Phase I clinical trials in the United States demonstrated immediate and complete reversal of dabigatran’s effects, with sustained action for more than 12 hours after 4 g of intravenous idarucizumab was given in all three groups of patients: middle-aged, elderly, and renal-impaired. Idarucizumab is a monoclonal antibody fragment that binds to dabigatran with 350 times higher affinity than thrombin, thereby preventing dabigatran from inactivating thrombin. Ongoing clinical trials demonstrated promising results for specific antidotes that directly neutralized the actions of NOACs: idarucizumab (Boehringer Ingelheim, Germany) for dabigatran, andexanet-alfa (Portola, USA) for factor Xa inhibitors, and aripazine (Perosphere, USA) as a universal NOAC antidote. The call for a clinical antidote to NOAC is thus urgent. However, the effectiveness of prothrombin complex concentrate or activated prothrombin complex concentrate is not demonstrated in clinical trials and because of conflicting data, no consensus is available for treatment protocols or dosage. In the event of life-threatening hemorrhage, replenishment of clotting factors through off-label use of prothrombin complex concentrate (Kcentra ®, CSL Behring, Germany which contains factors II, VII, IX, X, protein C and protein S), activated prothrombin complex concentrate (Factor Eight Inhibitor Bypassing Activity ®, Baxter, USA), or recombinant-activated factor VIIa (Novoseven ®, Novo Nordisk, USA) may be considered. Hemodialysis is only effective in eliminating dabigatran as this is bound to 35% of plasma proteins, in contrast to the factor Xa inhibitors, which exhibit plasma protein-bound fractions in excess of 85%. Only dabigatrans absorption has been shown to be reduced by activated charcoal, while rivaroxaban is not, and the effect is unclear for abixaban and edoxaban. At the moment, these assays are not available in most hospitals. Instead, the only accurate means to gauge NOACs’ activity and plasma drug level is through specific clotting assays: diluted thrombin time assay (dTT) for dabigatran and drug-specific anti-Xa chromogenic assay for factor Xa inhibitors. The activated partial thromboplastin time (APTT) and prothrombin time (PT) do not exhibit a linear relationship with NOACs’ anticoagulant effects. It is often feared that for patients with major bleeding, an inability to rapidly reverse the anticoagulant effects of NOAC may seriously compromise the clinical outcome and even render the situation unsalvageable. In the emergency setting, multidisciplinary discussion with hematologists, cardiologists, intensive care specialists, and anesthetists is mandatory. Bridging anticoagulation is usually not necessary because of their short half-lives. As all NOACs have short half lives, it is recommended to delay non-life threatening surgery until the effects have worn off. Ideally, NOACs should be stopped 18–48 hours before non-lifesaving elective surgery and resumed 6–72 hours post-operatively. As factor Xa catalyzes the activation of prothrombin into thrombin, all NOACs exert an anti-thrombin effect and prevent activation of fibrinogen into fibrin. NOACs are classified into two groups: direct thrombin inhibitor (notably dabigatran) or factor Xa inhibitors (including rivaroxaban, apixaban, and edoxaban). Elderly patients with impaired renal function are especially vulnerable. They do not require frequent laboratory monitoring, but there is a lack of validated reversal strategies for these agents in cases of emergency surgery, life-threatening bleeding, and overdose. Unlike warfarin, NOACs have more predictable pharmacokinetics, fewer drug interactions, shorter half-lives, and quicker onset of action.
Novel oral anti-coagulants are used more often for the prevention of systemic embolism in atrial fibrillation and for the treatment of venous thromboembolism.
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