Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage ANNEXA-4 Substudy

被引：55

作者：

Demchuk, Andrew M. ^{[1
,2
]}

Yue, Patrick ^{[3
]}

Zotova, Elena ^{[4
]}

Nakamya, Juliet ^{[4
]}

Xu, Lizhen ^{[4
]}

Milling, Truman J., Jr. ^{[5
]}

Ohara, Tomoyuki ^{[6
]}

Goldstein, Joshua N. ^{[7
]}

Middeldorp, Saskia ^{[8
]}

Verhamme, Peter ^{[9
]}

Lopez-Sendon, Jose Luis ^{[10
]}

Conley, Pamela B. ^{[3
]}

Curnutte, John T. ^{[3
]}

Eikelboom, John W. ^{[4
]}

Crowther, Mark ^{[4
]}

Connolly, Stuart J. ^{[4
]}

机构：

[1] Univ Calgary, Cumming Sch Med, Dept Clin Neurosci, Calgary, AB, Canada

[2] Univ Calgary, Cumming Sch Med, Dept Radiol, Calgary, AB, Canada

[3] Alexion Pharmaceut Inc, San Francisco, CA USA

[4] McMaster Univ, Dept Med, Hamilton, ON, Canada

[5] Stroke Inst, Seton Dell Med Sch, Dept Neurol, Austin, TX USA

[6] Kyoto Prefectural Univ Med, Dept Neurol, Kyoto, Japan

[7] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA

[8] Univ Amsterdam, Amsterdam UMC, Dept Vasc Med, Amsterdam Cardiovasc Sci, Meibergdreef, Netherlands

[9] Univ Leuven, Ctr Mol & Vasc Biol, Leuven, Belgium

[10] Univ Autonoma Madrid, IdiPaz, Hosp Univ La Paz, Dept Cardiol, Madrid, Spain

来源：

STROKE | 2021年 / 52卷 / 06期

基金：

美国国家卫生研究院;

关键词：

andexanet alfa; direct factor Xa inhibitor reversal; intracranial hemorrhage; PROTHROMBIN COMPLEX CONCENTRATE; WARFARIN; ANTICOAGULATION; RIVAROXABAN; ASSOCIATION; MANAGEMENT; EDOXABAN; EVENTS; GROWTH;

D O I：

10.1161/STROKEAHA.120.030565

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

BACKGROUND AND PURPOSE: Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH). METHODS: ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding <= 18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as <= 35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days. RESULTS: A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population). CONCLUSIONS: Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation.

引用

页码：2096 / 2105

页数：10

共 34 条

[1]

ANDEXXA ® (coagulation factor Xa [recombinant] inactivated-zhzo), 2021, ANDEXXA COAGULATION

[2] Determinants of intracerebral hemorrhage growth - An exploratory analysis [J].

Broderick, Joseph P. ;

Diringer, Michael N. ;

Hill, Michael D. ;

Brun, Nikolai C. ;

Mayer, Stephan A. ;

Steiner, Thorsten ;

Skolnick, Brett E. ;

Davis, Stephen M. .

STROKE, 2007, 38 (03) :1072-1075

[3] Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors [J].

Connolly, S. J. ;

Crowther, M. ;

Eikelboom, J. W. ;

Gibson, C. M. ;

Curnutte, J. T. ;

Lawrence, J. H. ;

Yue, P. ;

Bronson, M. D. ;

Lu, G. ;

Conley, P. B. ;

Verhamme, P. ;

Schmidt, J. ;

Middeldorp, S. ;

Cohen, A. T. ;

Beyer-Westendorf, J. ;

Albaladejo, P. ;

Lopez-Sendon, J. ;

Demchuk, A. M. ;

Pallin, D. J. ;

Concha, M. ;

Goodman, S. ;

Leeds, J. ;

Souza, S. ;

Siegal, D. M. ;

Zotova, E. ;

Meeks, B. ;

Ahmad, S. ;

Nakamya, J. ;

Milling, T. J., Jr. .

NEW ENGLAND JOURNAL OF MEDICINE, 2019, 380 (14) :1326-1335

[4] Defining hematoma expansion in intracerebral hemorrhage Relationship with patient outcomes [J].

Dowlatshahi, D. ;

Demchuk, A. M. ;

Flaherty, M. L. ;

Ali, M. ;

Lyden, P. L. ;

Smith, E. E. .

NEUROLOGY, 2011, 76 (14) :1238-1244

[5] Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal [J].

Dzik, W. H. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2015, 13 :S187-S194

[6]

Ezekwudo DE, 2017, BLOOD, V130

[7] Effect of Tranexamic Acid on Prevention of Hemorrhagic Mass Growth in Patients with Traumatic Brain Injury [J].

Fakharian, Esmaeil ;

Abedzadeh-Kalahroudi, Masoumeh ;

Atoof, Fatemeh .

WORLD NEUROSURGERY, 2018, 109 :E748-E753

[8] Association of Prothrombin Complex Concentrate Administration and Hematoma Enlargement in Non-Vitamin K Antagonist Oral Anticoagulant-Related Intracerebral Hemorrhage [J].

Gerner, Stefan T. ;

Kuramatsu, Joji B. ;

Sembill, Jochen A. ;

Spruegel, Maximilian I. ;

Endres, Matthias ;

Haeusler, Karl Georg ;

Vajkoczy, Peter ;

Ringleb, Peter A. ;

Purrucker, Jan ;

Rizos, Timolaos ;

Erbguth, Frank ;

Schellinger, Peter D. ;

Fink, Gereon R. ;

Stetefeld, Henning ;

Schneider, Hauke ;

Neugebauer, Hermann ;

Roether, Joachim ;

Classen, Joseph ;

Michalski, Dominik ;

Doerfler, Arnd ;

Schwab, Stefan ;

Huttner, Hagen B. .

ANNALS OF NEUROLOGY, 2018, 83 (01) :186-196

[9] Cerebrovascular Events in 21 105 Patients With Atrial Fibrillation Randomized to Edoxaban Versus Warfarin Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 [J].

Giugliano, Robert P. ;

Ruff, Christian T. ;

Rost, Natalia S. ;

Silverman, Scott ;

Wiviott, Stephen D. ;

Lowe, Cheryl ;

Deenadayalu, Naveen ;

Murphy, Sabina A. ;

Grip, Laura T. ;

Betcher, Joshua M. ;

Duggal, Anil ;

Dave, Jay ;

Shi, Minggao ;

Mercuri, Michele ;

Antman, Elliott M. ;

Braunwald, Eugene ;

Vogelmann, O. ;

Gonzalez, C. ;

Ahuad Guerrero, R. ;

Rodriguez, M. ;

Albisu, J. ;

Rosales, E. ;

Allall, O. ;

Reguero, M. ;

Alvarez, C. ;

Garcia, M. ;

Ameriso, S. ;

Ameriso, P. ;

Amuchastegui, M. ;

Caceres, M. ;

Beloscar, J. ;

Petrucci, J. ;

Berli, M. ;

Budassi, N. ;

Valle, M. ;

Bustamante Labarta, G. ;

Saravia, M. ;

Caccavo, A. ;

Fracaro, V. ;

Cartasegna, L. ;

Novas, V. ;

Caruso, O. ;

Saa Zarandon, R. ;

Colombo, H. ;

Morandini, M. ;

Cuello, J. ;

Rosell, M. ;

Cuneo, C. ;

Bocanera, M. ;

D'Amico, A. .

STROKE, 2014, 45 (08) :2372-2378

[10] Edoxaban versus Warfarin in Patients with Atrial Fibrillation [J].

Giugliano, Robert P. ;

Ruff, Christian T. ;

Braunwald, Eugene ;

Murphy, Sabina A. ;

Wiviott, Stephen D. ;

Halperin, Jonathan L. ;

Waldo, Albert L. ;

Ezekowitz, Michael D. ;

Weitz, Jeffrey I. ;

Spinar, Jindrich ;

Ruzyllo, Witold ;

Ruda, Mikhail ;

Koretsune, Yukihiro ;

Betcher, Joshua ;