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Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial.

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posted on 17.01.2018, 10:30 by Philip M. Bath, Lisa J. Woodhouse, Jason P. Appleton, Maia Beridze, Hanne Christensen, Robert A. Dineen, Lelia Duley, Timothy J. England, Katie Flaherty, Diane Havard, Stan Heptinstall, Marilyn James, Kailash Krishnan, Hugh S. Markus, Alan A. Montgomery, Stuart J. Pocock, Marc Randall, Annemare Ranta, Thompson G. Robinson, Polly Scutt, Graham S. Venables, Nikola Sprigg, TARDIS Investigators
BACKGROUND: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. METHODS: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. FINDINGS: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67-1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05-3·16, p<0·0001). INTERPRETATION: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. FUNDING: National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

Funding

The trial was designed in 2007 and initial funding was confirmed in 2008. The TARDIS start-up phase was funded by the British Heart Foundation (grant PG/08/083/25779, April 1, 2009, to Sept 30, 2012). The NIHR HTA programme funded the main phase of this project (10/104/24, Oct 1, 2012, to Sept 30, 2017). This paper presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Indirect funding was provided by The Stroke Association through its funding of the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham. HSM acknowledges infrastructural support from the Cambridge University Hospitals NIHR Comprehensive BRC. The trial was sponsored by the University of Nottingham. We thank the participants, investigators and research staff at the participating sites and the members of the trial steering committee and independent data monitoring committee, for their involvement in and support for, the study. TARDIS acknowledges the support of the National Institute for Health Research Stroke Research Network/Clinical Research Network (Stroke); the large recruitment in the UK would not have been possible without this network support. PMB is Stroke Association Professor of Stroke Medicine; PMB, HSM, and TGR are NIHR Senior Investigators.

History

Citation

Lancet, 2017

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

VoR (Version of Record)

Published in

Lancet

Publisher

Elsevier

issn

0140-6736

eissn

1474-547X

Acceptance date

02/11/2017

Copyright date

2017

Available date

17/01/2018

Publisher version

http://www.sciencedirect.com/science/article/pii/S0140673617328490?via=ihub

Language

en

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