There is something strange about apixaban

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.

See also:

• 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.

Transcript:

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.

Your comments

	There is something strange about apixaban
	# 1 of 12	June 27, 2012 06:11 (EDT)
	Ken Grauer, MD	THANK YOU for presenting this. I could not agree with you more. I must admit that I have lost faith in the FDA as a regulatory body charged with doing the right thing. One obvious problem are the billions of dollars potentially involved ... Credit to you for your call for transparency.
	# 2 of 12	July 4, 2012 08:54 (EDT)
	Arzt88	It's 1984 again. The government, in all its orwellian splendor, is "protecting" physicians and the public from themselves again. That being said, in the same way the public have become more sophisticated in their knowlege of medical treatment options, so physicians have evolved as well. There should be more transparency in the way the FDA makes decisions especially for the sake of the medical comunity that they serve.
	# 3 of 12	July 4, 2012 12:31 (EDT)
	Fernando Elijovich, MD, FAHA	Perhaps the most scientific way to address a situation such as this would be via a "Letter to the Editor" from the FDA, explaining possible issues at stake. Such a letter should be released within a reasonable period after the appearance of an article that seems to indicate major effectiveness of a drug, if the FDA has reasons for delaying its approval. With such mechanism, the FDA would be acting like any other reader/researcher who has questions or comments about any publication, with the added benefit (for the readership) of the data in possesion of the FDA that are not in the public domain.
	# 4 of 12	July 5, 2012 11:47 (EDT)
	Stephen M. Grant, MD Division Cardiovascular and Renal Products	There seems to be some confusion about what FDA can disclose about pending New Drug Applications (NDA).  FDA is generally prohibited by statutes and regulations from disclosing the existence, status, or contents of an investigational application submitted to the Agency, until the product has been approved. So not only can FDA not disclose any information related to an NDA for apixaban but FDA could not even acknowledge that a complete response letter had been issued if the manufacturer had not publicly done so (http://www.bms.com/news/press_releases/pages/default.aspx). However, nothing prevents the manufacturer from disclosing the contents of a complete response letter if they choose to do so. It should be noted that in response to the call for greater transparency in the regulations of medical products the current FDA Commissioner initiated FDA’s Transparency Initiative (http://www.fda.gov/AboutFDA/Transparency/TransparencyInitiative/default.htm). In May 2010 the resulting task force recommended that FDA should disclose the fact that the Agency has issued a complete response letter in response to an NDA at the time the complete response letter is issued, and should, at the same time, disclose the complete response letter, which contains the reasons for issuing the letter.
	# 5 of 12	July 8, 2012 05:40 (EDT)
	Steven Rourke	Note that three comments were removed from this thread as they were found to be hostile in nature. We welcome respectful exchange and a divergence of opinion however as stated below:  We reserve the right to remove posts containing inappropriate language, promotional content, personal agendas or hostile intent, and posts from patients asking for medical advice. Steven Rourke theheart.org
	# 6 of 12	August 1, 2012 11:58 (EDT)
	Clark	Hello. I am 57 years old with good arteries and veins and a good strong (enlarged now) heart that just got a On-X valve put into its Aorta due to Atrial Stenosis (caused by calcification). Started the Warfarin regime (a week now) and am getting headaches and nose-bleeds (and Auras in my visiual). The nose bleeds and the auras with migraines I have a history of as a younger man (8 years old for nose-bleeds, and in my teens and 20's with occasional, and very much spread out over the years with very little occurance (3 4 times total).   Anyway, I have just started telling the Coumadin people, and my surgeon, what is going on, and am waiting their reply.   Liked your video.   Clark L. Hays, Jr.
	# 7 of 12	September 5, 2012 04:23 (EDT)
	StevenP	12 months ago, I was a partipant in the Warfarin/Apixiban study, after being diagnosed with Deep Vein Thrombosis in my left leg. Half way through the study, I was found to have Leiden Factor 5. Anyway, to this day, I still don't know if I was taking Wafarin or Apixiban. The only side-effect was gaining a little weight (from 70Kg to 80Kg) - but that could be because I'm just geting old (43  now)! After 9 months on the medication, tests showed no DVT, and all is good, and no more medication! So whatever I was taking was fantastic! I'm most interested in hearing that there's some question as to the data quality of the study, because if Apixiban is as good as everyone seems to have found, it would be a shame to shelve the product and the whole study would be a waste of time. I look forward to hearing about the long term prospects of Apixiban.
	# 8 of 12	September 16, 2012 09:12 (EDT)
	CG Dahlstrom	The newer anticoagulants differ from all other new drugs in the respect that they meet with resistance from our own profession (i.e. chiefs of large warfarin clinics who obviously have an interest in the perpetuation of Warfarin as the 1st. drug of choice). As you mentioned in your presentation Apixaban is probably the strongest contender for the replacement of Warfarin. So has pressure been brought to bear ? It is blatantly clear that the decisions of the FDA are not allways rational as exemplified in the decision to approve the 75 mg. dose of Dabigatran (which has never been investigated in AFIB in a clinical trail), and not to approve the 110 mg. dose, which is well documentes in the RELY-trail.
	# 9 of 12	September 25, 2012 10:29 (EDT)
	ED LEWIS	I HAVE READ THAT WHILE THE DIRECT THROMBIN  INHIBITOR DABIGATRAN (PRADAXA) IS GOOD FOR ISCHEMIC STROKE AS WELL AS HEMARRAGIC STROKE, THAT RIVARAXABAN(XARELTO) MIGHT BE NEAR USELESS TO STOP ISCHEMIC STROKE IN HEART PROBLEMS. I HAVE TAKEN PRADAXA 150MG FOR OVER A YEAR AND HAVE NO KNOWN BLEEDING  I HAD BLEEDING WITH WARFARIN. THE PRADAXA TWICE A DAY SEEMS LOGICALLY BETTER THAN A ONCE PER DAY PILL WHERE THE BLEEDING MIGHT BE HARDER TO STOP BY STOPPING THE 2ND PRADAXA PILL TO FLUSH OUT THE PRADAXA.
	# 10 of 12	October 2, 2012 01:15 (EDT)
	robert	I am 83 years old and on wafarin for 10 years following a quad bypass. My cardiologist would not prescribe Pradaxa because data for the elderly are missing. A couple of months ago while enjoying a protime of about 2.4 I suffered a mini stroke - minor speech and face effects. My diagnosis is atrial flutter. Have tests with apixaban indicated value for the elderly with atrial flutter?    r
	# 11 of 12	November 4, 2012 10:46 (EST)
	Ron Burke	I appreciate your comments and can only agree the FDA probably has reasons ($$$) for withholding approval of this drug.
	# 12 of 12	November 12, 2012 08:52 (EST)
	RJD	I think you are missing some data on both Warfarin and Pradaxa. with Warfarin, in an emergency, you can be "re-coagulated" immediately with drugs such as octoplex and with vitamin K IV. With Pradaxa, your only option is dialysis. The half life of Dabigatran may be only 12 hours but it's 2-5 days to get your clotting back to normal. That's a potential death sentence in a serious bleed situation.

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