Direct oral anticoagulants (DOACs)

Four direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban and edoxaban, have been developed as an alternative therapy to vitamin K antagonists (VKA) - for the prevention and treatment of venous thromboembolism (VTE), stroke prevention in non-valvular AF

• various terms have been used to describe these drugs, including new/ novel oral anticoagulants or non-vitamin K oral anticoagulants
  • International Society on Thrombosis and Haemostasis recommends using the term 'DOAC' (1)
  • DOACs directly inhibit specific proteins within the coagulation cascade; in contrast, VKAs inhibit the synthesis of vitamin K-dependent clotting factors
    
    
    • dabigatran, a direct thrombin inhibitor, and rivaroxaban, apixaban and edoxaban, the factor Xa inhibitors, produce a more predictable, less labile anticoagulant effect than VKAs
      • have been shown to be at least as safe and effective as warfarin in stroke prevention in AF
      • licensed for use in stroke prevention in non-valvular AF, the treatment of VTE and as thromboprophylaxis following major orthopaedic surgery
      • rivaroxaban has also been approved in Europe for the prevention of atherothrombotic events following acute coronary syndrome (ACS)

Clinical trials have shown that DOACs are all non-inferior to vitamin K antagonists such as Warfarin for treatment of DVT and PE, as well as evidence for their long term use for protection against recurrent DVT or PE. There are no clinical trials comparing the DOACs, so there is no evidence that one DOAC is superior to any other with respect to efficacy or side effects (2)

A switch between anticoagulants would be required in certain situations, such as (2):

• Intolerance of vitamin K antagonists or one of the DOACs,
• Poor INR control or time in therapeutic range with vitamin K antagonists,
• Patient choice

Full guidance about how to switch between parenteral anticoagulants or warfarin and DOACs can be found on the summary of product characteristics (SPC) of the DOAC being initiated (2)

There are scenarios where specific certain DOACs would be preferred (2)

• Apixaban (Eliquis) or low dose Rivaroxaban (Xarelto) if there are concerns about an individual's bleeding risk
• High dose Rivaroxaban (Xarelto), Dabigatran etexilate (Pradaxa) or Edoxaban (Lixiana) if the patient suffered from an extensive thrombosis

However, in most cases any of the DOACs would be a suitable option. If advice about which DOACs to consider for an individual patient is required, please refer to Consultant Haematologist for review (2).

DOACs have a rapid onset of action and short half-life and attain more predictable blood concentrations than vitamin K antagonists (such as warfarin), allowing standard fixed dosing regimens and obviating the need for laboratory monitoring (3)

• these factors, along with lower risk of major bleeding including intracranial hemorrhage, provide considerable advantages of DOACs over warfarin for
  thromboembolic prophylaxis in patients with atrial fibrillation

Although DOACs have a safer bleeding profile than warfarin, major bleeding still occurs in about 3-4% of patients taking DOACs every year (3)

• despite a lower incidence than warfarin, intracranial hemorrhage associated with DOAC usage remains a concern
• intracranial hemorrhage is responsible for up to 45% of all bleeding related deaths in DOAC treated patients and carries a fourfold increased risk of mortality compared with major extracranial bleeds

DOACs are contraindicated in patients with mechanical valve prostheses owing to an increased thrombosis risk (3,4)

When starting or switching to a DOAC it is important to consider certain factors such as (2):

• body weight (initial clinical trials only included patients between 50kg and 120kg, but there is increasing evidence that these medications can safely be used up to 150kg)
• renal function
• interacting medications

Reversibility may be an important consideration in certain cases (e.g. high risk of bleeding or patient choice). There is a reversal agent available for:

• warfarin,
• dabigatran etexilate

Andexanet alfa is recommended as an option for reversing anticoagulation from apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding, only if (5):

• the bleed is in the gastrointestinal tract, and
• the company provides andexanet alfa according to the commercial arrangement

There is no specific reversal agent yet available for (and although there are strategies available to manage patients on these agents in the context of major bleeding, they are not fully effective):

• Edoxaban

Reference:

• Barnes GD, Ageno W, Ansell J, Kaatz S. Recommendation on the nomenclature for oral anticoagulants: communications from the SSC of the ISTH: reply. J Thromb Haemost. 2015;13((11)):2132-3.
• Notts APC (July 2018). Direct Oral Anticoagulants (DOACs) for treatment of DVT or PE, or prevention against recurrent DVT or PE (in Adults).
• Ponamgi SP et al. Screening and management of atrial fibrillation in primary care. BMJ 2021;372:mn379 http://dx.doi.org/10.1136/bmj.mn379
• MRHA. National Patient Safety Alert - NHS England & NHS Improvement (July 14th 2021)
• NICE (May 2021). Andexanet alfa for reversing anticoagulation from apixaban or rivaroxaban