Direct oral anticoagulants: a review on the current role and scope of reversal agents

Chaudhary R, Sharma T, Garg J, Sukhi A, Bliden K, Tantry U, Turagam M, Lakkireddy D and Gurbel P. J Thromb Thrombolysis. 2020; 49(2):271–286.

In the last decade, DOACs have increasingly become the agent of choice in atrial fibrillation and venous thromboembolism over vitamin K antagonists (VKAs) in most non-pregnant patients due to a favourable safety profile (Zhu et al., 2018).

New guidelines now endorse this (January et al., 2019), however, evidence shows that major bleeding still occurs in 3–4% of patients receiving DOACs every year (Raval et al., 2017). Consequently, despite the recommendations and a safer profile, Chaudhary et al. suggest that the lack of specific reversal agents for DOACs has led to slow uptake of these agents.

Chaudhary et al. propose that DOAC use could become increasingly common with the recent FDA approval of idarucizumab in dabigatran-treated patients (Boehringer Ingelheim, 2018) and andexanet alfa for factor Xa inhibitor-treated patients for the emergency reversal of anticoagulation (Portola, 2018).

In this review, Chaudhary et al. aim to assess the current clinical evidence and scope of idarucizumab and andexanet alfa and their potential impact on the use of DOACs in clinical practice.

Clinical trial evidence for idarucizumab and andexanet alfa efficacy

Clinical trials have provided promising evidence for the efficacy of idarucizumab in reversal of anticoagulation. In a randomised, double-blind, placebo-controlled Phase I study by Glund et al., idarucizumab resulted in immediate and complete reversal of dabigatran-induced anticoagulation in a dose-dependent manner in healthy volunteers (Glund et al., 2015).

The REVERSE-AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran) Phase III single-cohort trial showed that bleeding ceased approximately 2.5 hours after idarucizumab administration. While this a significant gap for life-threatening bleeding, Chaudhary et al. suggest could be attributable to incomplete dabigatran reversal with the recommended 5g dose (Pollack et al., 2017). This is important to consider as a quarter of idarucizumab-treated patients had elevated dabigatran levels after 12 hours with some needing an additional dose of idarucizumab.

Similar to the REVERSE-AD trial, the ANNEXA A and R parallel trials and the ANNEXA-4 study similarly evaluated the efficacy of andexanet alfa.

The ANNEXA parallel trials found that after receiving andexanet alfa, anti-factor Xa activity was reduced by 94% among the apixaban-treated participants and 92% among the rivaroxaban-treated participants compared with 21% and 18% who received placebo, respectively (P<0.001) (Siegal et al., 2015). The ANNEXA-4 study showed that andexanet alfa was associated with reductions in anti-factor Xa activity by 92%, 92% and 75% in patients on apixaban, rivaroxaban and enoxaparin, respectively. The study also showed that 82% were able to achieve excellent or good haemostasis 12 hours after the infusion.

What is the real-world evidence for idarucizumab and andexanet alfa?

Since the approval of idarucizumab and andexanet alfa, there has been little study on the real-world clinical evidence of both agents.

The largest case-series for idarucizumab, observing only thirteen patients, found 72.7% of patients with major bleeding achieved clinical haemostasis with none experiencing thrombotic events or side effects attributable to idarucizumab (Sheikh-Taha, 2019). Various other small-scale reviews and studies similarly found idarucizumab to be safe and effective (Held et al., 2016; Tsai et al., 2018; Van der Wall et al., 2019; Victor et al., 2019)).

There have however been some conflicting studies on the safety and efficacy of idarucizumab. A retrospective cohort study for dabigatran-associated major bleeding showed no difference in the in-hospital mortality of patients with gastrointestinal bleeding with or without idarucizumab (Singh et al., 2019). Likewise, a case series reported higher than expected thrombotic events after administration of idarucizumab (Raco et al., 2018) and a multi-centre observational registry study reported high mortality (31%) and poor clinical outcomes (Küpper et al., 2019).

Similarly, the evidence for the use of andexanet alfa in clinical practice is limited. There is only one case-series of fifteen patients in which an inpatient mortality of 40% was observed, despite no prior thrombotic events (Culbreth et al., 2018). There is also however a case report of the successful reversal of apixaban with andexanet alfa prior to aortic surgery, with no subsequent major adverse events (Flaherty et al., 2019).

There is certainly a need for more real-world clinical data to definitively determine which patients would benefit from the use of idarucizumab and andexanet alfa. In light of the available evidence, Chaudhary et al. proposed an algorithm for determining which patients should consider DOAC reversal agents.

Figure 1: Proposed algorithm for the management of patients taking DOACs, (adapted from Chaudhary et al., 2019). DOAC, direct oral anticoagulant; PRBC, packed red blood cells; PCC, prothrombin complex concentrate.

They suggest that the post-reversal of anticoagulation with DOACs due to life-threatening bleeding DOACs and the decision to re-introduce anticoagulant agents warrants a case-by-case assessment and individual risk–benefit analysis including considerations of bleeding severity, recurrent bleed risk, thrombotic event risk and patient preferences.

Chaudhary et al. also recommend shared decision-making between the clinician and the patient about the risks and benefits in the prevention of thrombotic events and the risk of recurrent bleeding.

In this review, Chaudhary et al. demonstrated the evidence for the efficacy and safety of DOACs. However, they note that DOAC anticoagulation reversal warrants individual risk-benefit analysis. It is also made clear that more research is needed about the effects on hard clinical outcomes, such as mortality, as well as the patient populations and clinical settings in which reversal agents can be used most effectively.