Idarucizumab in the ‘real world’: possibilities and limitations

This editorial refers to ‘Performance of idarucizumab as antidote of dabigatran in daily clinical practice’ by S. J. van der Wall et al., on pages 414--420. Ever since the non-vitamin K antagonist oral anticoagulants (NOACs) were introduced into clinical practice, the concern about dealing with bleedings in the absence of a ‘specific reversal agent’ was raised, even though such a substance is also not available for vitamin K antagonists (VKA). Despite the absence of specific reversal agents, the risk of severe and life-threatening bleeding is reduced with NOACs compared to VKA, and the outcome of major bleeding under NOACs is better than with VKA. Moreover, various data pointed to the possibility to use prothrombin complex concentrates (PCC) and activated PCC (aPCC) to rapidly counter NOAC anticoagulant effects, i.e. a similar strategy as employed in life-threatening bleedings with VKA. It was not until 7 years after the introduction of the first NOAC on the market (dabigatran) that idarucizumab, a monoclonal antibody specifically binding to and thereby neutralizing dabigatran, was successfully tested in patients with severe bleeding and in patients who needed to undergo emergency surgery.1 In the current issue of EP-Europace, van der Wall et al.2 investigated idarucizumab in 88 patients from ‘daily clinical practice’ in the Netherlands, both patients with bleeding and requiring urgent surgery. Intriguingly, the use of idarucizumab was considered inappropriate in 25 patients (28%). Effective haemostasis was obtained in 67% of the bleeding patients. Despite treatment, 17 patients (19%) died out of which 10 (11%) within 5 days. Within 30 days, 4 patients (4.2%) developed thromboembolism and 4 patients (4.2%) re-bleeding. These findings mirror the results of REVERSE-AD, where after 30 days ∼12% and after 90 days ∼19% of patients had died. They also underline several important notions about bleeding in patients on NOACs (and on anticoagulation in general). The prognosis of a life-threatening bleed—particularly intracranial bleeding—is serious, even in the presence of a ‘perfect’ antidote such as idarucizumab which eliminates dabigatran from the equation of a bleeding patient within minutes of its administration. Therefore, although certainly of value in various situations, a directly acting antidote will not save every patient with a life-threatening bleed. More importantly, the mere availability of an antidote does not substitute for careful and individualized decision making in choosing the right NOAC for the right patient. Another important issue raised (again) by these data is the open question on the appropriateness and optimal timing of re-introduction of anticoagulation after a severe bleeding event, given the risks for thromboembolism and re-bleeding. In the absence of randomized clinical trial data, judicious clinical judgement is required. Finally, the high level of ‘inappropriate’ use observed in the current analysis—mainly due to interventions which could have been delayed until the drug had cleared—raises concerns for several reasons including cost, hypersensitivity reactions, and the theoretical fear of a prothrombotic effect as well as antibody formation. Although attractive from an organizational viewpoint, such ‘logistical’ indication should be avoided until further prospective data on its safety are available. Instead, we recommend to follow current recommendations for pre-operative interruption, possibly combined with plasma level measurement of the drug in special situations (e.g. prior to major surgical interventions or operations with a substantial bleeding risk).3 Hospital wide ‘standard operating procedures’ for management of patients on NOAC in emergency situations can increase proper use and patient outcome, while avoiding unnecessary and costly interventions, that could compromise future patient well-being.2 Soon, a specific reversal agents for the FXa inhibitor NOACs will be available (andexanet alpha), enriching but also complicating our clinical armamentarium. Continuing efforts to document the use and performance of these reversal agents, ideally in the context of prospective (instead of retrospective) registries, should be applauded to further evaluate the role of NOAC antidotes in daily clinical care. Conflict of interest: J.