Apixaban Eliquis was supposed to sail through the FDAapproval process. It’s now been 10 months since the highly celebrated ARISTOTLE trial was published in theNew 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 Atrial Fibrilation 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.

The superiority of apixaban in overallstroke 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.

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-AFtrial 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.

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 and we should have far more transparency about what is going on.

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 Medicinesacrosanct? Good questions, indeed. I was wondering the same things


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