Direct Oral Anticoagulant

Aka: Direct Oral Anticoagulant, DOAC, Direct Acting Anticoagulant, Non-Vitamin K Antagonist Oral Anticoagulant, NOAC

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II. Definitions

  1. Direct Oral Anticoagulants (DOACs) or Non-Vitamin K Antagonist Oral Anticoagulant (NOACs)
    1. Factor Xa Inhibitors (e.g. Rivaroxaban, Apixaban, Edoxaban)
    2. Indirect Xa Inhibitors (e.g. Fondaparinux)
    3. Direct Thrombin Inhibitors (e.g. Dabigatran)

III. Indications

  1. Anticoagulation (e.g. Venous Thromboembolism, Atrial Fibrillation)

IV. Contraindications: Cases in which Warfarin is the Preferred Agent

  1. Mechanical Heart Valve
    1. Pradaxa and Apixaban have both shown higher thrombosis risk than Warfarin
  2. Moderate to severe Mitral Stenosis and Atrial Fibrillation
    1. Higher mortality and stroke risk with Rivaroxaban compared with Warfarin
  3. Left Ventricular Assist Device (LVAD)
  4. Antiphospholipid Antibody Syndrome and Thrombosis history
  5. Breakthough stroke on DOAC
  6. DOAC Drug Interactions that decrease Anticoagulation efficacy (e.g. Rifampin, Carbamazepine)

V. Mechanism

  1. Factor Xa Inhibitors (e.g. Apixaban, Rivaroxaban, Edoxaban, Betrixaban)
    1. Directly and reversibly bind the active site on Factor Xa
      1. Block Thrombin formation as a part of the Common Clotting Pathway
    2. Factor Xa Inhibitors are based on naturally occurring substances
      1. Antistasin
        1. Isolated in 1980s from Mexican leach extract
      2. Tick Anticoagulant peptide (TAP)
        1. Isolated from the tick Ornithodoros moubata
  2. Indirect Xa Inhibitors (e.g. Fondaparinux)
    1. Binds Antithrombin III and modifies its form, substantially increasing its activity by 300 fold
    2. Super-charged Antithrombin III neutralizes Factor Xa at a markedly increased rate, resulting in Anticoagulation
  3. Direct Thrombin Inhibitors (e.g. Dabigatran)
    1. Selectively and reversibly inhibit free and clot-bound Thrombin
    2. Prevent conversion of Fibrinogen to Fibrin (which in turn prevents clot)

VI. Precautions: Dosing

  1. Direct Oral Anticoagulants (DOACs) are under-dosed in up to 25% of Atrial Fibrillation cases
  2. Check the dosing guidelines when prescribing (instead of relying on memory)
  3. Write the DOAC indication and the intended duration on the prescription (enlist pharmacy second check)
  4. Consider Warfarin or other Anticoagulation in obese patients with weight >120 kg or BMI >40
  5. Review any non-standard dosing with consultants (e.g. cardiology, hematology, renal)
  6. Renal Dosing
    1. Reduced doses apply only to Atrial Fibrillation, not to Venous Thromboembolism (except for Edoxaban)
    2. Apixaban (Eliquis) dose is halved in a. fib if 2 of 3 criteria (age >80, wt <60 kg, Creatinine >1.5 mg/dl)
    3. Rivaroxaban (Xarelto) dose is reduced in a. fib and crCl 15-50 ml/min (avoid if <15 ml/min)
    4. Edoxaban (Savaysa) dose in a.fib and VTE is halved for weight <50 kg, or CrCl 15-50 ml/min (avoid <15 ml/min)
    5. Avoid Dabigatran (Pradaxa) if CrCl <30 ml/min
    6. Only Apixaban (Eliquis) could be considered in Hemodialysis (Exercise caution)
  7. Drug Interactions: Strong CYP3A4 Inhibitors and P-gp Inhibitors
    1. Decrease Apixaban (Eliquis) dose
    2. Avoid Rivaroxaban (Xarelto)
  8. References
    1. (2022) Presc Lett 29(8): 46

VII. Medications

  1. See Factor Xa Inhibitor (Rivaroxaban, Apixaban)
  2. See Direct Thrombin Inhibitor (e.g. Dabigatran)
  3. See Fondaparinux (Arixtra)

VIII. Drug Interactions

  1. Unknown safety and bleeding risk when combined with antiplatelet agents
  2. Reducing DOAC dose due to Drug Interaction risk may render it ineffective
  3. Review specific agents for Drug Interactions (e.g. P-Glycoprotein, CYP3A4)
    1. Apixaban and Rivaroxaban are metabolized by CYP3A4, and their absorption is reduced by P-glyoprotein
  4. Strong CYP3A4 and P-Glycoprotein Inducers decrease DOAC levels (increase thrombosis risk)
    1. Carbamazepine (Tegretol)
    2. Phenytoin (Dilantin)
    3. Rifampin
    4. St Johns Wort
  5. Strong CYP3A4 and P-Glycoprotein Inhibitors increase DOAC levels (increase bleeding risk)
    1. Ritonavir
    2. Verapamil
      1. Avoid combining with Rivaroxaban if GFR <80 ml/min (Apixaban may still be used)
    3. Antifungals (Ketoconazole, Fluconazole, Itraconazole)
      1. Single dose Fluconazole is not expected to alter DOAC levels significantly

IX. Labs: Drug Interactions

  1. Direct Oral Anticoagulants (DOACs) may result in inaccurate results on clot and coagulation based assays
  2. Tests impacted by DOACs with alternative options
    1. Lupus Anticoagulant panel
      1. Consider ELISA Anticardiolipin Antibody and anti-beta2 GP1 Antibody as an alternative
    2. Activated Protein C resistance
      1. Consider Factor V Leiden as an alternative
  3. Tests impacted by DOACs (test when DOAC at trough level before next dose and interpret with caution)
    1. Protein C Activity
    2. Protein S Activity
    3. Antithrombin Activity
  4. References
    1. Choosing Wisely (American College of Clinical Pathology)
      1. https://www.choosingwisely.org/clinician-lists/ascp-hypercoagulable-workup/
    2. Adcock (2015) Thromb Res 136(1):7-12 +PMID:25981138 [PubMed]
    3. Murer (2016) Lab Med 47(4): 275-78 +PMID:27474775 [PubMed]

X. Management: Reversal

  1. See DOAC Protocol in the Perioperative Period
  2. General measures
    1. Stop offending DOAC
    2. Consider Activated Charcoal if presenting within 2 hours of suspected Overdose ingestion
    3. No readily available, single test measures DOAC overactivity
      1. INR (PT) and PTT are typically normal in patients taking Factor Xa Inhibitors
        1. Dabigatran, as an exception, does increase PTT level
      2. Anti-Xa activity level requires drug-specific calibrators and results are delayed
        1. Bleeding is unlikely due to Xa agent if Anti-Xa activity level <0.1 IU/ml
    4. Hemodialysis is not effective (Protein bound)
    5. No human data to suggest any non-specific reversal agent is significantly effective
  3. For serious, life threatening bleeding (e.g. CNS Hemorrhage following Head Trauma)
    1. See Emergent Reversal of Anticoagulation
    2. Reversal may need to be continued for up to 3 days in severe renal disease
    3. Prothrombin Complex Concentrate 4 (PCC4, Kcentra or outside U.S. Octaplex, Beriplex)
      1. Dose 25 to 50 units/kg IV contingent on INR and bleeding severity
      2. PCC4 may have similar efficacy to Andexxa at half the cost (based on weak evidence)
  4. Older agents (not recommended, or unavailable)
    1. Andexxa or Andexanet Alfa (Inactivated Recombinant Factor Xa)
      1. Released in 2018 and off the U.S. market in 2025
      2. Antidote for Eliquis (Apixaban) or Xarelto (Rivaroxaban), but not other Xa agents
      3. Binds Factor Xa Inhibitors
      4. Limits progression of bleeding within 12 hours of dose (onset as early as 1 hour)
      5. Expensive: $25,000 to 50,000 per patient ($12-15,000 per dose)
      6. Risk of Hypercoagulability complications (CVA, VTE)
      7. Ineffective in the 25% of patients who have low anti-Factor Xa Inhibitor
  5. References
    1. Deloughery and Orman in Herbert (2013) EM:Rap 13(9): 1
    2. Nordt and Rech in Swadron (2023) EM:Rap 23(4): 8-9
    3. Sun (2016) Crit Dec Emerg Med 30(8): 28
    4. Connolly (2019) N Engl J Med 380(14):1326-35 +PMID:30730782 [PubMed]

XI. Management: Other bleeding complications

  1. See DOAC Protocol in the Perioperative Period
  2. Menorrhagia
    1. Expect Menses to be heavier than typical while on Factor Xa Inhibitors
    2. However, severe Menstrual Bleeding on Factor Xa Inhibitors is uncommon
    3. Patients should seek medical attention for 4 soaked pads in 4 hours or more than 10 pads in 24 hours
      1. Consider holding Factor Xa Inhibitor for one day and then restarting at same dose
    4. References
      1. Orman and Klein in Herbert (2017) EM:Rap 17(7): 9-11

XII. Efficacy

  1. DOACs are as effective as conventional agents at preventing VTE, and all cause mortality
  2. DOACs have a less risk of major bleeding when compared with conventional agents
    1. Some studies show DOACs with 50% less major bleeding when compared with Warfarin
    2. However, life threatening bleeding rate with DOACs is still 1.6% to 3.6% per year
      1. Intracranial Bleeding annual rates are 0.3 to 0.5%
  3. References
    1. Wang (2023) Cochrane Database Syst Rev 4(4):CD010956 +PMID: 37058421 [PubMed]

XIII. References

  1. (2023) Presc Lett 30(5): 27-8
  2. Hoag, Jundoria, Dave and Lopez (2026) Crit Dec Emerg Med 40(7): 4-13
  3. Wigle (2019) Am Fam Physician 100(7): 426-34 [PubMed]

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