Novel Oral Anticoagulants (NOACs)

Also known as “Non-Vitamin-K-antagonist Oral Anticoagulants” (NOACs) or “Direct Oral Anticoagulants” (DOACs). Previously, warfarin was the only oral anticoagulant available in Australia however since the introduction of NOACs, this has increased the drug choices available for oral anticoagulation. NOACs currently registered for use in Australia include: dabigatran (Pradaxa), rivaroxaban (Xarelto) and apixaban (Eliquis).

Most concerns regarding NOACs in the ED relate to reversal or commencement.

Reversal of NOACs

General principles for reversal

  • Organise urgent FBC, group and hold, creatinine.
  • Send coagulation profile, including relevant levels (dabigatran level, aPTT, TT, prothrombin time and/or anti-Xa level).
  • Withhold further doses of anticoagulant.
  • For ingestion within 2 hours: activated charcoal.
  • Early haematology consultation.
  • Recombinant factor VIIa (NovoSeven® RT) is no longer recommended but other pro-haemostatic agents may be considered in consultation with haematology for life-threatening bleeding (significant risk of thrombotic complications).

Dabigatran reversal

  • Consider idarucizumab (Praxbind) - study dose: 5 g IV as a single dose (Pollack, 2015).

Give as 2 consecutive IV infusions of 2.5 g over 5–10 minutes each OR as 2 consecutive 2.5 g bolus injections

Rivaroxaban / Apixaban reversal

  • For life-threatening bleeding or emergency surgery, consider the use of prothrombin complex concentrate (Prothrombinex®-VF) in consultation with haematology (risk of thrombotic complications). It has been shown to normalise prothrombin time in a trial of 12 healthy male subjects at a dose of 50 IU/kg (administered as a slow IV injection) (Eerenberg et al., 2011).
  • Rivaroxaban and apixaban are highly protein-bound and hence NOT dialysable.

Commencement of NOACs

Consider the advantages and disadvantages of starting treatment with a NOAC as opposed to LMWH and warfarin.

Indications

NOAC Guidelines: Registered indications (CEC, July 2017).

  • Treatment of acute DVT or PE, and secondary prevention of same (often in ED).
  • Atrial fibrillation with one or more additional risk factors for stroke (possibly in ED).
  • Prevention of VTE after elective hip or knee replacement (not in ED).

Contraindications

  • Significant valvular heart disease or mechanical heart valve.
  • Moderate-to-severe renal failure (CrCl <30mL/min for dabigatran and rivaroxaban; CrCl <25mL/min for apixaban).
  • Significant liver failure.
  • Significant active bleeding or bleeding disorder.
  • Organ lesions at risk of bleeding including ICH in previous 6 months.
  • Indwelling spinal or epidural catheter and during the first 6 hours after removal.
  • Pregnancy or breastfeeding.
  • Known hypersensitivity.
  • Significant drug interactions – see general principles.
  • Extremes of body weight (£ 50 kg or ³ 120 kg).
  • Antiphospholipid antibody syndrome.

General principles

  • Renal impairment (CrCl <30 mL/min for dabigatran and rivaroxaban; CrCl <25mL/min for apixaban) will preclude use. Do not use the eGFR reported in pathology results – estimated CrCl should be calculated using the Cockcroft-Gault equation.
  • Baseline FBC, EUC, LFT, PT, aPTT.
  • Seek advice for patients with a history of GI bleeding.
  • Seek specialist advice for patients with VTE associated with active malignancy.
  • Consider potential for drug interactions, especially: azole antifungals (itraconazole, ketoconazole, voriconazole, etc.); immunosuppressants (cyclosporin, tacrolimus, etc.); HIV protease inhibitors (e.g. darunavir, ritonavir).
  • NOAC studies included only a minority of obese patients so clinical data on efficacy and safety of NOACs for obese patients are limited. Available pharmacokinetic data suggest that in obese patients, there may be decreased drug exposure, reduced peak drug concentration and shorter half-lives of NOACs. This raises concerns about underdosing. Consequently, the International Society on Thrombosis and Haemostasis (ISTH) recommends standard dosing in patients up to 120 kg or with a BMI up to 40 kg/m2, and recommends avoiding use of NOACs in patients who exceed these levels.

Dosing

Dabigatran

Not usually commenced in ED.

NOAC Guidelines: Dabigatran Summary (CEC, July 2017).

Apixaban

NOAC Guidelines: Apixaban dosing for VTE and Apixaban Summary (CEC, July 2017).

For treatment of acute VTE:

  • Patient should follow up with haematologist or GP within the first week.
  • Commence at 10mg orally twice daily (for 7 days).
  • Then continue at 5mg orally twice daily (duration is according to patient requirement).
  • May be taken with or without food, but as whole tablet.
  • For a missed dose: if less than 6 hours since missed dose, take the dose immediately; or if more than 6 hours since missed dose, then do not take the missed dose and take the next dose at the usual time without double dosing.
  • Patient Information Factsheet - Apixaban (CEC, August 2016).

For prevention of recurrent VTE:

  • An assessment of the risks of recurrence and bleeding is required to determine if extended anticoagulation is indicated and if at the full-dose (5mg orally twice daily) or lower dose (2.5mg orally twice daily).

Rivaroxaban

See NOAC Guidelines: Rivaroxaban dosing for VTE and Rivaroxaban Summary (CEC, July 2017).

For treatment of acute VTE:

  • Patient should follow up with haematologist or GP within the first 3 weeks.
  • Commence at 15mg orally twice daily (for 3 weeks).
  • Then continue at 20mg orally once daily (duration is according to patient requirement).
  • Take tablets with food for optimal oral bioavailability.
  • For a missed dose:
    • ONCE daily dosing
      • Take it as soon as you remember on the same day
      • Do not take extra tablets to make up for the forgotten tablet
      • Take the next tablet on the following day and carry on taking a tablet once a day as normal.
    • 15mg tablet TWICE DAILY dosing
      • Take it as soon as you remember on the same day
      • You can take two 15 mg tablets at the same time to get a total dose of 30mg in one day
      • The following day onwards, you should take one tablet twice a day as normal.
  • Patient Information Factsheet - Rivaroxaban (CEC, August 2016).

For prevention of recurrent VTE:

  • An assessment of the risks of recurrence and bleeding is required to determine if extended anticoagulation is indicated and if at the full-dose (20mg orally once daily) or lower dose (10mg orally once daily).

Advantages compared to warfarin

  • Fixed doses and no need for frequent blood tests as pharmacokinetics are more predictable however renal function should be monitored particularly in those with chronic kidney disease or those who are elderly.
  • Onset of action within 2-3 hours (apixaban and rivaroxaban does not require bridging with heparin or LMWH).
  • Less likely to interact with foods, other drugs or illnesses.
  • Possibly lower incidence of life-threatening bleeding.

Disadvantages compared to warfarin

  • Less experience with reversal of dabigatran; at the time of writing, no specific reversal agent for rivaroxaban and apixaban available.
  • Not suitable for prosthetic heart valves or in those with moderate-to-severe renal failure.
  • Authority prescription required.
  • Possible increase in incidence of GI bleeding.

(Fox et al., 2012 and EINSTEIN Investigators, 2010)

Further References and Resources

Clinical Excellence Commission (2017) NOAC Guidelines: Non-Vitamin K Antagonist Oral Anticoagulant, July 2017.

Presentation: NOAC for Peripheral DVT, Tim Brighton, Haematologist, Prince of Wales Hospital at the ECI ED Leadership Forum 1 April 2016

Dabigatran Background Reading and Various References

EINSTEIN Investigators (2010) Oral Rivaroxaban for Symptomatic Venous ThromboembolismNew England Journal of Medicine, vol. 363, pp. 2499-2510. DOI: 10.1056/NEJMoa1007903

Fox B.D. et al. (2012) Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials, BMJ, November 2012, 345:e7498.

Martin, K., et al. (2016) Use of the Direct Oral Anticoagulants in Obese Patients: Guidance from the SSC of the ISTH. Journal of Thrombosis and Haemostasis, vol. 14, no. 6, pp. 1308–13.

Pollack C. V. et al. (2015) Idarucizumab for Dabigatran Reversal, New England Journal of Medicine, August 2015, vol. 373, no. 6, pp. 511-520.

The Bottom Line -  Blog Review of the Pollock 2015 paper

Stevens, Hannah, et al. (2019) Venous Thromboembolism: Current Management. Australian Prescriber, vol. 42, no. 4, pp. 123–26.

Tran, H. et al. (2014) New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural / bleeding management, Internal Medicine Journal, vol. 44, pp. 525-36

Patient Factsheets

  • Rivaroxaban - Clinical Excellence Commission, August 2016

Apixaban - Clinical Excellence Commission, August

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