b26172cbebf3ed149b0972efe2a1e7fb pmc_10488897.pdf cd66bb78ad315fcb65b8714ed7e1f572d8202bec pmc_10488897.pdf 13fb700abc096ac8b6870b572c67564d91d6835941007fb70b1329392a4a8b8d pmc_10488897.pdf Title: Efficacy and Safety of Oral Factor XIa Inhibitors in Stroke Prevention: A Systematic Review and Meta-Analysis Subject: Introduction: Despite preventive measures, stroke rates remain high in the primary and secondary prevention settings. Factor XIa inhibition may offer a novel, safe and effective antithrombotic option for stroke prevention. Methods: We conducted a systematic review and meta-analysis including all available randomized controlled clinical trials (RCTs) that investigated the efficacy and safety of factor XIa inhibitors versus controls in primary or secondary stroke prevention. The primary efficacy and safety outcomes of interest were symptomatic ischemic stroke (IS) and the composite of major bleeding and clinically relevant non-major bleeding. Results: Four phase II dose-finding RCTs were included, comprising a total of 4732 patients treated with factor XIa inhibitors versus 1798 controls. Treatment with factor XIa inhibitors did not reduce the risk of IS compared to controls (RR: 0.89; 95% CI: 0.67–1.17). The composite of symptomatic IS and covert infarcts on brain MRI (RR: 1.01; 95% CI: 0.87–1.18), the composite of symptomatic IS and transient ischemic attack (TIA; RR: 0.78; 95% CI: 0.61–1.01), and the composite of major adverse cardiovascular events (RR: 1.07; 95% CI: 0.87–1.31) did not differ between the treatment groups. Treatment with factor XIa inhibitors did not increase the risk of the composite of major bleeding and clinically relevant non-major bleeding (RR: 1.19; 95% CI: 0.65–2.16), major bleeding alone (RR: 1.19; 95% CI: 0.64–2.22), intracranial bleeding (RR: 0.91; 95% CI: 0.26–3.19) or all-cause mortality (RR: 1.21; 95% CI: 0.77–1.90). Conclusion: This meta-analysis provides reassuring evidence regarding the safety of factor XIa inhibitors. These findings, coupled with potential signals of efficacy in reducing IS (and TIA), underscore the importance of ongoing phase III RCTs for providing definitive data regarding the effect of factor XIa inhibition on stroke prevention. Keywords: ischemic stroke; stroke prevention; antithrombotic treatment; anticoagulation; factor Xia inhibitors; meta-analysis; randomized-controlled clinical trials Author: Lina Palaiodimou, Georgia Papagiannopoulou, Aristeidis H. Katsanos, Andreas Eleftheriou, Theodore Karapanayiotides, Panayiotis D. Mitsias, Robin Lemmens, Carlos A. Molina, Andrei Alexandrov, Valeria Caso, Ashkan Shoamanesh, Mukul Sharma and Georgios Tsivgoulis Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Aug 28 11:34:17 2023 CEST ModDate: Mon Aug 28 11:38:57 2023 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2684777 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MIKRSI+VnURWPalladioL Type 1 Custom yes yes no 10 0 TQWZGS+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 RCDVXL+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 MMMHIU+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 XPUSBJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 42 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 45 0 IKKWKP+CMSY10 Type 1 Builtin yes yes no 73 0 OKDGHN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 84 0 OKDGHO+PalatinoLinotype CID TrueType Identity-H yes yes yes 87 0 OKDGHP+PalatinoLinotype TrueType WinAnsi yes yes no 93 0 OKDGIB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 96 0 OKDGHN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 114 0 OKDGHO+PalatinoLinotype CID TrueType Identity-H yes yes yes 117 0 OKDGHP+PalatinoLinotype TrueType WinAnsi yes yes no 123 0 OKDGIB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 126 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes no 133 0 OKDGHN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 147 0 OKDGHO+PalatinoLinotype CID TrueType Identity-H yes yes yes 150 0 OKDGHP+PalatinoLinotype TrueType WinAnsi yes yes no 156 0 OKDGIB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 159 0 OKDHOJ+PalatinoLinotype TrueType MacRoman yes yes no 162 0 OKDGHN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 177 0 OKDGHO+PalatinoLinotype CID TrueType Identity-H yes yes yes 180 0 OKDGHP+PalatinoLinotype TrueType WinAnsi yes yes no 186 0 OKDGIB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 189 0 OKDHOJ+PalatinoLinotype TrueType MacRoman yes yes no 192 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-09-01 08:22:12 CEST RepresentationInformation: pmc_10488897.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-06-29 02:38:00 CEST Size: 2684777 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 383 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Methods Destination: section.2 Children: Item: Title: Standard Protocol Approvals, Registrations, and Patient Consent Destination: subsection.2.1 Item: Title: Data Sources, Searches and Study Selection Destination: subsection.2.2 Item: Title: Quality Control, Bias Assessment and Data Extraction Destination: subsection.2.3 Item: Title: Outcomes Destination: subsection.2.4 Item: Title: Statistical Analysis Destination: subsection.2.5 Item: Title: Results Destination: section.3 Children: Item: Title: Literature Search and Included Studies Destination: subsection.3.1 Item: Title: Quality Control of Included Studies Destination: subsection.3.2 Item: Title: Quantitative Analyses Destination: subsection.3.3 Item: Title: Efficacy Outcomes Destination: subsection.3.4 Item: Title: Safety Outcomes Destination: subsection.3.5 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.A. Info: Title: Efficacy and Safety of Oral Factor XIa Inhibitors in Stroke Prevention: A Systematic Review and Meta-Analysis Author: Lina Palaiodimou, Georgia Papagiannopoulou, Aristeidis H. Katsanos, Andreas Eleftheriou, Theodore Karapanayiotides, Panayiotis D. Mitsias, Robin Lemmens, Carlos A. Molina, Andrei Alexandrov, Valeria Caso, Ashkan Shoamanesh, Mukul Sharma and Georgios Tsivgoulis Subject: Introduction: Despite preventive measures, stroke rates remain high in the primary and secondary prevention settings. Factor XIa inhibition may offer a novel, safe and effective antithrombotic option for stroke prevention. Methods: We conducted a systematic review and meta-analysis including all available randomized controlled clinical trials (RCTs) that investigated the efficacy and safety of factor XIa inhibitors versus controls in primary or secondary stroke prevention. The primary efficacy and safety outcomes of interest were symptomatic ischemic stroke (IS) and the composite of major bleeding and clinically relevant non-major bleeding. Results: Four phase II dose-finding RCTs were included, comprising a total of 4732 patients treated with factor XIa inhibitors versus 1798 controls. Treatment with factor XIa inhibitors did not reduce the risk of IS compared to controls (RR: 0.89; 95% CI: 0.67 1.17). The composite of symptomatic IS and covert infarcts on brain MRI (RR: 1.01; 95% CI: 0.87 1.18), the composite of symptomatic IS and transient ischemic attack (TIA; RR: 0.78; 95% CI: 0.61 1.01), and the composite of major adverse cardiovascular events (RR: 1.07; 95% CI: 0.87 1.31) did not differ between the treatment groups. Treatment with factor XIa inhibitors did not increase the risk of the composite of major bleeding and clinically relevant non-major bleeding (RR: 1.19; 95% CI: 0.65 2.16), major bleeding alone (RR: 1.19; 95% CI: 0.64 2.22), intracranial bleeding (RR: 0.91; 95% CI: 0.26 3.19) or all-cause mortality (RR: 1.21; 95% CI: 0.77 1.90). Conclusion: This meta-analysis provides reassuring evidence regarding the safety of factor XIa inhibitors. These findings, coupled with potential signals of efficacy in reducing IS (and TIA), underscore the importance of ongoing phase III RCTs for providing definitive data regarding the effect of factor XIa inhibition on stroke prevention. Keywords: ischemic stroke; stroke prevention; antithrombotic treatment; anticoagulation; factor Xia inhibitors; meta-analysis; randomized-controlled clinical trials Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Aug 28 11:34:17 CEST 2023 ModDate: Mon Aug 28 11:38:57 CEST 2023 ID: 0xbfe3152511f7348de5fccc3257fc0305, 0xbfe3152511f7348de5fccc3257fc0305 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: RCDVXL+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: RCDVXL+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QLBIEB+URWPalladioL-BoldItal FontSubset: true FirstChar: 110 LastChar: 112 FontDescriptor: FontName: QLBIEB+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: MMMHIU+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 121 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