Chapter 39  ·  Module 4

Direct Oral Anticoagulants

Mechanisms, pharmacokinetics, indications, reversal, and special populations at a glance

Abbreviations: DOAC = direct oral anticoagulant  ·  FXa = factor Xa  ·  DTI = direct thrombin inhibitor  ·  CrCl = creatinine clearance  ·  P-gp = P-glycoprotein  ·  4F-PCC = four-factor prothrombin complex concentrate  ·  VTE = venous thromboembolism  ·  AF = atrial fibrillation  ·  ICH = intracranial hemorrhage  ·  APS = antiphospholipid syndrome

Mechanism & Pharmacokinetics

Agent Target Key PK Feature Renal Dose Adjust Key Interaction Reversal
Dabigatran Thrombin (free + fibrin-bound) Prodrug; 80% renal; do not crush capsule; dialyzable Reduce: CrCl 15–30; avoid: CrCl <15 P-gp inhibitors/inducers (not CYP) Idarucizumab 5 g IV
Rivaroxaban Factor Xa (free + prothrombinase-bound) Take 15/20 mg with food; ~33% renal, ~67% hepatic AF: reduce to 15 mg daily if CrCl 15–49 Combined CYP3A4 + P-gp inhibitors Andexanet alfa or 4F-PCC
Apixaban Factor Xa (free + prothrombinase-bound) Multi-pathway; least renal-sensitive; best CKD profile Reduce if ≥2 of 3: age >80, wt ≤60 kg, Cr ≥1.5 Combined CYP3A4 + P-gp inhibitors Andexanet alfa or 4F-PCC
Edoxaban Factor Xa (free + prothrombinase-bound) ~50% renal; NOT for AF if CrCl >95 mL/min Reduce to 30 mg if CrCl 15–50 P-gp inhibitors/inducers 4F-PCC (no approved specific agent)

Indications & Advantages Over Warfarin

AF Stroke Prevention

Non-Valvular AF

  • All four DOACs approved; preferred over warfarin
  • 40 to 50% relative ICH reduction vs warfarin across trials
  • Apixaban only agent showing superiority on both efficacy and major bleeding
  • Not for AF with mechanical valves or moderate-to-severe mitral stenosis

VTE Treatment

DVT and PE

  • Rivaroxaban, apixaban: oral-only strategy (no heparin lead-in)
  • Dabigatran, edoxaban: require 5 to 10 days parenteral lead-in
  • Extended secondary prevention: rivaroxaban 10 mg or apixaban 2.5 mg daily
  • Cancer-associated VTE: DOACs over LMWH for most cancers

Contraindications

Where DOACs Cannot Be Used

  • Mechanical heart valves (all DOACs)
  • AF with mitral stenosis (all DOACs)
  • Triple-positive APS (warfarin superior)
  • Severe hepatic impairment (Child-Pugh C)
  • Pregnancy and breastfeeding

Reversal Agent Selection — Life-Threatening Bleeding

Dabigatran: idarucizumab 5 g IV (two 2.5 g infusions) — first choice; 4F-PCC 25 to 50 units/kg if unavailable; hemodialysis removes ~65% over 4 hours. Rivaroxaban or apixaban: andexanet alfa (low or high dose per timing and dose of last DOAC); 4F-PCC 25 to 50 units/kg as alternative. Edoxaban: 4F-PCC only (no approved specific agent). All: resume anticoagulation minimum 24 hours after reversal; reassess thrombotic vs. bleeding risk first.