Full Length ArticleReversal of dabigatran-associated major bleeding with activated prothrombin concentrate: A prospective cohort study
Introduction
Major bleeding on dabigatran can be effectively managed with supportive care, as demonstrated from post hoc analyses of the phase III randomized trials with dabigatran in venous thromboembolism or atrial fibrillation [1], [2], [3]. Only a handful of those patients received either prothrombin complex concentrate or recombinant factor VIIa with uncertain benefit. A specific antidote for reversal of dabigatran, idarucizumab, has recently been approved in Europe, the United States and Canada. Idarucizumab has immediate, complete and sustained reversal effect on dabigatran [4] and has now become the agent of choice for patients with major bleeding or need for emergency surgery.
Another reversal agent that has been used in a very limited number of cases is activated prothrombin complex concentrate (aPCC) [5], [6], [7], which otherwise has been used for a few decades for treatment of bleeding in patients with hemophilia and inhibitors. The dose of aPCC for reversal of dabigatran–associated bleeding was at the lower end (around 50 units/kg) of the spectrum used in hemophilia (50–100 units/kg/dose; maximum 200 units/kg/24 h). This “conservative” dose of aPCC was chosen because ex vivo studies showed that those higher doses resulted in supranormal levels of some of the thrombin generation parameters [8], and patients on dabigatran with their underlying disease have a higher risk of thrombotic complications than patients with hemophilia.
The aim of this study was to evaluate the safety and effectiveness of aPCC at a dose of 50 units/kg for reversal of major bleeding on dabigatran in a prospective cohort study.
Section snippets
Methods
This was an observational multicenter cohort study performed at hospitals in Canada where aPCC (FEIBA NF®, Baxter Healthcare Corporation – currently: Baxalta now part Shire, Westlake Village, CA, USA) was readily available and where a hospital protocol existed that suggested or recommended the use of aPCC for reversal of dabigatran-associated bleeding. The study was designed, conducted and analyzed by the investigators. It was funded by an unrestricted grant from the manufacturer, which had no
Results
The first patient was included in February 2014 and the study closed prematurely in July 2016. At that point 3 of the 4 recruiting sites had idarucizumab approved and available and further recruitment to this study was no longer feasible. By then 15 patients had met the eligibility criteria, 1 declined consent and 14 were included in the study. The characteristics of the patients, their antithrombotic treatment and the qualifying bleeding event are shown in Table 1.
Discussion
Major bleeding in patients randomized to the non-vitamin K antagonist oral anticoagulants (NOACs) in the long-term atrial fibrillation or venous thromboembolism trials occurred in 4% [12]. In clinical practice, based on Medicare data from 67,207 patients on dabigatran the incidence rate of major bleeding per 1000 person-years was 42.7, similar to that of warfarin [13]. There is thus a need to manage these bleeding episodes appropriately. Many can be managed with supportive care without worse
Addendum
S. Schulman, B. Ritchie and M. Carrier were involved in the research concept and design. A. Majeed and H.-G. Hwang performed the secondary effectiveness adjudication. M. Zondag coordinated the study. S. Schulman wrote the manuscript and all authors revised the manuscript and gave final approval.
Conflicts of interest
Dr. Schulman has grant support/honoraria from Boehringer Ingelheim, Octapharma, Baxter, Bayer, Sanofi, and Bristol-Myers-Squibb; Dr. Carrier has grant support/honoraria from Bristol-Myers-Squibb, Leo Pharma, Boehringer Ingelheim, Pfizer, and Bayer; Dr. Gross has received speaker honoraria from Bayer, Pfizer and Bristol Myers Squibb and has intellectual property on a method to test direct oral anticoagulants; Dr. Majeed has received research support from Octapharma and Leo-Pharma, lecture fees
Acknowledgements
Martin Feuring, Boehringer Ingelheim for providing permission to use the matched controls from the randomized trials. The study was funded by an unrestricted grant from Baxalta, now part of Shire.
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2022, Journal of Cardiothoracic and Vascular AnesthesiaCitation Excerpt :The PCC or aPCC at a dose of 25-to- 50 units/kg is recommended for use in patients taking factor Xa inhibitors,45 and PCC or aPCC at a dose of 50 units/kg is recommended for reversal of dabigitran.49 The reversal of dabigatran has been studied at a range of 24-to-98 units/kg of PCC, with a median initial dose of 44 units/kg,50 and factor Xa inhibitor-associated bleeding has been studied at doses ranging from 25-to-50 units/kg.51,52 Because of risk of thrombosis with PCCs, some authors chose the lower range of 25 units/kg.51
Clinical protocols for oral anticoagulant reversal during high risk of bleeding for emergency surgical and nonsurgical settings: a narrative review
2021, Brazilian Journal of Anesthesiology (English Edition)Citation Excerpt :The literature shows controversial results for the use of PCCs as a reversal agent for dabigatran. Limited evidence of efficacy was observed in reported case series in which aPCC reversed dabigatran, controlled bleeding, with no thromboembolic events.94,95 One patient was reported to have a rapid response after the administration of aPCC during cardiac ablation,96 and one patient responded to PCCs and FFP.97
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The investigators are listed in the online appendix.