But Where is the Antidote to the Poison @NEJM?

Andexanet alfa is the long-awaited antidote for the Factor Xa inhibitors – rivaroxaban, apixaban, edoxaban, and their ilk. This publication, featured at the European Stroke Congress and in the New England Journal of Medicine, is Portola’s latest update regarding its utility. Is it better than their previous update – their failure to receive initial FDA approval – or just another “incomplete” like their publication last fall?

This is ANNEXA-4, an open-label, single-group study purporting to evaluate the efficacy and safety of andexanet for clinical hemostasis in actively bleeding patients with concomitant use of Factor Xa inhibitors. Or, more specifically, these are interim results – the first 67 of 250 planned for enrollment. The clinical efficacy endpoint is a complex series of adjudicated judgements regarding the cessation of bleeding, hematoma expansion, or change in hematocrit, depending on the type of bleeding enrolled. The primary safety endpoint is death or thrombotic event within 30 days – stroke, myocardial infarction, venous thromboembolism, etc.

There is virtually nothing positive to relate here. The authors, of course, relate that somewhere around 80% of the 47 patients included in their efficacy analysis obtained “good” or “excellent” hemostasis with 12 hours following their andexanet infusion. But, these essentially arbitrary labels at a potentially clinically unimportant timepoint tells us virtually nothing regarding its value versus observation, or an alternative treatment such as prothrombin concentrate complexes.

On the negative side, the list is endless. There is the baffling offensiveness of publishing what amounts to a quarter of a trial in the New England Journal of Medicine.  The mean time to andexanet bolus was nearly 5 hours, raising concern regarding the acuity and severity of bleeding in enrolled patients.  The vague, patient-oriented endpoints are meaningless – with or without a comparator – and thus, this boils down to basically a pharmacokinetic observational study. Even then, the pharmacokinetics don’t appear terribly favorable – andexanet dramatically reduces Factor Xa activity during infusion, but pops back to therapeutic anticoagulation following cessation. A concerning 18% had thrombotic events within 30 days – but, again, without any control group, little can be concluded regarding safety.

Finally, clearly, the NEJM has given up publishing the conflicts-of-interest for the authors because it would sum up to half the journal – this article directs the reader to the disclosure forms on the web. For the eagle-eyed reader, however, they can pick out this text as part of the author affiliations: “Portola Pharmaceuticals, San Francisco (J.T.C., A.G., M.D.B., G.L., P.B.C., S.G., J.L., B.L.W.)”. Yes, eight of the authors are employees of Portola Therapeutics, the manufacturer. Better even, are their ICJME form disclosures. John Curnutte, the Head of Research and Development, has checked the box stating he has no relevant conflicts of interest with the work under consideration for publication – but, you know, outside the submitted work he happens to be an employee for Portola. In fact, from what I can tell, every employee authoring this article declared they have no COI with the work under consideration for publication.

Inconceivable!

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors
http://www.nejm.org/doi/full/10.1056/NEJMoa1607887

1 thought on “But Where is the Antidote to the Poison @NEJM?”

  1. NEJM will not change.

    Look up (same issue) Drazen et al.’ somewhat pro domo self indulgent paper:

    http://www.nejm.org/doi/full/10.1056/NEJMra1510064

    We can sadly yet unsurprizingly note that “effect size” and clinical relevance are ominously absent, and the only risks quoted obviously are the glowing relative risks, while the lacklustre absolute risks are despised.

    You’ve got to make a living.

    NEJM misbehaves just as other IF stars do, and gladly welcomes authors who switch the failing prespecified outcome to chance products as shown at :

    http://compare-trials.org/blog/how-did-nejm-respond-when-we-tried-to-correct-20-misreported-trials/

    The result is that “the evidence used to make clinical decisions remains distorted”.

    The COMPARE group is polite enough not to use the F word. Well, F for fraud of course.

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