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Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial

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dc.contributor.author Sharma, Mukul
dc.contributor.author Molina, Carlos A.
dc.contributor.author Toyoda, Kazunori
dc.contributor.author Bereczki, Daniel
dc.contributor.author Bangdiwala, Shrikant I.
dc.contributor.author Kasner, Scott E.
dc.contributor.author Lutsep, Helmi L.
dc.contributor.author Tsivgoulis, Georgios
dc.contributor.author Ntaios, George
dc.contributor.author Czlonkowska, Anna
dc.contributor.author Shuaib, Ashfaq
dc.contributor.author Amarenco, Pierre
dc.contributor.author Endres, Matthias
dc.contributor.author Yoon, Byung-Woo
dc.contributor.author Tanne, David
dc.contributor.author Toni, Danilo
dc.contributor.author Yperzeele, Laetitia
dc.contributor.author von Weitzel Mudersbach, Paul
dc.contributor.author Sampaio Silva, Gisele
dc.contributor.author Ameriso, Sebastián Francisco
dc.date.accessioned 2024-01-30T11:22:45Z
dc.date.available 2024-01-30T11:22:45Z
dc.date.issued 2024-01
dc.identifier.citation Sharma M, Molina CA, Toyoda K, Bereczki D, Bangdiwala SI, Kasner SE, Lutsep HL, Tsivgoulis G, Ntaios G, Czlonkowska A, Shuaib A, Amarenco P, Endres M, Yoon BW, Tanne D, Toni D, Yperzeele L, von Weitzel-Mudersbach P, Sampaio Silva G, Avezum A, Dawson J, Strbian D, Tatlisumak T, Eckstein J, Ameriso SF, Weber JR, Sandset EC, Goar Pogosova N, Lavados PM, Arauz A, Gailani D, Diener HC, Bernstein RA, Cordonnier C, Kahl A, Abelian G, Donovan M, Pachai C, Li D, Hankey GJ. Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. 2024 Jan;23(1):46-59. doi: 10.1016/S1474-4422(23)00403-9. es_ES
dc.identifier.uri https://doi.org/10.1016/s1474-4422(23)00403-9
dc.identifier.uri https://repositorio.fleni.org.ar/xmlui/handle/123456789/965
dc.description.abstract Background: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). Methods: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). Findings: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. Interpretation: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. es_ES
dc.language.iso eng es_ES
dc.publisher Lancet Pub. Group es_ES
dc.subject Stroke es_ES
dc.subject Ischemic Stroke es_ES
dc.subject Accidente Cerebrovascular Isquémico es_ES
dc.subject Accidente Cerebrovascular es_ES
dc.title Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial es_ES
dc.type info:eu-repo/semantics/article es_ES
dc.description.fil Fil: Sharma, Mukul. McMaster University; Canadá.
dc.description.fil Fil: Molina, Carlos A. Vall d'Hebron Hospital; España.
dc.description.fil Fil: Toyoda, Kazunori. National Cerebral and Cardiovascular Center; Japón.
dc.description.fil Fil: Bereczki, Daniel. Semmelweis University; Hungría.
dc.description.fil Fil: Bangdiwala, Shrikant I. McMaster University; Canadá.
dc.description.fil Fil: Kasner, Scott E. University of Pennsylvania; Estados Unidos.
dc.description.fil Fil: Lutsep, Helmi L. Oregon Health & Science University; Estados Unidos.
dc.description.fil Fil: Tsivgoulis, Georgios. National and Kapodistrian University of Athens; Grecia.
dc.description.fil Fil: Ntaios, George. University of Thessaly; Grecia.
dc.description.fil Fil: Czlonkowska, Anna. Institute of Psychiatry and Neurology de Warsaw; Polonia.
dc.description.fil Fil: Shuaib, Ashfaq. University of Alberta Hospital; Canadá.
dc.description.fil Fil: Amarenco, Pierre. Bichat Hospital; Francia.
dc.description.fil Fil: Endres, Matthias. Charité Universitätsmedizin Berlin; Alemania.
dc.description.fil Fil: Yoon, Byung Woo. Eulji University; Corea.
dc.description.fil Fil: Tanne, David. Rambam Health Care Campus; Israel.
dc.description.fil Fil: Toni, Danilo. Sapienza University of Rome; Italia.
dc.description.fil Fil: Yperzeele, Laetitia. Antwerp University Hospital; Bélgica.
dc.description.fil Fil: von Weitzel Mudersbach, Paul. Aarhus University Hospital; Dinamarca.
dc.description.fil Fil: Sampaio Silva, Gisele. Federal University of São Paulo; Brasil.
dc.description.fil Fil: Ameriso, Sebastian Francisco. Fleni. Departamento de Neurología. Servicio de Neurología Vascular; Argentina.
dc.relation.ispartofVOLUME 23
dc.relation.ispartofNUMBER 1
dc.relation.ispartofPAGINATION 46-59.
dc.relation.ispartofCOUNTRY Reino Unido
dc.relation.ispartofCITY Londres
dc.relation.ispartofTITLE The Lancet. Neurology
dc.relation.ispartofISSN 1474-4465
dc.type.snrd info:ar-repo/semantics/artículo es_ES


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