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

Bath, Philip M.W. and Woodhouse, Lisa J. and Appleton, Jason P. and Beridze, M. and Christensen, Hanne and Dineen, Robert A. and Duley, Lelia and England, Timothy J. and Flaherty, Katie and Havard, Diane and Heptinstall, Stan and James, Marilyn and Krishnan, Kailash and Markus, H.S. and Montgomery, Alan A. and Pocock, Stuart J. and Randall, Marc and Ranta, A. and Robinson, Thompson G. and Scutt, Polly and Venables, Graham S. and Sprigg, Nikola (2018) 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. Lancet, 391 (10123). pp. 850-859. ISSN 1474-547X

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Abstract

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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Rehabilitation and Ageing
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Clinical Neuroscience
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Medical Sciences and Graduate Entry Medicine
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Units > Clinical Trials Unit
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Units > Radiology and Imaging Sciences
Identification Number: 10.1016/S0140-6736(17)32849-0
Depositing User: Eprints, Support
Date Deposited: 09 Jan 2018 09:25
Last Modified: 04 Mar 2018 17:17
URI: http://eprints.nottingham.ac.uk/id/eprint/48990

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