Oral Anticoagulation: Reversing the Current View in Bleeding Events

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Spontaneous bruising caused by use of warfarin.
Spontaneous bruising caused by use of warfarin.

Oral anticoagulation is a clinical therapeutic that is frequently prescribed by numerous providers in many medical settings. There are two different types of oral anticoagulation, including vitamin-K antagonists (VKAs), such as warfarin, and the new class of direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and endoxaban.1 Until recently, warfarin has been the standard therapy for oral anticoagulation.2 However, according to the most recent CHEST guidelines on antithrombotic therapy for venous thromboembolism (VTE), experts in the field of anticoagulation agreed that DOACs provide advances in efficacy, overall safety, and patient and provider simplicity as the preferred anticoagulant when compared with warfarin in patients without cancer.3 

This expert consensus was largely driven by multiple recent, large clinical trials that have established the efficacy and safety of DOACs for stroke prevention and VTE treatment and prevention. Since 2009, four large multicenter, randomized, double-blind, placebo-controlled trials demonstrated that DOACs were noninferior in the prevention of stroke in patients with nonvalvular atrial fibrillation and had a lower risk of bleeding compared with warfarin.4-7 Several other large phase 3 clinical trials have shown that DOACs were noninferior to warfarin regarding acute VTE treatment and prevention of recurrent VTE. In addition, DOACs had a lower risk of bleeding and similar risk of major fatal bleeding compared with warfarin.4,8-14 Furthermore, a recent systematic review and meta-analysis of 13 randomized control trials evaluated mortality data and showed that DOACs were associated with lower rates of fatal bleeding, cardiovascular mortality, and all-cause mortality compared with warfarin.15 These trials have even led to the recent update in guidelines on antithrombotic therapy for VTE released by the CHEST Guideline and Expert Panel in January 2016. The panel suggests that a DOAC should be used preferably over a VKA for initial and long-term therapy of VTE in patients without cancer (Grade 2B).3

Reversal agents for DOACs

Given these recent new guidelines, expert consensus statements, and multiple promising large trials, DOACs will be at the forefront of antithrombotic therapy. However, despite their noninferior efficacy and lower risk of bleeding compared with warfarin, there is still a bleeding risk with any anticoagulant drug and a paucity of data regarding reversal agents for the new DOACs.16

Idarucizumab recently received accelerated approval to reverse the anticoagulant effects of dabigatran in patients requiring emergent surgery/urgent procedures or life-threatening/uncontrolled bleeding based on findings from the Reversal Effects of Idarucizumab on Active Dabigatran trial (RE-VERSE AD).17,18

Early trial results for idarucizumab 

Schiele et al presented the first report of a specific antidote for DOACs, referred to as aDabi-Fab, now known as idarucizumab.18,19 The research group characterized aDabi-Fab as a monoclonal antibody fragment that binds and neutralizes the anticoagulant effects of dabigatran. They showed that the antidote exhibited a high affinity for dabigatran, roughly 350 times greater than for thrombin in vitro and in vivo. Additionally, the researchers showed that aDabi-Fab demonstrated quick reversal of dabigatran as measured by thrombin time (TT) and activated partial thromboplastin (aPTT) time in vivo in a rat model.19 These key findings were essential in the translation of idarucizumab as a humanized clinical therapeutic for future studies. 

In March 2015, Glund et al conducted a two-part randomized, double-blind, placebo-controlled phase 1 trial on humanized idarucizumab. In the first part of the study, the group investigated the safety, tolerability, and pharmacokinetics of different doses of idarucizumab in 110 healthy male volunteers aged 18 to 45. They concluded that idarucizumab was safe and tolerable at all doses administered in the study. In addition, maximum concentrations of idarucizumab were achieved at the end of infusion followed by quick elimination without any effect on coagulation parameters.20 In the second part of the study, the group investigated the safety, tolerability, and efficacy of idarucizumab as a reversal agent for dabigatran in 47 men from the first part of the study. They showed that idarucizumab exhibited quick reversal of dabigatran with persistent effect at all doses tested without any major adverse events.21 Also, Glund et al concluded that idarucizumab was safe, tolerable, and exhibited persistent effect at all administered doses in elderly and renally impaired patients.22

REVERSE-AD trial

Following the promising results from several studies on the safety, tolerability, and efficacy of idarucizumab, Pollack et al developed a multicenter, prospective cohort study, referred to as REVERSE-AD, to evaluate the safety of 5 grams of idarucizumab, which was given as two separate 2.5-gram infusions, and its ability to reverse dabigatran in patients who had serious bleeding (group A) or required an urgent procedure/surgery that could not be delayed for at least 8 hours and required hemostasis (group B). The study began in June 2014 and completed enrollment in July 2016. The primary outcome of the study was maximum reversal of dabigatran's anticoagulant effects as measured by direct thrombin time (dTT) and ecarin clotting time (ECT) in the first 4 hours after initial infusion.

The maximum reversal was calculated as a percentage using the following equation: percentage reversal = (predose test result [in seconds] − minimum postdose test result [in seconds] ∕ (predose test result [in seconds] − upper limit of normal range [in seconds]) × 100. In an interim analysis of the first 90 patients enrolled, 68 patients with elevated dTT and 81 patients with elevated ECT at baseline were found to have maximum reversal of dabigatran's anticoagulant effects of 100%, immediately after infusion of idarucizumab. Furthermore, dTT normalized in 98% of patients in group A and 93% of patients in group B

ECT normalized in 89% of patients in group A and 88% of patients in group B. The study found that similar maximum reversal and normalization findings of aPTT and TT were seen among each group. Furthermore, following the administration of idarucizumab, the concentration of unbound dabigatran was decreased to a level that produces little to no anticoagulant effect in all patients but one in the cohort. There were no safety concerns with administration of idarucizumab at the study dose.17

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