Clinical experience with idarucizumab in patients with atrial fi brillation taking dabigatran etexilate

Dabigatran etexilate (DE) is a direct thrombin inhibitor that has been shown to be eff ective and safe in preventing thrombotic events in a number of studies. Currently idarucizumab, which is a monoclonal antibody and a DE antagonist, is used to immediately inactivate the DE-induced eff ect.

Objective. Еvaluation of the effi  ciency and safety of idarucizumab in patients receiving DE.

Material and methods. 6 patients (2 men, 4 women) aged 61 to 86 years (mean age 72.8 ± 10.6 years) receiving DE, who are expected to use idarucizumab in achieving the goal of sTLT or surgery.

Results. In none of the patients the use of idarucizumab was accompanied by a decrease in thrombin time of less than 11 seconds which could indicate a hypercoagulable phenomenon. Before inactivation of dabigatran etexilate thrombin time was signifi cantly higher (p < 0.05) than after the administration of the drug. There were no statistically signifi cant diff erences in the concentration of D-dimer before and after the administration of idarucizumab which indicates the absence of procoagulant properties of this drug. None of the patients developed clinically signifi cant arterial and/ or venous thrombotic events such as recurrent IS, myocardial infarction, deep vein thrombosis of the lower extremities and pulmonary embolism, during the entire period of hospitalization.

Conclusion. The use of idarucizumab is allowed for systemic thrombolytic therapy and emergency surgical treatment in patients taking DE. Idarucizumab quickly and safely neutralizes the anticoagulant eff ect of DE and doesn’t have a prothrombotic activity.

1. Connolly S.J., Wallentin L., Ezekowitz M.D., Eikelboom J., Oldgren J., Reilly P.A. et al. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation. 2013;128(3):237– 43. https://doi.org//10.1161/CIRCULATIONAHA.112.001139

2. Schulman S., Kakkar A.K., Goldhaber S.Z., Schellong S., Eriksson H., Mismetti P. et al. RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764–772. https://doi.org//10.1161/CIRCULATIONAHA.113.004450

3. Schulman S., Kearon C., Kakkar A.K., Mismetti P., Schellong S., Eriksson H. et al.; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–52. https://doi.org//10.1056/NEJMoa0906598.

4. Bovio J.A., Smith S.M., Gums J.G. Dabigatran etexilate: a novel oral thrombin inhibitor for thromboembolic disease. Ann Pharmacother. 2011;45(5):603–614. https://doi.org//10.1345/aph.1P644.

5. Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldgren J., Parekh A. et al.; RE-LY Steering Committee and Investigators. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139–1151. https://doi.org/10.1056/NEJMoa0905561

6. Patel M.R., Mahaff ey K.W., Garg J., Pan G., Singer D.E., Hacke W. et al.; ROCKET AF Investigators. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011;365(10):883–891. https://doi.org/10.1056/NEJ-Moa1009638

7. Granger C.B., Alexander J.H., McMurray J.J., Lopes R.D., Hylek E.M., Hanna M. et al.; ARISTOTLE Committees and Investigators.Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2011;365(11):981–992. https://doi.org/10.1056/NEJMoa1107039

8. Giugliano R.P., Ruff C.T., Braunwald E., Murphy S.A., Wiviott S.D., Halperin J.L. et al.; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fi brillation. N Engl J Med. 2013;369(22):2093–2104. https://doi.org/10.1056/NEJMoa1310907

9. Ahmatkhanova L.Kh.-B., Ramazanov G.R., Klychnikova E.V., Muslimov R.S., Parkhomenko M.V. Systemic Thrombolytic Therapy for Ischemic Stroke in the Course of Anticoagulants. Russian Sklifosovsky Journal “Emergency Medical Care”. 2021;10(3):598–603. (In Russ.)]. https://doi.org/10.23934/2223-9022-2021-10-3-598-603

10. Ikram M.A., Wieberdink R.G., Koudstaal P.J. International epidemiology of intracerebral hemorrhage. CurrAtheroscler Rep. 2012:14(4):300–306. https://doi.org//10.1007/s11883-012-0252-1.

11. Schols A.M., Schreuder F.H., van Raak E.P., Schreuder T.H., Rooyer F.A., van Oostenbrugge R.J., Staals J. Incidence of oral anticoagulant-associated intracerebral hemorrhage in the Netherlands. Stroke. 2014;45(1):268–270. https://doi.org//10.1161/STROKEAHA.113.003003

12. Flaherty M.L., Kissela B., Woo D., Kleindorfer D., Alwell K., Sekar P. et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology. 2007;68(2):116–21. https://doi.org//10.1212/01.wnl.0000250340.05202.8b

13. Pollack C.V. Jr., Reilly P.A., van Ryn J., Eikelboom J.W., Glund S., Bernstein R.A. et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. N Engl J Med. 2017;377(5):431–441. https://doi.org/10.1056/NEJMoa1707278

14. Tomaselli G.F., Mahaff ey K.W., Cuker A., Dobesh P.P., Doherty J.U., Eikelboom J.W. et al. ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants:A Report of the American College of Cardiology Solution Set Oversight Committee. J Am CollCardiol. 2020;76(5):594–622. https://doi.org/10.1016/j.jacc.2020.04.053

15. von Wowern F., Brizzi M., Holst J. Reversal of the anticoagulation eff ects of dabigatran etexilate by idarucizumab in three patients needing urgent surgical intervention and one case of intravenous thrombolysis in ischaemic stroke. Eur J Case Rep Intern Med. 2017;4(4):000569. https://doi.org/10.12890/2017_000569

16. Schmohl M., Glund S., Harada A., Imazu S., De Smet M., Moschetti V. et al. Idarucizumab does not have procoagulant eff ects: Assessment of thrombosis biomarkers in healthy volunteers. Thromb Haemost. 2017;117(2):269–276. https://doi.org//10.1160/TH16-05-0385.

17. January C.T., Wann L.S., Calkins H., Chen L.Y., Cigarroa J.E., Cleveland J.C. Jr. et al. AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons Circulation. 2019;140(2):e125–e151. https://doi.org/10.1161/CIR.0000000000000665

18. Powers W.J., Rabinstein A.A., Ackerson T., Adeoye O.M., Bambakidis N.C., Becker K. et al.; American Heart Association Stroke Council. Guidelines for the Early Management of Patients with Acute Ischemic Stroke A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46–e110. https://doi.org/10.1161/STR.0000000000000158

19. Ischemic stroke and transient ischemic attack in adults. Clinical guidelines. Moscow; 2021. URL: https:// cr.minzdrav.gov.ru/recomend/171_2 (In Russ.)].

20. Khatri P., Wechsler L.R., Broderick J.P. Intracranial hemorrhage associated with revascularization therapies. Stroke. 2007;38(2):431–440. https://doi.org/10.1161/01.STR.0000254524.23708.c9

21. Rosand J., Eckman M.H., Knudsen K.A., Singer D.E., Greenberg S.M. The eff ect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004;164(8):880–884. PMID: 15111374

22. Wu T., Lv C., Wu L., Chen W., Lv M., Jiang S., Zhang J. Risk of intracranial hemorrhage with direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Neurol. 2022;269(2):664–675. https://doi.org/10.1007/s00415-021-10448-2

23. Yasaka M., Yokota H., Suzuki M., Yamane T., Ono Y. Incidence Rates of Bleeding and Emergency Surgery Due to Trauma or Fracture Among Japanese Patients with Non-valvular Atrial Fibrillation Receiving Oral Anticoagulation Therapy. Cardiol Ther. 2020;9(1):189–199. https://doi.org/10.1007/s40119-02000171-w