Author + information
- Oliver Grottke, MD, PhD∗ (, )
- Markus Honickel, MD,
- Joanne van Ryn, PhD,
- Hugo ten Cate, MD, PhD,
- Rolf Rossaint, MD and
- Henri M. Spronk, PhD
- ↵∗Department of Anesthesiology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany
Idarucizumab is a humanized antibody fragment that specifically reverses dabigatran and provides immediate and sustained reversal of dabigatran anticoagulation (1–3). However, its effect on life-threatening bleeding following major trauma has not been studied. Thus, we investigated whether idarucizumab reverses dabigatran anticoagulation in a lethal porcine blunt liver injury model.
After obtaining ethical approval, male pigs (mean weight 42 kg) received oral dabigatran etexilate 30 mg/kg twice daily for 3 days and dabigatran infusion for 90 min on day 4 (n = 24) or placebo (n = 6). On day 4, all 30 pigs underwent surgery under anesthesia (4). Dabigatran-treated animals were randomized to intervention with idarucizumab 30, 60, or 120 mg/kg or saline control. Standardized blunt liver injury was induced, and 15 min post-injury, idarucizumab or saline was administered intravenously. Blood loss and coagulation parameters were recorded for 240 min post-trauma or until death. Plasma levels of dabigatran and idarucizumab were measured using liquid chromatography-mass spectrometry and enzyme-linked immunosorbent assay. Data were assessed using analysis of variance and presented as mean ± SD. All p values <0.05 were considered significant.
Anticoagulation with dabigatran approximately doubled blood loss during the first 12 min post-trauma (786 ± 39 ml vs. 409 ± 53 ml, p < 0.0001) (Figure 1A). Subsequently, among control animals (dabigatran/saline), blood loss increased over time to 2,977 ± 316 ml. In comparison, idarucizumab 30, 60, and 120 mg/kg significantly decreased total blood loss to 1,586 ± 619 ml, 1,065 ± 97 ml, and 1,140 ± 109 ml, respectively (reductions of 47%, 64%, and 62%, respectively) (Figure 1A). All control animals died early (121 ± 26 min), compared with 1 of 6 in the idarucizumab 30 mg/kg group. Survival in the remaining idarucizumab animals was 100%.
Dabigatran significantly prolonged plasma-based clotting tests versus sham before trauma, for example, activated partial thromboplastin time (aPTT) 61 ± 17 s versus 13 ± 1 s at baseline. Idarucizumab reduced the aPTT dose dependently. For example, at 60 min post-trauma the aPTT was 40 ± 11 s, 28 ± 7 s, and 16 ± 1 s for 30, 60, and 120 mg/kg, respectively; this effect was immediate and was maintained over time.
Thrombin generation at baseline was 302 ± 47 nm·min (endogenous thrombin potential) and was completely inhibited by dabigatran, 0 ± 0 nm·min. The ETP increased dose-dependently after idarucizumab; for example, at 60 min post-trauma, 30, 60, and 120 mg/kg resulted in thrombin generation of 131 ± 38 nm·min, 212 ± 42 nm·min, and 372 ± 42 nm·min versus 353 ± 42 nm·min in the sham group. Similarly, all coagulation tests were restored to baseline, with the highest dose of 120 mg/kg idarucizumab. The dTT and ECT are sensitive measures for dabigatran, whereas the aPTT provides an approximate assessment. All tests showed similar patterns of reversal, consistent with observations in healthy volunteers (2).
Peak dabigatran concentration on day 4 was 1,161 ± 372 ng/ml just before injury. There was a large increase in total plasma dabigatran after idarucizumab administration (Figure 1B), without increased anticoagulation. Total dabigatran includes molecules bound to idarucizumab or plasma proteins and unbound (active) molecules. Idarucizumab remains predominantly in plasma, and this initiates a shift in equilibrium of dabigatran molecules from tissues to the blood compartment where they bind to idarucizumab. The process continues until idarucizumab becomes saturated with dabigatran or all active dabigatran is bound, as with 120 mg/kg idarucizumab. No further anticoagulant activity was observed with the 120 mg/kg dose, suggesting that the idarucizumab–dabigatran complex remains stable and the 2 drugs are cleared together.
Post-mortem macroscopic evaluation of the heart, lungs, kidneys, and liver showed no evidence of thromboembolism. However, limitations of this study such as the high dabigatran concentrations and species differences between humans and pigs must be considered. Clinical trials are warranted to confirm whether our results are applicable to patients.
This study demonstrates that idarucizumab reduces dabigatran-associated bleeding and mortality in a porcine trauma model. Treatment with idarucizumab stopped bleeding within 15 min and was associated with an immediate decrease in dabigatran anticoagulant effects. There was no evidence of safety concerns associated with the administration of idarucizumab.
Please note: Financial support for this study was provided by Boehringer Ingelheim. The study sponsor had no role in the collection, analysis, and interpretation of data and approved the final version of the manuscript. Dr. Grottke has received research funding from Novo Nordisk, Biotest, CSL Behring, Boehringer Ingelheim and Nycomed; and has received honoraria/travel support for consultancy from Bayer Healthcare, Boehringer Ingelheim, CSL Behring, and Portola. Dr. Honickel has received travel support from Boehringer Ingelheim. Dr. van Ryn is an employee of Boehringer Ingelheim. Dr. ten Cate has received research funding from CSL Behring, Bayer, Philips, Pfizer, and Boehringer Ingelheim; and has received honoraria for lectures and consultancy from Bayer, Leo Pharma, Stago, Boehringer, and Pfizer. Dr. Rossaint has received institutional grant support from Boehringer Ingelheim; and has received honoraria for lectures and consultancy from CSL Behring, Boehringer Ingelheim, and Novo Nordisk. Dr. Spronk has received research funding from Boehringer Ingelheim; and has received honoraria for consultancy from Bayer.
- American College of Cardiology Foundation
- Schiele F.,
- van Ryn J.,
- Canada K.,
- et al.
- Glund S.,
- Stangier J.,
- Schmohl M.,
- et al.