Letter to the Editor

Antidotes for patients taking novel oral anti-coagulants

Dear Sir:

Novel oral anti-coagulants [NOACs: dabigatran (Pradaxa?, Boehringer Ingelheim, Germany), rivaroxaban (Xarelto?, Bayer, Germany), apixaban (Eliquis?, Bristol-Myers Squibb, USA), edoxaban (Savaysa?, Daiichi-Sankyo, Japan)] are used more often for the prevention of systemic embolism in atrial fibrillation and for the treatment of venous thromboembolism. Unlike warfarin, NOACs have more predictable pharmacokinetics, fewer drug interactions, shorter half-lives, and quicker onset of action.[1]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.[2]Elderly patients with impaired renal function are especially vulnerable.

NOACs are classif ed into two groups: direct thrombin inhibitor (notably dabigatran) or factor Xa inhibitors (including rivaroxaban, apixaban, and edoxaban). As factor Xa catalyzes the activation of prothrombin into thrombin, all NOACs exert an anti-thrombin effect and prevent activation of fibrinogen into fibrin. Ideally, NOACs should be stopped 18–48 hours before nonlifesaving elective surgery and resumed 6–72 hours postoperatively.[3]As all NOACs have short half lives, it is recommended to delay non-life threatening surgery until the effects have worn off. Bridging anticoagulation is usually not necessary because of their short half-lives.[4]

In the emergency setting, multidisciplinary discussion with hematologists, cardiologists, intensive care specialists, and anesthetists is mandatory. 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. The activated partial thromboplastin time (APTT) and prothrombin time (PT) do not exhibit a linear relationship with NOACs' anticoagulant effects.[2]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.[3]At the moment, these assays are not available in most hospitals. 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. 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 proteinbound fractions in excess of 85%.[2]

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),[5]activated prothrombin complex concentrate (Factor Eight Inhibitor Bypassing Activity?, Baxter, USA), or recombinant-activated factor VIIa (Novoseven?, Novo Nordisk, USA) may be considered.[6]However, the effectiveness of prothrombin complex concentrate or activated prothrombin complex concentrate is not demonstrated in clinical trials and because of conf icting data, no consensus is available for treatment protocols or dosage.

The call for a clinical antidote to NOAC is thus urgent. Ongoing clinical trials demonstrated promising results for specif c 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. Idarucizumab is a monoclonal antibody fragment that binds to dabigatran with 350 times higher affinity than thrombin, thereby preventing dabigatran from inactivating thrombin.[2]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.[6]As the kidneys are responsible for 80% of dabigatran's excretion,[3]this illustrates how idarucizumab is effective even in those with chronic renal insuff ciency.

An intravenous antidote that is effective against all factor Xa inhibitors is andexanet-alfa, a modified recombinant factor Xa that binds avidly to rivaroxaban, apixaban, and edoxaban. Recently, the ANNEXA-A Study, a phase 3, randomized, double-blind, placebocontrolled trial that assessed the use of andexanet-alfa for the reversal of apixaban-induced anticoagulation in older patients involving 34 participants aged 50 to 75 yearswho were randomly assigned at a 3:1 ratio to andexanetalfa (n=24) or placebo (n=9) with all participants received apixaban 5 mg twice daily for 4 days showed that a single intravenous 400 mg bolus of andexanet-alfa induced prompt and complete dose-dependent reversal of rivaroxaban and apixaban in phase 1 and 2 studies in the United States.[7]

Aripazine (also known as PER977) is a universal NOAC antidote that binds to both factor Xa inhibitors and dabigatran through hydrogen bonds. Aripazine completely reversed the anticoagulant effects of dabigatran, rivaroxaban, and apixaban in ex-vivo human plasma studies.[2]This is corroborated by recently released phase 1 study results on edoxaban-treated subjects, showing total return to baseline hemostasis, indicated by whole-blood clotting time, 10–30 minutes after a single intravenous dose of aripazine.[8]The reversal was sustained for 24 hours without any increase in pro-coagulant activity, although some subjects reported transient peri-oral and facial flushing. Phase 2 trials for aripazine are ongoing.

With a growing number of patients taking NOACs, physicians should be equipped with the knowledge on their pharmacology and ways to counteract their effects in emergency. In order to support the widespread international clinical application of NOACs, blood tests on their efficacy and antidotes ought to become readily available, as it is anticipated that NOACs may herald the dawn of a new era in anticoagulation where stringent dietary restrictions and tedious monitoring soon would become recollections of the past. The most important f nal message is that despite the soon available antidotes, the priority in the acute settings should be the continual clinical evaluation of the patient, to review the indication for the NOAC, and the timing of the last dosage, so as to determine whether reversal of the anticoagulation is required. These antidotes are likely to be very costly, and sometimes, watchful waiting in addition to resuscitatory or supportive measures may be adequate.

Stefanie W Yip, Yiu Che Chan

Division of Vascular & Endovascular Surgery,

Department of Surgery K 14 South, Queen Mary Hospital Pokfulam, University of Hong Kong Medical Centre,

Hong Kong, China

1 Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev 2013; 8: CD008980.

2 Enriquez A, Lip GY, Baranchuk A. Anticoagulation reversal in the era of the non-vitamin K oral anticoagulants. Europace 2015 Mar 26. pii: euv030. [Epub ahead of print]

3 Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. EHRA practical guide on the use of new oral anticogulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094–2106.

4 Lai A, Davidson N, Galloway SW, Thachil J. Perioperative management of patients on new oral anticoagulants. Br J Surg 2014; 101: 742–749.

5 Dinkelaar J, Patiwael S, Harenberg J, Leyte A, Brinkman HJ. Global coagulation tests: their applicability for measuring direct factor Xa- and thrombin inhibition and reversal of anticoagulation by prothrombin complex concentrate. Clin Chem Lab Med 2014; 52: 1615–1623.

6 Greinacher A, Thiele T, Selleng K. Reversal of anticoagulants: an overview of current developments. Thromb Haemost 2015; 113: 931–942.

7 Crowther M. CS.03: Management of Cardiovascular Disease. Presented at: American Heart Association Scientific Sessions; Nov. 15–19, 2014; Chicago.

8 Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371: 2141–2142.

Received May 12, 2015

Accepted after revision September 20, 2015

Yiu Che Chan, Email:

World J Emerg Med 2015;6(4):311–312

10.5847/wjem.j.1920–8642.2015.04.012

ycchan88@hkucc.hku.hk