- Email: [email protected]
Antidotes for the new oral anticoagulants: Reality and expectations
Med Clin (Barc). 2016;146(11):488–490
www.elsevier.es/medicinaclinica
Editorial article
Antidotes for the new oral anticoagulants: Reality and expectations夽 Antídotos de los nuevos anticoagulantes orales: realidad y expectativas Antonio Gómez-Outes a,∗ , Ramón Lecumberri b a b
División de Farmacología y Evaluación Clínica, Agencia Espa˜ nola de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain Servicio de Hematología, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
Various oral anticoagulants have been marketed in the last decade, dabigatran etexilate being among them, a direct thrombin inhibitor (Pradaxa® ; Boehringer Ingelheim), and the direct inhibitors of x activated factor (FXa), rivaroxaban (Xarelto® ; Bayer HealthCare), apixaban (Eliquis® ; Bristol-Myers Squibb) and edoxaban (Lixiana® /Savaysa® ; Daiichi Sankyo-).1 These (not so new) oral anticoagulants of direct action (DOAC) are authorized for use in various indications related to the prophylaxis and treatment of venous thromboembolism and the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The DOAC have shown a positive risk–benefit relationship in such indications and a lower haemorrhagic tendency (especially in the case of intracranial haemorrhage [ICH]) than vitamin K antagonists (VKA). The relatively short half-life (between 11 and 17 h in patients with normal renal function) can be an advantage in case of bleeding, as it quickly decreases its anticoagulant action between 12 and 24 h after administration.1 However, the absence of a specific antidote and tools for the biological control of the anticoagulant effect which are well standardized and available in any emergency laboratory has generated some distrust between prescribers and patients.2–4 The treatment of haemorrhage associated with DOAC is based on the interruption of all antithrombotic medications and the establishment of supportive care (local haemostasis, transfusion, activated carbon, dialysis in the case of dabigatran, etc.). In the absence of specific antidotes, unspecific procoagulant agents have been used (prothrombin complex concentrates and recombinant factor vii) in the case of severe bleeding, but with little evidence and increased risk of thrombosis.5,6 Various analyses of the treatment for major haemorrhages observed during the pivotal studies have shown similar (or even better in some cases) results regarding bleeding associated to DOAC compared with those related to treatment with VKA.7–10 However, mortality after severe bleeding with DOAC, although not
夽 Please cite this article as: Gómez-Outes A, Lecumberri R. Antídotos de los nuevos anticoagulantes orales: realidad y expectativas. Med Clin (Barc). 2016;146:488–490. ∗ Corresponding author. E-mail address: [email protected] (A. Gómez-Outes). ˜ S.L.U. All rights reserved. 2387-0206/© 2015 Elsevier Espana,
being higher than VKA in selected populations of clinical trials, it remains significant, ranging between 10% for non-intracranial severe bleeding9 and 35–45% for ICH.8,9 Therefore, up to now, the availability of an antidote is an unmet medical need. Currently, several DOAC-specific antidotes are being developed, aiming to reverse the anticoagulant activity and restore an adequate haemostasis in cases of severe bleeding or when there is a need to perform invasive emergency procedures. Among these, we find Idarucizumab (BI 655075; Boehringer Ingelheim), andexanet alfa (r-Antidote, PRT064445, Portola Pharmaceuticals) and aripazine (PER977, ciraparantag; Perosphere Inc.).11 Idarucizumab is an antibody fragment that binds to dabigatran with an affinity 350 times superior to that of thrombin by acting as a specific antidote (Table 1).11–15 In September 2015, idarucizumab received a positive European opinion in adult patients treated with dabigatran when a quick reversal of the anticoagulant effect is required, both in surgery/invasive emergency procedures as well as in life-threatening or uncontrolled bleeding.16 The positive opinion was based mainly on surrogate efficacy data obtained in healthy volunteers,13,14 and in the interim analysis of the REVERSE-AD study conducted in 90 patients.15 These data showed the ability of the antidote, at a dose of 5 g, administered intravenously, to decrease (unbound to proteins) the free fraction of dabigatran in plasma and normalize coagulation parameters altered by the treatment with dabigatran in more than 90% of subjects, with an acceptable safety profile. The study expected to include 450 patients in total and final results are expected in 2017 (ClinicalTrials.gov Identifier: NCT02104947). Among the strengths of the REVERSE-AD study, we highlight the good correlation between clotting test normalization and decreased concentrations of free dabigatran in plasma. Regarding its limitations, we find the lack of a control group (as currently, there are no other strategies available for the specific neutralization of dabigatran) and the inclusion of a limited number of patients in the interim analysis, inadequate to evaluate mortality, making the quantification of idarucizumab regarding its contribution to improving the clinical outcome of severe bleeding associated with dabigatran in addition to the usual support treatment difficult. In fact, there is great variability between the 20% mortality published in the interim analysis of the REVERSE-AD study15 and previous data published on mortality rates of major bleeding with dabigatran, which range from 9% of major bleeding with dabigatran in an aggregate analysis of
A. Gómez-Outes, R. Lecumberri / Med Clin (Barc). 2016;146(11):488–490 Table 1 Main characteristics of the antidotes of direct oral anticoagulants. Characteristics
Idarucizumab
Andexanet alfa
Aripazine
Tradename Name of product under investigation Company
Praxbind® BI 655075 aDabi-Fab UNII97RWB5S1U6 Boehringer Ingelheim Humanized monoclonal antibody fragment Dabigatran
NA PRT064445 r-Antidote
NA PER977 Ciraparantag
Portola Pharmaceuticals Truncated recombinant factor Xa
Perosphere Inc.
Chemical characteristics
Potential targets
Molecular weight Tmax Half-life Dosage researched in clinical trials
47,800 Da 5 min 45 min 5 g IV bolus or perfusion in 5–10 min
Synthetic, cationic, water soluble molecule
Direct FXa inhibitors (rivaroxaban, apixaban, edoxaban) and indirect (LMWH and fondaparinux) 39,000 Da
Rivaroxaban, apixaban, edoxaban, dabigatran, UFH, LMWH and fondaparinux
2 min ≈1 h 400–800 mg IV bolus, followed by perfusion of 4–8 mg/min
<30 min ≈1.5 h 100–400 mg IV
512 Da
RNA: ribonucleic acid; FXa: activated factor x; LMWH: low molecular weight heparins; UFH: unfractioned heparin; IV: intravenous; NA: not available; Tmax : maximum time.
phase iii7 studies, 20% of ICH with dabigatran in a study conducted on routine practice,17 and 35–41% of ICH in a post hoc analysis of the RE-LY study in patients with NVAF.10 It is therefore likely that the bleeding location and the injury degree, as well the patient’s concomitant disease and treatments may have a more important effect on the bleeding prognosis than the ability to quickly neutralize the anticoagulant.18 For practical purposes, idarucizumab is therefore a complement, not a replacement, in the support treatment that has been in use so far. On the other hand, a quarter of the patients in the REVERSEAD study showed very low or undetectable levels of anticoagulant activity (according to Thrombin Time Dilution Test [TTDT] or ecarin time) on study entry, probably because more than 12 h had elapsed since the last dose of dabigatran in two thirds of cases.15 These patients received the antidote but were excluded from the efficacy analysis. In practice, the quantification of the activity of dabigatran could avoid unnecessary administration of the antidote. For the specific biological control (DOAC do not require routine monitoring) of dabigatran, currently the test of choice in our area is the TTDT, but for the moment is not available in many non-specialized laboratories. Alternatively, the partial activated thromboplastin time may be of some help to rule out supratherapeutic levels. If the TTDT is normal, it is reasonable to assume that dabigatran levels are very low and the bleeding risk is not increased.19 Andexanet alfa (r-Antidote, PRT064445, Portola Pharmaceuticals) is a truncated form of FXa, non-functional from an hemostatic point of view, and obtained by recombinant technology, which competes with native FXa to bind direct FXa inhibitors, reversing its anticoagulant activity (Table 1).11,20 The results of two studies to evaluate the surrogate safety and efficacy of andexanet alpha in reversing the anticoagulant effects of apixaban 5 mg/12 h and rivaroxaban 20 mg/day in healthy volunteers (ANNEXA-A and ANNEXA-R studies, respectively) have been recently published.21 Andexanet alpha, administered as an intravenous bolus (400–800 mg) showed a reversion > 90% of the anti-xa activity of apixaban and rivaroxaban in all subjects after 2–5 min of bolus administration, which gradually decreased to levels
489
similar to those in the placebo group in the following 2 h (first part of the studies).21 Plasma concentrations of apixaban and rivaroxaban, as well as levels of thrombin generation, followed a time course similar to the anti xa activity.21 The second part of the studies showed that a longer reversal can be obtained with a continuous perfusion (4–8 mg/min) after the initial bolus, since the effect is transient (≈2 h) following a single intravenous administration.21 Also, there is another ongoing study, open, uncontrolled, to assess the hemostatic efficacy and safety of andexanet alfa in patients with major bleeding due to oral direct FXa inhibitors, the final results are expected for 2022 (ANNEXA-4 phase 3b-4 study. ClinicalTrials.gov Identifier: NCT02329327). However, this does not mean that it cannot be authorized in advance, as it was the case with idarucizumab, assuming that the interim study data evaluation, along with reversal data of the anti-xa anticoagulant activity, coagulation times and safety profile, show a favourable risk–benefit ratio. Finally, aripazine (PER-977, ciraparantag; Perosphere Inc.) It is a small synthetic molecule (≈500 Da) with the potential to reverse both thrombin inhibitors (dabigatran) and oral direct FXa inhibitors, as well as fondaparinux and low molecular weight heparins in vivo.11,22 The binding is made via links by hydrogen bonds and charge-charge interactions, which prevents the anticoagulant from binding to its target in the coagulation cascade. A recent study in 80 healthy volunteers has shown that aripazine, intravenously administered at doses of 100–300 mg, reverses edoxaban-induced anticoagulation after the administration of 60 mg of the same.22 The reversal occurred in the first 10–30 min and was sustained for 24 h. In this study, aripazine was well tolerated and no signs of procoagulant activity were observed. Several phase i–ii studies are currently underway to characterize the metabolism and disposition of aripazine in humans, and to identify the dose of antidote required to reverse the effect of various anticoagulants.11 In conclusion, the advent of specific antidotes for DOAC fulfils an unmet need and will help to build confidence and improve the safe use of these anticoagulants. Idarucizumab, the specific antidote to dabigatran, was the first of them in obtaining a positive opinion in the European Union. However, it is necessary to have the results of currently ongoing studies and experience of use in everyday practice to outline in more detail the real benefit of the specific reversal of DOAC regarding improving the clinical outcome of patients. Among other things, it will be essential to pay particular attention to the possible development of thrombotic complications associated with the reversal of the anticoagulant effect. Finally, the development of multidisciplinary clinical practice guidelines will help clinicians in defining the scenarios in which the use of an antidote is appropriate. Statement The opinions and views expressed in this article are those of the authors and do not necessarily represent the official views of their institutions or any other parties. Financing No funding has been received for the preparation of this article. References 1. Gómez-Outes A, Suárez-Gea ML, Lecumberri R, Terleira-Fernández AI, VargasCastrillón E. Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives. Eur J Haematol. 2015;95:389–404. 2. Wallace H, Davies MW. The lack of antidotes for new oral anticoagulants. BMJ. 2014;348:g1438. 3. Barcellona D, Luzza M, Battino N, Fenu L, Marongiu F. The criteria of the Italian Federation of Thrombosis Centres on DOACs: a “real world” application in
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6.
7.
8.
9.
10.
11.
12.
13.
A. Gómez-Outes, R. Lecumberri / Med Clin (Barc). 2016;146(11):488–490 nonvalvular atrial fibrillation patients already on vitamin K antagonist. Intern Emerg Med. 2015;10:157–63. Palacio AM, Kirolos I, Tamariz L. Patient values and preferences when choosing anticoagulants. Patient Prefer Adher. 2015;9:133–8. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15:625–51. Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, et al. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: Proposals of the working group on perioperative haemostasis (GIHP) – March 2013. Arch Cardiovasc Dis. 2013;106:382–93. Majeed A, Hwang HG, Connolly SJ, Eikelboom JW, Ezekowitz MD, Wallentin L, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation. 2013;128:2325–32. Piccini JP, Garg J, Patel MR, Lokhnygina Y, Goodman SG, Becker RC, et al. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J. 2014;35:1873–80. Held C, Hylek EM, Alexander JH, Hanna M, Lopes RD, Wojdyla DM, et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J. 2015;36:1264–72. Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke. 2012;43:1511–7. Gomez-Outes A, Suarez-Gea ML, Lecumberri R, Terleira-Fernandez AI, VargasCastrillon E. Specific antidotes in development for reversal of novel anticoagulants: a review. Recent Pat Cardiovasc Drug Discov. 2014;9:2–10. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554–62. Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect
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of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015;386:680–90. Glund S, Moschetti V, Norris S, Stangier J, Schmohl M, van Ryn J, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015;113:943–51. Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511–20. Committee for Medicinal Products for Human Use (CHMP). Summary of opinion (initial authorisation) for Praxbind (idarucizumab). Documento EMA/CHMP/575990/2015; 2015. Available at: http://www.ema.europa.eu/ docs/en GB/document library/Summary of opinion - Initial authorisation/ human/003986/WC500194147.pdf [accessed 06.11.15]. Alonso A, Bengtson LG, MacLehose RF, Lutsey PL, Chen LY, Lakshminarayan K. Intracranial hemorrhage mortality in atrial fibrillation patients treated with dabigatran or warfarin. Stroke. 2014;45:2286–91. Bauer KA. Targeted anti-anticoagulants. N Engl J Med. 2015;373:569–71. Escolar Albaladejo G, García Frade J, Lopez Fernandez MF, Roldán Schilling V. ˜ de Guía sobre los anticoagulantes orales de acción directa (Sociedad Espanola ˜ Hematología y Hemoterapia/Sociedad Espanola de Trombosis y Hemostasia); 2015. Available at: http://www.sehh.es/images/stories/recursos/ 2015/documentos/guias/GUIA NAO MODIFICADA octubre 2012 R GEA.pdf [accessed 06.11.15]. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19:446–51. Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2416–24. 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;371:2141–2.
www.elsevier.es/medicinaclinica
Editorial article
Antidotes for the new oral anticoagulants: Reality and expectations夽 Antídotos de los nuevos anticoagulantes orales: realidad y expectativas Antonio Gómez-Outes a,∗ , Ramón Lecumberri b a b
División de Farmacología y Evaluación Clínica, Agencia Espa˜ nola de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain Servicio de Hematología, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
Various oral anticoagulants have been marketed in the last decade, dabigatran etexilate being among them, a direct thrombin inhibitor (Pradaxa® ; Boehringer Ingelheim), and the direct inhibitors of x activated factor (FXa), rivaroxaban (Xarelto® ; Bayer HealthCare), apixaban (Eliquis® ; Bristol-Myers Squibb) and edoxaban (Lixiana® /Savaysa® ; Daiichi Sankyo-).1 These (not so new) oral anticoagulants of direct action (DOAC) are authorized for use in various indications related to the prophylaxis and treatment of venous thromboembolism and the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The DOAC have shown a positive risk–benefit relationship in such indications and a lower haemorrhagic tendency (especially in the case of intracranial haemorrhage [ICH]) than vitamin K antagonists (VKA). The relatively short half-life (between 11 and 17 h in patients with normal renal function) can be an advantage in case of bleeding, as it quickly decreases its anticoagulant action between 12 and 24 h after administration.1 However, the absence of a specific antidote and tools for the biological control of the anticoagulant effect which are well standardized and available in any emergency laboratory has generated some distrust between prescribers and patients.2–4 The treatment of haemorrhage associated with DOAC is based on the interruption of all antithrombotic medications and the establishment of supportive care (local haemostasis, transfusion, activated carbon, dialysis in the case of dabigatran, etc.). In the absence of specific antidotes, unspecific procoagulant agents have been used (prothrombin complex concentrates and recombinant factor vii) in the case of severe bleeding, but with little evidence and increased risk of thrombosis.5,6 Various analyses of the treatment for major haemorrhages observed during the pivotal studies have shown similar (or even better in some cases) results regarding bleeding associated to DOAC compared with those related to treatment with VKA.7–10 However, mortality after severe bleeding with DOAC, although not
夽 Please cite this article as: Gómez-Outes A, Lecumberri R. Antídotos de los nuevos anticoagulantes orales: realidad y expectativas. Med Clin (Barc). 2016;146:488–490. ∗ Corresponding author. E-mail address: [email protected] (A. Gómez-Outes). ˜ S.L.U. All rights reserved. 2387-0206/© 2015 Elsevier Espana,
being higher than VKA in selected populations of clinical trials, it remains significant, ranging between 10% for non-intracranial severe bleeding9 and 35–45% for ICH.8,9 Therefore, up to now, the availability of an antidote is an unmet medical need. Currently, several DOAC-specific antidotes are being developed, aiming to reverse the anticoagulant activity and restore an adequate haemostasis in cases of severe bleeding or when there is a need to perform invasive emergency procedures. Among these, we find Idarucizumab (BI 655075; Boehringer Ingelheim), andexanet alfa (r-Antidote, PRT064445, Portola Pharmaceuticals) and aripazine (PER977, ciraparantag; Perosphere Inc.).11 Idarucizumab is an antibody fragment that binds to dabigatran with an affinity 350 times superior to that of thrombin by acting as a specific antidote (Table 1).11–15 In September 2015, idarucizumab received a positive European opinion in adult patients treated with dabigatran when a quick reversal of the anticoagulant effect is required, both in surgery/invasive emergency procedures as well as in life-threatening or uncontrolled bleeding.16 The positive opinion was based mainly on surrogate efficacy data obtained in healthy volunteers,13,14 and in the interim analysis of the REVERSE-AD study conducted in 90 patients.15 These data showed the ability of the antidote, at a dose of 5 g, administered intravenously, to decrease (unbound to proteins) the free fraction of dabigatran in plasma and normalize coagulation parameters altered by the treatment with dabigatran in more than 90% of subjects, with an acceptable safety profile. The study expected to include 450 patients in total and final results are expected in 2017 (ClinicalTrials.gov Identifier: NCT02104947). Among the strengths of the REVERSE-AD study, we highlight the good correlation between clotting test normalization and decreased concentrations of free dabigatran in plasma. Regarding its limitations, we find the lack of a control group (as currently, there are no other strategies available for the specific neutralization of dabigatran) and the inclusion of a limited number of patients in the interim analysis, inadequate to evaluate mortality, making the quantification of idarucizumab regarding its contribution to improving the clinical outcome of severe bleeding associated with dabigatran in addition to the usual support treatment difficult. In fact, there is great variability between the 20% mortality published in the interim analysis of the REVERSE-AD study15 and previous data published on mortality rates of major bleeding with dabigatran, which range from 9% of major bleeding with dabigatran in an aggregate analysis of
A. Gómez-Outes, R. Lecumberri / Med Clin (Barc). 2016;146(11):488–490 Table 1 Main characteristics of the antidotes of direct oral anticoagulants. Characteristics
Idarucizumab
Andexanet alfa
Aripazine
Tradename Name of product under investigation Company
Praxbind® BI 655075 aDabi-Fab UNII97RWB5S1U6 Boehringer Ingelheim Humanized monoclonal antibody fragment Dabigatran
NA PRT064445 r-Antidote
NA PER977 Ciraparantag
Portola Pharmaceuticals Truncated recombinant factor Xa
Perosphere Inc.
Chemical characteristics
Potential targets
Molecular weight Tmax Half-life Dosage researched in clinical trials
47,800 Da 5 min 45 min 5 g IV bolus or perfusion in 5–10 min
Synthetic, cationic, water soluble molecule
Direct FXa inhibitors (rivaroxaban, apixaban, edoxaban) and indirect (LMWH and fondaparinux) 39,000 Da
Rivaroxaban, apixaban, edoxaban, dabigatran, UFH, LMWH and fondaparinux
2 min ≈1 h 400–800 mg IV bolus, followed by perfusion of 4–8 mg/min
<30 min ≈1.5 h 100–400 mg IV
512 Da
RNA: ribonucleic acid; FXa: activated factor x; LMWH: low molecular weight heparins; UFH: unfractioned heparin; IV: intravenous; NA: not available; Tmax : maximum time.
phase iii7 studies, 20% of ICH with dabigatran in a study conducted on routine practice,17 and 35–41% of ICH in a post hoc analysis of the RE-LY study in patients with NVAF.10 It is therefore likely that the bleeding location and the injury degree, as well the patient’s concomitant disease and treatments may have a more important effect on the bleeding prognosis than the ability to quickly neutralize the anticoagulant.18 For practical purposes, idarucizumab is therefore a complement, not a replacement, in the support treatment that has been in use so far. On the other hand, a quarter of the patients in the REVERSEAD study showed very low or undetectable levels of anticoagulant activity (according to Thrombin Time Dilution Test [TTDT] or ecarin time) on study entry, probably because more than 12 h had elapsed since the last dose of dabigatran in two thirds of cases.15 These patients received the antidote but were excluded from the efficacy analysis. In practice, the quantification of the activity of dabigatran could avoid unnecessary administration of the antidote. For the specific biological control (DOAC do not require routine monitoring) of dabigatran, currently the test of choice in our area is the TTDT, but for the moment is not available in many non-specialized laboratories. Alternatively, the partial activated thromboplastin time may be of some help to rule out supratherapeutic levels. If the TTDT is normal, it is reasonable to assume that dabigatran levels are very low and the bleeding risk is not increased.19 Andexanet alfa (r-Antidote, PRT064445, Portola Pharmaceuticals) is a truncated form of FXa, non-functional from an hemostatic point of view, and obtained by recombinant technology, which competes with native FXa to bind direct FXa inhibitors, reversing its anticoagulant activity (Table 1).11,20 The results of two studies to evaluate the surrogate safety and efficacy of andexanet alpha in reversing the anticoagulant effects of apixaban 5 mg/12 h and rivaroxaban 20 mg/day in healthy volunteers (ANNEXA-A and ANNEXA-R studies, respectively) have been recently published.21 Andexanet alpha, administered as an intravenous bolus (400–800 mg) showed a reversion > 90% of the anti-xa activity of apixaban and rivaroxaban in all subjects after 2–5 min of bolus administration, which gradually decreased to levels
489
similar to those in the placebo group in the following 2 h (first part of the studies).21 Plasma concentrations of apixaban and rivaroxaban, as well as levels of thrombin generation, followed a time course similar to the anti xa activity.21 The second part of the studies showed that a longer reversal can be obtained with a continuous perfusion (4–8 mg/min) after the initial bolus, since the effect is transient (≈2 h) following a single intravenous administration.21 Also, there is another ongoing study, open, uncontrolled, to assess the hemostatic efficacy and safety of andexanet alfa in patients with major bleeding due to oral direct FXa inhibitors, the final results are expected for 2022 (ANNEXA-4 phase 3b-4 study. ClinicalTrials.gov Identifier: NCT02329327). However, this does not mean that it cannot be authorized in advance, as it was the case with idarucizumab, assuming that the interim study data evaluation, along with reversal data of the anti-xa anticoagulant activity, coagulation times and safety profile, show a favourable risk–benefit ratio. Finally, aripazine (PER-977, ciraparantag; Perosphere Inc.) It is a small synthetic molecule (≈500 Da) with the potential to reverse both thrombin inhibitors (dabigatran) and oral direct FXa inhibitors, as well as fondaparinux and low molecular weight heparins in vivo.11,22 The binding is made via links by hydrogen bonds and charge-charge interactions, which prevents the anticoagulant from binding to its target in the coagulation cascade. A recent study in 80 healthy volunteers has shown that aripazine, intravenously administered at doses of 100–300 mg, reverses edoxaban-induced anticoagulation after the administration of 60 mg of the same.22 The reversal occurred in the first 10–30 min and was sustained for 24 h. In this study, aripazine was well tolerated and no signs of procoagulant activity were observed. Several phase i–ii studies are currently underway to characterize the metabolism and disposition of aripazine in humans, and to identify the dose of antidote required to reverse the effect of various anticoagulants.11 In conclusion, the advent of specific antidotes for DOAC fulfils an unmet need and will help to build confidence and improve the safe use of these anticoagulants. Idarucizumab, the specific antidote to dabigatran, was the first of them in obtaining a positive opinion in the European Union. However, it is necessary to have the results of currently ongoing studies and experience of use in everyday practice to outline in more detail the real benefit of the specific reversal of DOAC regarding improving the clinical outcome of patients. Among other things, it will be essential to pay particular attention to the possible development of thrombotic complications associated with the reversal of the anticoagulant effect. Finally, the development of multidisciplinary clinical practice guidelines will help clinicians in defining the scenarios in which the use of an antidote is appropriate. Statement The opinions and views expressed in this article are those of the authors and do not necessarily represent the official views of their institutions or any other parties. Financing No funding has been received for the preparation of this article. References 1. Gómez-Outes A, Suárez-Gea ML, Lecumberri R, Terleira-Fernández AI, VargasCastrillón E. Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives. Eur J Haematol. 2015;95:389–404. 2. Wallace H, Davies MW. The lack of antidotes for new oral anticoagulants. BMJ. 2014;348:g1438. 3. Barcellona D, Luzza M, Battino N, Fenu L, Marongiu F. The criteria of the Italian Federation of Thrombosis Centres on DOACs: a “real world” application in
490
4. 5.
6.
7.
8.
9.
10.
11.
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