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Platelet function/reactivity testing and prediction of risk of recurrent vascular events and outcomes after TIA or ischaemic stroke: systematic review and meta-analysis

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Abstract

Background

The prevalence of ex vivo ‘high on-treatment platelet reactivity (HTPR)’ and its relationship with recurrent vascular events/outcomes in patients with ischaemic cerebrovascular disease (CVD) is unclear.

Methods

A systematic review and meta-analysis was performed in accordance with the PRISMA statement. MEDLINE, EMBASE and Cochrane Library were searched for completed manuscripts until May 2019 on TIA/ischaemic stroke patients, ≥ 18 years, treated with commonly-prescribed antiplatelet therapy, who had platelet function/reactivity testing and prospective follow-up data on recurrent stroke/TIA, myocardial infarction, vascular death or other cerebrovascular outcomes. Data were pooled using random-effects meta-analysis. Primary outcome was the composite risk of recurrent stroke/TIA, myocardial infarction or vascular death. Secondary outcomes were recurrent stroke/TIA, severe stroke (NIHSS > 16) or disability/impairment (modified Rankin scale ≥ 3) during follow-up.

Results

Antiplatelet–HTPR prevalence was 3–65% with aspirin, 8–56% with clopidogrel and 1.8–35% with aspirin–clopidogrel therapy. Twenty studies (4989 patients) were included in our meta-analysis. There was a higher risk of the composite primary outcome (OR 2.93, 95% CI 1.90–4.51) and recurrent ischaemic stroke/TIA (OR 2.43, 95% CI 1.51–3.91) in patients with vs. those without ‘antiplatelet–HTPR’ on any antiplatelet regimen. These risks were also more than twofold higher in patients with vs. those without ‘aspirin–HTPR’ and ‘dual antiplatelet–HTPR’, respectively. Clopidogrel–HTPR status did not significantly predict outcomes, but the number of eligible studies was small. The risk of severe stroke was higher in those with vs. without antiplatelet–HTPR (OR 2.65, 95% CI 1.00–7.01).

Discussion

Antiplatelet–HTPR may predict risks of recurrent vascular events/outcomes in CVD patients. Given the heterogeneity between studies, further prospective, multi-centre studies are warranted.

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Acknowledgements

All collaborators qualified for authorship because they either contributed to the study concept (STL, SJXM, VT, JM, LM, PMB, GAF, DC, CIP, PAB, JD, DJHM), study design (STL, VT, SJXM, PMB, IFC, PJK, DJW, RP, LZ, DJHM), data acquisition (STL, SYL, VT, IFC, DJHM) or data analysis (STL, SYL, VT, CO, LZ, DJHM), and all critically-appraised the manuscript for important intellectual content and approved the final version of the manuscript for submission.

Funding

Dr. Lim’s research was funded by The Meath Foundation, The Irish Institute of Clinical Neuroscience/Novartis Ireland Fellowship Grant, The Vascular Neurology Research Foundation Ireland, the Irish Heart Foundation Stroke Prevention Bursary programme, and by an unrestricted educational grant from Biogen Idec, Ireland. Dr. Murphy’s research was funded by the Trinity College Dublin Innovation Bursary, The Meath Foundation, Joint Irish Institute of Clinical Neuroscience/Merck Serono Fellowship in Neuroscience Grant, The Vascular Neurology Research Foundation Ireland, and by an unrestricted educational grant from Bayer HealthCare, Ireland and Verum Diagnostica, GmbH. Dr Offiah’s Research is funded by The Meath Foundation and The Vascular Neurology Research Foundation Ireland and by an unrestricted educational grant from SINNOWA Medical Science & Technology Co., China. Prof Thijs’ research is supported by The Florey Institute of Neuroscience and Mental Health, which acknowledges support from the Victorian Government and funding from an Operational Infrastructure Support Grant. Prof Prodan’s research is supported by a United States Department of Veterans Affairs Merit Award (1I01CX000340). Prof Kelly is supported by grants from the Health Research Board Ireland. Prof Barber is supported by grants from the Canadian Institute of Health Research and the Heart and Stroke Foundation of Canada. Prof Werring receives research support from the Stroke Association and the British Heart Foundation. Prof Thijs has received personal fees for lectures and consulting fees from Bayer, Boehringer Ingelheim, BMS/Pfizer and Amgen. Prof. Bath is a Stroke Association Professor of Stroke Medicine and NIHR Senior Investigator, a non-executive Director of ‘Platelet Solutions Ltd.®, and owns 3 shares; he has received personal fees for consulting from DiaMedica, Moleac, Nestle, Sanofi and Phagenesis. Prof Werring has received honoraria for consulting and lectures from Bayer and Portola, and for consulting from Alnylam.

Author information

Authors and Affiliations

  1. Department of Neurology, The Adelaide and Meath Hospital, Dublin, Incorporating the National Children’s Hospital (AMNCH)/Tallaght University Hospital, Dublin, Ireland

    Soon Tjin Lim, Stephen J. X. Murphy, Chika Offiah & Dominick J. H. McCabe

  2. Stroke Service, The Adelaide and Meath Hospital, Dublin, Incorporating the National Children’s Hospital (AMNCH)/Tallaght University Hospital, Dublin, Ireland

    Soon Tjin Lim, Stephen J. X. Murphy, Chika Offiah & Dominick J. H. McCabe

  3. Vascular Neurology Research Foundation, C/O Department of Neurology, The Adelaide and Meath Hospital, Dublin, Incorporating the National Children’s Hospital (AMNCH)/Tallaght University Hospital, Tallaght, Dublin 24, Ireland

    Dominick J. H. McCabe

  4. Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Victoria, Australia

    Vincent Thijs

  5. Department of Neurology, Austin Health, Heidelberg, Victoria, Australia

    Vincent Thijs

  6. Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Israel Fernandez-Cadenas

  7. Neurovascular Research Laboratory, Vall d’Hebron Institute of Research (VHIR), Barcelona, Spain

    Joan Montaner

  8. Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville & Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Seville, Spain

    Joan Montaner

  9. Department of Neurology, Asklepios Klinik Wandsbek, Hamburg, Germany

    Lars Marquardt

  10. Neurovascular Clinical Science Unit, Mater University Hospital, University College Dublin, Dublin, Ireland

    Peter J. Kelly

  11. Stroke Trials Unit, University of Nottingham, Nottingham, UK

    Philip M. Bath

  12. Faculty of Health and Medical Sciences, Taylor’s University School of Medicine, Sungai Buloh, Malaysia

    Su-Yin Lim

  13. University of Oxford, Oxford, UK

    Gary A. Ford

  14. Oxford University Hospital NHS Foundation Trust, Oxford, UK

    Gary A. Ford

  15. Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden

    Bo Norrving

  16. Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

    Dermot Cox

  17. Irish Centre for Vascular Biology, Dublin, Ireland

    Dermot Cox & Dominick J. H. McCabe

  18. Department of Neurology, University of Oklahoma Health Sciences Center and VA Medical Center, Oklahoma, USA

    Calin I. Prodan

  19. Department of Clinical Neurosciences, University of Calgary, Calgary, Canada

    Philip A. Barber

  20. Department of Brain Repair and Rehabilitation, Stroke Research Centre, UCL Queen Square Institute of Neurology, London, UK

    David J. Werring & Richard Perry

  21. Department of Public Health and Primary Care, Trinity College Dublin, University of Dublin, Dublin, Ireland

    Lina Zgaga

  22. Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

    Jesse Dawson

  23. Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK

    Jesse Dawson

  24. Department of Clinical Neurosciences, Royal Free Campus, UCL Queen Square Institute of Neurology, London, UK

    Soon Tjin Lim & Dominick J. H. McCabe

  25. Stroke Clinical Trials Network Ireland, Dublin, Ireland

    Peter J. Kelly & Dominick J. H. McCabe

  26. Academic Unit of Neurology, School of Medicine, Trinity College Dublin, Dublin, Ireland

    Dominick J. H. McCabe

Authors
  1. Soon Tjin Lim
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  2. Vincent Thijs
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  3. Stephen J. X. Murphy
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  4. Israel Fernandez-Cadenas
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  5. Joan Montaner
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  6. Chika Offiah
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  7. Lars Marquardt
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  8. Peter J. Kelly
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  9. Philip M. Bath
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  10. Su-Yin Lim
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  11. Gary A. Ford
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  12. Bo Norrving
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  13. Dermot Cox
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  14. Calin I. Prodan
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  15. Philip A. Barber
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  16. David J. Werring
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  17. Richard Perry
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  18. Lina Zgaga
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  19. Jesse Dawson
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  20. Dominick J. H. McCabe
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Corresponding author

Correspondence to Dominick J. H. McCabe.

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Conflicts of interest

On behalf of all authors, we state that there are no conflicts of interest to declare.

Ethical approval

These data were collated as part of a systematic review and meta-analysis, our Local Research Ethics Committee (LREC) hospital guidelines indicate that formal LREC approval for such a study is not required. However, all data were securely stored in electronic format and no individual patient could be identified from the data contained within. The study and analyses were conducted in accordance with best ethical practice and supervised by experienced Consultants who are International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice (ICH GCP)-certified.

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Lim, S.T., Thijs, V., Murphy, S.J.X. et al. Platelet function/reactivity testing and prediction of risk of recurrent vascular events and outcomes after TIA or ischaemic stroke: systematic review and meta-analysis. J Neurol 267, 3021–3037 (2020). https://doi.org/10.1007/s00415-020-09932-y

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  • DOI: https://doi.org/10.1007/s00415-020-09932-y

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