Evaluation of combined idarucizumab and prothrombin complex concentrate treatment for bleeding related to dabigatran in a lethal porcine model of double trauma.

Abstract

Idarucizumab (IDA) is approved for emergency reversal of dabigatran; prothrombin complex concentrates (PCCs) are recommended in the absence of specific antidote. The combined effects of IDA and PCC in trauma-related bleeding are unknown. The efficacy and safety of combined IDA + PCC were assessed in a lethal porcine model of double trauma under dabigatran anticoagulation. Male pigs (n = 28) received oral dabigatran etexilate (30 mg/kg bid) for 3 days; a non-dabigatran control group (n = 7) received placebo. On Day 4, dabigatran-treated animals were randomized 1:1:1:1 to receive placebo + placebo (dabigatran-treated control), IDA + PCC (60 mg/kg + 50 IU/kg), PCC + IDA, or IDA + IDA. Trauma was induced at t = 0 (bilateral femur fractures and blunt liver injury) and t = 60 minutes (second blunt liver injury). Study treatment was administered 15 minutes after each trauma. Animals were monitored for 5 hours or until death. Total blood loss in IDA + PCC, PCC + IDA, and IDA + IDA was 1673 ± 370, 1981 ± 361, and 1417 ± 135 mL, respectively, with 100% survival at 5 hours. Blood loss in dabigatran-treated controls was 4427 ± 162 mL with 100% mortality. With IDA + IDA, plasma coagulation parameters and thrombin generation were similar to non-dabigatran control group levels after the second dose and remained stable over time. In the IDA + PCC and PCC + IDA groups, thrombin generation and d-dimer levels after the second dose were higher than with IDA + IDA. No thromboembolic complications were found. IDA and PCC are effective in treating trauma-related bleeding with dabigatran anticoagulation. IDA is preferable for emergency reversal of dabigatran, but PCC may be valuable when the anticoagulant is unknown.