Apixaban (Eliquis) was supposed to beat dabigatran (Pradaxa) and rivaroxaban (Xarelto). . . . What gives?

Atrial-fibrillation patients and doctors received surprising news yesterday.

Apixaban (Eliquis) was supposed to sail through the FDA approval process. It's now been 10 months since the highly celebrated ARISTOTLE trial was published in the New England Journal of Medicine. Yesterday, we learned from apixaban makers, Bristol-Myers Squibb and Pfizer, that the FDA has further delayed the apixaban review process. The FDA has requested "additional information on data management and verification from the ARISTOTLE trial." Earlier this year, the FDA pushed back evaluation of the drug by three months.

A brief review of Apixaban and ARISTOTLE: The 18 000-patient strong trial showed that apixaban was superior to warfarin for the prevention of stroke in patients with AF. Compared with patients treated with warfarin, those on apixaban suffered fewer strokes and less bleeding. Most important, it was the first of the three nonwarfarin agents that conferred a statistically significant improvement in mortality. The main critique of these strikingly positive results was that apixaban did not reduce ischemic strokes. Rather, the superiority of apixaban in overall stroke reduction came because the drug greatly reduced hemorrhagic stroke. For the patient with AF, though, the means of stroke prevention is less important than the bottom line: fewer major CNS events.

Apixaban also showed benefit in another large trial of AF patients who were deemed not eligible to take warfarin. In AVERROES, not only did apixaban beat aspirin in stroke prevention, it did so without increasing the risk of bleeding. That apixaban looked as safe as aspirin made a strong statement.

These incredibly positive trials led most to believe apixaban would become the superior blood thinner for AF. Maybe it will still reach that lofty status. But now one has to wonder whether something is amiss. Or perhaps the FDA is just squeamish about all that's happened with dabigatran.

Let's muse a bit more about apixaban vs dabigatran/rivaroxaban

Expert thinking had apixaban being shielded from the headwinds that have slowed the acceptance of dabigatran and rivaroxaban.

Two factors plague the real-world use of dabigatran: One is its acidic nature, which gives rise to a significant amount of GI intolerance. This is a strong headwind. You spend oodles of time with the patient explaining the drug, then fight with third parties getting it approved, and then four days later it's all for nothing; the patient has to stop the drug because of stomach pain. For doctors without armies of nurses and MD-extenders, this is a real problem. The second issue with dabigatran has less to do with the drug and more to do with its overly aggressive early acceptance. After 50 years of struggling with warfarin, there was pent-up demand. A not-insignificant amount of dabigatran-related bleeding occurred as a result of its less-than-nuanced prescribing.

Apixaban will not likely suffer any of these issues: GI intolerance has not been reported; and, as the third nonwarfarin blood thinner, doctors will have benefited from the learning curve with dabigatran.

Rivaroxaban has struggled in the real world too: The primary source of headwinds for rivaroxaban includes its less-than-robust data compared with warfarin. While dabigatran and apixaban beat warfarin in their clinical trials, rivaroxaban merely tied warfarin in the ROCKET-AF trial This has led many doctors to think—call it a gut feeling—that rivaroxaban, given at a once-daily dose of 20 mg, isn't quite enough blood thinning for AF. The inadequacy-of-dose argument was strengthened by the recently published Einstein PE trial, where a higher initial dose of rivaroxaban proved its mettle by successfully treating pulmonary embolism—a disorder that typically requires robust blood thinning. The Einstein PE trial showed us that rivaroxaban is a capable blood thinner; we just wonder about the dosing. (Don't misunderstand, I am not saying we should assume a higher dose would work for AF. We don't know that; it could be worse.)

Apixaban was supposed to overcome the rivaroxaban problem because it's used twice daily and its clinical trial showed superiority to warfarin in both safety and efficacy.

Although some are still uncomfortable with rivaroxaban, I have used it in lower-risk AF patients, many of whom have had GI intolerance to dabigatran. Thus far, my experience has been positive. Of note, I have yet to do a major ablation procedure on a patient taking rivaroxaban.

I have no inside information on what's going on with apixaban. I guess we will just have to wait and go slow. With the new and novel blood thinners, going slow might be a good thing.

JMM

PS. Most likely you have already viewed Dr Topol's post about apixaban. On the off chance that you happened onto my post first, I'd recommend watching his short clip on the mystery surrounding the delay in approving apixaban. He makes the point that in this age of information, we should have far more transparency about what is going on. Dr Topol asks: Why the cloak of secrecy? What's the cause of disconnect between the amazing data in ARISTOTLE and the lack of approval? Isn't data published in the New England Journal of Medicine sacrosanct? Good questions, indeed. I was wondering the same things.

Your comments

	Apixaban (Eliquis) was supposed to beat dabigatran (Pradaxa) and rivaroxaban (Xarelto). . . . What gives?
	# 1 of 10	June 27, 2012 06:25 (EDT)
	Ken Grauer, MD	THANKS for your post John. I've become much more skeptical of new drugs that initially look "great" - and subsequently evolve problematic. The situation becomes more complicated when FDA actions seem not necessarily directed in overall best interests (in this case - the lack of transparency both you & Dr. Topol allude to) - especially when billions of dollars are potentially involved ... I'm much more an advocate of your last sentence: "With the new and novel blood thinners - going slow might be a good thing".
	# 2 of 10	June 27, 2012 01:02 (EDT)
	F.C. Pearce	I don't find any reference to the reversal aspect of Apixaban use -vs- Warfarin or the other two newer drugs both of which don't have adequate reversal. Does that mean that Warfarin remains the drug of choice despite all the claims for the newer drugs, incl. Apixaban?
	# 3 of 10	July 3, 2012 04:44 (EDT)
	Henk, pharmacist	I wonder what's your opinion om acenocoumarol, wicht is used in Europe in stead of warfarin, in relation of apixaban.
	# 4 of 10	July 7, 2012 11:23 (EDT)
	T.D.GARTIN, MD DABFP	Do not see any infor re reversing anti clotting situation if bleed occurs.  tdg
	# 5 of 10	July 20, 2012 04:56 (EDT)
	Robin M. Lake, MD, FACC	Perhaps if one believes that their patients are incapable of understanding the concepts of blood clotting and thromboembolism there could be some justification for using the fanciful (and totally inaccurate) term “blood thinner” in communications with them, but in a professional publication intended for physicians? Does the author believe that anyone in the target audience really thinks that the medications under discussion actually thin the blood or affect its viscosity in any way—or that if they did, this “thinning” would have some beneficial clinical effect? What is the value of perpetuating this misguided term? Does it help to have your patients conclude that their circulation will improve because their “thinned” blood will flow more easily, even, therefore, possibly improving control of their blood pressure? Or worry that they will chill more easily because of the thinned blood? Or correlate thinned blood with anemia and reduced oxygen-carrying capacity? (All of these concerns have been expressed to me by one or another of my anticoagulation patients over the years.) It may be claimed, “Everyone will know what is meant” by such terms, and that is probably true in most cases, but the same excuse could be used to justify all sorts of errors, illiteracies and inappropriate colloquialisms. But when it’s just as easy to use accurate terms and concepts, why not do so?
	# 6 of 10	July 21, 2012 04:00 (EDT)
	John Mandrola	Hi Dr Lake, Thanks for reading and taking the time to write.  And thanks for calling me an author. That sounds pretty cool. Your point is well taken and absoultely accurate. Of course, anti-coagulants do not actually thin the blood. Transgression noted.  Best, John
	# 7 of 10	August 26, 2012 11:28 (EDT)
	Pat	I have been having all over body pain since taking xaralto.  I can't identify where the pain is coming from but it seems to be getting worse.  I don;t know if it is a fibromyalgia flare-up or artheritis from the daily rains we have had lately.  anyone else having body, muscle, pain from this drug?
	# 8 of 10	September 12, 2012 11:53 (EDT)
	Denise	I totally agree.  As a patient currently taking Pradaxa I am frustrated by the term 'blood thinner'.  This is also generally used by my cardiologist.  While taking Coumadin for AF I had a pretty intense TIA with total left paralysis which did resolve 100% within 12 hours.  I had been having difficulty with proper dosage of Coumadin.  I have been on Pradaxa for over a year.  Now my cardiologist is suggesting I switch to Xarelto.  After doing quite lengthy research, I am not sure that I want to change.  I have not experienced significant side effects from the Pradaxa.  Any suggestions or thoughts?
	# 9 of 10	September 19, 2012 08:23 (EDT)
	Anna R	I was on Pradaxa for approximately one year for AF.  I am 77 years old and also have diabetes and polymyalgia rheumatica.  From the very beginning, the Pradaxa caused me to have gastrointestinal issues but my cardiologist thought I should continue it.  I had severe stomach and chest pains one night which landed me in the ER with subsequent admission to the hospital for observation and tests.  It was determined that, according to my cardiologist, Pradaxa and I were not compatible; and I was subsequently switched to Xarelto 20 mg once daily.  I have been on Xarelto now for a little over a month and it seems to be kinder to my overall system than the Pradaxa.  As stated, I have also had polymyalgia rheumatica for more than 5 years and have been on varying dosages of prednisone, which is now at a dose of 2.5 mg daily.  I read in the accompanying literature for Xarelto that it could possibly cause muscle aches and pains or bone and joint paints.  I now have a noticeable increase in my overall body pains.  I am not sure whether it is because of the reduced dose of prednisone or the Xarelto.  I would be interested in knowing if others on Xarelto are experiencing this type of pain.  I am also anxious to learn if anyone has had to have surgery while on Pradaxa or Xarelto as I now have gallstones and need to have surgery.  I am greatly worried about bleeding during and after the surgery.  I do know that I have to be off of Xarelto and on aspirin before the surgery but are there guidelines of how long after the surgery.  It's all very scary to me.  I guess there are risks in everything but the bleeding factor and the stroke factor weigh heavily on my mind.  Thanks for any recommendations.
	# 10 of 10	September 20, 2012 11:58 (EDT)
	Bill	Thanks for the analysis. As a patient with occassional AF and two heart stents (2.5 yrs. ago), I was for nearly two years on Coumadin, Plavix and aspirin (83). Switched over the dabigatran and dropped Plavix. No side effects and bleeding problems even as compared to post Plavix disappeared.That included urinary bleeding, hemmroidial bleeding, gum bleeding, small cut or minor wound bleeding problems. Some indigestion symptoms were solved by taking dab. with food and not lying down. Still, I'm concerned with possible hemmoraging ( though 78, I play racquetball, other sports, active, etc.) I did trip on stairs and hit my head on the wall, but did not have any bleeding. Lucky, i guess. Thinking of switching to rivaroxaban, but not sure I will be reducing risk. My son-in-law is a cardiologist and switched his patients over. Haven't had a chance to explore it with him. He seemed to indicate that rivaroxaban was reversible. Apixaban seems to be the answer and it is strange it hasn't passed approval.

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