Elsevier

Thrombosis Research

Volume 152, April 2017, Pages 44-48
Thrombosis Research

Full Length Article
Reversal of dabigatran-associated major bleeding with activated prothrombin concentrate: A prospective cohort study

https://doi.org/10.1016/j.thromres.2017.02.010Get rights and content

Highlights

  • An antidote for dabigatran reversal was recently approved.

  • If the antidote is unavailable we propose activated prothrombin complex concentrate.

  • aPCC had Good or Moderate effectiveness in 14 of 14 cases with major bleeds.

  • No thromboembolic events occurred within 30 days.

Abstract

The reversal of dabigatran-associated major bleeding can now be achieved with the antidote idarucizumab. We evaluated activated prothrombin complex concentrate (aPCC) as an alternative for this purpose.

Patients treated with dabigatran and suffering a major bleed were treated as per existing hospital protocol with aPCC. They were subsequently recruited for a 30-day follow-up. Effectiveness was evaluated by the treating physician, using an Assessment Guide. Safety outcomes were arterial or venous thromboembolism or death. A comparison was also made with historic cases with dabigatran-associated major bleeds treated with supportive care, by matching 1:2 for type of bleed, age and sex.

We aimed at 32 evaluable cases but the study was prematurely discontinued after 14 cases due to the availability of the approved antidote. The effectiveness of aPCC was assessed as Good in 9 (64%), moderate in 5 (36%) and poor in none. There were no thromboembolic events and one death. In the secondary adjudication of effectiveness, using the same criteria and by the same adjudicators as previously done for the historic cases, the outcome was graded for the current cases versus the historic cases as Good, Moderate, or Poor in 10 (71%) versus 16 (57%), 3 (21%) versus 4 (14%), and 1 (7%) versus 8 (29%), respectively.

Although supportive care is sufficient to manage many patients with dabigatran-associated bleeding, aPCC might provide an additional benefit to control life-threatening bleeding in selected cases and does not appear to cause an excess of thromboembolic events.

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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