Mukul Sharma1, Robert G Hart1, Eric E Smith2, Jackie Bosch1,3, Fei Yuan1, Amparo Casanova1, John W Eikelboom1, Stuart J Connolly1, Gloria Wong1, Rafael Diaz3,4, Patricio Lopez-Jaramillo5, Georg Ertl6, Stefan Störk6, Gilles R Dagenais7, Eva M Lonn1, Lars Ryden8, Andrew M Tonkin9, John D Varigos9, Deepak L Bhatt10, Kelley Rh Branch11, Jeffrey L Probstfield12, Jae-Hyung Kim13, Jong-Won Ha14, Martin O'Donnell15, Dragos Vinereanu16, Keith Aa Fox17, Yan Liang18, Lisheng Liu18, Jun Zhu18, Nana Pogosova19, Aldo P Maggioni20, Alvaro Avezum21, Leopoldo S Piegas22, Katalin Keltai23, Matyas Keltai23, Nancy Cook Bruns24, Scott Berkowitz24, Salim Yusuf1. 1. 1 Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. 2. 2 Hotchkiss Brain Institute, University of Calgary, Calgary Canada. 3. 3 School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada. 4. 4 Estudios Clínicos Latino America and Instituto Cardiovascular de Rosario, Rosario, Argentina. 5. 5 Research Institute, FOSCAL-Bucaramanga, Bucaramanga, Colombia. 6. 6 Comprehensive Heart Failure Center, University and University Hospital Würzburg, Würzburg, Germany. 7. 7 Institut Universitaire de Cardiologie et Pneumologie de Quebec, Quebec City, Quebec, Canada. 8. 8 Karolinska Institutet, Stockholm, Sweden. 9. 9 Monash University, Melbourne, Australia. 10. 10 Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts, USA. 11. 11 University of Washington Medical Centre, Seattle, WA, USA. 12. 12 University of Washington, Seattle, WA, USA. 13. 13 The Catholic University of Korea, Seoul, Korea. 14. 14 Yonsei University College of Medicine, Seoul, Korea. 15. 15 National University of Ireland, Galway, Ireland. 16. 16 University of Medicine and Pharmacology Carol Davila University and Emergency Hospital, Bucharest, Romania. 17. 17 Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland. 18. 18 FuWai Hospital, Beijing, China. 19. 19 National Research Centre for Preventative Medicine (Moscow), Moscow, Russia. 20. 20 ANMCO Research Center, Florence, Italy. 21. 21 Instituto Dante Pazzanese de Cardiologia, Sao Paulo, Brazil. 22. 22 University of Sao Paulo, Sao Paulo, Brazil. 23. 23 Semmelweis University, Budapest, Hungary. 24. 24 Bayer AG, Leverkusen, Germany.
Abstract
BACKGROUND: Covert vascular disease of the brain manifests as infarcts, white matter hyperintensities, and microbleeds on MRI. Their cumulative effect is often a decline in cognition, motor impairment, and psychiatric disorders. Preventive therapies for covert brain ischemia have not been established but represent a huge unmet clinical need. AIMS: The MRI substudy examines the effects of the antithrombotic regimens in COMPASS on incident covert brain infarcts (the primary outcome), white matter hyperintensities, and cognitive and functional status in a sample of consenting COMPASS participants without contraindications to MRI. METHODS: COMPASS is a randomized superiority trial testing rivaroxaban 2.5 mg bid plus acetylsalicylic acid 100 mg and rivaroxaban 5 mg bid against acetylsalicylic acid 100 mg per day for the combined endpoint of MI, stroke, and cardiovascular death in individuals with stable coronary artery disease or peripheral artery disease. T1-weighted, T2-weighted, T2*-weighted, and FLAIR images were obtained close to randomization and near the termination of assigned antithrombotic therapy; biomarker and genetic samples at randomization and one month, and cognitive and functional assessment at randomization, after two years and at the end of study. RESULTS:Between March 2013 and May 2016, 1905 participants were recruited from 86 centers in 16 countries. Of these participants, 1760 underwent baseline MRI scans that were deemed technically adequate for interpretation. The mean age at entry of participants with interpretable MRI was 71 years and 23.5% were women. Coronary artery disease was present in 90.4% and 28.1% had peripheral artery disease. Brain infarcts were present in 34.8%, 29.3% had cerebral microbleeds, and 93.0% had white matter hyperintensities. The median Montreal Cognitive Assessment score was 26 (interquartile range 23-28). CONCLUSIONS: The COMPASS MRI substudy will examine the effect of the antithrombotic interventions on MRI-determined covert brain infarcts and cognition. Demonstration of a therapeutic effect of the antithrombotic regimens on brain infarcts would have implications for prevention of cognitive decline and provide insight into the pathogenesis of vascular cognitive decline.
RCT Entities:
BACKGROUND: Covert vascular disease of the brain manifests as infarcts, white matter hyperintensities, and microbleeds on MRI. Their cumulative effect is often a decline in cognition, motor impairment, and psychiatric disorders. Preventive therapies for covert brain ischemia have not been established but represent a huge unmet clinical need. AIMS: The MRI substudy examines the effects of the antithrombotic regimens in COMPASS on incident covert brain infarcts (the primary outcome), white matter hyperintensities, and cognitive and functional status in a sample of consenting COMPASS participants without contraindications to MRI. METHODS: COMPASS is a randomized superiority trial testing rivaroxaban 2.5 mg bid plus acetylsalicylic acid 100 mg and rivaroxaban 5 mg bid against acetylsalicylic acid 100 mg per day for the combined endpoint of MI, stroke, and cardiovascular death in individuals with stable coronary artery disease or peripheral artery disease. T1-weighted, T2-weighted, T2*-weighted, and FLAIR images were obtained close to randomization and near the termination of assigned antithrombotic therapy; biomarker and genetic samples at randomization and one month, and cognitive and functional assessment at randomization, after two years and at the end of study. RESULTS: Between March 2013 and May 2016, 1905 participants were recruited from 86 centers in 16 countries. Of these participants, 1760 underwent baseline MRI scans that were deemed technically adequate for interpretation. The mean age at entry of participants with interpretable MRI was 71 years and 23.5% were women. Coronary artery disease was present in 90.4% and 28.1% had peripheral artery disease. Brain infarcts were present in 34.8%, 29.3% had cerebral microbleeds, and 93.0% had white matter hyperintensities. The median Montreal Cognitive Assessment score was 26 (interquartile range 23-28). CONCLUSIONS: The COMPASS MRI substudy will examine the effect of the antithrombotic interventions on MRI-determined covert brain infarcts and cognition. Demonstration of a therapeutic effect of the antithrombotic regimens on brain infarcts would have implications for prevention of cognitive decline and provide insight into the pathogenesis of vascular cognitive decline.
Authors: Christopher Traenka; Henrik Gensicke; Sabine Schaedelin; Andreas Luft; Marcel Arnold; Patrik Michel; Georg Kägi; Timo Kahles; Christian H Nolte; Lars Kellert; Sverre Rosenbaum; Roman Sztaizel; Alex Brehm; Christoph Stippich; Marios Psychogios; Philippe Lyrer; Stefan T Engelter Journal: Eur Stroke J Date: 2020-06-29