Direct oral anticoagulants — choice, dosing and reversal

Drugs and mechanism. Dabigatran is a direct thrombin (factor IIa) inhibitor. Rivaroxaban, apixaban and edoxaban are direct factor Xa inhibitors. Advantages over warfarin: predictable pharmacokinetics, no routine monitoring, rapid onset and offset, fewer food and drug interactions, and lower intracranial haemorrhage risk.

Indications and contraindications. Indicated for stroke prevention in non-valvular atrial fibrillation, treatment and secondary prevention of DVT and pulmonary embolism, and VTE prophylaxis after hip or knee arthroplasty. Contraindicated in mechanical prosthetic heart valves and moderate-to-severe (rheumatic) mitral stenosis — these require warfarin, an important point in Indian practice. Also avoid in severe hepatic impairment (Child–Pugh C) and active major bleeding.

Standard doses in atrial fibrillation. Apixaban 5 mg twice daily; Rivaroxaban 20 mg once daily with food; Edoxaban 60 mg once daily; Dabigatran 150 mg twice daily (110 mg twice daily if aged ≥ 80 or on verapamil).

Dose reduction criteria (high-yield).

Choice in the older adult. Apixaban has the most favourable geriatric profile — lowest major and gastrointestinal bleeding and the safest in chronic kidney disease. Avoid dabigatran if there is dyspepsia or gastrointestinal bleeding risk, or in significant renal impairment. Once-daily rivaroxaban or edoxaban may aid adherence. Avoid concurrent NSAIDs and antiplatelets; beware P-gp and CYP3A4 interactions (rifampicin, carbamazepine, phenytoin, azoles, verapamil, amiodarone). Check renal function at least annually — more often if CrCl < 60 (a practical rule is CrCl ÷ 10 = review interval in months).

Reversal and bleeding management. Stop the drug, note the time of the last dose, apply local haemostatic measures, restore volume, transfuse as needed and give tranexamic acid for mucosal bleeding. Specific antidotes: Idarucizumab 5 g IV — a monoclonal antibody fragment reversing dabigatran; Andexanet alfa — a modified factor Xa decoy reversing apixaban and rivaroxaban. Where antidotes are unavailable (common in India), give 4-factor prothrombin complex concentrate 50 units/kg. Activated charcoal if ingestion was within 2–4 hours; dabigatran is dialysable (the factor Xa inhibitors are not, being highly protein-bound).

ANNEXA-I (NEJM 2024) — in acute intracranial haemorrhage on a factor Xa inhibitor, andexanet alfa achieved significantly better haemostatic efficacy than usual care (largely PCC), but at the cost of more thrombotic events, including ischaemic stroke. Current guidance therefore recommends specific reversal agents as first-line for life-threatening or intracranial bleeding, with 4-factor PCC as the alternative, and stresses early restarting of anticoagulation once haemostasis is secure.