Direct Oral Anticoagulants

Direct oral anticoagulants selectively inhibit a single clotting enzyme, thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban), with fixed dosing, rapid onset, short half-life and no routine coagulation monitoring. They are at least as effective as warfarin with less intracranial bleeding, and are now first line for non-valvular atrial fibrillation and venous thromboembolism.

Members. Dabigatran etexilate, rivaroxaban, apixaban, edoxaban.

Pharmacokinetics. Peak 1 to 4 hours, half-life 9 to 17 hours. Renal clearance: dabigatran about 80%, edoxaban 50%, rivaroxaban 35%, apixaban 27%. Dabigatran etexilate, rivaroxaban and apixaban are substrates of P-glycoprotein. Rivaroxaban, apixaban and (less) edoxaban depend on CYP3A4. Rivaroxaban 15 and 20 mg doses must be taken with food.

• Apixaban: lowest major bleeding; twice daily; least renal clearance.
• Rivaroxaban: once daily with food; more gastrointestinal bleeding.
• Edoxaban: once daily; dose reduction criteria; lower efficacy if creatinine clearance is over 95 mL/min in atrial fibrillation.
• Dabigatran: capsule must stay in its container; dyspepsia; reversal agent available in many regions.

• Non-valvular atrial fibrillation, apixaban: 5 mg twice daily (2.5 mg twice daily if at least two of: age 80 years or over, weight 60 kg or under, creatinine 133 micromol/L or over).
• Atrial fibrillation, rivaroxaban: 20 mg once daily with the evening meal (15 mg if creatinine clearance is 15 to 49 mL/min).
• Atrial fibrillation, edoxaban: 60 mg once daily (30 mg if creatinine clearance 15 to 50 mL/min, weight 60 kg or under, or on strong P-glycoprotein inhibitors).
• Atrial fibrillation, dabigatran: 150 mg twice daily (110 mg twice daily at 80 years or over or on verapamil).
• Treatment of venous thromboembolism: apixaban 10 mg twice daily for 7 days then 5 mg twice daily; rivaroxaban 15 mg twice daily for 21 days then 20 mg once daily; dabigatran 150 mg twice daily and edoxaban 60 mg once daily after at least 5 days of parenteral anticoagulant.
• Extended prophylaxis after 6 months: apixaban 2.5 mg twice daily or rivaroxaban 10 mg daily.
• Prophylaxis after hip or knee replacement: apixaban 2.5 mg twice daily, rivaroxaban 10 mg daily, or dabigatran 220 mg daily.
• Peri-procedural: omit 24 hours (low bleeding risk) or 48 hours (high bleeding risk) before the procedure when creatinine clearance is over 50 mL/min, with longer intervals for dabigatran in renal impairment. Restart 24 to 72 hours after the procedure once haemostasis is secure.
• Missed dose: take within 6 hours (twice daily) or 12 hours (once daily), otherwise skip.
• Selection: prefer when creatinine clearance is over 30 mL/min, no mechanical valve and no moderate to severe mitral stenosis. Warfarin remains the option where direct oral anticoagulants are unaffordable or contraindicated.

Contraindications. Mechanical heart valves, atrial fibrillation with moderate to severe rheumatic mitral stenosis, triple-positive antiphospholipid syndrome, pregnancy and breastfeeding, severe renal impairment (dabigatran under 30 mL/min, others under 15 mL/min), severe hepatic impairment (Child-Pugh C), active bleeding and strong dual CYP3A4 and P-glycoprotein inhibitors or inducers.

Adverse effects. Bleeding (gastrointestinal bleeding more with dabigatran at high dose, rivaroxaban and edoxaban 60 mg), dyspepsia (dabigatran), anaemia, and liver enzyme rise.

Interactions. Avoid with ketoconazole, itraconazole, ritonavir, cobicistat (raise levels), rifampicin, carbamazepine, phenytoin, phenobarbital and St John's wort (lower levels). Dronedarone, verapamil, amiodarone and clarithromycin raise dabigatran and edoxaban. Antiplatelet drugs and NSAIDs raise bleeding. Antiretroviral regimens need checking before use.

Reversal.

• Dabigatran: idarucizumab 5 g intravenously, and haemodialysis.
• Factor Xa inhibitors: andexanet alfa where available, or four-factor prothrombin complex concentrate 25 to 50 units/kg.
• Charcoal for ingestion within 2 to 6 hours, and tranexamic acid as adjunct.

Monitoring. Kidney function and haemoglobin at least yearly, every 3 to 6 months if creatinine clearance is under 60 mL/min or age 75 years or over, liver function, adherence, and bleeding. Calibrated anti-Xa or dilute thrombin time where levels are needed in emergencies.

Referral and escalation. Major bleeding, stroke on treatment, and creatinine clearance falling under 30 mL/min need review.

Special groups. Pregnancy: contraindicated. Obesity (weight over 120 kg): apixaban or rivaroxaban acceptable, avoid others. Older adults: apixaban is often preferred. Kidney disease: adjust or change drug. Cancer: apixaban, edoxaban or rivaroxaban.