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

This was truncated following the approval of the dabigatran-reversal agent idarucizumab. In all cases, the effectiveness of aPCC was rated as either good (64%; n = 9) or moderate (36%; n = 5). Due to the reduced scope of the experiment, there were no significant differences identified between the intervention group and the matched controls.

Major dabigatran-related bleeding events can be managed with supportive care as per the phase III randomised-controlled trials; only small numbers received a reversal agent with uncertain benefit. Idarucizumab has recently been approved and is the reversal agent of choice, while prothrombin complex concentrate (PCC) has also been used in a limited number of cases. The aim of this study was to evaluate the safety and effectiveness of aPCC for reversal of major bleeding related to dabigatran anticoagulation.

This observational multicentre cohort study recruited people with acute and major active bleeding who were on dabigatran. The centres had aPCC readily available and on their treatment protocols, and patients were treated with aPCC at 50 units per kg. No additional haemostatic agents were administered, although a repeat infusion was indicated if required. The investigators contacted the treating physicians within 7 days, providing them with all relevant clinical data and asking them to rate the level of effectiveness of the anticoagulant reversal as either good, moderate or poor. Safety outcomes were also assessed and any thromboembolic events during the 30-day post infusion period were collated. The safety assessment was then compared with matched historical cases in a 2:1 ratio where patients had been managed supportively.

The patients were treated between February 2014 and July 2016, with 14 patients included in the analysis. There was a large variation between onset of bleeding and treatment initiation (5–222 hours), four patients required a further dose of aPCC, and one patient was included who had initially received idarucizumab but continued bleeding. The effectiveness of aPCC was considered ‘good’ in 9 cases (64%; 95% CI: 35–87%), ‘moderate’ in 5 cases (36%) and poor in 0 cases. Three patients required transfusion of two additional units of red cells. The comparators with matched cases did not detect any significant differences between aPCC and supportive care – although due to the reduced numbers recruited, it is unlikely that the experiment was sufficiently powered to detect a difference.

In their discussion, the authors reiterate that some cases of dabigatran related bleeding will likely benefit from prompt bleeding control. The fact that the study was terminated prematurely has limited the applicability of the data, but the authors hope it is of use in areas where idarucizumab is not yet approved. They note that aPCC seemed to be associated with numerically fewer deaths and a better effectiveness rating, although this did not meet significance. The delay in administration (mean 6 h 25 mins admission to infusion time) was down to some physicians not being aware of the availability of the drug. That there were no thromboembolic events suggests that there is at least not an excessive risk of thromboembolism; this is backed up by data from 1990–1999 showing that the risk of these events in haemophilia was 4 per 100,000 infusions. The authors suggest the prospective design and comparison with supportive management are strengths of the study. They acknowledge that the small number of subjects, inconsistency of effectiveness rating, lack of accounting for variable strengths of dabigatran, lack of validation of their assessment tool, lack of randomisation and lack of control for plasma levels of dabigatran are all weaknesses.

This study was clearly cut short which has affected its usefulness, and it is very difficult to derive any meaningful conclusions from it. Its applicability is very limited, and with the advent of idarucizumab, is likely to be irrelevant to the practice of most people.