This news story was first published in print and online by The Medical Republic on the 18th November 2015.


Reversal agent for factor Xa inhibitors could broaden the clinical use of these anticoagulants, a study in NEJM has found.

The factor Xa inhibitors rivaroxaban and apixaban are approved in Australia for the prevention and treatment of venous thromboembolism during elective hip and knee replacement surgery and for prophylaxis in non-valvular atrial fibrillation.

The total prescription volume of direct oral anticoagulants (DOACs, also including the thrombin inhibitor dabigatran) in 2014 was 647 481 as compared to Warfarin which was 920,289. Leading cardiologist, Professor David Brieger, said that current lack of a specific antidote has been one limitation to the wider uptake of DOACs.

“The inability to reverse them urgently if you need to, is a concern for some doctors and certainly for some patients, but despite that they’re still used quite widely,” said Professor Brieger, head of coronary care at Concord Hospital. “Patients feel much more comfortable knowing that there’s that option available.”

In the NEJM study, healthy participants were given apixaban (5 mg, twice daily) or rivaroxaban (20 mg, once daily) to stimulate anti-coagulation. Twenty-four patients were randomly allocated to treatment with the antidote andexanet administered as a bolus.

Andexanet treatment caused a 94% reduction in anti-factor Xa activity and a complete restoration of thrombin generation in all patients. Reversal of the anticoagulant effect by andexanet was achieved within 2 to 5 minutes. For 9 participants receiving placebo there was only a 21% reduction in anti-factor Xa activity, and thrombin generation was restored in only one case.

“This is an early stage trial, but if the promise of this is realised it’s going to be a good thing to have it available as long as it’s affordable,” said Professor Brieger.

Andexanet is a modified factor Xa decoy protein designed to bind factor Xa inhibitors with high affinity and neutralise them. No thrombotic events were observed with use of andexanet and the only adverse event was the recurrence of hives in one patient.

The authors of the trial noted that andexanet would need to be tested in the emergency setting to prove its real value. “That would be an essential step,” said Professor Brieger. He gives the example of an antidote to the direct thrombin inhibitor dabigatran (Pradaxa), currently being evaluated in the USA in patients with serious bleeding.

“That has been approved in the US and we might be seeing this drug in the middle of next year in Australia,” said Professor Brieger. “Andexanet is almost certainly going to need to follow that path; it’s about 18 months behind.”

For some patients, DOACs are more easily managed than Warfarin because they have rapid onset, fewer interactions and regular routine monitoring is not required, said Professor Brieger. “There is a process of putting patients onto Warfarin which involves adjusting the doses over a period of weeks,” he explained. “It’s difficult to do and always has been. Even in the best hands you manage to stabilise patients on a therapeutic dose about 70% of the time.”

But he stressed that deciding whether to give up that tried-and-tested therapy for a new drug combination was a shared decision for doctor and patient. “If the trials do show that this is effective agent at turning off anticoagulant activity, that’s a piece of information that I’ll give my patients. And it might sway their decision.”

NEJM 2015 Dec 17;373(25):2413-24