Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity

Abstract

SummaryDabigatran etexilate is an oral, reversible direct thrombin inhibitor that is approved in the EU and several other countries for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for other thromboembolic disorders. Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for routine coagulation monitoring. In certain clinical situations such as serious bleeding into critical organs (e.g. intracerebral bleeding), potential overdose and emergency surgery, clinicians will need to make an assessment of the anticoagulant status of a patient receiving dabigatran before deciding on future management strategies. If available, thrombin clotting time (TT), ecarin clotting time (ECT) and TT determined by Hemoclot ® thrombin inhibitor assay are sensitive tests to evaluate the anticoagulant effects of dabigatran. Prothrombin time (INR) is less sensitive than other assays and cannot be recommended. The activated partial thromboplastin time (aPTT) can provide a useful qualitative assessment of anticoagulant activity but is less sensitive at supratherapeutic dabigatran levels. There are limited data for activated clotting time (ACT). Overall, the aPTT and TT are the most accessible qualitative methods for determining the presence or absence of anticoagulant effect. Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. In case of potential overdose, the feasibility of early administration of activated charcoal and subsequent charcoal filtration are undergoing preclinical evaluation. Dabigatran can also be dialysed in patients with renal impairment. In instances of life-threatening bleeding, where conventional measures have failed or are unavailable, other non-specific prohaemostatic agents such as recombinant activated factor VII and prothrombin complex concentrates can be considered.

Safety, pharmacokinetics and pharmacodynamics of idarucizumab, a specific dabigatran reversal agent in healthy Japanese volunteers: a randomized study

“…The plasma concentration–time profile of active dabigatran alone was as expected13 (Figure 4A). Plasma concentrations of unbound dabigatran (Figure 4B) and active dabigatran decreased to below the limit of quantification (BLQ) or close to BLQ immediately post‐idarucizumab.…”

“…Owing to the relatively short half‐life of dabigatran (12‐14 hour),13 cessation of treatment and standard supportive care (eg, volume replacement) can be used to manage bleeding in many patients with adequate renal function, but this may be inadequate in emergency situations 13, 14, 15, 16…”

A dabigatran iv. antidótumának, az idarucizumabnak első hazai alkalmazásai sürgős műtétek esetén

“…A rutin, jelenlegi gyakorlatban sajnos nem áll rendelkezésre megbízható módszer, paraméter a dabigatrannal elért alvadásgátlás intenzitásának a pontos megítélésére a dabigatran vérszinten kívül. Az APTI értéke csak megközelítőleg jelzi az antikoaguláns hatást, a vizsgálatok nem standardizáltak, az eredményeket pedig körültekintéssel kell értékelni (10). Hasznos lehet a trombinidő (TI), a higított trombinidő (h-TI) és az ecarin alvadási idő (ECI) meghatározása is, de ezek sem standardizáltak, az eredményeket szintén körültekin-téssel kell fogadni (10, 16).…”

“…antidótum adásával. A DOAC-gyógyszerek közül elsőként a direkt trombin-inhibitor dabigatran antidótuma, az idarucizumab került kifejlesztésre, amely specifi kusan kötődik a dabigatranhoz és semlegesíti annak antikoaguláns ha tását (10,11,12). Az idarucizumab egy humanizált, monoklonális, dabigatrant megkötő antitest-fragmens, amely a gyógyszer szelektív véralvadásgátló hatását azonnal, teljesen és tartósan felfüggeszti.…”

“…Az antitest-fragmentum kizárólag a szabad dabigatran mo le kulákhoz és metabolitjaihoz kötődik, körülbelül 350-szer erősebb affi nitással, mint amilyen a dabigatran-trombin kötődés. Az idarucizumab-dabigatran komp lexet a nagy stabilitás jellemzi, mivel igen gyors a képződése, de extrém lassú a lebomlási képessége (10,11,12). Laboratóriu-mi vizsgálatok igazolták, hogy az idarucizumab prompt helyreállítja, normalizálja a dabigatran által megnyúlt, említett paramétereket.…”