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Oral Anticoagulants Dosing 

Table of Contents

Overview #

Oral anticoagulants are commonly prescribed medications used in the prevention and management of thromboembolism.. These are high risk medications and all decisions concerning these should be made in consultation with a senior clinician. This guideline will focus on the most common oral anticoagulants prescribed in Australian Hospitals: factor Xa inhibitors (apixaban, rivaroxaban), direct thrombin inhibitors (dabigatran) and vitamin K antagonists (Warfarin). 

Indications #

Direct Oral Anticoagulants (DOACs): Apixaban, Rivaroxaban, Dabigatran

  • Venous thromboembolism (VTE) prophylaxis and treatment 
  • Thromboembolic stroke prevention in AF(1)

Warfarin

  • Thromboembolism prevention in patients with moderate to severe mitral stenosis or mechanical heart valve 
  • Thromboembolic stroke prevention in AF 
  • Thromboembolic stroke prevention in patients with prior myocardial infarction and increased stroke risk (particularly mural thrombus) (1)

Contraindications #

Warfarin 

  • Absolute
    • Severe active bleeding or states that carry an increased risk of severe bleeding (2)
  • Relative
    • Increased bleeding risk (see below)
    • Likelihood of poor compliance especially risk of unintentional overdose 
    • Protein C or protein S deficiency- increased risk of skin necrosis when commencing therapy 
    • Pregnancy (except with subspecialist input) 
    • Alcoholism (2)

DOACs

  • Absolute
    • Severe active bleeding or states that carry an increased risk of severe bleeding (uncontrolled hypertension, severe thrombocytopaenia)
    • Severe renal impairment
      • Dabigatran: CrCl <30 ml/min (contraindicated)
      • Apixaban : CrCl <25 ml/min (dose reduce)
      • Rivaroxaban: CrCl <15 ml/min (contraindicated), if CrCl <50 consider dose reduction
    • GI Haemorrhage within the last 12 months (dabigatran only)
    • Pregnancy and breastfeeding (lack of evidence, other agents preferred)
    • Situations where warfarin is preferred
      • Mechanical heart valve or moderate to severe mitral stenosis (including valvular AF)
      • Antiphospholipid syndrome (3,4,5)
  • Relative
    • Increased bleeding risk (see below)
    • # Severe hepatic impairment (3,4,5)
Factors associated with increased bleeding risk on oral anticoagulant therapy Age >65Hypertension Abnormal liver function Abnormal renal function Past history of bleeding Malignancy Previous haemorrhagic stroke Thrombocytopenia Frequent falls Alcohol misuseConcurrent antiplatelet or NSAID use Anaemia Diabetes Reduced functional capacity Recent surgery (1)

Risks and Adverse Effects  #

Adverse effects of common oral anticoagulants (2,3,4,5)

Common (>1%)Uncommon (<1%)
Warfarin Bleeding Skin necrosis, GI upset (nausea/ vomiting, diarrhoea), Allergic reaction, Alopecia, Fever  Rash, Hepatic dysfunction
Apixaban Bleeding, Nausea Thrombocytopenia, Deranged LFTs
Rivaroxaban Bleeding, Peripheral oedema, Itch, Skin blisters, Muscle spasm Hepatotoxicity 
Dabigatran Bleeding, Gastritis, Dyspepsia, GI bleeding Oesophageal ulcers, Deranged LFTs

Dosing #

Pharmacokinetics and pharmacodynamics:

DOACs: 

  • Onset 1-4 hours
  • Apixaban: onset of 3-4 hours, half-life elimination approx 12 hours (6)
  • Rivaroxaban: time to peak plasma level is 2-4 hours, half-life elimination in adults is 5-9 hours (7)
  • Dabigatran: time to peak plasma levels is 1-2 hours, half-life elimination in adults is 12-17 hours (8)

Warfarin:

  • Initial effect on INR is seen within the first 24-72 hours, this also means that any change in dose may take 24-72 hours to impact INR
  • Full therapeutic effects is usually reached within 5-7 days
  • Half life elimination is 20-60 hours and generally takes 4-5 days for INR to drop below 1.5 (2,9)

DOACs

Common doses for DOACs based on indication (3,4,5)

Indication DrugDose Practice Points
VTE (therapeutic) Apixaban 10 mg BD for 7 days, then 5 mg BD, oral Consider reducing to 2.5 mg BD if duration >6 months
Rivaroxaban 15 mg BD for 3 weeks, then 20mg daily, oralConsider dose reduction if duration >6 months
Dabigatran 150 mg BD, oral
OR
110 mg BD if CrCl: 30-49 ml/min, age >75		Requires 5 days parental anticoagulation prior to commencing 
Stroke prevention in AFApixaban5 mg BD, oral
OR 
2.5 mg BD if 2 of the following: weight <60 kg, age >80 years, Creatinine >133 micromol/L
Rivaroxaban 20 mg daily, oral
OR
15 mg daily if CrCl: 15-49 ml/min
Dabigatran 150 mg BD, oral
OR
110 mg BD if CrCl: 30-49 ml/min, age >75

Warfarin 

Age- adjusted protocol for commencing warfarin therapy, see: How to manage warfarin therapy – Australian Prescriber 

Bridging for warfarin therapy 

  • Alongside inhibition of the production of vitamin K dependent clotting factors (II, VII, IX, X) warfarin also effects anticoagulant proteins C and S and a rapid fall in these anticoagulant proteins alongside a delayed period to reach therapeutic anticoagulation leads to an initial hypercoagulable state when commencing warfarin
  • It is therefore recommended to provide bridging therapy with a parental anticoagulant when immediate therapeutic effect is required. # Seek senior advice regarding whether parental anticoagulation is required for the patient when commencing warfarin.
Example bridging regimen:1 mg/kg enoxaparin subcut BD until INR is within target therapeutic range (2)

Periprocedural bridging for warfarin therapy:

  • Warfarin is generally ceased 4-5 days prior to surgery with the aim of achieving an INR of 1.5 or lower
  • In the meantime if a patient requires ongoing anticoagulation a parental anticoagulant is usually commenced as bridging therapy once INR is below the therapeutic range
  • This should be done with the #advice of a senior clinician and is generally indicated when there is a necessity for ongoing anticoagulation (eg. mechanical heart valve in situ) 
  • Generally heparin or LMWH is used as bridging therapy (2)
  • This topic is discussed further in the “perioperative anticoagulation and antiplatelet”guideline

Monitoring and maintenance dose: 

  • Target INR is normally 2-3, it may be higher if the patient has a mechanical valve, usually 2.5-3.5 (seek advice of senior clinician)
  • INR should be monitored daily in the inpatient setting.
  • The usual maintenance dose of warfarin is 1-10mg. It is important that the patient is always prescribed the SAME BRAND of warfarin (Coumadin or Marevan) (1)
  • Warfarin monitoring usually occurs in the community and can be undertaken by the patient’s GP. 
  • If INR is stable, monitoring can occur up to every 4 weeks. (2)

Troubleshooting #

Management of bleeding in patients on DOACs (1) 

DOACReversal agent availabilityManagement
ApixabanNoIf patient is bleeding, withhold dose and seek haematology advice
RivaroxabanNoIf patient is bleeding, withhold dose and seek haematology advice 
DabigatranYes – idarucizumabFor patients with life-threatening or uncontrolled bleeding, or patients that need emergency surgery, idarucizumab is available (use with haematology advice)

Management of bleeding in patients on Warfarin (10) 

SituationManagement 
Elevated INR with NO evidence of active bleedingINR <4.5Lower or withhold dose of warfarinRecheck INR in 24 hours
INR 4.5-10Withhold warfarinConsider vitamin K (1-2 mg oral, 0.5-1 mg IV) if patient is at high risk of bleeding Recheck INR within 24 hours, restart once INR approaches therapeutic range
INR >10Withhold warfarinGive vitamin K (3-5 mg oral or IV)Consider prothrombinex VF (15-30 units/kg IV)Monitor INR 12-24 hourly, restart at lower dose once INR approaches therapeutic range
Evidence of active bleedingMinor bleedingWithhold warfarin and repeat the following day 
Clinically significant, non-life-threatening bleeding AND INR >2Withhold warfarinGive vitamin K (5-10 mg IV) and prothrombinex VF (35-50 units/kg IV)Monitor INR 12-24 hourly, restart at lower dose once INR approaches therapeutic range
Life-threatening bleeding AND INR >1.5Withhold warfarinGive vitamin K (5-10 mg IV), prothrombinex VF (50 units/kg IV), and fresh frozen plasma (150-300 ml)Monitor INR 12-24 hourly, restart at lower dose once INR approaches therapeutic range

References #

  1. eTG Complete [internet]. West Melbourne, VIC: Therapeutic Guidelines Ltd; 2017. Anticoagulant Therapy; updated Aug 2020 [cited 2021 Aug 23]: Available from: https://tgldcdp-tg-org-au.ap1.proxy.openathens.net/viewTopic?topicfile=anticoagulant-therapy&sectionId=cvg7-c31-s2#toc_d1e772 
  2. Australian Medicines Handbook Online [internet]. Adelaide, SA: Australian Medicines Handbook pty ltd; 2000. Warfarin; updated July 2021 [cited 2021 Aug 23]: Available from: https://amhonline-amh-net-au.ap1.proxy.openathens.net/chapters/blood-electrolytes/anticoagulants/other-anticoagulants/warfarin 
  3. Australian Medicines Handbook Online [internet]. Adelaide, SA: Australian Medicines Handbook pty ltd; 2000. Dabigatran; updated July 2021 [cited 2021 Aug 23]: Available from: https://amhonline-amh-net-au.ap1.proxy.openathens.net/chapters/blood-electrolytes/anticoagulants/direct-thrombin-inhibitors/dabigatran 
  4. Australian Medicines Handbook Online [internet]. Adelaide, SA: Australian Medicines Handbook pty ltd; 2000. Apixaban; updated July 2021 [cited 2021 Aug 23]: Available from: https://amhonline-amh-net-au.ap1.proxy.openathens.net/chapters/blood-electrolytes/anticoagulants/factor-xa-inhibitors/apixaban 
  5. Australian Medicines Handbook Online [internet]. Adelaide, SA: Australian Medicines Handbook pty ltd; 2000. Rivaroxaban; updated July 2021 [cited 2021 Aug 23]: Available from: https://amhonline-amh-net-au.ap1.proxy.openathens.net/chapters/blood-electrolytes/anticoagulants/factor-xa-inhibitors/rivaroxaban 
  6. UpToDate [internet]. Waltham, MA: UpToDate Inc; 2019. Apixaban: Drug Information; updated 2021 [cited 2021 Sep 3]: Available from: https://www.uptodate.com/contents/apixaban-drug-information?search=DOAC&selectedTitle=1~139&usage_type=panel&display_rank=1&kp_tab=drug_general&source=search_result#references 
  7. UpToDate [internet]. Waltham, MA: UpToDate Inc; 2019. Rivaroxaban: Drug Information; updated 2021 [cited 2021 Sep 3]: Available from: https://www.uptodate.com/contents/rivaroxaban-drug-information?search=DOAC&selectedTitle=1~139&usage_type=panel&display_rank=1&kp_tab=drug_general&source=search_result#F6724145 
  8. UpToDate [internet]. Waltham, MA: UpToDate Inc; 2019. Dabigatran: Drug Information; updated 2021 [cited 2021 Sep 3]: Available from: https://www.uptodate.com/contents/dabigatran-drug-information?search=DOAC&selectedTitle=1~139&usage_type=panel&display_rank=1&kp_tab=drug_general&source=search_result#F6211464 
  9. UpToDate [internet]. Waltham, MA: UpToDate Inc; 2019. Warfarin: Drug Information; updated 2021 [cited 2021 Sep 3]: Available from: https://www.uptodate.com/contents/warfarin-drug-information?search=Warfarin&source=search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F234855 
  10. Tran H.A, Chunilal S.D, Harper P.L, Tran H, Wood E.M, Gallus A.S. An update of consensus guidelines for warfarin reversal. Med J Aust [internet]. 2013 [cited 2021 Aug 24]: 198 (4): 198-199. Available from: doi: 10.5694/mja12.10614

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