Saturday, April 9, 2011

Apixaban: It's been a while since I've read about a new drug that I actually like

In the March 3rd NEJM, Apixaban makes its debut on the scene of stroke prevention in Atrial Fibrillation with the AVERROES trial (see: ), and I was favorably impressed. The prophylaxis of stroke in atrial fibrillation is truly an unmet need because of the problematic nature of chronic anticoagulation with coumarin derivatives. So a new player on the team is welcome.

A trusted and perspicacious friend dislikes the AVERROES study for the same reason that I like it - he says that comparing Apixaban to aspirin (placebo, as he called it) is tantamount to a "chump shot". But I think the comparison is justified. There are numerous patients who defer anticoagulation with coumarins because of their pesky monitoring requirements, and this trial assures any such patient that Apixaban is superior to aspirin, beyond any reasonable doubt (P=0.000002). (Incidentally, I applaud the authors for mentioning, in the second sentence of the discussion, that the early termination of the trial might have inflated the results - something that I'm less concerned with than usual because of the highly statistically significant results which all go basically in the same direction.) Indeed, it was recently suggested that "me-too" agents or those tested in a non-inferiority fashion should be tested in the population in which they are purported to have an advantage (see: ). The AVERROES trial does just that.

Had Apixiban been compared to warfarin in a non-inferiority trial (this trial is called Aristotle and is ongoing) without the AVERROES trial, some[busy]body would have come along and said that non-inferiority to warfarin does not demonstrate superiority over aspirin +/- clopidogrel, nor does it demonstrate safety compared to aspirin, etc. So I respectfully disagree with my friend who thinks it's a useless chump shot - I think the proof of efficacy from AVERROES is reassuring and welcome, especially for patients who wish to avoid coumarins.

Moreover, these data bolster the biological plausability of efficacy of oral factor Xa antagonists, and will increase my confidence in the results of any non-inferiority trial, e.g., ARISTOTLE. And that train of thought makes me muse as to whether the prior probability of some outcome from a non-inferiority trial might not depend on the strength of evidence for efficacy of each agent prior to the trial (self-evident, I know, but allow me to finish). That is, if you have an agent that has been used for decades compared to one that is a newcomer, is there really equipoise, and should there be equipoise about the result? Shouldn't the prior be higher that the old dog will win the fight or at least not be beat? These musings might have greater gravity in light of the high rate of recall from the market of new agents with less empirical evidence of safety buttressing them.

One concerning finding, especially in light of the early termination, is illustrated in Figure 1B. The time-to event curves for major bleeding were just beginning to separate between 9 and 14 months, and then, inexplicably, there were no more bleeding events documented after about 14 months. It almost looks as if monitoring for severe bleeding stopped at 14 months. I'm not sure I fully understand this, but one can't help but surmise that, if this agent truly is a suitable replacement for warfarin, it will come with a cost - and that cost will be bleeding. I wager that had the trial continued there would have been a statistically significant increase in major bleeding with apixaban.

It is one interesting that not a single mention is made by name in the article to a competitor oral factor Xa inhibitor, indeed one that is going to make it to market sooner than Apixaban albeit for a different indication: Rivaroxaban. Commercial strategizing is also seen foreshadowed in the last paragraph of the article before the summary: the basic tenets of a cost benefit analysis are laid bare before us with one exception: cost of Apixaban. Surely the sponsor will feel justified in usurping all but just a pittance of the cost savings from obviated INR monitoring and hospitalizations when they price this agent. Only time will tell.


  1. I don't know if you will check this post, but I want to thank you for your article. My mother just started eliquis and I am concerned about any new drug. She is 87 and has a-fib. She had a bad reaction to coumadin and is hesitant to try this, but her doctor said she has to be on a blood thinner. She's 87 and I am worried about bleeding with her. She hemorraghed on coumadin on the left side of her face and eye. I am hoping for better things with this new drug. Thank you.

  2. Hi, thanks for your comment. I think your first question is whether your mother should be on blood thinners at all - and that question will hinge on the risks versus the benefits with each possible drug. See:

  3. Is this news article simply sensationalism, or is there something to be really worried about?

    (Do you get notified of new comments? This is the best place I could find to ask the question.)