Specific antidotes for bleeding associated with direct oral anticoagulants

Dear Editor,
We appreciate the contribution by Burnett et al on specific antidotes for direct oral anticoagulants.1 Their reference to the phase III, industry-sponsored, Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study regarding the time to establishment of hemostasis and idarucizumab as an antidote for hemorrhage following therapeutic dabigatran dosing merits further discussion.

The effectiveness of idarucizumab 5 grams to neutralize the body dabigatran burden and correct clotting times following therapeutic dabigatran dosing was demonstrated in the first 90 patients enrolled in the RE-VERSE AD study.2 However, the rapid neutralization of dabigatran activity and normalization of coagulation assays do not appear to rapidly establish hemostasis as the median time to bleeding cessation was 11.4 hours following idarucizumab administration. This dissociation between normalization of coagulation parameters and establishment of effective hemostasis is unsettling. In an update that included information on 494 patients enrolled in the RE-VERSE AD study,3 there were 298 patients with “uncontrolled bleeding” of which 201 patients had extracranial hemorrhage and 97 patients had intracranial hemorrhage. The median time to effective hemostasis in the 158 (78.6%) patients with extracranial hemorrhage was 3.5 to 4.5 hours; 43 (21.4%) patients were not evaluable. This update did not inform on the median time to effective hemostasis in patients with intracranial hemorrhage, which comprised 32.6% of patients with “uncontrolled bleeding.” If we were to impute the time to hemostasis is the same for patients with extracranial and intracranial hemorrhage, the revised median time to hemostasis of 3.5 to 4.5 hours, albeit less than 11.4 hours, by excluding patients with intracranial hemorrhage, remains a significant dissociation between normalization of coagulation parameters following idarucizumab administration and establishment of hemostasis.

Is it clinically reasonable to administer only idarucizumab to a patient who is hemorrhaging while on therapeutic dabigatran dosing? We believe most clinicians would be apprehensive with the sole treatment being idarucizumab and hope their patient does not succumb while waiting for hemostasis to be established. Perhaps, a more reasonable approach would be to administer blood component therapy (e.g., pack red blood cells, four-factor prothrombin complex concentrate, and activated prothrombin complex concentrate), as clinically indicated, in addition to idarucizumab. The rationale is neutralization of body dabigatran burden precedes clinical hemostasis by a median of 11.4 hours; 3.5 to 4.5 hours if excluding patients with intracranial hemorrhage. Blood component therapy is a reasonable bridge between normalization of coagulation parameters and establishment of hemostasis based on in vitro and preclinical data.4 In the RE-VERSE AD study, blood products (e.g., packed red cells, fresh frozen plasma, cryoprecipitate, aPCC, platelets, tranexamic acid, and whole blood), in addition to idarucizumab, were administered to 55.6% of patients.2 The reported overall mortality was 20.0%; 27.8% being fatal hemorrhagic events. The causes of death included hemorrhagic shock and acute or progressive intracranial hemorrhage. However, the reasons for hemorrhagic shock and acute or progressive intracranial hemorrhage following administration of idarucizumab and blood products are not reported. It is possible that variables such as inadequate blood products administration and delayed in blood products administration were contributory to these deaths. It can be reasonably argued that in selected patients the establishment of effective hemostasis with blood component and idarucizumab therapy outweigh its potential risk of thrombotic adverse events in patients who are hemorrhaging.

While idarucizumab is effective in neutralizing dabigatran activity, it is not an “antidote” for hemorrhage associated with therapeutic dabigatran dosing given the dissociation between normalization of coagulation parameters and establishment of effective hemostasis. Thus, it is reasonable to administer blood component therapy to bridge the time between normalization of coagulation parameters and establishment of hemostasis.

References
1. Burnett A, Siegal D, Crowther M: Specific antidotes for bleeding associated with direct oral anticoagulants. BMJ 2017 May 25;357:j2216. doi: 10.1136/bmj.j2216.

2. Pollack CV Jr, Reilly PA, Eikelboom J, et al: Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-220.

3. Pollack CV Jr: Idarucizumab for dabigatran reversal: Updated results of the REVERSE-AD study. In: Scientific Sessions. New Orleans, Louisiana, USA; 2016.

4. Siegal DM: Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis 2015;39:395-402.

Authors:
Luke Yip, MD*
Denver Health
Rocky Mountain Poison and Drug Center
Department of Medicine, Section of Medical Toxicology
777 Bannock Street, MC 0180
Denver, CO 80204-4507

Jou-Fang Deng, MD
Veterans General Hospital-Taipei, Medicine
201, Shih-pai Road, section 2
Taipei, Taiwan 11217

*Corresponding author: Email: luke.yip@rmpdc.org