COMMENTARY

Reversing New Oral Anticoagulants: New Agents on the Horizon

Samuel Z. Goldhaber, MD; Charles V. Pollack, Jr, MD

Disclosures

September 10, 2015

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New Data on Dabigatran Reversal Agent

Samuel Z. Goldhaber, MD: This is Dr Sam Goldhaber for the Clot Blog at theheart.org at Medscape, speaking to you from the European Society of Cardiology Congress in London. Today we are going to discuss reversal of novel oral anticoagulants (NOACs). I am pleased to have as our guest Dr Charlie Pollack. Dr Pollack is a professor of emergency medicine and a provost at Thomas Jefferson University in Philadelphia.

Charlie, you recently had a key publication in the New England Journal of Medicine about the reversal of dabigatran.[1] Could you speak to us about antidotes for the NOACs, starting with dabigatran and then the anti-factor Xa agents (eg, rivaroxaban, apixaban, edoxaban)?

Charles V. Pollack, Jr, MD: Reversal Effects of Idarucizumab on Active Dabigatran (REVERSE-AD) is an ongoing, phase 3 study of idarucizumab, which is a fragment antigen-binding monoclonal antibody directed specifically at dabigatran. We are studying it in two types of patients taking dabigatran that are pertinent to clinical practice: those who present with serious, uncontrolled, or life-threatening bleeding, and those who present with an urgent or emergent need for surgery that cannot be postponed.

REVERSE-AD is an open-label study. In preclinical and early human volunteer studies, idarucizumab had promising results. It binds dabigatran with about 350 times the avidity with which dabigatran binds to thrombin. In healthy volunteers, it has worked great, so we are hopeful that it does the same thing in patients who are bleeding and in those who need these emergency procedures.

The study aims to enroll about 300 patients. The interim analysis that we presented at the International Society on Thrombosis and Haemostasis (ISTH) congress—which, as you mentioned, was published in the New England Journal of Medicine—focused on the first 90 patients enrolled. Among these 90 patients, 51 patients had bleeding and 39 patients had to undergo surgical procedures. We looked at the anticoagulation effect of dabigatran by measuring dilute thrombin time or ecarin clotting time, neither of which are readily available but have been shown in the laboratory to reflect—very well—dabigatran levels and intensity. What we found was that idarucizumab, in a fixed 5-g dose given to these patients, quickly, completely, durably, and safely reversed the anticoagulant effects of dabigatran.

Dr Goldhaber: Just to clarify, you gave idarucizumab as an intravenous (IV) push in two doses?

Dr Pollack: Yes; it was a 5-g dose given in 2.5-g aliquots. We actually drew clotting studies in between these two aliquots.

Dr Goldhaber: How much time do you allow between the two aliquots?

Dr Pollack: By protocol they have to be given within 15 minutes of each other. We have asked investigators to draw the blood in between aliquots and give the two aliquots as quickly as they can, which is typically what sites have been doing. It can be given either as a rapid infusion or IV push, with the latter being most common, as these are very ill patients.

Reversing Anti-Factor Xa Agents

Dr Goldhaber: What about reversing the anti-factor Xa NOACs?

Dr Pollack: There is a parallel program for a drug called andexanet alfa, which works in a different way from idarucizumab. First of all, it is effective against anti-factor Xa NOACs. Because of its mechanism, idarucizumab has no activity against anti-Factor Xa NOACs. It is very specific for dabigatran, and similarly, andexanet alfa has no activity against dabigatran. It is very specific for the oral anti-factor Xa NOACs (eg, apixaban, rivaroxaban, edoxaban) and, potentially, the injectable anti-factor Xa anticoagulants (eg, enoxaparin, fondaparinux).

Andexanet alfa works not as an antibody but—as ”faux" or inactive factor Xa, which binds the factor Xa inhibitors—pulls them off of the active factor Xa so that it can once again actively function in the coagulation system. The drug is being studied in a series of phase 3 studies looking at different factor Xa substrates and different dosing regimens, with some just being bolus only and others being bolus plus infusion. This development program is not quite as far along as the idarucizumab program, so we are still waiting for results.

Dr Goldhaber: I'm very interested to hear about reversing fondaparinux because, as far as I know, we have no antidote for fondaparinux. It is particularly important because fondaparinux has a very long half-life. Tell us more about how this agent might reverse fondaparinux.

Dr Pollack: That is still under investigation, but because fondaparinux, like enoxaparin, has indirect anti-factor Xa activity, it is hypothesized that by occupying the drug with this inactive but very attractive factor Xa substitute, it might actually pull fondaparinux out of the circulation.

Dr Goldhaber: Can we think of andexanet alfa as a decoy drug? But is it inert?

Dr Pollack: Yes. It doesn't seem to have any procoagulant or anticoagulant activity, but its doses and dosing regimens are still under investigation, so it is too early to say.

Reversal Agents: Clinical Need or Reassurance

Dr Goldhaber: Well, we survived for 10 or 15 years without a reversal agent for fondaparinux and we hardly ever give reversal agents for low-molecular-weight heparin. Do you think that once clinical trials are completed for these drugs and they presumably get approved, that they will pretty much sit on the shelf for reassurance purposes? Or do you envision that emergency medicine physicians and other clinicians, such as ICU doctors and coronary care unit doctors, are going to become familiar with these drugs and use them with realistic frequency?

Dr Pollack: I don't think we are going to need them often. The fact is that the NOACs, as a class, are safer than warfarin. We certainly see fewer intracranial hemorrhages, which is one of the most feared complications of warfarin therapy. However, there are situations in which we would like to be able to supplement the general supportive measures we currently use for NOAC-related bleeding with a specific reversal agent. The things that come to mind, as an emergency medicine physician, are intracranial bleeds, multiple system trauma with hemorrhagic shock, and exsanguinating GI hemorrhage. These are things where we really would like to have a specific reversal agent, but they're not things we see on a regular basis, so I think these new agents will supplement our clinical armamentarium. They will probably make us more psychologically secure about using NOACs and I think that we will use them enough to justify their existence, but they certainly won't be everyday drugs.

Dr Goldhaber: Among cardiologists, we are always worrying about rebound thrombosis. Is that a real fear we should have with NOACs?

Dr Pollack: Patients who are taking NOACs, presumably, are on them for the right reason. They have some thrombotic proclivity or else they wouldn't be taking a NOAC. What we saw in REVERSE-AD was an absence of any thrombotic complications after dosing of idarucizumab, with the exception of one case early on and two other cases later on (days to weeks later). However, in all three of these cases, any thrombotic therapy had not been reinitiated, so these patients were back to their native state. There is no indication that idarucizumab, at least, has any procoagulant effect. I know that this is being studied for andexanet-alfa as well.

Dr Goldhaber: What should our viewers be looking for over the next year or so in terms of future development?

Dr Pollack: We are going to finish the REVERSE-AD study.[2] The regulatory packet for idarucizumab is well under review on both sides of the Atlantic for idarucizumab. Of course, we don't know when it will be approved or if it will be approved, but we are optimistic and hopeful. The andexanet program is a little bit further behind, but I think the company's public position is that they expect approval in 2016. Over the next 15 months or so we may likely have at least two specific reversal agents for NOACs. I think these agents will contribute to a greater sense of security, as the physicians who prescribe NOACs—many of whom are cardiologists—might have held back a little because of the absence of a specific reversal agent.

Dr Goldhaber: Well, we will certainly increase our armamentarium and that is always a good thing.

Charlie, thank you so much. This is Dr Sam Goldhaber, signing off for the Clot Blog.

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