Since the U.S. Food and Drug Administration’s (FDA) approval of the first direct-acting oral anticoagulant (DOAC) in 2010, the field of oral anticoagulation has broadened considerably. The approval of the first DOAC reversal agent in 2015 and the continuing development of at least two additional reversal agents present both new opportunities and challenges. At the same time, the reversal of warfarin is not performed effectively or consistently across institutions. The current state of play in oral anticoagulant reversal, beginning with a comparison of warfarin and the DOACs, is reviewed here, followed by an examination of current reversal practices for both drug types and an overview of the new reversal agents.

There remain considerable misconceptions about the relative benefits and drawbacks of warfarin and DOACs. Warfarin is perceived by some to be safer than a DOAC, because it can be monitored and adjusted in response to international normalized ratio (INR) levels. Additionally, as Mark Crowther, MD, MSc, explains, there is also “a perception…that DOACs are less safe than warfarin, because there is no reversal agent.” A related concern is that DOACs can cause bleeding. Some have also faulted DOACs for their cost. Together these factors may have affected the adoption of DOACs. Charles Pollack, MD, opines that DOAC uptake “has not been as quick or easy as many people expected it would be.”

It is worth grappling with each of these claims about warfarin and DOACs. Most importantly, it must be recognized that the ability to monitor warfarin activity does not automatically confer efficacy or safety. Geno Merli, MD, explains that “in all the trials done…the best you can get is maybe 60 percent time in therapeutic range.” Conversely, the lack of monitoring of DOAC levels should not be associated with additional danger or ineffectiveness. Much like low-molecular-weight heparins (LMWHs), DOACs have a wide therapeutic window and a predictable dose response, rendering monitoring unnecessary. Moreover, as Crowther vividly explains, “unless fired from a cannon, DOACs do not cause bleeding.”

Nor should it be assumed that DOACs cannot be reversed. In addition to the use of prothrombin complex concentrates (PCCs), a number of DOAC reversal agents are in development or have received FDA approval (outlined below). While DOAC reversal remains complex, DOACs are associated with lower risks of major bleeding than warfarin, making reversal seldom necessary. Most notably, as Adam Cuker, MD, MS, explains, “they reduce the risk of intracranial bleeding compared with warfarin, by about one-half to two-thirds.” The absence of dietary interactions and the smaller number of drug-drug interactions associated with DOACs also add up to greater patient safety and adherence than many may have anticipated.

A corollary of the argument that DOACs are irreversible is the notion that warfarin is generally reversed safely and consistently. Rather, as Crowther observes, “we do a terrible job of reversing warfarin.” Although evidence favors the use of PCCs over fresh frozen plasma (FFP), the latter remains in common use. Beyond problems with FFP, Merli has observed confusion and inconsistency: “Everyone’s using a different agent for rescuing the patient.”

One force driving this inconsistency is perceived cost. Although KCentra – a 4-factor prothrombin complex concentrate – is the only product with FDA approval for rescuing patients taking warfarin, it is significantly more expensive than FFP, leading many institutions to adopt the cheaper product.

Perceived savings also may be a motivator for institutions and clinicians electing to use FFP. But Crowther opines that decision makers appear to “underestimate the cost of plasma and overestimate the cost of PCCs.” Crowther also cited “physician familiarity and comfort” as a motivator for the continued use of FFP. Physician comfort was also raised by Pollack in relation to a tendency on the part of many clinicians to not scrupulously follow their institutions’ reversal protocols. Finally, beyond cost and comfort lies a lack of awareness of different agents.

So, what is a clinician to do when faced with a bleeding patient who has been taking warfarin? Ideally, PCCs should be administered to restore the patient’s INR to a normal level. Vitamin K should also be administered to maintain reversal of anticoagulant – a commonly omitted step, according to Cuker. Where PCCs are not available, FFP may be used. However, as Dr. Crowther warns, administration of FFP introduces “a whole series of fixed delays,” potentially resulting in “hours of ongoing bleeding while waiting for the reversal effect to kick in.”

PCCs also may be used for reversal in patients who have taken edoxaban and rivaroxaban, according to evidence published in 2015 and 2011, respectively.^1,2 “That’s what we do right now,” notes Pollack, adding that this comes with a “prothrombotic concern that is not yet well-quantified.” PCCs have been found to be ineffective for reversing dabigatran; however, patients taking this particular DOAC are fortunate insofar as a reversal agent is now available for them.

Currently the only agent to have received FDA approval for reversal of a DOAC, idarucizumab is indicated exclusively for dabigatran reversal. Based on data supporting its approval, idarucizumab – a monoclonal antibody that binds dabigatran with about 350-times the avidity with which dabigatran binds to thrombin – completely reverses the anticoagulant effect of dabigatran within minutes.³ Notably, since its approval in October 2015, idarucizumab has been used infrequently in many centers. Cuker attributes this to dabigatran’s relatively low market share and, more importantly, the fact that “major bleeding is reduced in patients on DOACs compared with warfarin, and the DOACs have a much shorter half-life than warfarin.” Thus, one of the benefits of idarucizumab may be indirect – it offers reassurance to potential prescribers and users.

Whereas idarucizumab has been approved to reverse a factor IIa inhibitor, andexanet alfa holds promise as a broad-spectrum reversal agent for factor Xa inhibitors and enoxaparin, a LMWH. A biologic agent, andexanet alfa functions as a decoy receptor to which factor Xa inhibitors bind in preference to natural factor Xa. The most recently published data on andexanet’s safety and efficacy come from ANNEXA-4, a multicenter, prospective, open-label, single-arm study funded by the drug developer.⁴ Sixty-seven patients who presented with acute major bleeding were administered an initial bolus followed by a two-hour infusion of the agent. At four hours after infusion completion, patients who had been taking rivaroxaban showed a mean 39 percent decrease from baseline in anti-factor Xa activity, with a 30 percent decrease among those who had taken apixaban. At the end of the 12-hour assessment period, in the 47 patients in whom efficacy was assessed, 37 patients were judged to have excellent or good clinical hemostasis. During the 30-day follow-up, 12 of the 67 patients experienced thrombotic events. The rate of thrombotic events in the ANNEXA-4 study leads Cuker to wonder whether the drug potentially has a prothrombotic effect, although he emphasizes that his concern is “speculative at this point.” However, Crowther – an investigator for the study and a consultant for the drug developer – notes that it would be impossible to determine whether such complications stemmed from andexanet or from a patient’s underlying prothrombotic state. Additionally, data on both idarucizumab and andexanet suggest that anticoagulation re-initiation is frequently foregone, even in those patients whose anticoagulant should be restarted. Portola, the developer of andexanet, is in the process of providing additional, primarily manufacturing-related, information to the FDA and will resubmit its Biologic License Application in 2017.

Also under development is ciraparantag, a reversal agent for factor Xa inhibitors, factor IIa inhibitors, unfractionated heparin, and LMWH. As one of the drug’s developer’s, Jack Ansell, MD, explains, “Ciraparantag binds through ionic charge interaction, unlike idarucizumab or andexanet alfa, and It removes the anticoagulant from its respective target.”

The recently published results of a phase I trial involving reversal of edoxaban in healthy volunteers showed that the initial intravenous bolus administration of ciraparantag provided full reversal of anticoagulation within 10 minutes, with results maintained for 24 hours.⁵ A prothrombotic effect was not seen based on biomarkers, although it cannot be ruled out yet, and Ansell notes that “there’s little reason, based on the mechanism of action, that there should be any such effect.”

Ciraparantag also binds in a charged fashion to the reagent anticoagulants in collection tubes used in standard assays. Phase I trials therefore employed whole blood clotting time to measure reversal activity – a measure that cannot be used in the clinic. Ansell explains the company therefore developed and is currently conducting clinical trials of “a point-of-care assay that mirrors whole blood clotting time” for assessment of the reversal of any anticoagulant in blood without the need for reagents. FDA approval of ciraparantag will be highly dependent upon approval of this novel assay.

Finally, regardless of the anticoagulant or reversal agent used, the question of restarting anticoagulation in patients who have experienced bleeding remains relatively neglected. Concern about bleed risk is often coupled with underestimation of thrombotic risk. The period after a bleeding event should include a holistic appraisal of the patient’s status followed by a decision to restart on the same or another anticoagulant, or, if sufficient contraindications exist, to forego restarting.

Looking ahead, the ACC is developing the 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants to provide more specific guidance on the question of reversal strategies and restarting anticoagulation. This document, anticipated in summer 2017, along with the 2017 Expert Consensus Decision Pathway on Periprocedural Management of Anticoagulation in Nonvalvular AFib Patients is aimed at providing practical guidance to improve anticoagulation management and patient care.

References

1. Zahir H, Brown KS, Vandell AG, et al. Circulation 2015;131:82-90.
2. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Circulation 2011;124:1573-9.
3. Pollack CV JR, Reilly PA, Eikelboom J, et al. N Engl J Med 2015;373:511-20.
4. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. N Engl J Med 2016;375:1131-41.
5. Ansell JE, Bakhru SH, Laulicht BE, et al. Thromb Haemost 2017;117:238-45.

Keywords: ACC Publications, Cardiology Magazine, Anticoagulants, Biological Products, Biomarkers, Blood Coagulation, Blood Coagulation Factors, Confusion, Consensus, Drug Interactions, Factor Xa, Factor Xa Inhibitors, Follow-Up Studies, Hemostasis, Heparin, Indicators and Reagents, International Normalized Ratio, Patient Care, Point-of-Care Systems, Prospective Studies, Pyrazoles, Pyridines, Pyridones, Thiazoles, United States Food and Drug Administration