Retrospective Analysis of the Effectiveness of a Reduced Dose of Idarucizumab in Dabigatran Reversal

Abstract

Background The recommended dose of idarucizumab, the specific reversal agent for dabigatran etexilate, is 5 g. However, published data showed biochemical reversal after an initial 2.5 g dose.

Objectives This study aims to retrospectively compare the clinical effectiveness of 2.5 and 5 g doses of idarucizumab used in dabigatran reversal in three hospitals in Auckland, New Zealand.

Methods All patients receiving idarucizumab for dabigatran reversal between April 1, 2016 and December 31, 2018 were included. The primary outcome was the likelihood of receiving a second dose of idarucizumab during the same admission. Secondary outcomes included normalization of coagulation profiles, and 30-day thrombotic, bleeding, and mortality rates.

Results Of 329 patients included, 206 received an initial 2.5 g dose and 123 received a 5 g dose. The median age was 78 years and median creatinine clearance was 50 mL/min. Most patients (62.6%) required idarucizumab for an urgent procedure, while 37.4% presented with bleeding. A 2.5 g dose was not associated with an increased rate of receiving a second dose (odds ratio [OR]: 0.686, 95% confidence interval [CI]: 0.225–2.090). A similar proportion of patients in each group achieved a normal activated partial thromboplastin time (73.8 vs. 80.0%, p = 0.464) and dilute thrombin clotting time (95.9 vs. 91.4%, p = 0.379) following idarucizumab infusion. There was no increase in the rate of death (OR: 0.602, 95% CI: 0.292–1.239), thrombosis (OR: 0.386, 95% CI: 0.107–1.396), or bleeding (OR: 0.96, 95% CI: 0.27–3.33) in the 2.5 g dose group compared with the 5 g dose group.

Conclusion An initial 2.5 g dose of idarucizumab appears effective for dabigatran reversal in the real-world setting.

Keywords

dabigatran - idarucizumab - anticoagulant - bleeding - thrombosis

Publikationsverlauf

Eingereicht: 29. Juli 2021

Angenommen: 21. November 2021

Accepted Manuscript online:
23. November 2021

Artikel online veröffentlicht:
20. Januar 2022

• References

• 1 Camm AJ. The RE-LY study: Randomized Evaluation of Long-term anticoagulant therapY: dabigatran vs. warfarin. Eur Heart J 2009; 30 (21) 2554-2555
• 2 Greig SL, McKeage K. Dabigatran etexilate: a review of its use in the treatment of acute venous thromboembolism and prevention of venous thromboembolism recurrence. Drugs 2014; 74 (15) 1785-1800
• 3 Reilly PA, van Ryn J, Grottke O, Glund S, Stangier J. Idarucizumab, a specific reversal agent for dabigatran: mode of action, pharmacokinetics and pharmacodynamics, and safety and efficacy in phase 1 subjects. Am J Med 2016; 129 (11S): S64-S72
• 4 Pollack Jr CV, Reilly PA, van Ryn J. et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377 (05) 431-441
• 5 Glund S, Stangier J, Schmohl M. et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015; 386 (9994): 680-690
• 6 Yasaka M, Ikushima I, Harada A. et al. Safety, pharmacokinetics and pharmacodynamics of idarucizumab, a specific dabigatran reversal agent in healthy Japanese volunteers: a randomized study. Res Pract Thromb Haemost 2017; 1 (02) 202-215
• 7 Glund S, Stangier J, van Ryn J. et al. Effect of age and renal function on idarucizumab pharmacokinetics and idarucizumab-mediated reversal of dabigatran anticoagulant activity in a randomized, double-blind, crossover phase Ib study. Clin Pharmacokinet 2017; 56 (01) 41-54
• 8 Reilly PA, Lehr T, Haertter S. et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
• 9 Schiele F, van Ryn J, Canada K. et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121 (18) 3554-3562
• 10 Glund S, Moschetti V, Norris S. et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015; 113 (05) 943-951
• 11 Schmohl M, Glund S, Harada A. et al. Idarucizumab does not have procoagulant effects: assessment of thrombosis biomarkers in healthy volunteers. Thromb Haemost 2017; 117 (02) 269-276
• 12 Levy JH, van Ryn J, Sellke FW. et al. Dabigatran reversal with idarucizumab in patients requiring urgent surgery: a subanalysis of the RE-VERSE AD study. Ann Surg 2021; 274 (03) e204-e211
• 13 Hegemann I, Ganter C, Widmer CC, Becker M, Müller D, Spahn DR. Ongoing redistribution of dabigatran necessitates repetitive application of idarucizumab. Br J Anaesth 2018; 121 (02) 505-508
• 14 Simon A, Domanovits H, Ay C, Sengoelge G, Levy JH, Spiel AO. The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran. J Thromb Haemost 2017; 15 (07) 1317-1321
• 15 Marino KK, Santiago RA, Dew III RB. et al. Management of dabigatran-associated bleeding with two doses of idarucizumab plus hemodialysis. Pharmacotherapy 2016; 36 (10) e160-e165
• 16 Athavale A, Jamshidi N, Roberts DM. Incomplete responses to the recommended dose of idarucizumab: a systematic review and pharmacokinetic analysis. Clin Toxicol (Phila) 2020; 58 (08) 789-800
• 17 Ezekowitz MD, Reilly PA, Nehmiz G. et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100 (09) 1419-1426
• 18 Eikelboom JW, van Ryn J, Reilly P. et al. Dabigatran reversal with idarucizumab in patients with renal impairment. J Am Coll Cardiol 2019; 74 (14) 1760-1768
• 19 Gendron N, Gay J, Lemoine M, Gaussem P, Lillo-Le-Louet A, Smadja DM. Usefulness of initial plasma dabigatran concentration to predict rebound after reversal. Haematologica 2018; 103 (05) e226-e229
• 20 Fang CW, Tsai YT, Chou PC. et al. Intravenous thrombolysis in acute ischemic stroke after idarucizumab reversal of dabigatran effect: analysis of the cases from Taiwan. J Stroke Cerebrovasc Dis 2019; 28 (03) 815-820
• 21 Meyer D, Chu F, Derry K, Hailey L. Acute reversal of dabigatran with Idarucizumab for intravenous thrombolysis as acute stroke treatment. J Clin Neurosci 2019; 59: 355-357
• 22 Ohya Y, Makihara N, Wakisaka K. et al. Thrombolytic therapy in severe cardioembolic stroke after reversal of dabigatran with idarucizumab: case report and literature review. J Stroke Cerebrovasc Dis 2018; 27 (07) e128-e131
• 23 Pikija S, Sztriha LK, Sebastian Mutzenbach J, Golaszewski SM, Sellner J. Idarucizumab in dabigatran-treated patients with acute ischemic stroke receiving alteplase: a systematic review of the available evidence. CNS Drugs 2017; 31 (09) 747-757
• 24 Barber PA, Wu TY, Ranta A. Stroke reperfusion therapy following dabigatran reversal with idarucizumab in a national cohort. Neurology 2020; 94 (19) e1968-e1972
• 25 Beharry J, Waters MJ, Drew R. et al. Dabigatran reversal before intravenous tenecteplase in acute ischemic stroke. Stroke 2020; 51 (05) 1616-1619