direct oral anticoagulants
4 min read
Updated 2026-03-25
Contents
direct oral anticoagulants
Direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and direct thrombin inhibitor (dabigatran). Replaced warfarin for most AF and VTE indications — more predictable pharmacology, lower ICH, no routine monitoring. Apixaban has the best bleeding profile, now confirmed head-to-head vs rivaroxaban in COBRRA (2026).
dosing
| Apixaban | Rivaroxaban | Edoxaban | Dabigatran | |
|---|---|---|---|---|
| AF standard | 5 mg BID | 20 mg OD with food | 60 mg OD | 150 mg BID |
| AF reduced dose | 2.5 mg BID (≥2 of: age ≥80, weight ≤60 kg, Cr ≥133 µmol/L or CrCl 15–29) | 15 mg OD (CrCl 15–49) | 30 mg OD (CrCl 15–50, weight ≤60 kg, or P-gp inhibitor) | 110 mg BID (age ≥80, or verapamil) |
| VTE treatment | 10 mg BID × 7d → 5 mg BID | 15 mg BID × 21d → 20 mg OD | 60 mg OD (after ≥5d parenteral) | 150 mg BID (after ≥5d parenteral) |
| VTE extended | 2.5 mg BID | 10 mg OD | — | — |
| Renal cutoff | avoid if CrCl <15 | avoid if CrCl <15 | avoid if CrCl <15 | avoid if CrCl <30 |
| Reversal | andexanet alfa | andexanet alfa | andexanet alfa | idarucizumab |
DOAC selection in practice
Apixaban has the lowest rates of major bleeding and GI bleeding across the DOAC AF trials and is the only DOAC non-inferior to warfarin for stroke prevention that also reduced mortality — ARISTOTLE (2011). COBRRA (2026) is the first head-to-head RCT: apixaban vs rivaroxaban in acute VTE showed 46% lower clinically relevant bleeding (3.3% vs 7.1%; RR 0.46), NNT 26, with no loss in efficacy.
pharmacokinetics
| Apixaban | Rivaroxaban | Edoxaban | Dabigatran | |
|---|---|---|---|---|
| Food | optional | required (15–20 mg; ↑AUC 39%) | optional | optional (delays Tmax) |
| PPI effect | none | none | none | ↓levels 20–40% |
| P-gp substrate | yes | yes | yes | yes |
| CYP3A4 metabolism | significant | moderate | minimal | none |
| Crushing/tube | yes (NG/OG) | yes — gastric tube only (↓absorption 29–56% if post-pyloric) | yes | open capsule onto food; do not crush pellets |
key drug interactions —
- Strong P-gp/CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, dronedarone) → ↑levels of all DOACs — avoid or dose-reduce
- Verapamil → ↑dabigatran and rivaroxaban bleeding risk; reduce dabigatran to 110 mg BID
- Amiodarone → ↑rivaroxaban levels; monitor clinically
- Strong inducers (rifampicin, phenytoin, carbamazepine) → ↓DOAC levels 35–66% — avoid concomitant use with apixaban/rivaroxaban; can cause undetectable dabigatran levels
key points
- apixaban — best bleeding profile; preferred if high GI bleed risk or elderly
- rivaroxaban — OD dosing (adherence advantage); must take with food; higher GI bleeding vs apixaban
- dabigatran — only DOAC with specific reversal (idarucizumab); higher dyspepsia; requires acid environment (avoid PPIs if possible); CrCl <30 is contraindication
- edoxaban — requires ≥5d parenteral anticoagulation before starting for VTE; less effective at CrCl >95 (don’t use)
- low-dose rivaroxaban (2.5 mg BID) + ASA in stable CAD/PAD — COMPASS (2017) reduced MACE but increased major bleeding; NNT ~77 for CV death, NNH ~200 for fatal bleeding
special populations
- Obesity (>120 kg or BMI >40): limited trial data; consider anti-Xa monitoring for apixaban/rivaroxaban or use warfarin if extreme weight
- Pregnancy: all DOACs contraindicated — use LMWH
- Severe CKD (CrCl <15): avoid all DOACs; use warfarin or UFH
reversal
| Agent | Reversal | Notes |
|---|---|---|
| apixaban / rivaroxaban / edoxaban | andexanet alfa; PCC if unavailable | andexanet carries thrombotic risk (~10%) |
| dabigatran | idarucizumab 5 g IV | complete reversal within minutes |
adverse effects
- all DOACs: bleeding (GI, intracranial, surgical site)
- dabigatran: dyspepsia (20%), higher GI bleeding
- rivaroxaban: higher GI bleeding vs apixaban — COBRRA (2026)
evidence
- RE-LY (2009) — dabigatran 150 mg BID superior to warfarin for stroke prevention in AF; 110 mg non-inferior with less bleeding
- ROCKET AF (2011) — rivaroxaban non-inferior to warfarin for stroke in AF
- ARISTOTLE (2011) — apixaban superior to warfarin for stroke, major bleeding, and mortality in AF
- ENGAGE AF (2013) — edoxaban non-inferior to warfarin for stroke in AF, lower bleeding
- COMPASS (2017) — rivaroxaban 2.5 mg BID + ASA reduced MACE vs ASA alone in stable CAD/PAD
- COBRRA (2026) — apixaban vs rivaroxaban in acute VTE: 46% lower clinically relevant bleeding (NNT 26), no efficacy trade-off