically relevant level: >50 ng/mL before urgent procedures 4
Timing: Sample at trough (before next dose) or peak (1-3 hours post-dose) depending on clinical question
Reversal Agents 10, 11
Specific Reversal
Idarucizumab (for dabigatran):
- Dose: 5 g IV (two 2.5 g vials)
- Indication: Life-threatening bleeding or emergency surgery
- Only FDA-approved specific reversal agent
Andexanet alfa (for Xa inhibitors):
- Approved for apixaban and rivaroxaban bleeding
- NOT approved for surgical patients
- NOT recommended before cardiac surgery (inhibits heparin needed for bypass)
- Cost: $12,500/gram
- Short duration of effect
Nonspecific Reversal 10, 11
Prothrombin Complex Concentrate (PCC):
- 4-factor PCC: 25-50 units/kg
- Increasing evidence supports off-label use
- Consider for emergency surgery when specific reversal unavailable
Activated PCC (FEIBA): Alternative option
Recombinant Factor VIIa: Insufficient data, no recommendation
Hemodialysis: Only effective for dabigatran (removes ~60% in 2-3 hours)
Switching Anticoagulants 1
VKA to DOAC:
- Start DOAC when INR <2.0 (ideally <1.5)
DOAC to VKA:
- Overlap for 2-3 days until INR therapeutic
- Check INR before next DOAC dose
DOAC to DOAC:
- Start new DOAC at time of next scheduled dose
- No overlap needed
Parenteral to DOAC:
- Start DOAC at time of next scheduled parenteral dose
DOAC to Parenteral:
- Start parenteral 12-24 hours after last DOAC dose
Special Populations
Cancer-Associated VTE 7
LMWH remains preferred (superior efficacy in trials)
DOACs are alternatives:
- Use with caution in GI/GU malignancies (higher bleeding risk)
- Monitor for drug interactions with chemotherapy
- Consider nephrotoxic/hepatotoxic chemotherapy effects
Contraindications:
- Active GI/GU tract lesions or recent bleeding
- Thrombocytopenia <50,000
Pregnancy/Lactation
All DOACs contraindicated in pregnancy - use LMWH
Extremes of Body Weight 6
Obesity (>120 kg or BMI >40):
- Apixaban and rivaroxaban: Likely adequate
- Dabigatran: Limited data
- Consider anti-Xa monitoring
Low weight (<50 kg):
- Edoxaban: Reduce to 30 mg once daily
- Apixaban: May need dose reduction per criteria
Elderly (≥75-80 years) 4
- Increased bleeding risk
- Dabigatran: Consider 110 mg twice daily
- Apixaban: Often meets dose reduction criteria
- Monitor renal function closely
Combination with Antiplatelet Therapy 3, 2
AF + PCI
Preferred strategy: DOAC + clopidogrel (avoid ticagrelor/prasugrel due to higher bleeding)
Duration:
- Elective PCI: DOAC + clopidogrel for 6 months, then DOAC alone
- ACS: DOAC + DAPT for 1 month, then DOAC + clopidogrel to 12 months
Aspirin: 75-100 mg (not 325 mg)
Reduced-dose DOACs after 6 months:
- Rivaroxaban 15 mg once daily
- Apixaban 2.5 mg twice daily (if meets criteria)
Avoid triple therapy beyond 1 month unless very high ischemic risk
Contraindications (Absolute)
- Active clinically significant bleeding
- Lesions at high risk of bleeding
- Recent brain/spinal/ophthalmic surgery
- Severe renal impairment (CrCl <15-30 mL/min, drug-specific)
- Severe hepatic impairment with coagulopathy
- Mechanical heart valves
- Moderate-to-severe mitral stenosis
- Pregnancy
- Strong dual P-gp/CYP3A4 inhibitors (for rivaroxaban/apixaban)
Key Practical Considerations
Rivaroxaban and betrixaban MUST be taken with food (absorption requirement)
Dabigatran: Avoid proton pump inhibitors if possible (may reduce absorption, though clinically minor)
Edoxaban paradox: Less effective at CrCl >95 mL/min - FDA restriction
Apixaban: Safest bleeding profile across trials 6
Dabigatran: Only DOAC with approved reversal agent
Betrixaban: Least drug interactions, safest in severe renal impairment 6
Monitor renal function: At baseline, annually, and when clinically indicated (acute illness, nephrotoxic drugs)
GI bleeding risk: Highest with dabigatran and rivaroxaban; consider PPI prophylaxis in high-risk patients 2