학술논문
Andexanet alfa versus non-specific treatments for intracerebral hemorrhage in patients taking factor Xa inhibitors - Individual patient data analysis of ANNEXA-4 and TICH-NOAC.
Document Type
Academic Journal
Author
Siepen BM; Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland.; Graduate School for Health Sciences, University of Bern, Bern, Switzerland.; Polymeris A; Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.; Shoamanesh A; Population Health Research Institute, McMaster University, Hamilton, ON, Canada.; Connolly S; Population Health Research Institute, McMaster University, Hamilton, ON, Canada.; Steiner T; Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.; Department of Neurology, Höechst Hospital Frankfurt, Germany.; Poli S; Department of Neurology and Stroke, Eberhard-Karls University Tuebingen, Tuebingen, Germany.; Hertie Institute for Clinical Brain Research, Eberhard-Karls University Tuebingen, Tübingen, Germany.; Lemmens R; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.; Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, Leuven, Belgium.; Goeldlin MB; Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland.; Graduate School for Health Sciences, University of Bern, Bern, Switzerland.; Müller M; Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland.; Graduate School for Health Sciences, University of Bern, Bern, Switzerland.; Branca M; CTU Bern, University of Bern, Bern, Switzerland.; Rauch J; Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland.; Meinel T; Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland.; Kaesmacher J; University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland.; Z'Graggen W; Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland.; Department of Neurosurgery, Inselspital, University Hospital Bern, Bern, Switzerland.; Arnold M; Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland.; Fischer U; Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland.; Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.; Peters N; Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.; Department of Neurology and Neurorehabilitation, University of Basel, Basel, Switzerland.; University Department of Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland.; Stroke Center Hirslanden, Klinik Hirslanden Zurich, Zurich, Switzerland.; Engelter ST; Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.; Department of Neurology and Neurorehabilitation, University of Basel, Basel, Switzerland.; University Department of Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland.; Lyrer P; Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.; Seiffge D; Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland.
Source
Publisher: SAGE Publications Country of Publication: United States NLM ID: 101274068 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1747-4949 (Electronic) Linking ISSN: 17474930 NLM ISO Abbreviation: Int J Stroke Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Data comparing the specific reversal agent andexanet alfa with non-specific treatments in patients with non-traumatic intracerebral hemorrhage (ICH) associated with factor-Xa inhibitor (FXaI) use are scarce.
Aim: The study aimed to determine the association between the use of andexanet alfa compared with non-specific treatments with the rate of hematoma expansion and thromboembolic complications in patients with FXaI-associated ICH.
Methods: We performed an individual patient data analysis combining two independent, prospective studies: ANNEXA-4 (180 patients receiving andexanet alfa, NCT02329327) and TICH-NOAC (63 patients receiving tranexamic acid or placebo ± prothrombin complex concentrate, NCT02866838). The primary efficacy outcome was hematoma expansion on follow-up imaging. The primary safety outcome was any thromboembolic complication (ischemic stroke, myocardial infarction, pulmonary embolism, or deep vein thrombosis) at 30 days. We used binary logistic regression models adjusted for baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively.
Results: Among 243 participants included, the median age was 80 (IQR 75-84) years, baseline hematoma volume was 9.1 (IQR 3.4-21) mL and anti-Xa activity 118 (IQR 78-222) ng/mL. Times from last FXaI intake and symptom onset to treatment were 11 (IQR 7-16) and 4.7 (IQR 3.0-7.6) h, respectively. Overall, 50 patients (22%) experienced hematoma expansion (ANNEXA-4: n=24 (14%); TICH-NOAC: n=26 (41%)). After adjusting for pre-specified confounders (baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively), treatment with andexanet alfa was independently associated with decreased odds for hematoma expansion (aOR 0.33, 95% CI 0.13-0.80, p = 0.015). Overall, 26 patients (11%) had any thromboembolic complication within 30 days (ANNEXA-4: n=20 (11%); TICH-NOAC: n=6 (10%)). There was no association between any thromboembolic complication and treatment with andexanet alfa (aOR 0.70, 95% CI 0.16-3.12, p = 0.641).
Conclusion: The use of andexanet alfa compared to any other non-specific treatment strategy was associated with decreased odds for hematoma expansion, without increased odds for thromboembolic complications.
Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.M.S. received research funding from the Swiss Academy of Medical Sciences/Bangerter-Rhyner Foundation and the Swiss Heart Foundation. M.B.G. received grants from Swiss Academy of Medical Sciences/Bangerter-Rhyner Foundation, Insel Gruppe AG, Swiss Stroke Society, European Stroke Organization, U.F. received research support of the Swiss National Science Foundation, and the Swiss Heart Foundation; research grants from Medtronic (and from Stryker, Rapid medical, Penumbra, and Phenox); consultancies for Medtronic, Stryker, and CSL Behring; and participation in an advisory board for Alexion/Portola, Boehringer Ingelheim, Biogen, and Acthera; S.P. received research support from BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, Helena Laboratories, and Werfen; and speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen. R.L. has no personal disclosures, but reports institutional fees for consultancy from Bioxodes and Pfizer. D.S. received grants from Alexion/AstraZeneca, personal fees from Bayer, and consultancy fees from VarmX.
Aim: The study aimed to determine the association between the use of andexanet alfa compared with non-specific treatments with the rate of hematoma expansion and thromboembolic complications in patients with FXaI-associated ICH.
Methods: We performed an individual patient data analysis combining two independent, prospective studies: ANNEXA-4 (180 patients receiving andexanet alfa, NCT02329327) and TICH-NOAC (63 patients receiving tranexamic acid or placebo ± prothrombin complex concentrate, NCT02866838). The primary efficacy outcome was hematoma expansion on follow-up imaging. The primary safety outcome was any thromboembolic complication (ischemic stroke, myocardial infarction, pulmonary embolism, or deep vein thrombosis) at 30 days. We used binary logistic regression models adjusted for baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively.
Results: Among 243 participants included, the median age was 80 (IQR 75-84) years, baseline hematoma volume was 9.1 (IQR 3.4-21) mL and anti-Xa activity 118 (IQR 78-222) ng/mL. Times from last FXaI intake and symptom onset to treatment were 11 (IQR 7-16) and 4.7 (IQR 3.0-7.6) h, respectively. Overall, 50 patients (22%) experienced hematoma expansion (ANNEXA-4: n=24 (14%); TICH-NOAC: n=26 (41%)). After adjusting for pre-specified confounders (baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively), treatment with andexanet alfa was independently associated with decreased odds for hematoma expansion (aOR 0.33, 95% CI 0.13-0.80, p = 0.015). Overall, 26 patients (11%) had any thromboembolic complication within 30 days (ANNEXA-4: n=20 (11%); TICH-NOAC: n=6 (10%)). There was no association between any thromboembolic complication and treatment with andexanet alfa (aOR 0.70, 95% CI 0.16-3.12, p = 0.641).
Conclusion: The use of andexanet alfa compared to any other non-specific treatment strategy was associated with decreased odds for hematoma expansion, without increased odds for thromboembolic complications.
Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.M.S. received research funding from the Swiss Academy of Medical Sciences/Bangerter-Rhyner Foundation and the Swiss Heart Foundation. M.B.G. received grants from Swiss Academy of Medical Sciences/Bangerter-Rhyner Foundation, Insel Gruppe AG, Swiss Stroke Society, European Stroke Organization, U.F. received research support of the Swiss National Science Foundation, and the Swiss Heart Foundation; research grants from Medtronic (and from Stryker, Rapid medical, Penumbra, and Phenox); consultancies for Medtronic, Stryker, and CSL Behring; and participation in an advisory board for Alexion/Portola, Boehringer Ingelheim, Biogen, and Acthera; S.P. received research support from BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, Helena Laboratories, and Werfen; and speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen. R.L. has no personal disclosures, but reports institutional fees for consultancy from Bioxodes and Pfizer. D.S. received grants from Alexion/AstraZeneca, personal fees from Bayer, and consultancy fees from VarmX.