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Triple versus guideline antiplatelet therapy to prevent recurrence after acute ischaemic stroke or transient ischaemic attack: the TARDIS RCT

Bath, Philip M.; Woodhouse, Lisa J.; Appleton, Jason P.; Beridze, Maia; Christensen, Hanne; Dineen, Robert A.; Flaherty, Katie; Duley, Lelia; England, Timothy J.; Havard, Diane; Heptinstall, Stan; James, Marilyn; Kasonde, Chibeka; Krishnan, Kailash; Markus, Hugh S.; Montgomery, Alan A.; Pocock, Stuart; Randall, Marc; Ranta, Annamarei; Robinson, Thompson G.; Scutt, Polly; Venables, Graham S.; Sprigg, Nikola

Authors

Philip M. Bath

Lisa J. Woodhouse

Jason P. Appleton

Maia Beridze

Hanne Christensen

Robert A. Dineen

Katie Flaherty

Lelia Duley

Timothy J. England

Diane Havard

Stan Heptinstall

Marilyn James

Chibeka Kasonde

Kailash Krishnan

Hugh S. Markus

Alan A. Montgomery

Stuart Pocock

Marc Randall

Annamarei Ranta

Thompson G. Robinson

Polly Scutt

Graham S. Venables

Nikola Sprigg

Abstract

Background: Two antiplatelet agents are better than one for preventing recurrent stroke after acute ischaemic stroke or transient ischaemic attack (TIA). Therefore, intensive treatment with three agents might be better still, providing it does not cause undue bleeding.
Objective: To compare the safety and efficacy of intensive therapy with guideline antiplatelet therapy for acute ischaemic stroke and TIA.
Design: International prospective randomised open-label blinded end-point parallel-group superiority clinical trial.
Setting: Acute hospitals at 106 sites in four countries.
Participants: Patients > 50 years of age with acute non-cardioembolic ischaemic stroke or TIA within 48 hours of ictus (stroke).
Interventions: Participants were allocated at random by computer to 1 month of intensive (combined aspirin, clopidogrel and dipyridamole) or guideline (combined aspirin and dipyridamole, or clopidogrel alone) antiplatelet agents, and followed for 90 days.
Main outcome measures: The primary outcome was the incidence and severity of any recurrent stroke (ischaemic, haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days by blinded telephone follow-up. Analysis using ordinal logistic regression was by intention to treat. Other outcomes included bleeding and its severity, death, myocardial infarction (MI), disability, mood, cognition and quality of life.
Results: The trial was stopped early on the recommendation of the Data Monitoring Committee after recruitment of 3096 participants (intensive, n = 1556; guideline, n = 1540) from 106 hospitals in four countries between April 2009 and March 2016. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy in 3070 (99.2%) participants with data [93 vs. 105 stroke/TIA events; adjusted common odds ratio 0.90, 95% confidence interval (CI) 0.67 to 1.20; p = 0.47]. Major (encompassing fatal) bleeding was increased with intensive as compared with guideline therapy [39 vs. 17 participants; adjusted hazard ratio (aHR) 2.23, 95% CI 1.25 to 3.96; p = 0.006]. There were no differences between the treatment groups in all-cause mortality, or the composite of death, stroke, MI and major bleeding (aHR 1.02, 95% CI 0.77 to 1.35; p = 0.88).
Limitations: Patients and investigators were not blinded to treatment. The comparator group comprised two guideline strategies because of changes in national guidelines during the trial. The trial was stopped early, thereby reducing its statistical power.
Conclusions: The use of three antiplatelet agents is associated with increased bleeding without any significant reduction in recurrence of stroke or TIA.
Future work: The safety and efficacy of dual antiplatelet therapy (combined aspirin and clopidogrel) versus aspirin remains to be defined. Further research is required on identifying individual patient response to antiplatelets, and the relationship between response and the subsequent risks of vascular recurrent events and bleeding complications.

Journal Article Type Article
Publication Date Sep 1, 2018
Journal Health Technology Assessment
Print ISSN 1366-5278
Electronic ISSN 2046-4924
Publisher NIHR Journals Library
Peer Reviewed Peer Reviewed
Volume 22
Issue 48
Pages 1-76
DOI https://doi.org/10.3310/hta22480
Keywords Health Policy
Publisher URL https://www.journalslibrary.nihr.ac.uk/hta/hta22480#/abstract
Additional Information Contractual start date: 10-2012; Editorial review begun: 11-2017; Accepted for publication: 5-2018

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