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

Demchuk, Andrew M.; Yue, Patrick; Zotova, Elena; Nakamya, Juliet; Xu, Lizhen; Milling, Truman J.; Ohara, Tomoyuki; Goldstein, Joshua N.; Verhamme, Peter; López‐Sendón, José; Conley, Pamela B.; Curnutte, John T.; Eikelboom, John W.; Crowther, Mark; Connolly, Stuart J.

doi:10.1161/strokeaha.120.030565

Cited by 45 publications

(47 citation statements)

References 38 publications

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“…The current retrospective, single-center, observational study included 46 patients with an acute FXa-inhibitor-associated, non-traumatic ICH and evaluated efficacy and safety of reversal the FXa inhibitors with andexanet alfa compared to usual care. In addition to the registration study and some other retrospective studies, there is little experience with AA till today [ 9 , 25 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

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Andexanet Alfa for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage: Observational Cohort Study

Rauch

Müller

Dreyhaupt

et al. 2022

JCM

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Background: Intracranial hemorrhage (ICH) is associated with high mortality and morbidity, especially in patients under anticoagulative treatment. Andexanet alfa (AA) is a modified recombinant form of human factor Xa (FXa) developed for reversal of FXa-inhibitors, e.g., in the event of ICH, but experience is still limited. Methods: This monocentric retrospective observational cohort study included 46 patients with acute FXa-inhibitor-associated non-traumatic ICH (FXa-I-ICH) of whom 23 were treated with AA within 12 h after symptom onset, compared to 23 patients with usual care (UC). Volumetrically analyzed hematoma expansion (HE) in brain imaging, clinical outcome and incidence of adverse events were analyzed. Results: All patients (mean age 79.8 ± 7.2 years) were effectively anticoagulated. The cohort included severely ill patients with large hematoma volumes (median 20.4, IQR 7.8–39.0 mL). Efficacy, as assessed by HE in imaging, was very good in the AA-group. There was no (0.0%) relevant HE (>33%) in contrast to UC-group (26.1%). Nevertheless, we observed a high incidence of thromboembolic events (30.4% vs. 4.4%) and non-favorable outcomes (death/palliative condition) in 43.5% vs. 26.1%. Conclusions: There was no HE in the volumetric neuroimaging assessment in the AA-group, but clinical outcomes remained often worse. Large randomized trials for the use of AA in patients with acute FXa-inhibitor-associated ICH are needed to investigate the clinical outcome in consideration of the rates of thromboembolism.

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Section: Discussionmentioning

confidence: 99%

“…Hematoma volume was measured on MRI or CT scans. The Tensor Imaging and Fiber Tracking (TIFT) software was used for processing of the imaging data [ 23 , 24 , 25 ]. MRI or CT scans were transformed into a 3-dimensional isotropic grid with a size resolution of 0.5 mm.…”

Section: Methodsmentioning

confidence: 99%

Andexanet Alfa for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage: Observational Cohort Study

Rauch

Müller

Dreyhaupt

et al. 2022

JCM

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“…In the ANNEXA-4 study, in patients with acute major bleeding associated with the use of a FXa inhibitor (including enoxaparin), treatment with andexanet alfa markedly reduced anti-FXa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 h [101]. The ANNEXA-4 sub-study results, evaluating the hemostatic efficacy of andexanet alfa in ICH secondary to anti-FXa, reported a reduced anti-FXa activity in FXa inhibitor-treated patients with ICH, with a high rate of hemostatic efficacy [102]. Andexanet alfa has been recently approved by the US Food and Drug Administration, but some issues slow down its widespread use, such as its brief half-life, poor correlation between in vitro activity and clinical efficacy, and finally, regarding its safety profile, given the in vitro effects and clinical thrombosis rates of up to 18% in early studies [103].…”

Section: Secondary Prevention Of Ischemic Strokementioning

confidence: 99%

Treatments in Ischemic Stroke: Current and Future

Mosconi¹,

Paciaroni²

2022

Eur Neurol

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Background and Aim: Despite progress made over the last 30 years, stroke is still a leading cause of disability and mortality; likewise, its burden is expected to increase over the next decades, due to population growth and aging. The development of drugs with better safety-efficacy profiles as well as strategies able to improve ischemic stroke management from the pre-hospital setting is needed. Summary: The pathophysiology of ischemic stroke involves multiple pathways resulting in cerebral artery obstruction and brain tissue ischemia. To date, the only approved drug for acute ischemic stroke is intravenous thrombolytic alteplase. Intravenous thrombolysis (IVT) can be administered alone or in combination with endovascular treatment (EVT) with mechanical thrombectomy, in case of large vessel occlusion and generally within 6 h from symptoms onset. The risk of potential bleeding complications, especially symptomatic intracerebral hemorrhage, is one of the reasons for the reluctance to administer IVT. Tenecteplase is a promising alternative fibrinolytic agent, having a better safety profile than alteplase. Moreover, recent evidences have allowed an extension of the IVT ± EVT time window for patients with unknown onset time and for those with a known onset time thanks to the new “tissue-window” approach guided by advanced neuroimaging techniques, which also helps in collateral circulation estimation. Regarding primary-secondary prevention, researchers are focused on improving the efficacy of antithrombotic drugs with a “hemostasis-sparing” approach. Neuroprotective agents are also under development, particularly stem cells. The COVID-19 pandemic has critically stressed global healthcare systems, with collateral damage resulting in access delivery of only emergency care, such as ischemic stroke. Regarding telemedicine, it has had a minor role in acute stroke management, and with the onset of COVID-19, this role will most likely be adopted to increase access and delivery in stroke assessment, but also in the follow-up.

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“…183 Subgroup analyses showed that a high rate of effective hemostasis post-andexanet was achieved in patients with major GIB or ICH while on apixaban or rivaroxaban. 182,184 Another sub-study of ANNEXA-4 looked at the effect of andexanet on TGT in patients with MBE treated with DOACs. 185 Andexanet bolus increased ETP, which was maintained during infusion up to 18 hours.…”

Section: Specific Antidotesmentioning

confidence: 99%

A Historical Perspective on the Reversal of Anticoagulants

Salter

Crowther

2022

Semin Thromb Hemost

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There has been a landmark shift in the last several decades in the management and prevention of thromboembolic events. From the discovery of parenteral and oral agents requiring frequent monitoring as early as 1914, to the development of direct oral anticoagulants (DOACs) that do not require monitoring or dose adjustment in the late 20th century, great advances have been achieved. Despite the advent of these newer agents, bleeding continues to be a key complication, affecting 2 to 4% of DOAC-treated patients per year. Bleeding is associated with substantial morbidity and mortality. Although specific reversal agents for DOACs have lagged the release of these agents, idarucizumab and andexanet alfa are now available as antagonists. However, the efficacy of these reversal agents is uncertain, and complications, including thrombosis, have not been adequately explored. As such, guidelines continue to advise the use of nonspecific prohemostatic agents for patients requiring reversal of the anticoagulant effect of these drugs. As the indications for DOACs and the overall prevalence of their use expand, there is an unmet need for further studies to determine the efficacy of specific compared with nonspecific pro-hemostatic reversal agents. In this review, we will discuss the evidence behind specific and nonspecific reversal agents for both parenteral and oral anticoagulants.

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

Cited by 45 publications

References 38 publications

Andexanet Alfa for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage: Observational Cohort Study

Andexanet Alfa for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage: Observational Cohort Study

Treatments in Ischemic Stroke: Current and Future

A Historical Perspective on the Reversal of Anticoagulants

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