There’s nothing hotter than idarucizumab, the reversal agent for dabigatran. It’s so hot, the New England Journal of Medicine once published a farcical 91 patient interim analysis of a planned 500 patient enrollment. Now, two years later, we have the full cohort and it’s, well, more of the same, with all the flaws previewed in the previous iteration.
To recap, there are no viable reversal options for dabigatran besides this antibody fragment. And, in full sucker-born-every-minute fashion, Boehringer Ingelheim is both good cop and bad cop, selling us both the poison and the antidote.
There are 503 patients enrolled in this open-label study with two arms: Group A, with uncontrolled bleeding, or Group B, anticoagulated and requiring an urgent procedure. The primary outcome is, essentially, utterly unrelated to any of the context of enrollment – “maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab”, which is frankly already well-documented in the healthy-volunteer pharmacokinetic studies.
Theoretically, the interesting portion here is supposed to be the clinical relevance of the reversal effect – which is measured by secondary outcomes of subjective assessment of median time to cessation of bleeding in Group A or by periprocedural hemostasis in Group B. The most striking result in the interim result was a median time to cessation of bleeding of 11.4 hours – a concerningly high number calling into question the entire purpose of reversal. In this new publication, the median time to reversal is now reported as 2.5 hours. This also, oddly, differs from nearly identical cohort results presented to the American Heart Association – explicitly broken down as shown below:
Then, compare with this slide passed along by @bloodman from #ISTH2017 in Berlin:
Considering this was an easily critiqued result – and essentially the most clinically relevant – it’s not surprising the sponsor and their funded- and fee-supported collaborators solved the issue in the most expeditious fashion possible: exclude >55% of Group A from time-to-bleeding assessment. Just toss out the patients who didn’t have cessation of bleeding within 24 hours, or – despite inclusion criteria of “signs and symptoms of (overt) uncontrolled bleeding” – the “bleeding location could not be identified”.
Most (93.4%) of patients in Group B were assessed as having normal hemostasis during their procedures, which occurred a median of 1.6 hours after completion of idarucizumab infusion. That said, many of the procedures were minimally invasive (catheter placement for dialysis, lumbar puncture, cutaneous abscess drainage) and likely favorably influenced both the fraction reported having normal hemostasis, as well as driving down the time to the intended procedure.
About 10% of the cohort had normal hemostasis at baseline as judged by the central laboratory, meaning they were likely not taking the dabigatran as reported or suspected – a smaller percentage than the interim analysis, where almost 25% were not. Whether this reflects better enrollment screening, or simply moving the goalposts again, cannot be reliably discerned from the results provided. Adverse events relating to the study drug, likewise, are difficult to parse without a true unexposed comparator. Most of the cohort was elderly, with multiple comorbid conditions, in addition to their serious bleeding event or need for urgent procedural intervention. A handful of early thrombotic events and hypersensitivity-type reactions occurred, demonstrating there may yet be some consequential, but poorly quantified, risk to idarucizumab administration.
But, hand-wringing aside, we’re in the same place we were yesterday. Idarucizumab clearly and effectively removes dabigatran from circulation, unlike andexanet alfa and Factor-Xa inhibitors, and this ought to be occasionally clinically useful. I would certainly exhaust all potential supportive and expectant management options first, as well as try to definitively confirm dabigatran as the culprit for abnormal hemostasis. Ultimately, the best way to avoid idarucizumab? Don’t use dabigtran in the first place.
“Idarucizumab for Dabigatran Reversal — Full Cohort Analysis”
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