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Erschienen in: Journal of Thrombosis and Thrombolysis 2/2020

11.09.2019

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

verfasst von: Rahul Chaudhary, Tushar Sharma, Jalaj Garg, Ajaypaul Sukhi, Kevin Bliden, Udaya Tantry, Mohit Turagam, Dhanunjaya Lakkireddy, Paul Gurbel

Erschienen in: Journal of Thrombosis and Thrombolysis | Ausgabe 2/2020

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Abstract

New guideline recommendations prefer direct oral anticoagulants (DOACs) over warfarin in DOAC-eligible patients with atrial fibrillation and patients with venous thromboembolism. As expected with all antithrombotic agents, there is an associated increased risk of bleeding complications in patients receiving DOACs that can be attributed to the DOAC itself, or other issues such as acute trauma, invasive procedures, or underlying comorbidities. For the majority of severe bleeding events, the widespread approach is to withdraw the DOAC, then provide supportive measures and “watchful waiting” with the expectation that the bleeding event will resolve with time. However, urgent reversal of anticoagulation may be advantageous in patients with serious or life-threatening bleeding or in those requiring urgent surgery or procedures. Until recently, the lack of specific reversal agents, has affected the uptake of these agents in clinical practice despite a safer profile compared to warfarin in clinical trials. In cases of life-threatening or uncontrolled bleeding or when patients require emergency surgery or urgent procedures, idarucizumab has been recently approved for reversal of anticoagulation in dabigatran-treated patients and andexanet alfa for factor Xa inhibitor-treated treated patients. The current review summarizes the current clinical evidence and scope of these agents with the potential impact on DOAC use in clinical practice.
Literatur
2.
4.
Zurück zum Zitat Sandau KE, Funk M, Auerbach A, Barsness GW, Blum K, Cvach M, Lampert R, May JL, McDaniel GM, Perez MV, Sendelbach S, Sommargren CE, Wang PJ, American Heart Association Council, American Heart Association Council on C, Stroke N, Council on Clinical C, Council on Cardiovascular Disease in the Y (2017) Update to practice standards for electrocardiographic monitoring in hospital settings: a scientific statement from the American Heart Association. Circulation 136(19):e273–e344. https://doi.org/10.1161/CIR.0000000000000527 CrossRefPubMed Sandau KE, Funk M, Auerbach A, Barsness GW, Blum K, Cvach M, Lampert R, May JL, McDaniel GM, Perez MV, Sendelbach S, Sommargren CE, Wang PJ, American Heart Association Council, American Heart Association Council on C, Stroke N, Council on Clinical C, Council on Cardiovascular Disease in the Y (2017) Update to practice standards for electrocardiographic monitoring in hospital settings: a scientific statement from the American Heart Association. Circulation 136(19):e273–e344. https://​doi.​org/​10.​1161/​CIR.​0000000000000527​ CrossRefPubMed
5.
Zurück zum Zitat Benjamin EM, Klugman RA, Luckmann R, Fairchild DG, Abookire SA (2013) Impact of cardiac telemetry on patient safety and cost. Am J Manag Care 19(6):e225–e232PubMed Benjamin EM, Klugman RA, Luckmann R, Fairchild DG, Abookire SA (2013) Impact of cardiac telemetry on patient safety and cost. Am J Manag Care 19(6):e225–e232PubMed
8.
Zurück zum Zitat Pokorney SD, Simon DN, Thomas L, Fonarow GC, Kowey PR, Chang P, Singer DE, Ansell J, Blanco RG, Gersh B, Mahaffey KW, Hylek EM, Go AS, Piccini JP, Peterson ED, Registry Outcomes, Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I (2015) Patients’ time in therapeutic range on warfarin among US patients with atrial fibrillation: results from ORBIT-AF registry. Am Heart J 170(1):141–148.e141. https://doi.org/10.1016/j.ahj.2015.03.017 CrossRefPubMed Pokorney SD, Simon DN, Thomas L, Fonarow GC, Kowey PR, Chang P, Singer DE, Ansell J, Blanco RG, Gersh B, Mahaffey KW, Hylek EM, Go AS, Piccini JP, Peterson ED, Registry Outcomes, Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I (2015) Patients’ time in therapeutic range on warfarin among US patients with atrial fibrillation: results from ORBIT-AF registry. Am Heart J 170(1):141–148.e141. https://​doi.​org/​10.​1016/​j.​ahj.​2015.​03.​017 CrossRefPubMed
11.
14.
Zurück zum Zitat Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L, Committee R-LS, Investigators (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139–1151. https://doi.org/10.1056/NEJMoa0905561 CrossRefPubMed Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L, Committee R-LS, Investigators (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139–1151. https://​doi.​org/​10.​1056/​NEJMoa0905561 CrossRefPubMed
15.
Zurück zum Zitat Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM, Investigators RA (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10):883–891. https://doi.org/10.1056/NEJMoa1009638 CrossRefPubMed Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM, Investigators RA (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10):883–891. https://​doi.​org/​10.​1056/​NEJMoa1009638 CrossRefPubMed
16.
Zurück zum Zitat Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L, Committees A, Investigators (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365(11):981–992. https://doi.org/10.1056/NEJMoa1107039 CrossRefPubMed Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L, Committees A, Investigators (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365(11):981–992. https://​doi.​org/​10.​1056/​NEJMoa1107039 CrossRefPubMed
17.
Zurück zum Zitat Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM, Investigators EA-T (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369(22):2093–2104. https://doi.org/10.1056/NEJMoa1310907 CrossRefPubMed Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM, Investigators EA-T (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369(22):2093–2104. https://​doi.​org/​10.​1056/​NEJMoa1310907 CrossRefPubMed
20.
Zurück zum Zitat Investigators E, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363(26):2499–2510. https://doi.org/10.1056/NEJMoa1007903 CrossRef Investigators E, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363(26):2499–2510. https://​doi.​org/​10.​1056/​NEJMoa1007903 CrossRef
21.
Zurück zum Zitat Investigators E-P, Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366(14):1287–1297. https://doi.org/10.1056/NEJMoa1113572 CrossRef Investigators E-P, Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366(14):1287–1297. https://​doi.​org/​10.​1056/​NEJMoa1113572 CrossRef
23.
Zurück zum Zitat Hokusai VTEI, Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369(15):1406–1415. https://doi.org/10.1056/NEJMoa1306638 CrossRef Hokusai VTEI, Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369(15):1406–1415. https://​doi.​org/​10.​1056/​NEJMoa1306638 CrossRef
25.
Zurück zum Zitat Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383(9921):955–962. https://doi.org/10.1016/S0140-6736(13)62343-0 CrossRefPubMed Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383(9921):955–962. https://​doi.​org/​10.​1016/​S0140-6736(13)62343-0 CrossRefPubMed
26.
28.
Zurück zum Zitat Kakkos SK, Kirkilesis GI, Tsolakis IA (2014) Editor’s Choice—efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. Eur J Vasc Endovasc Surg 48(5):565–575. https://doi.org/10.1016/j.ejvs.2014.05.001 CrossRefPubMed Kakkos SK, Kirkilesis GI, Tsolakis IA (2014) Editor’s Choice—efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. Eur J Vasc Endovasc Surg 48(5):565–575. https://​doi.​org/​10.​1016/​j.​ejvs.​2014.​05.​001 CrossRefPubMed
29.
Zurück zum Zitat Raval AN, Cigarroa JE, Chung MK, Diaz-Sandoval LJ, Diercks D, Piccini JP, Jung HS, Washam JB, Welch BG, Zazulia AR, Collins SP, American Heart Association Clinical Pharmacology Subcommittee of the Acute Cardiac C, General Cardiology Committee of the Council on Clinical C, Council on Cardiovascular Disease in the Y, Council on Quality of C, Outcomes R (2017) Management of patients on non-vitamin k antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation 135(10):e604–e633. https://doi.org/10.1161/cir.0000000000000477 CrossRefPubMedPubMedCentral Raval AN, Cigarroa JE, Chung MK, Diaz-Sandoval LJ, Diercks D, Piccini JP, Jung HS, Washam JB, Welch BG, Zazulia AR, Collins SP, American Heart Association Clinical Pharmacology Subcommittee of the Acute Cardiac C, General Cardiology Committee of the Council on Clinical C, Council on Cardiovascular Disease in the Y, Council on Quality of C, Outcomes R (2017) Management of patients on non-vitamin k antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation 135(10):e604–e633. https://​doi.​org/​10.​1161/​cir.​0000000000000477​ CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Xu Y, Schulman S, Dowlatshahi D, Holbrook AM, Simpson CS, Shepherd LE, Wells PS, Giulivi A, Gomes T, Mamdani M, Khuu W, Frymire E, Johnson AP, Bleeding Effected by Direct Oral Anticoagulants Study G (2017) Direct oral anticoagulant- or warfarin-related major bleeding: characteristics, reversal strategies, and outcomes from a multicenter observational study. Chest 152(1):81–91. https://doi.org/10.1016/j.chest.2017.02.009 CrossRefPubMed Xu Y, Schulman S, Dowlatshahi D, Holbrook AM, Simpson CS, Shepherd LE, Wells PS, Giulivi A, Gomes T, Mamdani M, Khuu W, Frymire E, Johnson AP, Bleeding Effected by Direct Oral Anticoagulants Study G (2017) Direct oral anticoagulant- or warfarin-related major bleeding: characteristics, reversal strategies, and outcomes from a multicenter observational study. Chest 152(1):81–91. https://​doi.​org/​10.​1016/​j.​chest.​2017.​02.​009 CrossRefPubMed
35.
Zurück zum Zitat Gomez-Outes A, Lecumberri R, Suarez-Gea ML, Terleira-Fernandez AI, Monreal M, Vargas-Castrillon E (2015) Case fatality rates of recurrent thromboembolism and bleeding in patients receiving direct oral anticoagulants for the initial and extended treatment of venous thromboembolism: a systematic review. J Cardiovasc Pharmacol Ther 20(5):490–500. https://doi.org/10.1177/1074248415575154 CrossRefPubMed Gomez-Outes A, Lecumberri R, Suarez-Gea ML, Terleira-Fernandez AI, Monreal M, Vargas-Castrillon E (2015) Case fatality rates of recurrent thromboembolism and bleeding in patients receiving direct oral anticoagulants for the initial and extended treatment of venous thromboembolism: a systematic review. J Cardiovasc Pharmacol Ther 20(5):490–500. https://​doi.​org/​10.​1177/​1074248415575154​ CrossRefPubMed
36.
Zurück zum Zitat Bliden KP, Chaudhary R, Mohammed N, Muresan AA, Lopez-Espina CG, Cohen E, Raviv G, Doubleday M, Zaman F, Mathew B, Tantry US, Gurbel PA (2017) Determination of non-vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system. J Thromb Thrombolysis 43(4):437–445. https://doi.org/10.1007/s11239-017-1477-1 CrossRefPubMed Bliden KP, Chaudhary R, Mohammed N, Muresan AA, Lopez-Espina CG, Cohen E, Raviv G, Doubleday M, Zaman F, Mathew B, Tantry US, Gurbel PA (2017) Determination of non-vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system. J Thromb Thrombolysis 43(4):437–445. https://​doi.​org/​10.​1007/​s11239-017-1477-1 CrossRefPubMed
38.
45.
Zurück zum Zitat Ingelheim B (2014) U.S. FDA grants breakthrough therapy designation to pradaxa (dabigatran etexilate) specific investigational antidote Ingelheim B (2014) U.S. FDA grants breakthrough therapy designation to pradaxa (dabigatran etexilate) specific investigational antidote
47.
Zurück zum Zitat Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI (2015) Idarucizumab for dabigatran reversal. N Engl J Med 373(6):511–520. https://doi.org/10.1056/NEJMoa1502000 CrossRefPubMed Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI (2015) Idarucizumab for dabigatran reversal. N Engl J Med 373(6):511–520. https://​doi.​org/​10.​1056/​NEJMoa1502000 CrossRefPubMed
48.
Zurück zum Zitat Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, Lang B, Ramael S, Moschetti V, Gruenenfelder F, Reilly P, Kreuzer J (2015) Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet 386(9994):680–690. https://doi.org/10.1016/S0140-6736(15)60732-2 CrossRefPubMed Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, Lang B, Ramael S, Moschetti V, Gruenenfelder F, Reilly P, Kreuzer J (2015) Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet 386(9994):680–690. https://​doi.​org/​10.​1016/​S0140-6736(15)60732-2 CrossRefPubMed
50.
Zurück zum Zitat Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI (2017) Idarucizumab for dabigatran reversal: full cohort analysis. N Engl J Med 377(5):431–441. https://doi.org/10.1056/NEJMoa1707278 CrossRefPubMed Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI (2017) Idarucizumab for dabigatran reversal: full cohort analysis. N Engl J Med 377(5):431–441. https://​doi.​org/​10.​1056/​NEJMoa1707278 CrossRefPubMed
52.
Zurück zum Zitat Pollack CV Jr, Reilly PA, Bernstein R, Dubiel R, Eikelboom J, Glund S, Huisman MV, Hylek E, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Sellke F, Stangier J, Steiner T, Wang B, Weitz JI (2015) Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost 114(1):198–205. https://doi.org/10.1160/TH15-03-0192 CrossRefPubMed Pollack CV Jr, Reilly PA, Bernstein R, Dubiel R, Eikelboom J, Glund S, Huisman MV, Hylek E, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Sellke F, Stangier J, Steiner T, Wang B, Weitz JI (2015) Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost 114(1):198–205. https://​doi.​org/​10.​1160/​TH15-03-0192 CrossRefPubMed
53.
Zurück zum Zitat Spronk HMH, Jv Ryn, Zentai C, Ht Cate, Rossaint R, Grottke O (2013) Resuscitation With different volume expanders does not influence coagulation after antidoting dabigatran with its specific fab in a pig model of hemorrhagic shock. Blood 122(21):3649CrossRef Spronk HMH, Jv Ryn, Zentai C, Ht Cate, Rossaint R, Grottke O (2013) Resuscitation With different volume expanders does not influence coagulation after antidoting dabigatran with its specific fab in a pig model of hemorrhagic shock. Blood 122(21):3649CrossRef
54.
Zurück zum Zitat Ryn JV, Schmoll M, Pillu H, Gheyle L, Brys J, Moschetti V, Glund S, Reilly P, Stangier J (2018) Effect of dabigatran on the ability to generate fibrin at a wound site and its reversal by idarucizumab, the antidote to dabigatran, in healthy volunteers: an exploratory marker of blood loss. Circulation 130(suppl_2):18403 Ryn JV, Schmoll M, Pillu H, Gheyle L, Brys J, Moschetti V, Glund S, Reilly P, Stangier J (2018) Effect of dabigatran on the ability to generate fibrin at a wound site and its reversal by idarucizumab, the antidote to dabigatran, in healthy volunteers: an exploratory marker of blood loss. Circulation 130(suppl_2):18403
55.
Zurück zum Zitat Glund S, Moschetti V, Norris S, Stangier J, Schmohl M, van Ryn J, Lang B, Ramael S, Reilly P (2015) A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 113(5):943–951. https://doi.org/10.1160/TH14-12-1080 CrossRefPubMed Glund S, Moschetti V, Norris S, Stangier J, Schmohl M, van Ryn J, Lang B, Ramael S, Reilly P (2015) A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 113(5):943–951. https://​doi.​org/​10.​1160/​TH14-12-1080 CrossRefPubMed
58.
Zurück zum Zitat Pharmaceuticals P (2013) Portola pharmaceuticals receives breakthrough therapy designation from FDA for andexanet alfa (PRT4445*), investigational factor Xa inhibitor antidote Pharmaceuticals P (2013) Portola pharmaceuticals receives breakthrough therapy designation from FDA for andexanet alfa (PRT4445*), investigational factor Xa inhibitor antidote
59.
Zurück zum Zitat Pharmaceuticals P (2015) Portola pharmaceuticals receives FDA orphan drug designation for andexanet alfa, its breakthrough-designated factor Xa inhibitor antidote Pharmaceuticals P (2015) Portola pharmaceuticals receives FDA orphan drug designation for andexanet alfa, its breakthrough-designated factor Xa inhibitor antidote
62.
Zurück zum Zitat Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U (2013) A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 19(4):446–451. https://doi.org/10.1038/nm.3102 CrossRefPubMed Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U (2013) A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 19(4):446–451. https://​doi.​org/​10.​1038/​nm.​3102 CrossRefPubMed
64.
Zurück zum Zitat Genmin Lu JPL, Curnutte John T, Conley Pamela B (2017) Effect of andexanet-TFPI interaction on in vitro thrombin formation and coagulation markers in the TF-pathway. Blood 130(Suppl 1):629 Genmin Lu JPL, Curnutte John T, Conley Pamela B (2017) Effect of andexanet-TFPI interaction on in vitro thrombin formation and coagulation markers in the TF-pathway. Blood 130(Suppl 1):629
66.
Zurück zum Zitat Grottke O, Akman N, Conley PB, Honickel M (2018) The impact of andexanet alfa in a porcine polytrauma model under apixaban anticoagulation: investigation of hemostatic safety and efficacy. Circulation 136(Suppl 1):A20205 Grottke O, Akman N, Conley PB, Honickel M (2018) The impact of andexanet alfa in a porcine polytrauma model under apixaban anticoagulation: investigation of hemostatic safety and efficacy. Circulation 136(Suppl 1):A20205
69.
Zurück zum Zitat Genmin Lu PP, De Guzman F, Canivel D, Malinowski J, Pratikhya P, Lin J, Leeds JM, Curnutte JT, Conley PB (2017) Reversal of anticoagulation effects of rivaroxaban and associated bleeding in a rabbit acute hemorrhage model by andexanet alfa vs. coagulation replacement factors. Neurology 88(16 supplement):5.054 Genmin Lu PP, De Guzman F, Canivel D, Malinowski J, Pratikhya P, Lin J, Leeds JM, Curnutte JT, Conley PB (2017) Reversal of anticoagulation effects of rivaroxaban and associated bleeding in a rabbit acute hemorrhage model by andexanet alfa vs. coagulation replacement factors. Neurology 88(16 supplement):5.054
71.
Zurück zum Zitat Mark Crowther GGL, Genmin Lu, Leeds Janet, Lin Joyce, Pratikhya Pratikhya, Conley Pamela B, Connolly Stuart, Curnutte John T (2014) A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Blood 124(21):4269CrossRef Mark Crowther GGL, Genmin Lu, Leeds Janet, Lin Joyce, Pratikhya Pratikhya, Conley Pamela B, Connolly Stuart, Curnutte John T (2014) A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Blood 124(21):4269CrossRef
72.
Zurück zum Zitat Mark Crowther GL, Leeds Janet M, Lin Joyce, Conley Pamela B, Gold Alexander, Connolly Stuart J, Curnutte John T (2016) Reversal of betrixaban-induced anticoagulation in healthy volunteers by andexanet alfa. Blood 128(22):143CrossRef Mark Crowther GL, Leeds Janet M, Lin Joyce, Conley Pamela B, Gold Alexander, Connolly Stuart J, Curnutte John T (2016) Reversal of betrixaban-induced anticoagulation in healthy volunteers by andexanet alfa. Blood 128(22):143CrossRef
76.
Zurück zum Zitat Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M, Investigators A (2016) Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 375(12):1131–1141. https://doi.org/10.1056/NEJMoa1607887 CrossRefPubMedPubMedCentral Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M, Investigators A (2016) Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 375(12):1131–1141. https://​doi.​org/​10.​1056/​NEJMoa1607887 CrossRefPubMedPubMedCentral
77.
Zurück zum Zitat Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Demchuk AM, Pallin DJ, Concha M, Goodman S, Leeds J, Souza S, Siegal DM, Zotova E, Meeks B, Ahmad S, Nakamya J, Milling TJ Jr, Investigators A (2019) Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 380(14):1326–1335. https://doi.org/10.1056/NEJMoa1814051 CrossRefPubMedPubMedCentral Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Demchuk AM, Pallin DJ, Concha M, Goodman S, Leeds J, Souza S, Siegal DM, Zotova E, Meeks B, Ahmad S, Nakamya J, Milling TJ Jr, Investigators A (2019) Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 380(14):1326–1335. https://​doi.​org/​10.​1056/​NEJMoa1814051 CrossRefPubMedPubMedCentral
87.
Zurück zum Zitat Kupper C, Feil K, Klein M, Feuerecker R, Lucking M, Thanbichler F, Dietrich D, Zerkaulen I, Jandl M, Marziniak M, Poppert H, Wunderlich S, Topka H, Dieterich M, Kellert L (2019) Idarucizumab administration in emergency situations: the Munich Registry of Reversal of Pradaxa(R) in clinical routine (MR REPAIR). J Neurol. https://doi.org/10.1007/s00415-019-09492-w CrossRefPubMed Kupper C, Feil K, Klein M, Feuerecker R, Lucking M, Thanbichler F, Dietrich D, Zerkaulen I, Jandl M, Marziniak M, Poppert H, Wunderlich S, Topka H, Dieterich M, Kellert L (2019) Idarucizumab administration in emergency situations: the Munich Registry of Reversal of Pradaxa(R) in clinical routine (MR REPAIR). J Neurol. https://​doi.​org/​10.​1007/​s00415-019-09492-w CrossRefPubMed
Metadaten
Titel
Direct oral anticoagulants: a review on the current role and scope of reversal agents
verfasst von
Rahul Chaudhary
Tushar Sharma
Jalaj Garg
Ajaypaul Sukhi
Kevin Bliden
Udaya Tantry
Mohit Turagam
Dhanunjaya Lakkireddy
Paul Gurbel
Publikationsdatum
11.09.2019
Verlag
Springer US
Erschienen in
Journal of Thrombosis and Thrombolysis / Ausgabe 2/2020
Print ISSN: 0929-5305
Elektronische ISSN: 1573-742X
DOI
https://doi.org/10.1007/s11239-019-01954-2

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