REVISED Anticoagulation module 3: anticoagulant therapy

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Reversal of NOACs

A reversal agent for dabigatran – idarucizumab – is now licensed in the US and Europe. For the Xa inhibitors, reversal agents are in the late stages of development, and can be expected to be available soon.

Idarucizumab is a fully humanised monoclonal antibody fragment, which binds dabigatran and nullifies its anticoagulant activity. The RE-VERSE AD trial, a phase 3 trial of efficacy of idarucizumab, is still ongoing, but interim results were published recently which showed impressive correction rates of both laboratory parameters and bleeding.9

Andexanet alfa is a recombinant, modified factor Xa molecule with no pro-coagulant activity, which binds and inactivates all Xa inhibitors. Phase 2 trials have yielded promising results, and phase 3 trials are underway. This agent may also be useful in the reversal of low molecular weight heparins (as discussed above, these mostly target factor Xa, and are incompletely reversed by the available antidote, protamine).

Andexanet’s manufacturer, Portola Pharmaceuticals, has provided a video illustrating its mechanism of action:
https://www.portola.com/clinical-development/andexanet-alfa-prt4445-fxa-inhibitor-antidote/

Other reversal agents in development include Ciraparantag (PER 977). This is a small molecule which can bind inhibitors of both factor IIa and factor Xa – in effect a universal NOAC reversal agent.

Pending licensing of these agents, the British Committee for Standards in Haematology have issued guidance on the management of bleeding in patients on all anticoagulants, including NOACs.10 In an emergency, prothrombin complex concentrate is suggested based on limited data from animal and human studies. Expert help should be sought early, and local guidance followed.

Figure 3 demonstrates how the NOACs act on the coagulation pathway.

Figure 4. Sites of action of NOACs
Figure 3. Sites of action of NOACs

Indications for anticoagulation in cardiology

These can be grouped into three areas: acute coronary syndromes (ACS), non-valvular AF, and diseases of the heart valves.

Heart valves

Where patients with valvular heart disease require anticoagulation, this should usually be with a vitamin K antagonist – none of the NOACs is licensed for valvular AF, and none has been shown to be adequate for the anticoagulation of patients with mechanical heart valves. The RE-ALIGN study of dabigatran versus warfarin for this indication was terminated early due to an excess of both thrombotic complications and bleeding in the dabigatran group.11

Anticoagulation for patients with valvular heart disease is considered in detail in another BJC Learning module, ‘Heart valve disease module 7: antithrombotic therapy for valvular heart disease’.