‘Round EMLoN headquarters, we’re big fans of a few medications. Oseltamivir
. And, finally, dabigatran
. After all, a blog needs content – and controversy begets content. Dabigatran, if you need any reminder, is an irreversible direct thrombin inhibitor, whose sponsored trial results continue to receive “updates” for additional "newly discovered" adverse events. It was also subject to a $650M legal settlement related to its under-emphasized risks to patients.
This pair of articles, presumably, addresses one critical issue with dabigatran – lack of effective reversal options. The first, published in the Lancet, relates to controlled pharmacokinetics of the monoclonal antibody fragment binding dabigatran, idarucizumab. Healthy volunteers, all men, were loaded with four days of dabigatran, and the four cohorts of 12 participants each were assigned to receive various doses of idarucizumab. By every measure of coagulation function, the two highest-dose cohorts effectively reversed dabigatran. However, given the small number of participants, it is impossible to claim idarucizumab is safe, even in the setting of only a handful of adverse events. Entertainingly, almost half the research participants complained of at least two subjective adverse symptoms during the dabigatran load.
The second article, in the NEJM, is bizarrely an interim analysis of the first 90 patients enrolled of a planned 300 patient phase III study of idarucizumab. The appropriateness of reporting a fraction of enrollment from a sponsored phase III study, let alone in the NEJM, is unfathomable. Regardless, the study enrolled patients requiring urgent reversal for life-threatening bleeding or urgent surgery. As in the Lancet publication, administration of idarucizumab reversed coagulation parameters almost instantly. There was, however, a small rebound in anticoagulation and dabigatran activity approximately 12 hours after the initial dose, suggesting a limit to the durability of the reversal in some patients.
Clinically, outcomes are a little difficult to evaluate without a specific control or comparison group. The patients generally did poorly – 18 of 90 died – but, probably as expected in an elderly, anticoagulated cohort confronted by acute medical issues. In the patients with life-threatening bleeding, time to resolution was 11.4 hours following administration of idarucizumab – not dissimilar to the use of prothrombin-concentrate complexes for warfarin or Factor Xa inhibitors. Of course, nearly a quarter of patients were enrolled despite what turned out to be normal initial coagulation profiles – inflating any measure of apparent reversal or bleeding time cessation. And, again, in such a small sample, without a control population, no obvious statement on safety may be made, even in the setting of just a handful of thromboembolic events.
In short, Boehringer Ingelheim, having scattered the nails in the street, is almost ready to sell you new tires. Certainly, whatever the adverse effects of idarucizumab, it is better than uncontrolled bleeding – and will doubtless be a welcome addition to many formularies. The costs, however, will be quite unwelcome – and without a method to readily detect dabigatran activity in the clinical setting, this expensive antidote will likely be uselessly given to many patients without the possibility of benefit, as seen in a quarter of patients here.
Finally, as a bit of an aside, the accompanying editorial
is penned by a physician who receives consulting fees from both Boehringer Ingelheim and Portola specifically for his work on the antidotes for dabigatran and the Factor Xa inhibitors. Is it really so difficult to identify qualified editorialists without the most egregious possible COI?
“Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial”http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60732-2/abstract
“Idarucizumab for Dabigatran Reversal”http://www.nejm.org/doi/full/10.1056/NEJMoa1502000