Saturday, September 10, 2016

Idarucizumab: An Imperfect Reversal Agent for Dabigatran

We waited with bated breath for idarucizumab, the antidote for dabigatran, to be approved by the FDA. We heard whispers that it was coming for a number of years, even during those rough first few relatively recent years following the approval and widespread use of dabigatran, during which time patients presented to emergency departments across the globe with life-threatening bleeding secondary to dabigatran. Craig and I discussed it in our podcast episode on pipeline reversal agents on target-specific oral anticoagulants nearly two years ago.

Some time later, after reviewing preliminary findings of the REVERSE-AD trial while enrollment was still ongoing, I recall having posed many questions about this reversal agent (which I still have a somewhat difficult time pronouncing). At that point, I was skeptical regarding its practical application in the emergency department, and more importantly, I considered how we would actually monitor its effects, since most institutions are still not able to measure surrogate endpoints such as serum concentrations of dabigatran, (dilute) thrombin time, and ecarin clotting time. Even in those that do, we know that various interventions for correcting coagulopathy may make these numbers look pretty, but do not actually provide us with solid evidence of actual cessation of bleeding. The issue of the rebound distribution phenomenon associated with dabigatran in the setting of toxicity and/or life-threatening bleeding observed in several published reports that were not necessarily resolved by extracorporeal methods of removal raised more questions as to whether idarucizumab would actually counter this effect as well (1).

Also, the fact that the manufacturer of the antidote was the very same company that produced the agent that required use of the antidote raised several eyebrows. Let us also not forget the fact that idarucizumab was granted priority review by the FDA as a means of accelerating its eventual approval (2).


Then, the interim analysis of REVERSE-AD was published (3), and that is when the situation became even more interesting. I will not rehash the methodology and results of the study; several others have already done so (here, here, here, and here, to name a few #FOAMed critiques of the trial). The mortality rate was still nearly 20% despite administration of idarucizumab. These and several other issues in the methodology and findings of the study made many of us even more skeptical of the ability of idarucizumab to completely reverse the effects of dabigatran, particularly as it was evaluated in the real-world population, typical of those patients who would present to us in the emergency department with steady state concentrations of the drug with or without acute or chronic kidney disease (4).

Idarucizumab was shortly thereafter officially approved by the FDA, and became widely available, prompting institutions across the country to formally add it to their formulary and create specific guidelines for use in the setting of life-threatening bleeding induced by dabigatran. After all, what other choice did we have (besides not having it available ready at the healm for our next hemodynamically unstable patient who presented with dabigatran-induced life-threatening bleeding)?

All that blood (pun intended), sweat, and tears...and for what?

Since its approval in October 2015, just shy of one year, there have already been four case reports of idarucizumab failing to reach effective and timely hemostasis in critically ill patients with bleeding secondary to dabigatran. One case of ineffective reversal of dabigatran-induced bleeding with idarucizumab is simply one too many, particularly given the fact that it was recently approved specifically for this indication, let alone these four cases reported thus far. The four cases are briefly summarized below:

Case 1 (5):
  • 79-year-old female on maintenance therapy with dabigatran for atrial fibrillation (last known previous dose was 19 hours prior to arrival)
  • Found to have rectal perforation and peritonitis with abnormal coagulation parameters confirmed with thromboelastography (TEG)
  • One dose of idarucizumab 5 g was administered and hemorrhage and coagulation parameters normalized immediately
  • At 72 hours, recurrence of severe bleeding with elevated serum dabigatran concentration
  • Second dose of idarucizumab was considered, but not given due to declining status of patient
Case 2 (6):
  • 79-year-old male with history of atrial fibrillation on chronic therapy with dabigatran requiring emergent surgery for type A aortic dissection
  • A 5 g dose of idarucizumab was administered prior to surgery with confirmed normalization of coagulation parameters
  • Complicated surgical course followed with cardiopulmonary bypass and after six hours, coagulation parameters became elevated with confirmation via TEG 
  • Patient required resuscitative measures with inotropes for cardiopulmonary failure, but decision made to withdraw care
Case 3 (7):
  • 65-year-old male with atrial fibrillation on chronic therapy with dabigatran presented to emergency department with gastrointestinal hemorrhage and hemodynamic instability
  • Prolonged thrombin time (> 120 sec)
  • A 5 g dose of idarucizumab administered along with fluid resuscitation, packed red blood cells, and continuous intravenous pantoprazole infusion 
  • Thrombin time normalized within one hour following administration of idarucizumab, but with esophagogastroduodenoscopy, continuous hemorrhage observed in duodenum, requiring additional packed red blood cells and factor eight inhibitor bypassing activity (FEIBA)
  • Emergent angiography with coiling was performed, leading to stabilization of duodenal hemorrhage
  • Patient discharged home on hospital day 4
Case 4 (8):
  • 58-year-old female with progressive bruising, epistaxis, anuria, vaginal bleeding, hematuria  on chronic therapy with dabigatran for atrial fibrillation
  • Exhibited abnormal coagulation parameters and elevation in serum creatinine, prompting initiation of hemodialysis and one dose of idarucizumab 5 g to be administered on hospital day 3
  • Coagulation parameters normalized within two hours, but at 16 hours post-administration of idarucizumab, parameters rebounded and increased, with patient continuing to experience hematuria
  • Hemodialysis continued, and on hospital day 6, with sustained elevation in coagulation parameters, patient was given a second 5 g dose of idarucizumab
  • Thrombin time continued to remain elevated
  • Hemodialysis-dependent with eventual formal diagnosis of end-stage kidney disease
With these documented cases of idarucizumab failing to clinically reverse the effects of dabigatran (and perhaps more to be published in the future), this begs the question of whether this reflects approval of the reversal agent for dabigatran in haste and now repenting at leisure.

Of course, one can make the case that these patients may have already been too critically ill and idarucizumab was bound to exhibit little if any clinical effect in reversing dabigatran-induced bleeding. That is all fine and well, but it is clear now that its effects are imperfect, and with these documented cases, I especially now have a hard time referring to idarucizumab as an "antidote."

It seems as though the FDA may have taken notice, given their recent actions in rejecting approval of andaxenet alfa (9), the purported agent for reversal of the effects of direct and indirect factor Xa inhibitors - at least for now.

Of course, time will tell what the future holds for idarucizumab.

References:
  1. Awad NI, Brunetti L, Juurlink DN. Enhanced elimination of dabigatran through extracorporeal methods. J Med Toxicol 2015; 11(1):85-95.
  2. FDA Grants Priority Review to Boerhringer Ingelheim's Biologics License Application for Idarucizumab. Available at: http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2015/4-23-2015-fda-grants-priority-review-boehringer-ingelheims-biologics-license-application-idarucizumab.html [Accessed 9 September 2016].
  3. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373(6):511-20.
  4. Stöllberger C, Pommer P, Schneider B, et al. Concerns about idarucizumab for dabigatran reversal. Blood Coagul Fibrinolysis 2016; 27(4):473-4.
  5. Thorborg C, Horn EP, Mofid H, Langer F. Reversal by the specific antidote, idarucizumab, of elevated dabigatran exposure in a patient with rectal perforation and paralytic ileus. Br J Anaesth 2016; 117(3):407-9.
  6. Henderson RS, Deshpande S, Williams B, Taylor BS, Tanaka KA. Idarucizumab for Dabigatran Reversal in Emergency Type-A Aortic Dissection. J Cardiothorac Vasc Anesth 2016 [Epub ahead of print]
  7. Alhashem HM, Avendano C, Hayes BD, Winters ME. Persistent life-threatening hemorrhage after administration of idarucizumab. Am J Emerg Med 2016 [Epub ahead of print]
  8. Marino KK, Santiago RA, Dew RB, et al. Management of dabigatran-associated bleeding with two doses of idarucizumab plus hemodialysis. Pharmacotherapy 2016 [Epub ahead of print]
  9. Portola Pharmaceuticals Receives Complete Response Letter from FDA for Biologics Application for AndexXa (Andexanet Alfa). Available at: https://globenewswire.com/news-release/2016/08/18/865027/0/en/Portola-Pharmaceuticals-Receives-Complete-Response-Letter-from-FDA-for-Biologics-License-Application-for-AndexXa-andexanet-alfa.html [Accessed 9 September 2016]