Author + information
- Stephan Glund, PhD∗ (, )
- Joachim Stangier, PhD,
- Joanne van Ryn, PhD,
- Michael Schmohl, PhD,
- Viktoria Moschetti, MD,
- Wouter Haazen, MD,
- Marina De Smet, PhD,
- Dietmar Gansser, PhD,
- Stephen Norris, PhD,
- Benjamin Lang, Dipl-Math oec,
- Paul Reilly, PhD and
- Jörg Kreuzer, MD
- ↵∗Boehringer Ingelheim Pharma GmbH and Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany
Idarucizumab is a specific reversal agent that rapidly neutralizes dabigatran’s anticoagulant activity (1–3). We investigated restoration of dabigatran anticoagulation 24 h after idarucizumab treatment and the safety and effectiveness of a second idarucizumab treatment.
Six male and 6 female volunteers (age 52 ± 6, creatinine clearance 104 ± 23 ml/min) received dabigatran etexilate 220 mg twice a day for 3 days, with a single dose on day 4. Participants were then randomized to idarucizumab (2.5 or 5 g) or placebo, administered as a 5-min intravenous infusion 1 h 55 min after the final dabigatran etexilate dose. Dabigatran etexilate was restarted 24 h after idarucizumab/placebo and continued for 3 days. Crossover treatment occurred after a ≥6-day wash out. The anticoagulant effects of dabigatran and the reversal by idarucizumab were determined by diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time (aPTT). Plasma concentrations of unbound dabigatran (approximately active dabigatran) and idarucizumab were measured. Plasma levels are described as geometric mean, and clotting times as arithmetic mean ± SE.
Peak steady-state unbound dabigatran levels of 166 to 212 ng/ml were achieved ∼2 h after final dabigatran etexilate administration on day 4. This was associated with elevations of aPTT ∼2.2-fold (Figure 1A), diluted thrombin time ∼1.8-fold, and ecarin clotting time ∼3-fold (not shown). Concentrations of unbound dabigatran decreased to <20 ng/ml 24 h later by normal dabigatran elimination (placebo treatment). Idarucizumab administration resulted in immediate reduction of dabigatran to ≤1 ng/ml and normalization of prolonged clotting times, which was sustained for the entire observation period of 24 h. Full reversal was achieved with both the 2.5- and 5-g idarucizumab doses, which is consistent with previous studies (1).
Reinitiation of dabigatran etexilate 220 mg twice a day after 24 h led to similar levels of anticoagulation irrespective of previous treatment with idarucizumab or placebo. Figure 1A shows aPTT before and 2 h after the first dabigatran etexilate dose during pre-treatment, directly after placebo or 5 g idarucizumab, and before and 2 h after the first dabigatran etexilate dose 24 h later. The unbound dabigatran concentrations at these time points were (placebo/idarucizumab): 0/0 and 125/127 ng/ml before and 2 h after the first dabigatran etexilate dose, respectively; 166/≤1 ng/ml directly after placebo/idarucizumab; and 16/5 and 159/134 ng/ml before and 2 h after the first reinitiation dose of dabigatran etexilate, respectively. These observations were consistent with the short half-life of idarucizumab (∼45 min). Similar results were obtained for dabigatran at steady-state and following 2.5-g idarucizumab/placebo treatment.
Idarucizumab concentrations declined from 24,000 nmol/l at the end of a 5-g infusion to 160 and 67 nmol/l after 12 and 24 h, respectively (<0.7% of peak). At 24 h, unbound dabigatran levels were above the lower limit of quantitation in all subjects, suggesting that the residual idarucizumab was already combined with dabigatran and no further dabigatran binding would be expected. Thus, idarucizumab provides an option for rapid reversal of dabigatran-induced anticoagulation and allows reinitiation of dabigatran etexilate treatment 24 h after a surgical intervention or after major bleeding to reduce thromboembolic risk. Alternatively, other antithrombotics could be introduced at any time since idarucizumab binding is dabigatran-specific.
Safety and efficacy of idarucizumab re-exposure was assessed ∼2 months later in 3 male and 3 female subjects who initially received 2.5 g idarucizumab. As described, dabigatran etexilate 220 mg twice a day for 3.5 days was followed by 2.5 g idarucizumab 1 h 55 min after the last dose. Reduction in unbound dabigatran concentrations and reversal of anticoagulation (Figure 1B) were similar to the first idarucizumab treatment, with no adverse events indicative of allergic/immunologic reactions. No anti-idarucizumab antibodies were detected prior to re-exposure with idarucizumab. After re-exposure, 1 of 6 subjects tested positive with a low titer at 3 months. Thus, a second administration of idarucizumab appears safe and effective and could be given to patients requiring this for life-threatening bleeds or urgent surgery.
Please note: This study was funded by Boehringer Ingelheim Pharma GmbH and Co. KG. Drs. Glund, Stangier, van Ryn, Schmohl, Moschetti, Gansser, Lang, and Kreuzer are employees of Boehringer Ingelheim Pharma GmbH and Co. KG. Dr. Haazen was the principal investigator of this trial and was an employee of SGS Life Science Services, the contract research organization that was funded by Boehringer Ingelheim Pharma GmbH and Co. KG to perform the clinical trial. Dr. De Smet was an employee of SCS Boehringer Ingelheim. Drs. Norris and Reilly are employees of Boehringer Ingelheim Pharmaceuticals, Inc. Editorial assistance in formatting the article for submission, supported financially by Boehringer Ingelheim Pharma GmbH and Co. KG, was provided by PAREXEL. (Safety, Tolerability, PK and PD of BI 655075 and Establishment of BI 655075 Dose[s] Effective to Reverse Prolongation of Blood Coagulation Time by Dabigatran; NCT01955720).
- 2016 American College of Cardiology Foundation