November 26th, 2013

Edoxaban and the Changing Landscape of Novel Anticoagulants for Atrial Fibrillation

CardioExchange’s John Ryan interviews Christian Thomas Ruff, a coauthor of the ENGAGE AF-TIMI 48 trial of edoxaban versus warfarin in patients with atrial fibrillation. The study was published in The New England Journal of Medicine and presented at the 2013 American Heart Association conference. Click here for CardioExchange’s news coverage of the trial.

Ryan: Where does edoxaban fall on the spectrum of available anticoagulants?

Ruff: Edoxaban is the fourth factor-specific anticoagulant. Both the high- and low-dose exoxaban regimens tested in our trial performed similarly to well-managed warfarin in reducing the total incidence of stroke and systemic embolism, and the higher dose tended to outperform warfarin. However, the lower-dose regimen was associated with a higher rate of ischemic stroke. Both doses were significantly safer than warfarin, yielding substantial reductions in hemorrhagic stroke, major bleeding, and intracranial bleeding. The higher dose was associated with an increase in gastrointestinal bleeding. Both doses were associated with lower cardiovascular mortality. I think the high dose has certainly demonstrated good efficacy and better safety than warfarin. Although the lower dose was associated with an increase in ischemic stroke, it was remarkably safe and could be useful in patients at very high risk for bleeding, especially given the mortality benefit. Edoxaban’s once-daily dosing is also convenient for patients.

Ryan: How should we decide which dose of edoxaban to use in clinical practice?

Ruff: We have to wait for the regulatory authorities, but I can envision the higher dose being indicated for most patients except those at very high risk for bleeding. An important feature of the ENGAGE-AF trial was a very well-defined dose-reduction strategy that allowed more than a quarter of patients to have their dose reduced by 50%. This dose reduction did not sacrifice efficacy but resulted in even less bleeding with edoxaban than with warfarin.

Ryan: Will the introduction of edoxaban start to influence the price points of the novel anticoagulants?

Ruff: I hope that competition does bring down the cost of these medications. Price remains one of the biggest obstacles to widespread use, especially in the United States.

Ryan: Part of the attraction of edoxaban is its reversibility. Is the reversibility available in most hospitals? How long does it take?

Ruff: No reversal agents for edoxaban are currently approved, but several studies have reported exciting preliminary results. Edoxaban is being tested with a potential antidote, PER977, from Perosphere. Results show that PER977 reverses the anticoagulant activity within 30 minutes of IV administration, offering the promise of safe and effective reversal of edoxaban in cases of serious and life-threatening bleeding. Many of the other novel anticoagulants are also testing reversal agents, and it is likely that the same reversal agent may be effective for multiple drugs.


Given the data from ENGAGE-AF and Dr. Ruff’s comments, what effect do you think edoxaban will have on how patients with atrial fibrillation are treated in clinical practice?

5 Responses to “Edoxaban and the Changing Landscape of Novel Anticoagulants for Atrial Fibrillation”

  1. Leon Hyman, Ms M.D. says:

    The big question is how does Edoxaban compare to Xarelto and Eliquis? The latter two are quite effective although more costly than Warfarin.

  2. Sergio Kaiser, M.D., MSc, PhD, F.A.C.C. says:

    We will have to wait for head-to-head comparison studies. Meanwhile, all we can say is that edoxaban is another good option, tested in two different dosages. Regarding my own personal feeling, I would rather use once-daily instead of twice-daily regimens.

  3. Sergio Kaiser, M.D., MSc, PhD, F.A.C.C. says:

    Dr. Christian Ruff and colleagues have just published a meta-analysis of the main randomized trials of new oral anticoagulants. Science moves forward very fast! After ENGAGE and this meta-analysis, I feel, as a practicing physician, much more encouraged to prescribe the new oral anticoagulants. Intracranial bleedings are a devastating complication and these compounds lead to a robust 52% reduction in risk when compared to effective warfarin therapy, while being non-inferior regarding stroke prevention. By the way, new antidotes are on their way and will probably soon be available.

  4. David Powell , MD, FACC says:

    The niche for this agent among its “novel” associates is unclear. The data seems comparable to rivaroxaban as a once daily agent, possibly with a better bleeding profile ( really just conjecture). But the study does not establish superiority in ITT analysis compared with warfarin, whereas RELY and ARISTOTLE do show superiority in the primary endpoint. Dabigatran has the most robust reduction in ischemic stroke, and apixaban has an excellent bleeding profile, particularly if you look at AVEROES as well.

    What are the chances of a head-to-head study?

    I am already exasperated with listening to these sales reps. We allow them in because they provide samples and lunch, which at least the staff appreciates.

    Cost is a big issue, but I don’t know how to get unbiased insurance-specific data, so I will often write the options down and ask the patient to find out the price differentials.