Prothrombin Complex Concentrate or Idarucizumab in a Multimodal Hemostatic Approach with Tranexamic Acid and Fibrinogen for the Acute Reversal of Dabigatran
Authors: Grottke Oliver , Honickel Markus , Rossaint Rolf , Braunschweig Till 
Published: October 2019

Abstract
Background: Reversal of dabigatran anticoagulation in traumatized patients with massive bleeding using idarucizumab (IDA) or prothrombin complex concentrate (PCC) together with other resuscitation measures will be first line treatment. In cases of continuous bleeding and/or elevated dabigatran levels, further hemostatic therapy with coagulation factors (tranexamic acid: TX, fibrinogen concentrate: FGN) may be required. This study tested the safety and efficacy of IDA or PCC, given as first or second line therapy in a two hit polytrauma model under dabigatran anticoagulation. A multimodal approach using TX plus FGN was also tested. In addition to the primary endpoint, reduction in blood loss (BL), a panel of coagulation parameters and the safety of these hemostatic measurements was investigated.
Methods: Dabigatran etexilate (30 mg/kg bid) was given to 28 male pigs for 3 days after ethical approval. On day 4, pigs were anesthetized and given a dabigatran infusion before blunt liver injury and bilateral femur fractures. Animals were randomized to receive either 60 mg/kg IDA or 50 U/kg PCC after the first injury. One hour later these animals received the opposite treatment post second liver injury. In a second step, TX (20 mg/kg) plus FGN (100 mg/kg) were added to hemostatic therapy (IDA or PCC) after the first injury, and received the opposite hemostatic therapy (IDA 60 mg/kg or PCC 50 U/kg) after the second liver injury. BL, hemodynamic and coagulation parameters were monitored over 5 h or until death.
Results: IDA as first line treatment resulted in a significant reduction in BL (IDA: 1040±202 mL) as compared to PCC (1389 ±194 mL) 60 min post injury. Despite increasing blood loss following the second trauma, the difference between groups remained significant (IDA-PCC: 1556 ± 205 mL, PCC-IDA: 1981±361 mL, P<0.0001). Likewise, in the initial TX+FGN+PCC (1696 ± 186 mL) and TX+FGN+IDA group (1416 ± 139 mL) blood loss was significantly lower compared to PCC mono-therapy (P=0.023 and P<0.0001). However, no significant difference between IDA monotherapy or TX+FGN+IDA was observed. Survival in all groups was 100%. Animals that received first IDA showed a complete reversal of coagulation parameters (e.g. aPTT, PT, thromboelastometry variables); PCC showed an improvement of clot initiation (CT) and PT, but parameters were not normalized to baseline values. The addition of FGN increased plasma concentration of fibrinogen and improved clot strength. Pathological analyses and clinical parameters including pulmonary pressure exhibited no adverse events in any of the investigated groups.
Conclusion: Under conditions of ongoing blood loss after polytrauma and dabigatran anticoagulation, both IDA and PCC prevented exsanguination, although therapy with IDA was more effective. This can be explained by differences in mechanisms, IDA binds dabigatran and inhibits its anticoagulant effect, whereas PCC has no impact on dabigatran anticoagulation but nonspecifically enhances thrombin generation. Their different effects on coagulation parameters also reflect this. Moreover our data imply that clinically used multimodal hemostatic therapy with TX plus FGN and PCC or IDA appears safe under these conditions.

Disclosures
Grottke: NovoNordisk: Research Funding; Portola Pharmaceuticals: Consultancy; CSL Behring: Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Biotest: Research Funding. Rossaint:CSL Behring: Research Funding; Bayer Healthcare: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding.