Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS): protocol for a randomized controlled, phase IIb proof-of-principle trial

Prabal Mittal; Rafael Gafoor; Zara Sayar; Maria Efthymiou; Ibrahim Tohidi-Esfahani; Stella Appiah-Cubi; Deepa J. Arachchillage; David Atkinson; Ekaterina Bordea; M. Jorge Cardoso; Emilia Caverly; Arvind Chandratheva; Marisa Chau; Nick Freemantle; Carolyn Gates; H. Rolf Ja¨ger; Arvind Kaul; Chris Mitchell; Hanh Nguyen; Bunis Packham; Jaye Paskell; Jignesh P. Patel; Chris Round; Giovanni Sanna; Abbas Zaidi; David J. Werring; David Isenberg; Hannah Cohen

doi:10.1016/j.rpth.2024.102468

Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS): protocol for a randomized controlled, phase IIb proof-of-principle trial

Prabal Mittal^*, Rafael Gafoor, Zara Sayar, Maria Efthymiou, Ibrahim Tohidi-Esfahani, Stella Appiah-Cubi, Deepa J. Arachchillage, David Atkinson, Ekaterina Bordea, M. Jorge Cardoso, Emilia Caverly, Arvind Chandratheva, Marisa Chau, Nick Freemantle, Carolyn Gates, H. Rolf Ja¨ger, Arvind Kaul, Chris Mitchell, Hanh Nguyen, Bunis PackhamJaye Paskell, Jignesh P. Patel, Chris Round, Giovanni Sanna, Abbas Zaidi, David J. Werring, David Isenberg, Hannah Cohen

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation. Objectives: The Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations. Methods: This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling. Conclusion: Should RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials.

Original language	English
Article number	102468
Journal	Research and practice in thrombosis and haemostasis
Volume	8
Issue number	5
DOIs	https://doi.org/10.1016/j.rpth.2024.102468
Publication status	Published - Jul 2024

Keywords

antiphospholipid syndrome
ischemic stroke
rivaroxaban
thrombosis
warfarin

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10.1016/j.rpth.2024.102468

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Mittal, P., Gafoor, R., Sayar, Z., Efthymiou, M., Tohidi-Esfahani, I., Appiah-Cubi, S., Arachchillage, D. J., Atkinson, D., Bordea, E., Cardoso, M. J., Caverly, E., Chandratheva, A., Chau, M., Freemantle, N., Gates, C., Ja¨ger, H. R., Kaul, A., Mitchell, C., Nguyen, H., ... Cohen, H. (2024). Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS): protocol for a randomized controlled, phase IIb proof-of-principle trial. Research and practice in thrombosis and haemostasis, 8(5), Article 102468. https://doi.org/10.1016/j.rpth.2024.102468

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title = "Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS): protocol for a randomized controlled, phase IIb proof-of-principle trial",

abstract = "Background: Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation. Objectives: The Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations. Methods: This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling. Conclusion: Should RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials.",

keywords = "antiphospholipid syndrome, ischemic stroke, rivaroxaban, thrombosis, warfarin",

author = "Prabal Mittal and Rafael Gafoor and Zara Sayar and Maria Efthymiou and Ibrahim Tohidi-Esfahani and Stella Appiah-Cubi and Arachchillage, {Deepa J.} and David Atkinson and Ekaterina Bordea and Cardoso, {M. Jorge} and Emilia Caverly and Arvind Chandratheva and Marisa Chau and Nick Freemantle and Carolyn Gates and Ja¨ger, {H. Rolf} and Arvind Kaul and Chris Mitchell and Hanh Nguyen and Bunis Packham and Jaye Paskell and Patel, {Jignesh P.} and Chris Round and Giovanni Sanna and Abbas Zaidi and Werring, {David J.} and David Isenberg and Hannah Cohen",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = jul,

doi = "10.1016/j.rpth.2024.102468",

language = "English",

volume = "8",

journal = "Research and practice in thrombosis and haemostasis",

issn = "2475-0379",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "5",

}

Mittal, P, Gafoor, R, Sayar, Z, Efthymiou, M, Tohidi-Esfahani, I, Appiah-Cubi, S, Arachchillage, DJ, Atkinson, D, Bordea, E, Cardoso, MJ, Caverly, E, Chandratheva, A, Chau, M, Freemantle, N, Gates, C, Ja¨ger, HR, Kaul, A, Mitchell, C, Nguyen, H, Packham, B, Paskell, J, Patel, JP, Round, C, Sanna, G, Zaidi, A, Werring, DJ, Isenberg, D & Cohen, H 2024, 'Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS): protocol for a randomized controlled, phase IIb proof-of-principle trial', Research and practice in thrombosis and haemostasis, vol. 8, no. 5, 102468. https://doi.org/10.1016/j.rpth.2024.102468

TY - JOUR

T1 - Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS)

T2 - protocol for a randomized controlled, phase IIb proof-of-principle trial

AU - Mittal, Prabal

AU - Gafoor, Rafael

AU - Sayar, Zara

AU - Efthymiou, Maria

AU - Tohidi-Esfahani, Ibrahim

AU - Appiah-Cubi, Stella

AU - Arachchillage, Deepa J.

AU - Atkinson, David

AU - Bordea, Ekaterina

AU - Cardoso, M. Jorge

AU - Caverly, Emilia

AU - Chandratheva, Arvind

AU - Chau, Marisa

AU - Freemantle, Nick

AU - Gates, Carolyn

AU - Ja¨ger, H. Rolf

AU - Kaul, Arvind

AU - Mitchell, Chris

AU - Nguyen, Hanh

AU - Packham, Bunis

AU - Paskell, Jaye

AU - Patel, Jignesh P.

AU - Round, Chris

AU - Sanna, Giovanni

AU - Zaidi, Abbas

AU - Werring, David J.

AU - Isenberg, David

AU - Cohen, Hannah

PY - 2024/7

Y1 - 2024/7

N2 - Background: Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation. Objectives: The Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations. Methods: This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling. Conclusion: Should RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials.

AB - Background: Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation. Objectives: The Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations. Methods: This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling. Conclusion: Should RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials.

KW - antiphospholipid syndrome

KW - ischemic stroke

KW - rivaroxaban

KW - thrombosis

KW - warfarin

UR - http://www.scopus.com/inward/record.url?scp=85199094193&partnerID=8YFLogxK

U2 - 10.1016/j.rpth.2024.102468

DO - 10.1016/j.rpth.2024.102468

M3 - Article

AN - SCOPUS:85199094193

SN - 2475-0379

VL - 8

JO - Research and practice in thrombosis and haemostasis

JF - Research and practice in thrombosis and haemostasis

IS - 5

M1 - 102468

ER -

Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS): protocol for a randomized controlled, phase IIb proof-of-principle trial

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Keywords

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