Prothrombin complex concentrate for non‐vitamin K oral anticoagulant reversal: good enough for now?

Vitamin K antagonists have been the main oral anticoagulants in use worldwide for > 50 years. They are highly effect in preventing recurrence of venous thromboembolism and thrombotic stroke in patients with atrial fibrillation [1,2]. Despite this high degree of efficacy, they have a number of limitations, including the need for regular monitoring and significant interactions with multiple medications, and are associated with bleeding complications. The overall risk of bleeding in patients receiving warfarin has been reported to be 3.0% annually for serious bleeding and 0.6% for fatal bleeding [3]. The recent introduction of three new oral non-vitamin K direct-acting anticoagulants (NOACs) is transforming the landscape of thrombosis management, and patients are now changing from vitamin K antagonists to the NOACs. NOACs are taken at a fixed dose once or twice daily without the need for monitoring. Dabigatran inhibits thrombin, whereas rivaroxaban and apixaban are factor Xa inhibitors [4]. In a meta-analysis that compared NOACs with warfarin in the treatment of acute symptomatic venous thromboembolism, NOACs were as effective as warfarin and were associated with a significantly lower risk of bleeding complications [5]. The main adverse effect of all anticoagulants is bleeding, and hematologists are frequently consulted on how to optimally reverse their effect in an emergency, either because of major bleeding or because of urgent surgery that cannot be delayed. Despite the fact that the reversal of the effect of oral vitamin K antagonists may appear to be straightforward, with vitamin K and replacement of the deficient clotting factors with prothrombin complex concentrates (PCCs), several issues remain. For example, there is debate as to whether three-factor PCCs (which contain no FVII) are as effective as four-factor PCCs, which contain FII, FVII, FIX, and FX [6]. Furthermore, despite the widespread use of PCCs for warfarin reversal in Europe for decades, these products were only recently licensed in the USA [7]. Proving efficacy and safety to the US regulators was a difficult task. One of the main concerns with the use of NOACs is the lack of a specific antidote [8]. Fortunately, severe bleeding complications requiring emergency reversal are rare, and the relatively short half-life of NOACs in patients without renal impairment means that waiting and providing supportive care are often sufficient [8]. The lack of a specific antidote for commonly used anticoagulants is not a new issue, as it is not possible to completely reverse the anticoagulant effect of low molecular weight heparin even with protamine, but this has not held back their international adoption in clinical practice [9]. Currently, there are no specific NOAC antidotes, and several guidelines recommend the off-label use of activated PCC (aPCC) and non-activated PCCs for reversal of the anticoagulant effect [8,10,11]. A large number of publications have reported the effect of activated and non-activated PCCs on NOAC reversal in vitro, ex vivo, and in several animal models [12]. Unfortunately, the experimental conditions, animal species and type of model vary enormously, and it is not possible to compare directly the different results. The literature on in vitro and animal studies of PCCs for NOAC reversal has been reviewed recently, and the main conclusion is that they are at least partially effective [12]. For reversal of the Correspondence: Mike Makris, Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. Tel. : +44 114 2712760; fax: +44 114 2756126. E-mail: m.makris@sheffield.ac. uk