Efficacy of idarucizumab, prothrombin complex concentrate (PCC) and activated PCC to reverse the anticoagulatory potential of dabigatran in a porcine polytrauma model
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Abstract
Introduction
The anticoagulant effect of dabigatran can be reversed with idarucizumab or PCCs in
porcine blood in vitro [1]. However, the impact on clinical parameters such as blood
loss is not known. Thus, this study assessed the efficacy of idarucizumab in comparison
with PCC and aPCC in dabigatran-anticoagulated swine following polytrauma on clinically
relevant endpoints.
Methods
After ethical approval, 28 male pigs were administered dabigatran etexilate (30 mg/kg
twice daily p.o.) for 3 days. Dabigatran was administered intravenously in anaesthetised
animals on day 4 to achieve consistent high concentrations. Animals were randomised
to receive idarucizumab (60 mg/kg, n = 7), PCC (50 U/kg; n = 7), aPCC (50 U/kg; n
= 7) or placebo (n = 7). Intervention started 12 minutes after bilateral femur fractures
and a standardised blunt liver injury. The primary endpoint was blood loss (observation
period 300 minutes). Further, histopathology, haemodynamics and several coagulation
variables were also assessed. Data were analysed by repeated-measures ANOVA (mean
± SD).
Results
Dabigatran levels were comparable between groups (571 ± 174 ng/ml) and resulted in
altered coagulation variables. Blood loss was comparable 12 minutes post trauma between
groups (801 ± 49 ml) and increased to 3,816 ± 236 ml in anticoagulated control animals
post injury. Idarucizumab treatment reduced total blood loss to 1,086 ± 55 ml (P <
0.005 vs. all), aPCC to 1,639 ± 104 ml (P < 0.05 vs. control) and PCC to 1,797 ± 80
ml (P < 0.05 vs. control) after 5 hours. All animals in the intervention groups survived,
whereas control animals died within the observation period (mean survival: 89 minutes,
range: 62 to 145 minutes). In histopathology no signs of thromboembolic events were
present. Altered coagulation variables returned to baseline levels after idarucizumab
application and were also significantly, although inconsistently and to a lesser extent,
ameliorated following PCCs.
Conclusion
All medical interventions were associated with reduced blood loss and increased survival.
However, idarucizumab, a specific antidote to dabigatran, reduced total blood loss
more prominently and normalised coagulation parameters to a greater degree as compared
with either PCC or aPCC.
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Conference name:
35th International Symposium on Intensive Care and Emergency Medicine