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Use of a specific antidote to dabigatran (idarucizumab) reduces blood loss and mortality in dabigatran-induced and trauma-induced bleeding in pigs

Introduction

The reversal of the anticoagulant effects of the new oral anticoagulants in severely bleeding patients requires new therapeutic strategies. This study investigated the effectiveness of a specific antidote for idarucizumab to reverse bleeding in a dabigatran anticoagulated pig trauma model.

Methods

After ethical approval, male pigs (n = 30) were given dabigatran etexilate for 3 days (30 mg/kg bid p.o.), and the sham group (n = 6) received placebo. To achieve supra-therapeutic anticoagulation, dabigatran was infused prior to injury on day 4 in anesthetized pigs, and the sham group received placebo. A standardized blunt liver injury was inflicted and blood loss (BL) was recorded 10 minutes post trauma. The dabigatran-treated animals were randomized (n = 6/group) to a single injection of idarucizumab at 30, 60 or 120 mg/kg i.v. or vehicle (control animals). Blood loss and hemodynamic variables were monitored over 4 hours or until time of death. Data were analyzed by ANOVA (± SD) and by the log-rank test.

Results

Dabigatran levels were 1,147 ± 370 ng/ml with no differences between groups prior to injury. BL in sham animals was 409 ± 53 ml 10 minutes after injury and 700 ± 107 ml after 4 hours (survival rate 100%). Anticoagulation with dabigatran (control animals) resulted in significantly higher BL 10 minutes after injury (801 ± 66 ml, P < 0.05). Mortality in these animals was 100%, with a mean survival time of 121 minutes (range: 90 to 153 minutes; P < 0.05 vs. sham and idarucizumab-treated animals). Total BL in dabigatran-treated animals was 2,977 ± 316 ml. In contrast, treatment with idarucizumab was associated with a dose-dependent reduction in BL. The lowest dose of 30 mg/kg resulted in 17% mortality (1/6 animals) and BL was reduced by 50% (1,586 ± 619 ml). BL was further reduced in animals receiving 60 (1,077 ± 103 ml) or 120 mg/kg idarucizumab (1,137 ± 121 ml; both 100% survival). Hemodynamic parameters and markers of shock were similar to pre-trauma levels in latter groups receiving idarucizumab.

Conclusion

This study demonstrates for the first time that anticoagulation with dabigatran can be reversed effectively and safely by idarucizumab. Even under supra-therapeutic dabigatran concentrations, the antidote decreased blood loss and mortality in this lethal pig animal model. Thus, data from clinical studies are warranted to confirm the findings of this study.

Author information

Correspondence to M Honickel.

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Honickel, M., Grottke, O., Van Ryn, J. et al. Use of a specific antidote to dabigatran (idarucizumab) reduces blood loss and mortality in dabigatran-induced and trauma-induced bleeding in pigs. Crit Care 18, P99 (2014). https://doi.org/10.1186/cc13289

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Keywords

  • Blood Loss
  • Sham Group
  • Dabigatran
  • Dabigatran Etexilate
  • Reduce Blood Loss