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There is something strange about apixabanJun 26, 2012 13:45 EDT
When the ARISTOTLE trial was published last year in the New England Journal of Medicine, results for apixaban were hailed as the best results seen in a large randomized trial vs warfarin, better even than the trials using dabigatran or rivaroxaban in patients with atrial fibrillation. So why is the FDA reluctant to approve the drug?
Disclosure: Dr Topol has no financial interests or connections with Bristol-Myers Squibb or Pfizer and has no disclosures to make relevant to this topic.
- No US approval yet for apixaban for stroke prevention in AF
- ARISTOTLE: A major win for apixaban in AF
- FDA unexpectedly delays move on anticlotting drug
- Apixaban (Eliquis) was supposed to beat dabigatran (Pradaxa) and rivaroxaban (Xarelto). . . . What gives?
- Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365:981-992. Abstract.
Eric Topol MD: This segment is about "There is something strange about apixaban." What I'm referring to is the New England Journal [of Medicine] ARISTOTLE paper; this is the front page of it, published in September 15, 2011. It is a trial of over 18 000 patients, over 9000 patients each receiving apixaban or warfarin in a double-blind, double-dummy randomized trial with a very good compliance of warfarin INR, as good as one has seen in any of the trials. This [apixaban] is a factor Xa inhibitor new anticoagulant and in the group of new anticoagulants such as dabigatran, rivaroxaban; and these are the replacements, if you will, for warfarin.
Now what's fascinating about this particular trial, the one that was published back last September, was that it had the best look of all three of these agents. So whether it was a direct thrombin inhibitor in the case of dabigatran, or these factor Xa inhibitors, they each were compared in atrial fibrillation patients to reduce stroke, hopefully reduce bleeding. And what was found in this trial, in the New England Journal paper, was that there was a significant reduction of stroke, all-cause stroke, whether it's hemorrhagic or particularly embolic in these patients with atrial fibrillation, but also an improved survival, 11% statistically significant survival, all-cause death, and then a decrease, a significant decrease in major bleeding.
This is more favorable than what was seen with either [of] the other two agents in these large trials of pushing 20 000 patients with atrial fibrillation. Not the kind of trials that I would like to see, but nonetheless providing classic, definitive evidence of benefit.
Now, the shock about this is that, here, going from September to the end of June 2012, this drug has not been approved, even though there is no direct comparisons with the other drugs (dabigatran or rivaroxaban). This has the best-looking profile and it's very straightforward. You look at the New England Journal paper [and think] that this drug should get rapid approval. But in late June, we have learned that there is communication between the FDA and the manufacturers that this drug is not approvable and there is more information that is needed. In fact, there are issues about data management and data quality.
So we have learned before that what is published in the New England Journal is not necessarily sacrosanct and doesn't always match up with the actual data that the FDA gets to audit. But the problem here is a lack of transparency. No one in the medical community is given the precise reason for this holdup for a drug that could have a particularly favorable impact and could easily become the real replacement for warfarin in patients with atrial fibrillation, trying to prevent stroke, trying to prevent bleeding, and of course the only one that has an improved survival.
So don't you think in this era of information, that this should be transparent? We should know what is going on here? What are the issues with the data quality, management, data integrity? Is there something really off the track with the New England Journal paper? And how long are we going to be kept in suspension?
This is a really big issue: this cloaked way, secretive way in which the FDA communicates with the manufacturer about a trial that is already in the public domain, in one of the most prestigious medical journals in the world. So there is really something strange about apixaban and ARISTOTLE.
I would be interested in your views about what is going on here, but this is really peculiar, and hopefully some day we will get the answer. But I would suggest that we should have the knowledge of what the issues are, now, and not be kept in this clandestine, secretive mode. So I look forward to your comments; thanks for your attention.
To download this transcript in PDF format, click here.